www.arquivosonline.com.br
Sociedade Brasileira de Cardiologia • ISSN-0066-782X • Volume 102, Nº 5, May 2014
Figure 3 – Cross-sectional views of porcine coronary arteries on day 28 after bare-metal stent
implantation (Group I, left) and biodegradable polymer-coated stent with sirolimus elution on the
abluminal surface (Group V) (right). Magnification 40X. Page: 438
Editorial
Temporal Variation in the Prognosis and Treatment of Advanced Heart
Trajectories of Cardiovascular Health: Life Course Epidemiology
Failure – Before and After 2000
in Brazil
Special Article
I Cardiovascular Prevention Guideline of the Brazilian Society of
Cardiology – Executive Summary
Original Articles
Preclinical Study of a Biodegradable Polymer-based Stent with
Abluminal Sirolimus Release
Effects of Skeletonized versus Pedicled Radial Artery on Postoperative
NHETS − Necropsy Heart Transplantation Study
Review Article
Systems Biology Applied to Heart Failure With Normal Ejection
Fraction
Letter to the Editor
Obesity and Abnormalities in Echocardiographic Parameters
Extracellular Matrix Turnover: a Balance between MMPs and their Inhibitors
Graft Patency and Flow
Does C-reactive Protein Add Prognostic Value to GRACE Score in
Erratum
Acute Coronary Syndromes?
Relationship between Fibrosis and Ventricular Arrhythmias in Chagas
Eletronic Pages
Heart Disease Without Ventricular Dysfunction
Impact of Psychotropic Drugs on QT Interval Dispersion in Adult Patients
Prevalence of Cardiovascular Risk Factors in Hemodialysis Patients –
The CORDIAL Study
Anatomopathological Session
Case 2/2014 – 51-Year Old Patient with Systemic Lupus
Erythematosus and Fever after Valve Replacement
Case Report
LINE-1 Hypomethylation is Associated with the Risk of Coronary
Prolonged Cardiopulmonary Arrest Treated Successfully in the São
Heart Disease in Chinese Population
Paulo’s Subway
Incidence of Ventricular Arrhythmias after Stem Cell Therapy in
Viewpoint
Patients with Chagas Cardiomyopathy
Is Heart Team Fundamental to Aortic Stenosis Transcatheter Treatment?
REVISTA DA SOCIEDADE BRASILEIRA DE CARDIOLOGIA - Publicada desde 1948
Contents
Editorial
Trajectories of Cardiovascular Health: Life Course Epidemiology in Brazil
Lucia Campos Pellanda
.....................................................................................................................................................................page 418
Special Article
I Cardiovascular Prevention Guideline of the Brazilian Society of Cardiology – Executive Summary
Antonio Felipe Simão, Dalton Bertolim Précoma, Jadelson Pinheiro de Andrade, Harry Correa Filho, José
Francisco Kerr Saraiva, Gláucia Maria Moraes de Oliveira
.....................................................................................................................................................................page 420
Original Articles
Coronary Angioplasty with and without Stent
Preclinical Study of a Biodegradable Polymer-based Stent with Abluminal Sirolimus Release
Celso Kiyochi Takimura, Carlos Augusto Homem M. Campos, Pedro Henrique Magualhães Craveiro Melo,
Julliana Carvalho Campos, Paulo Sampaio Gutierrez, Thiago Francisco Costa Borges, Luciano Curado, Spero
Penha Morato, Francisco Rafael Martins Laurindo, Pedro Alves Lemos Neto
.....................................................................................................................................................................page 432
Heart Surgery - Adults
Effects of Skeletonized versus Pedicled Radial Artery on Postoperative Graft Patency and Flow
Rômulo C. Arnal Bonini, Rodolfo Staico, Mario Issa, Antoninho Sanfins Arnoni, Paulo Chaccur, Camilo Abdulmassih
Neto, Jarbas Jackson Dinkhuysen, Paulo Paredes Paulista, Luiz Carlos Bento de Souza, Luiz Felipe P. Moreira
.....................................................................................................................................................................page 441
Acute Coronary Artery Disease
Does C-reactive Protein Add Prognostic Value to GRACE Score in Acute Coronary Syndromes?
Luis Cláudio Lemos Correia, Isis Vasconcelos, Guilherme Garcia, Felipe Kalil, Felipe Ferreira, André Silva, Ruan
Oliveira, Manuela Carvalhal, Caio Freitas, Márcia Maria Noya-Rabelo
.....................................................................................................................................................................page 449
Chagas’ Disease
Relationship between Fibrosis and Ventricular Arrhythmias in Chagas Heart Disease Without
Ventricular Dysfunction
Eduardo Marinho Tassi, Marcelo Abramoff Continentino, Emília Matos do Nascimento, Basílio de Bragança
Pereira, Roberto Coury Pedrosa
.....................................................................................................................................................................page 456
Arquivos Brasileiros de Cardiologia - Volume 102, Nº 5, May 2014
Electrocardiography
Impact of Psychotropic Drugs on QT Interval Dispersion in Adult Patients
Bruno de Queiroz Claudio, Marcelle Azevedo Nossar Costa, Filipe Penna, Mariana Teixeira Konder, Bruno
Miguel Jorge Celoria, Luciana Lopes de Souza, Roberto Pozzan, Roberta Siuffo Schneider, Felipe Neves
Albuquerque, Denilson Campos Albuquerque
.....................................................................................................................................................................page 465
Epidemiology
Prevalence of Cardiovascular Risk Factors in Hemodialysis Patients – The CORDIAL Study
Jayme Eduardo Burmeister, Camila Borges Mosmann, Veridiana Borges Costa, Ramiro Tubino Saraiva, Renata
Rech Grandi, Juliano Peixoto Bastos, Luiz Felipe Gonçalves, Guido Aranha Rosito
.....................................................................................................................................................................page 473
LINE-1 Hypomethylation is Associated with the Risk of Coronary Heart Disease in Chinese
Population
Li Wei, Shuchuan Liu, Zhendong Su, Rongchao Cheng, Xiuping Bai, Xueqi Li
.....................................................................................................................................................................page 481
Heart Failure
Incidence of Ventricular Arrhythmias after Stem Cell Therapy in Patients with Chagas Cardiomyopathy
Adriana Sebba Barroso de Souza, Weimar Kunz Sebba Barroso Souza, Sandra Araujo Costa, Elis Marra de
Moreira Freitas, Gustavo Carvalho, Luís Antônio Batista Sá, Salvador Rassi
.....................................................................................................................................................................page 489
Temporal Variation in the Prognosis and Treatment of Advanced Heart Failure – Before and After 2000
Carlos Henrique Del Carlo, Juliano Novaes Cardoso, Marcelo Eidi Ochia, Mucio Tavares de Oliveira Jr., José
Antonio Franchini Ramires, Antonio Carlos Pereira-Barretto
.....................................................................................................................................................................page 495
Cardiac Transplantation - Clinical
NHETS − Necropsy Heart Transplantation Study
Thiago Ninck Valette, Silvia Moreira Ayub-Ferreira, Luiz Alberto Benvenuti, Victor Sarli Issa, Fernando Bacal,
Paulo Roberto Chizzola, Germano Emilio Conceição Souza, Alfredo Inácio Fiorelli, Ronaldo Honorato Barros
dos Santos, Edimar Alcides Bocchi
.....................................................................................................................................................................page 505
Review Article
Systems Biology Applied to Heart Failure With Normal Ejection Fraction
Evandro Tinoco Mesquita, Antonio Jose Lagoeiro Jorge, Celso Vale de Souza Junior, João Paulo Pedroza Cassino
.....................................................................................................................................................................page 510
Letter to the Editor
Obesity and Abnormalities in Echocardiographic Parameters
Roberta Casanova Wilhelms, Eduardo Maffini da Rosa, Mauricio Lizott, Raphael Martin de Melo
.....................................................................................................................................................................page 518
Extracellular Matrix Turnover: a Balance between MMPs and their Inhibitors
Emre Yalcinkaya, Murat Celik, Baris Bugan
.....................................................................................................................................................................page 519
Erratum
.....................................................................................................................................................................page 521
Arquivos Brasileiros de Cardiologia - Volume 102, Nº 5, May 2014
Arquivos Brasileiros de Cardiologia - Eletronic Pages
Anatomopathological Session
Case 2/2014 – 51-Year Old Patient with Systemic Lupus Erythematosus and Fever after Valve Replacement
Wilma Noia Ribeiro, Alice Tatsuko Yamada, Paulo Sampaio Gutierrez
.................................................................................................................................................................. page e44
Case Report
Prolonged Cardiopulmonary Arrest Treated Successfully in the São Paulo’s Subway
Renan Gianotto-Oliveira, Maria Helena Favarato, Maria Margarita Gonzalez, Thiago Liguori, Sergio Timerman,
Roberto Kalil Filho
.................................................................................................................................................................. page e52
Viewpoint
Is Heart Team Fundamental to Aortic Stenosis Transcatheter Treatment?
Vitor Emer Egypto Rosa, Antônio Sergio de Santis Andrade Lopes, Tarso Augusto Duenhas Accorsi, Pedro Alves
Lemos Neto, Pablo Maria Alberto Pomerantzeff, Flávio Tarasoutchi
.................................................................................................................................................................. page e55
* Indicate manuscripts only in the electronic version. To view them, visit: http://www.arquivosonline.com.br/2014/english/10205/edicaoatual.asp
Arquivos Brasileiros de Cardiologia - Volume 102, Nº 5, May 2014
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Back to the Cover
Editorial
Trajectories of Cardiovascular Health: Life Course Epidemiology
in Brazil
Lucia Campos Pellanda
Programa de Pós-graduação em Ciências da Saúde: cardiologia, Fundação Universitária de Cardiologia. Universidade Federal de Ciências da Saúde,
Porto Alegre, RS - Brazil
Cardiovascular epidemiology has advanced enormously
in the study of risk factors for atherosclerosis1, as evidenced
by publications in Arquivos Brasileiros de Cardiologia (ABC)
in the last years2-4.
Based on this information, it is possible to explore new
hypotheses and, therefore, new frontiers for prevention.
The different perspectives for the study of these risk factors
include the life course epidemiology. This perspective
considers that the onset of the disease may occur long
before the establishment of traditional risk factors in
adulthood. Thus, health and diseases can be considered as
a result of long-term effects of exposure to different factors
throughout the various stages of life, including intrauterine
life, childhood, adolescence and adulthood5.
This significantly increases the complexity of analysis6,
but also adds dimensions previously little explored in
epidemiology and cardiovascular prevention. A basic
concept within this line of epidemiological interpretation
is that of critical or sensitive periods, that is, the idea that
stimulus acting for a certain critical period of development
may bring long‑lasting consequences on the structure or
function of organs. For example, the intrauterine period
in which tissues and organs are forming, is critical for the
establishment of a risk profile for the rest of the course of life.
Metabolic adaptations of the fetus occurred in this period
could persist for the rest of life, thus increasing the risk of
chronic diseases such as coronary artery disease, diabetes
and obesity during adulthood. This process has been called
intrauterine programming of chronic diseases7.
The ABC have been publishing interesting articles on this
topic, providing insights into the discussions that have been
occurring in the international arena8-10.
In a study carried out in Goiânia11, the authors compared
the pressures measured by ABPM, of a group of children
with low birth weight with those with adequate birth weight,
observing that those with underweight had higher blood
pressure and abnormal circadian rhythm of blood pressure
with reduced nocturnal dipping.
Keywords
Cardiovascular diseases / epidemiology; Life change events;
Risk factors; Periodicals as topic.
Mailing Address: Lucia Campos Pellanda •
Instituto de Cardiologia / Fundação Universitária de Cardiologia (IC-FUC).
Endereço: Avenida Princesa Isabel, 370 / 3º andar, Unidade de Pesquisa.
Porto Alegre, Rio Grande do Sul - Brazil. Postal Code: 90620-000.
e-mail: [email protected]
DOI: 10.5935/abc.20140065
On the other hand, Souza et al.12 studied the association
between birth weight and cardiovascular risk factors in
adolescents in Salvador, and observed two and a half
higher prevalence of obesity and three times higher blood
pressure in the group with high birth weight compared to
the normal weight group.
These apparently conflicting findings may actually
represent a U-shaped curve, in which both low weight and
high weight would represent risk over normal weight at
birth. In observational studies, newborns weighing less than
2,500 g had a higher incidence of cardiovascular diseases,
hypertension and atherosclerosis – and glucose intolerance,
– type II diabetes or metabolic syndrome in adulthood. –
Babies with birth weight higher than 4 kg, regardless of
gestational age or gender, have abnormal metabolism of
carbohydrates and lipids associated with later development
of obesity, diabetes and dyslipidemia13-15.
Besides the nonlinear association, there are many ways
by which intrauterine factors can influence the pattern of
disease in later stages. These effects may interact with other
stimuli that occur in other periods, undergoing changes
throughout life. Therefore, for example, birth weight
considered in isolation would not be enough to explain the
CAD. It is necessary to consider the relationship between
this marker and the events following the moment of birth,
such as the rapid recovery of growth in early childhood,
that may further promote increased risk16,17.
Therefore, the life course model supports studies on
initial exposures and but their potential interaction with
other intermediate factors. Gaining acquaintance with this
sequence of events and with the idea of critical periods
has important consequences in the adoption of preventive
strategies, because it helps identify periods of increased
need for intervention and helps consider social inequality
in health as factors that affect the entire life cycle of
many generations5.
The study of Rio de Janeiro 18 evaluated the blood
pressure of adolescents and, again, the same individuals
18 years later. Adolescents with abnormal blood pressure
in the first assessment presented higher average weight,
insulin, leptin, apolipoprotein B100 and A1, the highest
prevalence of overweight, obesity, increased waist
circumference and hypertension in the group with normal
blood pressure in adolescence. Adolescence is a phase
that deserves special attention. Good nutrition during this
phase permanently affects the individual’s life, since in
this phase, 25% of adult height and 50% of body mass are
acquired. Therefore, it is an important phase for weight
control and acquisition of good eating habits.
418
Trajectories of cardiovascular health
Editorial
Another interesting study published in ABC19 evaluated
individuals at three different times in life. Adults diagnosed
with metabolic syndrome presented, as early as in adolescence,
significantly higher values for weight, waist circumference and
body mass index. This fact has important implications for
prevention, since early detection of these risk factors can mean
significant benefit in the future20,21.
The aThe adoption of a life course model, therefore,
has the potential to significantly change the paradigm
of prevention of cardiovascular diseases, of the current
emphasis on control of risk factors in adulthood to
a broader approach to prevention of risk factors per
se throughout the course of life, including childhood
and adolescence. Further Brazilian studies, including
potential mechanisms, such as gene expression 22, and
interactions among the phases of life, body composition
and environment23 may add evidence to this set, opening
new possibilities of intervention in our community.
References
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Barreto SM, et al. Chronic non-communicable diseases in Brazil: burden
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2. Fuchs SC, Biolo A, Polanczyk CA. Cardiovascular epidemiology: the legacy of
sound national and international studies. Arq Bras Cardiol. 2013;101(2):98-100.
14. Schilithz AO, Silva CM, Costa AJ, Kale PL. Ecological analysis of the
relationship between infant mortality and cardiovascular disease mortality at
ages 45-69 in the Brazilian 1935 birth cohort. Prev Med. 2011;52(6):445-7.
3. Evora PR, Nather JC, Rodrigues AJ. Prevalência das doenças cardíacas
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Moreira LF. Os Arquivos Brasileiros de Cardiologia e a divulgação da pesquisa
em ciências cardiovasculares no Brasil. Arq Bras Cardiol. 2014;102(1):1-2.
5. Ben-Schlomo Y, Kuh D. A life course approach to chronic disease
epidemiology: conceptual models, empirical challenges and interdisciplinary
perspectives. Int J Epidemiol. 2002;31(2):285-93.
6. Davey-Smith G, Hart C. Life-course socioeconomic and behavioral
influences on cardiovascular mortality: the collaborative study. Am J Public
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7. Barker DJ. The origins of the developmental origins theory. J Intern Med.
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Desai M, Beall M, Ross MG. Developmental origins of obesity: programmed
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Hallal PC, Dumith SC, Ekelund U, Reichert FF, Menezes AM, Victora CG, et al.
Infancy and childhood growth and physical activity in adolescence: prospective
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10. Schilithz AO, da Silva CM, Costa AJ, Kale PL. Ecological analysis of the
relationship between infant mortality and cardiovascular disease mortality at
ages 45-69 in the Brazilian 1935 birth cohort. Prev Med. 2011;52(6):445-7.
11. Salgado CM, Jardim PC, Teles FB, Nunes MC. Baixo peso ao nascer como
marcador de alterações na monitorização ambulatorial da pressão arterial.
Arq Bras Cardiol. 2009;92(2):107-21.
12. Sousa MA, Guimarães IC, Daltro C, Guimarães AC. Associação entre peso
de nascimento e fatores de risco cardiovascular em adolescentes. Arq Bras
Cardiol. 2013;101(1):9-17.
13. Victora CG, Adair L, Fall C, Hallal PC, Martorell R, Richter L, et al.
Maternal and Child Undernutrition Study Group. Maternal and child
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Back to the Cover
Special Article
I Cardiovascular Prevention Guideline of the Brazilian Society of
Cardiology – Executive Summary
Antonio Felipe Simão, Dalton Bertolim Précoma, Jadelson Pinheiro de Andrade, Harry Correa Filho, José Francisco
Kerr Saraiva, Gláucia Maria Moraes de Oliveira
Sociedade Brasileira de Cardiologia (SBC) − Brazil
Introduction
Brazil currently faces a major health challenge: the
pandemic scenario of cardiovascular morbidity and mortality.
According to Brazilian Health Ministry data, 326,000 deaths
due to cardiovascular diseases (CVD) occurred in 2010,
corresponding to approximately 1,000 deaths/day, 200,000
deaths due exclusively to ischemic heart and cerebrovascular
diseases, reflecting a gloomy scenario far from the minimally
acceptable control.
This current scenario can be attributed to many reasons,
such as the insufficiency and inadequacy of public health
policies for CVD prevention, leading to the well-known lack of
infrastructure in primary health care, hindering the fight against
preventable affections, mainly in the neediest areas.
In addition, it is worth mentioning the well-known
sociocultural factors, such as the excessive consumption of
high-caloric foods in association with physical inactivity, and,
consequently, the development of obesity and diabetes,
and excessive salt intake. Those factors contribute to the
development of arterial hypertension, being decisive to
the high prevalence of CVD and no opportunity to provide
instructions on lifestyle changes.
The medical societies, in partnership with governments
and universities, have endeavored to elaborate valuable
documents containing strategic plans of CVD prevention
and fight. However, simple and objective guidelines,
which can be easily accessed and managed by health care
personnel, are required to implement that which has been
long discussed by specialists and scientists, although with
modest results.
For the first time, guidelines and consensus documents,
most of which already published in several other guidelines
of specialties, have been gathered in a single document to
provide the clinician with easy access to the recommendations
for primary and secondary CVD prevention. For that, the
Brazilian Society of Cardiology (SBC) has gathered specialized
physicians with large experience in preventive actions to
elaborate the present document.
Chapter 1 presents the cardiovascular risk stratification
for atherosclerosis prevention and treatment. In this chapter,
the authors discuss questions such as acute coronary event
as the first manifestation of atherosclerotic disease in at least
half of the individuals with that complication. Thus, the
identification of predisposed asymptomatic individuals is
crucial to the effective prevention with correct definition of
therapeutic goals, especially the criteria to identify high-risk
patients (Table 1). The authors discuss the so-called risk scores,
through which the overall risk is calculated, enabling the
clinician to quantify and qualify the patients’ individual risk,
for both women (Tables 2 and 3) and men (Tables 4 and 5).
The combination of those different scores allow the clinician
to better estimate the risk, stratifying it gradually: presence of
significant atherosclerotic disease or its equivalents; calculation
of risk score; aggravating factors (Chart 1) and risk stratification
based on lifespan. The authors propose a simplified algorithm
for cardiovascular risk stratification, which is exemplified in
Figure 1. The recommendations listed as class I and level of
evidence A are few, because the other recommendations
still require more comprehensive studies with long-term
follow‑up (Table 6).
Chapter 2 approaches tobacco smoking, the major
avoidable risk factor. It is known that 50% of the deaths of
smokers, most of which caused by CVD, could be prevented
with smoking cessation. In this chapter, the authors discuss
preventive measures for tobacco use. Data from the
Surveillance of Risk Factors and Protection Against Chronic
Diseases via Telephone Inquiry (VIGITEL, in Portuguese),
disclosed on April 2012, revealed advances in tobacco use
control in Brazil, with 14.8% of smokers older than 18 years.
They also approached the primordial prevention of tobacco
use, enumerating factors that contribute to smoking initiation
and proposing practical strategies for its combat. In addition,
the authors discuss techniques to treat the psychological
Keywords
Cardiovascular Diseases/prevention & control; Risk
Factors; Socioeconomic Factors; Primary Prevention;
Health Promotion; Cardiovascular Diseases/guidelines.
Mailing Address: Gláucia Maria Moraes de Oliveira •
Visconde de Pirajá 330/1114. Postal Code 22410-000, Rio de Janeiro, RJ – Brazil.
E-mail: [email protected]; [email protected]
Manuscript received January 29, 2014; revised manuscript January 30, 2014;
accepted January 30, 2014.
DOI: 10.5935/abc.20140067
Table 1 – Criteria to identify patients at high risk for coronary
events (phase 1)
Atherosclerotic coronary artery, cerebrovascular or obstructive peripheral
diseases with clinical manifestations (cardiovascular events) and still in
the subclinical form, documented by use of diagnostic methodology;
Arterial revascularization procedures;
Type 1 and type 2 diabetes mellitus;
Chronic kidney disease.
* To access the complete document with references requested access the link: http://publicacoes.cardiol.br/consenso/2013/Diretriz_Prevencao_Cardiovascular.aspIntroduction
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Table 2 – Scoring according to overall risk for women
Points
Age (years)
HDL-C
TC
-3
SBP (untreated)
SBP (treated)
Smoking
Diabetes
No
No
< 120
-2
60+
-1
50-59
0
30-34
1
2
35-39
< 120
45-49
< 160
120-129
35-44
160-199
130-139
< 35
140-149
3
200-239
120-129
130-139
4
40-44
240-279
150-159
5
45-49
280+
160+
6
Yes
Yes
140-149
150-159
7
50-54
8
55-59
9
60-64
10
65-69
11
70-74
12
75+
160+
Points
Total
HDL-C: high-density lipoprotein cholesterol; TC: total cholesterol; SBP: systolic blood pressure
Table 3 – Overall cardiovascular risk in 10 years for women
Points
Risk (%)
Points
Risk (%)
≤-2
<1
13
10.0
-1
1.0
14
11.7
0
1.2
15
13.7
1
1.5
16
15.9
2
1.7
17
18.5
3
2.0
18
21.6
4
2.4
19
24.8
5
2.8
20
28.5
6
3.3
21+
> 30
7
3.9
8
4.5
9
5.3
10
6.3
11
7.3
12
8.6
dependence of smokers with general and specific behavioral
approaches. Furthermore, this chapter presents instruments
to help to assess and understand the patient’s profile
by using universally accepted scales, such as Prochaska
and Di Clemente’s and Fagerström’s. Finally, the authors
approach, in a practical way, pharmacological treatment
strategies of tobacco use, such as nicotine replacement
with bupropion and varenicline, in addition to second-line
drugs (nortriptyline), with their possible associations. Table 7
summarizes the classification of recommendation and level
of evidence of those strategies.
Chapter 3 discusses the real benefits of primary and
secondary CVD prevention, with evident confirmation of diet,
supplements and vitamins, aiming at helping the clinician
to guide the community in choosing and consuming those
products. In addition to supplements, omega-3 fatty acids,
vitamins B, C, D and E, folates, alpha-linolenic acids and
carotenoids were assessed (Tables 8).
Chapter 4 approaches obesity, overweight and nutrition
transition, as well as the consequences for cardiovascular
morbidity and mortality of their association with arterial
hypertension, dyslipidemias, type 2 diabetes, osteoarthritides
and cancer. Tables 9 and 10 list the classification of
recommendation and levels of evidence for primary and
secondary prevention.
Chapter 5 summarizes the recommendations for systemic
arterial hypertension (SAH), emphasizing its importance for
the development of several pathologies, such as coronary
artery disease, heart failure, cerebrovascular disease and
chronic kidney disease. Table 11 shows the routine initial
assessment of hypertensive patients, and Table 12, its
complementary assessment. Therapeutic decision should
consider the patient’s additional risk. Table 13 shows
nonpharmacological measures, which are listed according to
their recommendation class and level of evidence. Figure 2
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Table 4 – Scoring according to overall risk for men
Points
Age (years)
HDL-C
-2
60+
-1
50-59
0
30-34
1
2
35-39
TC
SBP (untreated)
< 160
120-129
160-199
130-139
< 35
200-239
140-159
120-129
240-279
160+
130-139
280+
40-44
6
45-49
Diabetes
No
No
< 120
35-44
4
Smoking
< 120
45-49
3
5
SBP (treated)
140-159
Yes
Yes
160+
7
8
50-54
9
10
55-59
11
60-64
12
65-69
13
14
70-74
15
75+
Points
Total
HDL-C: high-density lipoprotein cholesterol; TC: total cholesterol; SBP: systolic blood pressure
Table 5 – Overall cardiovascular risk in 10 years for men
Points
422
Risk (%)
Points
Risk (%)
≤-3 or less
<1
13
15.6
-2
1.1
14
18.4
-1
1.4
15
21.6
0
1.6
16
25.3
1
1.9
17
29.4
2
2.3
18+
> 30
3
2.8
4
3.3
5
3.9
6
4.7
7
5.6
8
6.7
9
7.9
10
9.4
11
11.2
12
13.2
Arq Bras Cardiol. 2014; 102(5):420-431
shows the algorithm of pharmacological treatment based
on the patients’ hypertension stages. Monotherapy can be
initiated with any drug class, but SAH control is only achieved
in one-third of the cases with that strategy. Chart 2 shows
the goals to be met according to patients’ characteristics.
Chapter 6 was aimed at discussing dyslipidemias, in an
attempt to, after stratifying the individual risk, establish the
therapeutic goals according to the overall risk level (low,
intermediate or high). Specific goals are listed for high- and
intermediate-risk patients. Patients at low cardiovascular
risk should have their goals individualized at their clinician’s
discretion and according to lipid reference values. Table 14
presents strategies for lifestyle changes. Table 15 lists the
pharmacological alternatives based on their recommendation
class and level of evidence.
Chapter 7 discusses diabetes, emphasizing its high
prevalence in the adult population, up to 13.5% in some
municipalities, which could represent a current population
of 17 million individuals with diabetes. Those numbers are
increasing due to factors such as population growth and
aging, and increasing urbanization, sedentary lifestyle and
obesity. This important chapter discusses essential measures
for prevention, such as lifestyle changes (Table 16).
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Chart 1 – Aggravating risk factors
• Family history of early coronary artery disease (male first-degree relative < 55 years-old or female first-degree relative < 65 years-old);
• Criteria of metabolic syndrome according to the International Diabetes Federation;
• Microalbuminuria (30-300 mg/min) or macroalbuminuria (>300 mg/min);
• Left ventricular hypertrophy;
• High-sensitivity C-reactive protein > 3 mg/L;
• Evidence of subclinical atherosclerotic disease:
carotid stenosis/thickening > 1mm
coronary calcium score > 100 or > 75th percentile for age or sex
ankle-brachial test < 0.9
Table 6 – Classification of recommendation and level of evidence for risk stratification in cardiovascular prevention
Recommendation
Class
Level of evidence
I
A
IIa
B
I
A
I
A
For individuals at intermediate risk, aggravating factors should be used, and when present (at least one) reclassify the individual
as high-risk
IIa
B
Use of risk according to lifespan for low- and intermediate-risk individuals aged >45 years
IIa
B
•
Clinical manifestations of atherosclerotic disease or equivalents (type 1 or 2 diabetes mellitus and significant chronic kidney disease),
even in primary prevention, have a risk > 20% in 10 years of new cardiovascular events or of the first cardiovascular event
•
Patients classified as intermediate-risk with a family history of early cardiovascular disease will be reclassified as high-risk
•
Men with a calculated risk for any of the events cited ≥5% and ≤20% and women with that calculated risk ≥5% and ≤10% are
considered intermediate-risk
•
Men with a calculated risk >20% and women with that calculated risk >10% are considered high-risk
•
•
ORS < 5% in men and women
ORS ≥ 5% and ≤ 20% in men
or ≤ 10% in women
LOW RISK
INTERMEDIATE RISK
If family history of early CAD, reclassify
Use aggravating: if an aggravating
factor is present
INTERMEDIATE RISK
HIGH RISK
High-risk condition present or ORS > 20% in
men and > 10% in women
Risk based on lifespan
If risk based on lifespan
• > 39% for men or
• > 20.2 % for women,
• High risk of CV events
HIGH RISK
Figure 1 – Algorithm for cardiovascular risk stratification. ORS: overall risk stratification; CAD: coronary artery disease; CV: cardiovascular.
Chapter 8 provides a review on metabolic syndrome.
There are several versions of the metabolic syndrome
definition, and this guideline adopted the joint position
paper of several international organizations on the topic.
The authors discuss the epidemiological aspects of its
prevalence, approaching different population groups,
and aspects related to cardiovascular and metabolic risks,
in addition to metabolic syndrome risk factors. Table 17
shows the recommendation class and level of evidence of
interventions in metabolic syndrome.
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Table 7 – Classification of recommendation and level of evidence for the treatment of smoking in cardiovascular prevention
Recommendation
Class
Level of evidence
•
Smoking is an independent risk factor for cardiovascular disease, therefore should be avoided
I
B
•
Passive tobacco exposure increases the risk for cardiovascular diseases and should be avoided
I
B
•
Pharmacological treatment of smoking
I
A
Nicotine replacement
I
A
Bupropion hydrochloride
I
A
Varenicline tartrate
I
A
Table 8 – Summary of the recommendations for not using vitamin supplements to prevent cardiovascular disease (CVD) and recommendations
for the consumption of products rich in omega-3 fatty acids
Indication
Class
Level of evidence
•
There is no evidence that supplementation of vitamin A or beta-carotene is beneficial to the primary or secondary prevention of CVD
III
A
•
Supplementations of vitamin B and folic acid are not effective to the primary or secondary prevention of CVD
III
A
•
There is no evidence that supplementation of vitamin C is beneficial to CVD prevention, progression or mortality
II
A
•
Supplementation of vitamin D is not recommended to CVD prevention in individuals with normal serum levels of that vitamin.
Likewise, there is no evidence that supplementation in individuals with deficiency of that vitamin will prevent CVD.
III
C
•
Marine omega-3 supplementation (2-4g/day) or even at higher doses should be recommended for severe hypertriglyceridemia
(>500mg/dL), at risk for pancreatitis, refractory to nonpharmacological measures and drug treatment
I
A
•
At least two fish-based meals per week, as part of a healthy diet, are recommended to reduce the cardiovascular risk. That is
particularly recommended for high-risk individuals, such as those with previous myocardial infarction.
I
B
•
Supplementation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is not recommendedfor individuals at risk for
cardiovascular disease undergoing evidence-based preventive treatment.
III
A
•
The consumption of polyunsaturated omega-3 fatty acids of vegetable origin, as part of a healthy diet, should be recommended to
reduce the cardiovascular risk, although the real benefit of that recommendation is arguable and the evidence is inconclusive.
IIb
B
•
Alpha-linolenic acid (ALA) supplementation is not recommended for cardiovascular disease prevention.
III
B
Class
Level of evidence
Table 9 – Summary of the recommendations for obesity and overweight in cardiovascular disease primary prevention
Indication
•
Three healthy meals (breakfast, lunch and dinner) and two snacks per day
II
A
•
Read food labels and choose those with the lowest amounts of trans fats
II
A
•
Avoid sodas and industrialized juices, cakes, cookies and stuffed cookies, sweet desserts and other sweet treats
I
A
•
Prefer having water between meals
II
A
•
Exercise at least 30 minutes per day, everyday
I
A
•
Individuals with a tendency to obesity or with a familial trend should exercise moderately 45-60 minutes per day; those previously
obese, who lost weight, should exercise 60-90 minutes to prevent regaining weight
I
A
•
Avoid the excessive consumption of alcoholic beverages
I
A
Chapter 9 discusses the role played by physical activity,
physical exercise and sports in CVD prevention. Physically
active individuals tend to be healthier and have better
quality of life and longer life expectancy. Table 18 lists the
recommended physical exercise levels. In addition, the risks of
physical activity are approached, as well as the basic principles
for exercise prescription and strategies to encourage referral,
implementation and adherence.
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Chapter 10 discusses psychosocial factors in CVD
prevention. Beginning with the definition of the concept,
the chapter discusses the psychosocial conditions frequently
associated with cardiovascular risk, such as low socioeconomic
status, lack of social support, stress at work place and family
life, depression, anxiety, hostility and type D personality.
In addition, it assesses the recommendation class and level
of evidence of approaching the psychosocial factors in
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Table 10 – Summary of the recommendations for obesity and overweight in cardiovascular disease secondary prevention
Indication
Class
Level of evidence
•
Dietary caloric reduction of approximately 500 kcal/day
I
A
•
Intensification of physical activity, such as walking, biking, swimming, aerobic exercises, 30-45 minutes, 3 to 5 times a week.
I
A
•
Reduce sedentary activities, such as being seated for long periods watching TV, at computers or playing video games
I
B
•
Encourage healthy eating for children and adolescents
I
B
•
Sibutramine for weight loss in patients with cardiovascular disease
III
B
•
Bariatric surgery for selected patients
I
B
Class
Level of evidence
Table 11 – Routine initial assessment of the hypertensive patient
Recommendation
•
Urinalysis
I
C
•
Serum potassium
I
C
•
Serum creatinine
I
B
•
Estimated glomerular filtration rate
I
B
•
Fasting glycemia
I
C
•
Total cholesterol, HDL-C, serum triglycerides
I
C
•
Serum uric acid
I
C
•
Conventional electrocardiogram
I
B
Class
Level of evidence
Chest X-ray
IIa
C
Echocardiography: • stage 1 and 2 hypertensives without LVH on ECG
IIa
C
HDL-C: high-density lipoprotein cholesterol
Table 12 – Complementary assessment of hypertensive patients
Recommendation
I
C
Microalbuminuria: • hypertensives and diabetic individuals
• hypertensives with clinical suspicion of HF
I
A
• hypertensives with metabolic syndrome
I
C
• hypertensives with 2 or + risk factors
I
C
Carotid ultrasound
IIa
B
Treadmill test when coronary artery disease is suspected
IIa
C
Glycosylated hemoglobin
IIa
B
Pulse wave velocity
IIb
C
LVH: left ventricular hypertrophy; ECG: electrocardiogram; HF: heart failure
primary prevention (Table 19) and for adherence (Table 20)
by using cognitive-behavioral methods and indicating the
‘ten strategic steps’ to improve counseling for behavioral
changes. Interventions on depression, anxiety and distress are
also proposed as potential tools for adherence to preventive
strategies (Chart 3), which can also be improved with the
simple measures.
Chapter 11 approaches dyslipidemia, obesity and SAH in
childhood and adolescence. Brazilian population studies have
shown a 10%-35% prevalence of dyslipidemia in children and
adolescents. Table 21 shows the reference values for lipids and
lipoproteins in those age groups.
Table 22 shows the classification of SAH for children and
adolescents. Changes in lifestyle are the initial therapeutic
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Table 13 – Nonpharmacological treatment of hypertensive patients
Recommendation
Class
Level of evidence
Diet • DASH
I
A
• Mediterranean
I
B
• Vegetarian
IIa
B
Sodium: daily intake of 2g
I
A
Alcohol: do not exceed 30g of ethanol per day
I
B
Physical activity: 30 minutes/day/3 times a week (minimum)
I
A
Body weight control: BMI between 18.5 and 24.9 kg/m
2
Psychosocial stress control
Multiprofessional team
I
A
IIa
B
I
B
DASH: Dietary Approaches to Stop Hypertension; BMI: body mass index
Stage 1 arterial hypertension
Low and moderate cardiovascular risk
Stage 2 and 3 arterial hypertension
High and very high cardiovascular risk
Monotherapy
All classes of antihypertensive drugs,
except direct vasodilators
Combinations
Two antihypertensive drugs of different classes and at low doses
Inadequate response or intolerable adverse events
Increase
monotherapy dose
Change monotherapy
Add the seconddrug
Increase combination
dose
Change the
combination
Add the thirddrug
Inadequate response
Add other antihypertensive drugs
Figure 5.1 – Algorithm for the treatment of arterial hypertension according to the VI Brazilian Guidelines on Arterial Hypertension
Chart 2 – Blood pressure goals according to individual characteristics
Category
Consider
•
Stage 1 and 2 hypertensives at low and moderate CV risk
•
Hypertensives and borderline behavior with high and very high CV risk, or with 3 or + risk factors, DM, MS or TOL
130/80 mm Hg
Hypertensives with kidney failure and proteinuria > 1.0 g/L
130/80 mm Hg
•
< 140/90 mm Hg
CV: cardiovacular; DM: diabetes mellitus; MS: metabolic syndrome; TOL: target-organ lesions.
recommendation for primary SAH in children and adolescents.
Pharmacological treatment is indicated for individuals with
symptomatic hypertension, secondary hypertension, SAH
target-organ lesion, types 1 and 2 diabetes mellitus, and
persistent SAH despite the adoption of nonpharmacological
measures, a situation in which such measures are an adjunct
to the pharmacological treatment.
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The diagnosis of obesity or overweight in children is clinical,
and should be established via history and physical exam,
followed by comparison of anthropometric data with population
parameters, by using curves of body mass index (BMI) for age.
Prevention comprises adequate nutrition during pregnancy,
breastfeeding encouragement, identification of familial risk
factors, careful child’s growth and development follow-up, habit
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Table 14 – Recommendations for the nonpharmacological treatment of dyslipidemia in cardiovascular prevention
Indication
Class
Level of evidence
•
Control LDL-C
I
A
•
Meet the recommended LDL-C level (primary goal)
I
A
•
No goals proposed for HDL-C
I
A
•
Reduce the intake of saturated fatty acids and trans fatty acids, and consume phytosterols (2-3 g/day) and soluble fibers
I
A
•
Increase physical activity
I
A
•
Reduce body weight and increase the ingestion of soy proteins; replace saturated fatty acids with mono- and polyunsaturated fatty acids
I
B
•
Meet the recommended non-HDL-cholesterol level (secondary goal)
II
A
•
Use proper therapy when triglyceride levels > 500 mg/dL to reduce the risk of pancreatitis, and use individualized therapy when
triglyceride levels are between 150 and 499 mg/dL
II
A
•
No goals proposed for apolipoproteins or lipoprotein(a)
II
A
Table 15 – Recommendations for the pharmacological treatment of dyslipidemia
Indication
Class
Level of evidence
•
Statins as the first drug option in primary and secondary prevention
I
A
•
Use fibrates in monotherapy or in association with statins to prevent microvascular disease in patients with type 2 diabetes
I
A
•
Association of ezetimibe or resins with statins when the LDL-C goal is not met
IIa
C
•
Association of niacin with statins
III
A
•
Use omega-3 fatty acids for cardiovascular disease prevention
III
A
Class
Level of evidence
Table 16 – Dietary and physical activity interventions in diabetes mellitus (DM) to prevent cardiovascular disease
Indication
•
Moderate physical exercise for at least 150 minutes in association with moderate diet and energy restriction to prevent DM in
individuals at risk
I
A
•
Because of the effects of obesity on insulin resistance, weight loss is an important therapeutic goal for individuals at risk for DM
I
A
•
Reduction in fat to less than 30% of the energy ingestion and reduced energy ingestion for overweight individuals
I
A
Class
Level of evidence
Table 17 – Interventions in metabolic syndrome (MS) to prevent cardiovascular disease
Indication
•
A 5%-10% reduction in body weight in one year and long-term maintenance of weight lossare recommended
I
B
•
A diet with low amounts of total, saturated and trans fats, in addition to adequate amounts of fibers, is recommended
I
B
•
Physical activity for at least 30 minutes/day, preferably 45-60 minutes/day, 5 days a week, is recommended
I
B
•
Individuals with impaired glucose tolerance on drug therapy can have a more expressive reduction in the incidence of MS or type
2 diabetes mellitus
I
B
•
Individuals at metabolic risk and with abdominal circumference beyond the recommended limits should undergo a 5%-10% body
weight reduction in one year
IIa
B
•
Ingestion of less than 7% of total calories from saturated fat and of less than 200 mg/day of cholesterol in the diet is recommended
IIa
B
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Table 18 – Recommended exercise levels for health promotion and maintenance
Exercise characteristics
Health benefits
Comments
•
< 150 min/week of mild to moderate intensity
some
some exercise is certainly better than a sedentary lifestyle
•
150-300 min/week of moderate intensity
substantial
longer-duration and/or more intense exercise provides more benefits
•
> 300 min/week of moderate to high intensity
additional
Current scientific data specifyan upper limit neither for benefits nor for damages to an
apparently healthy individual
Table 19 – Classification of recommendation and level of evidence in approaching psychosocial factors in primary prevention
Recommendation
Class
Level of evidence
•
Behavioral changes with cognitive-behavioral strategy (motivational)
I
A
•
Integration of education and motivational strategies with a multiprofessional team whenever possible
I
A
•
Psychological or psychiatric consultation for more severe cases
I
C
•
Assessment of psychosocial risk factors
IIa
B
•
Pharmacological treatment and psychotherapy for patients with severe depression, anxiety and hostility, aimed at improving
the quality of life, despite lack of evidence
IIb
B
Chart 3 – Clinical strategy to improve adherence
Strategies to improve adherence
•
Simplify dosage regimen
•
Reduce the number of tablets and doses per day
•
Reduce costs
•
•
•
Lower cost drug
Generic drugs
Government subsidies and low-cost programs
•
Proper communication
•
•
•
•
Provide clear information about the benefits, possible adverse effects and duration of treatment
Assess without judging or criticizing the presence of poor adherence
Assess actively the presence of possible side effects (sexual dysfunction, cough, bleeding)
Avoid using technical terms and overloading the patient with a lot of information
Behavioral strategies
•
•
•
•
•
•
Incorporate the use of drugs to the patients’ routine, suiting the dosage regimen to activities, meals and bedtime
Use tablet holders, electronic alarm devices, diaries, packages with calendars
Online support groups
Positive reinforcement (incentives, rewards)
Self-monitoring
Motivation counseling
•
Table 20 – Classification of recommendation and level of evidence of adherence to strategy in cardiovascular prevention, lifestyle and medication
Recommendation
428
•
Assess and identify the causes of lack of adherence to define the proper orientation
•
Use behavioral and motivational strategies for patients with persistent lack of adherence
Class
Level of evidence
I
A
IIa
A
changes, especially the adoption of a healthy diet and global
increase in physical activity. It is important to involve the child’s
entire family, parents, teachers and health care professionals,
in addition to count on a multidisciplinary team.
and when the educational actions involve environmental and
health policies.
The systematic analysis of studies on the effectiveness of
interventions to promote physical activity in the pediatric age
group (more particularly adolescents) has shown better results
when the actions associate school, family and community,
Chapter 12 discusses topics related to legislation and
prevention of CVD risk factors. The authors approach specific
sanitary laws, discussing their effective role in health promotion
and prevention, by creating healthy environments, in addition
Arq Bras Cardiol. 2014; 102(5):420-431
Table 23 shows the recommendations and their levels of
evidence to prevent CVD in children and adolescents.
Simão et al.
Cardiovascular Prevention Guideline
Special Article
Table 21 – Reference values for lipids and lipoproteins in children and adolescents
Parameter
Acceptable
Borderline
High (p95)
TC
< 170
170-199
> 200
LDL-C
< 110
110-129
> 130
n-HDL-C
123
123-143
> 144
TG (0-9a)
< 75
75-99
> 100
TG (10-19a)
< 90
90-129
> 130
HDL-C
> 45
35-45
Apo A1
> 120
110-120
Apo B
< 90
90-109
Low (p5)
< 35
< 110
> 110
TC: total cholesterol; LDL-C: low-density-lipoprotein cholesterol; n-HDL-C: non-high-density-lipoprotein cholesterol; TG: triglycerides; HDL-C: high-density-lipoprotein
cholesterol; Apo A1: apolipoprotein A1; Apo B: apolipoprotein B.
Table 22 – Classification of arterial blood pressure in children
and adolescents
Class
Percentile of systolic or diastolic blood pressure
Normal
< 90
Prehypertension (9)
Normal-high (10)
90 to <95 or ≥ 120x80 mm Hg
Stage 1 SAH
95 to 99 increased by 5 mm Hg
Stage 2 SAH
> 99 increased by 5 mm Hg
SAH: systemic arterial hypertension
to emphasizing the importance of surveillance, prevention,
health care, rehabilitation and health promotion
Chapter 13 discusses specific aspects of prevention of CVD
associated with autoimmune diseases, influenza, chronic
kidney disease, obstructive arterial disease, socioeconomic
factors, obstructive sleep apnea, erectile dysfunction and
periodontitis (Table 24).
We provide the medical class with a guideline that gathers,
in one single publication, compiled and updated essential
prevention topics to be used as a reference in CVD prevention.
Author contributions
Conception and design of the research: Simão AF, Précoma
DB, Andrade JP, Correa Filho H, Saraiva JFK, Oliveira GMM;
Acquisition of data: Simão AF, Précoma DB, Correa Filho H,
Oliveira GMM; Analysis and interpretation of the data: Simão
AF, Correa Filho H, Saraiva JFK, Oliveira GMM; Writing of the
manuscript: Simão AF, Précoma DB, Correa Filho H, Saraiva
JFK, Oliveira GMM; Critical revision of the manuscript for
intellectual content: Simão AF, Précoma DB, Andrade JP,
Correa Filho H, Saraiva JFK, Oliveira GMM; Revision of the
manuscript: Oliveira GMM.
Potential Conflict of Interest
The author Harry Correa Filho declares have conflict with
the companies: Pfizer, Astra Zeneca.
Sources of Funding
There were no external funding sources for this study.
Study Association
This study is not associated with any thesis or dissertation
work.
Arq Bras Cardiol. 2014; 102(5):420-431
429
Simão et al.
Cardiovascular Prevention Guideline
Special Article
Table 23 – Classification of recommendation and level of evidence for the presence of cardiovascular diseases (CVD) in children and adolescents
Recommendation
Class
Level of evidence
Obesity screening by use of BMI in children ≥ 6 years, providing or indicating intensive behavioral interventions directed to
achieving a healthy weight
Ask about early CAD family history to identify children at risk
In the presence of positive family history, assess all family members, especially the parents
I
B
•
In children aged > 2 years with BMI ≥ 85th percentile:
Reinforce preventive instructions (see below)
Identify complications and RF: SBP, gallbladder disease symptoms, diabetes, sleep apnea, hypothyroidism, orthopedic disorders,
lipid profile
I
C
•
In children aged > 2 years with BMI ≥ 85th– 94th percentile,all measures above plus:
control of weight gain and fat ingestion, focusing on nutrition and development
treatment of RF and complications
multidisciplinary approach of moderate to high intensity
measure aspartate aminotransferase (AST), alanine aminotransferase (ALT) and blood sugar in children ≥ 10 years of age
I
C
•
In children aged > 2 years with BMI ≥ 95th percentile, all measures above plus:
Long-term objective: maintain BMI < 85
I
B
•
•
Consider more aggressive approaches if conservative strategies fail
Check urea and creatinine every 2 years
I
A
Exclusive maternal breastfeeding for the first 6 months
I
B
From the 12th to the 24th month, transition to non-aromatic low-fat milk (2% or skim)
I
B
From 2 to 21 years of age, non-aromatic skim milk should be the major beverage
I
A
Avoid sugar beverages, encourage water ingestion
I
B
Fat ingestion by infants should not be restricted without medical indication
I
C
From the 12th to the 24th month, transition to family meals with fat corresponding to 30% of the total caloric ingestion, 8%-10% of which
of saturated fat
I
B
From 2 to 21 years of age, fat should correspond to 25%-30% of the total caloric ingestion, 8%-10% of which of saturated fat
I
A
Avoid trans fat
I
B
Cholesterol < 300 mg/dL
I
A
I
B
Parents should create an environment that promotes physical activity and limit sedentary activities, and be role models
I
C
Limit sedentary activities, especially TV/video
I
B
Moderate to vigorous physical activity every day
I
A
Obesity screening
•
•
•
Nutrition – Milk/other beverages
Dietary fat
Others
From 2 to 21 years of age, encourage fiber ingestion, limit sodium ingestion and encourage healthy life habits: family meals, breakfast,
limit fast snacks
Physical activity
BMI: body mass index; CAD: coronary artery disease; RF: risk factors; SBP: systolic blood pressure
430
Arq Bras Cardiol. 2014; 102(5):420-431
Simão et al.
Cardiovascular Prevention Guideline
Special Article
Table 24 – Recommendation for approaching special conditions in cardiovascular disease prevention
Recommendation
class
level of evidence
IIb
C
I
B
•
In the context of preventing cardiovascular events, the benefit of using more strict therapeutic targets, especially due to the
presence of autoimmune diseases, is uncertain.
•
Annual influenza vaccination for patients with established coronary artery or cerebrovascular disease, regardless of age
•
Annual influenza vaccination for patients at high risk for coronary events, but with no cardiovascular disease, regardless of age.
IIa
C
•
Patients with chronic kidney disease should be considered at very high risk for cardiovascular risk factors, requiring the
assessment of glomerular filtration rate reduction and presence of co-morbidities.
I
C
•
Patients with obstructive arterial disease should be considered at very high risk, similarly to that of manifest coronary artery
disease, for approaching cardiovascular risk factors.
I
C
•
Socioeconomic indicators should be investigated in clinical assessment and considered when approaching a patient, to
improve quality of life and the prognosis of cardiovascular diseases.
IIa
B
•
All patients with obstructive sleep apnea should be considered as potential candidates to primary prevention, undergo
cardiovascular risk stratification and be treated according to estimated risk.
IIa
A
•
All men with erectile dysfunction should be considered as potential candidates to primary prevention, undergo cardiovascular
risk stratification and be treated according to estimated risk.
IIa
B
•
Patients with periodontitis should be considered for cardiovascular risk stratification and intensive local treatment.
IIa
B
Arq Bras Cardiol. 2014; 102(5):420-431
431
Back to the Cover
Original Article
Preclinical Study of a Biodegradable Polymer-based Stent with
Abluminal Sirolimus Release
Celso Kiyochi Takimura1, Carlos Augusto Homem M. Campos1, Pedro Henrique Magualhães Craveiro Melo1,
Julliana Carvalho Campos1, Paulo Sampaio Gutierrez1, Thiago Francisco Costa Borges2, Luciano Curado2, Spero
Penha Morato3, Francisco Rafael Martins Laurindo1, Pedro Alves Lemos Neto1
Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (USP)1; Scitech Produtos Médicos
Ltda2; Lasertools Tecnologia Ltda3, São Paulo, SP – Brazil
Abstract
Background: Bioabsorbable polymer stents with drug elution only on the abluminal surface may be safer than durable
polymer drug-eluting stents.
Objective: To report the experimental findings with the Inspiron™ stent – a bioabsorbable polymer-coated stent with
sirolimus release from the abluminal surface only, recently approved for clinical use.
Methods: 45 stents were implanted in the coronary arteries of 15 pigs. On day 28 after implantation, angiographic,
intracoronary ultrasonographic and histomorphological data were collected. Five groups were analyzed: Group I (nine
bare-metal stents); Group II (nine coated with bioabsorbable polymer on the luminal and abluminal surfaces); Group
III (eight stents coated with bioabsorbable polymer on the abluminal surface); Group IV (nine stents with bioabsorbable
polymer and sirolimus on the luminal and abluminal surfaces); and Group V (ten stents with bioabsorbable polymer and
sirolimus only on the abluminal surface).
Results: The following results were observed for Groups I, II, III, IV and V, respectively: percentage stenosis of 29 ± 20;
36 ± 14; 33 ± 19; 22 ± 13 and 26 ± 15 (p = 0.443); late lumen loss (in mm) of 1.02 ± 0.60; 1.24 ± 0.48; 1.11 ± 0.54;
0.72 ± 0.44 and 0.78 ± 0.39 (p = 0.253); neointimal area (in mm2) of 2.60 ± 1.99; 2.74 ± 1.51; 2.74 ± 1.30; 1.30 ± 1.14
and 0.97 ± 0.84 (p = 0.001; Groups IV and V versus Groups I, II and III); and percentage neointimal area of 35 ± 25;
38 ± 18; 39 ± 19; 19 ± 18 and 15 ± 12 (p = 0.001; Groups IV and V versus Groups I, II and III). Injury and inflammation
scores were low and with no differences between the groups.
Conclusion: The Inspiron™ stent proved to be safe and was able to significantly inhibit the neointimal hyperplasia
observed on day 28 after implantation in porcine coronary arteries. (Arq Bras Cardiol. 2014; 102(5):432-440)
Keywords: Drug-Eluting Stents; Sirolimus; Epidemiology, Experimental.
Introduction
In the years of 2002 and 2003, the Cypher™ (Cordis
Corp, Miami Lakes, USA) and Taxus™ (Boston Scientific,
Natick, USA) drug-eluting coronary stents were approved
for clinical use and provided a major breakthrough in the
percutaneous treatment of coronary stenoses, thanks to a
significant reduction of the incidence of in-stent restenosis
and of the need for a new target-vessel revascularization1,2.
However, the occurrence of cases of late and very late
thrombosis3,4 after implantation was an alert for the safety
of these drug-eluting stents.
Mailing Address: Celso Kiyochi Takimura •
Avenida Açocê 92, apto. 162, Indianópolis. Postal Code 04075-020,
São Paulo, SP – Brazil
E-mail: [email protected], [email protected]
Manuscript received September 23, 2013; revised manuscript November
04, 2013; accepted November 13, 2013.
DOI: 10.5935/abc.20140044
432
Among the multiple pathophysiological processes pointed as
predisposing factors for late and very late thrombosis are: delayed
strut endothelialization; positive remodeling with acquired poor
apposition; endothelial dysfunction; and inflammatory reaction
due to the presence of a durable polymer5.
With the purpose of overcoming the limitations and
adverse events related to first-generation stents, several new
drug‑eluting stents have been developed. These new stents
show variations either in the composition of the alloy, in
the strut thickness, in the mesh design, in the drug-carrying
polymer, in the drug class and dosage, or in the place on the
stent surface from which the drug is released.
We hypothesized that, after drug release and degradation
of the biodegradable polymer, only the metallic platform
would remain in the arterial wall (like in a bare-metal stent),
thus reducing the late and very late thrombosis rates of these
stents, without compromising the anti-restenotic efficacy.
Drug release from the abluminal surface only (stent surface
in contact with the vessel wall) could also prevent delayed
endothelialization of the stent struts, which is another
mechanism pointed as responsible for thrombosis.
Takimura et al.
Preclinical study of the Inspiron™ stent
Original Article
This study presents preclinical data on the Inspiron™
stent (Scitech ® Medical Products Inc., Goiânia, Goiás,
Brazil) – a stent composed of a chromium-cobalt L605
alloy, which is coated with a sirolimus and biodegradable
polymer mixture only on its abluminal surface, and was
recently approved for clinical use.
In this experimental study, the results observed in porcine
coronary arteries by means of angiographic, intracoronary
ultrasonographic, and histomorphological assessment on day
28 after implantation of the Inspiron™ stent versus stents
with polymer and sirolimus on the luminal and abluminal
surfaces, and bare-metal stents were compared.
Methods
Ethical Aspects
The study protocol was approved by the Institutional
Research Ethics Committee and was carried out according to
the Good Laboratory Practices guidelines.
Animal species
A total of 15 non-atherosclerotic juvenile pigs from a
commercial farm were used. Their mean weight was 28.9 kg
(26 to 31.5 kg), and they received oral acetylsalicylic acid (200 mg)
and clopidogrel (300 mg) one day prior to stent implantation.
Stents
Forty five pre-assembled stents manufactured by Scitech™
Medical Products, Inc., with 2.5, 3.0 and 3.5-mm diameters
and 19-mm length were used. These stents are made of a
chromium-cobalt L605 alloy, and have a thin strut (75-µm
thickness), forming rings with short cells (1.1 mm) linked to
each other by 65-µm struts6.
Except for 9 stents with no polymer or drug coating, the
other stents were coated with biodegradable polymer, a mixture
of poly (lactic acid) and poly (lactic acid‑co‑glycolic acid); this
layer was 5-µm thick, and water- and CO2 degradable within
6 to 9 months (Figure 1).
The drug used in the drug-eluting stents was sirolimus,
with 60% release in the first week and 90% within up to
4 weeks. The sirolimus dose used was 8.8 µg per mm of
stent in the sirolimus-releasing stent from the luminal and
abluminal stent surfaces; or 4.4 µg per mm of stent, on the
sirolimus-releasing stent only from the abluminal surface
(Inspiron™ stent).
Thus, five types of stents were assessed: nine stents
without polymer or antiproliferative drug coating (Group
I, bare-metal stent); nine bioabsorbable polymer-coated
stents on the luminal and abluminal surfaces (Group
II); eight bioabsorbable polymer-coated stents on the
abluminal surface (Group III); nine bioabsorbable polymer
and sirolimus coated stents on the luminal and abluminal
surfaces (Group IV) and ten bioabsorbable polymer- and
sirolimus-coated stents only on the abluminal surface
(Group V, Inspiron™ stent).
Stent implantation procedure
Intramuscular preanesthetic medications were administered
(ketamine 3 mg/kg and midazolam 0.5 mg/kg). Then, after
intravenous infusion of thiopental, the animals underwent
endotracheal intubation, mechanical ventilation, maintenance
of the anesthetic plan with isoflurane and monitoring of their
heart rhythms, heart rates, and oxygen saturation.
An arterial line for the stent implantation procedure was
obtained by dissecting the common femoral artery, with
arterial puncture under direct visualization and insertion of
a 6-French valved introducer. Under fluoroscopy (Philips
BV – The Netherlands), a 6-French Judkins Right therapeutic
catheter was manipulated for selective catheterization of the
coronary arteries; next, intracoronary nitroglycerin (200 µg) was
administered and coronary angiography was performed in the
left anterior oblique view at 45 degrees.
Then, a 0.014-inch Choice PR™ guidewire (Boston Scientific,
Natick, USA) was inserted with its distal tip positioned in the
target-coronary artery. Following a previous raffle, one stent per
artery was implanted, preferably in an arterial segment with
few lateral branches and without significant lumen reduction
and deployment pressure enough to reach a stent deployment
balloon diameter: artery rate of 1.1:1 (Table 1).
Post-Procedure follow-up
After the procedure, the animals were observed regarding
their anesthetic recovery and were given prophylactic
intramuscular antibiotic therapy with benzyl penicillin
1,200,000 units and gentamicin 40 mg. They were extubated
when well awake, and sent to individual pens. They later
received commercial feed for growing pigs (Cooper™, São
José dos Campos, São Paulo, Brazil) and water ad libitum.
For 28 days, oral antiplatelet agents were administered
(acetylsalicylic acid 100 mg a day and clopidogrel 75 mg a day);
the animals were seen daily by veterinarians, who observed
them and made notes on their general status, level of physical
activity, feed intake, and presence of fever; they also diagnosed
and treated occasional surgical wound infections.
On day 28 after stent implantation, the animals were
sent back to the animal experimentation laboratory and
underwent control coronary angiography with quantitative
coronary angiography and intracoronary ultrasonography.
They were euthanized by deepening the level of anesthesia
and administration of a lethal intravenous injection of
potassium chloride (30 to 40 mL).
Histological processing
After euthanasia and left paramedian thoracotomy, the
heart of each animal was carefully removed, with minimal
handling, to prevent external stent compression; the blood
in the cardiac chambers was washed out with drinking water
and 0.9% saline solution. A 10% formaldehyde solution was
then infused in the aortic root at a 100-mmHg pressure for
30 minutes. The arterial segments containing the stents were
dissected from the adjacent tissues, removed, and placed
in a 10% formaldehyde solution for 24 hours, and later, in
Arq Bras Cardiol. 2014; 102(5):432-440
433
Takimura et al.
Preclinical study of the Inspiron™ stent
Original Article
Figure 1 – Detail of the metal mesh (left), strut thickness (top right), and polymer (bottom right) of the chromium-cobalt L605 coronary stent (Scitech© Medical Products
Inc., Goiânia, Goiás, Brazil).
70% absolute alcohol. These arterial segments containing
the stents were desiccated in alcohol solutions, embedded
in methacrylate plastic resins, and subsequently subjected
to cross sections (mean thickness of 3.5 µm), with a tungsten
knife in a proper microtome (RM 2265, Leica, Germany).
Statistical Analysis
All angiographies of the stent implants and the control
studies performed at day 28 were analyzed by means of off-line
quantitative coronary angiography using the CASS II software
(Pie Medical, Maastrich, The Nederlands). The minimum lumen
diameter (MLD, in mm), reference diameters (RD, in mm),
percentage angiographic stenosis (%), and late lumen losses
(in mm) were determined.
Quantitative data are expressed as mean ± standard
deviation (SD) or median. After verifying that the data
were normally distributed, the simple analysis of variance
(one‑way ANOVA) was calculated for comparison of the
means between the groups; post-hoc analysis was carried
out when statistically significant differences were observed
between these groups. The Statistical Package for the Social
Sciences (SPSS) software, version 20.0, was used for data
analysis and the significance level was set at 5%.
Intracoronary ultrasonography
Financial disclosure
40-MHZ Atlantis™ SR Pro (Boston Scientific, Natick,
MA, USA) intracoronary sonography catheters were used,
with automatic pull back at 0.5 mm/s. The images acquired
were analyzed by the built-in measurement software of the
intracoronary ultrasound imaging system (Ilab®, Boston
Scientific, Natick, MA, USA); using planimetry, the lumen
areas (in mm2), stent areas (in mm2), neointimal hyperplasia
areas (in mm2), and percentage neointimal hyperplasia areas
(%) were determined.
Results
Quantitative Coronary Angiography
Histomorphology
Three histological slides were obtained per third of stent
segment (proximal, mid-, and distal). These slides were
stained with hematoxylin-eosin and Verhoeff’s method
for elastic fibers; later, they underwent histomorphological
analyses. These analyses were blind as regards the type of
434
stent implanted and semiquantitative scores were used
for the assessment of inflammation7, fibrin deposits8, and
degree of injury9.
Arq Bras Cardiol. 2014; 102(5):432-440
Office of Science and Technology and Strategic Inputs
(SCTIE)/Department of Science and Tecnnology (DECIT) of
the Ministry of Health (MS), National Council of Scientific
and Technological Development (CNPq), Studies and
Projects Financer (FINEP) of the Ministry of Science and
Technology (MCT) and Foundation for Research Support of
the State of São Paulo (Fapesp).
The stents were successfully implanted in all target coronary
arteries, with no complications during the implantation
procedures or in the immediate post-procedure period.
One animal (number 10) died on day six after stent
implantation. The death cause determined by pathological
study of the heart was acute inferior myocardial infarction
due to occlusion of the right coronary artery in which a
Takimura et al.
Preclinical study of the Inspiron™ stent
Original Article
Table 1 – Individual data on the stent implantation procedure
Animal number
1
Weight (kg)
31
2
30
3
30
4
31.5
5
28.5
6
30
7
30
8
26
9
31
10
11
12
13
14
15
27.5
26.5
27.5
27
26.5
31.5
Target coronary-artery
Group
Stent size (mm) (diameter x length)
Implantation pressure (ATM)
RC
I
3.0 x 19
8
CX
III
3.0 x 19
6
AD
IV
3.0 x 19
7
RC
I
3.0 x 19
10
CX
III
3.5 x 19
8
AD
II
3.0 x 19
10
RC
II
3.0 x 19
6
CX
IV
3.5 x 19
10
AD
III
3.0 x 19
5
RC
IV
3.0 x 19
8
CX
I
3.0 x 19
6
AD
II
3.0 x 19
9
RC
IV
3.0 x 19
10
CX
II
3.0 x 19
6
AD
III
3.0 x 19
7
RC
III
3.0 x 19
10
CX
V
3.0 x 19
10
AD
I
3.5 x 19
10
RC
V
3.0 x 19
10
CX
I
3.0 x 19
12
AD
III
3.0 x 19
11
RC
III
3.0 x 19
10
CX
V
2.5 x 19
8
AD
I
2.5 x 19
9
RC
V
2.5 x 19
6
CX
II
3.0 x 19
7
AD
IV
2.5 x 19
10
RC
II
3.0 x 19
8
CX
I
3.5 x 19
8
AD
V
2.5 x 19
7
RC
IV
3.0 x 19
12
CX
IV
3.5 x 19
10
AD
V
3.0 x 19
10
RC
III
3.5 x 19
7
CX
V
3.0 x 19
5
AD
II
3.5 x 19
10
RC
II
3.5 x 19
8
CX
IV
3.0 x 19
7
AD
V
3.0 x 19
11
RC
V
3.0 x 19
11
CX
III
3.5 x 19
5
AD
I
3.0 x 19
7
RC
I
3.0 x 19
10
CX
IV
3.5 x 19
10
AD
V
3.5 x 19
10
RC: right coronary artery; CX: circumflex artery; AD: anterior descending artery; Group I: bare-metal stents; Group II: stents with bioabsorbable polymer on the luminal
and abluminal surfaces; Group III: stents with bioabsorbable polymer on the abluminal surface; Group IV: stents with bioabsorbable polymer and sirolimus on the luminal
and abluminal surfaces; Group V: stents with bioabsorbable polymer and sirolimus only on the abluminal surface.
Arq Bras Cardiol. 2014; 102(5):432-440
435
Takimura et al.
Preclinical study of the Inspiron™ stent
Original Article
stent coated with biodegradable polymer on the luminal
and abluminal surfaces had been implanted (Group II stent).
The other arteries – anterior descending and circumflex,
and the stents implanted in these arteries, were patent,
with no firmly adherent intraluminal thrombi. This early
death determined an early mortality rate of 6.6% (one in
15 animals), which, according to an Investigators Consensus,
is representative of “good implantation technique and stent
technology”10 (rate should be lower than 10%).
On day 28 after stent implantation, control coronary
angiography performed in the surviving animals showed arterial
segments with patent stents and no image suggestive of thrombus.
Findings of quantitative coronary angiography, intracoronary
ultrasonography and histopathology are described in Table 2.
Quantitative Coronary Angiography
On quantitative coronary angiography, the porcine
coronary arteries had a reference diameter of approximately
2.6 mm during the stent implantation procedure. The inflation
pressure for stent implantation was, on average, of 8.5 ATM
(5 to 12 ATM; p = 0.348), reaching a balloon: artery ratio of
1.1:1 to cause moderate injury to the arterial wall.
Control quantitative coronary angiography on day 28 after
the procedure did not show any statistically significant
difference between the groups.
Intracoronary ultrasonography
On intracoronary ultrasonography, adequate stent
strut apposition was observed in all cases on day 28 after
implantation. Also, statistically significant larger luminal
areas (mm 2) were observed in the drug-eluting stents
(Groups IV and V) in relation to control stents (Groups I,
II and III) (p = 0.001). Likewise, the neointimal area and
percentage neointimal area were significantly smaller
in these drug-eluting stents in relation to control stents
(p = 0.001 for comparisons of Groups IV and V individually
versus Groups I, II and III), as shown in Figure 2.
The neointimal hyperplasia observed in the stents coated
with bioabsorbable polymer and sirolimus only on the
abluminal surface (Group V, Inspiron™ stent) was equivalent
to that observed in stents with the same coating on the
luminal and abluminal surfaces (Group IV), with no statistically
significant difference (p = 0.913).
Histomorphology
The injury and inflammation scores were low and
showed no statistically significant differences between the
groups (p = 0.999). Figure 3 shows histological images of
the neointimal hyperplasia on day 28 after implantation of
a bare-metal stent (on the left) and of a drug-eluting stent
(on the right) in arteries.
Table 2 – Results of quantitative coronary angiography, intracoronary ultrasonography and histomorphology
Group
p value
I (N = 9)
II (N = 9)
III (N = 8)
IV (N = 9)
V (N = 10)
2.59 ± 0.21
2.62 ± 0.20
2.63 ± 0.30
2.61 ± 0.24
2.50 ± 0.43
0.901
9.0 ± 1.9
8.0 ± 1.7
7.6 ± 2.2
9.3 ± 1.6
9.0 ± 2.1
0.348
Balloon diameter (mm)
2.76 ± 0.27
2.79 ± 0.24
2.89 ± 0.32
2.83 ± 0.19
2.71 ± 0.26
0.716
Balloon/artery ratio
1.06 ± 0.04
1.06 ± 0.08
1.10 ± 0.07
1.09 ± 0.10
1.10 ± 0.10
0.845
MLD at procedure termination (mm)
2.67 ± 0.23
2.74 ± 0.22
2.69 ± 0.21
2.73 ± 0.22
2.59 ± 0.26
0.749
RD on control angiography (mm)
2.30 ± 0.30
2.49 ± 0.32
2.39 ± 0.30
2.48 ± 0.22
2.54 ± 0.30
0.470
MLD on control angiography (mm)
1.64 ± 0.61
1.59 ± 0.45
1.57 ± 0.49
1.95 ± 0.43
1.85 ± 0.36
0.379
29 ± 20
36 ± 14
33 ± 19
22 ± 13
26 ± 15
0.443
Late lumen loss (mm)
1.02 ± 0.60
1.24 ± 0.48
1.11 ± 0.54
0.72 ± 0.44
0.78 ± 0.39
0.253
Luminal area (mm²)
4.49 ± 2.16
4.29 ± 1.53
4.33 ± 1.40
5.77 ± 3.32
6.03 ± 2.18
0.001*
Vessel area (mm²)
6.95 ± 1.40
6.90 ± 1.27
6.97 ± 0.87
7.00 ± 1.10
7.00 ± 1.58
0.305
Stent area (mm²)
7.09 ± 1.40
7.03 ± 1.27
7.07 ± 0.87
7.07 ± 1.10
7.00 ± 1.70
0.676
Neointimal area (mm²)
2.60 ± 1.99
2.74 ± 1.51
2.74 ± 1.30
1.30 ± 1.14
0.97 ± 0.84
0.001*
Baseline RD (mm)
Ballon inflation pressure (ATM)
Percentage stenosis (%)
Percentage neointimal area (%)
35 ± 25
38 ± 18
39 ± 19
19 ± 18
15 ± 12
0.001*
Inflammation (median) (min-max)
1 (0 - 2)
1 (0 - 2)
1 (0 - 3)
1 (0 - 1)
1 (0 - 1)
0.999
Schwartz injury (median) (min-max)
1 (0 - 3)
1 (0 - 2)
1 (1 - 3)
1 (0 - 2)
1 (0 - 2)
0.999
* Group IV versus Groups I, II, III and Group V versus Groups I, II, III.
Group I: bare-metal stents; Group II: stents with bioabsorbable polymer on the luminal and abluminal surfaces; Group III: stents with bioabsorbable polymer on the
abluminal surface; Group IV: stents with bioabsorbable polymer and sirolimus on the luminal and abluminal surfaces; Group V: stents with bioabsorbable polymer and
sirolimus only on the abluminal surface; RD: reference diameter; MLD: minimum lumen diameter.
436
Arq Bras Cardiol. 2014; 102(5):432-440
Back to the Cover
Takimura et al.
Preclinical study of the Inspiron™ stent
Original Article
Figure 2 – Luminal area (mm2), neointimal area (mm2), and percentage neointimal area (%) observed in the experimental groups I to V. * p value < 0.05 for Group IV
versus Groups I, II and III, and Group V versus Groups I, II and III.
Figure 3 – Cross-sectional views of porcine coronary arteries on day 28 after bare-metal stent implantation (Group I, left) and biodegradable polymer-coated stent with
sirolimus elution on the abluminal surface (Group V) (right). Magnification 40X.
Arq Bras Cardiol. 2014; 102(5):432-440
437
Takimura et al.
Preclinical study of the Inspiron™ stent
Original Article
Discussion
Preclinical studies in laboratory animals for the development
and improvement of coronary stents are important to provide an
initial idea of the mechanical performance, safety and efficacy
profile of the stents, in addition to being required by regulatory
agencies for the approval of these devices for clinical use11.
Despite all the benefits from the first-generation drug‑eluting
stents which brought a revolution in the treatment of
atherosclerotic coronary disease, questions arose on the
long-term safety of these devices, especially in relation to
late thrombosis12.
After the initial reduction in the number of drug-eluting
stents implantation observed at that time, new efforts have
focused on the development of stents with the use of
different alloys (chromium-cobalt and platinum-chromium),
new biocompatible or biodegradable polymers, and the
incorporation of new drugs (everolimus, zotarolimus and
biolimus A9), aiming to increase the safety of these devices.
Although the pathophysiology of stent thrombosis is
multifactorial, several animal and clinical evidences have
pointed to the presence of durable polymers as responsible for
inflammation and delayed vascular repair13. These evidences
have fostered the development of biodegradable polymer-based
stents and bioabsorbable stents.
In the present preclinical study on porcine coronary
arteries, we observed that biodegradable polymer-coated
stents with sirolimus release only from the abluminal surface
(Group V, Inspiron™ stent) showed neointimal hyperplasia
quantitatively similar to that of polymer and sirolimus‑coated
stents on the luminal and abluminal surfaces (Group IV).
The groups with sirolimus-releasing stents (Groups IV
and V) showed lower neointimal area in relation to the
bare-metal stents (Groups I, II and III). No difference was
observed between the five groups in relation to the injury
and inflammation scores, thus showing that both the
bioabsorbable polymer and the antiproliferative drug used
were safe and effective.
The Inspiron™ eluting-stent is characterized by being
composed of a chromium-cobalt L605 alloy, biodegradable
polymer coating , and sirolimus elution only on the
abluminal surface. Possibly because of being coated with
a biodegradable polymer, it is safer than durable-polymer
stents. In a meta-analysis of randomized clinical trials
comparing stent thrombosis rates up to 4 years after use
of the Yukon (Translumina, Hechingen, Germany) and
Biomatrix™ Flex (Biosensors International, Singapore)
biodegradable polymer-based drug-eluting stents versus
the Cypher™ (Cordis Corp, Miami Lakes, Fl, USA)
durable-polymer stent, the biodegradable polymer-based
stents showed less definitive stent thrombosis, less clinical
endpoints and less target-lesion revascularization than the
Cypher™ durable-polymer stent14.
An experimental study in a porcine model compared
the endothelial activity and inflammation scores in animals
undergoing Nobori™ stent implantation – a stent coated with
bioabsorbable polymer and biolimus only on its abluminal
surface, to that of animals undergoing Cypher™ stent
implantation, and found increased endothelial relaxation,
438
Arq Bras Cardiol. 2014; 102(5):432-440
decreased production of superoxide anion, and less
inflammation in the coronary segments in the group receiving
the Nobori™ stent15.
Recent findings, however, suggest that the presence of a
durable polymer per se does not determine a greater risk of
late thrombosis16,17. In an experimental study, Kolandaivelu
et al 18 observed that drug-eluting stents with durable
polymer (XIENCE) showed less early thrombogenicity than
a corresponding bare-metal stent (Multilink Vision), i.e.,
polymer and drug coating provided a protective effect for
acute thrombogenicity. Factors such as the stent design
and strut thickness emerged as other important factors
predisposing stent thrombosis.
Several other stents using biodegradable polymer and
antiproliferative drugs released only from the abluminal surface
have been developed. Examples of these stents are the stainless
steel biolimus A9-eluting Nobori™ (Terumo Corp., Japan)
and Biomatrix™ (Biosensors International, Singapore) stents
; the stainless steel paclitaxel-eluting JACTAX™ stent (Boston
Scientific, Natick, USA) , and the chromium-cobalt sirolimuseluting Firehawk™ stent (MicroPort Medical, Shanghai, China).
The Inspiron™ stent has been extensively studied in
experimental animals with results comparable to those
of other drug-eluting stents as regards safety, stent-strut
endothelialization, and neointimal hyperplasia19,20.
Clinical studies are underway to evaluate the efficacy of
this new drug-eluting stent. The preliminary clinical results
of the Inspiron™ stent (INSPIRON I) have shown a good
angiographic response, with late lumen loss of 0.18 mm;
good ultrasonographic response, with percentage neointimal
obstruction of 8.2%; and target-vessel revascularization of 0%.
A randomized clinical trial (DESTINY) comparing the
Inspiron™ stent with Biomatrix™ stent is currently being
conducted, expected to include 165 randomized patients
2:1 (Inspiron™ stent versus Biomatrix™).
Study limitations
The model used in the present study was healthy porcine
coronary arteries, which may not represent the progression in a
vascular segment with atherosclerotic disease. Atherosclerotic
animal models have been developed in rabbits and pigs;
however, these models are still uncommonly used in
preclinical studies for the development and improvement of
coronary stents.
Intracoronary ultrasonography was used only in the
control on day 28 after stent implantation with the purpose
of assessing in-stent neointimal hyperplasia, and not to guide
stent implantation. However, despite the known limitations of
quantitative coronary angiography, the findings of this method
revealed that the stents were adequately implanted (balloon:
artery ratio of 1.1:1) and the intracoronary ultrasonographic
findings showed adequate stent strut apposition in all cases.
Optical coherence tomography is a method that has been
widely used in preclinical and clinical validation studies of
new stents; however, this method was not yet available for
experimental animal use in our institution at the time the
study was carried out.
Takimura et al.
Preclinical study of the Inspiron™ stent
Original Article
Conclusions
In this experimental study, the drug-eluting stents
coated with sirolimus and bioabsorbable polymer
in porcine coronary arteries showed less neointimal
hyperplasia when compared to control bare-metal stents.
The bioabsorbable polymer-based stent with sirolimus
released only from its abluminal surface (Inspiron™ stent)
showed the same neointimal antiproliferative efficacy as
the stent with sirolimus released from both the luminal
and abluminal surfaces.
Author contributions
Conception and design of the research: Takimura CK,
Campos CAH; Acquisition of data: Takimura CK, Campos
CAH, Campos JC, Gutierrez PS; Statistical analysis: Takimura
CK; Analysis and interpretation of the data: Takimura CK;
Writing of the manuscript: Takimura CK, Craveiro PHM;
Supervision / as principal investigator: Takimura CK; Critical
revision of the manuscript for intellectual content: Campos
CAH, Craveiro PHM, Borges TFC, Curado L, Morato SP,
Laurindo FRM, Lemos Neto PA.
Potential Conflict of Interest
The authors Celso Kiyochika Takimura, Francisco Rafael
Martins Laurindo Alves and Pedro Lemos Neto are scientific
consultants of Scitech Medical Products. The authors Luciano
Spero Penha Morato Curado and are employed of Scitech
Medical Products.
Sources of Funding
This study was partially funded by SCTIE/ DECIT do
Ministério da Saúde, CNPQ, FINEP, FAPESP.
Study Association
This study is not associated with any thesis or dissertation work.
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Arq Bras Cardiol. 2014; 102(5):432-440
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Original Article
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Arq Bras Cardiol. 2014; 102(5):432-440
Back to the Cover
Original Article
Effects of Skeletonized versus Pedicled Radial Artery on Postoperative
Graft Patency and Flow
Rômulo C. Arnal Bonini1, Rodolfo Staico2, Mario Issa2, Antoninho Sanfins Arnoni2, Paulo Chaccur2, Camilo Abdulmassih
Neto2, Jarbas Jackson Dinkhuysen2, Paulo Paredes Paulista2, Luiz Carlos Bento de Souza2, Luiz Felipe P. Moreira1
Instituto do Coração (Incor), Faculdade de Medicina da Universidade de São Paulo1, São Paulo, SP; Instituto Dante Pazzanese de Cardiologia2,
São Paulo, SP - Brazil
Abstract
Background: Radial artery (RA) was the second arterial graft introduced in clinical practice for myocardial revascularization.
The skeletonization technique of the left internal thoracic artery (LITA) may actually change the graft’s flow capacity with
potential advantages. This leads to the assumption that the behavior of the RA, as a coronary graft, is similar to that of
the LITA, when skeletonized.
Objective: This study evaluated ‘free’ aortic-coronary radial artery (RA) grafts, whether skeletonized or with adjacent tissues.
Methods: A prospective randomized study comparing 40 patients distributed into two groups was conducted. In group I, we
used skeletonized radial arteries (20 patients), and in group II, we used radial arteries with adjacent tissues (20 patients).
After the surgical procedure, patients underwent flow velocity measurements.
Results: The main surgical variables were: RA internal diameter, RA length, and free blood flow in the radial artery. The mean
RA graft diameters as calculated using quantitative angiography in the immediate postoperative period were similar, as well
as the flow velocity measurement variables. On the other hand, coronary cineangiography showed the presence of occlusion
in one RA graft and stenosis in five RA grafts in GII, while GI presented stenosis in only one RA graft (p = 0.045).
Conclusion: These results show that the morphological and pathological features, as well as the hemodynamic
performance of the free radial artery grafts, whether prepared in a skeletonized manner or with adjacent tissues, are
similar. However, a larger number of non-obstructive lesions may be observed when RA is prepared with adjacent
tissues. (Arq Bras Cardiol. 2014; 102(5):441-448)
Keywords: Coronary Diseases / surgery; Radial Artery / abnormalities; Radial Artery / surgery; Vascular Patency.
Introduction
Radial artery (RA) was the second arterial graft introduced
in clinical practice for myocardial revascularization1. Initially,
it presented unfavorable angiographic results. However, with
changes in the surgical technique and the use of spasm‑preventing
vasodilators, RA started to be used safely and with good results
in the treatment of coronary diseases2.
RA skeletonized dissection was introduced by Taggart
et al in 20013, based on the good results obtained with
skeletonization of the left internal thoracic artery (LITA),
which started with Cunningham et al in 19924. There is no
question about the effects of pedicled LITA for myocardial
revascularization, and notwithstanding these excellent results,
the skeletonization technique of LITA may actually change the
Mailing Address: Rômulo César Arnal Bonini •
Divisão de Cirurgia Cardiovascular do Hospital Regional. Rua Winston
Churchill, 234, apto. 1.402, Jardim Paulistano. Postal Code 19013-710,
Presidente Prudente, SP - Brazil
E-mail: [email protected]
Manuscript received September 26, 2013; revised manuscript October 04,
2013; accepted October 04, 2013.
DOI: 10.5935/abc.20140016
441
graft’s flow capacity with potential advantages4-6. This leads
to the assumption that the behavior of the RA, as a coronary
graft, is similar to that of the LITA, when skeletonized.
Therefore, the purpose of this study was to randomly
compare the hemodynamic and functional performance
of RA aorto-coronary grafts, prepared in a skeletonized
manner or with adjacent tissues, by means of post-surgical
angiography and flowmetry performed in the immediate
postoperative period. Morphological and pathological
features of these grafts were also compared.
Methods
Study population
This study was designed as a randomized clinical trial
with distribution of twenty patients per group, according
to RA dissection technique and preparation (Group I –
skeletonized RA graft and Group II – RA graft with adjacent
tissues). Patients diagnosed with stable angina, unstable
angina, or a history of non-acute myocardial infarction
(with or without ST-segment elevation) were included
after free and clear discussion of risks, alternatives, and
perceived benefits of the operations. The study protocol was
approved by the institutional Research Ethics Committee
Bonini et al.
Skeletonization x Pedicle Preparation of Radial Artery
Original Article
and Scientific Review Board, and registered on the National
Council of Research Ethics (CONEP). All patients gave
written informed consent.
Patients with cineangiographic exams showing coronary
stenoses above 70% and good distal anatomy7 in at least two
main branches including the circumflex territory, and negative
classic and modified Allen test8,9 in the forearm, which is
intended for RA dissection, were selected. The following
exclusion criteria were applied: (a) age over 70 years; (b) severe
obesity; (c) positive Allen test10,11; (d) patients with arteriovenous
fistula for hemodialysis, vasculitis, or Raynaud’s disease; (e)
RA presenting macroscopically visible calcifications or diffuse
atherosclerotic disease; (f) redo operation; (g) additional
procedure; (h) severely depressed left ventricular function;
(i) contraindications for use of calcium-channel blockers;
(j) contraindication for postoperative angiography; (j) acute
myocardial infarct with or without ST-segment elevation; (k)
patients with kidney failure, or peripheral arterial disease.
Forty patients were selected for this study. All patients had
angina class 2–4 according to the Canadian Cardiovascular
Society. Previous myocardial infarction (MI), number of
diseased vessels, age, gender, diabetes mellitus, hypertension
and others characteristics were similar for both groups and are
shown in Table 1. All patients were operated on electively.
Surgical technique and pharmacological protocol
All patients were operated on under cardiopulmonary
bypass with mild hypothermia (32-34°C) and intermittent
aortic cross-clamping . Soon after discontinuation of
cardiopulmonary bypass, intravenous nitroglycerin was
administered for 48 hours, and replaced by an oral calciumchannel antagonist after this period.
The RA was dissected and prepared concomitantly
with LITA dissection. The RA dissection technique was
that proposed by Reyes et al12, and skeletonization, when
applied, was performed out of the forearm with the use of
scissors; collateral vessels were ligated using 4.0-cotton suture.
Intraluminal filling of the RA grafts was performed using
heparin-treated blood, and topical papaverine. LITA was used
to graft the left anterior descending artery and all RA were used
to graft the obtuse marginal artery, the intermediate branch or
the first diagonal branch with lesions > 75%. RA grafts were
anastomosed proximally in the aorta (retro-aortic), through
the orifice performed with a scalpel, using continuous suture
with 6.0 or 7.0 polypropylene, and distally to the coronary
branches, using continuous end-to-side anastomosis with
7.0 polypropylene suture. The right coronary artery and its
branches, as well as arteries with lesions > 75% received
saphenous vein grafts.
The following intraoperative variables were analyzed:
RA length and free RA flow. Pathological examination of RA
endothelial behavior was also performed in both groups.
All patients received isosorbide mononitrate (0.8 mg/kg per
min) and diltiazem (2 mg/kg per min) infused intraoperatively
and up to 24 h after operation, followed by 20 mg and
180 mg/day orally, respectively, in addition to antiplatelet therapy
for at least 6 months. The incidence of MI was monitored by
electrocardiograms and serial analyses of serum CK-MB.
Angiography and flowmetry protocol
Patients underwent angiography and flowmetry between
postoperative days 7 and 10. The test was performed via
the femoral access. The grafts were analyzed by a senior
cardiologist and classified according to presence or absence of:
non‑obstructive stenosis (< 50%), obstructive stenosis (> 50%)
and total occlusion.
The average peak velocity and the RA graft flow were
recorded in the initial portion (3 cm of the proximal
anastomosis) of the RA in both groups. For these
measurements, we used a 12-MHz Doppler guide of 0.014
inches (0.035 cm) in diameter, and 175 cm in length (Flowire;
Cardiometrics Inc)13. The records were performed at rest and
in hyperemia, which was induced by the injection of 30 µg of
adenosine directly into the graft. Graft flow reserve consisted
of the ratio between the peak velocities in hyperemia and
at rest. The blood flow at the proximal portion of the grafts
was calculated using the Doucette method13, with the time
average of peak velocity and the cross-sectional area of the
graft. This area was obtained after determining the diameter
by quantitative angiography for the analysis of the margin
contour. Absolute dimensions were calculated, using the
diagnostic catheter diameter as reference.
Statistical analysis
Data are expressed as mean ± standard deviation or
as percentages, and were analyzed using Mann-Whitney
non-parametric test, chi-square or Fisher’s exact test, when
appropriate. The sample size was projected for a 90% power to
identify a 10% difference in graft patency, with the significance
level set at 5%. P values lower than 0.05 were considered
significant, as determined using the SPSS for Windows, version
13.0 (SPSS, Inc., Chicago, IL).
Results
Each group comprised 20 patients. There was no hospital
mortality. The surgical variables are shown in Table 1.
The postoperative complications were: atrial fibrillation (five
cases), paroxysmal supraventricular tachycardia (one case),
bronchial pneumonia (one case), re-operation due to bleeding
in the immediate post-operative period (two cases), surgical
wound infection (one case). The length of the RA grafts in the
intraoperative period was 171 ± 22.5 mm, on average, in GI,
and 163.5 ± 24.4 mm in GII (p = 0.414); and the free RA
stroke volume, as calculated with a similar mean blood pressure,
was 84.6 ± 53.1 ml/min in GI, and 95.5 ± 63.3 ml/min in GII
(p = 0.627). There were no differences between the groups as
regards pathological examinations.
Angiographic data
Thirty-nine patients underwent cardiac catheterization
in the immediate postoperative period. At the moment of
the procedure, there were no variations in blood pressure,
heart rate, and hematocrit between the groups. The previous
global patency between the groups was similar (p = NS), of
100% in GI (n = 19), and of 95% in GII (n = 20); however,
perfect patency was different (p = 0.045) due to the fact
Arq Bras Cardiol. 2014; 102(5):441-448
442
Bonini et al.
Skeletonization x Pedicle Preparation of Radial Artery
Original Article
Table 1 – Clinical and surgical variables
Group I ( n = 20)
Group II (n = 20)
p-Value
52 ± 6.8
54 ± 5
0.221
17/3
16/4
NS
High Blood Pressure (n)
17 (85%)
19 (95%)
0.605
Dislipidemia (n)
8 (40%)
9 (45%)
0.749
Age (y)
Sex (M/F)
Diabetes (n)
6 (30%)
5 (25%)
0.723
Smoking habit (n)
11 (55%)
10 (50%)
0.752
Stable Angina (n)
17 (85%)
17 (85%)
NS
Previous AMI (n)
3 (15%)
3 (15%)
NS
CPB Time (min)
86 ± 23.76
89.1 ± 21.3
0.862
Anoxia Time (min)
60.5 ± 13.6
64.7 ± 16.9
0.429
Arterial Graft Revasc. (n)
2.2 ± 0.44
2.2 ± 0.4
NS
Total Revasc. Vessels (n)
3.25 ± 0.8
3.15 ± 0.8
NS
RITA (n)
2
4
NS
Saphenous veins(n)
17
15
NS
M: Male; F: Female; AMI: Acute myocardial infarction; CPB: Cardiopulmonary bypass; RITA: Right Internal Thoracic Artery.
that GI presented only one RA graft with non-obstructive
stenosis (< 50%), while GII presented five RA grafts with
stenosis (Figure 1), in addition to one occlusion (Figure 2).
Quantitative Angiography
The mean proximal diameter of the RA was 2.66 ± 0.11 mm
in GI, and 2.53 ± 0.05 mm in GII, with 95% CI (Figure 3).
The average peak velocities in the initial portion of the
RA at rest was 18.92 ± 1.75 cm/s in GI, and 18 ± 1.9 cm/s
in GII. The RA graft flow reserve was 2.12 ± 0.11 in GI, and
2.01 ± 0.1 in GII (Figure 4). The blood flow in the initial
portion of the RA was 54.92 ± 7.66 ml/min in GI, and
44.19 ± 5.13 in GII (Figure 5).
Discussion
The present study did not demonstrate differences between
the surgical characteristics of RA grafts. Taggart et al3 identified
some advantages of the skeletonized RA, anticipating clearly its
length, providing an option for the surgeon to choose the type
of anastomosis (using it for more than one graft, sequentially,
or also serving as an extension for other vessels)3. In this study,
although we did not find any statistical differences between
the groups regarding the RA length, skeletonization provided
us with a better notion of the graft extension. Rukosujem
observed the difference in the length of the skeletonized RA
in relation to RAs with adjacent tissues, dissected with the use
of scissors and clips14.
There were no anatomical and pathological differences
between the groups. This includes severe endothelial lesion
due to electrocauterization and intimal thickening. Rukosujem
observed a larger number of endothelial lesions in patients
that had RA skeletonized with ultrasonic scalpels14.
Achouh and Acar15 discussed the follow-up results of 629
radial artery grafts performed over 20 years. Focal stenosis
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Arq Bras Cardiol. 2014; 102(5):441-448
occurred in 3% of RAs, while string signs were observed in
0.9%. Overall graft patency was 83%. Graft patency decreased
exponentially during the first postoperative year, but patency
declined at a linear rate with low attrition afterwards,
suggesting a lack of radial graft disease15.
In the present study, the postoperative angiography
showed evidences of a similar global patency between
the groups, but a difference in perfect patency, due to
the larger number of non-obstructive stenosis (<50%)
and to an occlusion in the RA grafts with adjacent tissues.
Skeletonization allows, thorough more faithful visual
inspection, the identification of spasms or areas with lesions,
which may not be visible in the grafts with adjacent tissues,
thus improving the angiographic quality of the graft.
The difference between the global and perfect patency
of the RA with adjacent tissues has been demonstrated since
the 1990’s by several authors. Parolari et al16 published a
literature review presenting an early global average patency
of 98.1%, and perfect patency of 90.8% of RA grafts with
adjacent tissues17. The authors also reported average global
and perfect patency rates of 93.3% and 78.8%, respectively,
between 6 and 36 months after surgery. Similar differences
were also observed by other authors18,19.
Corroborating the results of our angiographic investigation,
Amano et al, in a non-random series of cases, found RA total
patency of 98.6% and 98.8%, respectively, for skeletonized
RA and with adjacent tissues; while perfect patency was
of 96.5% and 84.9%, respectively20. Hirose et al showed
early angiographic results of skeletonized RA with ultrasonic
scalpels of 96% for perfect patency (free of stenosis), with
no differences in comparison to the patency of other arterial
grafts21. In 2004, Hirose et al also published angiographic
outcomes of a one-year follow-up, showing that 20 patients
who received skeletonized RA presented a perfect patency
rate of 95.2%22.
Bonini et al.
Skeletonization x Pedicle Preparation of Radial Artery
Original Article
Figure 1 – Pedicled radial artery with non-obstructive lesion in the proximal third.
Ali et al concluded that skeletonization of the RA provides
valuable patency results. Therefore, if the RA is to be used
as a conduit in Coronary Artery Bypass Graft surgery, it may
be harvested in either a skeletonized or pedicled fashion,
however, their study suggested that skeletonitazion may offer
the radial conduit some patency benefit when compared to the
pedicled technique23. Tokuda et al24 found that for grafts to the
left coronary system, a mean flow < 15 ml/min, and for grafts
to the right coronary system, a mean flow < 20 ml/min were
predictive of graft failure.
The proximal internal diameters of the RA grafts, as
calculated using the quantitative angiographic method were
similar in this study. There is no previous information comparing
the internal proximal diameter of RAs. However, when this
parameter was analyzed in the skeletonized and pediculated
LITA using quantitative angiography, a significant increase in the
proximal internal diameter with skeletonization was described5.
Webb et al reported a radial artery diameter by quantitative
coronary angiography of approximately 2.7 mm in 15 cases
after a 5-year follow-up25.
In the analysis of the flow variables (intravascular blood flow,
average peak velocity, RA graft flow reserve) using intravascular
Doppler flowmetry in the immediate postoperative period, we
did not observe any statistical difference between the two study
groups. The intravascular Doppler methodology employed in
this study for the collection of data (blood flow velocity) is highly
reliable13. The behavior of blood flow of the LITA graft to the left
anterior descending artery had already been studied by Akasaka
et al using Doppler flowmetry in 199526. They showed that
the blood flow was of 62±17 ml/min at rest and the coronary
flow reserve, of 1.8 ± 0.3. Similar results were also observed
by Gurné et al27. Takami and Ina5 compared two strategies
for the dissection of LITA – skeletonized and pediculated,
and, using intraoperative flowmetry, they found a superior
flow (42.6 ± 29.1 ml/min) of skeletonized LITA in relation to
pediculated LITA (26.4 ± 16.1 ml/min)21. On the other hand,
Rukosujew et al15 calculated the perivascular free blood flow
in 40 patients who received either skeletonized RA or with
adjacent tissues, and found no statistical differences between
the groups, similar to the results observed in the current study.
Webb et al25 calculated a mean coronary graft volume
blood flow baseline of 35 ml/min in graft radial artery.
The coronary flow reserve has also been a variable increasingly
used for the assessment of coronary lesions and outcomes of
percutaneous interventions. Similarly to average peak velocity,
this parameter may display large variations in patients with
angiographically normal arteries. Based on the experience with
the analysis of coronary flow reserve in LITA, and reported by
Webb et al25, the mean coronary flow reserve in radial graft
was 2.3 with the use of velocity measurements.
Arq Bras Cardiol. 2014; 102(5):441-448
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Bonini et al.
Skeletonization x Pedicle Preparation of Radial Artery
Original Article
Figure 2 – Pedicled radial artery proximally occluded.
Figure 3 – Mean proximal internal angiographic diameter of the radial artery (p = 0.492). Mean ± 95% CI.
445
Arq Bras Cardiol. 2014; 102(5):441-448
Bonini et al.
Skeletonization x Pedicle Preparation of Radial Artery
Original Article
Figure 4 – Coronary Flow Reserve of the radial artery (p = 0.624). Mean ± 95%CI.
Figure 5 – Blood flow of the radial artery at rest (p = 0.435). Mean ± 95% CI.
In this study the RA graft flow reserve was 2.12±0.11
in GI, and of 2.01±0.1 in GII. We can conclude that
it was satisfactory in this study, thus demonstrating a
significant perspective of RA adaptability to different
coronary territories.
In conclusion, the results of the present study, with a selected
group of patients, allow us to state that the morphologic,
functional and hemodynamic performances of RA aorto-coronary
grafts to left coronary branches are similar, whether it is prepared
in a skeletonized or pedicled manner. However, the higher
frequency of obstruction and stenosis occurring in pedicled grafts
may pose a limitation to their long-term performance.
Author contributions
Conception and design of the research and Statistical analysis:
Bonini RCA, Moreira, LFP; Acquisition of data and Analysis and
interpretation of the data: Bonini RCA, Staico R; Obtaining funding
Arq Bras Cardiol. 2014; 102(5):441-448
446
Bonini et al.
Skeletonization x Pedicle Preparation of Radial Artery
Original Article
and Writing of the manuscript: Bonini RCA; Critical revision of
the manuscript for intellectual content: Bonini RCA, Dinkhuysen
JJ, Moreira, LFP; Performed surgery: Issa M, Arnoni AS, Chaccur
P, Abdulmassih Neto C, Dinkhuysen JJ, Paulista PP, Souza LCB.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Sources of Funding
This study was funded by Instituto Dante Pazzanese de
Cardiologia.
Study Association
This article is part of the thesis of Doctoral submitted
by Rômulo C. Arnal Bonini from Faculdade de Medicina
da USP.
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Arq Bras Cardiol. 2014; 102(5):441-448
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448
Back to the Cover
Original Article
Does C-reactive Protein Add Prognostic Value to GRACE Score in
Acute Coronary Syndromes?
Luis Cláudio Lemos Correia1,2, Isis Vasconcelos1,2, Guilherme Garcia1,2, Felipe Kalil1,2, Felipe Ferreira1,2, André Silva1,2,
Ruan Oliveira1,2, Manuela Carvalhal1,2, Caio Freitas1,2, Márcia Maria Noya-Rabelo1,2
Escola Bahiana de Medicina e Saúde Pública1; Hospital São Rafael2, Salvador, BA - Brazil
Abstract
Background: The incremental prognostic value of plasma levels of C-reactive protein (CRP) in relation to GRACE score
has not been established in patients with acute coronary syndrome (ACS) with non-ST segment elevation.
Objective: To test the hypothesis that CRP measurements at admission increases the prognostic value of GRACE score
in patients with ACS.
Methods: A total of 290 subjects, consecutively admitted for ACS, with plasma material obtained upon admission
CRP measurement using a high-sensitivity method (nephelometry) were studied. Cardiovascular outcomes during
hospitalization were defined by the combination of death, nonfatal myocardial infarction or nonfatal refractory angina.
Results: The incidence of cardiovascular events during hospitalization was 15% (18 deaths, 11 myocardial infarctions, 13 angina
episodes) with CRP showing C-statistics of 0.60 (95% CI = 0.51-0.70, p = 0.034) in predicting these outcomes. After adjustment
for the GRACE score, elevated CRP (defined as the best cutoff point) tended to be associated with hospital events (OR = 1.89,
95% CI = 0.92 to 3.88, p = 0.08). However, the addition of the variable elevated CRP in the GRACE model did not result in
significant increase in C-statistics, which ranged from 0.705 to 0.718 (p = 0.46). Similarly, there was no significant reclassification
of risk with the addition of CRP in the predictor model (net reclassification = 5.7 %, p = 0.15).
Conclusion: Although CRP is associated with hospital outcomes, this inflammatory marker does not increase the prognostic
value of the GRACE score. (Arq Bras Cardiol. 2014; 102(5):449-455)
Keywords: C-Reactive Protein; Acute Coronary Syndrome; Prognosis; Probability.
Introduction
In patients with acute coronary syndrome (ACS) with
non‑ST-segment elevation, the inflammatory phenomenon
hinders the atherosclerotic plaque stabilization, making it
vulnerable to recurring coronary events1. This is the rationale
for the prognostic value of inflammatory markers in ACS.
Among these markers, High-Sensitivity C-Reactive Protein
(hs‑CRP) is the best studied as a risk predictor in clinical
practice2. Actually, several studies have shown an association
between CRP and cardiovascular risk in patients with ACS3.
The prognostic association, however, is not a sufficient
criterion to define the clinical usefulness. A new biomarker
usefulness depends on the demonstration of its incremental
value in prognostic models traditionally used in clinical
practice4. Our group previously demonstrated that CRP
Mailing Address: Luis Cláudio Lemos Correia •
Av. Princesa Leopoldina 19/402, Graça. Postal Code 40150-080, Salvador,
BA – Brazil
E-mail: [email protected]; [email protected].
Manuscript received July 30, 2013; revised manuscript October 30, 2013;
accepted December 18, 2013.
DOI: 10.5935/abc.20140056
449
modestly increases the TIMI risk score5. In recent years, the
GRACE score has shown to be the multivariate model with
the best accuracy6. However, the incremental value of CRP in
relation to GRACE score is yet to be established.
To test the hypothesis that the measurement of CRP
increases the prognostic value of the GRACE score, this
marker was measured at admission in patients with ACS with
non‑ST segment elevation and recurrent events were recorded
prospectively. Discriminatory analysis (C-statistics) and net
reclassification were used as measures of incremental value.
Methods
Sample Selection
Individuals consecutively admitted to the Coronary
Care Unit of two tertiary hospitals between August 2007
and December 2011, with a diagnosis of unstable angina
or myocardial infarction with non-ST segment elevation,
were candidates for the Acute Coronary Syndrome
Registry (RESCA). The inclusion criteria for this registry is
defined by typical chest discomfort and at rest in the past
48 hours, associated with at least one of the following:
1) positive myocardial necrosis marker, defined by
troponin T ≥ 0.01 ug/L or troponin I > 0.034 g/L, which
Correia et al.
C-reactive protein and GRACE
Original Article
correspond to values above the 99th percentile7,8; 2) ischemic
electrocardiographic alterations, consisting of T-wave
inversion (≥ 0.1 mV) or transient ST‑segment depression
(≥ 0.05 mV); 3) previously documented coronary artery
disease, defined as history of myocardial infarction or
previous angiography demonstrating coronary obstruction
≥ 50%. We excluded patients whose admission plasma
samples were insufficient for CRP measurement and those
that refused to participate in the study. The protocol complies
with the Declaration of Helsinki and was approved by the
Research Ethics Committee of the institution and all patients
signed the free and informed consent form.
High-Sensitivity C-Reactive Protein measurement
The measurement of hs-CRP was carried out in a blood
sample collected immediately after hospital admission,
aiming at attaining minimum delay between symptom onset
and material collection. The plasma was frozen at -70°C for
simultaneous measurement of the sample. The nephelometry
method (Dade - Behring, Newark, Delaware, USA) was used9.
The assistant team was blinded to the CRP values during
patient hospitalization.
GRACE score
To calculate the GRACE score, patients’ clinical data
collected at the emergency department, electrocardiograms
performed within 6 hours of treatment, troponin T
measurements related to the first 12 hours of care and the
value of the first plasma creatinine were used. Elevation of
myocardial necrosis marker as component of the scores was
defined as troponin > 99th percentile8. The Killip classification
was also applied to patients with unstable angina so that the
GRACE score could be calculated. The GRACE score consists of
eight variables: five of them are computed semiquantitatively,
i.e., different weight for each stratum of age, systolic blood
pressure, heart rate, plasma creatinine and Killip class; three
of them computed dichotomously (ST-segment depression,
myocardial necrosis marker elevation, cardiac arrest on
admission). The final score can range from 0 to 37210.
Cardiovascular outcomes
The primary outcome was defined by the combination
of cardiovascular death, nonfatal myocardial infarction or
nonfatal refractory angina during hospitalization. Nonfatal
myocardial infarction was recorded during hospitalization
when there was elevation of troponin > the 99th percentile
in patients whose values ​​were negative in the first 24 hours.
For patients with infarction on admission, a new CK-MB peak
(>50% of the previous value and above the normal value) was
required for the definition of reinfarction. Elevation of necrosis
markers induced by percutaneous coronary procedure or
CABG was not recorded as a recurrent event. Refractory
angina during hospitalization was defined by recurrent chest
pain at least twice, despite the use of nitrates and controlled
double product.
Additionally, patients were contacted by telephone after
30 days, 6 months, and annually thereafter for the detection
of combined cardiovascular death, myocardial infarction or
readmission for unstable angina. Readmission was identified
by telephone contact and the reason was checked through
an interview with the patient and medical record data.
Cardiovascular death was defined as sudden death or
cardiovascular hospitalization followed by death.
Statistical Analysis
Initially, a Receiver Operating Characteristic (ROC) curve
of CRP levels was constructed to be used as predictors of
cardiovascular outcome. Once the accuracy by the ROC
curve was demonstrated, the best cutoff point was identified.
This cutoff was used to define elevated CRP, which was
entered into a logistic regression model with the GRACE score.
If elevated CRP reached statistical significance at the 10% level
(p < 0.10), a new GRACE-CRP score would be created, by
adding points when CRP was elevated. Additional points were
determined by the ratio between the regression coefficient of
elevated CRP and the regression coefficient of the GRACE score.
In the discriminant analysis, C-statistics of the GRACE
and GRACE-CRP models were compared by the Hanley –
McNeil test11. The calibration of the models was described
by the Hosmer‑Lemeshow test. Furthermore, we evaluated
the capacity of the new model (GRACE- CRP) to correctly
reclassify information from the traditional GRACE model
(high risk versus low risk). The best cutoff from each model in
our sample was used for risk definition. The Pencina method
(Net Reclassification Improvement‑NRI) was used in the net
reclassification analysis12 (Figure 1).
CRP values were described as median and interquartile range
(IQR) and compared between groups by the non‑parametric
Mann-Whitney test. Statistically significant p value was defined
as < 0.05. SPSS software, version 21 (IBM North America,
New York, NY) was used.
Sample size calculation
The sample was sized to provide statistical power for two
predefined statistical analysis. First, the logistic regression
analysis, in which we evaluated the predictive value of CRP,
regardless of the GRACE score. As this analysis requires two
covariates (elevated CRP and GRACE), 20 outcomes are
necessary to maintain the recommended ratio of 10 outcomes
per covariable13. Second, comparison of the GRACE C-statistics
versus GRACE-CRP: assuming a correlation coefficient between
the values of two models of 0.95 for a statistical power of 80%
(one-tailed alpha of 0.05) in the detection of 0.05 superiority of
C-statistics (e.g., 0.65 versus 0.70) of the most complete model
(GRACE- CRP) a total of 42 outcomes are required11. Thus, we
sequentially included the number of patients necessary to total
42 hospital outcomes, which was enough for both analyses
described herein.
Results
Selected sample
A total of 290 patients aged 68 ± 13 years, 52 % females,
53% with a diagnosis of myocardial infarction with non-ST
segment elevation and the rest with unstable angina were studied.
Arq Bras Cardiol. 2014; 102(5):449-455
450
Correia et al.
C-reactive protein and GRACE
Original Article
ROC curve: prognostic value of CRP
Identification of the best CRP cutoff
Logistic regression: CRP adjustment for GRACE score
GRACE-CRP model: incorporation of CRP into the GRACE model
GRACE versus GRACE-CRP
Comparison of ROCs
Analysis of reclassification
Figure 1 – Flowchart of data analysis. CRP: C-reactive protein; ROC: Receiver operating characteristic.
The GRACE score showed a median of 115 (IQR = 94-140),
with 43% being low risk, 32% medium risk and 25% high risk.
The median time between symptom onset and CRP measurement
was 6.7 hours (IQR = 3.3 to 24). CRP showed a median
of 4.5 mg/L (IQR = 1.4 to 13 mg/L), showing increased
inflammatory activity exacerbated by the acute clinical picture.
The incidence of cardiovascular outcomes during hospitalization
was 15% (18 cardiovascular deaths, 11 nonfatal AMIs, 13 cases
of nonfatal refractory angina). After discharge, 244 patients were
followed for 518 ± 446 days, with an incidence of cardiovascular
outcomes of 24% (11 cardiovascular deaths, 18 hospitalizations
for AMI and 28 hospitalizations for angina).
Prognostic value of C-reactive protein
Patients who developed hospital outcome showed median
CRP of 9.1 mg/L (IQR = 2.1 to 22 mg/L), significantly higher
than the median of 4.3 mg/L (IQR = 1.3 to 11 mg/ L) observed
in patients free of outcomes (p = 0.034). The predictive capacity
of CRP in relation to hospital outcomes was characterized
by C-statistics of 0.60 (95% CI = 0.51-0.70). In this analysis,
the definition of elevated CRP that showed the best accuracy
corresponded to a cutoff of 8.83 mg/L.
Analysis of clinical characteristics showed that the group with
elevated CRP had modestly older mean age, higher prevalence
of positive troponin and Killip > 1, all variables found in the
GRACE score, not requiring their entering the multivariate
model. Variables not covered by GRACE, as well as treatment
variables, were similar between groups (Table 1). When the CRP
was adjusted for the GRACE score, statistical significance was
reduced to a borderline value (OR = 1.9, 95% CI = 0.92- 3.9,
p = 0.08). In this model, the association between the GRACE
regression coefficient and the CRP coefficient was 30. Thus,
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Arq Bras Cardiol. 2014; 102(5):449-455
at the construction of the GRACE-CRP score 30 points were
added when CRP was elevated.
Different from the in-hospital phase, CRP values showed
no predictive accuracy for cardiovascular outcomes in the late
follow-up, with C-statistics of 0.51 (95 % CI = 0.42 to 0.59,
p = 0.90). The same occurred when only the hard endpoints
of death and nonfatal myocardial infarction were considered
(C -statistics = 0.59, 95% CI = 0.49-0.69, p = 0.11).
Incremental value of CRP during hospitalization
The addition of the variable elevated CRP to the GRACE
model did not result in significant increase in C-statistics, which
ranged from 0.705 to 0.718 (p = 0.46) (Figure 2). The GRACE
score showed satisfactory calibration with |2 using the Hosmer
- Lemeshow test of 7.5 (p = 0.48). After inclusion of elevated
CRP in the model, there was no improvement in calibration,
which evolved into |2 of 12.1 and p value = 0.15 (Table 2).
Reclassification of the GRACE score by C-reactive protein
Among the 42 patients who had hospital outcomes, two
were wrongly reclassified from high to low risk, whereas there
was no correct reclassification. This resulted in negative net
reclassification index for patients with outcomes (- 4.8%).
Among the 248 patients free of hospital outcomes, 26 were
correctly reclassified from high to low risk, with no incorrect
reclassifications. This resulted in a positive net reclassification
index for patients without outcomes (10.5 %).
In the final analysis, when all patients were considered,
the net reclassification index was 5.7 % (p = 0.15),
indicating that CRP has no value as reclassifying variable
of the GRACE score (Table 3).
Correia et al.
C-reactive protein and GRACE
Original Article
Table 1 – Comparison of clinical characteristics between patients with and without elevated C-reactive protein
CRP ≥ 8.83 mg/L
Sample
CRP < 8.83 mg/L
p value
91
199
Age (years)
71 ± 13
67 ± 13
0.07
Male gender
48 (53%)
90 (45%)
0.23
Diabetes
38 (42%)
77 (39%)
0.62
Positive troponin
62 (68%)
93 (47%)
0.001
ST segment elevation
22 (24%)
35 (18%)
0.19
Killip > 1
29 (32%)
22 (11%)
< 0.001
Creatinine clearance (mL/min)
49 ± 25
57 ± 22
0.01
GRACE score
136 ± 39
113 ± 35
< 0.001
Aspirin
87 (97%)
197 (100%)
0.10
Clopidogrel /Ticagrelor
80 (89%)
184 (93%)
0.25
Subcutaneous enoxaparin
76 (84%)
167 (84%)
1.0
In-Hospital treatment
Intravenous unfractionated heparin
3 (88%)
4 (86%)
0.68
GP IIb / IIIa antagonist
6 (6.6%)
7 (3.5%)
0.36
Nitrate
69 (76%)
139 (70%)
0.33
Beta-blocker
67 (74%)
141 (72%)
0.77
Statin
85 (96%)
193 (98%)
0.38
Percutaneous coronary intervention
27 (30%)
60 (30%)
1.0
Coronary artery bypass grafting
10 (11%)
15 (8.0%)
0.30
CRP: C-reactive; GP: Platelet dycoprotein.
Figure 2 – Comparison of ROC curves between GRACE and GRACE-CRP shows similar C-statistics between the two scores (p = 0.46).
Arq Bras Cardiol. 2014; 102(5):449-455
452
Correia et al.
C-reactive protein and GRACE
Original Article
Table 2 – Logistic regression model containing GRACE and CRP in predicting hospital outcomes
Variable
Coefficient ®
Odds Ratio (95%CI)
p value
Elevated CRP (dichotomy)
0.638
1.89 (0.92 – 3.9)
0.08
GRACE score (numeri`cal)
0.021
1.02 (1.01 – 1.03)
< 0.001
CI: confidence interval
Table 3 – Analysis of net reclassification by CRP-GRACE score in relation to the GRACE score for the definition of high risk
N
Reclassification for more
Reclassification for less
NRI
Outcome
42
0
2
- 4.8%
No outcome
248
0
26
10.5%
Total
290
0
28
5.7%
Discussion
This prospective cohort study tested the prognostic
value of CRP measured at admission of patients with ACS
with non-ST segment elevation. Consistent with previous
studies, CRP was associated with cardiovascular outcomes
during hospitalization. However, CRP incremental analysis
indicated the lack of usefulness for this marker in clinical
practice. This apparent contradiction between association
with outcome and the lack of incremental value needs to
be interpreted.
The strength of the inflammatory hypothesis as a
mechanism of genesis and destabilization of atherosclerotic
plaques increased in the 1990s, based on experimental
studies1, followed by evidence of the association of CRP with
cardiovascular risk in the general population14. In the 2000s,
several studies were published in journals of high impact,
favorable to the prognostic value of CRP in patients with
ACS. These studies were analyzed as a systematic review
and meta-analysis by our group, which was published in
20103. Unlike the enthusiastic attitude of some authors, our
review concluded that there was no conclusive evidence
of the incremental prognostic value of CRP. Moreover, only
two studies had made incremental
​​
evaluation (preliminary
studies)5,15, while the remainder was limited to the assessment
of independent association .
It is noteworthy that an independent association is
not enough to establish the usefulness of a biomarker.
To interrupt the predictor evaluation at this stage, considering
it validated for clinical use, has been a common error16.
The most important question is whether the new risk marker
has incremental usefulness in models applied in clinical
practice. This response should be obtained by comparing
the performance of a predictive model that uses the usual
variables with the performance of an alternative model
resulting from the incorporation of the new marker into the
traditional model. That is, after inserting a new variable to
a risk score, how much does the performance of this score
improve? The most common way to evaluate this question
is to measure the increase in C-statistics after incorporation
of the new biomarker, which was not done by most of the
453
Arq Bras Cardiol. 2014; 102(5):449-455
p value
0.15
studies in that review. Furthermore, we analyzed the net
reclassification, which identifies the correct reclassifications
(upwards in a patient that will have an outcome and
downwards in a patient without outcome) and subtract from
the incorrect ones. This method shows the proportion of
patients in which the advent of the new biomarker promoted
a correct change in relation to the risk.
Over the past three years, two new studies have been
published. A Spanish study where Lopes-Cuenca et al.
showed no increase in CRP in the C-statistics of GRACE17 and
a French study, in which He et al18 seem to have demonstrated
positive data. However, when analyzing the details, one can
see that the data of He et al18 suggest the same negative
conclusion of our study. As for the discriminatory value,
those authors describe a modest increase in C-statistics, from
0.795 to 0.823. Although this difference was statistically
significant, its magnitude is of little clinical relevance. Second,
the authors take into account a correct reclassification
of 12%. However, the net reclassification in which the
incorrect are subtracted from the correct is not calculated.
If this had been done, absence of reclassification would have
been the conclusion. In the present study, we performed
C-statistical analysis and correctly applied the Pencina
method of reclassification, concluding realistically for the
absence of clinical usefulness in incorporating CRP into the
routine assessment of patients with ACS.
Thus, the apparent contradiction between the enthusiasm
of initial studies and recent evidence is explained by the lack
of careful analysis that the first studies performed in their
own data. In recent years, the evolution of the scientific
community regarding the concept of usefulness of a new
biomarker has become stricter regarding data analysis, which
ultimately should include incremental value. The CRP is not
approved according to this analysis and our study is further
evidence in this direction.
The main limitation of this study is its sample size, and
thus, our data cannot be considered definitive regarding
the lack of any prognosis increment with CRP. On the other
hand, we must emphasize that this result is in line with
previous studies, which showed no significant improvement
Correia et al.
C-reactive protein and GRACE
Original Article
in C-statistics17,18. In addition, our number of outcomes
resulted in enough statistical power to identify any clinically
relevant increase in C-statistics. As for the late follow-up,
there was a loss of 16% in the sample, which is not desirable.
Moreover, we emphasize that this follow-up represents a
secondary objective of the study and it is unlikely that there
would be such difference regarding the characteristics of
46 patients without follow-up to the point of modifying a
prior entirely negative result.
We must acknowledge that these data do not definitively
rule out the usefulness of other inflammatory markers such
as cytokines. In a previous study, our group demonstrated
the potential value of a composite score with several
inflammatory markers19 and this year a Spanish study showed
very significant increase and reclassification with interleukin
- 6 in relation to GRACE17.
Conclusion
The limited incremental value of CRP in relation to GRACE
score suggests that the incorporation of this new biomarker in
clinical practice for patients with ACS with non-ST-segment
elevation is not indicated.
Author contributions
Conception and design of the research: Correia LCL, Silva
A, Noya-Rabelo MM; Acquisition of data: Vasconcelos I,
Garcia G, Kalil F, Silva A, Oliveira R, Carvalhal M, Freitas C,
Ferreira F; Analysis and interpretation of the data: Correia
LCL, Carvalhal M, Noya-Rabelo MM; Statistical analysis:
Correia LCL; Writing of the manuscript: Correia LCL,
Noya-Rabelo MM; Critical revision of the manuscript for
intellectual content: Correia LCL, Vasconcelos I, Garcia G,
Kalil F, Silva A, Carvalhal M, Ferreira F, Noya-Rabelo MM.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Sources of Funding
There were no external funding sources for this study.
Study Association
This study is not associated with any thesis or dissertation work.
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Original Article
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Arq Bras Cardiol. 2014; 102(5):449-455
Back to the Cover
Original Article
Relationship between Fibrosis and Ventricular Arrhythmias in
Chagas Heart Disease Without Ventricular Dysfunction
Eduardo Marinho Tassi1, Marcelo Abramoff Continentino2, Emília Matos do Nascimento1,3, Basílio de Bragança
Pereira1,3, Roberto Coury Pedrosa1
Instituto de Cardiologia Edson Saad - Universidade Federal do Rio de Janeiro (UFRJ)1; Hospital Frei Galvão, Guaratinguetá, SP2, Coppe –
Instituto Alberto Luiz Coimbra de Pós-Graduação e Pesquisa de Engenharia - UFRJ3, Rio de Janeiro, RJ – Brazil
Abstract
Background: Patients with Chagas disease and segmental wall motion abnormality (SWMA) have worse prognosis
independent of left ventricular ejection fraction (LVEF). Cardiac magnetic resonance (CMR) is currently the best method
to detect SWMA and to assess fibrosis.
Objective: To quantify fibrosis by using late gadolinium enhancement CMR in patients with Chagas disease and
preserved or minimally impaired ventricular function (> 45%), and to detect patterns of dependence between fibrosis,
SWMA and LVEF in the presence of ventricular arrhythmia.
Methods: Electrocardiogram, treadmill exercise test, Holter and CMR were carried out in 61 patients, who were divided
into three groups as follows: (1) normal electrocardiogram and CMR without SWMA; (2) abnormal electrocardiogram
and CMR without SWMA; (3) CMR with SWMA independently of electrocardiogram.
Results: The number of patients with ventricular arrhythmia in relation to the total of patients, the percentage of fibrosis,
and the LVEF were, respectively: Group 1, 4/26, 0.74% and 74.34%; Group 2, 4/16, 3.96% and 68.5%; and Group 3,
11/19, 14.07% and 55.59%. Ventricular arrhythmia was found in 31.1% of the patients. Those with and without ventricular
arrhythmia had mean LVEF of 59.87% and 70.18%, respectively, and fibrosis percentage of 11.03% and 3.01%, respectively.
Of the variables SWMA, groups, age, LVEF and fibrosis, only the latter was significant for the presence of ventricular
arrhythmia, with a cutoff point of 11.78% for fibrosis mass (p < 0.001).
Conclusion: Even in patients with Chagas disease and preserved or minimally impaired ventricular function, electrical
instability can be present. Regarding the presence of ventricular arrhythmia, fibrosis is the most important variable, its
amount being proportional to the complexity of the groups. (Arq Bras Cardiol. 2014; 102(5):456-464)
Keywords: Arrhythmias, Cardiac; Myocardial Fibrosis; Chagas Heart Disease; Ventricular Dysfunction.
Introduction
Chagas disease (CD) remains epidemiologically
important 1 , because of the high number of infected
individuals who can develop severe forms of the disease.
In Brazil, two to three million people are estimated to be
affected, one third of whom have heart disease, of whom,
two thirds are minimally impaired2.
The annual death rate is approximately 24/1,000 patients‑year,
and most patients have preserved or minimally impaired left
ventricular (LV) ejection fraction (LVEF)3. Sudden death is
common in CD, can occur in any phase of that disease, and 10%
result from a first arrhythmic event. Complex cardiac arrhythmias
Mailing Address: Eduardo Marinho Tassi •
Hospital Universitário Gaffrée e Guinle, Ambulatório de Cardiologia. Rua Mariz
e Barros 775, Tijuca. Postal Code: 20270-004, Rio de Janeiro, RJ - Brazil
E-mail: [email protected]
Manuscript received August 22, 2013; revised manuscript December 09,
2013; accepted January 07, 2014
DOI: 10.5935/abc.20140052
456
(ventricular extrasystoles > 10/hour and/or ventricular
tachycardia) are markers of sudden death in CD4.
Patients with CD and normal electrocardiogram (ECG) are
known to have survival rate similar to that of the general population,
and initial studies have shown that those with CD, segmental wall
motion abnormality and preserved LVEF have worse prognosis5,6.
Cardiac magnetic resonance imaging (CMR) is currently the
best method to assess ventricular function7 and to detect segmental
wall motion abnormalities8; by adding the delayed enhancement
technique9, it can assess myocardial fibrosis. The ability of delayed
enhancement CMR to detect abnormalities in chronic Chagas heart
disease (CCHD) has already been reported10.
Patients with CCHD and ventricular arrhythmia have a worse
prognosis, and there is no study correlating the myocardial fibrosis
detected on CMR with the severity of arrhythmias in patients with
CD and preserved or minimally impaired ventricular function.
Methods
Patients were recruited between March and December
2010 at the CD Outpatient Clinic at our hospital.
Tassi et al.
Fibrosis and ventricular arrhythmias in CD
Original Article
All patients from this study provided written informed
consent, and the research protocol was approved by the
Ethics Committee of our hospital, in accordance with the
Declaration of Helsinki.
The inclusion criteria were as follows: asymptomatic
patients older than 21 years or those outside an endemic
area of CD for more than 20 years with positive serology
for CD, preserved or minimally reduced (> 45%) LVEF on
echocardiogram, who had undergone ECG, treadmill exercise
test (TET) and 24-hour Holter in the previous 12 months.
Patients with the following characteristics were excluded:
renal dysfunction (estimated creatinine clearance < 30 mL/min);
previous ablation via electrophysiological study; diabetes or more
than two risk factors for coronary artery disease; atrial fibrillation;
TET compatible with myocardial ischemia; previous myocardial
infarction; any myocardial or peripheral revascularization
procedure; contraindication to undergo CMR (permanent
pacemaker, implanted cardiac defibrillator, neurosurgical clips,
or cochlear implants).
Patients were classified according to ECG and CMR
findings, and distributed into three groups as follows: 1)
Group 1 - normal ECG and no segmental wall motion
abnormality on CMR; 2) Group 2 - altered ECG and no
segmental wall motion abnormality on CMR; and 3) Group 3
- segmental wall motion abnormality on CMR regardless of
ECG. The ECG was considered altered in the presence of
any incomplete or complete bundle-branch block, any type
of atrioventricular block, mono- or polymorphic ventricular
extrasystole , and nonsustained ventricular tachycardia
(NSVT). The CMR was considered altered in the presence
of any segmental wall motion abnormality.
On Holter, the following situations were considered electrical
instability: presence of ventricular extrasystoles > 30/hour;
episodes of monomorphic sustained ventricular tachycardia
(defined as ventricular rhythm with heart rate > 100 bpm and
duration > 30 seconds); and episodes of NSVT (defined as
three or more consecutive beats with duration < 30 seconds).
Regarding the TET, only the tests of patients reaching
7 MET, limit defined as a submaximal exercise level (good
correlation between the anaerobic threshold achieved and
the 7-MET load achieved), were considered for analysis11.
Two observers analyzed and compared the ECGs at
rest and during exercise (around 7 MET), identifying in
both situations the 30-second period with the greatest
number of ventricular arrhythmias and/or NSVT episodes.
Exertion‑induced arrhythmias were defined as the
appearance of ventricular arrhythmias on ECG during
exercise as compared to rest, or an increase > 10% in their
incidence, and/or presence of NSVT12.
The CMR was performed in a 1.5-Tesla GE HDX scanner
(Wakeusha, Wisconsin, USA), and two pulse sequences
were acquired: the first was a cine-CMR using Steady-State
Free Precession (SSFP) in long- and short-axis projections
to measure and calculate mass, volumes, LVEF and right
ventricular ejection fraction (RVEF). The most basal slice in
the short axis was positioned right after the atrioventricular
ring, and all subsequent respiratory pauses at maximum
exhalation were acquired with 8-mm slice thickness and
2-mm slice spacing up to the LV apex. The parameters used
were: field of view (FOV) of 400 mm; matrix of 224 × 224;
20‑24 lines/segment; temporal resolution < 50 ms; repetition
time (RT) = 3.9 ms, echo time (ET) = 1.5 ms; flip angle
of 50°; and NEX of 1.
Three minutes after injecting 0.3 mmol/kg of gadolinium
(Dotarem®, Guerbet), an echo-gradient sequence was
performed with inversion recovery (delayed enhancement)
in the long- and short-axis projections to investigate
myocardial fibrosis with the following parameters: FOV
of 360 mm; matrix of 224 × 192; 24 lines/segment;
ET = 2.9 ms; flip angle of 20°; 8-mm slice thickness; 2-mm
slice spacing; and NEX of 2.
Cardiac magnetic resonance postprocessing
The LV and RV measurements and calculations were
performed independently by two researchers blinded to the
patient’s groups, at a workstation dedicated to CMR, using
specific software (Report CARD®, 3.6 version, GE).
Maximum diastole and systole images were chosen on
cinematic display at maximum relaxation and maximum
contraction, respectively. Ventricular mass was calculated by
using manual tracings of endocardial and epicardial borders at
end-systole and end-diastole for each slice for both LV and RV.
Papillary muscles were excluded from volume measurements
and added to ventricular mass calculation. Such areas were
multiplied by slice thickness (8 mm + 2 mm of slice spacing)
and added to several slices to obtain end‑systolic and
end‑diastolic volumes, respectively. The EF was calculated as
follows: end-systolic volume subtracted from end-diastolic
volume and divided by end-diastolic volume. Each of
the 17 LV wall segments was classified as normokinetic,
hypokinetic, dyskinetic or akinetic.
The calculation of fibrosis mass was performed by using
a specific applicative of the software for semiquantitative
detection of hyperintense areas compatible with fibrosis on
short-axis delayed enhancement sequences. The researcher
was free to edit the limits of the area of fibrosis.
Statistical analysis
The statistical analysis comprised a nonparametric
classification tree and survival curves. The nonparametric
classification tree method is based on a decision rule
approach, implemented with a theory of conditional
inference procedures and selection of variables. The node
of the classification tree has a p value that corresponds
to the log-rank test. The classification tree is aimed at
reducing the impurity degree by finding the point that
provides greater homogeneity (higher probability of
purity) inside a node and greater heterogeneity between
nodes. Then, a log-linear model is used to select the most
significant variables and to confirm the results obtained
by using a regression tree. The 5% significance level was
adopted for the entire study.
The presence of ventricular arrhythmias was considered
a categorical variable according to ECG, Holter and/or
TET findings.
Arq Bras Cardiol. 2014; 102(5):456-464
457
Tassi et al.
Fibrosis and ventricular arrhythmias in CD
Original Article
Interobserver analysis was performed using the survival
analytical technique proposed by Luiz et al13 to assess the
reliability of the quantitative measures of EF, LV mass and
myocardial fibrosis. That method uses Kaplan-Meier curves
without data censoring, in which the failures occur in the
absolute difference between the values attributed to the
observers. Another improved method proposed by Llorca
and Delgado-Rodriguez14 was also used. It considers two
groups of different real values rather than global differences.
The equivalence of functions of the two observers obtained
through Llorca’s method was evaluated by using Tarone-Ware
test, a nonparametric weighted log-rank statistic.
On CMR, fibrosis was detected in 27 patients (45.8%)
(Figure 1), the mean amount of fibrosis being 15.02 g.
Detectable myocardial fibrosis was observed in 87 segments
(8.67% of the 1,003 possible segments), the infero‑lateral‑basal
LV wall segment being the most often affected (19.5%).
Then the explanation coefficient matrix was performed
to measure the predictive capacity of a continuous variable
to predict another, and the following were assessed: age;
LVEF; RVEF; fibrosis; and LV mass. The R software was used
for data analysis.
Electrical instability was detected on Holter or TET in
19 patients (32%), and Graph 1 shows the presence of
fibrosis or segmental wall motion abnormality in that group
of patients. Of the patients with electrical instability, 78.9%
had segmental wall motion abnormality and/or fibrosis on
CMR. Of the 42 patients without electrical instability, only
14 patients had myocardial fibrosis and 8 had segmental
wall motion abnormality.
Results
Graph 2 shows the amount of fibrosis and the LVEF in
each group.
Sixty-one patients (23 men) participated in the study.
Two women did not undergo the post-contrast phase (delayed
enhancement) as follows: one due to difficulty in the venous
access and another due to history of allergy to gadolinium;
they, however, underwent the noncontrast phase (cine-CMR).
The patients’ mean age was 62.32 ± 10.43 years. The body
mass index of the population studied was 26.02. Four patients
showed segmental wall motion abnormality with no ECG
abnormalities, being then considered Group 3. Table 1 shows
the number of patients with fibrosis in the three groups.
Figure 1 shows the number of patients with segmental
wall motion abnormality and fibrosis in each LV wall segment
according to the CMR findings. Segmental wall motion
abnormality was detected in 19 patients (31.1%). Abnormality
Table 1 – General data
Mean age
62.32 years
BMI
26.02 kg/m2
Group 1 BMI
26.56 kg/m2
Group 2 BMI
25.29 kg/m2
Group 3 BMI
25.24 kg/m2
Number of patients with fibrosis
27 (45.8%)
Group 1 (normal ECG and no SWMA on CMR)
26 (42.6%)
Group 2 (abnormal ECG and no SWMA on CMR)
16 (26.2%)
Group 3 (SWMA on CMR)
19 (31.1%)
Ventricular arrhythmia (TET or Holter)
19 (31.1%)
Patients with fibrosis in Group 1
5 (19.2%)
Patients with fibrosis in Group 2
7 (43.7%)
Patients with fibrosis in Group 3
15 (78.9%)
Patients with fibrosis and ventricular arrhythmia
13 (68.4%)
BMI: body mass index; ECG: electrocardiogram; CMR: cardiac magnetic
resonance imaging; SWMA: segmental wall motion abnormality; TET: treadmill
exercise test.
458
was identified in 113 wall segments (10.89% of the
1,037 possible segments), and the segments most frequently
affected were: infero-apical (9.7%); infero‑lateral‑medial
(10.6%); basal (7.9%); and LV apex (9.7%).
Arq Bras Cardiol. 2014; 102(5):456-464
The presence of ventricular arrhythmia in the groups
was as follows: four patients in Group 1; four patients in
Group 2; and 11 patients in Group 3.
Regarding interobserver agreement to detect ventricular
arrhythmias at rest and during exertion, a kappa of 0.87 was
obtained [95% confidence interval (95% CI): 0.72-0.92).
Kappa for intraobserver agreement was 0.93 (95% CI: 0.74-0.99).
The interobserver disagreement by using Llorca’s method
showed that the variables LVEF, RVEF and mass were not
significant (0.4 and 0.09 respectively; p = 0.5). Only the variable
‘percentage of fibrosis’ showed significance (p = 0.007) up to
6% of the absolute value of the difference of the result, after
which there was no difference.
The categorical analyses of the presence of segmental
wall motion abnormality and detection of fibrosis had an
interobserver kappa of 0.96. The variables used in the first
classification tree (Figure 2) were: segmental wall motion
abnormality on CMR; groups (1, 2 and 3); age; LVEF;
ventricular arrhythmia; and myocardial fibrosis. Myocardial
fibrosis was the only significant variable in the classification
tree for the presence of ventricular arrhythmia, with a cutoff
point of 11.78% for fibrosis mass (p < 0.001). In addition to
segmental wall motion abnormality on CMR and myocardial
fibrosis, the second classification tree considered the
interactions of those variables with the groups (1, 2 and 3).
Group 3 gathered the majority of patients with ventricular
arrhythmia (p < 0.001) (Figure 3).
The explanation coefficient matrix was built (Figure 4),
enabling R2 calculation of the variables analyzed without
using a response variable (ventricular arrhythmia, in the case),
and showing that LVEF was inversely proportional to fibrosis
(R2 = -0.37), while LVEF and RVEF were proportional to each
other (R2 = 0.30).
Discussion
This study shows objectively that, even in patients with CD
and preserved or minimally impaired LV function, electrical
instability can occur. It was demonstrated by the presence of
Tassi et al.
Fibrosis and ventricular arrhythmias in CD
Original Article
Figure 1 – Representation of the 17 left ventricular wall segments. (A) The figure in each segment indicates the number of patients with segmental wall motion
abnormality. The grey color represents the segments most frequently affected by segmental wall motion abnormality. (B) Number of patients with fibrosis in each left
ventricular wall segment. The grey color represents the segments most frequently affected by fibrosis.
9 (47.3%)
4 (21%)
4 (21%)
2 (10.5%)
No electrical instability
Fibrosis and segmental wall motion abnormality
Neither fibrosis nor segmental wall motion abnormality
Only fibrosis
Only segmental wall motion abnormality
Graph 1 – Ventricular arrhythmia on Holter or treadmill exercise test and presence of fibrosis.
exertion-induced or spontaneous ventricular arrhythmias in
one third of the patients (32%). In addition, a good inverse
correlation between LVEF and fibrosis (R2 = -0.37) was
identified, because of the 19 patients with electrical instability,
15 (79%) had segmental wall motion abnormality. Moreover,
by using logistic regression and tree classification, myocardial
fibrosis was identified as the most significant variable for the
presence of arrhythmia ventricular. The advantage of the
Arq Bras Cardiol. 2014; 102(5):456-464
459
Tassi et al.
Fibrosis and ventricular arrhythmias in CD
Original Article
Graph 2 – Ejection fraction and amount of fibrosis in the different groups. LVEF: left ventricular ejection fraction.
Figure 2 – Classification tree showing that fibrosis is the most significant variable for the presence of ventricular arrhythmia, with a cutoff point of 11.78%.
classification tree is that, in addition to identifying the most
relevant variable, it calculates the cutoff point (11.78% for
fibrosis mass). In the group with fibrosis > 11.78%, only two
460
Arq Bras Cardiol. 2014; 102(5):456-464
patients had no ventricular arrhythmia (p < 0.001), which
might mean that patients with a greater percentage of fibrosis
have an increased risk for frequent ventricular arrhythmia.
Tassi et al.
Fibrosis and ventricular arrhythmias in CD
Original Article
Figure 3 – Classification tree per group, showing that the group with segmental wall motion abnormality (Group 3) had the majority of patients with ventricular arrhythmia.
According to Myerburg et al15, three factors are required for
electrical sudden death: arrhythmogenic substrate; triggering
events; and functional changes. Fibrosis plays a relevant role
in the first factor. In patients with CD, those three factors
can be clearly identified: the arrhythmogenic substrate is
represented by the myocardial fibrosis and inflammation; the
triggering events, by the frequent ventricular extrasystoles; and
the functional changes, by the autonomous nervous system
physiological changes.
Ventricular arrhythmia in CD is associated with
ventricular dysfunction, and patients with ventricular
dysfunction and complex ventricular arrhythmias have
worse prognosis. The presence of ventricular electrical
instability in patients with preserved LVEF and segmental
wall motion abnormality is little studied.
It is possible that the 19.2% of Group 1 patients who had
myocardial fibrosis detectable on CMR could be in an initial
phase of CCHD, especially because four of them had ventricular
arrhythmia. According to pathological studies16,17, the initial
process is myocarditis with fibrosis, which can progress to
segmental wall motion abnormality and ventricular dysfunction.
Our population is considered of low risk according to
any prognostic score. Nevertheless, 45.7% of them have
myocardial fibrosis detectable on CMR. The presence and
amount of fibrosis were higher in Group 3 patients. That group
also had more patients with ventricular arrhythmia, which
could indirectly mean a higher arrhythmogenic potential.
Prospective studies on CCHD using CMR are scarce.
Recently, Regueiro et al18, in a descriptive study, have shown
the association of ECG changes (with segmental wall motion
abnormality) with the increase in fibrosis mass and right and
left ventricular dysfunctions. Mello et al19, assessing patients
with CCHD on CMR, have shown that transmural fibrosis
in more than two LV myocardial segments was more often
associated with ventricular tachycardia.
In the present study, the segments most often affected by
fibrosis were also those with more segmental wall motion
abnormalities. This suggests a topographical relationship
between sympathetic denervation, fibrosis and hypokinesia.
The temporal relationship between those variables can help
to understand the pathophysiological process and should be
the object of future studies.
It is worth noting the reliability of the imaging test.
Echocardiography is examiner-dependent and its interobserver
variability is a well-known limitation. The CMR is known for its
high reproducibility. In this study, the interobserver variability
was < 5% for LVEF and RVEF, thus, not significant (p = 0.5
and 0.4, respectively). The percentage of fibrosis mass showed
Arq Bras Cardiol. 2014; 102(5):456-464
461
Tassi et al.
Fibrosis and ventricular arrhythmias in CD
Original Article
Age
0.03
LVEF.1
0.30
-0.37
RVEF.1
-0.10
fibrosis.1
-0.05
0.03
LVmass.1
Figure 4 – Correlation matrix (values as R2). The more oval the tracing, the better the correlation. LV: left ventricular; LVEF: left ventricular ejection fraction; RVEF: right
ventricular ejection fraction.
a statistical difference of 6%; however, a variability of such
magnitude, regarding the small mean fibrosis amount found
(15.02 g), can be of little clinical and scientific relevance,
because, considering the standard deviation, it would be
15.02g ± 0.9 g. In addition, if regarded as categorical variable,
it would have an excellent correlation (kappa = 0.96).
Study limitations
The patients in this study have not undergone coronary
cineangiography to exclude coronary arterial disease as the
cause of myocardial fibrosis. However, patients with diabetes
and two or more risk factors for coronary arterial disease were
excluded, thus reducing that probability. In addition, no patients
with abnormalities suggestive of coronary arterial disease on TET
or CMR were identified. Recently, Carvalho et al20 have shown a
small prevalence of coronary arterial disease in patients with CD.
Most episodes of sudden death occur between the ages
of 20 and 50 years in men. This differs from our population,
462
Arq Bras Cardiol. 2014; 102(5):456-464
mainly comprised by women with a mean age of 63 years, a
fact that can underestimate prognostic events. Nevertheless,
in that low-risk group, there was significant substrate for the
presence of arrhythmias (segmental wall motion abnormality
and presence of myocardial fibrosis).
The definition of ventricular arrhythmia includes the
presence of frequent ventricular extrasystoles > 30/h,
which can be considered of little clinical relevance.
However, this study was aimed at assessing the triggering
mechanism of early ventricular instability (fibrosis and
segmental wall motion abnormality), rather than the
immediate clinical impact.
Conclusions
On CMR, both myocardial fibrosis and segmental wall
motion abnormality were associated with ventricular
arrhythmia in patients with CCHD.
Tassi et al.
Fibrosis and ventricular arrhythmias in CD
Original Article
Even in patients with CCHD and preserved or minimally
impaired ventricular function, the arrhythmogenic substrate
can be present. Myocardial fibrosis detected on CMR is the
most important variable associated with ventricular arrhythmia.
Acknowledgements
We thank Dr. Marco Lauzi, from Guerbet, for providing
the gadolinium (Dotarem®) used in this study.
Author contributions
Conception and design of the research: Tassi EM, Pereira BB,
Pedrosa RC; Acquisition of data: Tassi EM, Continentino MA;
Analysis and interpretation of the data: Tassi EM, Continentino
MA, Nascimento EM, Pereira BB, Pedrosa RC; Statistical
analysis: Nascimento EM, Pereira BB; Writing of the manuscript:
Tassi EM, Continentino MA, Pedrosa RC; Critical revision of
the manuscript for intellectual content: Tassi EM, Pedrosa RC.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Sources of Funding
This study was partially funded by FAPESP.
Study Association
This article is part of the thesis of master submitted by
Eduardo Marinho Tassi from Faculdade de Medicina da
Universidade Federal do Rio de Janeiro.
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Fibrosis and ventricular arrhythmias in CD
Original Article
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Back to the Cover
Original Article
Impact of Psychotropic Drugs on QT Interval Dispersion in Adult
Patients
Bruno de Queiroz Claudio1,2, Marcelle Azevedo Nossar Costa1, Filipe Penna1, Mariana Teixeira Konder1,
Bruno Miguel Jorge Celoria1, Luciana Lopes de Souza1, Roberto Pozzan2, Roberta Siuffo Schneider2,
Felipe Neves Albuquerque2, Denilson Campos Albuquerque1,2
Hospital Copa D’Or/IDOR1; Universidade do Estado do Rio de Janeiro – UERJ2, Rio de Janeiro, RJ - Brazil
Abstract
Background: Drug-induced increase in QT dispersion has been associated with potentially fatal ventricular arrhythmias.
Little is known about the use of psychotropic substances, alone or in combination with other drugs on QT dispersion.
Objectives: To evaluate the impact of psychotropic drugs on QT interval dispersion in adults.
Methods: An observational cohort study was designed involving 161 patients hospitalized from an emergency department
at a tertiary hospital, divided into psychotropic users or non-users. Demographic, clinical, laboratory data and drugs used
on a regular basis were collected on admission, in addition to 12-lead electrocardiogram with QT dispersion measurement.
Results: QT dispersion was significantly higher in the psychotropic user group compared to non-users (69.25 ± 25.5 ms vs.
57.08 ± 23.4 ms; p = 0.002). The QT interval corrected by Bazzett formula was also higher in the psychotropic drugs user
group, with statistical significance. (439.79 ± 31.14 ms vs. 427.71 ± 28.42 ms; p = 0.011). A regression analysis model
showed a positive association between the number of psychotropic drugs used and QT interval dispersion, with r = 0.341
and p < 0.001.
Conclusions: The use of psychotropic drugs was associated with increased QT dispersion and this increase was
accentuated, as the number of psychotropic drugs used was higher. (Arq Bras Cardiol. 2014; 102(5):465-472)
Keywords: Electrocardiography; Cardiovascular diseases; Torsades de Pointes; Ventricular fibrillation; Death, Sudden.
Introduction
The perception and interest in unexpected death are
secular. Sudden cardiac death received its first scientific
definition in 1707 with Giovanni Lancisi1, in his work De
mortibus subitaneis. The most prevalent cause of sudden death
is coronary artery disease, followed by cardiomyopathies and
primarily electrical cardiac causes, especially the long QT
syndrome, either congenital or acquired – the latter induced
by drugs, in most cases. Data indicate that QT prolongation is
a major contributor to the genesis of polymorphic ventricular
tachycardia or torsades de pointes, even in structurally normal
hearts2. This prolongation is not a pharmacological property
attributed only to antiarrhythmic drugs. A recent American
cohort showed that 5 million Americans are exposed to drugs
that prolong the QT interval, with antibiotics and psychotropic
drugs, especially antipsychotics, being the most common2,3.
Mailing Address: Bruno de Queiroz Claudio •
Rua Presidente João Pessoa, 95, apto. 801, bloco 1, Icaraí. Postal Code:
24220-330, Niterói, RJ - Brazil
E-mail: [email protected], [email protected]
Manuscript received September 12, 2013; revised manuscript November 01,
2013, accepted November 26, 2013.
DOI: 10.5935/abc.20140055
465
However, not all drugs that prolong the QT interval
increase the risk of ventricular arrhythmias4. It is currently
accepted that the electrical disturbance genesis is related
to blockage of ionic currents of potassium channels,
notably in M cells of the human ventricle, with subsequent
QT interval prolongation and dispersion (QTD) on the
electrocardiogram (ECG), closely related to the onset of
torsades de pointes4-7.
The concept of "QT interval dispersion", defined as the
difference between the maximum and minimum QT interval
measured at the 12-lead ECG, was introduced by Higham and
Campbell8 in the early 1990s. Initially proposed as an index of
electrical instability, it represents the expression of physiological
regional variation of myocardial excitability recovery.
Since then, the analysis of QTD was accepted as a
noninvasive method for the detection of ventricular
r e p o l a r i z a t i o n h e t e r o g e n e i t y, b e i n g a m a r k e r o f
arrhythmogenesis, especially in the presence of an ischemic
substrate and drug-induced ventricular arrhythmias.
Additionally, there have been studies associating it as
a prognostic index in heart failure and hypertrophic
cardiomyopathy8,9.
Little is known about the impact on QTD with the specific
use of antipsychotics and its associations with other drugs
acting on the central nervous or cardiovascular system.
Claudio et al.
Impact of psychotropic drugs on QT interval dispersion
Original Article
Methods
Study characterization
The present was a prospective, multicenter, observational
cohort study, carried out in a private hospital in Rio de
Janeiro, with an open emergency room, from September
2009 to January 2013. The research protocol was approved
by the Institutional Research Ethics Committee (REC)
(number 148/09).
Study population
Of the total number of patients admitted at the institution,
necessarily admitted through the emergency room, 194 met
the initial eligibility criteria for the study. After careful
evaluation, 33 patients were excluded and population
sample comprised 161 patients.
The subjects of the investigation were not submitted to
any interventions resulting from the study. A liability form was
completed by the main investigator on the use of information
contained in medical records and database, thus making it
unnecessary for patients to sign the Informed Consent form.
Inclusion criteria
The following inclusion criteria were used: age > 40 years;
emergency care and subsequent hospital admission for
more than 24 hours, regardless of the reason for admission;
performance of ECG with at least 12 leads in the emergency
room; performance of basic complementary laboratory tests
(glucose, potassium and magnesium).
Exclusion criteria
The exclusion criteria were: patients with artificial
cardiac pacing, either temporary or permanent; patients
with congenital long-QT syndrome; patients with calcium
metabolism alterations; patients with atrial fibrillation of
any cause and/or frequent ventricular arrhythmia; patients
using antiemetics, prokinetics and antibiotics that alter
ventricular repolarization.
According to the study design and construction of
methodology, the use of concomitant drugs that would
influence QT interval and its dispersion was cause for
careful analysis. Thus, we excluded patients on continuous
use of other drugs that prolong the QT interval, especially
domperidone, bromopride and metoclopramide.
The sample population was stratified into two groups
according to the use or nonuse of psychotropic drugs.
Group 1 (G1) consisted of patients who were not taking
psychotropic drugs, while Group 2 (G2) consisted of patients
taking psychotropic drugs.
Investigation procedures
Demographic data, present and past medical history,
information on regular use of drugs and diagnostic hypotheses
were collected on admission. Any drug that had more than
seven days of uninterrupted use before hospital admission
was defined as continuous use.
All antipsychotics, anticonvulsants, antidepressants and
drugs used in dementia syndromes used by the sample
population were taken into account. All drugs subject to
classification according to Vaughan Williams were considered
antiarrhythmic drugs.
A 12-lead ECG was performed on patient admission,
while still in the emergency department, being a routine
procedure for any patient older than 40 years of age,
symptomatic or not (hospital accreditation process protocol
by the Joint Commission).
Laboratory assessment
Laboratory evaluation consisted of measurements of
plasma glucose, potassium and magnesium, also assessed
on admission. Glycemia levels did not take into account
any criterion of fasting. Calcium ion was measured when
requested by the emergency team. A Vitros 250 analyzer
(Johnson & Johnson, New Brunswick, USA) was used for
biochemical measurement of magnesium and glucose, with
the dry-chemical method. The measurements of potassium
and calcium ion were performed using a Gem Premier
3000 analyzer (Instrumentation Laboratory, Bedford, USA)
using the selective electrode method. Normal values of these
tests were determined according to the institution protocols.
QT dispersion measurement
Each patient’s ECG was recorded in three-channel
conventional ECG equipment (HP - Hewlett Packard
Company, Palo Alto, United States) with recording speed
of 25 mm/s and recording of the 12 leads considered as
conventional (D1, D2, D3, aVR , aVL, aVF, V1, V2, V3,
V4, V5, V6). ECGs that did not have at least nine leads
with a QT interval technically capable of being measured
were excluded. The QT interval is measured from the first
deflection of the QRS complex to the end of the T wave,
defined as the meeting point of the descending branch of
T to the isoelectric line. In the presence of a U wave, the
end of the T wave is considered as the base of deflection
formed by the two waves. The presence of bundle branch
block did not exclude patients from the study.
Cardiac cycles succeeding early beats (extrasystoles)
were abandoned10. "QT interval dispersion" is defined as the
difference between the maximum and minimum QT interval
measured on the 12-lead (at least nine leads).
The digitized ECGs were analyzed with the help of Preview®
software, version 5.5.2 (719.25) (Apple Inc ®, Cupertino,
USA). Tracings were submitted to a 300% magnification
and QT measurement was made digitally. All ECG tracings
were digitalized with a 200 dpi resolution and saved in JPEG
format to allow use of the Preview® program measuring tool.
ECGs were captured by an Epson Stylus TX105 scanner (Long
Beach, United States) and amplified during digitalization.
However, in daily clinical practice, the measurements of
QT interval and QTD can be performed simply with the aid
of a triplicate magnifying glass8,9. Two QT interval and QTD
measures were performed by four examiners blinded to the
clinical characteristics of patients and the arithmetic mean of
the values were
​​
considered for the analysis.
Arq Bras Cardiol. 2014; 102(5):465-472
466
Claudio et al.
Impact of psychotropic drugs on QT interval dispersion
Original Article
Several methodologies have been described for the
measurement of QT interval 10, 11. In this study, we used the
difference between the second largest and the second smallest
QT interval (minimum of nine leads)10,11 to measure QTD, a
methodology also used by Campbell et al12. Studies can be
found in the literature13,14 that used the standard measure of
QTD or that corrected by heart rate. In the present study, we
used the default QT dispersion.
Statistical Analysis
Drugs used by the sample population
Tables 2 and 3 show the frequency of psychotropic drugs
and antiarrhythmic drugs used by the sample population.
This use may have been isolated or in associations. None of the
patients from the sample population used digitalis.
Univariate, bivariate, covariance and multivariate analysis
were used for the statistical analysis of the data.
Clinical and epidemiologic characteristics of the sample
population
Univariate analysis was used for the description of the
studied variables, using simple frequency and percentage
tables for discrete variables and mean (minimum-maximum),
and graphical representation of histograms and box-plots for
continuous variables. Bivariate analysis was used for discrete
variables, using contingency tables and chi-square, Fisher
exact and ML chi-square tests, when indicated; the Student’s
t test, paired or not, and Mann‑Whitney test were used for
continuous variables,.
Female gender were more prevalent in G2, with
statistical significance (p = 0.04). We sought to determine
whether, in G2, the gender difference would have an
impact the QTD, as there was no difference between men
and women regarding psychotropic drug use (p = 0.642).
There was a positive correlation between age and the use
of psychotropic drugs.
Levene's test was used to test whether the studied
samples had homoscedasticity, that is, whether they
had the same variance. A significant F ratio in this test
indicates that the differences in mean, or effects, probably
exist between the groups. In the case of heteroscedastic
samples, non‑parametric tests were used according to
the characteristics of the studied variable. Welch and
Brown‑Forsythe tests were used in the assessment of the
mean magnesium levels between groups.
Analysis of covariance was used with regression models
and analysis of variance (ANOVA), using the partial ETA
squared (η2), which allows inferring what proportion of the
total variance is attributed to the studied variable (effect
size). Multivariate analysis was used from a log-linear
model for discrete variables aiming to detect and resolve
the confusion effects. Pearson’s correlation coefficient was
used to demonstrate the correlation between two or more
variables. The ANOVA model was chosen for the analysis of
variance between the studied groups.
Results
Sample population
Of a total of 194 initially selected patients, 161 met the
inclusion criteria and constituted the sample population of this
study. The most prevalent cause of exclusion was the presence
of atrial fibrillation (11) in the electrocardiogram, followed
by artificial cardiac stimulation (7), calcium replacement
without the measured serum level of calcium ion (5), frequent
ventricular extrasystoles (4), incapacity of analyzing the ECG
due to technical problems (3), and documented hypercalcemia.
The sample population (n = 161) was stratified into two
groups according to the use or nonuse of psychotropic drugs:
G1 consisting of patients who did not use psychotropic drugs
(n = 85 patients) and G2 consisting of users of psychotropic
drugs (n = 76 patients).
467
The reasons for hospital admission of patients are shown
in Table 1, per group. There was no statistical significance
between the groups.
Arq Bras Cardiol. 2014; 102(5):465-472
The prevalence of hypertension, diabetes mellitus and
known coronary artery disease showed no statistically
significant difference between G1 and G2.
Regarding the laboratory variables, all patients (n = 161)
had serum potassium, magnesium and glucose levels measured
on admission at the emergency service, with no statistical
difference between the two groups. The study excluded
patients with hyper- and hypocalcemia. It is noteworthy that
plasma glucose levels were not measured in fasting. Levene’s
test was used to better understand the behavior of variance
in the two groups.
Therefore, glucose and potassium showed a homoscedastic
distribution, whereas magnesium had a heteroscedastic
distribution, after using the appropriate statistical test for each
situation. The results are shown in Table 4.
QT interval dispersion behavior
QTD was significantly higher in the group of psychotropic
drug users compared to non-users (p = 0.002). The QT
interval corrected by the Bazett’s formula was also higher
in the group using psychotropic drugs, with statistical
significance (p = 0.011), as shown in Table 5. The variance
was homogeneous in QTD, in the corrected QT interval and
heart rate between the groups.
The analysis of covariance between age and use of
psychotropic drugs was performed aiming to determine the
adjusted mean of the QTD. As measure of analysis of variance,
η2 was used. After adjusting the mean (G2 = 68.38 ± 8.11
milliseconds - ms and G1 = 57.85 ± 7.22 ms), the difference
between the groups remained significant (p = 0.009).
Analysis of use of multiple psychotropic drugs on QT
dispersion
In the sample population, 85 patients were not taking any
psychotropic drugs, 52 used one drug, 16 patients used two
drugs simultaneously, three patients used three drugs, four
used four psychotropic drugs and one patient in the study
used five psychotropic drugs simultaneously.
Claudio et al.
Impact of psychotropic drugs on QT interval dispersion
Original Article
Table 1 – Distribution of groups according to the reasons for hospital admission
Reasons for hospital admission
Total
Group 1 n (%)
Group 2 n (%)
Chi-square
Orthopedic surgical admissions
96
51 (60)
45 (59.21)
p = 0.19
Admissions for general and urological surgery
32
20 (23.53)
13 (17.11)
p = 0.065
Pulmonary sepsis
21
8 (9.41)
12 (15.79)
p = 0.085
Urinary sepsis
12
6 (7.06)
6 (7.89)
p = 0.32
Total
161
85 (100)
76 (100)
Table 2 – Psychotropics used by the sample population
Salt name
Patients using it
Salt name
Patients using it
Haloperidol
1
Phenobarbital
1
Chlorpromazine
1
Phenytoin
2
Levomepromazine
3
Lamotrigine
2
Risperidone
3
Carbamazepine
4
Clozapine
1
Oxcarbazepine
2
Quetiapine
23
Gabapentin
6
Olanzapine
2
Valproic acid
4
Ziprasidone
0
Topiramate
2
Aripiprazole
0
Venlafaxine
4
Promethazine
3
Memantine
7
Amitriptyline
3
Mirtazapine
4
Imipramine
1
Duloxetine
3
Clomipramine
2
Fluoxetine
3
Doxepin
1
Paroxetine
1
Desipramine
0
Sertraline
4
Nortriptyline
1
Citalopram
6
Trazodone
1
Citalopram
3
Bupropion
2
Donepezil
2
Maprotiline
1
Rivastigmine
4
Nefazodone
0
Galantamine
1
A linear regression model showed a positive association
between the number of psychotropic drugs used and QTD,
with r = 0.341. (Chart 1)
The intensity of the linear association between variables
was quantified. Pearson’s linear correlation showed a positive
correlation between the number of psychotropic drugs and
patient age in QTD (Table 6). In the regression model, when
the data are analyzed together, R = 0.329.
To better understand the association between these two
variables in QTD, a regression model was proposed, followed
by an ANOVA model, to allow the measurement of the
adjusted Beta of the number of psychotropic drugs and age,
with QTD being the dependent variable.
When the coefficients are adjusted, only the number of
psychotropic drugs shows statistical significance with QTD
(p <0.001).
Of the original sample population, the impact of concurrent
use of psychotropic and antiarrhythmic drugs was evaluated,
compared to the isolated use of antiarrhythmics. Table 3
details the type of antiarrhythmic drug used according to the
classification of Vaughan Williams, with no statistical difference
between the studied subgroups. The combined use of both
classes of drugs showed a statistically significant increase in
the QT interval. However, there was no statistical difference
in QTD between the two subgroups (Table 7).
Discussão
Aiming to assess the impact of psychotropic drug use on
QTD, it was necessary to study separately the clinical and
demographic variables, identifying the isolated and combined
action of these drugs with other cardiovascular action drugs.
Arq Bras Cardiol. 2014; 102(5):465-472
468
Claudio et al.
Impact of psychotropic drugs on QT interval dispersion
Original Article
Table 3 – Antiarrhythmic drugs used by the sample population
Vaughan-Williams
Class I
Class II
Class III
Class IV
----
Beta-blockers
Amiodarone
Sotalol
Diltiazen
Verapamil
Psychotropics + Antiarrhythmics
0
9
6
1
4
0
20
Antiarrhythmics
0
7
4
1
2
1
15
Total
Table 4 – Demographic, clinical and laboratory data
Variable
G1 (n = 85)
G2 (n = 76)
Statistical test
p value
67.68 ± 12.68
74.43 ± 11.37
t = 3.540
0.001
Male gender, %
50.60
34.20
Χ = 4.395
0.04
Female gender, %
49.40
65.80
SAH, %
40
39.50
Χ2 = 0.005
1
DM, %
25.90
23.70
Χ = 0.104
0.885
CAD, %
21.20
13.20
Χ2 = 1.796
0.214
Potassium, mean ± standard deviation (mEq/L)
4.29 ± 0.55
4.31 ± 0.69
F = 0.493
0.852
Magnesium, mean ± standard deviation (mg/dL)
1.88 ± 0.21
1.95 ± 0.34
F = 6.444*
0.109
115 ± 40
123 ± 46
F = 1.194
0.191
Age (years), mean ± standard deviation
Glycemia, mean ± standard deviation (mg/dL)
2
2
* Heteroscedastic sample. SAH: systemic arterial hypertension; DM: diabetes mellitus; CAD: coronary artery disease; F: Levene F ratio.
Table 5 – Electrocardiographic data and behavior of QT interval dispersion
Variable
Group 2 (n = 76)
QT interval dispersion, mean ± standard deviation (ms)
57.08 ± 23.4
69.25 ± 25.5
0.002
Corrected QT interval, mean ± standard deviation (ms)
427.71 ± 28.42
439.79 ± 31.14
0.011
79 ± 15
77 ± 18
0.379
Heart rate, mean ± standard deviation (bpm)
p value
Over the past 25 years, the QTD has been studied by several
authors in different clinical scenarios, in normal subjects and
patients with heart disease. Tran et al15 in a study that evaluated
the influence of age and sex on QTD, concluded that estrogen,
athoughit does not change the QT interval, significantly reduces
its dispersion. In a healthy population, Alici et al16 also confirmed
these findings. In the population evaluated in this study, the
results were similar.
Ebert et al19 demonstrated in an animal model that ionic
currents in females, specifically in potassium channels, are
significantly smaller than in males of the same species of
rats. This effect is accentuated in the presence of class III
antiarrhythmic drugs, increasing the QTD. Therefore, elderly
women are particularly susceptible to changes in the QT
interval and this fact should be considered when prescribing
psychotropic drugs.
The use of psychotropic drugs is more common in elderly
women17,18 and this population had a significantly higher
number of women in G2.
Regarding comorbidities found in the population, there
was no statistical difference between the groups of nonusers and users of psychotropic drugs on the prevalence of
hypertension, diabetes mellitus and coronary artery disease.
There was a high prevalence of these comorbidities in this
population, respectively 60.2%, 24.8% and 17.4%. This may
be related to the age of the sample, as well as the patient
selection method, carried out in the emergency room. The
profile of emergency patients and institution alignment
explain the high number of orthopedic surgical patients. It is
noteworthy that no patient was admitted for acute coronary
syndrome, which is therefore, not a bias.
In this context, we expected to find a higher number of
females in the group of psychotropic drug users. For this
reason, the QTD was analyzed separately in men and women
in the group of psychotropic drug users and it was greater in
men (71.15 ± 26.91 ms) than in women (68.26 ± 24.96 ms),
with no statistical significance. It is known that in the age
range of the female population, estrogen protection is not as
present any more. Thus, other mechanisms were studied to
understand this phenomenon.
469
t Test
Group 1 (n = 85)
Arq Bras Cardiol. 2014; 102(5):465-472
Claudio et al.
Impact of psychotropic drugs on QT interval dispersion
QT interval dispersion
Original Article
Series1
Linear (Series1)
Number of psychotropic agents
Chart 1 – Correlation between number of psychotropic agents and QT interval dispersion. r = 0.341, p value < 0.001.
Table 6 – Pearson’s linear correlation between the studied variables
Number of psychotropic agents
Age
Heart rate
Potassium
Glucose
Magnesium
0.341
0.177
-0.103
0.057
-0.054
0.095
< 0.001
0.024
0.195
0.471
0.495
0.232
Pearson’s
p value
Table 7 – Impact of concurrent use of psychotropic agents and antiarrhythmic drugs vs. isolated use of antiarrhythmic drugs
Analysis of subgroups
Sample (n. of patients)
QT Interval
Psychotropic + antiarrhythmic drugs
20
445.1 ± 23.77
Antiarrhythmics
15
421.7 ± 24.01
It is also worth mentioning that the doses used were not
considered, as it was not considered reliable information, either
due to the patient’s underlying disease or the frequent presence
of caregivers with little information about the drugs being used.
This factor, together with the large number of users of
domperidone, bromopride and metoclopramide in continuous
use justifies the extended time of patient selection, aiming at
attenuating a possible selection bias.
In the present study, we observed a positive correlation
between use of psychotropic drugs and increased QTD at the
p value
0.023
QT dispersion
63.55 ± 21.11
66.60 ± 23.22
p value
0.715
ECG. There was also a positive correlation between age and
QTD. The population studied had a minimum age of 40 years;
however, in practice, both groups had mean age > 65 years
(G1 = 67.68 ± 12.68 years and G2 = 74.43 ± 11.37 years).
The use of psychotropic drugs increases with age, according to
data collected by Maia et al17, similarly to the sample studied
here. After adjusting for age, as well as analyzing separately
the influence of age and the use of psychotropic drugs on
QTD, it was observed that only the use of psychotropic drugs
persisted with a statistically significant difference.
Arq Bras Cardiol. 2014; 102(5):465-472
470
Claudio et al.
Impact of psychotropic drugs on QT interval dispersion
Original Article
Other authors also confirmed these findings. Mangoni
et al 20 demonstrated that age has no association with
QTD. In the present sample, both the use of psychotropic
drugs and the number of psychotropic drugs had a
positive correlation with QTD. Of the 76 patients in the
psychotropic user group, 24 used a combination of more
than one psychotropic drug, corresponding to 31.5% of
the group. Thus 114 uses were documented, with the most
frequent drug being Quetiapine (20%).
Dispersion values > 60 ms were found in the group using
psychotropic drugs, which, in most studies performed to
date, are associated with increased cardiovascular death.
The Rotterdam Study21 evaluated a cohort of 2,358 men
and 3,454 women during a mean period of four years and
observed that the presence of QTD > 60 ms was associated
with a 2.5-fold higher risk of cardiac death, 1.9-fold higher
risk of sudden death and a 40% higher risk of overall death
than in the group with QTD <60 ms.
In our study, after adjusting for age, the mean QT
interval dispersion was 57.85 ± 7.22 ms in the group
of non-users and 68.38 ± 8.11 ms in the group of
psychotropic drug users, confirming the risk involved in
using these drugs.
It is noteworthy that digitalization, followed by enlargement
of electrocardiographic recordings, allowed a high level of
resolution, enabling a manual, easy, quick and effective
acquisition of the QT interval and its subsequent dispersion,
with negligible interobserver variation.
Thus, the QTc interval and its dispersion should be
thoroughly investigated in the general population, in
outpatient, as well as surgical and emergency settings22,23.
Health professionals involved in drug prescription and
monitoring of patients taking psychotropic drugs, especially
the elderly, should routinely include the ECG in the diagnosis
routine of this population, in addition to carefully assess the
combination of drugs used.
Conclusion
In the sample population studied, the use of psychotropic
drugs, used alone or with other drugs, is associated with
increased QT interval dispersion. The greater the number of
psychotropic drugs used, the greater the QT dispersion. There
was a positive correlation between the number of psychotropic
drugs used per patient and increased QT dispersion. The
simultaneous use of psychotropic and antiarrhythmic drugs
is associated with the increase in the corrected QT interval,
but not QT dispersion, when compared to the subgroup of
patients that use only antiarrhythmic drugs.
Author contributions
Conception and design of the research: Claudio BQ,
Albuquerque DC; Acquisition of data: Claudio BQ, Penna F,
Konder MT, Celoria BMJ, Souza LL; Analysis and interpretation
of the data: Claudio BQ, Costa MAN, Penna F, Celoria BMJ,
Souza LL, Schneider RS, Albuquerque DC; Statistical analysis:
Claudio BQ, Pozzan R, Albuquerque FN, Albuquerque DC;
Writing of the manuscript: Claudio BQ, Albuquerque DC;
Critical revision of the manuscript for intellectual content:
Claudio BQ, Costa MAN, Albuquerque DC.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Sources of Funding
There were no external funding sources for this study.
Study Association
This article is part of the thesis of master submitted by
Bruno de Queiroz Claudio from Universidade do Estado do
Rio de Janeiro.
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Original Article
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Arq Bras Cardiol. 2014; 102(5):465-472
472
Back to the Cover
Original Article
Prevalence of Cardiovascular Risk Factors in Hemodialysis Patients –
The CORDIAL Study
Jayme Eduardo Burmeister1,2, Camila Borges Mosmann2, Veridiana Borges Costa5, Ramiro Tubino Saraiva2, Renata
Rech Grandi2, Juliano Peixoto Bastos2, Luiz Felipe Gonçalves3,4, Guido Aranha Rosito1,2
Universidade Federal de Ciências da Saúde de Porto Alegre - Programa de Pós-graduação em Ciências da Saúde1; Universidade Luterana do
Brasil - Curso de Medicina2; Universidade Federal do Rio Grande do Sul - Faculdade de Medicina3; Hospital Mãe de Deus - Departamento de
Nefrologia4; Universidade Federal de Ciências da Saúde de Porto Alegre - Faculdade de Medicina5, Porto Alegre, RS – Brazil
Abstract
Background: There are scarce epidemiological data on cardiovascular risk profile of chronic hemodialysis patients in Brazil.
Objective: The CORDIAL study was designed to evaluate cardiovascular risk factors and follow up a hemodialysis
population in a Brazilian metropolitan city.
Methods: All patients undergoing regular hemodialysis for chronic renal failure in all fifteen nephrology centers of Porto
Alegre were considered for inclusion in the baseline phase of the CORDIAL study. Clinical, laboratory and demographic data
were obtained in medical records and in structured individual interviews performed in all patients by trained researchers.
Results: A total of 1215 patients were included (97.3% of all hemodialysis patients in the city of Porto Alegre). Their average
age was 58.3 years old, 59.5% were male and 62.8% were white. The prevalence of cardiovascular risk factors observed
was 87.5% for hypertension, 84.7% for dyslipidemia, 73.1% for sedentary lifestyle, 53.7% for tobacco use, and 35.8% for
diabetes. In a multivariate adjusted analysis, we found that sedentary lifestyle (p = 0.032, PR 1.08 – 95%CI: 1.01‑1.15),
dyslipidemia (p = 0.019, PR 1.08 – 95%CI: 1.01-1.14), and obesity (p < 0.001, PR 1.96 – 95%CI: 1.45-2.63) were
more frequent in women; and hypertension (p = 0.018, PR 1.06 – 95%CI: 1.01-1.11) and tobacco use (p = 0.006,
PR 2.7 – 95%CI: 1.79-4.17) were more often found among patients under 65 years old. Sedentary lifestyle was
independently associated with time in dialysis less than 12 months (p < 0.001, PR 1.23 – 95% CI: 1.14-1.33).
Conclusion: Hemodialysis patients in this southern metropolitan Brazilian city have a high prevalence of cardiovascular
risk factors resembling many northern countries. (Arq Bras Cardiol. 2014; 102(5):473-480)
Keywords: Patients; Renal dialysis; Risk factors; Prevalence.
Introduction
Cardiovascular diseases (CVD) are the main cause of death
in chronic kidney disease (CKD) patients on hemodialysis1-3.
In these patients, cardiovascular mortality is 10- to 20-fold
higher when compared to individuals from the general
population of the same sex, age and race2-5 and can be up
to 44 times higher in the presence of diabetes6. CVD are
present since the early stages of chronic kidney disease and
reach around 30 to 44% of those beginning hemodialysis7-10.
Strikingly, occult ischemic CVD are present in up to 50% of
asymptomatic dialysis patients7,11,12.
This high amount of CVD can be attributed to the high
prevalence of cardiovascular risk factors13. Although traditional
risk factors alone could not entirely explain such a high CVD
Mailing Address: Jayme Eduardo Burmeister •
Rua Cel. Lucas de Oliveira, 1270, Apto 301, Bela Vista. Postal Code 90440‑010,
Porto Alegre, RS - Brazil
E-mail: [email protected]
Manuscript received July 25, 2013; revised manuscript November 11, 2013;
accepted November 29, 2013.
DOI: 10.5935/abc.20140048
473
burden4,14, they seem to be highly predictive of cardiovascular
events12, especially in the elderly15. Likewise, cardiovascular
profile seems to allow risk stratification in CKD16.
A large percentage of patients entering dialysis have a
clustering of non-controlled risk factors for CVD14 leading to
an even higher chance of adverse outcomes17.
This high prevalence of traditional CVD risk factors on
chronic hemodialysis patients has been reported in several
studies in different world countries8-10,12,14,18-20. However, there
is a lack of consistent epidemiological data in our country for
this population, both for methodological biases and the use of
small samples restricted to a single hospital or clinic.
The main objective of this study was to evaluate the
prevalence of traditional cardiovascular risk factors in the
population of CKD outpatients on chronic hemodialysis in a
southern metropolitan city of Brazil.
Methods
Study Design and Research Population
The CORDIAL (Cardiovascular Outcomes Registry in
Dialysis Patients) study was designed to collect data on
Burmeister et al.
Cardiovascular risk factors in hemodialysis
Original Article
cardiovascular risk profile and carry out the follow-up of all
CKD patients enrolled in a regular outpatient hemodialysis
program in the city of Porto Alegre, Brazil. The present article
describes the baseline phase data and reports a cross-sectional
analysis of this population.
Eligibility criteria for enrollment included age 18 years
or more, being in chronic outpatient dialysis for more
than 30 days, and ability to provide informed consent for
participation. The study complies with the Declaration
of Helsinki and the protocol was approved by the Ethics
Committee for Research of Universidade Federal de Ciências
da Saúde de Porto Alegre (UFCSPA) and by the review boards
of the clinical centers included.
From August 2010 to March 2011, all CKD patients on
hemodialysis in each of the fifteen dialysis centers of the city
of Porto Alegre (Appendix 1) were considered for enrollment
and 1215 (97.3% of all) matched the inclusion criteria and
agreed to provide informed consent.
CORDIAL Data Collection
To collect the CORDIAL baseline data we used a standardized
case report form adapted and extended to our needs from the
REACH registry, a study performed in several countries including
Brazil21. The form was comprehensively filled after visits to each
center where patients, health care staff and electronic clinical
records were accessed.
Weight, height and blood pressure measured before and after
the dialysis session (mean of the last 3 sessions) were obtained
from reviewing the patients’ medical records. Prevalence of
atherosclerotic cardiovascular disease, diabetes, and hypertension
were established by reviewing all history and physical data in
the dialysis clinic medical charts and other available medical
documents. Furthermore, we considered as hypertensive any
patient in use of antihypertensive drugs, or those with mean pre
dialysis blood pressure in the stage 1 or up of the Seventh Report of
the Joint National Committee on Prevention, Detection, Evaluation,
and Treatment of High Blood Pressure (JNC 7) classification22.
The definition of diabetes included both type 1 and type
2, with or without oral hypoglycemic medication or insulin.
Tobacco use was registered as past or present. In accordance
with the Kidney Disease Outcomes Quality Initiative of the
National Kidney Foundation (K/DOQI‑NKF)23, dyslipidemia
was defined as the presence of any of the following –
total cholesterol > 200 mg/dL, low-density lipoprotein
(LDL)‑cholesterol > 100 mg/dL, high-density lipoprotein
(HDL)-cholesterol < 40 mg/dL, triglycerides > 150 mg/dL,
or the use of statin. Current physical activity was established
by an inquiry asking about “any moderate activity (as light
walking, bicycling, or gardening) or hard one (running, playing
football – soccer, hard swimming) at least 30 min two times
per week” and “how many minutes in a week”.
Laboratory data were obtained from the medical chart as
the most recent result in the six preceding months.
Data about gender were available for all CORDIAL
participants, about age for 1213 (99.8%), and race, height
and weight for 1206 (99.3%) each.
Information about hypertension status, cardiovascular
disease, physical activity, smoking and lipid profile were
available respectively for 1210 (99.6%), 1170 (96.3%),
1150 (94.7%), 1147 (94.4%), and 1121 (92.3%) of the
individuals in the cohort.
Statistics
Statistical analyses were carried out in STATA 9.0.
Descriptive statistics were used to characterize the sample.
Unadjusted and adjusted prevalence ratios were calculated
separately for each dependent variable (hypertension,
diabetes, dyslipidemia, tobacco use, sedentary lifestyle, and
obesity) with independent variables (gender, age, race, time
in dialysis, and diagnosis of cardiovascular disease). All tests
were two-tailed and the significance level used was 0.05.
Results
The present study included 1215 subjects (97.3%
population on chronic outpatient hemodialysis) with a mean
age of 58.3 years old, being 59.5% males and 62.8 % white.
Table 1 presents demographic and clinical data for
all the patients in the CORDIAL study and also stratified
by gender.
The prevalence of traditional cardiovascular risk factors
displayed in Table 2 reaches almost 90% for hypertension and
dyslipidemia, and about 75% of the subjects were sedentary.
Diabetes has a prevalence of 35.8 % in the hemodialysis
population of Porto Alegre (Table 2).
In a multivariate analysis (Table 3), older patients
presented a higher prevalence of diabetes and sedentary
lifestyle. Hypertension, tobacco use, and obesity, however,
were more prevalent in the younger ones. Tobacco use
was more prevalent in males, while obesity, dyslipidemia,
and sedentary lifestyle were more common in females.
Sedentary lifestyle was more prevalent in those who were
on dialysis for less than 12 months (linear tendency).
Hypertension, diabetes, dyslipidemia, and low physical
activity were more prevalent among those with diagnosis
of cardiovascular disease.
Discussion
The 1215 individuals included in our study represent
97.3 % of all outpatients on hemodialysis for chronic renal
failure during the collecting data period in Porto Alegre.
The demographic characteristics of our study population
were similar to other studies in several countries9,10,12,14,18,19.
The mean age was close to 60 years old (with 35% over
65 years old) and almost 60% of the participants were men.
Overall, the baseline cross-sectional phase of the CORDIAL
study describes a high prevalence of various traditional
cardiovascular risk factors. Prevalence of hypertension
(87.5%), dyslipidemia (84.7%), sedentary lifestyle (73.1%),
smoking (53.7%) and diabetes (35.8%) were similar to
recent studies developed all over the world9,12,14,18,19,24 and
also comparable to findings in pre‑dialysis CKD patients4.
Arq Bras Cardiol. 2014; 102(5):473-480
474
Burmeister et al.
Cardiovascular risk factors in hemodialysis
Original Article
Table 1 – Clinical and demographic data for the patients in the CORDIAL study
All
Male
Female
(n = 1215)
(n = 723)
(n = 492)
58.3 (15.0)
59.1 (14.6)
57.1 (15.4)
White
62.8
66.2
57.8
Black
25.9
23.1
30.1
Other
11.3
10.7
12.1
Demographics
Age (years) – mean(SD)
Race – %
Time in dialysis (months) – median (interquartile range)
34 (12-71)
35 (12-67)
34 (12-72)
Age of beginning dialysis (years-old) – mean (SD)
54.1 (15.9)
54.9 (15.6)
53.0 (16.2)
Clinical data
Diabetes
DM 1 – n (%)
27
15 (55.6)
12 (44.4)
DM 2 – n (%)
407
239 (58.7)
168 (41.3)
24.7 (4.7)
24.3 (4.2)
25.2 (5.4)
6.1
5.0
7.8
18.5 to 24.9 (kg/m ) - %
52.1
56.2
46.2
25 to 29.9 (kg/m2) - %
29.4
30.0
28.3
≥ 30 (kg/m ) - %
12.4
8.8
17.7
Systolic (mmHg) – mean (SD)
146.9 (23.4)
147.3 (23.3)
146.4 (23.5)
Diastolic (mmHg) – mean (SD)
82.5 (14.0)
82.8 (13.9)
81.9 (14.1)
Systolic ≥ 140 mmHg – %
70.2
71.6
68.6
Diastolic ≥ 90 mmHg – %
34.7
36.0
32.9
Systolic ≥ 140 mmHg and/or diastolic ≥ 90mmHg – %
72.2
74.7
70.0
Cholesterol, total (mg/dL) – mean (SD)
168.2 (48.3)
159.0 (44.1)
183.1 (50.6)
HDL-cholesterol (mg/dL) – mean (SD)
40.1 (14.8)
37.6 (12.6)
43,7 (16.8)
LDL-cholesterol (mg/dL – mean (SD)
94.3 (38.1)
88.6 (35.4)
102.4 (40.4)
Triglycerides (mg/dL) – mean (SD)
171.7 (133.0)
167.8 (145.3)
177.5 (112.6)
Total cholesterol >200 mg/dL – %
22.5
16.3
31.5
HDL-cholesterol <40 mg/dL – %
60.3
64.5
49.5
LDL-cholesterol >100 mg/dL – %
39.4
32.2
49.5
Triglycerides >150 mg/dL - %
45.2
41.6
50.6
Ex-smokers - %
40.5
46.8
31.2
Active smokers - %
13.2
15.2
10.2
Years of tobacco use for active smokers – mean (SD)
30.8 (15.0)
31.2 (14.9)
30.0 (15.3)
Number of cig/day for active smokers – mean (SD)
12.5 (10.8)
12.7 (11.2)
12.0 (10.0)
None - %
73.1
71.1
76.2
Up to 60 minutes/week - %
9.6
10.6
8.0
From 60 to 90 min/week - %
5.6
5.5
5.8
From 90 to 120 min/week - %
4.9
5.2
4.3
Over 120 min/week - %
6.8
7.6
5.6
BMI (kg/m2) – mean (SD)
< 18.5 (kg/m2) - %
2
2
Pre-dialysis blood pressure
Lipid profile
Tobacco use
Physical activity
DM: diabetes mellitus; BMI: body mass index; SD: standard deviation; HDL: high density lipoprotein; LDL: low density lipoprotein.
475
Arq Bras Cardiol. 2014; 102(5):473-480
Burmeister et al.
Cardiovascular risk factors in hemodialysis
Original Article
Hypertension
Hypertension was found in 87.5 % of our patients, a result
higher than that found by Portolés et al. (the MAR study) in a
multicenter cohort in Spain a decade ago (75.8 %)19, but similar
to others, like 87.1 % in the study by Ohsawa et al. in Japan
(KAREN Study, 2005)18, 86 % in a cohort of 2535 patients in
the USA (Agarwal, 2003)25, and around 86 % in two studies
in Spain9,12. The CHOICE study found a higher prevalence
Table 2 – Prevalence of cardiovascular risk factors in CORDIAL (%)
Hypertension
87.5
Diabetes
35.8
Dyslipidemia
84.7
Tobacco use
53.7
Sedentary lifestyle
73.1
Elderly (≥ 65 years)
34.9
Male
59.5
Obesity (BMI ≥ 30)
12.4
(96.0 % among 1041 individuals)14. Pre dialysis mean blood
pressure in our population (about 147/82 mmHg) is similar to
other studies (149/79 mmHg in CHOICE, and 147/80 mmHg
in DMMS Wave2)10,14. Uncontrolled blood pressure in the pre
dialysis measurements is 72 % in our cohort (Table 1), similar
to the 70 % in the study of Agarwal et al25 and to the 69 %
in the CHOICE study14. In CORDIAL, a multivariate adjusted
analysis found that patients under 65 years-old presented a
higher prevalence of hypertension.
Hypertension has been related to higher mortality in
hemodialysis patients26 and the importance of treating high
blood pressure in these individuals was highlighted in two recent
meta‑analysis suggesting a reduction in cardiovascular events and
all‑cause mortality in those treated with antihypertensive drugs27,28.
Dyslipidemia
Among our patients, the prevalence of dyslipidemia was
84.7 %, a higher rate comparing to other studies like 50% in
CHOICE14. The different criteria in each study preclude a more
accurate comparison. Our mean LDL-cholesterol (94.3 mg/L)
was similar to others9,12,14,18,19, with Kronnnenberg reporting a
higher value (115 mg/dL)24.
Table 3 – Adjusted prevalence rates (PR) of each cardiovascular risk factor in CORDIAL study
Hypertension
PR
(95%CI)
Gender
Female
Male
p
Diabetes
PR
(95%CI)
0.883
Dyslipidemia
p
PR
(95%CI)
0.453
p
Tobacco
PR
(95%CI)
0.019
Sedentary lifestyle
p
PR
(95%CI)
p
0.006
Obesity
PR
(95%CI)
0.032
< 0.001
1.00
1.00
1.00
1.00
1.00
1.00
1.00
(0.96-1.05)
0.94
(0.81-1.10)
0.93
(0.88-0.99)
1.57
(1.14-2.15)
0.93
(0.87-0.99)
0.51
(0.38-0.69)
Age – years-old
0.018
< 0.001
0.645
< 0.001
< 0.001
< 0.001
< 65
1.00
1.00
1.00
1.00
1.00
1.00
≥ 65
0.94
(0.90-0.99)
1.46
(1.26-1.69)
1.01
(0.95-1.08)
0.37
(0.24-0.56)
1.16
(1.09-1.24)
0.53
(0.37-0.77)
Race
0.232
0.753
0.534
0.057
0.884
0.840
White
1.00
1.00
1.00
1.00
1.00
1.00
Other
0.97
(0.93-1.02)
0.97
(0.83-1.14)
1.02
(0.96-1.08)
1.33
(0.99-1.78)
1.01
(0.94-1.08)
0.97
(0.71-1.31)
Time in dialysis
– months
1 – 12
0.384
0.334
0.442
0.091
< 0.001
0.936
1.00
1.00
1.00
1.00
1.00
1.00
13 – 24
1.01
(0.95-1.07)
1.09
(0.89-1.34)
1.04
(0.95-1.15)
1.23
(0.75-2.03)
0.86
(0.77-0.95)
0.98
(0.61-1.58)
25 – 36
0.98
(0.91-1.06)
1.05
(0.83-1.33)
1.06
(0.96-1.18)
1.60
(0.96-2.66)
0.90
(0.81-1.00)
0.72
(0.39-1.35)
> 36
0.98
(0.93-1.03)
0.92
(0.76-1.12)
1.03
(0.96-1.11)
1.39
(0.94-2.06)
0.81
(0.75-0.88)
1.03
(0.70-1.51)
Diagnosis of
cardiovascular
disease
< 0.001
< 0.001
0.009
0.564
p
0.049
0.230
No
1.00
1.00
1.00
1.00
1.00
1.00
Yes
1.14
(1.09-1.18)
1.42
(1.22-1.66)
1.08
(1.02-1.15)
0.91
(0.67-1.25)
1.07
(1.00-1.15)
1.21
(0.89-1.65)
Arq Bras Cardiol. 2014; 102(5):473-480
476
Burmeister et al.
Cardiovascular risk factors in hemodialysis
Original Article
The prevalence of elevated triglycerides was 45.2 % in
our cohort, higher than the study by Collado et al12 and
the CHOICE study (36.9 % over 200mg/dL)14. Mean values
were 171.7 mg/dL in CORDIAL, higher than in KAREN and
ANSWER, similar to the MAR study and Kronenberg et al24,
and lower than CHOICE (199mg/dL)9,14,18,19,24. HDL-cholesterol
under 40 mg/dL was more prevalent in our cohort (60.3 %)
than in others9,14,18,19. An exception was the 66 % reported
by Kronenberg et al24.
and CHOICE the prevalence was higher (20 and 26%,
respectively)9,14. Unlike the general population, overweight
dialysis patients have better prognosis, supposedly due to a
better nutritional status35. Recently, BMI has been considered
a non-efficient tool in the assessment of excess body fat
content and thereafter obesity36. Reverse epidemiology and
inadequate assessment of fat accumulation could explain the
“obesity paradox” in CKD37.
In CORDIAL, there was a higher adjusted prevalence
of dyslipidemia in female patients, while Ohsawa et al.
reported an opposite finding18. Although there is not a proven
association between serum lipids and the development CVD
outcomes in dialysis patients29, lipid measurements and
treatment remains a cornerstone approach to prevent CVD
even in CKD patients24.
Age
Smoking
Tobacco use is associated with a markedly increased risk of
heart disease in dialysis patients8,16. Smoking (past or present)
was described in 53.7 % of our patients, in accordance to
others studies9,10,12,14,19. Thirteen percent of our patients were
current smokers, similar to other authors9,14,19, except for
the KAREN study, with 28.2%18. In CORDIAL, the adjusted
prevalence of tobacco use was higher in males and in those
with less than 65 years.
Sedentary lifestyle
Sedentary lifestyle was identified in 73.1% of our patients.
In the CHOICE study14, only 14 % reported physical activity
to perspiration at least 3 times a week. Tentori et al. (2010)30
described results of 20,920 patients in the DOPPS study with a
self-reported regular physical activity of 47.4 %. Comorbidities
and physical limitations could explain the low adherence of
haemodialysis patients to exercise programs31. Besides, older age
could represent another limitation to physical activity – among
our patients, adjusted prevalence of physical inactivity was higher
in those over 65 years than in younger patients (Table 3).
Diabetes
Diabetes prevalence among dialysis patients is already
high and increasing32. The 5-year survival rate among diabetic
patients on hemodialysis is worse than in non‑diabetics.
A recent study in Brazil found 41.1 versus 62.7 %,
respectively33. According to the 2009 United States Renal
Data System (USRDS) database, only 30 % of the diabetic
patients survived five years after beginning hemodialysis1.
In CORDIAL, diabetics were 35.8 % of the population, a
lower rate than the one presented in CHOICE (54%)14, but
similar to the 38.5% in the 2012 USRDS Annual Report34,
with others ranging from 26 to 43 %9,10,18-20.
Obesity
Obesity estimated by body mass index (BMI) was present
in 12.4% of individuals in CORDIAL. The MAR study19
reported obesity in 14% of their patients, while in ANSWER
477
Arq Bras Cardiol. 2014; 102(5):473-480
In CKD patients on hemodialysis, older age confers a
cardiovascular risk that parallels the relationship described
in the general population38. There is a growing prevalence
of elderly in the hemodialysis population all-over the
world9,10,19. In the Brazilian dialysis census of 2000, those
with age 60 or more were 26 %39, while in 2011 there were
31.5 % with age 65 or more40. In CORDIAL, also in 2011,
we found a rate of 34.9 %.
Limitations
Our data presents the usual drawbacks of cross-sectional
studies limiting causal inferences. We had to rely on clinical
laboratory measurements of 15 dialysis centers instead of
using a core lab. We described similar rates observed in
other studies, but our data cannot be generalized to other
cities in our country. Our data, however, has the strength
of having been acquired from a large population with
few dropouts and double-checking structured individual
interviews and clinical charts.
Conclusion
The population in chronic hemodialysis in this large
metropolitan south-American city described in the CORDIAL
study presents a high prevalence of cardiovascular risk factors.
These findings confirm in Brazil what has been previously verified
in northern hemisphere countries, the high-risk cardiovascular
profile of hemodialysis patients. Prospective studies and clinical
trials are needed to further clarify interventions that can be
transformed in public health strategies to prevent cardiovascular
death in hemodialysis patients.
Acknowledgement
The authors thank the medical directors of all dialysis units
in the city of Porto Alegre for their consent and assistance
to this study.
Appendix 1 – Dialysis clinical centers of Porto Alegre, Brazil
Centro de Dialise e Transplante, CliniRim, Clinica Nefron,
Clinica Vita Rim, Hospital das Clinicas de Porto Alegre,
Hospital Divina Providência, Hospital Ernesto Dornelles,
Hospital Mãe de Deus, Hospital Moinhos de Vento, Hospital
N. Sra. da Conceição, Hospital Parque Belém, Hospital Santa
Casa Porto Alegre, Hospital São Lucas, Hospital Vila Nova,
Mãe de Deus Center.
Burmeister et al.
Cardiovascular risk factors in hemodialysis
Original Article
Appendix 2 – Associated researchers to the CORDIAL study
Amanda Galdino Macolmes, Camila Borges Mosmann,
Daiane Jaqueline Nascimento, Debora Wassaf Youssef,
Eduardo Hoffmann Miranda, Felipe Borsu Salles, Fernando
Mendonça Alvares, Fernando Augusto Dannebrock,
Gabriela Dotta Dornelles, Gisiane Munaro, Jaime Fracasso
Jr, Japão Drose Pereira, Jean Pierre W. Youssef, Liana
Pilau Abreu, Liz Lopes Sombrio, Luana Bringhenti, Luzia
Gross Lague, Maikel Alf Klein, Mariano Feraboli Fontana,
Mauricio Rodrigues, Natalia Fiorentin Caramori, Ramiro
Tubino Saraiva, Renata Rech Grandi, Renato Budzyn David,
Veridiana Borges Costa.
Burmeister JE, Bastos JP, Gonçalves LF, Rosito GA; Writing of
the manuscript: Burmeister JE, Mosmann CB, Costa VB, Saraiva
RT, Grandi RR, Bastos JP, Rosito GA; Critical revision of the
manuscript for intellectual content: Burmeister JE, Mosmann
CB, Costa VB, Bastos JP, Gonçalves LF, Rosito GA; Coordination
work of collecting and recording data: Burmeister JE; General
Coordinator of the Project: Rosito GA.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Author contributions
Sources of Funding
Conception and design of the research: Burmeister JE,
Rosito GA; Acquisition of data: Burmeister JE, Mosmann
CB, Costa VB, Saraiva RT, Grandi RR, Bastos JP; Analysis and
interpretation of the data: Burmeister JE, Mosmann CB, Costa
VB, Bastos JP, Gonçalves LF, Rosito GA; Statistical analysis:
There were no external funding sources for this study.
Study Association
This study is not associated with any thesis or dissertation work.
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Cardiovascular risk factors in hemodialysis
Original Article
Arq Bras Cardiol. 2014; 102(5):473-480
480
Back to the Cover
Original Article
LINE-1 Hypomethylation is Associated with the Risk of Coronary
Heart Disease in Chinese Population
Li Wei1, Shuchuan Liu2, Zhendong Su1, Rongchao Cheng1, Xiuping Bai1, Xueqi Li1
Department of Cardiology, The Fourth Affiliated Hospital of Harbin Medical University1; Department of Hematology, The First Affiliated
Hospital of Harbin Medical University2, Harbin – China
Abstract
Background: Global methylation level in blood leukocyte DNA has been associated with the risk of coronary heart
disease (CHD), with inconsistent results in various populations. Similar data are lacking in Chinese population where
different genetic, lifestyle and environmental factors may affect DNA methylation and its risk relationship with CHD.
Objectives: To examine whether global methylation is associated with the risk of CHD in Chinese population.
Methods: A total of 334 cases with CHD and 788 healthy controls were included. Global methylation in blood leukocyte
DNA was estimated by analyzing LINE-1 repeats using bisulfite pyrosequencing.
Results: In an initial analysis restricted to control subjects, LINE-1 level reduced significantly with aging, elevated
total cholesterol, and diagnosis of diabetes. In the case-control analysis, reduced LINE-1 methylation was associated
with increased risk of CHD; analysis by quartile revealed odds ratios (95%CI) of 0.9 (0.6-1.4), 1.9 (1.3-2.9) and 2.3
(1.6-3.5) for the third, second and first (lowest) quartile (Ptrend < 0.001), respectively, compared to the fourth (highest)
quartile. Lower (<median) LINE-1 methylation was associated with a 2.2-fold (95%CI = 1.7-3.0) increased risk of CHD.
The lower LINE-1-related CHD risk estimates tended to be stronger among subjects with the highest tertile of homocysteine
(Pinteraction = 0.042) and those with diagnosis of hypertension (Pinteraction = 0.012).
Conclusion: LINE-1 hypomethylation is associated with the risk of CHD in Chinese population. Potential CHD risk factors
such as older age, elevated total cholesterol, and diagnosis of diabetes may have impact on global DNA methylation,
whereby exerting their effect on CHD risk. (Arq Bras Cardiol. 2014; 102(5):481-488)
Keywords: Epigenetics; Coronary Heart Disease; Global Methylation; LINE-1; Blood Leukocyte DNA
Introduction
Coronary heart disease (CHD) constitutes 90-95% of
all cases with cardiovascular diseases, which rank the
leading cause of death in the world1,2. Age, sex, diets,
cigarette smoking, hypertension, diabetes, dyslipidemia,
homocysteine, obesity, family history of CHD and genetic
factors have been characterized to play a major role in the
CHD etiology2-4.
Epigenetic modification, especially aberrant global
DNA methylation pattern, is increasingly recognized as
a key factor in the development of CHD. Global DNA
hypomethylation may induce genomic instability and
deregulate gene transcription, thereby contributing to the
development of various human diseases including CHD5.
In animal models, global DNA hypomethylation has been
Mailing Address: Xueqi Li •
No. 37 Yiyuan Street, Nan Gang. Postal Code 150001, Harbin
E-mail: [email protected]
Manuscript received Octobrer 20, 2013; revised manuscript Decembrer 12,
2013; acceptea Decembrer 13, 2013.
DOI: 10.5935/abc.20140054
481
associated with aortic lipid deposition, a predictor of future
atherosclerosis6,7. Further, an association between global
DNA hypomethylation and susceptibility to subclinical
atherosclerosis has been reported in young adults 8 .
In addition, in healthy subjects, global methylation level
measured in blood leukocyte DNA has been associated
with risk factors for CHD, such as aging, cigarette smoking,
folate deficiency, hyperhomocysteinemia, higher levels
of low density lipoprotein and lower levels of high
density lipoprotein 9-14. Several epidemiological studies
have reported that global methylation level could be a
determinant risk factor for CHD, but the results were
inconsistent in various populations 15-17. Similar data are
lacking in Chinese population where different genetic,
lifestyle and environmental factors may affect DNA
methylation and its risk relationship with CHD18, 19.
About 55% of human genome consists of repetitive elements20,
including approximately 500,000 LINE-1 repeats which represent
approximately 17% of the human genome21. Because of high
representation throughout the genome and heavy methylation
in normal tissue, LINE-1 has been used as a surrogate marker for
estimating global DNA methylation levels22,23.
In the present study, we have investigated the relationship
between LINE-1 methylation and the risk of CHD in a Chinese
Wei et al.
LINE-1 hypomethylation and CHD risk
Original Article
population. We also examined the association between LINE-1
methylation and potential risk factors for CHD including age,
sex, body mass index (BMI), total cholesterol, triglyceride,
homocysteine, smoking status, hypertension and diabetes,
as well as their modifying effect on the LINE-1-related risk
estimate for CHD.
Methods
Study participants
This case-control study enrolled 334 patients with CHD
and 788 control subjects from the Fourth Affiliated Hospital,
Harbin Medical University, Harbin, China from March 2007 to
September 2010. All participants were unrelated individuals
from the Chinese Han population, and the controls were
frequency-matched to the cases by age (± 5 years) and
sex. The diagnosis of CHD was established by angiographic
evidence of ≥70% stenosis of 1 major coronary artery, or
≥ 50% of the left main coronary artery. The controls filled
a regular health survey and their detailed examination by
history analysis, physical examination, electrocardiography,
and echocardiography revealed absence of CHD or other
heart diseases. For both CHD and control groups, subjects
with spastic angina pectoris, peripheral artery disease, and
any kind of autoimmune‑related disease or cancers were
excluded. Information on age, sex, height, weight, cigarette
smoking, and diagnosis of hypertension and diabetes was
obtained by using a structured questionnaire through
in‑person interviews. An ever-smoker was defined as a
smoker of at least 1 cigarette per day for at least 6 months.
BMI was calculated using the formula: body weight in
kilograms divided by the square of body height in meters
(kg/m2). Information on serum total cholesterol, triglyceride
and plasma homocysteine was collected on the basis of
medical records. Written informed consent was obtained
from each participant. The study protocol was approved
by the ethics review committee of the Institutional Review
Board of the participant hospital.
DNA methylation analysis of LINE-1 repetitive elements
Genomic DNA was extracted from blood leukocytes using
the QIAamp DNA Blood Extraction kit (Qiagen, Shanghai,
China), and then modified by treatment with sodium bisulfite
using the Zymo EZ DNA Methylation kit (Zymo, CA, USA),
following the manufacturer’s protocol. A modified method
of PCR-based pyrosequencing originally described by Yang et
al22 was performed to quantitate methylation of the LINE-1
repetitive elements. In brief, PCR was carried out in a 50-μl
reaction volume containing 25 μl of GoTaq Green Master mix
(Promega, WI, USA), 1 pmol of forward primer (TTT TGA
GTT AGG TGT GGG ATA TA), 1 pmol of biotinylated reverse
primer (biotin-AAA ATC AAA AAA TTC CCT TTC), and 50 ng
of bisulfite-treated genomic DNA. PCR cycling conditions were
95°C for 30 s, 50°C for 30 s and 72°C for 30 s for 40 cycles.
PCR product was bound to streptavidin sepharose beads
(Amersham Biosciences, Uppsala, Sweden). These sepharose
beads containing the bound PCR product were purified, washed,
denatured and washed again. Then, 0.3-μM pyrosequencing
primer (AGT TAG GTG TGG GAT ATA GT) was annealed to
the purified single-stranded PCR product. Pyrosequencing
was performed using the PSQ HS 96 Pyrosequencing System.
For all assays we used built-in controls to verify bisulfite
conversion. Each sample was assayed in duplicate and their
average was used in final analysis. The degree of LINE-1
methylation was expressed as % 5-methylated cytosines (%5mC)
over total (methylated + unmethylated) cytosines.
Statistical analysis
Chi-square test was used to examine the differences in the
distributions of categorical variables and Student’s t-test for the
differences in means of continuous variables between CHD
cases and control subjects. Linear regression models were used
to evaluate LINE-1 differences among controls in relation to
age, sex, BMI, total cholesterol, triglyceride, homocysteine,
smoking status, hypertension and diabetes. Unconditional
logistic regression was used to estimate odds ratio (OR)
for CHD and 95% confidence interval (CI). Quartile and
median cut-points were based on LINE-1 distributions among
controls. All models were adjusted for age (as a continuous
variable), sex, and smoking status (ever-smoker: yes vs no).
Further adjustment by other potential confounding variables,
including BMI, total cholesterol, triglyceride, homocysteine,
hypertension and diabetes, did not materially alter the risk
estimates. Therefore, these variables were not included in
the final models. Effect modification by individual covariates
was assessed using likelihood-ratio tests. All tests were
two‑sided and a P value of <0.05 was considered significant.
Statistical analyses were conducted using the Stata 10.1 (Stata
Corporation, College Station, TX).
Results
The potential risk factors of study subjects by case and
control status are shown in Table 1. No significant differences
between CHD cases and control subjects were found in
the distributions of age, sex, BMI, or triglyceride. When
compared with the controls, CHD cases were more likely
to be ever-smoker, and tended to have higher levels of total
cholesterol and homocysteine. Cases also were likely to have
diagnosis of hypertension and diabetes.
The effects of potential risk factors on LINE-1 methylation
level among control subjects are shown in Table 2.
As expected, LINE-1 level reduced significantly with
increasing age (p = 0.016). We also observed that total
cholesterol (p < 0.001) and diagnosis of diabetes (p < 0.001)
were inversely associated with LINE-1 methylation levels.
No statistically significant relationships were observed between
LINE-1 methylation level and sex, smoking status, BMI,
triglyceride, homocysteine, or diagnosis of hypertension.
CHD cases had significantly reduced LINE-1 methylation
level than controls (mean (standard deviation, SD): 80.96
(2.40) vs 81.67 (2.46), p < 0.001) (Table 1). Analyses of
LINE-1 in quartiles, based on the distribution in controls,
show that the LINE-1 methylation level was inversely
associated with the risk of CHD (Table 3). Relative to subjects
in the fourth (highest) quartile of LINE-1 methylation, ORs
Arq Bras Cardiol. 2014; 102(5):481-488
482
Wei et al.
LINE-1 hypomethylation and CHD risk
Original Article
Table 1 – Potential risk factors of study subjects
Potential risk factors
Cases, n (%)
Controls, n (%)
p value*
< 59
96 (28.7)
266 (33.8)
60-65
119 (35.6)
236 (29.9)
> 65
119 (35.6)
286 (36.3)
Female
66 (19.8)
150 (19.0)
Male
268 (80.2)
638 (81.0)
No
156 (47.4)
590 (75.4)
Yes
173 (52.6)
193 (24.6)
< 22.0
97 (29.1)
262 (33.2)
22.0-25.4
122 (36.5)
264 (33.6)
> 25.4
115 (34.4)
262 (33.2)
< 2.9
57 (17.1)
262 (33.2)
2.9-4.8
123 (36.8)
263 (33.4)
> 4.8
154 (46.1)
263 (33.4)
113 (33.8)
265 (33.7)
1.1-1.6
111 (33.2)
258 (32.8)
> 1.6
110 (33.0)
263 (33.5)
<9
70 (21.6)
241 (32.3)
9-11
106 (32.7)
252 (33.7)
> 11
148 (45.7)
254 (34.0)
No
128 (38.3)
520 (66.0)
Yes
206 (61.7)
268 (34.0)
No
212 (63.5)
638 (81.0)
Yes
122 (36.5)
150 (19.0)
< 0.001
80.96 (2.40)
81.67 (2.46)
< 0.001†
Age (tertile), years
0.12
Sex
0.78
Ever-smoker
< 0.001
Body mass index (tertile), kg/m2
0.36
Total cholesterol (tertile), mmol/L
< 0.001
Triglyceride (tertile), mmol/L
< 1.1
0.98
Homocysteine (tertile), μmol/L
< 0.001
Hypertension
< 0.001
Diabetes
Mean LINE-1 (SD)
SD: standard deviation. *P value obtained from a X2-test comparing cases and controls. †P value obtained from a Student’s t-test comparing cases and controls.
for CHD were 0.9 (95% CI, 0.6-1.4), 1.9 (95% CI, 1.3-2.9)
and 2.3 (95% CI, 1.6-3.5) for the subjects with methylation
in the third, second and first (lowest) quartile (Ptrend < 0.001),
respectively. When using the alternative cut-point based
on the median, individuals with lower (<median) LINE-1
methylation had a 2.2-fold (95% CI, 1.7-3.0) increased risk
of CHD compared with subjects with higher (> median)
LINE-1 methylation.
483
Arq Bras Cardiol. 2014; 102(5):481-488
When stratified by potential risk factors, the lower
LINE‑1‑related CHD risk estimates tended to be stronger
among subjects with the highest tertile of homocysteine
(OR = 3.2, 95% CI, 3.2-5.2) and those with diagnosis
of hypertension (OR = 3.1, 95 %CI, 2.1-4.8) (Table 4).
Statistically significant interactions in relation to CHD
risk were observed between LINE-1 methylation and
homocysteine level (P interaction = 0.042), and between
Wei et al.
LINE-1 hypomethylation and CHD risk
Original Article
Table 2 – Relation of potential CHD risk factors to LINE-1 methylation levels among control subjects
Potential risk factors
n
LINE-1, mean (95% CI)*
< 59
266
81.58 (81.33-81.83)
60-65
236
81.47 (81.22-81.72)
> 65
286
81.21 (80.97-81.45)
150
81.47 (81.14-81.81)
638
81.40 (81.24-81.56)
No
590
81.59 (81.41-81.76)
Yes
193
81.05 (80.80-81.31)
< 22.0
262
81.41 (81.16-81.66)
22.0-25.4
264
81.24 (80.99-81.48)
> 25.4
262
81.58 (81.34-81.83)
< 2.9
262
81.83 (81.57-82.10)
2.9-4.8
263
81.57 (81.34-81.81)
> 4.8
263
80.95 (80.72-81.18)
< 1.1
265
81.39 (81.15-81.64)
1.1-1.6
258
81.43 (81.18-81.68)
> 1.6
263
81.42 (81.18-81.67)
<9
241
81.53 (81.26-81.80)
9-11
252
81.37 (81.12-81.63)
> 11
254
81.41 (81.17-81.65)
No
520
81.53 (81.34-81.72)
Yes
268
81.25 (81.03-81.47)
No
638
81.59 (81.43-81.75)
Yes
150
80.85 (80.56-81.14)
P value*
Age (tertile), years
†
0.016
Sex
‡
Female
Male
0.46
Ever smoker
§
0.35
Body mass index (tertile), kg/m2
0.54
Total cholesterol (tertile), mmol/L
< 0.001
Triglyceride (tertile), mmol/L
0.42
Homocysteine (tertile), μmol/L
0.91
Hypertension
0.59
Diabetes
< 0.001
CHD: Coronary heart disease; CI: Confidence interval. Adjusted for age, sex, and smoking status. Only adjusted for sex and smoking status. Only adjusted for age
and smoking status. §Only adjusted for age and sex.
*
LINE-1 methylation and hypertension (Pinteraction = 0.012).
Stratification by other potential risk factors including age
(tertile), sex (female, male), smoking status (ever-smoker:
no, yes), BMI (tertile), total cholesterol (tertile), triglyceride
(tertile), and diagnosis of diabetes (no, yes), produced
comparable risk estimates (data not shown). The interactions
between LINE-1 methylation and these factors on CHD risk
were not statistically significant (data not shown).
†
‡
Discussion
In the present study, we demonstrated a statistically
significant, inverse relationship between LINE-1 methylation
level and CHD risk in the Chinese population. Homocysteine
level and diagnosis of hypertension modified this inverse
relationship. Considering that CHD is one of the most
common diseases, along with its severity24, the risk factor
Arq Bras Cardiol. 2014; 102(5):481-488
484
Wei et al.
LINE-1 hypomethylation and CHD risk
Original Article
Table 3 – LINE-1 methylation levels in relation to CHD risk
LINE-1 (%5mC)
Cases, n (%)
Controls, n (%)
OR (95% CI)*
55 (16.5)
197 (25.0)
1.0 (reference)
Q3(81.52-82.72)
49 (14.7)
194 (24.6)
0.9 (0.6-1.4)
Q2(80.17-81.51)
101 (30.2)
199 (25.3)
1.9 (1.3-2.9)
Q1(< 80.16)
129 (38.6)
198 (25.1)
Quartile
†
Q4(> 82.73)
2.3 (1.6-3.5)
Ptrend < 0.001
Median†
High(≥ 81.52)
104 (31.1)
391 (49.6)
1.0 (reference)
Low(< 81.52)
230 (68.9)
397 (50.4)
2.2 (1.7-3.0)
%5mC: % 5-methylated cytosines; CHD: coronary heart disease; CI: confidence interval; OR: odds ratio. Adjusted for age, sex, and smoking status. †The quartiles and
the median of LINE-1 measures were based on values among control subjects.
*
Table 4 – LINE-1 level in relation to CHD risk, by homocysteine level and diagnosis of hypertension
Potential risk factors
LINE-1*
Cases, n (%)
Controls, n (%)
OR (95% CI) †
High
24 (34.3)
126 (52.3)
1.0 (reference)
Homocysteine, μmol/L
<9
9-11
> 11
Low
46 (65.7)
115 (47.7)
2.2 (1.2-4.0)
High
41 (38.7)
115 (45.6)
1.0 (reference)
Low
65 (61.3)
137 (54.4)
1.4 (0.9-2.3)
High
36 (24.3)
135 (53.1)
1.0 (reference)
Low
112 (75.7)
119 (46.9)
3.2 (2.0-5.2)
High
51 (39.8)
251 (48.3)
1.0 (reference)
Hypertension
No
Yes
Low
77 (60.2)
269 (51.7)
1.5 (1.0-2.3)
High
53 (25.7)
140 (52.2)
1.0 (reference)
Low
153 (74.3)
128 (47.8)
3.1 (2.1-4.8)
CHD: coronary heart disease; CI: confidence interval; OR: odds ratio. *The median of LINE-1 measure was based on values among control subjects. High: ≥ 81.52 (%5mC);
Low: < 81.52 (%5mC). †Adjusted for age, sex, and smoking status.
of global hypomethylation could have a sizable impact on
public health. Because DNA methylation is a reversible
epigenetic mechanism, this blood-based marker could
offer exciting new opportunities for population-based CHD
prevention as well as risk assessment25.
Global DNA methylation levels, assessed in repeat regions
from leukocyte-derived DNA, have been reported to be
associated with risk of CHD in American, Singapore, and
Indian populations, with inconsistent observations15-17. In a
cohort of 712 elderly men from American population, LINE‑1
hypomethylation was associated with increased risk for ischemic
heart disease in both cross-sectional and longitudinal analyses15.
This is consistent with the findings in the present study. However,
in our data, there were also significant relationships among
women as well as in different age groups between LINE-1
methylation and CHD risk, which provide further data to
485
Arq Bras Cardiol. 2014; 102(5):481-488
what was previously observed in the American population15.
On the other hand, in a Singapore population, higher
methylation levels of Alu/Sat2 repeats were reported in males
with a history of myocardial infarction or stroke (n = 8) than
in control males (n = 121)16; In an Indian population, higher
methylation levels of CCGG sequences were reported in
cases with coronary artery disease (n = 137) than in controls
(n = 150)17. The different lifestyle, environmental exposures,
and genetic backgrounds among the populations, and
differences in sample size and repetitive elements of DNA
targeted for measuring global hypomethylation levels26-28, might
contributed to the different findings across these studies.
The modifying effect of age on global DNA methylation
levels, consistent with previous data29, may reflect age-related
cumulative effects of enviromental exposures to risk factors for
CHD. Global hypomethylation in leukocyte DNA has been
Wei et al.
LINE-1 hypomethylation and CHD risk
Original Article
associated with exposure to multiple types of enviromental
pollutants such as polycyclic aromatic hydrocarbons, particulate
air pollution, black carbon and sulfates30-32. The present study
also showed that two recognized CHD risk factors, elevated total
cholesterol and diagnosis of diabetes, were related to reduced
LINE-1 methylation levels, further supporting a role of DNA
hypomethylation in the development of CHD.
In our data, there was a lack of association between
LINE-1 methylation and homocysteine level or diagnosis of
hypertension, which differs somewhat from what was observed
previously10,33. However, we observed that both homocysteine
level and diagnosis of hypertension modified the inverse
relationship between LINE-1 methylation and CHD risk.
Further studies are warranted to replicate these findings and
to elucidate the underlying mechanism of homocysteine level
and diagnosis of hypertension on their modifying role in the
association between global hypomethylation and CHD risk.
Our study had the advantages of being based on a relatively
large sample size, diagnosis of CHD by angiographic evidence,
and accurate quantitative analysis using pyrosequencing
methodology, which is suitable for measuring subtle changes
in DNA methylation. The chief limitation of the present study
was the retrospective nature of the study design, i.e., the
collection of blood samples from CHD patients took place
after their CHD diagnosis. If the diagnosis of CHD had any
direct or indirect impact on global DNA methylation through
changing subject’s lifestyle or environmental exposure, we
could have observed a confounded or biased association
between LINE-1 methylation and CHD risk. However, similar
risk estimates were observed when the logistic regression
analysis was restricted to 212 newly diagnosed CHD cases
as compared to controls (data not shown). Moreover, our
finding that LINE-1 methylation levels were reduced in control
subjects with CHD risk factors such as older age, elevated total
cholesterol, and diagnosis of diabetes, indicates that reduced
LINE-1 methylation in high-risk control subjects may result
from exposures related to the risk of CHD. In addition, in the
longitudinal analyses in the study by Baccarelli et al31, lower
LINE-1-related increased risk of ischemic heart disease has
been observed.
Conclusion
The findings of the present study support global DNA
hypomethylation measured in LINE-1 repeats is associated
with the risk of CHD in the Chinese population. Potential
CHD risk factors such as older age, elevated total cholesterol
and diagnosis of diabetes may have impact on global DNA
methylation, whereby exerting their effect on CHD risk.
Author contributions
Conception and design of the research and Analysis and
interpretation of the data: Wei L, Liu S, Su Z, Cheng R, Bai
X, Li X; Acquisition of data: Wei L, Su Z, Cheng R; Statistical
analysis: Wei L, Bai X, Li X; Writing of the manuscript: Wei L,
Liu S, Su Z, Cheng R, Bai X; Critical revision of the manuscript
for intellectual content: Li X.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Sources of Funding
There were no external funding sources for this study.
Study Association
This article is part of the thesis of master submitted by Li
Wei, from the Fourth Affiliated Hospital of Harbin Medical
University.
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488
Back to the Cover
Original Article
Incidence of Ventricular Arrhythmias after Stem Cell Therapy in
Patients with Chagas Cardiomyopathy
Adriana Sebba Barroso de Souza, Weimar Kunz Sebba Barroso Souza, Sandra Araujo Costa, Elis Marra de Moreira
Freitas, Gustavo Carvalho, Luís Antônio Batista Sá, Salvador Rassi
Hospital das Clínicas da Universidade Federal de Goiás, Goiânia (GO) − Brazil
Abstract
Background: Treatment with stem cells in several cardiomyopathies may be related to the increase in arrhythmias.
Objectives: To determine whether intracoronary injection of stem cells in patients with Chagas cardiomyopathy is
associated with increased incidence of ventricular arrhythmias, compared to the Control Group.
Methods: A retrospective cohort study that evaluated the medical records of 60 patients who participated in a previous
cross-sectional study. The following data were collected: age, gender, drugs used and Holter variables that demonstrated
the presence of arrhythmias. Holter was performed in four stages: randomization, 2, 6 and 12 months segments. The
Control Group received medical treatment and intracoronary injection of placebo and the Study Group had drug
treatment and autologous stem cell implant.
Results: There was no difference between Control Group and Study Group when analyzing the arrhythmia criteria. In
the intra-group analysis, significant difference was found between the Holter tests of the Study Group for the variable
total ventricular premature beats when compared with baseline, with p = 0.014 between Holter at randomization
and Holter at 2 months, p = 0.004 between Holter at randomization and Holter at 6 months, and p = 0.014 between
Holter at randomization and Holter at 12 months. The variable non-sustained ventricular tachycardia between Holter at
randomization and Holter at 6 months showed p = 0.036.
Conclusion: The intracoronary injection of stem cells did not increase the incidence of ventricular arrhythmias in
patients with Chagas cardiomyopathy compared to the Control Group. (Arq Bras Cardiol. 2014; 102(5):489-494)
Keywords: Arrhythmias, Cardiac; Stem Cell Transplantation; Chagas Cardiomyopathy.
Introduction
In the past decades, heart failure (HF) has emerged as a
public health problem. Kannel, based on epidemiological
studies obtained in the Framingham Heart Study, estimated
that in the United States, there are 5 million HF patients, with
approximately 400,000 new cases per year. The problem is
presumed to be of the same magnitude in Brazil1.
According to data from the World Health Organization
(WHO), although vectorial transmission has been interrupted
in countries such as Brazil, Chile and Uruguay, the prevalence
of patients with chronic chagasic cardiopathy was estimated
between 18 and 20 million people in Latin America, with
300,000 new cases each year, and 50,000 annual deaths
associated with the disease2.
Mailing Address: Adriana Sebba Barroso de Souza •
Universidade Federal de Goiás, - Av. Esperança, s/n - Setor Itatiaia. Postal
Code 74001-970, Goiânia, GO – Brazil
E-mail: [email protected]
Manuscript received September 22, 2013, revised manuscript December 17,
2013, accepted December 18, 2013.
DOI: 10.5935/abc.20140053
489
Despite the widely positive impact with new drugs for
the treatment of HF, the disease progresses and patient
prognosis remains reserved, with reduced quality of life and
survival. Thus, there is an enormous interest and need to
seek new therapies that may offer beneficial effects in the
evolution of these patients3.
Of the new therapeutic procedures, the most promising
seems to be stem cell therapy.
In Brazil, preliminary studies including a limited number
of patients have shown that the use of stem cells from bone
marrow is safe and potentially effective in patients with HF4,5.
Stem cells have an intrinsic potential for arrhythmia, mainly
related to their common lack of electromechanical integration
in the recipient myocardium; it is also important to recognize
that patients eligible for cell replacement therapy are likely to
develop arrhythmias due to underlying heart disease6.
The study by Satsuki Fukushima provided experimental
evidence that direct intramyocardial injection of stem cells
from bone marrow can induce severe ventricular arrhythmias
in the first 14 days after the injection in chronic HF models7.
The aim of this study was to compare the frequency of
ventricular arrhythmia in a group of patients who received
intracoronary injection of stem cells with a control group.
Souza et al.
Arrhythmias after stem cell injection
Original Article
Methods
This study was approved by the Ethics and Research
Committee of Hospital das Clinicas of Universidade Federal
de Goiás, protocol number 179/2011.
This is a retrospective analysis of a cohort of patients
enrolled in a prospective, double-blind, randomized clinical
trial, included in the Multicenter Randomized Study of Cell
Therapy in Cardiopathies (EMRTCC) - chagasic cardiopathy
arm, carried out at the Heart Failure Service of Hospital das
Clinicas of Universidade Federal de Goiás.
The sample consisted of 60 patients included in the
abovementioned protocol from April 2006 to November
2009, followed for at least 1 year after randomization.
This was a convenience sample. Inclusion criteria were:
having been included in the study and undergone Holter
monitoring during the follow-up period. Patients were
divided into two groups in a double-blind fashion: the
control group (CG) received appropriate medical treatment
and optimized for HF and intracoronary injection of
placebo; the Study Group (SG) received, in addition to
adequate drug treatment, autologous stem cell transplant
obtained from bone marrow aspirate.
A total of 34 patients were randomly assigned to the SG
and 26 to the CG. Data collection was performed from January
to July 2012 from medical records. This randomization was
carried out by the EMRTCC national study, which explains
the fact that the groups ended up with different samples at
the Heart Failure Service, Hospital das Clinicas, Universidade
Federal de Goiás.
Data regarding age (in years), gender (male or female);
death (yes or no), medications used (renin-angiotensin system
blocker, digitalis, angiotensin-converting enzyme inhibitors,
spironolactone, diuretics, amiodarone, beta-blockers), and
the number and viability of stem cells used for transplant
were collected.
The presence of arrhythmia was assessed from Holter
results. Holter monitoring was performed at randomization
(baseline - Holter 1) and after 2 (Holter 2), 6 (Holter 3) and
12 (Holter 4) months of follow-up.
The criteria assessed by Holter were total number of beats,
ventricular premature beats, supraventricular premature
beats, total episodes of Nonsustained Ventricular Tachycardia
(NSVT), and Sustained Ventricular Tachycardia (SVT).
The presence of three or more consecutive ventricular
premature beats in a 30-second interval with heart rate
above one hundred beats per minute was considered NSVT,
while SVT was considered in the presence of ventricular
premature beats for a period greater than 30 seconds or
causing hemodynamic instability at any time interval with
heart rate above one hundred beats per minute. For this
study, ventricular arrhythmia was considered as an increase
in the total incidence of NSVT and SVT episodes.
Statistical Analysis
Data were entered in Excel for Windows software
spreadsheets and analyzed using the Statistical Package for
Social Sciences (SPSS), releases 17.0 and 19.0.
Age was shown as mean and standard deviation and gender
as absolute and relative frequency.
Fisher’s test was used to compare the frequency of
medication use between the SG and the CG.
After applying the Kolmogorov-Smirnov test for quantitative
variables obtained at Holter, Student’s t test was performed
for normally distributed variables and the Mann Whitney’s
test for those with non-normal distribution. These tests were
used to compare the groups.
To compare the Holter variables at different intragroup
moments, the Student’s t test or Wilcoxon test was used
for choosing data distribution. Wilcoxon’s test was used
to compare the percentages of the findings in relation to
the total number of beats of the variables: salvos of NSVT
and total SVT episodes, in relation to Holter at different
intragroup moments, to verify whether there was a significant
difference between the Holter results.
A 95% level of confidence was established for all analyses,
i.e., p < 0.05 was considered significant.
Results
Patients included in the study had a mean age of
50.7 ± 9.6 years; 70% (42) were males and 30% (18) females.
There were ten deaths in the SG and nine in the CG during
the 12-month follow-up.
Stem cell viability was 98% in both groups. The amount of cells
in the CG was on average 2.75 x 108 and in the SG, 2.62 x 108.
There was no significant difference between the groups.
Holter data are shown in Table 1, with no difference
between groups regarding the variables that demonstrated
the presence of arrhythmia on Holter examinations at any
time (randomization, 2 months, 6 months and 12 months
of follow-up).
When comparing Holter 1 (randomization) to the others,
in the SG, there was a significant difference between total
ventricular premature beats in all comparisons, differences in
total number of beats and NSVT between Holter monitoring
tests 1 and 3 (Table 2). The same analysis was performed in
the CG (Table 3), which showed no statistical significance.
A statistical evaluation of the SG was carried out with
the variables NSVT and SVT, percentage-wise, in relation
to the total number of beats at Holter monitoring, which
showed no significance in the intragroup analysis (Table 4).
This evaluation was performed due to the observation that
the total number of beats, as well as the NSVT, increased at
Holter monitoring in the follow-up.
There was no statistical difference in terms of medications
for the treatment of HF used by the patients in both groups,
at the time of randomization (Table 5).
Discussion
The present study found no increase in numbers of
isolated ventricular premature beats compared with the CG,
in agreement with studies by Vilas Boas et al4,8. The studies
by Vilas Boas et al4,8 had a patient profile similar to ours.
We studied 28 chagasic patients in functional class III and IV
Arq Bras Cardiol. 2014; 102(5):489-494
490
Souza et al.
Arrhythmias after stem cell injection
Original Article
Table 1 – Variables obtained by Holter performed at randomization (Holter 1), 2 months (Holter 2), 6 months (Holter 3) and 12 months (Holter 4)
of study follow-up, n = 60, Goiânia, Goiás, 2010
Variable
Study Group
Control Group
Holter 1
(n = 34)
(n = 26)
81,209.33 ± 17,417.57
86,343.54 ± 17,474.21
0.189
2,685.18 ± 3,052.48
2,640.06 ± 3,412.12
0.435
926.77 ± 3,659.93
2.330.33 ± 9,875.09
0.514
5.15 ± 12.02
3.79 ± 5.68
0.744
0.00 ± 0.0
0.0 ± 0.0
-
(n = 32)
(n = 26)
89,474.62 ± 10,906.01
88,457.09 ± 20,175.04
0.994
Total ventricular premature beats
3,764.00 ± 5,313.65
3,611.22 ± 4,549.22
0.478
Total supraventricular premature beats
1.363.07 ± 4,609.85
457.41 ± 1,703.04
0.994
29.92 ± 135.33
14.77 ± 33.31
0.456
0.0 ± 0.0
0.0 ± 0.0
-
Total number of beats
Total ventricular premature beats
Total supraventricular premature beats
NSVT
Total SVT episodes
Holter 2
Total number of beats
NSVT
Total SVT episodes
Holter 3
p value
(n = 28)
(n = 21)
92,394.25 ± 11,519.21
94,715.06 ± 19,856.30
0.836
Total ventricular premature beats
4,817.48 ± 6,152.71
5,072.41 ± 7,508.33
0.379
Total supraventricular premature beats
1,893.07 ± 5,341.60
2,580.45 ± 9,623.00
0.809
30.11 ± 135.37
24.12 ± 56.53
0.956
2.11 ± 10.96
0.0 ± 0.0
0.277
(n = 26)
(n = 16)
Total number of beats
96,965.00 ± 10,386.72
91,487.25 ± 16,403.77
0.255
Total ventricular premature beats
9,713.17 ± 1,8607.40
4,234.29 ± 4,010.05
0.459
Total supraventricular premature beats
1,480.58 ± 2,957.37
2,477.79 ± 8,422.73
0.862
19.17 ± 36.47
2.25 ± 4.59
0.117
0.12 ± 0.61
0.0 ± 0.0
0.400
Total number of beats
NSVT
Total SVT episodes
Holter 4
NSVT
Total SVT episodes
Mann-Whitney test; p < 0.05. NSVT: nonsustained ventricular tachycardia; SVT: sustained ventricular tachycardia.
Table 2 – Comparison between Holter tests performed in the Study Group during the 12-month follow-up, n = 60, Goiânia, Goiás, 2010
Variable
Total number of beats*
Total number of ventricular premature beats**
Salvos of NSVT**
Total episodes of SVT**
Holter 1 vs. Holter 2
0.524
0.014***
0.070
1.000
Holter 1 vs. Holter 3
0.024***
0.004***
0.036***
0.317
Holter 1 vs. Holter 4
0.083
0.014***
0.375
0.102
* Student test was used; ** in total heartbeats and Wilcoxon test; p < 0.05. ***: in total ventricular extrasystoles NSVT and SVT episodes and was found significance p < 0,05
for both items. Holter 1: performed at randomization; Holter 2: performed at 2 months of follow-up; Holter 3: performed at 6 months of follow-up; Holter 4: performed at
12 months of follow-up. NSVT: nonsustained ventricular tachycardia; SVT: sustained ventricular tachycardia.
Table 3 – Comparison between Holter tests performed in the Control Group during the 12-month follow-up, n = 60, Goiânia, Goiás, 2010
Variable
Total number of beats*
Total number of ventricular premature beats**
Salvos of NSVT**
Total episodes of SVT**
Holter 1 vs. Holter 2
0.026***
0.239
0.984
1.000
Holter 1 vs. Holter 3
0.014***
0.161
0.975
0.317
Holter 1 vs. Holter 4
0.015***
0.128
0.061
1.000
* Student test was used; ** in total heartbeats and Wilcoxon test; p < 0.05. ***: in total ventricular extrasystoles NSVT and SVT episodes and was found significance
p < 0,05 for both items. Holter 1: performed at randomization; Holter 2: performed at 2 months of follow-up; Holter 3: performed at 6 months of follow-up; Holter 4:
performed at 12 months of follow-up. NSVT: nonsustained ventricular tachycardia; SVT: sustained ventricular tachycardia.
491
Arq Bras Cardiol. 2014; 102(5):489-494
Souza et al.
Arrhythmias after stem cell injection
Original Article
Table 4 – Comparison test of the variables: nonsustained ventricular tachycardia (NSVT) and sustained ventricular tachycardia (SVT) as
percentages in Holter examinations at 2 months, 6 months and 12 months of follow-up, n = 60, Goiânia, Goiás, 2010
Comparison
Control group
Study group
Salvos of NSVT (p)
Total episodes of SVT (p)
Salvos of NSVT (p)
Total episodes of SVT (p)
Holter 1 vs. Holter 2
0.904
1.000
0.286
1.000
Holter 1 vs. Holter 3
0.796
0.317
0.198
1.000
Holter 1 vs. Holter 4
0.753
1.000
0.381
0.317
Wilcoxon Test; p < 0.05. Holter 1: performed at randomization; Holter 2: performed at 2 months of follow-up; Holter 3: performed at 6 months of follow-up;
Holter 4: performed at 12 months of follow-up. NSVT: nonsustained ventricular tachycardia; SVT: sustained ventricular tachycardia.
Table 5 – Analysis of medications taken by patients at the time of randomization, n = 60, Goiânia, Goiás, 2010
Variable
Study Group (n = 34) n (%)
Control Group (n = 26) n (%)
p value
ARB
7 (25.9)
10 (30.3)
0.212
Digitalis
14 (51.9)
14 (42.4)
0.158
ACEI
8 (29.6)
10 (30.3)
0.222
Spironolactone
19 (70.4)
21 (63.6)
0.188
Diuretics
19 (70.4)
25 (75.8)
0.206
Amiodarone
10 (37.0)
11 (33.3)
0.204
Beta-blockers
2 (7.4)
12 (36.4)
0.171
Source: patients’ files. Fisher’s test. ARB: angiotensin-II receptor blocker; ACEI: angiotensin-converting enzyme inhibitor.
of the New York Heart Association (NYHA). Vilas Boas et al4,8,
similarly to this study, evaluated patients with advanced-stage
cardiomyopathy and demonstrated the safety regarding the
genesis of arrhythmias in this group of patients.
In the SG, which received the stem cell therapy, it is
possible to observe an increase in the density of ventricular
premature beats, when comparing the baseline Holter
monitoring with those subsequently performed after 2, 6
and 12 months of follow-up, with a statistically significant
difference. Thus, it is possible to consider that there was
an increase in the incidence of ventricular premature
beats when compared with the group baseline assessment.
In disagreement with the HEBE study 9 carried out in
Holland, which evaluated 200 ischemic patients who
received cell therapy and stem cell infusion within 12 hours
of the ischemic event, with excellent safety profile, the
present study showed no severe arrhythmia events.
When we analyzing the presence of NSVT, compared
with baseline of the SG itself, a difference was observed
between Holter 1 and Holter 3, with statistical significance.
This fact is in disagreement with the randomized multicenter
STAR‑HEART study10, which analyzed 191 patients with
ischemic cardiomyopathy, of which follow-up showed
improvement of arrhythmia in those treated with stem cells.
At the analysis of NSVT and SVT data, percentage-wise
when compared to the total number of beats, it became clear
that this increase was proportional and without statistical
significance, exactly as in the multicenter studies BOOST11
and TOPCARE-AMI12, which evaluated patients with ischemic
cardiomyopathy and found no increase in the number of
ventricular arrhythmia events.
Stem cell therapy has been used in several different
diseases, showing a good safety profile13.
Conclusion
Chronic heart failure is a progressive disease, in spite
of intensive pharmacological treatment, and remains a
severe health problem worldwide. Therefore, in addition
to conventional therapy, treatment regimens are needed
that can improve quality of life and increase ventricular
performance and survival.
Treatment with bone marrow cells does not cure Chagas
disease, but attempts to repair the damage that results from
years or even decades of aggression to the myocardium.
Our data suggest that patients with heart failure due to
Chagas disease and class III and IV heart failure submitted
to transplantation of stem cells from bone marrow to the
myocardium, showed no increase in the incidence of
sustained ventricular tachycardia, but showed increase
in nonsustained ventricular tachycardia between Holter
at randomization and Holter at 6 months in the Study
Group, as well as increased VPB density in the Study group.
At the percentage analysis, there was no significant increase
of nonsustained ventricular tachycardia, or sustained
ventricular tachycardia.
Arq Bras Cardiol. 2014; 102(5):489-494
492
Souza et al.
Arrhythmias after stem cell injection
Original Article
Author contributions
Sources of Funding
Acquisition of data:Costa SA, Freitas EMM, Carvalho G;
Analysis and interpretation of the data: Souza ASB, Sá LAB;
Statistical analysis: Souza ASB; Writing of the manuscript:
Souza ASB; Critical revision of the manuscript for intellectual
content: Souza WKSB, Souza ASB, Rassi S.
Study Association
There were no external funding sources for this study.
This article is part of the thesis of master submitted by Adriana
Sebba Barroso de Souza from Universidade Federal de Goiás.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
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Vilas-Boas F, Feitosa GS, Soares MB, Pinho-Filho JA, Mota AC, Almeida AJ, et
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Menasché P. Stem cell therapy for heart failure: are arrhythmias a real safety
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RA, et al; HEBE Investigators. Intracoronary infusion of mononuclear cells
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Souza et al.
Arrhythmias after stem cell injection
Original Article
Arq Bras Cardiol. 2014; 102(5):489-494
494
Back to the Cover
Original Article
Temporal Variation in the Prognosis and Treatment of Advanced
Heart Failure – Before and After 2000
Carlos Henrique Del Carlo1, Juliano Novaes Cardoso1,2, Marcelo Eidi Ochia1,2, Mucio Tavares de Oliveira Jr.1,
José Antonio Franchini Ramires1, Antonio Carlos Pereira-Barretto1
Instituto do Coração - Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (USP)1, São Paulo, SP; Hospital Auxiliar de
Cotoxó/Instituto do Coração - Hospital das Clínicas - Faculdade de Medicina - Universidade de São Paulo (USP)2, São Paulo, SP − Brazil
Abstract
Background: The treatment of heart failure has evolved in recent decades suggesting that survival is increasing.
Objective: To verify whether there has been improvement in the survival of patients with advanced heart failure.
Methods: We retrospectively compared the treatment and follow-up data from two cohorts of patients with systolic
heart failure admitted for compensation up to 2000 (n = 353) and after 2000 (n = 279). We analyzed in-hospital death,
re-hospitalization and death in 1 year of follow-up. We used Mann-Whitney U test and chi-square test for comparison
between groups. The predictors of mortality were identified by regression analysis through Cox proportional hazards
model and survival analysis by the Kaplan-Meier survival analysis.
Results: The patients admitted until 2000 were younger, had lower left ventricular impairment and received a lower
proportion of beta-blockers at discharge. The survival of patients hospitalized before 2000 was lower than those
hospitalized after 2000 (40.1% vs. 67.4%; p < 0.001). The independent predictors of mortality in the regression analysis
were: Chagas disease (hazard ratio: 1.9; 95% confidence interval: 1.3-3.0), angiotensin-converting-enzyme inhibitors
(hazard ratio: 0.6; 95% confidence interval: 0.4-0.9), beta-blockers (hazard ratio: 0.3; 95% confidence interval: 0.2-0.5),
creatinine ≥ 1.4 mg/dL (hazard ratio: 2.0; 95% confidence interval: 1.3-3.0), serum sodium ≤ 135 mEq/L (hazard ratio:
1.8; 95% confidence interval: 1.2-2.7).
Conclusions: Patients with advanced heart failure showed a significant improvement in survival and reduction in
re‑hospitalizations. The neurohormonal blockade, with angiotensin-converting-enzyme inhibitors and beta-blockers,
had an important role in increasing survival of these patients with advanced heart failure. (Arq Bras Cardiol. 2014;
102(5):495-504)
Keywords: Heart Failure / therapy; Prognosis; Heart Failure / mortality; Chagas Disease.
Introduction
Heart failure (HF) is a clinical syndrome of which
evolution is known to have high morbidity and mortality1,2.
In epidemiological studies, HF patients showed a significant
reduction in quality of life and a worse evolution than many
types of cancer3.
Treatment with neurohormonal blockers has modified
this history, reducing the high mortality, the rate of
re‑hospitalizations and improving quality of life in patients with
this syndrome4. This improvement has been demonstrated
Mailing Address: Carlos Henrique Del Carlo •
Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina,
Universidade de São Paulo, Avenida Dr. Enéas de Carvalho Aguiar, 44,
Cerqueira César. Postal Code 05403-900, São Paulo, SP, Brazil.
E-mail: [email protected]; [email protected]
Manuscript received September 22, 2013, revised manuscript November 24,
2013, accepted December 17, 2013.
DOI: 10.5935/abc.20140050
495
in clinical trials and controlled studies, but we do not know
whether this improvement has also been observed in the real
world, among patients in the institutions, clinics and offices,
and particularly, we have no data on the Brazilian population4.
Working in a tertiary hospital in São Paulo, we followed
the evolution of HF patients in the last two decades and
observed that the population we treated during these years
has not changed substantially regarding characteristics, as
the admission criteria have not changed. This fact allowed
us to compares the outcome of patients, considering two
periods: before and after the year 2000.
This study sought to assess whether the outcomes of
patients with HF changed when comparing the two periods
and verify, among the studied variables, which were
associated with prognosis of this syndrome.
Methods
A total of 632 hospitalized patients were prospectively
studied in a tertiary hospital in São Paulo, all with advanced
HF, systolic dysfunction with ejection fraction < 40%, in
Del Carlo et al.
Improvement in Heart Failure Prognosis
Original Article
NYHA (New York Heart Association) III / IV. Patients in
this hospital came from the emergency room and were
transferred there when they did not compensate after
the first measures or because they required inotropic
support for compensation. These selection criteria for
hospitalization led to the admission of more severe patients
with severe clinical manifestation.
All patients underwent clinical and laboratory assessment,
including biochemical analysis, CBC, echocardiography
and radiological examinations. Regarding the etiology of
heart disease, patients were divided into three groups:
those with chagasic etiology, those with ischemic etiology
and those with nonischemic etiology. The diagnosis of
Chagasic heart disease was established by the presence of
positive serological reactions, and ischemic heart disease
was confirmed by the presence of a history of heart attack,
angina or confirmed by coronary angiography. In the
absence of these characteristics, the patient was considered
to have non-ischemic heart disease.
These patients are part of a prospective study database
of patients hospitalized in our service, due to advanced,
decompensated HF and all met the same abovementioned
inclusion criteria2,5-8. Patients were included in different
years, which allowed us to perform a temporal analysis
regarding the evolution of prognosis and treatment of this
syndrome. For the purpose of this analysis, performed
retrospectively, the patients were divided into two groups:
those admitted until December 31, 2000 and those
admitted after that date. Patients included in the study
admitted before 2000 were part of prospective studies in
the years 1992, 1994, 1996 and 19995-8. Patients enrolled
after 2000 were studied in 2005 and 20062. We compared
the characteristics of the two groups, considering clinical,
laboratory, and evolution aspects.
Patients were followed for 1 year, and the vital status of
the patients, number of visits to the emergency room and
need for rehospitalization were determined by telephone
or by reviewing electronic medical records. The clinical
outcome analyzed was mortality from all causes during the
follow-up period.
Among these patients, a subgroup had the treatment
analyzed during and after discharge, and predictors of
mortality were assessed in this subgroup, consisting of
333 patients (52.7% of total)2,8. This subgroup was selected
based on the availability of data on drug therapy used during
hospitalization and pre-hospital discharge.
Continuous variables were shown as means ± standard
deviation and categorical variables as frequencies and
percentages. We compared the characteristics of patients
regarding mortality at the end of follow-up. Continuous variables
were analyzed by Mann-Whitney U test and categorical
variables by the chi-square test or Fisher exact test.
Predictors of mortality were determined by uni- and
multivariate analysis, using the Cox proportional hazards
method. A regression model was constructed for the primary
endpoint, adjusted for clinical and laboratory characteristics
as well as those of administered drugs. The criterion for model
variable selection was a p value < 0.200 in the univariate
analysis. The final model was built using a stepwise forward
procedure. All predictor variables with p < 0.05 were
mantained in the final model. Hazard ratio was shown, with the
corresponding confidence interval of 95% (95% CI) and p value.
Based on the follow-up data, survival curves were
constructed using the Kaplan-Meier method. All statistical
analyses were performed using the statistical software
Statistical Package for Social Sciences (SPSS).
P values are two-tailed and the significance level was
set at 5%.
Results
The mean age of patients was 54.8 ± 15.1 years and
most were males, 435 (68.8%). The mean left ventricular
ejection fraction (LVEF) was 28.2 ± 7.2% and mean Systolic
Blood Pressure (SBP) was 104.6 ± 22.9 mmHg. The most
frequent cause of heart disease was non-ischemic, followed
by chagasic and ischemic.
Most patients had non-dialytic kidney failure.
A total of 353 patients hospitalized from 1992 to
December 31, 2000, and 279 patients hospitalized between
2005 and 2006 were included in the study.
Table 1, shows the comparison of baseline characteristics
between patients admitted until 2000 and after 2000.
Patients hospitalized until the year 2000 were 7.5 years
younger than those admitted after 2000 and had a less impaired
LVEF and lower levels of plasma sodium. The percentage of
patients with Chagas disease was higher in admissions until 2000.
The survival of patients hospitalized until the year 2000
was 40.1% and 67.4%, among those hospitalized after the
year 2000, with a 68% increase in the survival rate in the first
year of follow-up (Figure 1).
To analyze the possible variables related to survival, we
evaluated the data of 333 patients (52.7% of the total).
These data are shown in Table 2. This analysis showed that
209 patients (62.8%) needed inotropes in the compensation
period. At discharge, most patients were receiving a
prescription of renin-angiotensin system blocker (72.4%) and
a beta-blocker (59.8%). A total of 186 (55.9%) patients were
treated with carvedilol and 13 patients (3.9%) with metoprolol
succinate. When comparing the two groups, patients admitted
until 2000 received a lower proportion of beta-blocker
prescriptions and a higher proportion of digoxin.
In this analysis, patients admitted until the year
2000 had higher in-hospital mortality (20.0% vs 8.7%,
p = 0.008) and a higher number of re-hospitalizations than
those admitted after 2000 (51.4% vs. 27.9%, p < 0.001).
At 1 year of follow up, mortality of those admitted until
the year 2000 was 62.9% vs. 23.6% for those hospitalized
after 2000 (p < 0.001).
The length of hospital stay did not differ between the
two groups, being 28.3 ± 21.1 days in those admitted until
2000 and 25.1 ± 16.7 days (p = 0.251) in those hospitalized
after the year 2000.
Arq Bras Cardiol. 2014; 102(5):495-504
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Del Carlo et al.
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Table 1 – Comparison of characteristics between the groups before and after 2000
Characteristics
Population (n = 632)
Year of treatment
Before 2000 (n = 353)
After 2000 (n = 279)
p value
Age (years)
54.8 ± 15.1
59.0 ± 14.8
51.5 ± 14.5
< 0.001
Male gender
435 (68.8)
255 (72.2)
180 (64.5)
0.037
Etiology:
Ischemic
132 (20.9)
56 (15.0)
76 (27.2)
< 0.001
Non-ischemic (non- chagasic)
312 (49.4)
173 (49.0)
139 (49.8)
0.839
188 (29.7)
124 (35.1)
64 (22.9)
0.001
LVEF (%)
Chagasic
28.2 ± 7.2
30.8 ± 5.9
24.7 ± 7.3
< 0.001
Creatinine (mg/dL)
1.5 ± 0.7
1.5 ± 0.5
1.5 ± 0.5
0.239
Sodium (mEq/L)
135.7 ± 5.0
136.7 ± 4.7
134.9 ± 5.1
< 0.001
SBP (mmHg)
103.6 (25.4)
102.6 ± 21.9
105.0 ± 30.1
0.163
264 (41.8)
200 (56.7)
63 (22.8)
< 0.001
Mortality (1 year)
LVEF: left ventricular ejection fraction; SBP: systolic blood pressure.
1.0
Probability of survival
0.8
After the year 2000
0.6
0.4
Before the year 2000
0.2
0.0
Log-Rank (Chi-square) = 23.82 - p<0.001
0
100
200
300
400
500
600
Days
Figure 1 – Survival of patients hospitalized for decompensated heart failure before and after the year 2000. The probability of survival at 1 year of follow-up was 40.1%
in hospitalized patients before 2000 and 67.4% in hospitalized patients after 2000 (p < 0.001).
Tables 3 and 4 show the comparison of patient characteristics
regarding mortality at 1 year of follow up and the univariate
and multivariate regression analysis of predictors of death in this
period. Chagasic etiology, presence of renal impairment (higher
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Arq Bras Cardiol. 2014; 102(5):495-504
urea levels and creatinine), lower levels of sodium and nitrate use
were predictors of increased mortality. Variables associated with
reduced mortality were the prescription of Angiotensin‑Converting
Enzyme Inhibitor (ACEI) and beta‑blockers. In the multivariate
Del Carlo et al.
Improvement in Heart Failure Prognosis
Original Article
Table 2 – Comparison of patients in relation to the year of treatment
Characteristics
Population (n = 333)
Year of treatment
Before 2000 (n = 70)
After 2000 (n = 263)
p value
Age (years)
58.7 ± 15.4
54.2 ± 15.8
59.9 ± 15.1
0.011
Male gender
213 (64.0)
48 (68.6)
165 (62.7)
0.366
Ischemic
94 (28.2)
18 (25.7)
76 (28.9)
0.599
Non-ischemic (non-chagasic)
163 (48.9)
33 (47.1)
130 (49.4)
0.734
Etiology:
76 (22.8)
19 (27.1)
57 (21.7)
0.333
LVEF (%)
Chagasic
28.0 ± 11.4
31.3 ± 8.4
27.1 ± 11.9
< 0.001
Hemoglobin (g/L)
13.2 ± 2.0
13.9 ± 2.1
13.0 ± 1.9
0.001
Urea (mg/dL)
74.7 ± 42.5
72.9 ± 35.2
75.1 ± 44.2
0.842
1.5 ± 0.7
1.4 ± 0.5
1.5 ± 0.8
0.699
Creatinine (mg/dL)
Sodium (mEq/L)
136.6 ± 4.9
135.9 ± 5.4
136.7 ± 4.7
0.083
SBP (mmHg)
105.3 ± 23.3
111.7 ± 25.4
103.5 ± 22.4
0.017
DBP (mmHg)
68.7 ± 18.1
76.7 ± 17.9
66.3 ± 17.5
< 0.001
187 (57.9)
36 (51.4)
151 (57.4)
0.216
6 (1.9)
0 (0.0)
6 (2.3)
0.346
Medications:
Dobutamine
Milrinone
Levosimendan
16 (5.0)
0 (0.0)
16 (6.1)
0.028
ACEI
241 (72.4)
60 (85.7)
181 (68.8)
0.005
Beta-blockers
199 (59.8)
8 (11.4)
191 (72.6)
< 0.001
Losartan
42 (12.7)
0 (0.0)
42 (16.0)
< 0.001
Nitrates
117 (35.2)
39 (55.7)
78 (29.7)
< 0.001
Hydralazine
108 (32.5)
16 (22.9)
92 (35.0)
0.052
Digoxin
194 (58.6)
64 (92.8)
130 (49.4)
< 0.001
Spironolactone
48 (14.5)
0 (0.0)
48 (18.3)
< 0.001
Furosemide
261 (78.6)
70 (100.0)
191 (72.6)
< 0.001
Hydrochlorothiazide
59 (17.8)
0 (0.0)
59 (22.4)
< 0.001
Mortality in-Hospital
37 (11.1)
14 (20.0)
23 (8.7)
0.008
Mortality at follow-up (1 year)
106 (31.8)
44 (62.9)
62 (23.6)
< 0.001
Rehospitalization
109 (32.8)
36 (51.4)
73 (27.9)
< 0.001
Clinical events
168 (49.2)
56 (80.0)
108 (41.1)
< 0.001
Clinical results:
Data are expressed as mean ± standard deviation or number (percentage). LVEF: left ventricular ejection fraction; SBP: systolic blood pressure; DBP: diastolic blood
pressure; ACEI: angiotensin-converting enzyme inhibitor.
Clinical events, death or rehospitalization within 1 year.
regression analysis, five variables were identified as independent
predictors of mortality, with three being associated with worse
prognosis (Chagas disease, creatinine ≥ 1.4 mg/dL, and sodium
≤ 135 mEq/L) and two associated with improved prognosis: the
prescription of ACEI and beta-blockers.
improvement in survival of patients who received the
combined therapy with the two medications.
Figures 2 and 3 show survival curves stratified for ACEI and
beta-blockers. In Figure 4, the survival curve was stratified for
the combined use of ACEI and beta-blockers, demonstrating
According to the results of this observational study, we
observed that in this new century, the survival of patients with
advanced HF has improved significantly, as well as the rates of
Discussion
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Table 3 – Comparison of patients in relation to 1-year mortality
1-year mortality
Characteristics
p value
Yes (n = 106)
No (n = 227)
Age (years)
58.2 ± 17.3
58.9 ± 14.5
0.928
Male gender
63 (59.4)
150 (66.1)
0.239
Etiology:
Ischemic
27 (25.5)
67 (29.5)
0.445
Non-ischemic (non-chagasic)
44 (41.5)
119 (52.4)
0.063
35 (33.0)
41 (18.1)
0.002
LVEF (%)
Chagasic
28.9 ± 9.5
27.6 ± 12.1
0.116
Hemoglobin (g/L)
13.3 ± 2.2
13.1 ± 1.8
0.311
Urea (mg/dL)
80.8 ± 42.8
71.8 ± 42.1
0.016
1.5 ± 0.5
1.5 ± 0.8
0.043
Creatinine (mg/dL)
Sodium (mEq/L)
135.3 ± 4.9
137.1 ± 4.8
0.001
SBP (mmHg)
103.1 ± 20.7
106.4 ± 24.5
0.505
DBP (mmHg)
69.3 ± 15.3
68.4 ± 19.3
0.503
Inotropic agents
75 (71.4)
127 (57.5)
0.015
ACEI
69 (65.1)
172 (75.8)
0.042
Beta-blocker
36 (34.0)
163 (71.8)
< 0.001
Losartan
12 (11.3)
30 (13.2)
0.649
Nitrates
47 (44.3)
70 (30.8)
0.014
Hydralazine
38 (35.8)
70 (30.8)
0.333
Digoxin
76 (71.7)
118 (52.0)
< 0.001
Medications
Spironolactone
11 (10.4)
37 (16.3)
0.161
Furosemide
90 (84.9)
171 (75.3)
0.032
Hydrochlorothiazide
18 (17.0)
41 (18.1)
0.839
Data are expressed as mean ± standard deviation or number (percentage). LVEF: left ventricular ejection fraction; SBP: systolic blood pressure; DBP: diastolic blood
pressure; ACEI: angiotensin-converting enzyme inhibitor.
re-hospitalization. Treatment with neurohormonal blockers,
especially ACEI and beta-blockers, was associated with this
increase in survival rates.
Heart failure, in its advanced form, is a malignant disease with
a higher mortality rate than a few types of cancer3. Even with the
current treatment, mortality can be high in the most severe forms,
as it has an association with the intensity of the heart disease and
its clinical manifestations9. Patients with advanced disease are
referred to our institution, a tertiary hospital in São Paulo, which
results in higher mortality than that observed in other institutions.
Our current mortality rate is approximately 8% and we observed
that approximately a quarter of patients who were discharged
died in the first year of follow-up2.
Although this mortality rate is still high, when we compared
data from patients hospitalized until the year 2000, we
found a significant reduction. It should be noted that when
comparing the characteristics of the study population in
two periods, before and after 2000, we observed that they
are quite similar, but the hospitalized population after
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Arq Bras Cardiol. 2014; 102(5):495-504
2000 shows alterations that indicate more pronounced
clinical manifestations, such as higher levels of urea and
creatinine at admission and lower LVEF. Despite these signs
of greater severity, when comparing the two periods, there
was a significant reduction in mortality, which decreased from
20% to the current 8.8%2. This reduction was probably due
to more aggressive management of cardiac decompensation
and the higher proportion of patients currently being treated
with ACEI and beta-blockers10,11.
In our institution, ACEI and beta-blockers are not
systematically withdrawn at hospitalization for cardiac
decompensation 12 . In general, ACEI have their dose
increased, as vasoconstriction is the major pathophysiological
alteration in cardiac decompensation. The beta-blocker is
maintained and in cases that need inotropes, the dose of the
beta-blocker is halved, which results in the fact many patients
continue taking 6.25 mg or 12.5 mg of carvedilol twice
daily. In the multivariate analysis, the prescription of ACEI
and beta-blockers was associated with reduced mortality.
Del Carlo et al.
Improvement in Heart Failure Prognosis
Original Article
Table 4 – Univariate and multivariate analysis regression (Cox) of predictors of death
Predictor (univariate analysis)
Hazard ratio
95% Confidence Interval (95%CI)
p value
Age > 60 years
1.0
0.7 – 1.5
0.998
Male gender
0.8
0.5 – 1.2
0.247
Ischemic
0.8
0.5 – 1.3
0.389
Non-ischemic (non-chagasic)
0.7
0.5 – 1.1
0.124
Chagasic
1.8
1.2 – 2.7
0.008
LVEF < 0.25
0.8
0.6 – 1.3
0.382
Anemia
1.0
0.7 – 1.6
0.939
Urea ≥ 60 mg/dL
1.7
1.1 – 2.5
0.013
Creatinine ≥ 1.4 mg/dL
1.6
1.1 – 2.4
0.013
Sodium ≤ 135 mEq/L
1.8
1.2 – 2.6
0.004
SBP < 90 mmHg
0.9
0.5 – 1.5
0.640
Inotropic agents
1.7
1.1 – 2.7
0.008
ACEI
0.6
0.4 – 0.9
0.020
Beta-blocker
0.3
0.2 – 0.5
< 0.001
Losartan
1.1
0.6 – 2.0
0.788
Nitrates
1.6
1.1 – 2.4
0.017
Hydralazine
1.4
0.9 – 2.1
0.097
Digoxin
1.4
0.9 – 2.2
0.106
Spironolactone
0.7
0.4 – 1.3
0.274
Hydrochlorothiazide
1.2
0.7 – 2.0
0.483
Etiology:
Medications
Furosemide
1.4
0.8 – 2.4
0.205
Hazard ratio
95% confidence Interval
p value
Creatinine ≥ 1,4 mg/dL
2.0
1.3 – 3.0
0.002
Chagasic etiology
1.9
1.3 – 3.0
0.002
ACEI
0.6
0.4 – 0.9
0.040
Beta-blocker
0.3
0.2 – 0.5
< 0.001
Sodium ≤ 135 mEq/L
1.8
1.2 – 2.7
0.003
Predictor (multivariate analysis)
LVEF: left ventricular ejection fraction; SBP: systolic blood pressure; ACEI: angiotensin-converting enzyme inhibitor.
Therefore, the most intense neurohormonal blockade played
an important role in this increase in in-hospital survival.
Thus, although the mortality rate is still high, it is decreasing,
when one considers the data from the two periods at our
institution. It is noteworthy the fact that data from the
National Health System (SUS) do not show the occurrence of
the reduction we observed, but showing in fact, an increase
in mortality (5.41 % to 6.97 %) from 1992 to 2002, when
analyzing all hospitalizations for HF in Brazil2.
When comparing our rates with data from Europe and
the United States in different registries of HF, mortality in
our hospitals is higher in general. But much of this high
mortality is probably due to the greater severity of patients
admitted to our service. When comparing the characteristics
of hospitalized patients, this greater severity can be observed
among Brazilian patients.
For instance, when we compare our data with those
of the U.S. ADHERE registry, it can be seen that 74.9%
of hospitalized patients in our hospital had systolic
BP < 115 mm Hg, whereas in the ADHERE registry only
18.5% were hypotensive9. Low BP is an important prognostic
marker in several studies, including the ADHERE registry.
An important point to note is that, despite the higher
overall mortality rate of our patients, when we analyzed the
total number of more severe patients (BUN > 43 mg/dL,
BP < 115 mmHg and creatinine > 2.75 mg/dL), mortality
did not differ significantly, with our patient population
being numerically lower than that of the American study
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1.0
Beta-blocker: YES (35/197)
Probability of survival
0.8
0.6
Beta-blocker: NO (70/134)
0.4
0.2
0.0
Log-Rank (Chi-square) = 36.46 - p<0.001
0
100
200
300
Days
400
500
600
Figure 2 – Survival at 1 year of follow-up of patients hospitalized for decompensated heart failure, according to the use of beta-blockers: 73.9% vs. 35.0% (p <0.001).
1.0
Probability of survival
0.8
ACEI: YES (69/241)
0.6
ACEI: NO (36/90)
0.4
0.2
0.0
Log-Rank (Chi-square) = 5.59 - p = 0.018
0
100
200
300
Days
400
500
600
Figure 3 – Survival at 1 year of follow-up of patients hospitalized for decompensated heart failure according to the use of angiotensin-converting enzyme inhibitors:
59.5% vs. 41.8% (p = 0.018).
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Del Carlo et al.
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1.0
BB: YES, ACEI: YES (24/153)
Probability of survival
0.8
BB: YES, ACEI: NO (11/44)
0.6
BB: NO, ACEI: YES (48/88)
0.4
BB: NO, ACEI: NO (25/46)
0.2
0.0
Log-Rank (Chi-square) = 42.16 - p<0.001
0
100
200
300
400
500
600
Days
Figure 4 – Survival at 1 year of follow-up of patients hospitalized for heart failure, according to the combined use of beta-blockers (BB) and angiotensin-converting
enzyme inhibitors (ACEI). Patients were stratified into four groups according to the use of BB / ACEI: yes/yes, yes/no, no/yes, no/no. The probability of survival was,
respectively: 78.7%, 58.5%, 38.9% and 25.5% (p < 0.001).
(14.0% vs. 15.3%), suggesting that our treatment, in addition
to being adequate, have reduced the mortality a severe
group of patients9.
Even regarding hospitals in Brazil, although data are scarce,
we observed that mortality in our hospital, despite the greater
severity of our cases, was lower than that observed in these
other institutions. In Rio de Janeiro, among patients treated
at the emergency room of a private institution, the mortality
was 10.6% and, in Porto Alegre, a teaching hospital like ours,
it was 11%13,14. These differences in mortality are probably
due to selection criteria for admission and the period of data
collection, but the numbers are very similar to ours.
More significant, however, was the reduction in mortality at
the follow-up. We observed a reduction in mortality in the first
year of follow up, going from more than 50% to the current
23.6%, a relative reduction of approximately 50%. This result
was similar to that observed in Spain, where mortality in the
1991-1996 period was 24%, decreasing to 16% in 2000 and
200115. Improved prognosis was also reported in Baltimore
and Sweden, and in these studies, the authors reported that
this improvement occurred after the establishment of treatment
with ACEI and beta-blockers, but did not specifically analyze the
role of their prescriptions, different from our study16,17.
The year 2000 can be considered a watershed for the
treatment of chronic HF, as in 1999, two important studies
were published on beta blockers in HF, the MERIT-HF
and the CIBIS-II study, which reinforced the indication of
beta‑blockers for treatment of chronic HF18,19. We observed
this increase in the prescription in our hospital as, until 2000,
at the outpatient clinic, the prescription of beta‑blockers
reached about 10% of patients, increasing 70% in the 2004
assessment20. This increased prescription of beta‑blockers
unquestionably played a key role in improving the prognosis
of HF in our hospital.
At the univariate analysis of predictors of mortality, it can
be observed that the prescription of ACEI and beta-blockers
was associated with improved prognosis. Markers of increased
cardiac and systemic involvement, usually identified in studies
evaluating prognosis (renal and ventricular function) were
associated with a worse prognosis, as well as Chagas etiology.
In the multivariate analysis, ACEI and beta blockers persisted
as markers, with the latter having a greater impact.
In addition to the recording of the neurohormonal blockade
value promoting increased survival, this study also shows
that Chagas disease was accompanied by worse prognosis,
confirming the findings of other Brazilian studies21,22.
Study limitations
Although the analyzed groups (before and after 2000) are
not homogeneous (Table 2) due to the nature of this study
Arq Bras Cardiol. 2014; 102(5):495-504
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Del Carlo et al.
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(observational and retrospective), it is noteworthy the fact that,
although patients in the group after 2000 were more severe
(older mean age, lower LVEF and lower mean SBP), this group the most severe - was precisely the one that had the best clinical
outcomes at follow-up with lower mortality and lower rates
of re-hospitalization. One must consider that these results are
observational and that other factors such as improved treatment
adherence and cointerventions (e.g., cardiac surgery and
interventional procedures), after discharge, were not quantified
and may have influenced the improvement in prognosis, in
addition to the higher rate of prescription of neurohormonal
blockers, particularly beta‑blockers. It should be noted that a
possible selection bias was the fact that we performed analyses
of survival in little more than 50% of the study patients, of
which data regarding therapy used was available. Moreover,
regarding therapy, we performed the qualitative analysis, while
the quantitative analysis of the dose at discharge and at followup would be important to evaluate the influence of optimized
dose of these medications on patients' prognosis. However,
these issues could be addressed in future studies.
Conclusion
This study provided some evidence that, in the real world,
the survival of patients with heart failure has increased and
that treatment optimization with neurohormonal blockers
have had an important role in improving prognosis.
Author contributions
Conception and design of the research, Analysis and
interpretation of the data and Critical revision of the
manuscript for intellectual content: Del Carlo CH, Cardoso
JN, Ochia ME, Oliveira Jr. MT, Ramires JAF, Pereira-Barretto
AC; Acquisition of data: Del Carlo CH, Cardoso JN, Ochia ME,
Oliveira Jr. MT; Statistical analysis: Del Carlo CH; Writing of the
manuscript: Del Carlo CH, Ramires JAF, Pereira-Barretto AC.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Sources of Funding
There were no external funding sources for this study.
Study Association
This study is not associated with any post-graduation program.
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13. VillaCorta H, Mesquita ET, Cardoso R, Bonates T, Maia ER, Silva AC, et al.
Preditores de sobrevida obtidos na unidade de emergência em pacientes
atendidos por insuficiência cardíaca descompensada. Rev Port Cardiol.
2003;22(4):495-507.
14. Rohde LE, Clausell N, Ribeiro JP, Goldraich L, Netto R, William Dec GW, et al.
Heath outcomes in decompensated congestive heart failure: a comparison of
tertiary hospitals in Brazil and United States. Int J Cardiol. 2005;102(1):71-7.
7. Canesin MF, Giorgi D, Oliveira MT Jr, Wajngarten M, Mansur A, Ramires
JA, et al. Ambulatory blood pressure monitoring of patients with heart
failure: a new prognosis marker. Arq Bras Cardiol. 2002;78(1):83-9.
15. Grigorian Shamagian L, Gonzalez-Juanatey JR, Roman AV, Acuna JM, Lamela
AV. The death rate among hospitalized heart failure patients with normal and
depressed left ventricular ejection fraction in the year following discharge:
evolution over a 10-year period. Eur Heart J. 2005;26(21):2251-8.
8. Del Carlo CH, Pereira-Barretto AC, Cassaro-Strunz C, Latorre Mdo R,
Ramires JA. Serial measure of cardiac troponin T levels for prediction of
clinical events in decompensated heart failure. J Card Fail. 2004;10(1):43-8.
16. Feinglass J, Martin GJ, Lin E, Johnson MR, Gheorghiade M. Is heart failure
survival improving? Evidence from 2323 elederly patients hospitalized
between 1989-2000. Am Heart J. 2003;146(1):111-4.
9. Fonarow GC, Adams KJ Jr, Abraham WT, Yancy CW, Boscardin WJ;
ADHERE Scientific advisory committee, study group and investigators. Risk
stratification for in-hospital mortality in acutely decompensated heart failure:
classification and regression tree analysis. JAMA. 2005;293(5):572-80.
17. Schaufelberger M, Swedberg K, Koster M, Rosen M, Rosengren A.
Decreasing one-year mortality and hospitalization rates for heart failure in
Sweden. Data from Swedish Hospital discharge Registry 1988 to 2000. Eur
Heart J. 2004;25(4):300-7.
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Del Carlo et al.
Improvement in Heart Failure Prognosis
Original Article
18. The cardiac insufficiency bisoprolol study II (CIBIS-II): a randomized trial.
Lancet. 1999;353(9146):9-13.
19. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL
Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF).
Lancet. 1999;353(9169):2001-7.
20. Pereira-Barretto AC. Tratamento da insuficiência cardíaca crônica. In: Nobre
F, Serrano Jr CV. Tratado de cardiologia SOCESP. Barueri (São Paulo): Editora
Manole; 2009. p 1065-74.
21. Freitas HG, Chizzola PR, Paes AT, Lima AC, Mansur AJ. Risk stratification
in a Brazilian hospital-based cohort of 1220 outpatients with heart failure:
role of Chagas’ disease. Int J Cardiol. 2005;102(2):239-47.
22. Silva CP, Del Carlo CH, Oliveira Jr MT, Scipioni A, Strunz-Cassaro C, Ramires
JAF, et al. Porque o portadores de cardiomiopatia chagásica têm pior
evolução que os não chagásicos? Arq Bras Cardiol. 2008;91(6):389-94.
Arq Bras Cardiol. 2014; 102(5):495-504
504
Back to the Cover
Original Article
NHETS − Necropsy Heart Transplantation Study
Thiago Ninck Valette, Silvia Moreira Ayub-Ferreira, Luiz Alberto Benvenuti, Victor Sarli Issa, Fernando Bacal, Paulo
Roberto Chizzola, Germano Emilio Conceição Souza, Alfredo Inácio Fiorelli, Ronaldo Honorato Barros dos Santos,
Edimar Alcides Bocchi
Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (USP), São Paulo, SP – Brazil
Abstract
Background: Discrepancies between pre and post-mortem diagnoses are reported in the literature, ranging from 4.1 to
49.8 % in cases referred for necropsy, with important impact on patient treatment.
Objective: To analyze patients who died after cardiac transplantation and to compare the pre- and post-mortem diagnoses.
Methods: Perform a review of medical records and analyze clinical data, comorbidities, immunosuppression regimen,
laboratory tests, clinical cause of death and cause of death at the necropsy. Then, the clinical and necroscopic causes of
death of each patient were compared.
Results: 48 deaths undergoing necropsy were analyzed during 2000-2010; 29 (60.4 %) had concordant clinical and
necroscopic diagnoses, 16 (33.3%) had discordant diagnoses and three (6.3%) had unclear diagnoses. Among the
discordant ones, 15 (31.3%) had possible impact on survival and one (2.1%) had no impact on survival. The main clinical
misdiagnosis was infection, with five cases (26.7 % of discordant), followed by hyperacute rejection, with four cases (20 %
of the discordant ones), and pulmonary thromboembolism, with three cases (13.3% of discordant ones).
Conclusion: Discrepancies between clinical diagnosis and necroscopic findings are commonly found in cardiac
transplantation. New strategies to improve clinical diagnosis should be made, considering the results of the necropsy, to
improve the treatment of heart failure by heart transplantation. (Arq Bras Cardiol. 2014; 102(5):505-509)
Keywords: Heart Transplantation; Autopsy.
Introduction
The necroscopic examination has contributed to the
evolution of medical knowledge. However, the frequency at
which medical centers perform necropsies has been declining
in recent decades, in different series. The assumed reasons for
this phenomenon are diverse and include cultural aspects, lack
of authorization by families, lack of financial resources for the
procedure, an aging population and less interest in necropsy
findings in the elderly, a decrease in the scientific interest in
the necroscopic findings and hesitation facing the possibility
of medical error detection. Considering this historical trend,
discrepancies between pre and post-mortem diagnoses
continue to be reported, ranging from 4.1 to 49.8% of cases
referred for necroscopic examination1. A recent study did not
evaluate the diagnoses obtained through pre-mortem clinical
data with the necroscopic diagnoses of patients undergoing
cardiac transplantation.
This study aimed to assess patients who died after
cardiac transplantation and were submitted to necropsy,
Mailing Address: Thiago Ninck Valette •
Avenida Interlagos, 871, bloco 7, apto. 43, Jardim Marajoara. Postal Code
04661-100, São Paulo, SP – Brazil
E-mail: [email protected], [email protected]
Manuscript revised August 20, 2013, revised manuscript November 17,
2013, accepted November 18, 2013.
DOI: 10.5935/abc.20140039
505
analyzing the causes of death and comparing the pre- and
post-mortem diagnoses.
Methods
Retrospective study was carried out by analysis of medical
records of deaths from heart transplantation that were
submitted necropsy in the period 2000-2010. Clinical data
for analysis of comorbidities, immunosuppression regimen,
laboratory test results, clinical cause of death and cause of
death at the necropsy were collected.
The pre-mortem death diagnosis was compared with the
post-mortem one and then the discrepancies between the
two diagnoses were classified according to Goldman et al2
criteria adapted by Battle et al3, while some cases were not
classified4. The classification was as follows:
• Major discrepancies:
- class I: discrepancies in major diagnosis, with impact
on survival;
- class II: discrepancies in major diagnosis, with no impact
on survival;
• Minor discrepancies:
- class III: discrepancies in minor diagnoses not directly
related to cause of death;
- class IV: discrepancies in minor occult diagnoses (non-
Valette et al.
Necropsy in heart transplantation
Original Article
diagnosable), but with possible epidemiological or genetic
importance;
Table 1 - Clinical characteristics of studied patients
Characteristics
n = 48
• Non-discrepancy:
Age (years )
41 ± 16
- class V: non-discrepant diagnoses;
Male gender (%)
Follow-up after transplantation (days)
• Non-classifiable cases:
67
991 ± 1,728
Etiology (%)
- class VI: patients whose clinical or necroscopic diagnoses
cannot be performed adequately.
Deaths were also differentiated as early or late,
with early being those that occurred up to 1 year after
transplantation and late the ones that occurred after
12 months. Discrepancies were evaluated in these two
groups, verifying the causes of death.
This study was approved by the Research Ethics Committee.
It was not necessary to obtain the signed free and informed
consent, as this was a retrospective study based on the analysis
of medical records.
The study received financial support from Fundação
de Amparo à Pesquisa do Estado de São Paulo, process
#2010/12278-5.
Ischemic
14.6
Idiopathic
29.2
Hypertensive
2.1
Chagas disease
31.3
Others
13
Systemic Arterial Hypertension (%)
44
Diabetes mellitus (%)
18
Dyslipidemia (%)
31
Leukocytes
8,590 ± 4,972
Sodium (mEq/L)
136 ± 4
Creatinine (mg/dL)
1.9 ± 0.6
Urea (mg/dL)
79 ± 56
Potassium (mEq/L)
4.5 ± 0.6
Results
Hemoglobin (g/dL)
12.5 ± 2.17
From 2000 to 2010, 124 patients submitted to cardiac
transplantation died. Cardiac transplantation of the
124 patients occurred from February 1987 to March 2010.
Of these 124 patients, 48 were submitted to necropsy, which
comprise the study sample. Figure 1 shows the case selection
flowchart of the study.
Medications (%)
The mean age was 41 years and 67% were men. The mean
post-transplantation follow-up duration was 991 ± 1,728 days.
The most frequent etiology of the disease (before transplantation)
was chagasic heart disease. Regarding comorbidities, 44% of the
384 Heart transplantations from 02/1987 to 03/2010
139 alive
6 retransplantation
239 deaths
115 deaths before 2000
124 deaths from 2000-2010
76
Necropsies
Not permitted or
Non-authorized
48 Deaths with necropsy from
de 2000-2010
Figure 1 - Flowchart of case selection.
Cyclosporine
Tacrolimus
50
14.6
Mycophenolate mofetil
54
Corticosteroids
77
Azathioprine
29.2
Sirolimus
14.6
patients had hypertension, 31% dyslipidemia, and 18% diabetes
mellitus. Table 1 shows the general characteristics of the patients.
Of the 48 analyzed cases, 29 (60.4 %) had concordant
clinical and necroscopic diagnoses (class V), 16 (33.3 %)
had discordant diagnoses and three (6.3%) had an
unclear diagnosis (class VI). Among the discordant ones,
15 (31.3%) had possible impact on survival (class I) and
one (2.1%) had no impact on survival (class II). The main
clinical misdiagnosis was infection, with five cases (26.7%
of discordant ones), followed by hyperacute rejection,
with four cases (20% of discordant ones) and pulmonary
thromboembolism with three cases (13.3% of discordant
ones). Figure 2 shows the chart distribution of necropsies,
based on the classification of discrepancies. Figure 3 and
Table 2 compare the clinical and necroscopic diagnoses of
class I discordant cases.
A total of 62.5 % (30 cases) were classified as early
deaths and 37.5 % as late ones (18 cases). Among the
early cases, 56% were concordant with impact on survival
(class V), 33% discordant with impact on survival (class I),
Arq Bras Cardiol. 2014; 102(5):505-509
506
Valette et al.
Necropsy in heart transplantation
Original Article
Figure 2 - Distribution of discrepancies between clinical and necroscopic diagnoses.
3% discordant with no impact on survival (class II) and
6 % had unclear diagnoses (Class VI). Among the late, 67%
were concordant with impact on survival (class V), 28%
discordant with impact on survival (class I) and 5.6% had
unclear diagnoses (Class VI).
The causes of death verified at the necropsies were acute
graft dysfunction (22.9%), acute rejection (20.8 %), infection
(18.8%), Graft Vascular Disease (GVD-16.7%), other causes
(14.6%) and unknown causes (6.3%).
In the group classified as early death, 37 % of deaths
were due to acute graft dysfunction, 20% acute humoral
rejection, 16.7% septic shock, 16.7% from other causes,
and 6% of unknown causes.
In the late group, 45% of deaths were due to GVD, 17%
to acute cellular rejection, 11% to septic shock, 22% from
other causes and 5% of unknown causes.
Discussion
Our study showed a significant frequency of discrepancies
between clinical and necroscopic diagnoses of the cause
of death, most often with a possible impact on survival.
In the literature, no recent studies were found comparing
the clinical and necroscopic causes of death in patients
undergoing cardiac transplantation, making this work a
current tool for information analysis.
On the other hand, the rate of discordance in the present
sample, on average, was higher than that observed in
other series of patients unrelated to heart transplantation.
Discrepancies values of
​​ 7.5 to 23 %, classified as major, were
found in patients admitted to the intensive care unit, with
11-13% for minor discrepancies5,6. For patients admitted to
507
Arq Bras Cardiol. 2014; 102(5):505-509
general hospitals, there were 6-37 % of major discrepancies
and 25-28 % of minor ones7-9.
The most difficult necroscopic diagnosis to be clinically
hypothesized was acute graft dysfunction. In this series, it was
misdiagnosed as hyperacute rejection, hemorrhagic shock
and septic shock. These data show the difficulty to confirm
this diagnosis in clinical practice, as it depends on situations
related to the perioperative period (the donor’s conditions,
time of ischemia, myocardial protection and the recipient’s
prior pulmonary hypertension) and the degree of suspicion
of the attending physician, as there is no specific marker for
the diagnosis.
Another premortem unsuspected necroscopic diagnosis
was GVD. This was confused with other conditions that
lead to ventricular dysfunction with cellular rejection and
pulmonary thromboembolism. Although GVD is one of the
main late causes of post-transplantation death10 a dose of
clinical suspicion is also needed to initiate the appropriate
diagnostic method.
Finally, another common diagnostic error was acute
humoral rejection, which is known by its diagnostic difficulties,
requiring advanced immunohistological methods, such as
immunofluorescence and immunoperoxidase, in addition to
the fact that the patient needs to be capable of being submitted
to endomyocardial biopsy procedure.
Taking into account only the necroscopic cause of death,
the data from this study are similar to those in the literature11,12,
with emphasis on acute graft dysfunction, infection, rejection
and GVD. Separating the deaths in early and late cases, acute
graft dysfunction and GVD stood out, respectively.
Regarding the cause of cardiomyopathy that led to
transplantation, this sample differs from that found in the
Valette et al.
Necropsy in heart transplantation
Original Article
3
N
e
c
r
o
s
c
o
p
i
c
2
1
Humoral rejection
Acute graft dysfunction
Disseminated intravascular coagulation
Mixed shock
Pulmonary thromboembolism
Graft vascular disease
Multiple organ and system failure
Hemorrhagic shock
Pulmonary thromboembolism
Cardiogenic shock
Septic shock
Humoral rejection
Acute cell rejection
hyperacute rejection
0
d
i
a
g
n
o
s
i
s
Clinical diagnosis
Figure 3 - Comparison between clinical and necroscopic diagnoses of class I discordant cases.
Table 2 - Comparison between clinical and necroscopic diagnoses of class I discordant cases
Necroscopic Diagnosis
Clinical Diagnosis
HR
GVD
ACR
AHR
SS
CS
2
MOSF
1
1
1
MS
1
DIC
AHR
HS
1
PTE
AGD
PTE
1
3
1
2
1
HR: hyperacute rejection; ACR: acute cellular rejection; AHR: acute humoral rejection, SS: septic shock, CS: cardiogenic shock; PTE: pulmonary thromboembolism,
HS: Hemorrhagic shock; MOSF: multiple organ and system failure; GVD: graft vascular disease, MS: mixed shock, DIC: disseminated intravascular coagulation; AGD:
acute graft dysfunction.
Arq Bras Cardiol. 2014; 102(5):505-509
508
Valette et al.
Necropsy in heart transplantation
Original Article
International Society of Heart and Lung Transplantation Annual
Report, 2012. While the most prevalent etiology in this
study was Chagas’ disease, followed by idiopathic dilated
cardiomyopathy, the global data showed the most prevalent
etiology was idiopathic dilated cardiomyopathy (54 %),
followed by ischemic heart disease (37 %)10. This difference
is due to the prevalence of Chagas disease in our country,
unlike what occurs in Europe and North America.
Among the limitations of this study is sample size, which
reflects the decrease in the number of necropsies in recent
decades, as mentioned before. Consequently, only 38.7 % of
deaths between 2000 and 2010 were submitted to necropsy
and were included in the study, which may interfere with
the results.
Moreover, the analysis of records may not accurately
reveal the clinical cause of death, as factors such as
incomplete filling out of medical records and difficulties in
understanding older records, which were not yet electronic,
can interfere with the impression of the presumed clinical
cause of death.
considering necroscopic results to improve the treatment of
heart failure by heart transplantation.
Author contributions
Conception and design of the research: Ayub-Ferreira SM,
Bocchi EA; Acquisition of data: Valette TN, Ayub-Ferreira
SM, Benvenuti LA, Issa VS, Bacal F, Chizzola PR, Souza
GEC, Fiorelli AI, Santos RHB; Analysis and interpretation
of the data: Valette TN, Ayub-Ferreira SM, Benvenuti LA,
Issa VS, Bacal F, Chizzola PR, Souza GEC, Fiorelli AI, Santos
RHB; Statistical analysis: Ayub-Ferreira SM; Writing of the
manuscript: Valette TN; Critical revision of the manuscript
for intellectual content: Ayub-Ferreira SM, Benvenuti LA,
Bocchi EA; Supervision / as principal investigator: Bocchi EA.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Sources of Funding
Conclusion
This study was partially funded by FAPESP.
Discrepancies between clinical diagnosis and necroscopic
findings are commonly found in cardiac transplantation.
New strategies to improve clinical diagnosis should be made,
Study Association
This study is not associated with any thesis or dissertation work.
References
1. Shojania KG, Burton EC, McDonald KM, Goldman L. Changes in rates of
autopsy-detected diagnostic errors over time: a systematic review. JAMA.
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M. The value of the autopsy in three medical eras. N Engl J Med.
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3. Battle RM, Pathak D, Humble CG, Key CR, Vanatta PR, Hill RB, et al.
Factors influencing discrepancies between premortem and postmortem
diagnoses. JAMA. 1987;258(3):339-44.
4. Bellwald M. [Autopsies with unsatisfactory results]. Schweiz Med
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5. Mort TC, Yeston NS. The relationship of pre mortem diagnoses and
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correlation]. An Med Interna. 2000;17(9):460-4.
8. Kotovicz F, Mauad T, Saldiva PH. Clinico-pathological discrepancies
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2008;63(5):581-8.
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AI, et al; International Society of Heart and Lung Transplantation. The
Registry of the International Society for Heart and Lung Transplantation:
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2012;31(10):1052-64.
11. Alexander RT, Steenbergen C. Cause of death and sudden cardiac death after
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12. Zuppan CW, Wells LM, Kerstetter JC, Johnston JK, Bailey LL, Chinnock RE.
Cause of death in pediatric and infant heart transplant recipients: review of a
20-year, single-institution cohort. J Heart Lung Transplant. 2009;28(6):579-84.
Back to the Cover
Review Article
Systems Biology Applied to Heart Failure With Normal Ejection
Fraction
Evandro Tinoco Mesquita, Antonio Jose Lagoeiro Jorge, Celso Vale de Souza Junior, João Paulo Pedroza Cassino
Universidade Federal Fluminense, Niterói, RJ - Brazil
Abstract
Heart failure with normal ejection fraction (HFNEF) is
currently the most prevalent clinical phenotype of heart
failure. However, the treatments available have shown no
reduction in mortality so far. Advances in the omics sciences
and techniques of high data processing used in molecular
biology have enabled the development of an integrating
approach to HFNEF based on systems biology.
This study aimed at presenting a systems-biology-based
HFNEF model using the bottom-up and top-down approaches.
A literature search was conducted for studies published
between 1991 and 2013 regarding HFNEF pathophysiology,
its biomarkers and systems biology. A conceptual model was
developed using bottom-up and top-down approaches of
systems biology.
The use of systems-biology approaches for HFNEF,
a complex clinical syndrome, can be useful to better understand
its pathophysiology and to discover new therapeutic targets.
Introduction
Heart failure (HF) is a complex clinical syndrome, and the
final pathway of different forms of aggression to the cardiac
muscle. It manifests as two distinct phenotypes: HF with
reduced ejection fraction (HFREF) and HF with normal ejection
fraction (HFNEF).
The HFNEF prevalence has increased, so that HFNEF will
become the most prevalent phenotype of HF in this decade,
affecting mainly elderly individuals of the female sex with
multiple co-morbidities1. Its pathophysiology has been mainly
centered on the presence of left ventricular (LV) structural
and diastolic functional changes, which cause an increase
in LV filling pressures and intolerance to physical exertion2-4.
The results of different randomized clinical studies, using
drug treatment directed at improving diastolic function,
have shown neutral results regarding patients’ survival5-7.
The oslerian approach classically used to describe the
Keywords
Heart Failure; Stroke Volume; Ventricular Dysfunction,
Left; Aged.
Mailing Address: Antonio Jose Lagoeiro Jorge •
Rua Coronel Bittencourt, 66, Boa Vista. Postal Code: 24900-000,
Marica, RJ - Brasil
E-mail:[email protected] , [email protected]
Manuscript received june 26, 2013; revised manuscript september 24, 2013;
accepted september 26, 2013.
DOI: 10.5935/abc.20140062
510
mechanisms of disease, as well as the construction of the
reasoning that is the basis of treatment for HFNEF might
need to be replaced by a new approach that uses systems
biology, recently introduced into other areas of internal
medicine, such as infectology and oncology. That new
approach has led to the development of successful new drugs
in those areas, allowing the construction of the so-called
personalized medicine, which has propitiated the advance
of that concept. That is important mainly because HFNEF
is a cardiovascular syndrome with multiple abnormalities of
the pathophysiological pathways, which interact through a
complex network8-9.
This review was aimed at presenting recent concepts of
systems biology and its potential use in complex cardiovascular
diseases, such as HFNEF, a syndrome with multiple
pathophysiological abnormalities and still limited therapeutic
arsenal in the light of current knowledge.
HFNEF and its pathophysiological complexity
From the clinical and epidemiological viewpoints, compared
to patients with HFREF, those with the HFNEF phenotype are
usually older, more obese, of the female sex and have a history
of arterial hypertension and atrial fibrillation 1,10,11.
The diagnosis of HFNEF is currently made from a clinical
suspicion (intolerance to exercise) in association with the
following Doppler echocardiographic findings, by using
tissue Doppler: LV ejection fraction ≥ 50%; final LV indexed
diastolic volume < 97 mL/m²; and diastolic functional
abnormalities12,13.
Patients with HFNEF have shown different subcellular
abnormalities, such as changes in the extracellular matrix
with increased deposits of advanced glycation end-products,
collagen profile changes, sarcomeric protein titin isoform
switch and hypophosphorilation, increased inflammatory
response, and reduced SERCA2 pump activity14,15. The changes
observed at cellular level were apoptosis, cardiomyocyte
stiffness and hypertrophy, which might be responsible for
concentric remodeling, even in the absence of LV hypertrophy.
Macroscopically, LV hypertrophy and increased left atrial
volume are observed, characterizing the major structural
changes of patients with HFNEF. Finally, all changes lead
to disorder of the cardiovascular system, which, integrated
with other systems, will cause or aggravate multisystem
abnormalities known as co-morbidities14 (Figure 1).
Briefly, such structural and functional changes increase
the risk of LV diastolic dysfunction. Although patients with
HFNEF have LV ejection fraction values considered normal,
they have changes in systolic performance, which can be
assessed through different systolic function indices, such as
Mesquita et al.
Systems Biology and HFNEF
Review Article
LV contractility, systolic volume, cardiac output and axial
systolic shortening velocity (S’). Abnormality of relaxation
and increased ventricular stiffness lead to increased LV filling
pressures, which are diastolic dysfunction markers2.
Changes in arterial stiffness and endothelial function
are present in different degrees in individuals with HFNEF,
contributing to aggravate diastolic dysfunction, increasing
afterload and causing or intensifying myocardial ischemia.
In addition, abnormalities of the microcirculation can also
contribute to intolerance to exercise by hindering the perfusion
of skeletal and respiratory muscles, which has been studied
in individuals with HFNEF.
Mesquita et al. and Matsubara have provided a more
detailed discussion of the pathophysiology of HFNEF in
two recent reviews published in the Arquivos Brasileiros
de Cardiologia3,4.
Defining the systems-biology approach
The contemporary translational model of developing
scientific knowledge in the medical area has allowed the
large-scale use of new effective treatments for diseases. That
model, derived from the oslerian system, has established that
the presence of a certain disease should be defined as changes
in a tissue (anatomico-clinical correlation), from which its
pathophysiology can be pursued and a specific therapeutic
target developed16,17. Based on the advances of molecular
biology and using the oslerian view, the identification of
individual genes, proteins and cells has been sought, as well
as the study of their functions, providing limited information
on complex diseases.
Systems biology allows, through the construction of
mathematical models, simulations and data processing
techniques, the integration of information from the omics
sciences and clinical-epidemiological data, to provide better
understanding of the interactions between the components
of live systems and their biological processes18-20.
Systems biology has its roots in the formulation of the
internal environment stability principle by Claude Bernard
in 1865, and has gained quantitative formalism with the
mathematical description of the potential of action biophysics,
first delineated by Hodgkin and Huxley in nervous cells, and
soon after extended to the cardiac potential of action by
Denis Noble21. That approach has been applied in medicine
since before the molecular biology revolution. However, in
the pregenomic era, systems biology was naturally hindered
by the lack of technologies necessary to reach that integration
and by the inability to investigate such systems in details21.
However, in the past decades, scientific advances in the areas
of molecular biology, engineering, bioinformatics, and physics,
in association with the omics sciences (Table 1), enabled the
acquisition of more complete information with a greater
capacity to define more detailed approaches.
Systems biology, whose major characteristics are shown
in Table 2, can be understood as the interaction of different
biological systems activated at the molecular, cellular, tissular
and organic levels, which can be assessed by use of tools,
many of which available in clinical practice8,22.
Systems biology allows a new understanding of the concept of
disease, which can be defined as the lack of cooperation between
some of the biological parts in an organic system, resulting in
impairment of the entire functioning of the organism14.
Disfunção
ventricularVentricular
dysfunction
Piora doworse
relaxamento
relaxation
Piora stiffness
da rigidez
aggravation
Doença
Pulmonar
pulmonary
disease
ironiron
deficiency
ande
deficiency
Deficiência
de ferro
anemia
and
anemia
anemia
Disfunção
Atrial
atrial dysfunction
Disfunção
renaland
e
kidney
dysfunction
sobrecarga
de volume
volume overload
chronotropicAutonômica
incompetence
Disfunção
incompetênciacronotrópica
cronotrópica
Incompetência
vascularVascular
dysfunction
Disfunção
ICFEN
HFNEF
Idade , sexo e
age, sex and physical
Descondicionamento
unfitness
físico
vascular stiffness
Rigidez vascular
ventricular-arterial
coupling
Acoplamento
ventrículo
arterial
Obesidade e
obesity
and sarcopenia
sarcopenia
Hipertensão
pulmonar
pulmonary hypertension
endothelial
Disfunção dysfunction
Endotelial
Doença
valvular
heart
valve
disease
Depressão
depression
Figure 1 – HFNEF – pathophysiology and co-morbidities. HFNEF – Heart failure with normal ejection fraction.
Arq Bras Cardiol. 2014; 102(5):510-517
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Table 1 - Omics sciences
Genomics
Science that studies all genes, and analyzes their interactions and influences on biological pathways and networks.
Transcriptomics
Science that studies the phenomena involved in mRNA transcription. Through microarray technology, it accesses the expression
of thousands of transcribed genes and identifies gene patterns (molecular signature) that can be used as biomarkers for etiology
identification, prognostic assessment, and HF treatment.
Proteomics
Science that studies all proteins encoded in the genome; can be used to identify HF prior to the appearance of symptoms, therefore
increasing the chances of an earlier and more effective treatment.
Metabolomics
Science that studies the molecular metabolites found in cells, tissues and organs, identifying their regulatory effects on genes and
proteins. Used to identify biomarkers in HF.
Epigenomics
Science that studies the mechanisms capable of influencing the reading and interpreting of a chain of genes based on
environmental factors on the genome.
Microbiomics
Science that studies the genomes of microbes and their interactions in a certain ecosystem. It is worth noting the study on interactions of
intestinal bacteria and trimethylamine-N-oxide production, which propitiate the development of atherosclerosis.
HF: heart failure.
Table 2 - Major characteristics of Systems Biology
• Studies biological systems globally, at molecular level;
• Distinguishes from the classical linear theory: one gene, one protein;
• Integrates knowledge from different disciplines;
• Proposes mathematical models to explain some biological phenomena;
• Manipulates a large amount of data from experimental studies;
• Performs studies that verify the quality of the models described by comparing numerical simulations and experimental data.
According to that concept of disease, two study approaches
can be identified: the bottom-up approach, aimed at defining
the specificities that compose a structure, enumerating elements
and identifying their individual characteristics to obtain an image
of the point to be studied; and the top-down approach, which
does not need to provide details of the network components,
but to understand the general principles of the network to better
understand it and to guide the identification of unpredicted
elements. Similarly, the bottom-up approach could be
compared to a ‘link the dots’ image, in which the real picture
can only be revealed when each dot is duly recognized and
linked to the others. The top-down approach can be understood
as an impressionist painting, which, when seen from a short
distance, does not allow us to identify the whole picture; it has
to be seen from a distance, with a more comprehensive view,
not requiring excessive details to reveal the image completely.
Combining both characteristics, the knowledge on the system
analyzed is amplified, allowing the identification of new
proposals and pathways14,19.
The network concept is aimed at providing a structure
in which its forming and functional components interact in
a self-organized biological network. The networks, rather
than the components themselves, create the physiological
behavior and disease. Each knot in a network represents a
component (a gene, a protein), and the interconnection of
the components describes the typical architecture imposed
by biological selection and evolution21 (Figure 2).
Working with networks simplifies complex systems,
synthesizing the elements as knots and their interactions as
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Arq Bras Cardiol. 2014; 102(5):510-517
lines between them, and identifies functional groups as module.
Many of those biological networks have a topology described
as scale-free, in which knots with few connections have
priority; when linked to knots that have an elevated number of
connections, those are called hubs (Figure 2). That architecture
provides a biologically strong evolutionary advantage,
considering that there are multiple alternative pathways to
go from one knot to the other. In addition, that ‘redundancy’
enables the networks to more easily adapt to environmental
changes. At each level, the network obtains new properties not
previewed in the preceding levels, demonstrating the concept
of emergent property8,18. Failure of the biological networks or
incapacity to obtain emergent property at the following level
causes disruptions in the physiological mechanisms, generating
complex pathological phenotypes.
The network approach might allow a change of paradigm
in HF treatment, because, instead of trying to adapt different
patients to one single treatment (reductionism), it is aimed at
directing the treatment profile at the different patients based
on their individual networks (personalized medicine)23.
The development of that approach is usually centered on a
molecular target. However, in complex human diseases, that
target is neither easily identified nor directed by one single factor23.
Recent analyses have shown that a large number of
traditional medications do not reach target proteins, but only
proteins of the neighboring networks, which can be a reason
for the modest effects obtained when some drugs are used for
patients with HFNEF8.
Mesquita et al.
Systems Biology and HFNEF
Review Article
Hub
knot
line (interaction)
Figure 2 – Overview of a biological network. Adapted from Chan SY, Loscalzo J. The emerging paradigm of network medicine in the study of human disease. Circulation
Res. 2012 Jul 20;111(3):359-74.
In contrast, a new pharmacology based on biological
systems begins to develop aimed at creating new drugs
that can be directed at one or more targets involved in the
pathophysiological processes of the most relevant networks.
That approach begins to be used in cancer and HIV/AIDS, and
can become useful for HFNEF, making a new view of HFNEF
under the systems biology perspective critical8.
An HFNEF model using the systems-biology approach
The HFNEF is obviously a complex syndrome, whose
pathophysiology and progression remain unclear, which makes
the construction of a network model for HFNEF potentially
useful and challenging in the current state of knowledge.
The heart involves different structural and functional
hierarchic scales, which, through multiple interactions of
subsystems, allow normal heart to achieve uniformity despite
its structural and functional complexities at different levels24
(Figure 3). That approach has identified different structural
and functional abnormalities of the heart in humans and
other animals7.
From the mechanistic viewpoint, HFNEF can be defined
as a complex condition, thus requiring an approach that
encompasses the current concepts of systems biology.
The analysis of omic data is crucial for understanding the
factors involved in HFNEF and for identifying biomarkers
with diagnostic and prognostic properties for clinical use5.
By using the systems-biology approach and integrating
different abnormalities observed in HFNEF, we propose
a model that combines environmental and genetic factors,
cardiac and vascular morphofunctional changes, abnormalities
in other systems, and interaction with different co-morbidities,
developing a holistic view of that syndrome and integrating the
bottom-up and top-down methodologies (Figure 4).
The HFNEF results from systemic diseases, such as
hypertension, diabetes, obesity and coronary artery disease,
in association with the female sexual dimorphism. In addition,
the aging process influences different cellular and subcellular
pathways, promoting functional and structural abnormalities
in the heart and great vessels. Recently, abnormalities in
the protein folding process have been observed during the
abnormal aging of the heart, and can contribute to HFNEF,
a phenomenon called “Alzheimer’s of the heart”.
In addition, experimental evidence has shown that,
in the heart of elderly rats, a reduction in the growth
differentiation factor 11 (GDF11), which modulates the
ligand-receptor activity in cardiomyocytes, contributes to
cardiac hypertrophy and to the decreased SERCA2 functional
activity, also causing an elevation in B-type natriuretic
peptide (BNP) levels. However, when GDF11 levels are
restored, a reduction in cardiac hypertrophy and an increase
in the SERCA2 pump activity are observed, with consequent
restoration of diastolic heart function25.
Eventually those abnormalities cause intolerance to
physical exertion, systemic and/or pulmonary congestion,
tissue hypoperfusion and cardiac arrhythmias, such as atrial
fibrillation, leading to HF signs and symptoms26.
Another important concept influenced by the systems
biology paradigm is that of the biomarker, considered
a clinical status indicator that can be obtained from the
integration of multiple biological activity levels in the network.
That approach is responsible for guiding the identification of
the biomarker based on deep understanding of its biological
Arq Bras Cardiol. 2014; 102(5):510-517
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Systems Biology and HFNEF
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systemic level
uniformity
tissue hypoperfusion
intolerance to exertion
volume overload
communication
between cells
through
non-uniformity
emergent
property
vascular stiffness
concentric remodeling
organic level
emergent
property
tissue level
hypertrophy
cardiomyocyte
stiffness
emergent
property
cell
level
emergent
sarcomeric protein
TIMPS
IL-6
mRNA
titin
SERCA 2A
collagen
crossbridges
property
interaction
ion flow
sarcoplasmic reticulum
genomics proteomics transcriptomics metabolomics
epigenomics
Figure 3 – Model of the left ventricle as a dissipative structure with emergent properties. Adapted from De Keulenaer GW, Brutsaert DL. Systolic and diastolic heart failure
are overlapping phenotypes within the heart failure spectrum. Circulation.2011;123(18):1996-2004.
mechanism. The BNP, released in the presence of increased
intraventricular pressure, is used for diagnostic confirmation
and prognosis in HFNEF, and, more recently, has shown
therapeutic usefulness in HFREF18.
Other biomarkers that assess fibrosis, inflammation and
necrosis have been studied in HFNEF. Current strategies using
micro RNA have shown promise to better characterize patients
with HFNEF. In addition, the use of multiple biomarkers in
clinical research has introduced an approach similar to that
of a system, and can significantly contribute to prognostic
assessment and therapeutic response in HFNEF27.
Understanding the pathophysiological abnormalities in
multiple pathways in HFNEF has led to the development of
new drugs directed at more than one pathway identified as
critical to HFNEF. The LCZ696 is a dual-acting angiotensin
receptor-neprilysin inhibitor composed of a neprilysin inhibitor
prodrug, AHU 377, and the angiotensin receptor antagonist
valsartan. Neprilysin degrades biologically active natriuretic
peptides, such as atrial natriuretic peptide (ANP), BNP, and
C-type natriuretic peptide, but not NT-pro-BNP, which is
biologically inactive. By increasing active natriuretic peptides,
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Arq Bras Cardiol. 2014; 102(5):510-517
neprilysin inhibitor increases the myocardial generation of
cyclic guanosine, which enhances myocardial relaxation
and reduces hypertrophy. In addition, natriuretic peptides
stimulate natriuresis, diuresis and vasodilation, and can
have an additional anti-fibrotic and anti-sympathetic effect.
Furthermore, neprilysin contributes to angiotensin collapse,
which is the rationale for the dual action of the compound,
which inhibits that enzyme and blocks angiotensin action or
generation28 (Figure 5).
The LCZ696 has been tested in patients with HFNEF
(PARAMOUNT Study – phase 2) and has shown a more
marked reduction in NT-pro-BNP than that caused by the
isolated valsartan use. In addition, LCZ696 was better than
valsartan to promote left atrial reverse remodeling and to
improve those patients’ functional class28.
Briefly, HF understanding from the systems-biology
perspective is still limited by the difficulty to integrate data from
that complex information system into a biopathological model,
mainly because of the several variables that interfere with the
existing relationships, such as the genetic variations of each
individual and the environmental influence on organisms8.
Mesquita et al.
Systems Biology and HFNEF
Figure 4 – Schematic model of a biological network for HFNEF.
Review Article
Arq Bras Cardiol. 2014; 102(5):510-517
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Systems Biology and HFNEF
Review Article
natriuretic peptide system
heart failure
renin-angiotensin system
angiotensinogen
(liver secretion)
pro-BNP
angiotensin I
BNP
NT-pro-BNP
LCZ696
angiotensin II
neprilysin
inactive
fragments
AT1 receptor
vasodilation
↓ blood pressure
↓ sympathetic tone
↓ aldosterone level
↓ fibrosis
↓ hypertrophy
natriuresis / diuresis
Valsartan
AHU377
↓
LBQ657
vasoconstriction
↑ blood pressure
↑ sympathetic tone
↑ aldosterone level
↑ fibrosis
↑ hypertrophy
Figure 5 – Mechanisms of action of the new drug LCZ696 that inhibits neprilysin and blocks the angiotensin receptor. Solomon SD, Zile M, Pieske B, et al; Prospective
comparison of ARNI with ARB on Management Of heart failure with preserved ejection fraction (PARAMOUNT) Investigators.Lancet;2012;380:1387-95.
Conclusion
Author contributions
The systems-biology approach in HFNEF is at an
initial stage and can offer the possibility to widen the
knowledge on pathophysiology, to refine the diagnosis
and to lead to the development of new biomarkers and
therapeutic targets.
Conception and design of the research: Mesquita ET;
Writing of the manuscript: Mesquita ET, Jorge AJL, Souza
Junior CV, Cassino JPP; Critical revision of the manuscript for
intellectual content: Mesquita ET, Jorge AJL.
Currently, the combination of a reductionist view with a
holistic view is still necessary to better understand HFNEF,
which involves a network of complex interactions between
biological entities in different scales.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Sources of Funding
There were no external funding sources for this study.
Thus, the complex pathophysiology of HFNEF and
the lack of a treatment capable of reducing its impact on
mortality make it the ideal cardiovascular condition for a new
approach using systems biology, allowing the development
of future therapeutic targets.
Study Association
This study is not associated with any thesis or dissertation work.
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Chan SY, Loscalzo J. The emerging paradigm of network medicine in the study
of human disease. Circ Res. 2012;111(3):359-74.
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failure with preserved ejection fraction in a population-based study. N Engl
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11. Redfield MM, Jacobsen SJ, Burnett Jr JC, Mahoney DW, Bailey KR, Rodeheffer
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12. Paulus WJ, Tschope C, Sanderson JE, Rusconi C, Flachskampf FA,
Rademakers FE, et al. How to diagnose diastolic heart failure: a
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Associations of the European Society of Cardiology. Eur Heart J.
2007;28(20):2539-50.
13. Tschope C, Kasner M, Westermann D, Gaub R, Poller WC, Schultheiss HP.
The role of NT-proBNP in the diagnostics of isolated diastolic dysfunction:
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2005;26(21):2277-84.
14. Louridas GE, Lourida KG. A conceptual paradigm of heart failure and
systems biology approach. Int J Cardiol. 2012;159(1):5-13.
15. Borbély A, Papp Z, Edes I, Paulus WJ. Molecular determinants of heart
failure with normal left ventricular ejection fraction. Pharmacol Rep.
2009;61(1):139-45.
16. Norman G. Medical education: past, present and future. Perspect Med
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17. Chen R, Snyder M. Systems biology: personalized medicine for the future?
Curr Opin Pharmacol. 2012;12(5):623-8.
18. Lusis AJ, Weiss JN. Cardiovascular networks: systems-based approaches
to cardiovascular disease. Circulation. 2010;121(1):157-70.
19. Barabasi AL, Gulbahce N, Loscalzo J. Network medicine: a network-based
approach to human disease. Nat Rev Genet. 2011;12(1):56-68.
20. Maclellan WR, Wang Y, Lusis, AJ.Systems-based approaches to
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22. De Keulenaer GW, Brutsaert DL. Systolic and diastolic heart failure are
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2011;123(18):1996-2004.
23. Voora D, Ginsburg GS. Clinical application of cardiovascular
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Yalamanchi P, et al. Growth differentiation factor 11 is a circulating factor
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27. Azuaje FJ, Dewey FE, Brutsaert DL, Devaux Y, Ashley EA, Wagner DR.
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al; Prospective comparison of ARNI with ARB on Management Of heart
failUre with preserved ejectioN fracTion (PARAMOUNT) Investigators.
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preserved ejection fraction: a phase 2 double-blind randomised controlled
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Arq Bras Cardiol. 2014; 102(5):510-517
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Back to the Cover
Letter to the Editor
Obesity and Abnormalities in Echocardiographic Parameters
Roberta Casanova Wilhelms, Eduardo Maffini da Rosa, Mauricio Lizott, Raphael Martin de Melo
Universidade de Caxias do Sul – UCS, Caxias do Sul, RS - Brazil
Dear Editor,
We congratulate the authors of the manuscript published
under the title “The Impact of Isolated Obesity on Right
Ventricular Function in Young Adults”1. We believe that
the hemodynamic changes that characterize obesity could
modify the echocardiographic parameters found abnormal
in this study, that is, increased volemia would readjust the
parameters of ventricular function without any concomitant
changes in ventricular function. What is the authors’ opinion
about this analysis?2.
Keywords
Obesity; Echocardiography.
Mailing Address: Roberta Casanova Wilhelms •
Rua Humberto de Campos, 1113, Cristo Redentor. Postal Code: 95084-440,
Caxias do Sul, RS - Brazil
E-mail: [email protected], [email protected]
Manuscript received October 13, 2013; revised manuscript October 16,
2013; accepted November 29, 2013.
DOI: 10.5935/abc.20140059
References
1. Sokmen A, Sokmen G, Acar G, Akcay A, Koroglu S, Koleoglu M, et al. The
impact of isolated obesity on right ventricular function in young adults. Arq
Bras Cardiol. 2013;101(2):160-8.
518
2. Schusterova I, Jurko A, Minarik M. Left ventricular systolic and diastolic
function in children with overweight and obesity. Bratisl Lek Listy.
2013;114(9):526-30.
Back to the Cover
Letter to the Editor
Extracellular Matrix Turnover: a Balance between MMPs and their
Inhibitors
Emre Yalcinkaya1, Murat Celik2, Baris Bugan3
Aksaz Military Hospital - Departamento de Cardiologia1, Mugla, Turquia; Gulhane Military Medical Faculty - Departamento de Cardiologia2,
Ankara, Turquia; Malatya Military Hospital - Departamento de Cardiologia3, Malatya, Turkey
To the Editor,
We read with great interest the article by Santos et
al 1, entitled “Early Change of Extracellular Matrix and
Diastolic Parameters in Metabolic Syndrome”, which was
published in october of Arquivos Brasileiros de Cardiologia.
The authors1 aimed to compare diastolic function, biomarkers
representing extracellular matrix activity (MMP9 and TIMP1),
inflammation and cardiac hemodynamic stress in patients
with the metabolic syndrome and healthy controls. We thank
authors for their excellent data and valuable study but some
comments may be of beneficial.
Matrix metalloproteinases (MMPs) play major roles in
tissue development, matrix collagen turnover, repair and
remodeling2-5. The TIMPs are usually secreted together with
Keywords
Matrix Metalloproteinase 1; Matrix metalloproteinase
inhibitors; Metabolic X Syndrome; Extracellular matrix.
variable amounts of their MMPs and regulate MMPs’ proteolytic
activities by binding tightly to their catalytic sites2.
Extracellular matrix (ECM) turnover is largely modulated by
the interaction between MMPs and their TIMPs.2-5A correlation
and reciprocal influences between MMP and their TIMP
determines the combined effect on ECM turnover4,5.
Expression patterns of MMP9 andTIMP1 (a specific
inhibitor of MMP9), are closely correlated with physiological,
pathological and micro - environmental processes
characterized by the degradation and accumulation of
the ECM 3. A balance between MMP9 and TIMP1 is a
major parameter in regulating both the enzyme activation
and functionality in the tissue3-5. Consequently, MMP9/
TIMP1 ratio could be viewed as a more reliable, useful and
determinative marker in the evaluation of their potential
prognostic capacities compared with MMP9 and TIMP1
separately. Determining the changes in the ECM balance and
activity with a more appropriate method could give a chance
to observe the influences on the results more precisely.
Mailing Address: EmreYalcinkaya •
Aksaz Military Hospital Department of Cardiology; Aksaz Asker Hastanesi,
Kardiyoloji Bolumu, 48750, Aksaz/Marmaris/Mugla, Turkey
Email: [email protected]
Manuscript received December 13, 2013; revised manuscript January 7,
2014; accepted January 7, 2014.
DOI: 10.5935/abc.20140061
References
1. Santos AB, Junges M, Silvello D, Macari A, Araújo BS, Seligman BG, et al.
Early change of extracellular matrix and diastolic parameters in metabolic
syndrome. Arq Bras Cardiol. 2013;101(4):311-6.
4. Cogni AL, Farah E, Minicucci MF, Azevedo PS, Okoshi K, Matsubara BB,
et al. Metalloproteinases-2 and -9 predict left ventricular remodeling after
myocardial infarction. Arq Bras Cardiol. 2013;100(4):315-21.
2. Roderfeld M, Graf J, Giese B, Salguero-Palacios R, Tschuschner A, MüllerNewen G, et al. Latent MMP-9 is bound to TIMP-1 before secretion. Biol
Chem. 2007;388(11):1227-34.
5.
3.Avădanei R, Căruntu ID, Amălinei C, Lozneanu L, Balan R, Grigoraş A, et al.
High variability in MMP2/TIMP2 and MMP9/TIMP1 expression in secondary
liver tumors. Rom J Morphol Embryol. 2013;54(3):479-85.
519
Kim Y, Remacle AG, Chernov AV, Liu H, Shubayev I, Lai C, et al. The MMP-9/
TIMP-1 axis controls the status of differentiation and function of myelinforming Schwann cells in nerve regeneration. PLoS One. 2012;7(3):e33664.
Yalcinkaya et al.
Determination of an extracellular matrix turnover
Letter to the Editor
Reply
We appreciate the thoughtful and valuable comments. It is
currently known that the balance between metalloproteinase
(MMP) and their tissue inhibitors (TIMP) partly regulates
the myocardial extracellular matrix homeostasis.
The commenters suggested that the description of the
MMP/TIMP ratio would provide additional information
about degradation and modulation of collagen synthesis.i,ii.
This could be inferred from our previous analysis where
patients with Metabolic Syndrome (MS) had higher levels of
MMP9 compared to healthy controls, despite similar levels
of TIMP1.iii We primarily opted to show these biomarkers
individually providing a more comprehensive description
of the scenario, considering the individual response and
interplay between these biomarkers.
Performing the suggested analysis, the MMP9/TIMP1 ratio
was higher in MS compared to controls (2.4 ± 1.1 in MS vs.
1.5± 0.6 in control group, p < 0.001), reflecting the original
findings. Additionally, in multivariate analysis, higher MMP9/
TIMP1 remained associated with MS (p = 0.006), independently
of the remaining relevant covariates. The higher MMP9/TIMP1
ratio reinforces the concept that an increased turnover of collagen
is associated with MS even in this young population. Whether
changes in MMP9 individually or in MMP9/TIMP1 ratio have
prognostic value in MS remains to be determined.
Arq Bras Cardiol. 2014; 102(5):519-520
520
Back to the Cover
Erratum
Edition of September 2013, vol. 101 (3), Suppl. 3, page 1-93
The “Brazilian Guidelines on Antiplatelet Agents and Anticoagulants in Cardiology,” published as supplement number three
to the September 2013 edition of the Arquivos Brasileiros de Cardiologia [Arq Bras Cardiol. 2013;101 (3Suppl.3):1-93], was
fixed as follows:
On page 17, Table 2, change the Class of recommendation of “Exchange of heparins (UFH and enoxaparin)” to III.
On page 31, Table 5, last line, consider correct the wording “In situations of CHADSVasc zero or up to 1 (if it is only by the
female sex), the non-use of oral anticoagulation (such as rivaroxaban) may be considered,” Class of recommendation: II and
Level of evidence: A.
On page 47, table 13, consider as correct the wording “Indications”: “Treatment of acute and chronic VTE at a dose
of 15 mg twice a day in the first 21 days followed by 20 mg once a day for 3, 6, or 12 months or for a longer time at the
physician’s discretion.”
Edition of December 2013, vol. 101 (6), Suppl. 3, page 1-63
In “I Brazilian Guidelines on Cardiovascular Prevention”, consider Izar MC as the correct form for the name of the author
Maria Cristina de Oliveira Izar.
DOI: 10.5935/abc.2013S009e
521
Back to the Cover
Anatomopathological Session
Case 2/2014 – 51-Year Old Patient with Systemic Lupus
Erythematosus and Fever after Valve Replacement
Wilma Noia Ribeiro, Alice Tatsuko Yamada, Paulo Sampaio Gutierrez
Instituto do Coração (InCor), HC-FMUSP, São Paulo, SP – Brazil
A 51-year old female patient presented with precordial
pain and dyspnea at moderate exertion, being diagnosed with
severe aortic stenosis, with indication for surgical treatment.
The patient had arterial hypertension, mixed dyslipidemia,
was a smoker and had systemic lupus erythematosus, which
initiated at the age of 16, as well as nephritis. She reported
anemia and seizures, which were attributed to lupus. In the
past months, she had presented with pleuritic precordial pain,
which became worse in the decubitus position and improved
at the sitting position, which was attributed to pericarditis.
The physical examination (25/10/2011) revealed the
patient had good general status, was hydrated, eupneic,
with 60 bpm heart rate, and 110 x 70 mmHg blood
pressure. Pulmonary auscultation was normal, and cardiac
auscultation revealed rhythmic sounds, hypophonesis of the
aortic component of the second sound and systolic murmur
++++/6+. The abdominal examination was normal, with
no edema, and wrists were symmetric.
ECG (31/10/2011) revealed sinus rhythm, 48 bpm heart
rate, 200 ms PR interval, 113 ms QRS duration, 464 ms QT,
disorder in the intraventricular conduction of the stimulus, and
changes in ventricular repolarization (Figure 1).
Laboratory examinations (24/10/2011) revealed;
hemoglobin, 7 g/dL; hematocrit level, 21%; MCV, 95 fL;
leukocytes, 6,940/mm3 (72% neutrophils, 1% eosinophils,
1% basophils, 22% lymphocytes, and 4% monocytes);
platelets, 303,000/mm 3 ; urea, 62 mg/dL; creatinine,
1.21 mg/dL (glomerular filtration, 50 mL/min/1.73m 2);
AST, 36 UI/L; ALT, 42 UI/L; calcium, 4.3 mEq/L;
magnesium, 2.30 mEq/L; total protein, 7.4 g/dL; lactate
dehydrogenase, 447 U/L; sodium, 138 mEq/L; and
potassium, 4.7 mEq/L; PT (INR), 1.1; TTPA (rel), 0.99;
total cholesterol, 301 mg/dL; HDL-c, 46 mg/dL; LDL-c,
169 mg/dL; and triglycerides, 378 mg/dL.
Keywords
Systemic lupus erythematosus; Hypertension; Dyslipidemia;
Aortic valve stenosis / surgery.
Section editor: Alfredo José Mansur ([email protected])
Associated editors: Desidério Favarato ([email protected])
Vera Demarchi Aiello ([email protected])
Mailing Address: Vera Demarchi Aiello •
Avenida Dr. Enéas de Carvalho Aguiar, 44, subsolo, bloco I, Cerqueira César.
Postal Code 05403-000, São Paulo, SP – Brazil
E-mail: [email protected], [email protected]
DOI: 10.5935/abc.20140069
e44
The echocardiogram (26/10/2011) showed left atrium of
40 mm, aorta of 32 mm, septum of 16 mm, posterior wall of
15 mm, left ventricle of 50/32 mm (diastole/systole), ejection
fraction of 65%, left ventricle with normal dimensions and
severe hypertrophy; mitral valve with discrete thickening,
with a 3.7 cm 2 valve area; aortic valve with severe
calcification, 0.5 cm2 valve area; maximal systolic gradient
of 138 mmHg, mean gradient of 83 mmHg; the relationship
between the velocity of the exit path of the left ventricle and
the aortic valve was of 0.14 (severe stenosis when <0,25);
there was discrete pericardial stroke.
The patient received transfusion of red cell concentrate.
High digestive endoscopy (3/11/2011) revealed mild antral
gastritis and erosive duodenitis.
Cardiac catheterization and cinecoronariography
(7/11/2011) showed severe calcification of the aortic and
coronary valves; there was a 70% lesion in the medium third
of the right coronary and irregularities in the other coronaries.
The consulted rheumatologist indicated pulse therapy with
1 mg/kg of methylprednisolone for nine days due to probable
lupus activity, and, afterwards, 40 mg of daily prednisone
were maintained.
The patient was submitted to surgery for aortic valve
replacement by bovine pericardial bioprosthesis and
myocardial revascularization with right aortocoronary
saphenous graft (23/11/2011). At the end of the surgery, she
presented with bradycardia and severe hypotension, and
needed to use an epicardial pacemaker to revert the picture.
Decreasing doses of vasoactive drugs were necessary
to control hypotension, and examinations on the third
post‑operative day (26/11/2011) showed hemoglobin levels at
7.2 g/dL; hematocrit, 23%; leukocytes, 13,900/mm2, with 92%
of neutrophils, 122,000/mm3 of platelets, urea of 71 mg/dL,
creatinine of 1.4 mg/dL, sodium of 143 mEq/L, and potassium
of 3 mEq/L.
The patient was delusional and with pulmonary
congestion. Antibiotic therapy was initiated with tazobactam
and piperacillin, and, two days later, vancomycin was added.
The symptoms of delirium and pulmonary congestion
improved, and she was discharged from cardiac recovery
on the seventh post-operative day.
Hemocultures and urocultures were negative (29/11/2011).
ECG (30/11/2011) revealed sinus rhythm and inactive
septal area (Figure 2).
A new laboratory evaluation (5/12/2011) revealed
hemoglobin levels at 8.8 g/dL; hematocrits, 28%; leukocytes,
9,240/mm 3 ; platelets, 34,800/mm 3 ; urea, 50 mg/dL;
creatinine, 2.92 mg/dL; sodium, 139 mEq/L; potassium,
3.6 mEq/L; PCR, 97 mg/L.
Ribeiro et al.
Correlação AnatomoclínicaAnatomoclinical correlation
Anatomopathological Session
Figure 1 – Electrocardiogram - Sinus bradycardia, intraventricular conduction disorder and ST-T segment changes.
Figure 2 – Eletrocardiogram - Sinus rhythm, septal inactive area, ST-T segment changes.
A new echocardiogram (5/12/2011) revealed aorta of
37 mm, left atrium of 41 mm, right ventricle of 25 mm,
septum of 13 mm, left atrium of 41 mm, left ventricle of 53/41,
ejection fraction of 35%. There was severe hypertrophy in the
left ventricle, apical akinesis of the other walls and atypical
movements of the interventricular septum. The prosthesis was
normofunctional, with maximal gradient of 19 mmHg and
mean gradient of 12 mmHg, and the relationship of velocities
of exit path LV/aortic prosthesis was of 0.43.
Uroculture (7/12/2012) was negative.
Laboratory examinations (9/12/2011) revealed: hemoglobin
levels at 7.8 g/dL; hematrocrit, 25%; MCV, 100 fL; leukocytes,
9,040/mm3 (bands, 1%; segmented, 76%; lymphocytes, 21%;
and monocytes, 2%); platelets, 330,000/mm3; urea, 60 mg/dL;
creatinine, 2.48 mg/dL (FG = 22 mL/min/1.73 m2); sodium,
138 mEq/L; potassium, 3.8 mEq/L; PCR, 91.5 mg/L; PT (INR),
1.0; and TTPA rel, 1.11.
The patient was discharged with a prescription for
hydralazine, carvedilol, furosemide, prednisone, chloroquine,
atorvastatin, ferrous sulfate, folic acid, ASA.
The physical examination at hospital discharge showed
serous secretion in the scar from the saphenous vein stripping
in the left lower limb.
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Anatomopathological Session
The patient was readmitted on 20/1/2012 (about one
month after hospital discharge) due to an infection in
the surgery wound from the saphenous vein stripping.
Hemocultures were positive for multi sensitive Enterococcus
sp, and the patient received intravenous ampicillin for 14 days.
The transesophageal echocardiogram (24/1/2012) revealed
aorta of 35 mm, left atrium of 41mm, right ventricle of 28 mm,
septum of 13 mm, posterior wall of 12 mm, left ventricle
of 53 mm, and ejection fraction of 35%. The left ventricle
was hypertrophic, and presented apical akinesis and diffuse
hypokinesis; the aortic prosthesis was normofunctional, with
no changes, with maximal gradient of 22 mmHg and mean
gradient of 12 mmHg. The other valves were normal.
Thoracic tomography (20/1/2012) did not show signs of
mediastinitis, osteomyelitis or pneumonia.
The left lower extremity Doppler was negative for deep
vein thrombosis (27/1/2012).
The patient was discharged from the hospital on 3/2/2012,
and the lower limb infection was considered as healed, and
the wound would be healed by second intention.
The prescribed medications were: 100 mg ASA, 50 mg
carvedilol, 100 mg losartan, 25 mg spironolactone, 20 mg
atorvastatin, 20 mg omeprazole, 20 mg prednisone, 400 mg
hydroxychloroquine, 5 mg folic acid, 120 mg ferrous sulfate
per day.
In a doctor’s appointment (28/3/2012), the patient
complained of asthenia, and prednisone increased to 60 mg;
the administration of ivermectin was added.
Thoracic radiography (in March, 2012) – Figures 3 and 4
– revealed cardiomegaly +++/4+ and free lungs.
The left lower extremity Doppler was negative for deep
vein thrombosis (17/4/2012).
Three months later, she came to the emergency room of
the hospital in shock, with 40 bpm heart rate and inaudible
pressure, so the use of vasoactive amines and orotracheal
intubation were necessary for respiratory support.
Laboratory examinations (on May, 8) revealed: erythrocytes,
1,900,000/mm3; blood cell count, 5.8 g/dL; hematocrits, 19%;
reticulocyte, 12.1%; MCV, 100 fL; leukocytes, 12,500/mm3
(bands, 15%; segmented, 79%; lymphocytes, 5%; monocytes,
1%); sodium, 139 mEq/L; potassium, 4.5 mEq/L; calcium,
4 mEq/L; ionized calcium, 1.16; magnesium, 1.8 mEq/L; arterial
lactate, 14 mg/dL; PT (INR) 1; TTPA (rel) 0.76; ALT, 57 U/L; AST,
26 U/L; gamma-GT, 153 U/L; lactate dehydrogenase, 560 U/L;
total bilirubin, 0.35 mg/dL; right bilirubin, 0;10 mg/dL; urine I,
normal. Arterial gasometry showed: pH, 7;46; CO2p, 32 mmHg;
O2p, 104 mmHg; O2 saturation, 97.5%; bicarbonate, 22.2 mEq/L;
and base excess (-) 1.1 mEq/L.ENTRAM FIGURAS 3 E 4
Echocardiogram (8/5/2012) showed aorta of 37 mm,
left atrium of 43 mm, septum of 13 mm, posterior wall
of 11 mm, left ventricle of 51/39 mm, ejection fraction of
50%, and moderate hypertrophy of the left ventricle and
apical akinesis. The aortic graft presented thickened leaflets,
minimum central regurgitation, and maximal transvalvular
gradient was 58 mm Hg, mean gradient was 39 mm Hg; the
other valves were normal.
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Arq Bras Cardiol. 2014; 102(5):e44-e51
Some hours later, the patient presented cardiac arrest
caused by ventricular fibrillation. After recovery, there were
three more cardiac arrests with pulseless electrical activity,
which were reversed. Afterwards, there was a new cardiac
arrest with irreversible pulseless electrical activity, and the
patient passed away (8/5/2012).
Clinical aspects
The clinical case reports a 51-year old patient with
systemic lupus erythematosus, arterial hypertension and
mixed dyslipidemia, who went to the emergency room with
fever and in shock.
The systemic lupus erythematosus (SLE) is an autoimmune
inflammatory disease, which is characterized by the immune
complex deposition in the involved organs, including the
heart. Its clinical picture is determined by periods of
exacerbations and remission, with variable clinical course
and prognosis.
It affects around 20-150 per 100,000 inhabitants, being
mostly prevalent among women (8:1) and black people; 65%
of the patients present with symptoms between the ages of
16 and 65 years old. In the reported clinical case, there is
a patient who first presented the clinical picture with lupus
nephritis at the age of 16, which is in accordance with findings
in literature1.
Even though kidneys are classically the organs that are
mostly affected by SLE, the heart and the heart/lung circulation
can also be significantly affected2. This disease can have an
impact on the heart by means of several manifestations,
which include arrhythmia and conduction disorders,
pericardiopathies, myocardiopathies and coronariopathy.
These manifestations can be simultaneous and should
be rapidly recognized in order to establish the proper
immunosuppression combined with specific cardiology
therapy. The clinical recognition of cardiovascular aggression
can be difficult due to the common existence of multiple
clinical problems in patients with lupus, such as infections
and renal insufficiency.
The pathogenesis of the heart disease in systemic lupus
erythematosus is not clear yet. The model that is traditionally
considered for the pathogenesis of lupus carditis is very
similar to that of other sites affected by lupus, so it is believed
that the immune complex deposition and the activation of
the complement would lead to acute, chronic or recurring
inflammation in the vascular endothelium, pericardium,
myocardium, endocardium, conduction system and valve
leaflets, which can be supported by the common finding of
immune complexes, complement and antinuclear antibodies
in the affected tissues3.
Pericarditis is the most common cardiac manifestation,
which is clinically present in up to 25% of the patients. Series of
autopsies and imaging methods demonstrated the pericardial
involvement in more than 60% of the patients2. It can occur
as an initial manifestation of SLE, or at any point of the course
of the disease, as was the case of the mentioned patient, or it
can be a complication from chronic kidney disease.
Ribeiro et al.
Correlação AnatomoclínicaAnatomoclinical correlation
Anatomopathological Session
Figure 3 – Chest x-ray (postero-anterior view)- Metallic sutures in the sternum, normal lungs and enlarged heart image.
Figure 4 – Chest x-ray (lateral view)- Metallic sutures in the sternum, prosthetic valvar ring.
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Anatomopathological Session
Clinical picture is usually typical, and it can be manifested
by fever, tachycardia, substernal pain (which is aggravated
by the act of breathing, coughing or bending over), and
by the presence of pericardial friction at auscultation; the
electrocardiographic evaluation, with peaked T waves and
increasing ST segment, usually does not differ from other
causes of pericarditis3.
The patient was submitted to myocardial revascularization
and valve replacement, in November, 2011, and on the third
post-operative day, she presented with a suggestive picture
of decompensated heart failure with clinical signs of low
cardiac output associated with pulmonary congestion. Clinical
measures were taken to compensate the picture, including the
use of antibiotics, with clinical progress.
Despite the young age presented by most patients with
lupus, atherosclerosis remains as the most common cause
of ischemic heart disease. In these patients, it is possible
to observe the occurrence of accelerated atherosclerosis
associated with the presence of its habitual risk factors,
which makes this disease an independent risk factor for the
cardiovascular disease, as well as rheumatoid arthritis4.
The main differential diagnoses for the clinical picture of
the patient were infectious process, myocardial ischemia and
lupus myocarditis.
It presents coronariopathy prevalence of up to 10%,
and eight times more chances in relation to the general
population4. Some studies suggest that the acute myocardial
infarction can be the cause of death in up to 25% of the
cases, especially among patients who have had the disease for
longer. The risk of this complication can be 52 times higher
in relation to the population that is free of disease, when the
time of disease evolution is longer than five years4.
In the reported case, the patient presented not only SLE, but
also other risk factors that contributed with the development
of coronary artery disease: systemic arterial hypertension,
smoking and mixed dyslipidemia.
Additional causes of acute coronary syndromes in the
SLE include thrombosis – usually correlated to the presence
of antiphospholipid antibodies –, embolism resulting from
nonbacterial vegetative endocarditis (Liebman-Sacks), and
coronary arteritis.
The myocardial dysfunction of SLE is usually multifactorial,
and it can result from immunological lesion, ischemia, valve
disease or coexisting problems, such as systemic arterial
hypertension. The clinically evident acute myocarditis is not
common, and it can present itself by the presence of thoracic
pain and tachycardia, being disproportional to the presence
of fever. Clinical signs and symptoms of cardiac insufficiency
are uncommon, being present in only 5-10% of the patients5.
Arrhythmia and conduction disorders can occur in
the course of the disease, usually concomitantly to other
cardiac manifestations, such as pericarditis, myocarditis
and coronary ischemia6.
Sinus tachycardia is the most common manifestation, being
present in approximately 50% of the cases7. In this case, the
patient presented with sinus bradycardia, with prolonged
QT interval of 464 ms. The expected corrected QT interval
for that patient would be of less than 415 ms. According to
Okin et al8, the presence of this finding can be a predictive
of morbidity and mortality.
Valve involvement is common, being demonstrated
in transesophageal studies in more than 50% of the
patients with LSE9. Valve thickening is the most common
echographic finding, followed by vegetation and valve
insufficiency. Even though the severity of valve compromise
is usually mild and asymptomatic, in this clinical case we
observed severe valvular stenosis.
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The hypothesis of infection should be considered because
the patient was in the post-operative period and had SLE,
cardiopathy and nephropathy, and such conditions made her
more prone to infections. The absence of fever and negative
cultures made this diagnosis less likely.
Another diagnostic hypothesis to be considered in this
context is coronary ischemia, since the patient had already had
a previous coronary disease. Besides, the electrocardiogram
and the echocardiogram presented new segmental changes,
septal inactive area, and septal akinesis, respectively. In this
case, thromboembolic ischemic events and/or coronary
arteritis cannot be ruled out.
It is usually difficult to tell coronary arteritis from accelerated
atherosclerosis. In cinecoronariography, arteritis is suggested
when we find coronary aneurysms, focal lesions or ones that
develop rapidly, which could have been the case of the patient
assessed in this clinical case10.
Based on the presented case, the factor that apparently
triggered the clinical picture of the patient was lupus
myocarditis, since the patient presented with new ventricular
systolic dysfunction. The improved ventricular function shown
in the echocardiogram conducted in May, 2012, seemed to
corroborate this diagnosis, after the immunosuppressive
therapy began, in the appointment of March, 2012.
The diagnosis of lupus myocarditis is usually difficult,
since it normally progresses to mild and little symptomatic
myocardial dysfunction, and mainly due to the concomitance
of other factors that are potentially responsible for
myocardial damage, such as ischemia, anemia, and
secondary water retention to renal disease or to the use
of corticosteroids.
On 8/5/2012, the patient was in shock and presented with
bradycardia. Clinical measures to compensate the clinical
picture were initiated, including the use of vasoactive amines
and respiratory support. However, the patient had clinical
worsening and cardiorespiratory arrest on this same day.
The main differential diagnoses for the final clinical picture
were cardiogenic shock, hypovolemic shock and septic shock,
to be discussed afterwards.
The hypothesis of cardiogenic shock caused by myocardial
ischemia should be considered. This diagnosis is less likely
because, in the echocardiogram conducted in May, 2012, no
segmental changes were observed. In fact, it was possible to
observe improvements in ventricular function, in relation to the
echocardiogram performed in January, 2012. This improved
cardiac performance can be attributed to the optimized
treatment of lupus cardiomyopathy.
Ribeiro et al.
Correlação AnatomoclínicaAnatomoclinical correlation
Anatomopathological Session
This echocardiogram also detected moderate aortic
stenosis. Some level of valve dysfunction could also be
present in the immediate post-operative period, as a result
of the sub-stenosing graft implanted in a patient with a
small caliber aorta, which, in this patient, was masked by
the moderate ventricular dysfunction that occurred in the
post-operative period. Another factor that could justify
aortic stenosis would be a thrombotic process, especially
if the patient had antiphospholipid antibodies and not
under full anticoagulation. Another hypothesis is the one
of hypovolemic shock due to hemorrhage. Even though
the patient did not present exteriorization of bleeding, we
observed important decrease in hemoglobin levels (from
7.8 to 5.8). The high levels of reticulocytes associated with
low levels of bilirubin makes the peripheral destruction of
erythrocytes less likely as a causative factor for this anemia.
For the presented case, the factor that apparently was the
main trigger of the final clinical picture of this patient was
infectious, which is corroborated by the increasing count
of young neutrophils and by the reported fever, which was
mentioned in the beginning of the clinical case.
Among all possible focuses for this septic scenario, we
cannot rule out the hypothesis of acute infective endocarditis.
Infective endocarditis is the infectious process of the cardiac
endothelium, which can affect any cardiac structure:
septal defects, tendinous cords, mural endocardium and
intracavitary and arteriovenous shunts. However, these are
the most commonly involved cardiac valves, especially the
mitral (40%) and the aortic valve (34%)11.
Currently, for the diagnosis, modified Duke criteria
are used, which are based on clinical, laboratory and
echocardiographic findings 11 . The transesophageal
echocardiogram became the method of choice to visualize
vegetation, especially at the presence of degenerated and
calcified valves or mechanical prosthesis. Therefore, in
the patient of this clinical case, the absence of vegetation
at the transthoracic echocardiogram does not rule out
that diagnosis.
In spite of the advancements in clinical diagnosis, of
the advent of new antibiotics and the improvement of
surgical techniques, bacterial endocarditis still presents
high morbimortality, and its prognosis depends on
the etiological agent and on cardiac status before the
infectious picture 12 (Dr. Wilma Noia Ribeiro, Dr. Alice
Tatsuko Yamada).
Diagnostic hypotheses
Syndromic diagnosis: congestive heart failure; etiology:
lúpus cardiomyopathy; final event: septic shock (Dr. Wilma
Noia Ribeiro, Dr. Alice Tatsuko Yamada).
Necropsy
The patient had two diseases: atherosclerosis and lupus
erythematosus.
Atherosclerosis was mild in the aorta, moderate in the
branches of the left coronary, and reaching 70% levels of
obstruction in the right coronary artery, therefore being
submitted to revascularization with saphenous vein
interposition graft. At necropsy, the graft was obstructed in the
ostium and fibrosed, which means the premature closure after
surgery. In spite of that, there was no significant myocardial
ischemia injury, only areas of non-abundant myocardial
sclerosis, compatible with what usually occurs at the presence
of myocardial hypertrophy due to ay cause.
The lupus diagnosis is based on clinical and laboratory
data. Under the morphological focus, several aspects can be
attributed to the disease, and there is nothing characteristic
enough to allow the diagnosis. Therefore, the surgically
replaced valve had non-specific chronic valvulitis (Figure 5),
which could also have had another cause, such as rheumatic
disease, for example.
Necropsy showed the existence of bacterial endocarditis,
caused by Gram-positive cocci that affected the aortic valve
prosthesis and the ring around it (Figures 6 and 7), as well as
abundant abdominal bleeding, which was the final responsible
for the death of the patient.
In other organs, the most relevant finding was segmental
and focal glomerulopathy (Dr. Paulo Sampaio Gutierrez).
Main disease: bacterial endocarditis in biological aortic valve
prosthesis. Baseline disease: systemic lupus erythematosus
with aortic valvulopathy and arterial hypertension. Secondary
disease: coronary atherosclerosis. Causa mortis: abdominal
hemorrhage (Dr. Paulo Sampaio Gutierrez).
Comment
The cause of hemorrhage was not determined: nothing
was found in the arterial territory that is normally examined
during necropsies; possibly, there could be a downstream
lesion, in the circulatory tree. By considering the existence
of endocarditis, the main possibility is the occurrence of
secondary arteritis (mycotic aneurysm). Another possibility is
that the vascular lesion could be iatrogenic, since a catheter
passed through that region, but at hospital admission the
patient presented aggravation of previous anemia and certain
level of abdominal distension.
Segmental and focal glomerulopathy are usually a result
of immune complex deposition; in this case, it can be a
consequence both of lupus and endocarditis.
Even with necropsy, it was not clear why the patient
presented worsened cardiac function after surgery.
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Figure 5 – Histological cut of native aortic valve removed in surgery. It is possible to observe non-specific chronic valvulitis with calcification points. Hematoxylin and
eosin staining method; 5x objective lens.
Figure 6 – Left ventricular outflow tract and aortic root with aortic valve prosthesis of biological material partially detached. It is possible to observe the presence of
inflammatory tissue, both in the prosthesis (blue arrow) and in the ring around it (red arrow). It is also possible to see the occlusion in the ostium of the right aortocoronary
saphenous graft (white arrow).
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Figure 7 – Panel of histological cuts of the aortic valve ring (A and B) and of the vegetation in the aortic prosthesis (C and D), both with bacterial endocarditis. In A
and C, little enlargement (objective magnification: 5x), with general view of the inflammatory process, including fibrin deposition (F). In B, more enlargement (objective
enlargement: 20x), showing inflammatory infiltrate with prevalence of polymorphonuclear neutrophils. D, staining showing, in purple, the presence of Gram-positive
cocci (Brown and Hopps stain, objective magnification: 40x). A, B and C: hematoxylin and eosin staining method.
References
1. Shur PH, Hahn BH. Epidemiology and pathogenesis ofsystemic lupus
erythematosus. Up to date. [Internet] 2010 Jun 16. [Acessao do em 2010
out 25/10/.]. Disponível em: http://www.uptodate.com
2. Doria A, Iaccarino L, Sarzi-Puttini P, Atzeni F, Turriel 3. M, Petri M. Cardiac
involvement in systemic lupus erythematosus. Lupus. 2005; 14(9):683-6.
8. Okin PM, Devereux RB, Howard BV, Fabsitz RR, Lee ET, Welty TK.
Assessment of QT interval and QT dispersion for prediction of all-cause
and cardiovascular mortality in American Indians: The Strong Heart Study.
Circulation. 2000; 101(1):61-6.
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Falcão CA, Lucena N, lves IC, Pessoa AL, Godoi ET. Cardite lúpica. Arq Bras
Cardiol. 2000; 74(1):55-63.
9. Roldan CA, Crawford MH. Connective tissue diseases and the heart. In:
Crawford MH (ed). Current diagnosis & treatment in cardiology. Rio de
Janeiro: Prentice Hall do Brasil; 1995. p. 428-47.
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Simão AF, Precoma DB, Andrade JP, Correa Filho H, Saraiva JF, Oliveira GM,
et al; Sociedade Brasileira de Cardiologia. I Diretriz brasileira de prevenção
cardiovascular. Arq Bras Cardiol. 2013;101(6 supl 2):1-52.
10. Petri M. Cardiovascular systemic lupus erythematosus, systemic lupus
erythematosus. In: Lahita RG (ed). Systemic lupus erithematosus.
Amsterdam: Elsevier Academic Press; 2004. p. 913-42.Elsevier. 2004; ..
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Law WG, Thong BY, Lian TY, Kong KO, Chng HH. 5. Acute lupus myocarditis:
clinical features and outcome of an oriental case series. Lupus. 2005;
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Cardoso CR, Sales MA, Papi JA, Salles GF. QT-interval parameters are increased
in systemic lupus erythematosus patients. Lupus. 2005; 14(10):846-52.
11. Anguera IJM, Cabell CH, Chen AY, Stafford JA, Corey GR, et al;
International Collaboration on Endocarditis Merged Database Study
Group. Staphylococcus aureus native valve infective endocarditis: report of
566 episodes from the International Collaboration on Endocarditis Merged
Database. Clin Infect Dis. 2005; 41(4):507-14.
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Hejtmancik MR, Wright JC, Quint R, Jennings FL. The cardiovascular
manifestations of systemic lupus erythematosus. Am Heart J. 1964; 68:119-30.
12. Mansur AJ, Grinberg M, Galluci SD, Bellotti G, Jatene A, Pileggi F. Infective
endocarditis: analysis of 300 episodes. Arq Bras Cardiol. 1990;54(1):13-21.
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Back to the Cover
Case Report
Prolonged Cardiopulmonary Arrest Treated Successfully in the São
Paulo’s Subway
Renan Gianotto-Oliveira, Maria Helena Favarato, Maria Margarita Gonzalez, Thiago Liguori, Sergio Timerman,
Roberto Kalil Filho
Instituto do Coração - Hospital das Clínicas - Faculdade de Medicina - Universidade de São Paulo, São Paulo, SP - Brazil
Introduction
In Br a z i l , ci r c ul at o r y d i s e ase s, i n c l u d i n g CPA
(Cardiopulmonary Arrests), were the leading cause of death
in 20101. Estimates are that, in Brazil, around 220,000 CPAs
happen every year, including ventricular fibrillation, 180,000
in pre-hospital environment and 40,000 in-hospital2.
Recent observational studies of victims of CPA in extra‑hospital
environment revealed that only CCC (Continuous Chest
Compressions) – hands-only CPR – were equivalent or higher
than conventional CPR (Cardiopulmonary Resuscitation) (using a
30:2 ratio of compressions/ventilations) in adult patients, mainly
with regard to neurological benefits3-5.
We present a case of PCA occurred in Companhia do
Metropolitano de São Paulo (São Paulo’s Subway) attended
by lay rescuers who performed CCC and applied shocks by
means of AED (Automatic External Defibrillator).
Case Report
Man, 55, Japanese origin, trader, with a history of
hypertension. He was in one of the São Paulo’s Subway
stations when he felt sharp and constant pain in chest,
accompanied by dizziness and progressing to loss of
consciousness. The users triggered the subway employees
(laypersons trained in CPR) who identified the CPA and
started to assist him. They requested the AED and started
applying CCC immediately. In two minutes, the AED was
in place, with paddles applied to the chest of the victim.
The rhythm (ventricular fibrillation) was analyzed and shock
was indicated in less than 20 seconds. Chest compressions
were immediately resumed and the AED showed four shocks
over 8 minutes, all of them followed by CCC. After the fifth
shock, the victim was breathing again, though unconscious,
and defibrillation was no longer indicated in subsequent
analyzes. Assessing the AED reading after the last shock,
Keywords
Out-of-Hospital Cardiac Arrest; Ventricular Fibrillation;
Cardiopulmonary Resuscitation; Heart Massage; Electric
Countershock.
Mailing Address: Renan Gianotto-Oliveira •
Laboratório de Simulação em Emerg. Cardiovasculares (LTSEC) - Av. Dr. Enéas
de Carvalho Aguiar, 44 - 2º andar, Postal Code 05403-900, São Paulo, SP - Brazil
E-mail: [email protected]
Manuscript received June 02, 2013; revised manuscript August 20, 2013;
accepted August 20, 2013.
DOI: 10.5935/abc.20140058
e52
the patient evolved into sinus rhythm, which is the reason
why no more shocks were indicated (Figure 1). Rescuers
alternated at each two minutes of CCC. With the arrival
of SAMU (Emergency Mobile Healthcare Service), tracheal
intubation, medications and special care were administered.
The victim was sent to a secondary hospital, admitted
unconscious in sinus rhythm with a heart rate of 130 bpm,
blood pressure of 160 x 100 mmHg, respiratory rate of
16 rpm, and isochoric and reactive pupils, presenting
vesicular murmur, flaccid abdomen on palpation and
Glasgow of level 6. The acute myocardial infarction was
confirmed by ST segment elevation in lower leads and
elevation of troponin and CKMB. The patient underwent
thrombolytic therapy with streptokinase, under myocardial
reperfusion criteria. During hospitalization, he acquired
pneumonia associated with mechanical ventilation. He was
discharged after 19 days without neurological sequelae. After
one year, the patient was asymptomatic, with active life and
undergoing outpatient follow-up.
Discussion
The most common CPA rhythm in extra-hospital environment
is the fibrillation6. The probability of success in resuscitation
decreases significantly over time, from 7 to 10% by minute in
which defibrillation is delayed6,7. The performance of chest
compressions increases the time for effective defibrillation.
Needless to say that training laypersons on CPR skills and
structuring mobile emergency services is crucial for the approach
and, although the response time of emergency services is critical
to a successful resuscitation, the laypersons training in CPR and
handling of AED boost the success possibilities6-8.
Globally, the percentage of lay witnesses who initiate
CPR ranges from 20 to 70%, averaging 50%. The lowest
percentages are usually associated with delayed onset of
resuscitation and a worse prognosis, whereas the early
initiation of chest compressions results in higher number of
hospital admissions and up to three times higher hospital
discharges with survival6-9.
New international recommendations allow the practice of
CPR with CCC, without ventilation, in certain circumstances.
This practice has been called cardiocerebral resuscitation4.
It indicates that the quick start of CPR and early defibrillation
are associated with better neurological prognosis4,7,9.
Based on animal studies, the concept that the addition of
ventilations to compressions, made by witnesses, does not
increase the survival of ventricular fibrillation or myocardial
infarction has been increasingly accepted. Clinical studies in
humans have also shown the efficacy of CCC7-9.
Gianotto-Oliveira et al.
Cardiopulmonary Arrest in the São Paulo’s Subway
Case Report
Figure 1 - Application of five automated external defibrillator shocks followed by return of sinus rhythm and tachycardia.
Regarding the characteristics of training , CPR only
with compressions is associated with greater knowledge
retention and greater willingness of laypersons to perform
it. Furthermore, regardless of the cause and duration of
CPA and the availability of AED on site, CPR with CCC is
better than no CPR7-9.
In São Paulo’s Subway, staff is trained at least every two
years in resuscitation skills attending a standardized course
of AHA (American Heart Association), with practical training
on mannequins and handling of AED. During training, only
CCC is practiced without pauses for ventilation, according
to international guidelines. Systematic training is necessary,
as studies show that a larger number of courses and the short
time interval between them are predictors for obtaining
rapid and early compressions, thus improving the patient’s
prognosis. Public awareness programs should also be on
the agenda of public policies for reducing mortality from
sudden cardiac death6.
Another link in the chain of the survival of out-of-hospital
cardiac CPA is the easy access to AED by the rescuer.
The early defibrillation, before the arrival of the emergency
service, should be a priority6,10. The early defibrillation
with use of AED can improve the prognosis of patients,
including higher survival and better neurological between
survivors. The use of AED is extremely simple, and a trained
layperson can perform the defibrillation procedure with
the same fitness and safety of a healthcare professional.
Since 1991, AHA has encouraged the provision of easily
accessible AEDs in public places, in addition to courses on
CPR and on using AED10.
According to large population studies, PAD (Public Access
to Defibrillation), putting AEDs at the disposal of laymen
trained in its use, has the potential to be the intervention
which represents the greatest breakthrough in the treatment
of CPA in ventricular fibrillation, since the development of
CPR, as it allows the victims to be defibrillated within the
first minutes of CPA10. There is evidence that the handling
of AEDs, within PAD programs, may double the survival of
victims compared to access to SAMU. The early defibrillation
provided by PAD is still associated to better neurological
prognosis6,10. The Brazilian precedents is gradually evolving to
establish that the said devices be mandatory in several places.
Arq Bras Cardiol. 2014; 102(5):e48-e50
e53
Gianotto-Oliveira et al.
Cardiopulmonary Arrest in the São Paulo’s Subway
Case Report
In conclusion, as exemplified in this case, the implementation
of programs of access to defibrillation, in concert with
laypersons’ training in CPR with CCC and in the use of AED
actually contributes to reducing mortality and improves the
neurological prognosis in out-of-hospital CPA. Programs like
this should be mandatory in our country, especially in the
coming years, when Brazil will host major events, such as the
FIFA World Cup and the Olympics.
MH, Gonzalez MM; Critical revision of the manuscript for
intellectual content: Timerman S, Kalil Filho R.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Sources of Funding
Author contributions
There were no external funding sources for this study.
Conception and design of the research: Gianotto-Oliveira
R, Liguori T; Acquisition of data: Gianotto-Oliveira R, Gonzalez
MM; Analysis and interpretation of the data: Favarato MH;
Writing of the manuscript: Gianotto-Oliveira R, Favarato
Study Association
This study is not associated with any thesis or dissertation work.
References
1. Ministério da Saúde. Datasus: Indicadores de mortalidade: mortalidade
proporcional por grupos de causas. [Acesso em 2012 Jan 22]. Disponível
em: http://tabnet.datasus.gov.br/cgi/ tabcgi.exe?idb2010/c04.def
2. Canesin MF, Timerman S, Nazima W. Treinamento em emergências
cardiovasculares avançado da Sociedade Brasileira de Cardiologia. Barueri
(SP): Manole; 2013.
3.
Bohm K, Rosenqvist M, Herlitz J, Hollenberg J, Svensson L. Survival is similar after
standard treatment and chest compression only in out-of-hospital bystander
cardiopulmonary resuscitation. Circulation. 2007;116(25):2908-12.
4. Kern KB, Timerman S, Gonzalez MM, Ramires JA. Optimized approach in
cardiocerebral resuscitation. Arq Bras Cardiol. 2011;96(4):e77-80.
5.
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Sayre MS, Berg RA, Cave DM, Page RL, Potts J, White RD, et al. Hands-only
(compression-only) cardiopulmonary resuscitation: a call to action for bystander
response to adults who experience out-of-hospital sudden cardiac arrest: a
science advisory for the public from the American Heart Association Emergency
Cardiovascular Care Committee. Circulation. 2008;117(16):2162-7.
Arq Bras Cardiol. 2014; 102(5):e48-e50
6. Sasaki M, Iwami T, Kitamura T, Nomoto S, Nishiyama C, Sakai T, et. al.
Incidence and outcome of out-of-hospital cardiac arrest with public
access defibrillation- a descriptive epidemiological study in a large urban
community. Circ J. 2011;75(12):2821-6.
7. Ewy GA, Sanders AB. Alternative approach to improving survival of
patients with out-of-hospital primary cardiac arrest. J Am Coll Cardiol.
2013;61(2):113-8.
8.
Iwami Y, Kitamura T, Kawamura T, Mitamura H, Nagao K, Takayama M, et. al;
Japanese Circulation Society Resuscitation Science Study (JCS-ReSS) Group.
Chest compression only cardiopulmonary resuscitation for out-of-hospital
cardiac arrest with public-access defibrillation: a nationwide cohort study.
Circulation. 2012:126(24):2844-51.
9. Lee K. Cardiopulmonary resuscitation: new concept. Tuberc Respir Dis
(Seoul). 2012;72(5):401-8.
10. Atkins DL. Realistic expectations for public access defibrillation programs.
Curr Opin Crit Care. 2010;16(3):191-5.
Back to the Cover
Viewpoint
Is Heart Team Fundamental to Aortic Stenosis Transcatheter Treatment?
Vitor Emer Egypto Rosa, Antônio Sergio de Santis Andrade Lopes, Tarso Augusto Duenhas Accorsi, Pedro Alves
Lemos Neto, Pablo Maria Alberto Pomerantzeff, Flávio Tarasoutchi
Instituto do Coração - InCor – HC FMUSP, São Paulo, SP - Brazil
Demographic projections have shown that the contingent
of elderly people in Brazil will double within the next
20 years1, with a consequent increase in the prevalence
of aging-related diseases, such as degenerative aortic valve
stenosis (AoS), diagnosed in 3% to 5% of the population
older than 75 yeas2,3. New modalities of treatment for AoS
have been recently developed, mainly represented by
the transcatheter implantation of aortic prosthesis (TAVI –
Transcatheter Aortic Valve Implantation), which has become
a therapeutic option for patients whose conventional
surgical treatment is not feasible. In the current scenario,
characterized by the high demand of the increasing elderly
population, the availability of new treatment methods
provides clinical expertise for the accurate diagnosis of heart
valve disease, assessment of the comorbidities and risks of
interventions, in addition to the rationalization of resources,
considering the complexity and high costs involved in TAVI.
Clinical practice has shown that the adequate selection
of the best therapeutic method for high surgical-risk
AoS requires multidisciplinary medical interaction,
contemplating all the patients’ biopsychosocial characteristics.
Thus, several medical centers have continuously incorporated
the ‘Heart Team’ concept for decision-making. The Heart
Team, a group composed by different specialists involved
in managing heart valve disease, gathers opinions for the
individualized analysis of those patients, from eligibility criteria
and technical adequacy of the procedure to post-TAVI care.
Each cardiological sub-specialty also plays particular roles
in the procedure performance. The clinical cardiologist is
responsible for patients’ selection and indication and for
pre‑and post-procedure follow-up. The cardiovascular surgeon
is responsible for performing the transaortic and transapical
procedure, helping with the transfemoral approach, and
treating possible complications. The radiologist is responsible
for assessing the access path and valve diameters, and helping
choosing the adequate prosthesis. The echocardiographer is
responsible for the anatomical and functional characterization
of the valve disease and intraoperative assessment of the
adequate position of the prosthesis and post-procedure
complications. The interventional cardiologist is responsible
Keywords
Aortic valve stenosis / surgery; Patient care team; Heart failure.
Mailing Address: Vitor Emer Egypto Rosa •
Rua da Cristiano Viana, Cerqueira Cesar. Postal Code 05411-000, São Paulo,
SP - Brazil
E-mail: [email protected]
Manuscript received October 29, 2013; revised manuscript November 26,
2013; accepted November 27, 2013.
DOI: 10.5935/abc.20140060
e55
for indicating the procedure and performing it. In addition, the
Heart Team also comprises other professionals, such as nurses,
physical therapists, nutritionists, and psychologists. Worldwide,
there is an increasing incorporation of the Heart Team into
cardiological centers, in accordance with the considerations
of the last guidelines on heart valve diseases4,5. There is
consensus about not encouraging the performance of TAVI at
sites lacking a Heart Team, which emphasizes the importance
of institutional alignment with the new recommendations.
So far, TAVI indications have been restricted to subgroups
of patients with AoS considered inoperable or at high
surgical risk, supported by the results of the Placement
of Aortic Transcatheter Valves (PARTNER) trial (cohorts
B and A, respectively)6,7. In cohort B, published in 2010,
patients with inoperable AoS were randomized to either
TAVI or standard treatment (clinical or balloon-catheter
valvuloplasty), and a surprising 20% reduction in mortality
in one year was observed 6. It is worth noting that few
medical interventions assessed in randomized studies
have yielded similar results. Cohort A, a non-inferiority
study, however, has compared TAVI with the surgical aortic
valve replacement in patients at high surgical risk, and
has shown similar one-year survival rates7. In that study,
the preoperative risk has been established by use of the
Society for Thoracic Surgeons (STS) score8. However, on
daily practice the use of scores for high-risk patients has
been criticized, because they have not been developed on
populations submitted to TAVI, in addition to the exclusion
of the clinical variables that could significantly increase
morbidity and mortality. Of the risk variables for the elderly,
frailty, characterized as a weakened physiological reserve9,
still represents a challenge in preoperative assessment,
despite its high prevalence (one third of patients older
than 80 years) and impact on postoperative morbidity10.
To define and standardize a phenotype of frailty, Fried et al9
have developed a score using data from the Cardiovascular
Health Study (CHS) with 5,317 patients older than 65 years,
and have assessed the following items: unintentional weight
loss; self-reported exhaustion; weakness; slow walking
speed; and low physical activity. Individuals meeting at
least three of those criteria were considered frail, being
at higher risk for postoperative complications, including
mortality10. However, scores should be used as aiding tools
(second opinion) to clinical impression rather than absolute
classification tools (mathematization of Medicine)11. It is
worth noting that hematological changes, advanced liver
and lung diseases, malnourishment, aortic calcification
grade, difficult surgical approach, and surgical experience/
volume of the center are characteristics rarely included
in risk scores and known to have a large impact on the
increase of surgical risks.
Rosa et al.
The Heart Team Importance
Viewpoint
The increasing experience with the use of TAVI has
made it safer and has encouraged widening its indications
also for patients with AoS at intermediate surgical risk,
classified according to the EuroSCORE II12 and STS score8,
in addition to those with dysfunctional aortic bioprosthesis
(valve-in-valve). However, in most cases, those patients had
other variables not contemplated in those scores, which
added risk to surgery or even contraindicated it13. Ignoring
the durability of the prosthesis and the possible benefit of
surgical valve replacement makes the TAVI indication to that
group exceptional. Therefore, the results of large ongoing
randomized trials, such as the SURTAVI and PARTNER 2,
are awaited to extend TAVI indication for those patients.
Currently, the 2011 Brazilian and Inter-American Guidelines
on Valve Diseases14, one of the first to consider TAVI as
a therapeutic option for AoS, consider that procedure
only to patients to whom conventional aortic prosthesis
implantation is contraindicated.
That scenario is compounded by the scarcity of scientific data
definitively guiding that question and the high heterogeneity
of patients. Thus, the Heart Team undoubtedly benefits the
management of those patients. So far, the message is “there
is no TAVI if there is no Heart Team”4,11,13.
Author contributions
Conception and design of the research, Writing of the
manuscript and Critical revision of the manuscript for
intellectual content: Rosa VEE, Lopes ASSA, Accorsi TADA,
Lemos Neto PA, Pomerantzeff PMA, Tarasoutchi F.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
In conclusion, symptomatic patients with important AoS
have complex cardiac disease, which is life-threatening in
the short run, in addition to frequent multiple comorbidities.
Approximately 30% of those patients are not eligible for
conventional cardiac surgery, due to their prohibitive surgical
risk. For that subgroup of patients to benefit from a possible
TAVI, careful assessment should precede decision-making.
Sources of Funding
There were no external funding sources for this study.
Study Association
This study is not associated with any thesis or dissertation work.
References
1. Instituto Brasileiro de Geografia e Estatística (IBGE). [Internet]. Acesso em
em 2013 Out 22]. Disponível em: http://www.ibge.gov.br/home/
2. Lindroos M, Kupari M, Heikkila J, Tilvis R. Prevalence of aortic valve
abnormalities in the elderly: an echocardiographic study of a random
population sample. J Am Coll Cardiol. 1993;21(5):1220-5.
3. Freeman RV, Otto CM. Spectrum of calcific aortic valve disease:
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4. Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Baron-Esquivias G,
Baumgartner H, et al. Guidelines on the management of valvular heart
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Holmes Jr DR, Mack MJ. Transcatheter valve therapy: a professional society
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Transcatheter aortic-valve implantation for aortic stenosis in patients who
can not undergo surgery. N Engl J Med. 2010;363(17):1597-607.
7.
Kodali SK, Williams MR, Smith CR, Svensson LG, Webb JG, Makkar RR, et al.
Two-year outcomes after transcatheter or surgical aortic-valve replacement.
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8. O’Brien SM, Shahian DM, Filardo G, Ferraris VA, Haan CK, Rich JB, et al;
Society of Thoracic Surgeons Quality Measurement Task Force. The Society
of Thoracic Surgeons 2008 cardiac surgery risk models: part 2--isolated valve
surgery. Ann Thorac Surg. 2009;88(1 Suppl):S23-42.
9.
Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al;
Cardiovascular Health Study Collaborative Research Group. Frailty in older adults:
evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56(3):M146-56.
10. Ahmed N, Mandel R, Fain MJ. Frailty: an emerging geriatric syndrome. Am
J Med. 2007;120(9):748-53.
11. Van Mieghem NM, Serruys PW. The art of risk stratification in TAVI. Eur Heart
J. 2013;34(25):1859-61.
12. Nashef SA, Roques F, Sharples LD, Nilsson J, Smith C, Goldstone AR, et al;
EuroSCORE II. Eur J Cardiothorac Surg. 2012;41(4):734-44.
13. Wenaweser P, Stortecky S, Schwander S, Heg D, Huber C, Pilgrim T, et al.
Clinical outcomes of Patients with estimated low or intermediate surgical
risk undergoing transcatheter. Aortic valve implantation. Eur Heart J.
2013;34(25):1894-905.
14. Tarasoutchi F, Montera MW, Grinberg M, Barbosa MR, Piñeiro DJ, Sánchez CR,
et al. Diretriz Brasileira de Valvopatias - SBC 2011 / I Diretriz Interamericana
de Valvopatias - SIAC 2011. Arq Bras Cardiol. 2011;97(5 supl. 1):1-67.
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