www.arquivosonline.com.br
Sociedade Brasileira de Cardiologia • ISSN-0066-782X • Volume 104, Nº 6, June 2015
50.0%
45.0%
40.0%
35.0%
30.0%
30.3%
25.0%
20.4%
20.0%
14.6%
15.0%
10.8%
10.0%
12.4%
5.0%
0.0%
Ischemic
DCM*
Hypertensive
Chagas
Valvular
10.3%
0.4%
0.8%
QT†
Myocarditis
Others
Figure 1 – Distribution of etiologies of heart failure in the BREATHE registry.
* DCM: dilated cardiomyopathy; † QT: secondary to chemotherapy. page 436
Editorial
Heart Rate Variability Correlates to Functional Aerobic Impairment in
Distance Psychotherapy – New Reality
Hemodialysis Patients
Original Articles
Review Article
I Brazilian Registry of Heart Failure - Clinical Aspects, Care Quality
Reverse Cardiac Remodeling: A Marker of Better Prognosis in
and Hospitalization Outcomes
Heart Failure
Depression as a Clinical Determinant of Dependence and Low Quality
Letter to the Editor
of Life in Elderly Patients with Cardiovascular Disease
An Issue Waiting to be Clarified: Effects of the QT Prolonging Drugs on
Assessment of Autonomic Function by Phase Rectification of RR-
Tp-e Interval
Interval Histogram Analysis in Chagas Disease
Post-Acute Coronary Syndrome Alcohol Abuse: Prospective Evaluation
Eletronic Pages
in the ERICO Study
APOE and LDLR Gene Polymorphisms and Dyslipidemia Tracking. Rio
de Janeiro Study
Circulatory and Ventilatory Power: Characterization in Patients with
Coronary Artery Disease
Clinicoradiological Session
Case 5/2015 – Late Outcome of Corrected Aortopulmonary
Window in A 23-Year-Old Female Patient Who Underwent
Surgery in Childhood
Case Report
Blood Pressure and Hemodynamic Adaptations after a Training
Acute Myocardial Infarction and Severe Prosthetic Dysfunction after
Program in Young Individuals with Down Syndrome
Bentall Procedure
A JOURNAL OF SOCIEDADE BRASILEIRA DE CARDIOLOGIA - Published since 1948
Contents
Editorial
Distance Psychotherapy – New Reality
Protásio L. da Luz, Mayra L. Gagliani, Bellkiss W. Romano
.....................................................................................................................................................................page 431
Original Articles
Heart Failure
I Brazilian Registry of Heart Failure - Clinical Aspects, Care Quality and Hospitalization Outcomes
Denilson Campos de Albuquerque, João David de Souza Neto, Fernando Bacal, Luiz Eduardo Paim Rohde,
Sabrina Bernardez-Pereira, Otavio Berwanger, Dirceu Rodrigues Almeida, Investigadores Estudo BREATHE
.....................................................................................................................................................................page 433
Cardiogeriatrics
Depression as a Clinical Determinant of Dependence and Low Quality of Life in Elderly Patients with
Cardiovascular Disease
Giselle Helena de Paula Rodrigues, Otavio Celso Eluf Gebara, Catia Cilene da Silva Gerbi, Humberto Pierri,
Mauricio Wajngarten
.....................................................................................................................................................................page 443
Chagas Disease
Assessment of Autonomic Function by Phase Rectification of RR-Interval Histogram Analysis in
Chagas Disease
Olivassé Nasario-Junior, Paulo Roberto Benchimol-Barbosa, Roberto Coury Pedrosa, Jurandir Nadal
.....................................................................................................................................................................page 450
Epidemiology
Post-Acute Coronary Syndrome Alcohol Abuse: Prospective Evaluation in the ERICO Study
Abner Morilha, Samuel Karagulian, Paulo A. Lotufo, Itamar S. Santos, Isabela M. Benseñor, Alessandra C. Goulart
.....................................................................................................................................................................page 457
APOE and LDLR Gene Polymorphisms and Dyslipidemia Tracking. Rio de Janeiro Study
Rossana Ghessa Andrade de Freitas, Erika Maria Gonçalves Campana, Roberto Pozzan, Andréa Araujo Brandão,
Ayrton Pires Brandão, Maria Eliane Campos Magalhães, Dayse Aparecida da Silva
.....................................................................................................................................................................page 468
Ergospirometry
Circulatory and Ventilatory Power: Characterization in Patients with Coronary Artery Disease
Viviane Castello-Simões, Vinicius Minatel, Marlus Karsten, Rodrigo Polaquini Simões, Natália Maria Perseguini,
Juliana Cristina Milan, Ross Arena, Laura Maria Tomazi Neves, Audrey Borghi-Silva, Aparecida Maria Catai
.....................................................................................................................................................................page 476
Arquivos Brasileiros de Cardiologia - Volume 104, Nº 6, June 2015
Exercising
Blood Pressure and Hemodynamic Adaptations after a Training Program in Young Individuals
with Down Syndrome
Bruna Barboza Seron, Karla Fabiana Goessler, Everaldo Lambert Modesto, Eloise Werle Almeida, Márcia Greguol
.....................................................................................................................................................................page 487
Other Diagnostic Tests (not involving imaging)
Heart Rate Variability Correlates to Functional Aerobic Impairment in Hemodialysis Patients
Maria Angela Magalhães de Queiroz Carreira, André Barros Nogueira, Felipe Montes Pena, Marcio Galindo Kiuchi,
Ronaldo Campos Rodrigues, Rodrigo da Rocha Rodrigues, Jorge Paulo Strogoff de Matos, Jocemir Ronaldo Lugon
.....................................................................................................................................................................page 493
Review Article
Reverse Cardiac Remodeling: A Marker of Better Prognosis in Heart Failure
José Rosino de Araújo Rocha Reis Filho, Juliano Novaes Cardoso, Cristina Martins dos Reis Cardoso, Antonio
Carlos Pereira-Barretto
.....................................................................................................................................................................page 502
Letter to the Editor
An Issue Waiting to be Clarified: Effects of the QT Prolonging Drugs on Tp-e Interval
Omer Yiginer, Mehmet Dogan, Emrah Erdal
.....................................................................................................................................................................page 507
Arquivos Brasileiros de Cardiologia - Volume 104, Nº 6, June 2015
Arquivos Brasileiros de Cardiologia - Eletronic Pages
Clinicoradiological Session
Case 5/2015 – Late Outcome of Corrected Aortopulmonary Window in A 23-Year-Old Female Patient
Who Underwent Surgery in Childhood
Edmar Atik
.................................................................................................................................................................. page e55
Case Report
Acute Myocardial Infarction and Severe Prosthetic Dysfunction after Bentall Procedure
Viviane Tiemi Hotta, Pedro Gabriel de Melo Barros, Paulo Sampaio Gutierrez, Angela Cristina Pasiani Bolonhez,
Wilson Mathias, Ricardo Ribeiro Dias
.................................................................................................................................................................. page e58
* Indicate manuscripts only in the electronic version. To view them, visit: http://www.arquivosonline.com.br/2015/english/10406/edicaoatual.asp
Arquivos Brasileiros de Cardiologia - Volume 104, Nº 6, June 2015
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A JOURNAL OF SOCIEDADE BRASILEIRA DE CARDIOLOGIA - Published since 1948
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Interventionist Cardiology
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Back to the Cover
Editorial
Distance Psychotherapy – New Reality
Protásio L. da Luz, Mayra L. Gagliani, Bellkiss W. Romano
Instituto do Coração do HC – FMUSP, São Paulo, SP – Brazil
High technology progresses fast in the medical area.
The most recent advance is the “big data” study, in which
multiple technologies are applied to populations in order to
incorporate genetic data, biological markers and imaging, to
assess risks and predict the occurrence of clinical phenomena.
That is a global, multidisciplinary and multinational view, which
supports and helps the implementation of preventive actions.
Psychology practice in Brazil, however, still resists to this
modernity. Face-to-face psychotherapy is the only modality
of treatment accepted by the Brazilian Federal Council of
Psychology. However, distance counseling, via Internet
or mobile phone, has been increasingly used in the USA,
Europe and Oceania. Epstein et al. 1 have reported the
increasing use of “e-therapy”, as well as the exponential
growth of related publications. In New Zealand, Gibson
et al.2 have reported the experience of adolescents with
mobile phone therapy. Eight aspects were identified by
adolescents as advantageous: privacy, autonomy, control,
anonymity, easy access, personalization, individualization
of language, and connection.
The importance of these new methodologies relates to the
prevalence and incidence of emotional problems worldwide.
For example, depression will be the most common non-fatal
disease of the 21st century3, and an important cause of work
disability and loss of quality of life, in addition to being the
third cause of suicide among North-American young adults.
An extensive review published in the Journal of the American
College of Cardiology by Rozansky4 in 2014 showed that a
number of factors, such as sleep disorders, anxiety, several
forms of stress at home and in the workplace, lack of purpose
in life, anger and inability to face challenges, are significantly
associated with cardiovascular diseases, as well as with
cardiac and all-cause mortality. Those associations depend on
unhealthy life habits, such as sedentary lifestyle and smoking,
and activation of the sympathetic nervous system, which trigger
pathophysiological mechanisms that cause cardiovascular
diseases5. Thus, there is a biologically plausible mechanistic
connection of emotional and behavioral problems with organic
Keywords
Psychotherapy; Social Networking; Internet / utilization;
Internet / trends; Computer Communication Networks.
Mailing Adrress: Protásio Lemos da Luz •
Incor - FMUSP - Avenida Dr. Enéas de Carvalho Aguiar, n° 44, 5 andar BlocoII - sala 08. Postal Code 05403-000, São Paulo, SP - Brazil
E-mail: [email protected]
Manuscript received April 29, 2015; revised manuscript May 06, 2015;
accepted May 06, 2015.
DOI: 10.5935/abc.20150067
431
cardiovascular disease. If, on the one hand, the understanding
of the pathophysiological mechanisms belongs to the cellular
and molecular biology domains, on the other, when attempting
to change behaviors, physicians need the professional help of
psychologists. In addition, prevention is precisely one of the
pillars in the eradication of chronic non-communicable diseases,
such as atherosclerosis, diabetes and hypertension, which are
the major causes of mortality causes in the modern world.
The fundamental requirements in the preventive strategy are
changes in lifestyle, such as smoking cessation, exercise practice
and the adoption of healthy diets. This is the point where the
two sciences meet.
Moreover, physicians often fail to recognize emotional
problems, both the primary ones and those associated
with organic diseases. Several psychological treatments are
misused, and the number of cases treated is insufficient,
barely reaching 50%3.
On the other hand, the economic burden of depression
and dementia is astronomical 6,7. In the USA, the cost
of depression, mainly related to absenteeism and poor
work performance, has reached U$53 billion in one year.
Regarding dementia, Hurd et al.7 have estimated individual
costs between U$42,000 and 56,000/person/year, and
between U$ 157 billion and 250 billion/year in the USA.
In Brazil, such costs are unknown, but most likely high as well.
Given that scenario, the following measures are imperative:
a.to identify psychological factors, as well as primary
conditions, in organic diseases;
b. to adopt global health care, which are patient and not
only disease oriented;
c. to incorporate different methodologies of treatment,
such as new drugs and new behavioral treatment forms;
d. to improve the treatment of mental illness.
Concerning “distance psychotherapy”, we believe that
the brazilian law needs to be changed and adapted to the
new times. Not disregarding the classic face-to-face therapy,
distance counseling should not only be allowed, but encouraged
in special situations covered by appropriate legislation.
In Brazil, distance psychotherapy is currently allowed in
the research only and encourages debate on efficiency and
safety, privacy, ethical and legal questions, and other aspects8.
For example, one therapeutic process could begin with a few
initial interviews, followed by distance treatment and face-toface interviews at intervals. This would benefit patients living far
away from large centers, where modern therapeutic techniques,
such as cognitive behavioral therapy, are not available.
Such alternatives would certainly contribute to the preventive
processes so heartedly championed by modern medicine.
Both psychologists and their formal representatives should
pursue this inevitable update.
Luz et al.
Distance psychotherapy – New reality
Editorial
References
1. Epstein R. Distance therapy comes of age. Scientific American Mind
May/June 2011. [Cited in 2015 Jan 10]. Available from: http://www.
scientificamerican.com/mind
5.
2.
Gibson K, Cartwright C. Young people´s experiences of mobile phone text
counselling: Balancing connection and control. Children and youth services
review. 2014;43:96-104.
6. Wang PS, Simon G, Kessler RC. The economic burden of depression
and the cost-effectiveness of treatment. Int J Methods Psychiatr Res.
2003;12(1):22-33.
3. The National Alliance on Mentall Illness, 2013. [Cited in 2015 Jan 10].
Available from: http://www.nami.org
7. Hurd MD, Martorell P, Delavande A, Mullen KJ, Langa KM. Monetary costs
of dementia in the United States. N Engl J Med. 2013;368(14):1326-34.
4.
8.
Rozanski A. Behavioral cardiology: current advances and future directions.
J Am Coll Cardiol. 2014;64 (1):100-10.
Luz PL, Nishiyama M, Chagas AC. Drugs and lifestyle for the treatment and
prevention of coronary artery disease: comparative analysis of the scientific
basis. Braz J Med Biol Res. 2011;44(10):973-91.
Pieta MA, Gomes WB. Psicoterapia pela internet: viável ou inviável? Psicol
cienc prof. 2014;34(1):18-31.
Arq Bras Cardiol. 2015; 104(6):431-432
432
Back to the Cover
Original Article
I Brazilian Registry of Heart Failure - Clinical Aspects, Care Quality
and Hospitalization Outcomes
Denilson Campos de Albuquerque1, João David de Souza Neto2, Fernando Bacal3, Luiz Eduardo Paim Rohde4,
Sabrina Bernardez-Pereira5, Otavio Berwanger5, Dirceu Rodrigues Almeida6, Investigadores Estudo BREATHE
Universidade do Estado do Rio de Janeiro (UERJ)1, Rio de Janeiro, RJ; Hospital de Messejana2, Fortaleza, CE; Instituto do Coração (InCor) do
Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo3, São Paulo, SP; Hospital de Clínicas de Porto Alegre4, Porto
Alegre, RS; Instituto de Pesquisa, Hospital do Coração5, São Paulo, SP; Universidade Federal de São Paulo, UNIFESP6, São Paulo, SP; Sociedade
Brasileira de Cardiologia - Departamento de Insuficiência Cardíaca (DEIC) - Brazil
Abstract
Background: Heart failure (HF) is one of the leading causes of hospitalization in adults in Brazil. However, most of the
available data is limited to unicenter registries. The BREATHE registry is the first to include a large sample of hospitalized
patients with decompensated HF from different regions in Brazil.
Objective: Describe the clinical characteristics, treatment and prognosis of hospitalized patients admitted with acute HF.
Methods: Observational registry study with longitudinal follow-up. The eligibility criteria included patients older than
18 years with a definitive diagnosis of HF, admitted to public or private hospitals. Assessed outcomes included the causes of
decompensation, use of medications, care quality indicators, hemodynamic profile and intrahospital events.
Results: A total of 1,263 patients (64 ± 16 years, 60% women) were included from 51 centers from different regions in Brazil.
The most common comorbidities were hypertension (70.8%), dyslipidemia (36.7%) and diabetes (34%). Around 40% of the
patients had normal left ventricular systolic function and most were admitted with a wet-warm clinical-hemodynamic profile.
Vasodilators and intravenous inotropes were used in less than 15% of the studied cohort. Care quality indicators based on
hospital discharge recommendations were reached in less than 65% of the patients. Intrahospital mortality affected 12.6% of
all patients included.
Conclusion: The BREATHE study demonstrated the high intrahospital mortality of patients admitted with acute HF in Brazil,
in addition to the low rate of prescription of drugs based on evidence. (Arq Bras Cardiol. 2015; 104(6):433-442)
Keywords: Heart Failure/mortality; Epidemiology; Hospitalization; Inappropriate Prescribing.
Introduction
Heart failure (HF) has been pointed to as an important
public health problem and regarded as a new epidemic
with high mortality and morbidity, in spite of the advances
in current therapeutics. Updated data from the American
Heart Association (AHA) estimated a prevalence of 5.1 million
individuals with HF in the United States alone between 2007
and 2012. Projections show that the prevalence of HF will
increase 46% between 2012 and 2030, resulting in more
than 8 million individuals above the age of 18 years with HF1.
The rising prevalence is probably due to the increase in life
expectancy, since HF affects predominantly older age groups2.
HF is the leading cause of hospitalization, based on
data available from about 50% of the population in South
America3. The most comprehensive portrait of the situation
Mailing Address: Denilson Campos de Albuquerque •
Rua Voluntários da Pátria 445, 1402. Postal Code 22270000, Rio de Janeiro,
RJ – Brazil
E-mail: [email protected]
Manuscript received November 10, 2014; revised manuscript January 7,
2015; accepted January 7, 2015.
DOI: 10.5935/abc.20150031
433
of hospitalizations for HF in Brazil can be obtained through
analyses of DATA-SUS records, with the inherent limitations
of a database of an administrative nature. Data show that in
2012 alone there were 26,694 deaths in Brazil due to HF.
Of 1,137,572 admissions due to circulatory diseases in that
same year, around 21% were due to HF4.
The burden becomes even more significant when we consider
that almost 50% of all hospitalized patients with this diagnosis
are readmitted within 90 days after hospital discharge, and that
hospital readmission is one of the main risk factors for death in
this syndrome5,6. Several studies have focused on identifying the
factors associated with frequent readmissions7,8. Those usually
described in the international literature are inadequate therapy,
lack of adherence to treatment, social isolation, or worsening
cardiac function. However, in approximately 30-40% of the cases
it is not possible to identify the cause of clinical decompensation9.
Data on morbidity and consequent costs associated with
decompensated HF are undeniable all over the world. In Brazil,
there are only a few studies comprehensively and prospectively
assessing the demographic, clinical and prognostic characteristics
of patients who are admitted with a clinical diagnosis of HF.
Isolated initiatives suggest the existence of significant regional
differences in several characteristics of patients who are admitted
Albuquerque et al.
BREATHE: Characteristics, Indicators and Outcomes
Original Article
with HF in Brazil, but these comparisons are methodologically
limited by often divergent guidelines and inclusion criteria10-12.
Thus, the establishment of a national registry which incorporates
a group of public and private hospitals from different Brazilian
regions can portray more accurately which patients are admitted
with a diagnosis of HF, how these patients are treated in their
institutions and what are their short- and long-term prognoses.
The BREATHE study is the first national and multicenter
registry of acute HF that includes all regions of the country,
involving 51 public and private hospitals in 21 cities in Brazil.
The aim of this analysis is to describe the clinical features,
treatment and prognosis of hospitalized patients admitted with
acute HF in Brazil.
Methods
Delineation
Cross-sectional, observational study (registry) with
longitudinal follow-up.
Hospital Selection
The public and private hospitals that participated in the
Registry of Decompensated Heart Failure of the Department
of Heart Failure of the Brazilian Society of Cardiology were
chosen by the research committee. A fixed number of
institutions was allocated for each one of the five regions of
the country, and the number of patients per region was defined
based on the absolute number of hospitalizations by region in
the year 2004 according to the IBGE (Supplement II).
Inclusion and Exclusion Criteria
The methods of BREATHE, as well as its inclusion
and exclusion criteria, have been previously described13.
Patients older than 18 years, admitted to public or private
hospitals with a definitive clinical profile of HF confirmed by
the Boston criteria were considered eligible for the study14.
Those patients undergoing myocardial revascularization
procedures (coronary angioplasty or surgery) in the last month
of the selection and who presented signs of HF secondary to
sepsis were excluded from the study.
Definitions of the Study:
a) Clinical and Hemodynamic Profile:
The clinical and hemodynamic profile was defined according
to the classification of Stevenson15, in four hemodynamic profiles
according to the findings on physical examination of pulmonary
congestion and peripheral perfusion. Patients with acute HF
are generally in one of the following subgroups: 1) presence of
pulmonary congestion without signs of hypoperfusion (wet and
warm); 2) presence of pulmonary congestion associated with
hypoperfusion (wet and cold); and 3) hypoperfusion without
pulmonary congestion (dry and cold).
b) HF Treatment Targets Doses:
Target doses for the treatment of acute HF, for purposes of
evaluation of the data from this study, were the same as those
recommended by the II Guideline of Acute Heart Failure of
the Brazilian Society of Cardiology16.
c) Causes of HF Decompensation:
The main causes of decompensation analyzed included
infection, decompensation from acute valvular disease,
poor adherence to drug therapy, excessive sodium intake
in the last week, arrhythmias and pulmonary embolism.
The classification was determined by the clinical judgment
of the local investigator according to the patient’s report.
Follow-up
For the present analysis, in addition to hospital admission
data, data were collected during hospitalization until the date
of medical discharge or intrahospital death.
Outcomes of Interest
The primary outcome of this study was the all-cause
intrahospital mortality. Secondary outcomes included the
proportion of patients who received interventions with
proven benefit demonstrated by care quality indicators (use of
angiotensin converting enzyme inhibitors [ACEi] / angiotensin
II receptor blockers [ARB] and use of beta‑blockers),
readmissions due to HF and cardiovascular mortality.
Ethical Aspects
The protocol was approved by the Research Ethics
Committee (Comitê de Ética em Pesquisa, CEP) of the Hospital
do Coração de São Paulo, SP (HCor) on February 1st, 2011,
under the registration number 144/2011, and following that,
each participating center also had their protocols approved
by their own CEPs. All patients signed a Free and Informed
Consent Form and the clinical study was conducted in
accordance with the principles of the current revision of the
Declaration of Helsinki.
Data Management
The management of the data was performed using the
EDC (Electronic Data Capture) system. Medical charts were
transcribed by Web-charts, sent to the central coordinating
center, and incorporated into a database for validation.
Quality control of the data of the study occurred mainly by
central checking in search of possible inconsistencies (data
without biological plausibility) or incomplete data, and was
reported to the participating centers for confirmation and/or
correction. The Department of Heart Failure of the Brazilian
Society of Cardiology was responsible for the management
of the data of the study.
Sample Size
The first phase of the Brazilian Registry of Decompensated
HF predicted the evaluation of 1,200 admissions to the
public and private network in different regions of Brazil.
This sample size was determined to represent the largest
Brazilian prospective study of decompensated HF, involving
all regions of the country, allowing identification of regional
differences in intrahospital mortality.
Arq Bras Cardiol. 2015; 104(6):433-442
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Albuquerque et al.
BREATHE: Characteristics, Indicators and Outcomes
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Statistical Analysis
Continuous variables were described as medians
(interquartile range) or means (standard deviation)
according to the distribution of the variable, and the
categorical variables as absolute and relative frequencies.
Normality was evaluated with the visual inspection of
histograms and application of the Shapiro-Wilks test of
normality. Age distribution was compared among regions
according to a model of analysis of variance (ANOVA)
and the relationship between etiology and region was
determined by the chi-square test. The software SAS 9.3
(Statistical Analysis System, Cary, NC) was used for statistical
analysis of the data17.
Results
Between February 2011 and December 2012, 1,263
patients were included in 51 centers from different Brazilian
regions (2 centers in the Northern region [164 patients],
13 centers in the Northeast [209 patients], 5 centers in
the Midwest [66 patients], 33 centers in the Southeast
[652 patients] and 5 centers in the South [172 patients]).
Two patients were excluded from the analysis for meeting
exclusion criteria. The flow diagram can be found in
Supplement II.
The average age of the patients was 64 ± 16 years,
with 73.1% above the age of 75 years and 60% women.
Most patients were self-reportedly white (59%), admitted to
the public network/Unified Health System (Sistema Único
de Saúde, SUS; 64.8%) and from the South/Southeast
regions (65.2%). Slightly over half of the patients included
had left ventricular systolic dysfunction (58.7%), and the
vast majority (70.8%) was hypertensive. Table 1 shows the
baseline characteristics of the studied sample, including
demographics and prior medical history.
The average age distribution by region showed a
statistically significant difference with the inclusion of
patients of more advanced age in the Southeastern and
Southern regions and younger patients in the Northern
region (66 ± 15 years versus 59 ± 17 years, p = 0.019).
Table 4 lists the main procedures performed during
hospitalization, as well as the mortality rate during
hospitalization. The sum of the deaths in the first 24 hours
(17 patients) and after this period (140 patients) totaled
12.6% of the studied cohort. Valve replacement prevailed
among the procedures during hospitalization, occurring in
156 patients.
For the treatment of acute HF during hospitalization
the use of loop diuretics prevailed (89.8%), followed by
beta‑blockers (57.1%). The use of intravenous vasodilators
(6.6%) and inotropic agents (13.6%) represented a small
portion of the therapy in this population (Figure 3).
According to the indicators of the Joint Commission
on Accreditation of Healthcare Organizations (JCAHO),
63.7% of the patients received guidelines on hospital
discharge about the correct use of medications, whereas
only 34.9% and 16.2% were advised about the diet to be
followed at home and prescription of physical activity,
respectively (Figure 4).
Discussion
The main findings of this analysis of the study BREATHE
are: 1) baseline characteristics show a populational
profile of predominantly elderly patients, mainly in the
Southern and Southeastern regions of Brazil; 2) poor drug
adherence was the factor most frequently associated with
Table 1 – Baseline characteristics of the cohort
Variables
BREATHE
(n = 1,261)
Age (mean+/-SD*)
64.1 ± 15.9
Male gender (%)
40.0
Prior acute myocardial infarction (%)
26.6
Hypertension (%)
70.8
The hypertensive and ischemic etiologies prevailed in
the studied population, affecting 30.1% and 20.3% of the
patients, respectively. Around 11% of the patients had a
diagnosis of Chagas disease (Figure 1).
Dyslipidemia (%)
36.7
Prior stroke /TIA§ (%)†
12.6
Atrial fibrillation (%)
27.3
In the analysis of the etiologies by region, patients
from the South, Southeast and Northeast showed a
predominance of the ischemic etiology (33.6%, 32.6%,
and 31.9%, respectively). In patients in the Northern region
the hypertensive etiology (37.2%) predominated, while
among patients in the Northern region the Chagasic etiology
predominated (42.4%) (Table 2).
Depression (%)†
The main causes of HF decompensation were poor
adherence to medication (30%), followed by infections
(23%) and inadequate control of water and sodium intake
(9%), as shown in Table 3.
Sodium (mean+/-SD)
As for the clinical and hemodynamic profile on
hospital admission, the prevalence was for the wet-warm
profile, totaling 67.4% of the cases, whereas the wet-cold
435
and dry‑cold profiles accounted for 17.8% and 5.2%,
respectively (Figure 2).
Arq Bras Cardiol. 2015; 104(6):433-442
13.5
Occlusive peripheral arterial disease (%)
†
10.8
Chronic renal failure (%)†
24.1
Diabetes mellitus (%)
†
34.0
Chronic obstructive pulmonary disease (%)
12.7
Left ventricular ejection fraction (average/-+/-SD)
Creatinine (mean+/-SD)
BNP (median (IQR¶))
38.8 ± 16.5
137 ± 16
1.7 ± 4.8
1,075 (518; 1,890)
* SD: standard deviation; †Values calculated on a total of 1,255 patients
with complete information; §TIA: transient ischemic attack; BNP: brain
natriuretic peptide; ¶IQR: interquartile range.
Back to the Cover
Albuquerque et al.
BREATHE: Characteristics, Indicators and Outcomes
Original Article
50.0%
45.0%
40.0%
35.0%
30.0%
30.3%
25.0%
20.4%
20.0%
14.6%
15.0%
12.4%
10.8%
10.0%
10.3%
5.0%
0.0%
Ischemic
DCM*
Hypertensive
0.4%
0.8%
QT†
Myocarditis
Valvular
Chagas
Others
Figure 1 – Distribution of etiologies of heart failure in the BREATHE registry.
* DCM: dilated cardiomyopathy; † QT: secondary to chemotherapy.
Table 2 – Distribution of etiologies according to Brazilian regions
Etiology
South
Southeast
Midwest
Northeast
North
Total
n
%
n
%
n
%
n
%
n
%
n
%
Ischemic
58
33.6
213
32.6
15
22.8
67
31.9
27
16.5
380
30
Idiopathic dilated cardiomyopathy
12
7
93
14.3
4
6.1
41
19.6
33
20.1
183
14.5
Hypertensive
56
32.6
98
15
7
10.6
34
16.3
61
37.2
256
20.3
Chagas disease
4
2.3
80
12.3
28
42.4
13
6.2
11
6.7
136
10.8
Valvular disease
24
14
80
12.3
2
3
30
14.4
20
12.2
156
12.4
Secondary to chemotherapeutic agents
1
0.6
2
0.3
0
0
2
1
0
0
5
0.4
Myocarditis
2
1.2
5
0.8
2
3
1
0.5
0
0
10
0.8
Others
15
8.7
74
11.3
8
12.1
20
9.6
12
7.3
129
10.2
Missing
0
0
7
1.1
0
0
1
0.5
0
0
8
0.6
172
100
652
100
66
100
209
100
164
100
1,263
100
Total
decompensation; 3) the prescription of drugs, mainly
vasodilators, according to current evidence was below the
expected rate for this population; and 4) high intrahospital
mortality rate.
drug adherence leads to increased morbidity, mortality
and costs 18. In addition to that, advanced age is a risk
factor for poor adherence which increases even more with
polypharmacy, increasing the likelihood of adverse events.
Patients with advanced age accounted for an important
segment of the sample studied in BREATHE and
predominated in the South and Southeast regions, where
the ischemic etiology was also more prevalent.
Studies about drug adherence demonstrate highly
variable rates of adherence among patients with HF.
A study reported adherence rates of 79% for ACEi/ARB,
65% for beta-blockers and 56% for spironolactone after five
years from the first hospitalization for HF19. In contrast, the
noncompliance rate based on pill count was much lower
Among patients with chronic diseases, approximately
50% do not take medications as prescribed. This poor
Arq Bras Cardiol. 2015; 104(6):433-442
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Albuquerque et al.
BREATHE: Characteristics, Indicators and Outcomes
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Table 3 – Distribution of causes of heart failure decompensation
Table 4 – Events and procedures during hospitalization
% (n = 1,250)
Events/procedures
%
(n/total)
Infection
22.7
Intrahospital mortality
12.6
(1,57/1,245)
Poor medication adherence
29.9
Coronary artery bypass grafting
0.7
(9/197)
Increased ingestion of sodium and water *
8.9
Valve replacement
12.4
(156/197)
Acute valvular disease
6.6
Heart transplantation
1.2
(15/197)
Cardiac arrhythmia
12.5
Coronary angioplasty
1.5
(19/197)
Pulmonary embolism
0.4
Implantable defibrillator/Resynchronizer
1.2
(15/197)
Others
32.4
Cardiac pacemaker
1.7
(22/197)
Decompensation cause
*Total with complete information 1,242 patients.
* Of the total, only 197 patients had procedures performed during
hospitalization.
100.0%
90.0%
80.0%
67.4%
70.0%
60.0%
50.0%
40.0%
30.0%
20.0%
10.0%
0.0%
17.8%
9.6%
Dry-warm
5.2%
wet-warm
Wet-cold
Dry-cold
Figure 2 – Hemodynamic profile on hospital admission.
in the CHARM study, in which 11% of the patients took less than
80% of the prescribed pills20.
Adherence is associated with several factors and should
not be regarded as the sole responsibility of the patient.
The BREATHE study pointed out that only slightly more than
50% of the patients received guidelines for correctly taking
the medications, and only 43.5% were advised about the
recognition of worsening of symptoms and future appointments.
Preliminary evidence shows that around 35% of the inpatients
with acute HF receive appropriate instructions on hospital
discharge, with academic centers showing worse performance
in this indicator of the JCAHO21.
Of still greater relevance and impact on the prescription of
medication on discharge is the medication introduced during
the hospital phase. This analysis demonstrates that there are
still considerable gaps in the treatment of acute HF in Brazil.
437
Arq Bras Cardiol. 2015; 104(6):433-442
The treatment frequently does not follow current published
guidelines, which may contribute to the high morbidity, mortality
and economic cost of this syndrome16.
The IMPROVE-HF study showed that the addition of each
evidence-based therapy was associated with a decreased risk
of mortality in 24 months, with incremental benefit. This strong
positive association between the use of evidence-based therapies
and improved risk-adjusted survival reached a plateau after
4‑5 therapies included in the therapeutic armamentarium of
the patient with HF22.
Despite the fact that the clinical hemodynamic profile
wet‑warm was the most common in the present study, only
6.6% of the population received intravenous vasodilators,
whereas 42.2% of the patients received ACEi during the
hospital phase. Around 18% of the patients showed a wet‑cold
profile on hospital admission, but only 13.6% received
Albuquerque et al.
BREATHE: Characteristics, Indicators and Outcomes
Original Article
100.0%
89.9%
90.0%
80.0%
70.0%
57.1%
60.0%
50.0%
40.0%
30.0%
23.5%
20.0%
10.0%
0.0%
46.2%
42.2%
13.6%
6.6%
Intravenous
vasodilator
Inotropes
ACEi*
Loop
Diuretics
ARB†
Betablocker
Aldosterone
Antagonist
Figure 3 – Medications administered during the hospital stay.
* ACEi: angiotensin converting enzyme inhibitor; †ARB: angiotensin II receptor blocker.
100.0%
90.0%
80.0%
67.3%
70.0%
60.0%
50.0%
40.0%
44.2%
34.9%
30.0%
16.2%
20.0%
10.0%
10.0%
0.0%
Diet
Medications Use
Physical Activity
Symptom
Worsening
Quit Smoking†
Figure 4 – Guidelines on hospital discharge according to the indicators of care quality during hospitalization for heart failure (according to the JCAHO*).
* Joint Commission on Accreditation of Healthcare Organization. † Applicable to smokers
inotropes. Beta‑blockers were prescribed to only 57.1% of the
studied sample. In contrast, loop diuretics were prescribed to
approximately 90% of the patients.
Results from the analysis of the ADHERE registry suggest
that starting vasodilator therapy in the emergency department
correlates with shorter hospital stays and fewer transfers to the
intensive care unit, as well as higher percentages of asymptomatic
patients at hospital discharge23. Additionally, there was a
substantial improvement in the survival rate of patients receiving
intravenous vasodilators (nitroglycerin or nesiritide), compared
with those who received intravenous inotropes (dobutamine
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Albuquerque et al.
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or milrinone)24. However, it is possible that patients requiring
inotropic therapy have a more advanced form of HF than
patients who receive vasodilators.
Analysis of the Euro Heart Survey clearly showed that
patients included in randomized clinical trials are a highly
selected group and that only a small proportion of the patients
in this registry would be eligible. However, beta-blockers and
ACEi were prescribed for less than half of the eligible patients
and the doses used were below those which have proven to
be effective. Therefore, the lack of similarity between patients
with HF in clinical practice and those in clinical trials does not
adequately explain the underutilization of the therapy25.
Intrahospital treatment invariably has a direct impact on clinical
events during hospitalization. The prognosis of HF is reserved and
directly related to the loss of functional capacity. Data from the
Framingham study showed a median survival rate after diagnosis
of 1.7 years for men and 3.2 years for women. The high mortality,
morbidity and impairment of quality of life related to HF affects
primarily the elderly. Although we may observe a consistent
and significant survival benefit in patients with HF with use of
aggressive pharmacological strategies, the annual mortality of
this disease remains high26-31. The CONSENSUS (Cooperative
North Scandinavian Enalapril Survival Study)32 and PROMISE
(Prospective Randomized Milrinone Survival Evaluation)33 studies,
for example, identified a high proportion of patients with annual
mortality exceeding 30%. In more recent studies, the mortality
of patients with functional class III-IV after 1 year of optimized
treatment, including the routine use of ACEi and beta-blockers, was
approximately 10-15%34. Although these values are encouraging,
such mortality rates are also similar to those observed in many
neoplastic diseases.
As for intrahospital mortality, it affects between 3% to
4% of the patients admitted for acute HF in prior studies35,
whereas the mortality rate in the BREATHE registry exceeds
in two times the rates from American and European registries.
In the ADHERE study, intrahospital mortality was 4.0%,
and the average hospital stay was 4.3 days36. Similar to the
American registry, the Euro Heart Survey presented an overall
intrahospital mortality rate of 3.8%, with 90.1% due to a
cardiovascular cause. Higher mortality rates were observed
in the presence of cardiogenic shock37.
Some limitations inherent to the design of BREATHE should
be considered in the interpretation of its results. The diagnosis of
acute HF was based only on the Boston criteria and the date of
onset of symptoms was not defined, therefore it was not possible
to differentiate new acute HF from exacerbation of chronic
HF. Consequently, since the population is heterogeneous, the
analysis of treatment and prognosis will require appropriate
adjustment. In addition, the number of missing data was
elevated due to some variables whose completion was not
mandatory, interfering with the results found.
Conclusion
BREATHE is the first Brazilian registry of acute HF and its results
point to the high rate of intrahospital mortality related to low rates
of evidence-based therapy prescribed during hospitalization, as
well as low percentage of medical guidelines on hospital discharge
of patients hospitalized for acute HF in different regions of Brazil.
New strategies must be adopted to ensure improvement in the
quality of hospital care of this disease.
Author contributions
Conception and design of the research: Albuquerque
DC, Souza-Neto JD, Bacal F, Rohde LEP. Acquisition of
data: researchers BREATHE, Albuquerque DC, Souza-Neto
JD, Rohde LEP, Bernardez- Pereira S, Almeida DR. Analysis
and interpretation of the data: Albuquerque DC, Rohde
LEP, Bernardez-Pereira S, Berwanger O. Statistical analysis:
Bernardez-Pereira S. Obtaining financing: Albuquerque DC.
Writing of the manuscript: Albuquerque DC, Souza-Neto JD,
Bacal F, Rohde LEP, Bernardez-Pereira S, Almeida DR. Critical
revision of the manuscript for intellectual content: Albuquerque
DC, Souza- Neto JD, Bacal F, Rohde LEP, Bernardez-Pereira S,
Berwanger O, Almeida DR.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Sources of Funding
This study was funded by Departamento de Insuficiência
Cardíaca da Sociedade Brasileira de Cardiologia.
Study Association
This study is not associated with any thesis or dissertation work.
Supplement I – Distribution of the BREATHE patients by region (planned versus included)
Major Regions
Brazil
439
Hospitalization in health establishments in the year of 2004
Total IBGE
Total BREATHE referred
Total BREATHE Included
23,252,613 (100%)
1,200
1,263
North
1,746,554 (8%)
96
164
Northeast
5,254,978 (23%)
276
209
Southeast
10,794,799 (46%)
552
652
South
3,671,762 (16%)
192
172
Midwest
1,784,520 (8%)
96
66
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Included
(n = 1263)
Excluded. Presence
of exclusion criteria
(n = 2)
Analyzed
(n = 1261)
Without information at
hospital discharge
(n = 18)
Complete follow-up
(n = 1245)
Supplement II – Flow diagram of the BREATHE study.
List of participants BREATHE
Hospital de Clínicas Gaspar Viana: Helder José Lima Reis;
Hospital de Base FAMERP: Paulo Roberto Nogueira; Hospital
do Coração: Ricardo Pavanello; Hospital São Lucas – PUCRS:
Luiz Claudio Danzmann; Hospital de Messejana: João David
de Souza Neto; Instituto Dante Pazzanese: Elizabete Silva dos
Santos; Hospital de Clínicas de Porto Alegre: Luis Eduardo
Paim Rohde; InCor SP: Mucio Tavares de Oliveira Filho;
Real Hospital Português: Silvia Marinho Martins; Hospital
Universitário Clementino Fraga Filho: Marcelo Iorio Garcia;
Hospital Total Cor: Antonio Baruzzi; Hospital Universitário
Prof. Alberto Antunes: Maria Alayde Mendonça da Silva;
Hospital Barra D’Or: Ricardo Gusmão; Hospital do Coração
de Goiás: Aguinaldo Figueiredo de Freitas Júnior; Hospital
Vera Cruz: Fernando Carvalho Neuenschwander; Hospital
Universitário de Londrina: Manoel Fernandes Canesin; Hospital
Copa D’or: Denilson Campos de Albuquerque; Hospital das
Clínicas da Universidade Federal de Goiás: Salvador Rassi;
Instituto Cardiopulmonar: Eduardo Darzé; Santa Casa de
Votuporanga: Mauro Esteves Hernandes; Hospital Universitário
Pedro Ernesto: Ricardo Mourilhe Rocha; São Lucas Médico
Hospitalar: Antonio Carlos Sobral Sousa; Hospital Universitário
Presidente Dutra-HUUFMA: Jose Albuquerque de Figueiredo
Neto; Centro de Pesquisa da Clínica Médica e Cardiologia
da UNIFESP: Renato D. Lopes; Unidade de Insuficiência
Cardíaca – InCor: Edimar Alcides Bocchi; Hospital Quinta
Dor: Jacqueline Sampaio; Hospital Lifecenter: Estêvão Lanna
Figueiredo; Xeno Diagnósticos Dante Pazzanese: Abilio Augusto
Fragata Filho; Fundação Bahiana de Cardiologia: Alvaro Rabelo
Alves Júnior; Instituto de Cardiologia do Distrito Federal: Carlos
V. Nascimento; Hospital Auxiliar do Cotoxó: Antonio Carlos
Pereira-Barretto; Fundação Beneficência Hospital de Cirurgia/
Hospital do Coração: Fabio Serra Silveira; Hospital Santa Izabel:
Gilson Soares Feitosa; Hospital Regional Hans Dieter Schmidt:
Conrado Roberto Hoffmann Filho; Hospital Univ. Antonio
Pedro – UFF: Humberto Villacorta Júnior; Hospital Universitário
São Jose: Sidney Araújo; Hospital das Clínicas de Botucatu
UNESP Botucatu: Beatriz Bojikian Matsubara; Hospital Santa
Paula: Otávio Gebara; Casa de Saúde São José: Gustavo Luiz
Gouvea de Almeida; Hospital das Clínicas da UFMG: Maria
da Consolação Vieira Moreira; Hospital Madre Tereza: Roberto
Luiz Marino; São Bernardo Apart Hospital: João Miguel de Malta
Dantas; Instituto Nacional de Cardiologia: Marcelo Imbroinise
Bittencourt; Hospital da Cidade: Marcelo Silveira Teixeira;
Hospital Rios Dor: Elias Pimentel Gouvea; Hospital das Clínicas
de Ribeirão Preto/ USP-FMRP: Marcus Vinícius Simões; Santa
Casa de São Paulo: Renato Jorge Alves; Hospital Espanhol: Fabio
Villas-Boas; Unidade de Miocardiopatia InCor: Charles Mady;
Hospital Escola Alvaro Alvim: Felipe Montes Pena; Hospital
Univ. João de Barros Barreto – UFPA: Eduardo Costa.
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Arq Bras Cardiol. 2015; 104(6):433-442
442
Back to the Cover
Original Article
Depression as a Clinical Determinant of Dependence and Low
Quality of Life in Elderly Patients with Cardiovascular Disease
Giselle Helena de Paula Rodrigues, Otavio Celso Eluf Gebara, Catia Cilene da Silva Gerbi, Humberto Pierri,
Mauricio Wajngarten
Instituto do Coração de São Paulo - INCOR/HC-FMUSP, São Paulo, SP – Brazil
Abstract
Background: The aging process promotes a progressive increase in chronic-degenerative diseases. The effect of these
diseases on the functional capacity has been well recognized. Another health parameter concerns “quality of life
related to health”. Among the elderly population, cardiovascular diseases stand out due to the epidemiological and
clinical impact. Usually, these diseases have been associated with others. This set of problems may compromise both
independence and quality of life in elderly patients who seek cardiologic treatment. These health parameters have not
been well contemplated by cardiologists.
Objective: Evaluating, among the elderly population with cardiovascular disease, which are the most relevant clinical
determinants regarding dependence and quality of life.
Methods: This group was randomly and consecutively selected and four questionnaires were applied: HAQ, SF-36,
PRIME-MD e Mini Mental State.
Results: The study included 1,020 elderly patients, 63.3% women. The group had been between 60 and 97 years-old
(mean: 75.56 ± 6.62 years-old). 61.4% were independent or mild dependence. The quality of life total score was high
(HAQ: 88.66 ± 2.68). 87.8% of patients had a SF-36 total score ≥ 66. In the multivariate analysis, the association
between diagnoses and high degrees of dependence was significant only for previous stroke (p = 0.014), obesity
(p < 0.001), lack of physical activity (p = 0.016), osteoarthritis (p < 0.001), cognitive impairment (p < 0.001), and
major depression (p < 0.001). Analyzing the quality of life, major depression and physical illness for depression was
significantly associated with all domains of the SF-36.
Conclusion: Among an elderly outpatient cardiology population, dependence and quality of life clinical determinants
are not cardiovascular comorbidities, especially the depression. (Arq Bras Cardiol. 2015; 104(6):443-449)
Keywords: Depression; Aged; Cardiovascular Diseases; Frail Elderly; Quality of Life.
Introduction
With an aging population, the prevalence of chronic
diseases has progressively increased1. The impact of these
diseases on functional capacity, which corresponds to the
capacity and independence to perform certain daily tasks,
has been recognized2.
Another health parameter with a relatively recent evolution
is the concept of “quality of life” (QoL) or, preferably, “healthrelated quality of life” (HRQoL), which emphasizes the impact
of health status on the individual’s quality of life. It derives
from individuals’ experience regarding their health problems,
comprising several domains not always prioritized by health
professionals and has important implications for the assessment
of the effects of therapeutic interventions.
Mailing Address: Giselle Helena de Paula Rodrigues •
Rua Ministro Godoi, 1186, apto.12, Perdizes. Postal Code 05015-001,
São Paulo, SP – Brazil
E-mail: [email protected]; [email protected]
Manuscript received July 25, 2014; revised manuscript October 17,
2014; accepted October 30, 2014.
DOI: 10.5935/abc.20150034
443
Thus, the evaluation of these health parameters has
emerged as an important part of the clinical examination in
this population, making health teams start aiming at functional
status improvement and well-being, in addition to the survival
of elderly patients3.
In the elderly population, cardiovascular diseases stand
out due to their high epidemiological and clinical impact.
They are usually associated with other diseases, including
neuropsychiatric ones, which may have mutual influence.
One example is the association between systemic arterial
hypertension (SAH), cognitive decline and depression,
physiopathologically expressed by anatomical and functional
abnormalities of cerebral circulation4-6. Another interesting
association was found between major depression and
cardiovascular disease, also explained by changes in
microcirculation, which deserves further investigation7.
Obviously, this set of problems can impair independence
and quality of life of elderly individuals seeking cardiologic
treatment. In this sense, the role of neuropsychiatric conditions
has been emphasized, as expressed by the aphorism that
“there is no health without mental health”8.
According to the last IBGE (Brazilian Institute of Geography
and Statistics) census in 2010, there was a significant
change in the Brazilian scenario of disease distribution,
Rodrigues et al.
Depression in elderly patients with cardiovascular diseases
Original Article
when compared to that of 1990. Ischemic heart diseases
occupied the 1st position in 2010 in terms of prevalence,
whereas depression, the 6th position. Differently from what
was observed in 1990, when they occupied the 4th and the
10th positions, respectively9.
Another very interesting fact is that currently, life
expectancy in Brazil is 74.1 years. Of this total, only
63.8 years are lived in good health status9.
Based on these findings, we verify the importance of
adequate investigation of quality of health and depression
in patients in all health care levels. Clinical trials such as the
Improving Mood-Promoting Access to Collaborative Treatment
(IMPACT)10 and the Coronary Psychosocial Evaluation Studies
(COPES)11 showed not only the health benefits of individuals
systematically evaluated for depression in primary care, but
also reduced costs with future medical care.
Although some studies show the impact of chronicdegenerative diseases on elderly independence, especially
dementia and other chronic neurological diseases12, these
health parameters have been relatively disregarded by
cardiologists, both in research and in clinical practice13,14.
Researches tend to exclude elderly patients with
comorbidities 15 , in addition to rarely considering
independence and QoL as outcomes. Consequently, with
few exceptions 16, these studies fail to reflect the “real
world”, which has influence on Guidelines, education and
clinical practice.
The objective of this study is to evaluate, in a population
of elderly patients from a cardiology outpatient clinic
of a referral hospital, whether the most relevant clinical
determinants of dependency and QoL are cardiovascular
diseases or other highly prevalent comorbidities in this group,
such as depression.
Method
Clinical evaluation was made by a single physician in
accordance with data from patients’ medical records.
In parallel to the clinical evaluation, the patients were
assessed by a single psychologist who applied a set of four
questionnaires validated internationally and in Brazil:
Health Assessment Questionnaire (HAQ) 17 Short-Form
Health Survey (SF-36)18, New Procedure for Diagnosing
mental Disorders in Primary Care (PRIME-MD) 19 and
Mini‑mental State Examination (MMSE)20.
All diseases were classified as present or absent.
According to degree of dependence, the group was divided
in two:
• Independent and with mild dependence: HAQ score
from 0 to 1.4;
• Moderate and severe dependence: HAQ scores from
1.5 and 3.0.
Quality of life was assessed according to SF-36. Based on
the mean scores, the group was divided into two: above and
below the mean.
Patients with cognitive impairment that could interfere
with the final result of this analysis were excluded from the
calculations. The population was then divided into tertiles
of the SF-36 score: score between 0 and 33; > 33 and 66;
and those with scores > 66. All subjects with MMSE < 18
were considered as possible dementia cases.
Sample Size Calculation and Statistical Analysis
For this study, considering the chances of the above
listed events, according to the statistical inference theory
and taking into account that the confidence interval at the
level of (1-Ω)%, where Ω is 5%, we obtained an estimated
sample size of 870 patients. We chose to increase this sample
to 1,020 patients (approximately 25% more), to ensure that
the analysis of association strength of multiple assessed
diagnoses would be possible and to minimize the chance
of a statistical beta error.
Population
The studied individuals originated from the Geriatric
Cardiology Unit of Instituto do Coração, Hospital das Clínicas
of the School of Medicine of Universidade de São Paulo
(InCor – HC/FMUSP), and the study was approved by the
Research Ethics Committee of this institution.
The elderly participants were randomly selected, until a
total sample of 1,020 individuals was achieved.
Exclusion criteria
Patients that had cognitive impairment, i.e., score < 18
at the Mini-Mental State Examination (MMSE) were
not considered for the calculation of their QoL, as they
had some difficulty in answering the QoL questionnaire
questions (SF-36).
Methodology
This is an epidemiological, observational and crosssectional study, lasting approximately three years for the
selection of all individuals.
Statistical Analysis
Pearson’s chi-square test was used to test the significance
of associations between cardiovascular diseases and other
comorbidities with HAQ, while Student’s t test was used
to assess the association between cardiovascular diseases
and other comorbidities with each of the 8 domains of
the SF-36.
Uni- and multivariate tests were applied to study the
possible associations between the analyzed variables and
patients’ QoL. To verify the strength of these associations,
the odds ratio was calculated for each of these variables in
relation to the degree of dependence and QoL. In order
to evaluate which, among the analyzed variables, were
significantly and independently associated with the degrees
of dependence (HAQ) and QoL, a stepwise multivariate
logistic regression model was developed, which included
the statistically significant associations in the univariate
analyses. Significance level was set at 5% (p ≤ 0.05) in the
statistical tests and the Statistical Analysis Software (SAS
Institute Inc., NC, USA) was employed.
Arq Bras Cardiol. 2015; 104(6):443-449
444
Rodrigues et al.
Depression in elderly patients with cardiovascular diseases
Original Article
Results
Demographic and clinical characteristics of the study
population
The study included 1,020 individuals aged 60 years or
older, of which 646 were women and 374 men. Age ranged
from 60 to 97 years (mean: 75.56 years / SD: 6.62 years) and
17.74% were aged between 60 and 69 years; 55% between
70 and 79 years; 25.88% between 80 and 89 years and
1:37% between 90 and 97 years. Caucasians were 74.9% of
the total sample, with the other individuals being classified
as African-descendants (9.5%), Asian-descendants (2.0%)
and Mixed-race (13.5%).
The following were the most prevalent cardiovascular
diseases: heart failure (HF), coronary artery disease (CAD)
and atrial fibrillation (AF), followed by acute myocardial
infarction (AMI) and previous cerebrovascular accident (CVA).
Other comorbidities that showed high prevalence in the
group were: lack of regular physical activity, systemic arterial
hypertension (SAH) and dyslipidemia (DLP), in addition to
obesity, diabetes mellitus (DM), smoking, osteoarthritis (OA),
chronic obstructive pulmonary disease (COPD), chronic renal
failure (CRF), cognitive impairment and depression (Table 1).
It is noteworthy that 57.1% of the study population had
depression (major or minor). Of these patients, 37% had
depression due to physical illness.
When analyzing quality of life, it is verified that the
total QoL score was high and no patient had a SF-36 score
< 33. Most of the patients (87.7%) had a total SF-36 score
> 66 (Table 3).
Association between Diagnoses and Degrees of
Dependence
At the multivariate analysis, the association between diagnoses
and high degrees of dependence was significant only for previous
CVA (p = 0.014), obesity (p < 0.001), lack of physical activity
(p = 0.016), osteoarthritis (p < 0.001), cognitive impairment
(p < 0.001) and major depression (p < 0.001) (Table 4).
Association between Diagnoses and Quality of Life
When the multivariate analysis is performed, the
variables below are the ones that best explain a lower
quality of life in each of its domains (Table 5).
Table 2 – Degrees of dependence according to HAQ
Dependence (HAQ)
Number of patients (n)
Frequency (%)
< 1.5
624
61.2
≥ 1.5
396
38.8
HAQ: Health Assessment Questionnaire.
Additionally, most of the population (61.4%) showed to be
independent or slightly dependent (Table 2).
Table 3 – Quality of life of the Population, according to SF-36
Table 1 – Prevalence of the most common diagnoses in the population
Diagnoses
Number of patients (n)
Frequency (%)
SAH
882
86.5
DLP
492
48.2
COPD
95
9.31
Obesity
279
27.4
DM
267
26.2
Cognitive deficit
118
11.6
CRF
100
9.8
HF
338
33.2
CAD
331
32.5
AF
215
21.2
AMI
136
13.3
Stroke
85
8.3
Major Depression
472
46.3
Minor Depression
111
10.8
Depression Phys.Dis.
378
37.0
Absence of. physical activity
990
96.9
Smoking
65
6.4
SAH: hypertension; DLP: dyslipidemia; COPD: chronic obstructive pulmonary
disease; DM: diabetes; CRF: chronic renal failure; HF: heart failure; CAD: oronary
artery disease; AF: atrial fibrillation; AMI: acute myocardial infarction.
445
Arq Bras Cardiol. 2015; 104(6):443-449
SF-36 (total score)
Number of patients (n)
Frequency (%)
33 – 66
110
12.2
≥ 66
792
87.8
Table 4 – Multivariate analysis between diagnoses and high degrees
of dependence
Diagnoses
Stroke
Odds ratio
1.97
95%CI
LI
LS
1.15
3.37
p
0.014
HF
1.25
0.89
1.75
0.203
SAH
1.60
0.99
2.59
0.053
DM
1.21
0.82
1.77
0.336
Obesity
2.24
1.59
3.15
< 0.001
Physical Inactivity
0.08
0.01
0.62
0.016
OA
1.64
1.14
2.37
0.008
Cognitive deficit
3.17
2.02
4.98
< 0.001
Major Depression
2.76
1.86
4.10
< 0.001
Minor Depression
1.14
0.65
1.99
0.642
Depression Phys.
Dis.
1.31
0.90
1.89
0.160
HF: heart failure; SAH: hypertension; DM: diabetes; OA: osteoarthritis.
Rodrigues et al.
Depression in elderly patients with cardiovascular diseases
Original Article
Thus, the following were significantly associated with
lower degrees of quality of life, according to the following
domains of the SF-36 at the multivariate analysis:
• Limitation for physical activities due to health
problems (D1): HF, CAD, AMI, lack of physical activity,
hypertension, obesity, OA, major depression and
depression due to physical illness;
• Limitation for social activities due to physical and emotional
problems (D2): HF, AF, lack of physical activity, OA, and
major depression and depression due to physical illness;
• Limitation of daily activities due to physical changes (D3):
AF, lack of physical activity, SAH, obesity, OA, and major
depression and depression due to physical illness;
• Pain (D4): SAH, COPD, major depression and
depression due to physical illness;
• Less vitality (D7): CAD, DLP, major depression and
depression due to physical illness;
• Worse perception of one’s health (D8): CRF, major
depression and depression due to physical illness.
Discussion
Among the elderly patients studied, depression showed
high prevalence, with great impact on the independence and
QoL of these individuals. This fact is surprising, as we are
analyzing a group of individuals with multiple comorbidities,
apparently more significant than the depression.
Recently, three major challenges were identified by
physicians interested in improving care for their elderly
patients with multiple comorbidities:
1.Difficulty in applying the guidelines and need to
individualize according to the patients’ reality;
• Worse general mental health - stress and well-being
- (D5): COPD, major depression, minor depression
and depression due to physical illness;
2.Difficulty in choosing one of the strategies: prioritize
certain clinical entities, treat diseases individually,
considering the risk of each of them or start treatment
before adverse effects occur;
• Limitation in basic activities due to emotional
problems (D6): HF, CVA, DLP, and major depression
and depression due to physical illness;
Table 5 – Multivariate analysis between diagnosis and low degrees of quality of life
D1
D2
D3
OR
p
OR
p
HF
1.89
0.0057
1.56
0.0089
CAD
1.81
0.0092
6.77
< 0.001
AF
Physical Inactivity
SAH
2.21
0.0014
Obesity
1.65
0.0486
OA
2.14
0.0072
D4
OR
p
1.59
0.0110
2.03
0.0001
3.19
0.0048
4.78
0.0001
1.75
0.0085
2.04
0.0012
1.60
0.0146
COPD
OR
p
1.70
0.0073
1.88
0.0143
Major depression
3.05
< 0.0001
3.49
< 0.0001
2.31
< 0.0001
2.22
< 0.0001
Depression Phys. Dis.
2.83
0.0008
1.76
0.0052
2.12
< 0.0001
1.80
0.0007
D5
OR
D6
p
D7
OR
p
2.08
0.0006
Stroke
1.90
0.0159
DLP
1.39
0.0206
HF
CAD
COPD
2.05
D8
OR
p
1.52
0.0046
1.53
0.0023
OR
p
1.98
0.0044
0.0229
CRF
Major Depression
5.44
< 0.0001
Minor depression
1.91
0.0138
Depression Phys.Dis.
1.66
0.0309
3.16
< 0.0001
2.77
< 0.0001
6.08
< 0.0001
2.11
< 0.0001
1.43
0.0259
2.41
0.0001
HF: heart failure; CAD: coronary artery disease; AF: atrial fibrillation; SAH: hypertension; OA: osteoarthritis; COPD: chronic obstructive pulmonary disease;
DLP: dyslipidemia; CRF: chronic renal failure.
Arq Bras Cardiol. 2015; 104(6):443-449
446
Rodrigues et al.
Depression in elderly patients with cardiovascular diseases
Original Article
3. The conflict between physicians’ preferences and those
of their patients21.
The results of this study can help minimize these challenges
and improve elderly care, as the reduction of dependence
and QoL improvement are the fundamental objectives in
patient care22.
Additionally, it is known that there is a strong association
between depression in the elderly and factors that increase
mortality rates 23,24, such as poor adherence to medical
treatment or lack of self-care25 for conditions such as diabetes,
cardiovascular disease, smoking, sedentary life style 26,
cognitive decline27 and dependence28. Thus, it is essential not
only to perform the assessment of these factors, but mainly of
the correlation between them.
In this population, it is noteworthy the very high frequency
of depression: almost half with major depression, 11% with
minor depression and 37% of cases related to physical illness.
The number of depressed individuals exceeds the
expected, when compared to studies related to the topic29,30.
However, several factors may influence the variation in
the prevalence of depression, such as different diagnostic
methods and sociodemographic characteristics. Studies show
that women and individuals with lower education have more
criteria for the diagnosis of depression31, whereas among
the elderly, these criteria are less often identified, possibly
because depression in this population is underdiagnosed or
underreported32. Moreover, population studies have shown
that the greatest risk factors for mental illness are not only
chronic diseases, but also the socioeconomic differences
and the difficulty in access to general and mental health31.
Considering this is a population consisting exclusively of
elderly cardiac patients, the high rate of depression could be
explained by the known association between depression and
cardiovascular disease. It is known that the presence of major
depression may increase the risk of cardiovascular disease due
to microcirculation abnormalities, although genetic factors also
seem to be involved in this mechanism8.
Recent epidemiological data showed a similar profile also
among the very elderly, older than 85 years. It is remarkable
that, in addition to several comorbidities and the fact that
most are females, these elderly reported having good health
quality and low degree of dependence33.
In this study, the degree of dependence was low for more
than half of patients. However, despite being able to attend
the outpatient clinic, almost 40% showed high or moderate
dependence (HAQ ≥ 1.5).
Overall, the QoL score using the SF-36 was high, and no
patient had scores below 33 and almost 90% had scores over 66.
However, the score of the emotional domain was less
than 65 in 55% of individuals, anticipating a great influence
of depression on quality of life.
When we analyzed the associations between different
diagnoses and the patients’ degree of dependence, we
verified a significant association for cardiovascular diagnoses of
previous CVA, obesity and lack of regular physical activity, and
for non-cardiovascular diagnoses of osteoarthritis, cognitive
deficit and major depression (Table 2).
447
Arq Bras Cardiol. 2015; 104(6):443-449
It is relatively simple to explain higher levels of dependence
for patients with previous CVA, osteoarthritis, cognitive deficit
and major depressive disorder. On the other hand, lack of
regular physical activity and obesity could be the consequences
of dependence itself, justifying the observed association.
It is noteworthy, however, the fact that dependence was
more associated with non-cardiovascular comorbidities
than with the diagnoses of cardiovascular diseases and
risk factors. The lack of association between dependence
and heart failure, although the latter was diagnosed in
33% of the sample and is a condition related to increased
morbidity, can be explained by the compensation status and
lower clinical impact at the time the study was performed.
It should also be considered that the patients were able to
come to the outpatient clinic and could represent a group
of patients submitted to a lower degree of clinical impact.
The same justification can be used for the lack of association
with chronic obstructive pulmonary disease.
When analyzing the associations between clinical
diagnoses and the quality of life of individuals, we observed
that most of the conditions were significantly associated
with some of the SF-36 domains. However, the significant
association between major depression and physical illness
with all domains of the SF-36 should be especially noted,
which does not occur with cardiovascular diagnoses.
Similarly to what was observed regarding dependence,
we emphasize the poor association between cardiovascular
diagnoses and quality of life, whereas the diagnosis of
depressive disorder showed a strong association.
With the improvement of the assessment and intervention
on the “modifiable” factors associated with an increased
risk of disability 33, there has been a tendency toward
the reduction of the degree of functional limitation and
disability34. However, this parameter has been little studied
in cardiology.
Regarding quality of life, only recently there has been
a wider application of tools to assess it in the cardiology
setting35-37.
This study shows that non-cardiovascular comorbidities,
especially depressive disorders, have greater impact than
cardiovascular disease and dependence on the quality
of life of elderly individuals attending a cardiology clinic.
This scenario highlights the importance of knowing the profile of
elderly patients and including an effective geriatric assessment,
integrating a broad assessment for possible functional loss and
quality of life to the traditional clinical history38,39.
In 2008, the American Heart Association (AHA) had already
emphasized this necessity. In an important publication, the
AHA supported that screening tests for depression should be
applied to all patients with cardiovascular disease in all care
settings: inpatient, outpatient or cardiovascular rehabilitation
centers. The opportunity to diagnose and treat these patients
should not be missed, as it can promote major improvements
to patient health40.
Thus, the adequacy of care services and education
programs, as well as the training of professionals involved in
elderly care becomes necessary.
Rodrigues et al.
Depression in elderly patients with cardiovascular diseases
Original Article
This study has some limitations. As this is an observational
cross-sectional study, with only one assessment in time for all
variables, the observed associations may not fully represent the
reality of this population. Another limitation of this study refers to
the source of the assessed patients, which is a n outpatient clinic
of a high-complexity hospital, thus resulting in the selection bias of
a more severely-ill population, which prevents the generalization
of our findings to other groups. Moreover, only patients who were
able to come to the outpatient clinic were assessed, probably
excluding totally dependent and bedridden patients.
Conclusion
In a population of elderly patients treated in a cardiology
outpatient clinic of a referral hospital, the most relevant clinical
determinants of impairment dependence and quality of life are
non-cardiovascular comorbidities, mainly depression.
Author contributions
Conception and design of the research:Rodrigues GHP,
Gebara OCE, Pierri H, Wajngarten M. Acquisition of data:
Rodrigues GHP, Gerbi CCS. Analysis and interpretation of
the data: Rodrigues GHP, Gebara OCE, Wajngarten M.
Statistical analysis: Rodrigues GHP, Gebara OCE. Writing
of the manuscript: Rodrigues GHP, Wajngarten M. Critical
revision of the manuscript for intellectual content: Gebara
OCE, Pierri H, Wajngarten M.
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 Doctoral submitted by
Giselle Helena de Paula Rodrigues, from Universidade de São
Paulo - FMUSP/INCOR-SP.
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Back to the Cover
Original Article
Assessment of Autonomic Function by Phase Rectification of RRInterval Histogram Analysis in Chagas Disease
Olivassé Nasario-Junior1, Paulo Roberto Benchimol-Barbosa1,3, Roberto Coury Pedrosa2, Jurandir Nadal1
Programa de Engenharia Biomédica – COPPE/UFRJ1; Hospital Universitário Clementino Fraga Filho – UFRJ2; Hospital Universitário Pedro
Ernesto – UERJ3, Rio de Janeiro, RJ – Brazil
Abstract
Background: In chronic Chagas disease (ChD), impairment of cardiac autonomic function bears prognostic implications.
Phase‑rectification of RR-interval series isolates the sympathetic, acceleration phase (AC) and parasympathetic, deceleration
phase (DC) influences on cardiac autonomic modulation.
Objective: This study investigated heart rate variability (HRV) as a function of RR-interval to assess autonomic function in
healthy and ChD subjects.
Methods: Control (n = 20) and ChD (n = 20) groups were studied. All underwent 60-min head-up tilt table test under ECG
recording. Histogram of RR-interval series was calculated, with 100 ms class, ranging from 600–1100 ms. In each class, mean
RR-intervals (MNN) and root-mean-squared difference (RMSNN) of consecutive normal RR-intervals that suited a particular
class were calculated. Average of all RMSNN values in each class was analyzed as function of MNN, in the whole series
(RMSNNT), and in AC (RMSNNAC) and DC (RMSNNDC) phases. Slopes of linear regression lines were compared between groups
using Student t-test. Correlation coefficients were tested before comparisons. RMSNN was log-transformed. (α < 0.05).
Results: Correlation coefficient was significant in all regressions (p < 0.05). In the control group, RMSNNT, RMSNNAC, and
RMSNNDC significantly increased linearly with MNN (p < 0.05). In ChD, only RMSNNAC showed significant increase as a
function of MNN, whereas RMSNNT and RMSNNDC did not.
Conclusion: HRV increases in proportion with the RR-interval in healthy subjects. This behavior is lost in ChD, particularly in
the DC phase, indicating cardiac vagal incompetence. (Arq Bras Cardiol. 2015; 104(6):450-456)
Keywords: Chagas Disease; Chagas Cardiomyopathy; Heart Rate; Organ Dysfunction Scores; Sympathetic Nervous System;
Charts; Statistics as Topic.
Introduction
Chagas disease (ChD) is a major cause of cardiomyopathy
in Latin America. It has been estimated that 8–11 million
people are currently infected by Trypanosoma cruzi
worldwide, potentially becoming a significant healthcarerelated problem in Europe and in the United States due to
migration1,2. In chronic ChD, autonomic dysfunction has
been associated with impairment of both parasympathetic
and sympathetic limbs3-5, with prognostic implications6.
Heart rate variability (HRV) analysis is a powerful and
simple method for assessing autonomic influence on the
sinus node and risk stratification in many cardiac diseases7,8.
On routine clinical assessment, parameters in time domain
are usually estimated during a predefined time sequence
Mailing Address: Paulo Roberto Benchimol Barbosa •
Universidade do Estado do Rio de Janeiro. Boulevard Vinte e Oito de
Setembro, 77. Térreo. Sala da Coordenadoria de Assistência Médica, Vila
Izabel. Postal Code 20551-030, Rio de Janeiro, RJ – Brazil
E-mail: [email protected], [email protected]
Manuscript received November 10, 2014; revised manuscript January 24,
2015; accepted January 26, 2015.
DOI: 10.5935/abc.20150032
450
of normal-to-normal RR-intervals. Among the parameters
usually employed, root-mean-squared difference (RMSNN)
is particularly useful, as it expresses the amount of energy
associated with data variability7. However, none of these
indexes distinguish between vagal and sympathetic effects.
Recently, an approximate isolation of distinct autonomic
contribution on heart rate (HR) has been possible by
assessing the capability of RR-interval series to accelerate
(AC) or decelerate (DC), representing sympathetic and
parasympathetic contributions, respectively. To further
accomplish this task, it was initially detected that if a
particular RR-interval changed relative to the previous one, the
corresponding RR-interval was separated in a new series9,10.
In healthy subjects, it has been demonstrated that HRV
indices tended to increase as RR-intervals enlarged11,12.
On the other hand, this relationship may be lost during a
disease state and may further precipitate some forms of
ventricular arrhythmia, such as long QT syndrome, and
ischemic cardiomyopathy13. Thus, the aims of this study
were (i) to assess RMSNN index on AC and DC phases
of RR-interval series in order to isolate sympathetic and
parasympathetic effects, respectively, and (ii) to correlate
RMSNN and mean RR-intervals (MNN) to assess heart rate
dependence of autonomic modulation index in chronic ChD.
Nasario-Junior et al.
Phase RR-interval histogram in Chagas disease
Original Article
Methods
Study population
ECG signals were extracted from an existing high
resolution ECG database14. The study protocol was approved
by the Hospital Universitário Clementino Fraga Filho Ethics
Committee and informed consent was obtained from
each volunteer. A group of gender-matched 20 healthy
sedentary participants [Control group, (mean age ± SD)
51.1 ± 17.6 years] and 20 subjects with chronic ChD (Chagas
group, 55 ± 10.3 years) were studied. Chronic ChD subjects
were enrolled to the study based on spontaneous demand.
Due to the exploratory nature of the study, the number of
participants was arbitrarily defined and equally distributed
between groups.
According to surface ECG data analysis, in ChD
group, seven had normal ECG. Among 13 subjects with
abnormal ECG, nine showed left atrial overload based
on Morris criteria, nine had left anterior fascicular block,
nine had complete right bundle branch block and one
had first degree AV block. Two subjects showed isolated
supraventricular tachycardia and four showed isolated
ventricular premature beats.
Additionally, all participants met the following criteria: (i) no
intake of nutritional supplements or potential ergogenic aids
of any type (e.g., exogenous anabolic androgenic steroids); (ii)
non-smokers; (iii) normal blood pressure; (iv) non-diabetic;
(v) no history of alcohol addiction; (vi) no history of thyroid
dysfunction; and (vii) not taking medications that affect cardiac
electrical properties and/or autonomic function.
Signal acquisition and processing
All subjects underwent 60-min head-up tilt test (HUTT)
under modified Westminster protocol15 at 70° and continuous
high-resolution ECG recording in an acclimatized (27°C) and
quiet room. Subjects were oriented to withhold exercise for
48 h before the exam, fast for at least 4 h, and avoid taking
caffeine-containing beverages on the day of the exam.
Before ECG recording, subjects remained in the supine
position for at least 5 min in order to reduce orthostatic
autonomic memory on spontaneous RR-interval variations16,17.
ECG signal acquisition periods were characterized
by 10 min of supine rest followed by 40-min HUTT and
another 10-min supine rest. Accordingly, HRV was expected
to be influenced by two predominant autonomic inputs:
parasympathetic input during supine rest, and sympathetic
input during tilt7.
High-resolution ECG signals were acquired using modified
bipolar Frank XYZ orthogonal leads18. Digital data were
processed with custom-made pattern recognition software19-21.
The analysis of the HRV was done by extraction of the normal
RR-intervals, after detection of the QRS complex using a
low‑pass triangular filter. Any RR-interval that exhibited more
than 20% change from the previous RR-interval were excluded,
as they were likely to be related to measurement noise or
ectopic beats21,22.
Instantaneous RR-interval analysis
The RR-interval histogram was constructed for each
individual series and split into 100-ms width classes, ranging
from 600–1100 ms. For each histogram class, and respective
to each RR-interval series, mean (MNN) and root-mean-square
diference (RMSNN) of consecutive normal RR-intervals suiting a
particular class were calculated. Only the pairs of consecutive
normal RR-intervals for individual series that were inside a
particular class of the RR histogram were analyzed together.
For a particular histogram class (class) of the ith series,
containing Ni,class RR-intervals, calculation of the mean (Mi,class)
and the root-mean-squared difference (RMSi,class) of the normal
RR-intervals was performed as follows:
(1)
Ni,classe
Mi,classe = Σ K = 1
RRk
Ni,classe
(2)
Ni,classe
RMSi,classe =
Σk = 1
(RRk - RRk - 1)2
Ni,classe
For each histogram, classes with intervals of 30 or less were
excluded to avoid bias due to lack of statistical precision.
The values of the variables M i,class and RMS i,class were
aggregated to the respective histogram class. The ensemble mean
(MNNclass) and root-mean-squared difference (RMSNNclass) of
RR-intervals for each histogram class, weighed by the respective
degree‑of‑freedom (ηi,class), were calculated according to:
(3)
20
MNNclasse =
+1
Σ i = 1Mi,classe . (ηi,classe )
20
+1
Σ i = 1(ηi,classe )
(4)
RMSNNclasse =
20
2
+1
Σ i = 1(RMSi,classe) . (ηi,classe )
20
Σ i = 1(ηi,classe )
+1
Instantaneous AC and DC analysis
RR-interval histograms in AC and DC phases were also
built following the procedures described above; RMSNN in
AC (RMSNNAC) and RMSNN in DC (RMSNNDC) phases were
calculated accordingly. To further accomplish this task, data
points were initially isolated as acceleration (AC) or deceleration
(DC) capacities. If a particular RR-interval increased relative to
the previous one, a DC interval occurred. As the instantaneous
RR‑interval increased, it represented a parasympathetic action
(DC; lozenge symbols in Figure 1). Conversely, a sympathetic
effect on the RR-interval was represented whenever the
RR‑interval decreased relative to the previous one, and AC interval
was defined (AC; represented by circle symbols in Figure 1).
Arq Bras Cardiol. 2015; 104(6):450-456
451
Nasario-Junior et al.
Phase RR-interval histogram in Chagas disease
Original Article
Acceleration RR interval
RR-intervals histogram
RR-intervals (ms)
1000
(n)
Deceleration RR interval
900
800
700
600
3
8
13
18
Beat index (n)
23
Figure 1 – Deceleration and Acceleration anchor points are represented in RR-intervals samples that were derived from an ECG recording. RR-interval histogram is
represented on the right.
Statistical analysis
The RMSNN and MNN of each subject were pooled
and averaged on a class-by-class basis in the control
and ChD groups. RMSNN was analyzed in the whole
series (RMSNN T) as well as in the AC and DC phases.
Regression lines were analyzed and angular coefficient
was compared between ChD and control groups using
non‑paired Student’s t-test. Correlation coefficients (r)
were tested before each test. Due to strong asymmetry in
their probability density functions, the RMSNN variables
were log-transformed before analysis to fit appropriately in
the parametric statistical analysis. All tests were considered
significant at α level < 0.05.
Results
Table 1 shows the linear correlation coefficient (r) and
respective angular coefficient (slope) of the regression line
between MNN and other each pooled variable. The r-values
were significant in all regression lines (p < 0.05).
The log-transformed pooled RMSNN (T, AC, and DC), as
a function of pooled MNN, were presented for each group
(Figure 2). RMSNNAC were significantly different in both
groups, whereas, in the control group, RMSNNT, RMSNNAC,
and RMSNN DC significantly increased proportionally to
MNN (p < 0.05); in the ChD group, only RMSNNAC showed
significant increase as a function of MNN, whereas RMSNNT
and RMSNNDC did not.
Based on the total number of RR-intervals suiting a
particular histogram class, the percent value (mean ± SD)
of RR-interval pairs rejected as not pertaining to the same
histogram class was 31.7% ± 21.7% for the control group
452
Arq Bras Cardiol. 2015; 104(6):450-456
and 27.0% ± 14.7% for ChD. Figure 3 shows histograms
of RR-interval pairs for each group according to the AC and
DC phases, respectively.
Discussion
Cardiac autonomic dysfunction, characterized mainly
by parasympathetic depression, is an important aspect
of human ChD3-5. The observation of marked autonomic
dysfunction in association with normality of most ventricular
echocardiographic variables suggested that there was no
clear relationship between autonomic and ventricular
function23. Additionally, autonomic dysfunction seemed
to be a primary phenomenon, preceding ventricular
mechanical changes in chronic ChD evolution6,24,25.
In a previous study22, DC index adaptation was proposed
to measure cardiac vagal modulation by a phase-rectified
signal averaging (PRSA) procedure10,11 that was effective in
distinguishing athletes from sedentary healthy volunteers.
It was hypothesized that depending on vagal stimulus
intensity, the rate of ascent of the RR-interval series would
change accordingly, determining slope variation. Thus, the
strongest vagal stimulus determined the steepest slope and
vice-versa, potentially affecting the DC value. Although
PRSA has been originally developed to risk-stratify subjects
post myocardial infarction10, its application in assessing
physiological conditions that are strongly related to vagal
activity modulation has been shown to be highly pertinent
and feasible as well.
In the present study, the behavior of RR-intervals was
analyzed by grouping time domain RMSNN parameters
calculated at different histogram classes. This procedure
Nasario-Junior et al.
Phase RR-interval histogram in Chagas disease
Original Article
Table 1 – Correlation of parameters: MNN vs. Variables
Ln RMSNNT
Group
Control
ChD
Ln RMSNNAC
Ln RMSNNDC
r
0.96 *
0.99 *
0.99 *
slope
0.0011 **
0.0012
0.0008 **
r
-0.55 *
0.96 *
-0.75 *
slope
-0.0002
0.0010
-0.0003
(*) p < 0.05; (**) p < 0.05 for intergroup comparison. Log-transformed RMSNNT, RMSNNAC e RMSNNDC
In the control group, HRV (RMSNN T, RMSNN AC and
RMSNNDC) was strongly dependent on the instantaneous
RR-interval, confirming the previous findings of BenchimolBarbosa et al.13. In the physiological range of RR-interval
variation (600–1100 ms), RMSNN was lower during headup tilt and higher during supine position, representing
sympathetic and parasympathetic autonomic influences
on HRV, respectively. Moreover, it was notable that
RR‑interval variation had average inter-beat “jumps” that
were proportional to the average RR-intervals (Figure 2).
This relation was also represented by a strong linear
dependence between RMSNN and MNN (r > 0.96).
On the other hand, in the ChD group, only RMSNNAC
showed significant increase as a function of MNN (p < 0.05),
which assessed the isolated contribution of sympathetic
nervous system on HRV. RMSNNDC, which assessed the
isolated parasympathetic influence, not only had its mean
value lower than the control group, but also showed no
variations with changes in mean RR-interval. These findings
indicate that not only vagal modulation was reduced in this
population, but also the ability of parasympathetic system
to modulate RR-intervals at different heart rates throughout
a wide range of RR-intervals analyzed. We named this later
observation as parasympathetic incompetence.
This study has its limitations, including a relatively small
sample size and application of the method using two
physiologically well-defined groups. Although the groups
were not matched by age, both had their mean age above
40 years. Assessment of left ventricular systolic function was
not carried out in the present study; however, in Chagas
disease, there was no clear relationship between autonomic
and ventricular function24. Further studies are needed to
confirm present findings.
Ln RMSNNT (Ln ms)
3.5
3.0
2.5
4.0
Ln RMSNNAC (Ln ms)
The essential point of this study was to stratify HR and
HRV according to instantaneous RR-interval difference
using a parameter that expresses energy (RMSNN) from
all series and to isolate sympathetic and parasympathetic
contributions. Also, it introduced novel information that
represents insights into the dependence of autonomic
modulation on heart rate in a population of chronic ChD.
4.0
3.5
3.0
2.5
4.0
Ln RMSNNDC (Ln ms)
made it possible to cluster beats under the influence of
similar instantaneous time factors. Additionally, assessment
of the capacity of RR-interval series to accelerate or
decelerate enabled the isolation of both sympathetic (AC
phase) and parasympathetic (DC phase) contributions on
the RR-intervals series.
3.5
3.0
2.5
(a)
Control slope:
0.0011
Chagas slope:
-0.0002
p < 0.05
600 700 800 900 1000 1100
(b)
Control slope:
0.0012
Chagas slope:
0.0010
p = NS
600 700 800 900 1000 1100
(c)
Control slope:
0.008
Chagas slope:
-0.0003
p < 0.05
600 700 800 900 1000 1100
IM (ms)
Figure 2 – Comparison of control and ChD groups in terms of logtransformed of pooled RMSNNT (a), RMSNNAC (b), and RMSNNDC (c) as a
function of pooled RR-intervals (MNN), and the respective angular coefficient
(slope) of regression line. p value refers to Student’s t-test significance
for comparing slopes. Correlation was significant for all regression lines.
(See text for details)
Arq Bras Cardiol. 2015; 104(6):450-456
453
Nasario-Junior et al.
Phase RR-interval histogram in Chagas disease
Original Article
(a) Acceleration phase
Total
8000
6000
Control
Chagas
4000
2000
0
400
500
600
700
800
900
1000 1100 1200 1300 1400
(b) Decelaration phase
8000
Total
6000
Control
Chagas
4000
2000
0
400
500
600
700
800
900
1000 1100 1200 1300 1400
RR-interval classes (ms)
Figure 3 – RR-interval pairs histograms assessed for each group and phase: acceleration phase (a) and deceleration phase (b).
Conclusion
In subjects with chronic Chagas disease, a significant
reduction of autonomic modulation of the heart is observed
throughout a wide physiological range of RR-intervals.
Additionally, in healthy sedentary subjects, RMSNN increases
proportionally with RR-interval. This relationship is not observed
in chronic Chagas disease, particularly during parasympathetic
stimulation phase, indicating parasympathetic incompetence in
modulating heart rate variation in this scenario.
Acknowledgements
This work was partially supported by Fundação Carlos
Chagas Filho de Amparo à Pesquisa do Estado do Rio de
Janeiro (FAPERJ) and the Brazilian Agencies CNPq and CAPES.
We wish to thank Dr. Aline Medeiros for her dedication in the
acquisition of ECG data of the patients.
Author contributions
Conception and design of the research:Nasario-Junior
O, Benchimol-Barbosa PR. Acquisition of data: Pedrosa
454
Arq Bras Cardiol. 2015; 104(6):450-456
RC. Analysis and interpretation of the data: Nasario-Junior
O, Benchimol-Barbosa PR, Nadal J. Statistical analysis:
Nasario-Junior O, Benchimol-Barbosa PR, Nadal J.
Obtaining financing: Pedrosa RC, Nadal J. Writing of the
manuscript: Nasario-Junior O, Benchimol-Barbosa PR,
Pedrosa RC, Nadal J. Critical revision of the manuscript
for intellectual content: Nasario-Junior O, BenchimolBarbosa PR, Pedrosa RC, Nadal J. Supervision / as the
major investigador:Nadal J.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Sources of Funding
This study was partially funded by FAPERJ, CNPq e CAPES.
Study Association
This study is not associated with any thesis or dissertation work.
Nasario-Junior et al.
Phase RR-interval histogram in Chagas disease
Original Article
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Original Article
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Back to the Cover
Original Article
Post-Acute Coronary Syndrome Alcohol Abuse: Prospective
Evaluation in the ERICO Study
Abner Morilha, Samuel Karagulian, Paulo A. Lotufo, Itamar S. Santos, Isabela M. Benseñor, Alessandra C. Goulart
Centro de Pesquisa Clínica e Epidemiológica - Hospital Universitário, Universidade de São Paulo, São Paulo - Brazil
Abstract
Background: Some studies have indicated alcohol abuse as one of the contributors to the development of cardiovascular
disease, particularly coronary heart disease. However, this relationship is controversial.
Objective: To investigate the relationship between post-acute coronary syndrome (ACS) alcohol abuse in the Acute
Coronary Syndrome Registry Strategy (ERICO Study).
Methods: 146 participants from the ERICO Study answered structured questionnaires and underwent laboratory evaluations
at baseline, 30 days and 180 days after ACS. The Alcohol Use Disorders Identification Test (AUDIT) was applied to assess
harmful alcohol consumption in the 12 months preceding ACS (30 day-interview) and six months after that.
Results: The frequencies of alcohol abuse were 24.7% and 21.1% in the 12 months preceding ACS and six months after
that, respectively. The most significant cardiovascular risk factors associated with high-risk for alcohol abuse 30 days after
the acute event were: male sex (88.9%), current smoking (52.8%) and hypertension (58.3%). Six months after the acute
event, the most significant results were replicated in our logistic regression, for the association between alcohol abuse
among younger individuals [35-44 year-old multivariate OR: 38.30 (95% CI: 1.44-1012.56) and 45-54 year-old multivariate
OR: 10.10 (95% CI: 1.06-96.46)] and for smokers [current smokers multivariate OR: 51.09 (95% CI: 3.49-748.01) and past
smokers multivariate OR: 40.29 (95% CI: 2.37-685.93)].
Conclusion: Individuals younger than 54 years and smokers showed a significant relation with harmful alcohol
consumption, regardless of the ACS subtype. (Arq Bras Cardiol. 2015; 104(6):457-467)
Keywords: Alcoholism; Acute Coronary Syndrome; Myocardial Infarction; Alcohol Drinking; Questionnaires.
Introduction
According to recent data from the World Health
Organization (WHO), the prevalence of alcohol dependence
can reach 12% of the adult population. The probability of
alcohol dependence of subjects with any mental disorder
can be at least two times greater than that of individuals
without the disorder1. The burden is not equally distributed
among the countries. Alcohol consumption is the leading
risk factor for the burden of disease in developing countries
and the third largest risk factor in developed countries1.
It should be noted that drinking patterns have not only been
linked to acute health outcomes, such as injuries2,3, but also
to chronic diseases, such as coronary heart disease (CHD)4-7.
In fact, some studies even indicate alcohol abuse as one
of the contributors to the development of cardiovascular
diseases (CVD), particularly CHD 4-9 . However, this
Mailing Address: Alessandra C. Goulart •
Av. Prof. Lineu Prestes 2565, Cidade Universitária, Butantã.
Postal Code 05508-000, São Paulo, SP – Brazil
E-mail: [email protected]; [email protected]
Manuscript received July 14 , 2014; revised manuscript November 18, 2014;
accepted December 26, 2014.
DOI: 10.5935/abc.20150038
457
relationship is controversial 8. Although some beneficial
effects of moderate alcohol intake have been described, it
can become a risk factor for CHD if the alcohol consumption
pattern is characterized as “binge drinking or heavy episodic
drinking”, which is defined as more than five drinks for men
and four drinks for women in just one occasion1,6-9.
In developing countries, such as Brazil, alcohol is also
considered a risk factor that contributes most to the burden of
diseases, such as cirrhosis of the liver and several types of cancer1.
Therefore, we aimed to evaluate the hazardous and
harmful uses of alcohol and its dependence symptoms
30 days and 180 days after an acute coronary event
among participants from the ERICO study (Acute Coronary
Syndrome Registry Strategy)10.
Materials and Methods
Study design and population
This sub-study assessed harmful alcohol consumption,
hazardous alcohol consumption and dependence symptoms
in a subsample of the ERICO study, a prospective cohort study,
ongoing since 2009, which included potential participants with
ACS admitted to the São Paulo University-affiliated hospital
(HU-USP) in the city of São Paulo, Brazil10.
Morilha et al.
Alcohol abuse and acute coronary syndrome
Original Article
After signing the Informed Consent Form, patients
with confirmed medical diagnosis of ACS [ST-elevation
myocardial infarction (STEMI), non-ST-elevation acute
myocardial infarction (NSTEMI) or unstable angina (UA)]
were invited to participate in our sub-study 30 days after
the acute event. The eligibility criteria were: age ≥ 18 years,
confirmed diagnosis of ACS, and ability to understand and
speak Portuguese. The usual treatment for ACS has not
changed and the procedures followed were in accordance
with the ethical standards approved by the HU-USP
Institutional Review Board.
Exclusion criteria were based on a Psychological
Screening Questionnaire built on Structured Clinical
Interview for DSM Disorders (SCID - I) 11 to identify
individuals with psychotic, schizophrenia or bipolar
disorders, and on a test based on the Mini-Mental State
Exam (MMSE)12 to exclude those with cognitive impairment
or dementia 30 days after the acute event.
30- and 180-day follow-up
All participants who fulfilled the eligibility criteria
answered structured questionnaires and underwent clinical
and laboratory evaluations, including depression evaluation
using the Brazilian-Portuguese version of the Patient
Health Questionnaire (PHQ-9), which is composed of
nine questions that assess depressive mood and anhedonia
based on the Diagnostic and Statistical Manual of Mental
Disorders fourth edition (DSM-IV). The PHQ-9 scores each
of the nine DSM-IV criteria as “0” (not at all) to “3” (nearly
every day), the total score ranging from 0 to 27, and, in
this study, PHQ-9 was applied at baseline, and 30 and
180 days after ACS13,14.
In addition, hazardous and harmful alcohol consumption
and dependence symptoms were assessed by using the
Alcohol Use Disorders Identification Test (AUDIT) in a
personal and in a telephone interview, 30 and 180 days after
ACS, respectively15. Of note, 30 days after ACS, participants
were asked about alcohol abuse during the last 12 months,
and, during the 180-day interview, they were asked about
changes in their alcohol behavior six months after ACS.
Acute coronary syndrome definition
Myocardial infarction (MI) was defined as the presence
of symptoms consistent with cardiac ischemia in the
24 hours preceding hospital presentation and troponin
I levels above the 99th percentile with a test-specific
coefficient of variation < 10%16,17. STEMI was defined as
the presence of MI criteria plus one of the following: (a)
persistent ST-segment elevation ≥ 1 mm in two contiguous
electrocardiographic leads or (b) the presence of a new or
presumably new left bundle branch block. NSTEMI was
defined as the presence of MI criteria, but not of STEMI.
The UA diagnosis required the presence of symptoms
consistent with cardiac ischemia 24 hours prior to hospital
admission, absence of MI criteria and at least one of the
following: (a) history of CHD; (b) positive coronary disease
stratification test (invasive or non‑invasive); (c) transient
ST‑segment changes ≥ 0.5 mm in two contiguous leads,
new T-wave inversion ≥1 mm, and/or pseudonormalization
of previously inverted T waves; (d) troponin I >0.4 ng/mL
(which guarantees a troponin I level above the 99th
percentile regardless of the kit used); or (e) diagnostic
concordance between two independent doctors.
Alcohol abuse definition
Based on the AUDIT score that ranges from 1 to 40, the
following cutoff points were considered for main analyses:
≤ 7, low-risk drinking; and ≥ 8, high-risk alcohol abuse18-20.
In secondary analysis, the following three AUDIT domains
were also evaluated:
a) Hazardous alcohol use (1-7 points) - characterized as a
pattern that increases the risk of harmful consequences
for the user and/or others. These patterns are of public
health significance despite the absence of any current
disorder in the user;
b)Harmful alcohol use (8-19 points) - refers to alcohol
intake that might result in consequences for physical
and mental health. Some would also consider the social
consequences of the harm caused by alcohol;
c) Alcohol dependence symptoms (≥ 20 points) characterized by a cluster of behavioral, cognitive and
physiological phenomena, which may develop after
repeated alcohol use. Typically, these phenomena
include a strong desire to consume alcohol, impaired
control of its use, persistent drinking, despite harmful
consequences, a higher priority given to consumption
than to other activities and obligations, increased
substance tolerance and physical withdrawal reaction
when the substance use is discontinued18-20.
Two trained psychologists administered all questionnaires
during the follow-up.
Statistical analysis
The participants’ baseline characteristics, including ACS
subtypes, were described according to the alcohol abuse
symptoms assessed by using the AUDIT questionnaire, with
the following cutoff points suggested in the literature19-21:
≤ 7, low-risk drinking; and ≥ 8, high-risk alcohol abuse18-20.
In addition, the baseline characteristics were classified
according to the AUDIT domains (hazardous alcohol use,
harmful alcohol use and alcohol dependence symptoms).
Categorical variables were analyzed by using chi‑square
test, and continuous variables, by using Student t or
Mann‑Whitney test, according to continuous variables
distribution. Additionally, we performed multivariate logistic
regression adjusted to potential confounders (or those with a
p-value < 0.2 on univariate analysis) identified at 30 days to
evaluate the odds ratios (OR) with 95% confidence intervals
(CI) for the possible association of some classical cardiovascular
risk factors (CVRF) with alcohol abuse 180 days after the acute
event. All analyses with a p-value < 0.05 were considered
statistically significant. The SPSS software, version 19.0, was
used to perform all statistical analyses.
Arq Bras Cardiol. 2015; 104(6):457-467
458
Morilha et al.
Alcohol abuse and acute coronary syndrome
Original Article
Results
Case series
Of 225 patients with a confirmed diagnosis of ACS (STEMI,
NSTEMI or UA) and included in the main study, 146 (64.9%)
were enrolled in the present sub-study. At 180 days, 142 (63%)
were evaluated, because four died during the period.
The reasons for no inclusion in this study were early death
(16/225, 7.1%) within 30 days and exceeded time limit for
the interview (63/209, 30.1%).
Evaluation of alcohol abuse during follow-up
AUDIT score was almost the same (3.8 points) for the entire sample
and by sex (men: 5.1 vs. women: 1.6). The most significant results
observed at 30 days were replicated in our logistic regression
after 180 days, for the association between alcohol abuse among
younger individuals [35‑44 year‑old multivariate OR: 38.30
(95% CI: 1.44-1012.56) and 45‑54 year‑old multivariate
OR: 10.10 (95% CI: 1.06‑96.46)] and for smokers [current smokers
multivariate OR: 51.09 (95% CI: 3.49-748.01) and past smokers
multivariate OR: 40.29 (95% CI: 2.37-685.93)] (Table 3).
Depression versus alcohol abuse during follow-up
In this sub-sample, no statistical association was found
between depression and alcohol use after multivariate analysis
during the follow-up.
30-day follow-up
The baseline characteristics of all 146 participants in
the main study were described according to alcohol abuse
symptoms assessed by using the information obtained
from AUDIT (Table 1) in a personal interview 30 days after
ACS. The frequency of alcohol abuse was 24.7% in the
first period, reflecting the alcohol abuse in the 12 months
preceding ACS.
The overall mean AUDIT score was 4.8 points, being
higher in men as compared to women (6.3 vs. 2.0,
p ≤ 0.001). In addition, the frequency of alcohol abuse
(score ≥ 8) was higher among men as compared to women
(88.9% vs. 11.1%, p = 0.001) and among current smokers
as compared to past or non-smokers (52.8% vs. 38.9% vs.
8.3%, p = 0.004) and patients with hypertension (58.3%,
p = 0.03) (Table 1). Interestingly, the sample with alcohol
abuse suggested by AUDIT showed a statistically lower
frequency of classical CVRF, such as dyslipidemia, diabetes
and sedentary lifestyle, as compared to individuals without
alcohol abuse, but with no statistical significance (Table 1).
The frequency of alcohol abuse did not differ in the ACS
subtypes during follow-up (Figure 1).
At 30 days, we also found statistically significant associations
between some sociodemographic and cardiovascular risk
factors and each item of the AUDIT domains, except for
questions 7 (“Guilt after drinking”) and 8 (“Blackouts”) in the
“Harmful alcohol use” domain. In general, high frequencies
of positive answers were found among men and smokers
(Table 2). Interestingly, we found higher frequencies of positive
answers for question 5 (“Increased salience of drinking”)
from the “Dependence symptoms” domain among those
who had STEMI as compared to the other ACS subtypes
(Table 2). Further, we found higher frequencies of positive
answers among participants who had hypertension, diabetes,
dyslipidemia and a sedentary lifestyle as compared to those
without these comorbidities in the three domains, particularly
in the “Dependence symptoms” and the “Harmful alcohol
use” domains (Table 2).
180-day follow-up
Six months after the acute event, we observed a slight reduction
in the alcohol abuse frequency, which was 21.1% among the
142 survivors by the end of the follow-up. In addition, the mean
459
Arq Bras Cardiol. 2015; 104(6):457-467
Sensitivity analyses
In additional analyses, we compared ERICO participants
who were excluded (79) or did not complete the entire
follow‑up (four deaths between 30 days and 180 days after
the acute event) with those who completed the 180-day
follow‑up (142) in this sub-study. Individuals who were
followed up for six months after an acute event in this
sub‑study had a higher educational level (9-11 years of
formal education: 59.9% vs. 56.1, p = 0.04), were mostly
white or of mixed self-reported heritage (96.4% vs. 89%,
p = 0.03) and had a more sedentary lifestyle (63.8% vs.
81.5%, p = 0.006) than those who were not followed‑up
(Table 4). Moreover, comparing ERICO participants
included in this sub-study of alcohol abuse (146) with the
ERICO population (820), we found that the former had a
higher educational level (≥ 11 years of formal education:
12.3% vs. 6.8%, p=0.02) and most were married (69.2%
vs. 59.6%, p = 0.03). In addition, their frequencies of
diabetes (30.8% vs. 41.2%, p=0.02) and of sedentary
lifestyle (64.8% vs. 73.0%, p = 0.05) were lower than those
found in the ERICO population. Finally, a high proportion
of STEMI cases (36.3% vs. 26.5%, p = 0.02) was detected
in this sub-study (Table 5).
Discussion
This sub-study showed that three of ten patients were at
high risk for alcohol abuse. The alcohol abuse frequency was
24.7% 30 days after ACS, and decreased by 4% six months
later. As expected, higher frequencies of alcohol abuse were
observed in men, younger individuals and smokers.
Data from a Brazilian population-based study, the Megacity
Mental Health Survey, performed with 5,037 individuals in
the city of São Paulo, reported an overall lifetime prevalence
of alcohol abuse of 9.8%. In a sex-stratified analysis, a higher
prevalence of alcohol abuse was found among men (16.4%
vs. 4.0%) based on the DSM-VI and WHO-Composite
International Diagnostic Interview (WMH-CIDI)21.
Another Brazilian hospital-based study performed with
345 patients with ACS (206 with MI and 139 with UA)
interviewed about sociodemographic data, smoking status,
screening for depression (Prime-MD and Beck Depression
Inventory - BDI) and anxiety (State-Trait Anxiety Inventory for
Morilha et al.
Alcohol abuse and acute coronary syndrome
Original Article
Table 1 – Baseline characteristics of the 146 participants in the sub-study of alcohol abuse/dependence in the ERICO study, according to the
presence of harmful alcohol use 30 days after an acute coronary event
Sociodemographic characteristics
Low-risk
n = 110 (75.3%)
High-risk*
n = 36 (24.7%)
Total
n = 146 (100%)
p value
Age range (%)
35-44 years
4 (3.6)
3 (8.3)
7 (4.8)
45-54 years
19 (17.3)
13 (36.1)
32 (21.9)
55-64 years
39 (35.5)
12 (33.3)
51 (34.9)
65-74 years
28 (25.5)
3 (8.3)
31 (21.2)
≥ 75 years
20 (18.2)
5 (13.9)
25 (17.1)
Male
63 (57.3)
32 (88.9)
95 (65.1)
Female
47 (42.7)
4 (11.1)
51 (34.9)
0.046
Gender (%)
0.001
Educational level (%)
9 (8.2)
2 (5.6)
11 (7.5)
1-7 years of education
Illiterate
42 (38.2)
18 (50.0)
60 (41.1)
≥ 8 years of education
59 (53.6)
16 (44.4)
75 (51.4)
Single
8 (7.3)
4 (11.1)
12 (8.2)
Married
0.47
Marital Status (%)
73 (66.4)
28 (77.8)
101 (69.2)
Separated
8 (7.3)
3 (8.3)
11 (7.5)
Widow(er)
21 (19.1)
1 (2.8)
22(15.1)
White
75 (68.2)
19 (54.3)
94 (64.8)
0.20
Self-reported ethnicity (%)
Brown
31 (28.2)
14 (40.0)
45 (31.0)
Black
2 (1.8)
2 (5.7)
4 (2.8)
Yellow
2 (1.8)
-
2 (1.4)
0.25
Clinical comorbidities (%)
Smoking
Current
30 (27.3)
19 (52.8)
49 (33.6)
Past
45 (40.9)
14 (38.9)
59 (40.4)
Never
35 (31.8)
3 (8.3)
38 (26.0)
Hypertension
83 (76.9)
21(58.3)
104 (72.2)
0.004
0.03
Diabetes mellitus
37 (33.9)
7 (20.6)
44 (30.8)
0.14
Dyslipidemia
57 (56.4)
13(39.4)
70 (52.2)
0.09
Sedentary lifestyle
73 (68.9)
18 (51.4)
91 (64.5)
0.06
Major depression†
37 (33.6)
15 (41.7)
52 (35.6)
0.38
Acute Coronary Syndrome subtype (%)
Unstable angina
28 (25.5)
4 (11.1)
32 (21.9)
NSTEMI
46 (41.8)
16 (44.4)
62 (42.5)
STEMI
36 (32.7)
16 (44.4)
52 (35.6)
0.16
STEMI: ST-elevation myocardial infarction; NSTEMI: non-ST-elevation myocardial infarction.
Some proportions might not add up to 100% due to rounding or missing values. *Individuals who scored 8 points or more on the AUDIT were considered with tendency
to alcohol abuse. †The PHQ-9 score ≥ 10 points suggested major depression. P-values are derived from the Chi-square test.
Arq Bras Cardiol. 2015; 104(6):457-467
460
Morilha et al.
Alcohol abuse and acute coronary syndrome
Original Article
11.1%
10.0%
44.4%
43.3%
44.4%
46.7%
0.16
0.14
Figure 1 – Alcohol consumption suggestive of alcohol abuse detected by AUDIT in the subsample from the ERICO study.
UA: Unstable Angina; NSTEMI: non-ST-elevation acute myocardial infarction; STEMI: ST-elevation myocardial infarction.
Adults - STAI), and alcohol consumption (AUDIT) has reported
lower AUDIT scores for both sexes as compared to those found
in our study. Similar to our findings, that study has reported no
association between alcohol intake and depression22.
Regarding CVRF, participants at high risk for alcohol abuse
had a higher frequency of smoking but lower frequencies of
hypertension, dyslipidemia, diabetes and sedentary lifestyle as
compared to low-risk participants. However, when analyzing
each item separately, significant associations were observed
with some binging behaviors in the AUDIT domains, such as
“increased salience of drinking” and “morning drinking”, and
smoking, sedentary lifestyle, hypertension, diabetes, and
even ACS subtype. After six months, a high risk of alcohol
abuse remained among younger individuals (≤ 54 years)
and smokers.
The relationship between alcohol consumption and CVD,
particularly CHD, is controversial4-9,23.
Some studies have suggested that a light-moderate
alcohol consumption may have a favorable impact on
morbidity and mortality from ischemic heart disease6-8.
However, the cardioprotective effect of drinking
disappears with heavy drinking (binge) 6-8 . Russel et
al. 6 have tested a linear dose-response model for the
association between drinking patterns and MI6. A lower
MI risk was associated with the consumption of less than
4.55 drinks per day for men (95% CI: 2.77 to 7.18) and
less than 3.08 drinks per day for women (95% CI: 1.35 to
5.16), and that risk increased after these crossover points
were exceeded. The MI risk increased as drinking dosage
doubled, regardless of sex6.
461
Arq Bras Cardiol. 2015; 104(6):457-467
The Prospective Epidemiological Study of Myocardial
Infarction (PRIME) has investigated the effect of alcohol intake
patterns on ischemic heart disease in Northern Ireland and
France in 9,778 men aged 50-59 years, free of ischemic
heart disease at baseline, during a 10-year follow-up 7.
After multivariate analysis for classic CVRF and center, the
hazard ratio for hard coronary events (incident MI and
coronary death) compared with regular drinkers was as
follows: 1.97 (95% CI: 1.21 to 3.22) for binge drinkers;
2.03 (95% CI: 1.41 to 2.94) for never drinkers; and 1.57
(95% CI: 1.11 to 2.21) for former drinkers for the entire cohort.
Only wine drinking was associated with a lower risk of hard
coronary events, irrespective of the country7.
A systematic review that investigated the relationship
between alcohol consumption and some CVD endpoints
performed with more than 4,000 studies has described a
dose-response effect, demonstrated by the lowest risk of CHD
mortality occurring with one to two drinks per day23.
Another systematic review including 44 observational
studies (case-control or cohort) has reported a relative risk
of alcohol intake in relation to ischemic heart disease risk.
The analyses included 957,684 participants and substantial
heterogeneity across studies was found, making it difficult to
confirm any cardioprotective effect of alcohol use on ischemic
heart disease for all drinkers, even at low intake levels8.
The pathophysiology of the cardioprotective effects of
most alcoholic beverages is probably due to a high-density
lipoprotein elevation and the ability of alcohol to prevent
platelet aggregation and increase fibrinolysis; particularly an
increased favorable effect from red wine24.
Morilha et al.
Alcohol abuse and acute coronary syndrome
Original Article
Table 2 – Distribution of positive answers according to baseline characteristics by AUDIT domains 30 days after an acute event in the
sub‑sample of 146 participants from the ERICO study
Domains
Subgroup of risk
Hazardous alcohol consumption
p-value
Frequency of drinking (question 1)
Male gender (%)
46 (79.3)
0.003
Single
6 (10.3)
0.04
Married
43 (74.1)
Separated
6 (10.3)
Widow(er)
3 (5.2)
Marital status (%)
Smoking (%)
Current
28 (48.3)
Past
24 (41.4)
Never
6 (10.3)
< 0.001
Typical quantity (question 2)
Male gender (%)
21 (84,0)
0.003
Current
17(68,0)
< 0.001
Past
7 (28,0)
Never
1(4,0)
Smoking (%)
Frequency of heavy drinking (question 3)
Male gender (%)
36 (87.8)
< 0.001
Current
20 (48.8)
0.02
Past
16 (39.0)
Never
5 (12.2)
Smoking (%)
Dependence Symptoms
Impaired control over drinking (question 4)
Acute coronary syndrome subtype (%)
Unstable angina
0 (0)
NSTEMI
5 (38.5)
STEMI
8 (61.5)
Acute coronary syndrome subtype (%)
Unstable angina
0.053
Increased salience of drinking (question 5)
0 (0)
0.046
NSTEMI
2 (25.0)
STEMI
6 (75.0)
Morning drinking (question 6)
Male gender (%)
18 (85.7)
0.03
Hypertension (%)
11 (52.4)
0.03
Diabetes mellitus (%)
2 (10.0)
0.03
Harmful alcohol consumption
Guilt after drinking(question 7)
None
Arq Bras Cardiol. 2015; 104(6):457-467
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Morilha et al.
Alcohol abuse and acute coronary syndrome
Original Article
Continuation
Blackouts (question 8)
None
Alcohol-related injuries (question 9)
Male gender
Dyslipidemia (%)
9 (100,0)
0.02
1 (12,5)
0.02
Others concerned about drinking consumption
(question 10)
Age range (years) (%)
35-44
4 (9.8)
45-54
14 (34.1)
55-64
14 (34.1)
65-74
3 (7.3)
≥ 75
6 (14.6)
Male gender (%)
0.02
34 (82.9)
0.005
Current
24 (58.5)
< 0.001
Past
15 (36.6)
Smoking (%)
Never
2 (4.9)
Hypertension (%)
23 (56.1)
0.006
Sedentary lifestyle (%)
19 (47.5)
0.008
P-values are derived from the Chi-square test. Some proportions may not round up to 100% because of missing data
STEMI: ST-elevation myocardial infarction; NSTEMI: non-ST-elevation myocardial infarction.
Limitations
We did not evaluate the alcohol intake with a specific
food questionnaire. However, we used a very reliable
instrument to screen alcohol abuse/dependence 16. In
the present study, two well-trained and experienced
psychologists interviewed our patients; however the
presence of a psychiatrist during the study could have
contributed further to the detection of new cases of alcohol
abuse or even depression.
We found some significant differences in the frequency
of some sociodemographic factors, such as educational
level, self-reported ethnicity and marital status, as well
as, some CVRF, such as diabetes and sedentary lifestyle,
comparing participants from the alcohol abuse study with
those who did not participate in this sub-study. Of note,
all these characteristics are very subject to recall bias and
had no interference on the alcohol abuse pattern in our
main analyses.
Additionally, the extent to which the findings can be
generalized is limited due to the small sample size from one
single center. Thus, we cannot rule out the possibility of a
selection bias.
463
Arq Bras Cardiol. 2015; 104(6):457-467
Conclusions
We found high frequency of alcohol abuse, which
remained during the six-month follow-up, regardless of the
ACS subtype. Hazardous alcohol consumption was strongly
evident among younger individuals aged 35-54 years and
smokers. In the present study, the binge drinking pattern
was observed among smokers, individuals with a sedentary
lifestyle, hypertension, diabetes and STEMI.
Author contributions
Conception and design of the research: Morilha A,
Karagulian S, Goulart AC. Acquisition of data: Morilha A,
Karagulian S, Goulart AC. Analysis and interpretation of the
data: Lotufo PA, Santos IS, Goulart AC. Statistical analysis:
Morilha A, Lotufo PA, Santos IS, Benseñor IM, Goulart AC.
Obtaining financing: Goulart AC. Writing of the manuscript:
Morilha A, Karagulian S, Lotufo PA, Santos IS, Benseñor
IM, Goulart AC. Critical revision of the manuscript for
intellectual content: Morilha A, Karagulian S, Lotufo PA,
Santos IS, Benseñor IM, Goulart AC. Supervision / as the major
investigador: Morilha A, Goulart AC.
Morilha et al.
Alcohol abuse and acute coronary syndrome
Original Article
Table 3 – Factors associated with alcohol abuse/dependence assessed on logistic regression by AUDIT on 142 participants of the ERICO
study 180 days after an acute coronary event
Acute Coronary Syndrome
Low-risk
OR (95%CI)
High-risk *
multivariate OR (95%CI)
UA
Reference (1.0)
Reference (1.0)
NSTEMI
Reference (1.0)
1.27 (0.18-8.92)
STEMI
Reference (1.0)
1.77 (0.24-12.99)
Female
Reference (1.0)
Reference (1.0)
Male
Reference (1.0)
3.51 (0.78-15.82)
35-44 years
Reference (1.0)
38.30 (1.44-1021.56)
45-54 years
Reference (1.0)
10.10 (1.06-96.46)
55-64 years
Reference (1.0)
0.71 (0.09-5.87)
65-74 years
Reference (1.0)
1.07 (0.11-10.81)
≥ 75 years
Reference (1.0)
Reference (1.0)
Current
Reference (1.0)
51.09 (3.49-748.01)
Past
Reference (1.0)
40.29 (2.37-685.93)
Never
Reference (1.0)
Reference (1.0)
Hypertension
Reference (1.0)
1.43 (0.36-5.68)
Diabetes mellitus
Reference (1.0)
0.90 (0.19-4.25)
Dyslipidemia
Reference (1.0)
0.36 (0.10-1.30)
Sedentary lifestyle
Reference (1.0)
0.29 (0.09-0.99)
Gender
Age Range
Smoking
* Subjects who scored 8 points or more on the AUDIT were considered with high-risk alcohol abuse.
STEMI: ST-elevation myocardial infarction; NSTEMI: non-ST-elevation myocardial infarction; UA: unstable angina. OR (odds ratio), 95% confidence interval (95%CI).
Multivariate OR was adjusted for ACS subtype, gender, age, smoking, medical diagnosis or medication use for hypertension, diabetes mellitus and dyslipidemia, and
sedentary lifestyle. Except itself.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Study Association
This article is part of the thesis of master submitted by Abner
Morilha, from University of São Paulo (USP).
Sources of Funding
This study was funded by FAPESP.
Arq Bras Cardiol. 2015; 104(6):457-467
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Morilha et al.
Alcohol abuse and acute coronary syndrome
Original Article
Table 4 – Comparison of baseline characteristics of 142 individuals from the alcohol abuse sub-study and those of 83 individuals who were
not followed-up 180 days post-ACS in the ERICO study
Baseline characteristics
ERICO participants with 180-day follow-up in the alcohol abuse sub-study
YES (n = 142)
NO (n = 83)
7 (4.9)
2 (2.4)
0.21
Age range (years) (%)
35-44
p-value
45-54
34 (23.9)
14 (16.9)
55-64
50 (35.2)
24 (28.9)
65-74
28 (19.7)
23 (27.7)
≥ 75
23 (16.2)
20 (24.1)
Male
91 (64.1)
48 (57.8)
Female
51 (35.9)
35 (42.2)
28 (19.7)
15 (18.3)
Gender (%)
0.04
Educational level (years) (%)
Up to 8
0.35
9-11
85 (59.9)
46 (56.1)
≥ 11
29 (20.4)
20 (24.4)
0.18
Marital status (%)
Single
12 (8.5)
11 (13.4)
Married
99 (69.7)
44 ( 53.7)
Divorced
9 (6.3)
9 (11.0)
Widow(er)
22 (15.5)
18 (22.0)
0.03
Self-reported ethnicity (%)
White
91 (64.5)
57(69.5)
Brown
45 (31.9)
16 (19.5)
Black
3 (2.1)
8 (9.8)
Asian
2 (1.4)
1 (1.2)
Current
49 (34.5)
25 (30.5)
Past
56 (39.4)
28 (34.1)
Clinical comorbidities (%)
Smoking
0.34
Never
37 (26.1)
29 (35.4)
Hypertension
100 (71.4)
63 (75.9)
0.47
Diabetes mellitus
41 (29.5)
32 (38.6)
0.17
Dyslipidemia
67 (51.5)
41 (56.9)
0.46
Sedentary lifestyle
88 (63.8)
66 (81.5)
0.006
Unstable angina
36 (25.4)
30 (36.1)
NSTEMI
54 (38.0)
34 ( 41.0)
STEMI
52 (36.6)
19 (22.9)
0.09
Acute coronary syndrome (%)
STEMI: ST-elevation myocardial infarction; NSTEMI: non-ST-elevation myocardial infarction
Some proportions might not add up to 100% due to rounding or missing values. P-values are derived from the Chi-square test.
465
Arq Bras Cardiol. 2015; 104(6):457-467
Morilha et al.
Alcohol abuse and acute coronary syndrome
Original Article
Table 5 – Comparison of baseline characteristics of 146 participants from the alcohol abuse sub-study and those of the ERICO study population
Baseline characteristics
Participants (n = 146)
Non participants (n = 820)
p-value
62 (11.8)
63 (13.6)
0.26
Male
95 (65.1)
476 (58.0)
0.11
Female
51 (34.9)
344 (42.0)
Mean age ( ± SD)
Gender (%)
0.02
Educational level (years) (%)
Up to 8
98 (67.1)
631 (77.1)
9-11
30 (20.5)
131 (16.0)
≥ 11
18 (12.3)
56 (6.8)
Single
45 (30.8)
329 (40.4)
Married
101 (69.2)
486(59.6)
White
94 (64.4)
538(65.6)
Brown
45 (30.8)
224 (27.3)
Black
4 (2.7)
46(5.6)
Asian
3 (2.1)
12 (1.5)
Current
49 (33.6)
257 (28.8)
Past
59 (40.4)
325 (36.5)
Never
38 (26.0)
309 (34.7)
Hypertension
Marital status (%)
0.03
Self-reported ethnicity (%)
Clinical comorbidities (%)
Smoking
0.12
104 (72.2)
624 (78.0)
0.13
Diabetes mellitus
44(30.8)
326 (41.2)
0.02
Dyslipidemia
70 (52.2)
386 (55.4)
0.50
Sedentary lifestyle
92 (64.8)
552 (73.0)
0.05
0.02
Acute coronary syndrome (%)
Unstable angina
36 (24.7)
282 (34.4)
NSTEMI
57 (39.0)
321 (39.1)
STEMI
53 (36.3)
217 (26.5)
Some proportions might not add up to 100% due to rounding or missing values.
P-values are derived from the Chi-square test. STEMI: ST-elevation myocardial infarction; NSTEMI: non-ST-elevation myocardial infarction
Arq Bras Cardiol. 2015; 104(6):457-467
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Morilha et al.
Alcohol abuse and acute coronary syndrome
Original Article
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Arq Bras Cardiol. 2015; 104(6):457-467
Back to the Cover
Original Article
APOE and LDLR Gene Polymorphisms and Dyslipidemia Tracking.
Rio de Janeiro Study
Rossana Ghessa Andrade de Freitas1, Erika Maria Gonçalves Campana1,2, Roberto Pozzan1,2, Andréa Araujo
Brandão1,2, Ayrton Pires Brandão1,2, Maria Eliane Campos Magalhães1,2, Dayse Aparecida da Silva1,3
Universidade do Estado do Rio de Janeiro1; Hospital Universitário Pedro Ernesto2; Instituto de Biologia Roberto Alcântara Gomes3, Rio de
Janeiro, RJ – Brazil
Abstract
Background: Studies show an association between changes in apolipoprotein E (ApoE) and LDLR receptor with the
occurrence of dyslipidemia.
Objectives: To investigate the association between polymorphisms of the APOE (ε2, ε3, ε4) and LDLR (A370T) genes with
the persistence of abnormal serum lipid levels in young individuals followed up for 17 years in the Rio de Janeiro Study.
Methods: The study included 56 individuals (35 males) who underwent three assessments at different ages: A1 (mean age
13.30 ± 1.53 years), A2 (22.09 ± 1.91 years) and A3 (31.23 ± 1.99 years). Clinical evaluation with measurement of blood
pressure (BP) and body mass index (BMI) was conducted at all three assessments. Measurement of waist circumference
(WC) and serum lipids, and analysis of genetic polymorphisms by PCR-RFLP were performed at A2 and A3. Based on
dyslipidemia tracking, three groups were established: 0 (no abnormal lipid value at A2 and A3), 1 (up to one abnormal lipid
value at A2 or A3) and 2 (one or more abnormal lipid values at A2 and A3).
Results: Compared with groups 0 and 1, group 2 presented higher mean values of BP, BMI, WC, LDL-c and TG (p < 0.01)
and lower mean values of HDL-c (p = 0.001). Across the assessments, all individuals with APOE genotypes ε2/ε4 and
ε4/ε4 maintained at least one abnormal lipid variable, whereas those with genotype ε2/ε3 did not show abnormal values
(χ2 = 16.848, p = 0.032). For the LDLR genotypes, there was no significant difference among the groups.
Conclusions: APOE gene polymorphisms were associated with dyslipidemia in young individuals followed up
longitudinally from childhood. (Arq Bras Cardiol. 2015; 104(6):468-475)
Keywords: Polymorphism, Genetic; Dyslipidemias; Young Adult; Epidemiology; Apolipoproteins E.
Introduction
Cardiovascular diseases (CVDs) are the leading causes
of death in adults worldwide, contributing to high rates of
early morbidity and mortality1,2. In Brazil, CVDs concentrate
annually 1/3 of the overall deaths3,4.
Dyslipidemia is one of the risk factors (RF) for
development of CVDs 5. Given its importance, studies
are being conducted to determine the abnormalities
associated with plasma lipid changes and their implications
on the occurrence of CVDs6,7. In genetics, several gene
polymorphisms and mutations have been identified and
associated with atherosclerosis and coronary artery disease
(CAD)8,9. This is the case of the apolipoprotein E (ApoE),
which is essential for the transport and metabolism of
Mailing address: Rossana Ghessa Andrade de Freitas •
Laboratório de Diagnósticos por DNA. Universidade do Estado do Rio de
Janeiro. Instituto de Biologia Roberto Alcântara Gomes. Rua São Francisco
Xavier, 524, Pavilhão Haroldo Lisboa da Cunha. Postal Code 20550-900,
Rio de Janeiro, RJ – Brazil
E-mail: [email protected]
Manuscript received August 27, 2014; revised manuscript January 21, 2015;
accepted January 28, 2015.
DOI: 10.5935/abc.20150036
468
cholesterol and structural stability of lipoproteins 10,11, and
whose gene has three polymorphic alleles (ε2, ε3 and
ε4) 12. Population studies have shown higher plasma levels
of low-density lipoprotein cholesterol (LDL-c) in carriers
of the ε4 allele12, leading to an association of this allele
with the occurrence of CVDs13.
Mutations in the LDL receptor gene (LDLR) have also
been implicated with dyslipidemias, particularly in primary
forms of homozygous or heterozygous hypercholesterolemia
such as familial hypercholesterolemia (FH), a condition
associated with early severe atherosclerosis and CAD14‑16.
The LDLR gene encodes a protein with binding domains
for apolipoproteins B and E. Among the different
polymorphisms found in the LDLR gene, the A370T has
been investigated for its association with increased lipid
levels and cardiovascular risk17,18.
Dyslipidemias may be present from an early age,
and abnormal lipids tend to persist over time (tracking
effect) until adulthood. The identification of genetic
markers involved with abnormal lipid metabolism may
contribute to the recognition at a young age of patterns
of genetic susceptibility and guide interventions to correct
these abnormalities.
Freitas et al.
Genetic polymorphisms and dyslipidemia tracking
Original Article
Based on that, the aim of this study was to investigate
the distribution pattern of polymorphisms of the APOE and
LDLR genes and their associations with the dyslipidemia
phenotype, notably on its tracking effect, in a young
population followed up for 17 years.
Method
The sample of this study was retrieved from the
Study of Rio de Janeiro (Estudo do Rio de Janeiro, ERJ).
This longitudinal cohort study is part of a line of research on
blood pressure (BP) and other cardiovascular RFs in young
adults developed in 1983 at the Hypertension Unit of the
Hospital Universitário Pedro Ernesto (HUPE) at Universidade
do Estado do Rio de Janeiro (UERJ)19.
The ERJ included three different assessments, named A1, A2
and A3. Assessment A1 was conducted between 1987 and 1988
in individuals aged 10-16 years (mean 13.30 ± 1.53 years), A2
was conducted between 1996 and 1999 in individuals aged
18-26 years (mean 22.09 ± 1.91 years) and A3 was conducted
between 2004 and 2005 in individuals aged 27‑35 years
(mean 31.23 ± 1.99 years)19.
We selected for genetic evaluation 75 individuals from the
original ERJ cohort who had undergone all three assessments
(A1, A2 and A3). However, laboratory evaluation was not
performed in 19 individuals at A2 and these individuals
were excluded from the analysis, yielding a study sample of
56 individuals with serum lipid evaluation at assessments A2
and A3, as well as genetic profile evaluation.
Dyslipidemia was considered present when one or
more lipid values were increased (total cholesterol [Col-T],
LDL-c and triglycerides [TG]) or decreased (high-density
lipoprotein cholesterol [HDL-c]), alone or in combination,
using as cutoff values those recommended by the V Brazilian
Guideline on Dyslipidemias and Atherosclerosis Prevention20.
The tracking effect consists of a repeat behavior of these
abnormal variables (increase or decrease) at both assessments
conducted during young adulthood (A2 and A3).
Three groups were established based on the occurrence
of dyslipidemia tracking:
Measurement of BP
Measurement of BP was carried out according to
the recommendations of the VI Brazilian Guidelines of
Hypertension21. The BP was measured on the right arm, with
the individual lying down and then seated, using an aneroid
mercury sphygmomanometer (Romed) fixed to the wall, and
zeroed to the midaxillary line. We selected cuffs with size
and width suitable for the circumference and length of the
individuals’ arms. We considered as systolic BP (SBP) the
appearance of the first Korotkoff sound (Korotkoff phase I),
and for diastolic BP (DBP), the disappearance of the sound
(Korotkoff phase V). The BP was measured three times with
5-minute intervals between each measurement, and the last
measurement was used for the analysis. We considered the
BP to be increased in A1 when SBP and/or DBP was ≥ 95th
percentile for gender and age, and in A2 and A3 when SBP
was ≥ 140 mmHg and/or DBP ≥ 90 mmHg.
Anthropometric variables
Weight (W) and height (H) were measured on a platform
scale (Filizola, São Paulo, Brazil) with a 150-kilogram (kg)
capacity and 100-gram precision. Weight was expressed in
kg and determined with the individual barefoot and wearing
light clothes. Height was expressed in centimeters (cm) and
determined from the distance between the vertex of the
head to the soles of the feet with the individual in an upright
position and barefoot22.
From the measurements of weight and height, we
calculated the BMI using the formula BMI = W/H2 and
expressed the results in kg/m2.
The WC was measured parallel to the ground with a
flexible and inelastic tape measure with precision of 0.1 cm,
with the individual in an upright position and the abdomen
relaxed. The measurement was determined horizontally on
the shortest distance between the lower border of the last
rib and the iliac crest, with the tape held firmly but without
pressure against the skin22.
Laboratory variables
Group 0: No abnormal lipid variables in A2 and A3;
n = 11 individuals (10 women) with a mean age of
30.89 ± 1.64 years;
Blood was collected by antecubital venipuncture under
standard conditions in the morning (before 8:30 am) after a
12-hour fasting.
Group 1: At least one abnormal lipid variable in one of
the evaluations (A2 or A3); n = 12 individuals (10 men) with
a mean age of 31.47 ± 2.35 years;
All samples were placed in siliconized vacuum tubes and
processed in up to 30 minutes. Measurements were performed
in the serum obtained after centrifugation at a speed of 3,500
rotations per minute for five minutes.
Group 2: One or more abnormal lipid variables in two
evaluations (A2 and A3); n = 33 individuals (24 men) with a
mean age of 31.25 ± 1.99 years.
Clinical, anthropometric, laboratory, and genetic
evaluations
Both BP and BMI were evaluated at A1, A2 and A3.
The A2 and A3 assessments also included measurements of
Col-T, HDL-c and TG after a 12-hour fasting, and calculation
of LDL-c. Blood collection for genetic testing and measurement
of waist circumference (WC) were performed at A3.
For measurement of serum cholesterol and HDL-c, we
used the enzymatic colorimetric method CHOD/PAP and
for measurement of TG, we used the enzymatic method
GPD/BAP. To calculate the LDL-c levels, we used the
Friedewald formula when TG levels were < 400 mg/dl.
Genetic analysis
DNA was extracted by the salting-out method using
2-ml aliquots of whole blood23. The analyses of the allelic
variants of the APOE gene (ε2, ε3, ε4) were carried out with
Arq Bras Cardiol. 2015; 104(6):468-475
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Freitas et al.
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the technique of polymerase chain reaction (PCR) with the
primers APOE F 5'- TAA GCT TGG CAC GGC TGT CCA
AGG A-3' and APOE R 5'- ACA GAA TTC GCC CCG GCC
TGG TAC AC-3' in 35 PCR cycles (95ºC for 60 sec, 63ºC
for 60 sec and 72ºC for 120 sec) to amplify a product of
244 base pairs (bp)24. The products of PCR amplification
were digested with the enzyme HhaI (Fermentas) and the
fragments were visualized in 12% polyacrylamide gel by
silver nitrate staining. The fragments representing each
genotype are as follows: ε2ε3 (91, 83 and 48 bp), ε3ε4
(91, 72 and 48 bp), ε2ε4 (91, 83, 72 and 48 bp) and ε3ε3
(91 and 48 bp).
To genotype the A370T polymorphism, a region of
150 bp was amplified by PCR using the primers P1: 5’‑GAG
TGT CAG GAT CCC GAC ACC TGC GCC-3’ and P2: 5 '-AAG
TCG ACC CAC CCG CCT GCC TCC CGT-3' in 35 cycles
(95°C for 60 sec, 68°C for 60 sec and 72° C for 120 sec)25.
To determine the polymorphism, PCR products were
digested with the enzyme HaeIII (Biotech), and fragments
were separated on 3.5% agarose gel and visualized by
ethidium bromide staining. The fragments representing A
allele were 77, 47 and 26 bp, and those representing the
T allele were 124 and 26 bp.
To demonstrate the random genetic distribution of the
ERJ cohort, the genotype and allelic frequencies of the
polymorphisms analyzed in the study were compared with
those observed in a cohort of 75 non-hospitalized individuals
(41 men and 34 women) randomly selected from a DNA
database of more than 10,000 individuals who underwent
parental testing, provided for this study by the Laboratório
de Diagnósticos por DNA (LDD) at UERJ. This sample was
identified as LDD. It is worth noting that the populations
are not required to be phenotypically homogeneous for
comparison of genetic distribution.
The study was approved by the Ethics Committee for
Research of HUPE under the number 2130-CEP/HUPE, and
all participants signed an Informed Consent Form.
Statistical Analysis
For statistical treatment of the data, we used the software
SPSS for Windows version 12.0 (Chicago, Illinois, USA).
Gene and haplotype frequencies were estimated according
to Saitou and Nei26, using the program Arlequin, version
3.0 27. Chi-square test (χ²) and analysis of variance (F)
were used to compare the pattern of distribution of the
polymorphisms with clinical anthropometric and lipid
variables, with p < 0.05 results considered significant.
The test of homogeneity of variances was applied to
evaluate the normal distribution of the studied variables.
Results
The sample consisted of 56 individuals, 35 (62.5%) of
whom were males and 21 (37.5%) females, aged between
27-35 years (mean 31.23 ± 1.99 years). Table 1 presents
the clinical, anthropometric and laboratory variables of the
studied population at all three assessments (A1, A2 and A3).
Table 2 shows the results of clinical (SBP and DBP),
anthropometric (WC and BMI) and laboratory (Col-T,
HDL-c, LDL-c and TG) variables at A3 for all three groups
(groups 0, 1 and 2) stratified by dyslipidemia tracking.
When compared with groups 0 and 1, group 2 presented
higher mean values of SBP, BMI, WC, TG and LDL-c and
lower mean values of HDL-c.
The genetic analysis of the 56 individuals identified the
following genotypes for APOE: ε3ε3 (62.5%), ε3ε4 (25.0%),
ε2ε3 (5.4%), ε2ε4 (5.4%) and ε4ε4 (1.8%) (Table 3).
As for the distribution of the APOE genotypes in the
groups according to the occurrence of dyslipidemia
tracking, we observed that in group 0, genotype ε3ε3
affected 45.5% of the individuals, followed by ε2ε3 and
ε3ε4, each affecting 27.3% of the individuals. In group 1,
the ε3ε3 genotype was present in 83.3% of the individuals
and the ε3ε4 genotype in 16.7%. Genotypes ε2ε3, ε2ε4
and ε4ε4 were not observed in group 1. In group 2, which
Table 1 – Clinical, anthropometric and laboratory variables of the studied population at three assessments*
Evaluations
Variables
A1 (n = 56)
A2 (n = 56)
A3 (n = 75)
Age (years)
13.30 ± 1.53
22.09 ± 1.91
31.23 ± 1.99
SBP (mmHg)
115.28 ± 14.83
124.35 ± 13.79
125.43 ± 16.67
DBP (mmHg)
63.81 ± 12.84
79.86 ± 10.79
83.20 ± 13.72
BMI (kg/m )
20.26 ± 3.05
24.04 ± 3.64
26.79 ± 5.53
WC (cm)
-
-
92.96 ± 14.66
Col-T (mg/dL)
-
175.37 ± 34.34
181.44 ± 31.72
TG (mg/dL)
-
88.37 ± 42.34
103.71 ± 56.14
HDL-c (mg/dL)
-
45.87 ± 13.16
49.05 ± 15.87
LDL-C (mg/dL)
-
111.82 ± 27.58
111.23 ± 27.95
2
* Values are expressed as mean ± standard deviation; SBP: systolic blood pressure; DBP: diastolic blood pressure; BMI: body mass index; WC: waist circumference;
Col-T: total cholesterol; TG: triglycerides; HDL-c: high-density lipoprotein cholesterol; LDL-c: low-density lipoprotein cholesterol.
470
Arq Bras Cardiol. 2015; 104(6):468-475
Freitas et al.
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Table 2 – Clinical, anthropometric and laboratory variables at A3 in the studied groups according to dyslipidemia tracking*
Variables
Groups of dyslipidemia
0 (n = 11)
1 (n = 12)
2 (n = 33)
Test F
p
Age (years)
30.89 ± 1.64
31.47 ± 2.35
31.25 ± 1.99
0.239
0.788
SBP (mmHg)
114.36 ± 14.58
120.17 ± 13.05
129.76 ± 15.79
5.01
0.01
DBP (mmHg)
76.36 ± 8.66
78.17 ± 13.89
85.27 ± 13.44
2.69
0.07
BMI (kg/m2)
23.81 ± 3.72
24.34 ± 4.02
28.67 ± 5.81
5.43
0.007
WC (cm)
Col-T (mg/dL)
80.50 ± 6.74
86.91 ± 8.72
98.63 ± 14.26
10.86
< 0.001
164.45 ± 18.35
179.58 ± 29.12
187.78 ± 34.50
2.37
0.10
HDL-c (mg/dL)
62.09 ± 9.63
53.0 ± 11.55
43.51 ± 15.99
7.50
0.001
LDL-C (mg/dL)
89.47 ± 13.59
106.56 ± 28.60
119.90 ± 27.55
6.01
0.004
TG (mg/dL)
64.18 ± 31.44
81.33 ± 41.37
125.03 ± 57.68
7.48
0.001
10 F / 1 M
2 F/ 10 M
9 F/ 24 M
-
-
Gender
* Values expressed as mean ± standard deviation; group 0: no abnormal lipid variable at A2 and A3; group 1: one or more abnormal lipid variables at A2 or A3; group 2: one
or more abnormal lipid variables at A2 and A3; SBP: systolic blood pressure; DBP: diastolic blood pressure; BMI: body mass index; WC: waist circumference; Col-T: total
cholesterol; HDL-c: high-density lipoprotein cholesterol; LDL-c: low-density lipoprotein cholesterol; TG: triglycerides; F: female; M: male; F-test: analysis of variance.
Table 3 – APOE genotypes according to dyslipidemia group*
Dyslipidemia group
APOE genotypes
ε2ε3 n(%)
Total
0
n = 11 (19.6%)
1
n = 12 (21.4%)
2
n = 33 (59.0%)
n = 56 (100.0%)
3 (27.3%)
-
-
3 (5.4%)
ε3ε3 n(%)
5 (45.5%)
10 (83.3%)
20 (60.6%)
35 (62.5%)
ε3ε4 n(%)
3 (27.3%)
2 (16.7%)
9 (27.3%)
14 (25%)
ε2ε4 n(%)
-
-
3 (9.1%)
3 (5.4%)
ε4ε4 n(%)
-
-
1 (3.0%)
1 (1.8%)
* Values are expressed as n (%) χ = 16.848; p = 0.032; APOE: apolipoprotein E gene; group 0: no abnormal lipid variable at A2 and A3; group 1: one or more
abnormal lipid variables at A2 or A3; group 2: one or more abnormal lipid variables at A2 and A3.
2
featured the greatest genotype diversity in the sample, the
distribution was 60.6% for ε3ε3, 27.3% for ε3ε4, 9.1% for
ε2ε4 and 3% for ε4ε4. Genotype ε2ε3 was not observed
in this group. This distribution had statistical significance
(χ2 = 16.848, p = 0.0032) and showed that 39.4% of the
individuals in group 2 had genotypes containing the ε4
allele. It should be noted that all subjects with genotypes
ε2ε4 and ε4ε4 maintained at least one abnormal lipid
value in A2 and A3 (group 2 – one or more abnormal lipid
variables in A2 and A3), whereas none of the subjects with
genotype ε2ε3 had abnormal lipids (group 0 – no abnormal
lipid values in A2 and A3) (Table 3).
We also analyzed the polymorphisms of the LDLR gene and
identified the following genotypes: AA in 85.7%, AT in 12.5%
and TT in 1.8% of the individuals (Table 4).
The analysis of the distribution of LDLR genotypes according
to dyslipidemia tracking showed no statistically significant
difference between the groups (Table 4).
For comparison purposes, the genotype and allele
frequencies of APOE and LDLR gene polymorphisms of
the 56 individuals from the ERJ cohort and 75 individuals
from the LDD cohort are shown in Table 5. Fisher's exact
test showed no significant differences between the allele
distributions of the ERJ and LDD cohorts.
Discussion
Studies have shown an association between APOE and
LDLR genotypes with increased levels of lipid macromolecules
such as Col-T, TG and LDL-c, decreased levels of HDL-c, and
cardiovascular disease, especially CAD11,28.
In the present study, we investigated the distribution pattern
of APOE and LDLR gene polymorphisms in a population of
adolescents followed up for 17 years, considering the occurrence
of dyslipidemia based on change (increase or decrease) of one
or more lipid variables and their repetition (tracking) at two
different moments (A2 and A3) during young adulthood.
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Table 4 – LDLR genotypes according to dyslipidemia group*
Dyslipidemia group
LDLR genotypes
Total
0
n = 11 (19.6%)
1
n = 12 (21.4%)
2
n = 33 (59.0%)
n = 56 (100.0%)
AA n (%)
9 (81.8%)
10 (83.3%)
29 (87.9%)
48 (85.7%)
AT n (%)
2 (18.2%)
2 (16.7%)
3 (9.1%)
7 (12.5%)
TT n (%)
-
-
1 (3.0%)
1 (1.8%)
* Values expressed as n (%) χ2 = 1.500; p = 0.827; LDLR: low-density lipoprotein receptor gene; group 0: no abnormal lipid variable at A2 and A3; group 1: one or
more abnormal lipid variable at A2 or A3; group 2: one or more abnormal lipid variable at A2 and A3.
Table 5 – Genotype and allele frequencies of APOE and LDLR gene polymorphisms in the ERJ and LDD cohorts
APOE
Genotypes
LDLR
Frequency (%)
Genotypes
ERJ(n = 56)
LDD(n = 75)
5.3
4.2
ε2ε3
Frequency (%)
ERJ(n = 56)
LDD(n = 75)
AA
88.0
86.5
ε3ε3
66.7
75.0
AT
10.6
13.5
ε3ε4
22.7
18.0
TT
1.3
-
ε2ε4
4.0
2.8
ε4ε4
1.3
-
Alleles
Frequency (%)
Alleles
Frequency (%)
ε2
6.6
3.5
A
93.5
93.3
ε3
79.4
86.0
T
6.5
6.7
10.5
13.5
ε4
14.0
10.5
Ho
34.6
25.0
Ho
He
34.8
24.8
He
12.3
12.6
HWE
p = 0.5098
DP = 0.0005
p = 0.2128
DP = 0.0004
HWE
p = 0.2715
DP = 0.0004
p = 1.000
DP = 0.00
Fisher's exact test
p = 0.51528
DP = 0.001
-
Fisher's exact test
p = 0.990,
SD = 0.003
-
ERJ: participants of the Rio de Janeiro Study; LDD: cohort from the Laboratório de Diagnósticos por DNA; APO: apolipoprotein E gene; LDLR: low-density lipoprotein
receptor gene; He: expected heterozygosity, Ho: observed heterozygosity; HWE: Hardy-Weinberg equilibrium; SD: standard deviation.
In the analysis of APOE polymorphisms based on dyslipidemia
tracking, our study showed that individuals with genotype ε2ε3
were concentrated in group 0, that is, the group in which
lipid variables (Col-T, TG, HDL-c and LDL-c) were normal at
two evaluations (A2 and A3). These findings are in agreement
with those by Ferreira et al.29 who demonstrated in a study
with 216 individuals (109 with dyslipidemia and 107 without
dyslipidemia) a similar frequency of allele distribution for APOE
polymorphisms in both groups. However, in individuals with
normal lipid levels in that study, the presence of the ε2 allele
was strongly associated with low serum levels of Col-T and
LDL-c, which may suggest a possible protective role associated
with this allele29,30.
Similarly, Bazzaz et al. 31 , in a cohort study with
320 individuals in Iran, investigated the association between
APOE gene polymorphisms, lipid profile and BMI. The authors
472
Arq Bras Cardiol. 2015; 104(6):468-475
observed that the ε2 allele was more frequent in individuals
with Col-T < 200 mg/dl (p = 0.01), and found an even greater
association of the individuals with normal serum Col-T levels
with genotype ε2ε3 when compared with individuals with
abnormal levels of Col-T (p = 0.003)31.
As for the ε4 allele, studies in the general population and
hypertensive patients have shown an association of this allele
with an increase in levels of Col-T and LDL-c. Due to that, the
ε4 allele has been associated with higher risk of CAD even
in healthy individuals28,32. Fuzikawa et al.30, in a study with
1,406 adults of both genders, observed a high prevalence of
hypertension (61.3%) and higher average values of LDL-c in
patients with the ε4 allele (p = 0.036) when compared with
patients with the ε2 allele (p < 0.001)30. Similarly, Salazar et
al.33 showed an association of the ε4 allele with dyslipidemias
in a study that investigated APOE gene polymorphism in
Freitas et al.
Genetic polymorphisms and dyslipidemia tracking
Original Article
150 women with and without CAD. Compared with the
control group in that cohort, women with CAD showed
significantly higher levels of Col-T, TG and LDL-c and a higher
frequency of the ε4 allele and the ε3ε4 genotype33.
In the present study, 18 individuals (32.1%) were carriers of
the ε4 allele in different genotype combinations, 13 (72.2%)
of whom were in group 2 which aggregated higher values of
SBP, BMI and WC and therefore, worse cardiovascular risk
profile. It is worth noting that the only individual in the cohort
with genotype ε4ε4 was in group 2.
Thus, the evidence seems to point to a possible damaging
role for the ε4 allele and a protective role for the ε2 allele.
However, the combination of these alleles in different
genotypes can render these roles less clear. In this study for
example, all subjects with genotype ε2ε4 were in group 2
which had the worse risk profile and one or more abnormal
lipid variables at two evaluations. This result seems to suggest
that when the ε4 allele is present, the protective role of the
ε2 allele is either lost or decreased.
In the present study, we also observed a predominance
of males in group 2 (n = 24; 72.72%) (Table 2). This group
presented the worst cardiovascular risk profile, which is in
line with the premise that the male gender is associated with
increased cardiovascular risk21.
We found no association between LDLR gene
polymorphisms and dyslipidemia tracking in the young
individuals of this cohort. Frikke-Schmidt et al.25 also found
no significant association between plasma levels of Col-T,
LDL-c and individuals with AA genotype compared with
those with a TT genotype. However, these authors reported
increased risk (3.6 times) of ischemic stroke in homozygous
individuals with a TT genotype compared with those with
an AA genotype25.
We found five genotypes for the APOE polymorphism in
the ERJ cohort. As for the LDLR polymorphism, all three were
found in this cohort. The most frequent APOE genotypes were
ε3ε3 and the most frequent LDLR genotype was AA.
It is worth noting that the genotype and allele frequencies
found in the ERJ cohort for APOE gene polymorphisms were
similar to those found in cohorts from other states in Brazil, such
as the cohort from Rio Grande do Sul (Porto Alegre)12 and in
other cohorts worldwide34. The genotype and allele frequencies
of the ERJ cohort for the LDLR polymorphisms were similar
to those found in other populations, such as the one from
the study of Frikke-Schmidt et al.25. Similarly, the comparison
of the genetic distribution in the ERJ cohort with that from a
representative sample group randomly selected from the state of
Rio de Janeiro (LDD), and the confirmation of the homogeneity
of their distributions, suggests that the ERJ cohort has a random
profile, suitable for the development of the proposed study.
Despite the limitations of the study, the association
between a specific genetic profile with the presence
of dyslipidemia in young individuals over time in a
small population brings a novel and relatively unknown
perspective to the currently available medical literature.
Studies with more than 20 years of follow-up, such as the
ERJ, have losses associated with the longitudinal tracking
of the participants, but have unequivocally contributed to
a better understanding of the behavior of cardiovascular
risk factors in the Brazilian population.
Conclusion
A study of APOE gene polymorphisms in participants of
the ERJ showed that the presence of the ε4 allele was more
prevalent in group 2, which consisted of young individuals
with repeatedly abnormal lipid variables during longitudinal
follow-up (tracking effect). This group also showed aggregation
of worse anthropometric variables (higher BMI and WC) and
increased BP, rendering a worse cardiovascular risk profile to
these individuals.
This study was partially funded by the Coordenação de
Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and
Fundação Carlos Chagas de Amparo à Pesquisa do Estado do
Rio de Janeiro (FAPERJ).
Author contributions
Conception and design of the research:Freitas RGA,
Campana EMG, Brandão AA, Brandão AP, Magalhães MEC,
Silva DA. Acquisition of data: Freitas RGA, Campana EMG,
Brandão AP, Silva DA. Analysis and interpretation of the data:
Freitas RGA, Pozzan R. Statistical analysis: Pozzan R. Writing
of the manuscript: Brandão AA, Magalhães MEC, Silva DA.
Critical revision of the manuscript for intellectual content:
Freitas RGA. Supervision / as the major investigador:Magalhães
MEC, Silva DA.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Study Association
This article is part of the thesis of master submitted by
Rossana Ghessa Andrade de Freitas, from Universidade do
Estado do Rio de Janeiro.
Sources of Funding
This study was funded by CAPES E FAPERJ.
Arq Bras Cardiol. 2015; 104(6):468-475
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Arq Bras Cardiol. 2015; 104(6):468-475
Freitas et al.
Genetic polymorphisms and dyslipidemia tracking
Original Article
Arq Bras Cardiol. 2015; 104(6):468-475
475
Back to the Cover
Original Article
Circulatory and Ventilatory Power: Characterization in Patients with
Coronary Artery Disease
Viviane Castello-Simões1, Vinicius Minatel1, Marlus Karsten1,2, Rodrigo Polaquini Simões1, Natália Maria Perseguini1,
Juliana Cristina Milan1, Ross Arena3, Laura Maria Tomazi Neves1, Audrey Borghi-Silva1, Aparecida Maria Catai1
Laboratório de Fisioterapia Cardiovascular, Núcleo de Pesquisa em Exercício Físico, Universidade Federal de São Carlos1, São Carlos, SP;
Departamento de Fisioterapia, Universidade Federal de Ciências da Saúde de Porto Alegre2, Porto Alegre, RS – Brazil; Departamento de Fisioterapia e
Laboratório de Fisiologia Integrativa, Faculdade de Ciências Aplicadas da Saúde, Universidade de Illinois Chicago3, Chicago, IL – USA
Abstract
Background: Circulatory power (CP) and ventilatory power (VP) are indices that have been used for the clinical evaluation
of patients with heart failure; however, no study has evaluated these indices in patients with coronary artery disease (CAD)
without heart failure.
Objective: To characterize both indices in patients with CAD compared with healthy controls.
Methods: Eighty-seven men [CAD group = 42 subjects and healthy control group (CG) = 45 subjects] aged 40–65 years were
included. Cardiopulmonary exercise testing was performed on a treadmill and the following parameters were measured:
1) peak oxygen consumption (VO2), 2) peak heart rate (HR), 3) peak blood pressure (BP), 4) peak rate-pressure product
(peak systolic HR x peak BP), 5) peak oxygen pulse (peak VO2/peak HR), 6) oxygen uptake efficiency (OUES), 7) carbon
dioxide production efficiency (minute ventilation/carbon dioxide production slope), 8) CP (peak VO2 x peak systolic BP) and
9) VP (peak systolic BP/carbon dioxide production efficiency).
Results: The CAD group had significantly lower values for peak VO2 (p < 0.001), peak HR (p < 0.001), peak systolic BP (p < 0.001),
peak rate-pressure product (p < 0.001), peak oxygen pulse (p = 0.008), OUES (p < 0.001), CP (p < 0.001), and VP (p < 0.001)
and significantly higher values for peak diastolic BP (p = 0.004) and carbon dioxide production efficiency (p < 0.001) compared
with CG. Stepwise regression analysis showed that CP was influenced by group (R2 = 0.44, p < 0.001) and VP was influenced by
both group and number of vessels with stenosis after treatment (interaction effects: R2 = 0.46, p < 0.001).
Conclusion: The indices CP and VP were lower in men with CAD than healthy controls. (Arq Bras Cardiol. 2015;
104(6):476-486)
Keywords: Exercise; Oxygen Uptake; Cardiopulmonary Exercise; Cardiovascular Disease, Adults.
Introduction
Cardiopulmonary exercise testing (CPX) is considered
the gold standard for evaluating the response to aerobic
exertion in patients with cardiovascular diseases to determine
the physiological mechanisms of exercise intolerance1.
Some indices, such as peak oxygen consumption (VO2), carbon
dioxide production eficiency derived from the linear relationship
between minute ventilation (VE) and carbon dioxide production
(VCO2) (VE/VCO2 slope)2 and oxygen uptake efficiency (OUES),
derived from the linear relationship between VO2 and VE3,4,
Mailing Address: Viviane Castello-Simões •
Universidade Federal de São Carlos – Departamento de Fisioterapia. Rodovia
Washington Luis km 235, Jardim Guanabara. Postal Code 13565-905,
São Carlos, SP – Brazil
E-mail: [email protected]
Manuscript received August 8, 2014; revised manuscript January 23, 2015;
accepted January 23, 2015.
DOI: 10.5935/abc.20150035
476
have been used to assess healthy subjects2,4, patients with
heart failure5-8 and with other forms of heart disease9, such as
coronary artery disease (CAD)10,11. Circulatory power (CP) is a less
frequently assessed variable obtained from CPX and calculated as
the product of peak VO2 and peak systolic blood pressure (BP).
CP has shown some potential for clinical utility12-15 and has been
proposed as a surrogate for cardiac power. This index has also
been shown to be an independent predictor of mortality, with
a lower CP portending a worse prognosis12,14,15. More recently,
Forman et al. (2012)16 introduced and evaluated the prognostic
use of a novel index, named ventilatory power (VP), which was
calculated by dividing peak systolic BP by the VE/VCO2 slope.
According to the authors, better prognosis is reflected by a higher
VP value, i.e., greater systolic BP and/or lower VE/VCO2 slope.
While these variables have been assessed in heart failure
cohorts, we are unaware of any previous study that evaluated
the CP and VP indices in CAD patients without heart failure
who were managed using standard medication, angioplasty
or coronary artery bypass graft (CABG) surgery. Thus, the
purpose of this study was to test the hypothesis that both CP
and VP would be significantly lower in these CAD patients
Castello-Simões et al.
Circulatory and ventilatory power
Original Article
compared with healthy controls; therefore, could provide
another potentially valuable measure of cardiopulmonary
function in these patients.
Methods
This is an observational, cross-sectional, comparative study.
Participants
Men between 40–65 years of age were allocated to
two groups: 1) patients with CAD confirmed by cardiac
catheterization (CAD-G) and without heart failure and 2) an
apparently healthy control group (CG). Subjects in CAD-G
were recruited through a local hospital (hemodynamic section)
and CG subjects were identified from a registry database in our
laboratory and contacted to determine interest. Subjects were
invited to participate in this study between June 2008 and April
2013. The inclusion criteria for CAD-G were: 1) CAD patients
with or without myocardial infarction (1 month to 3 years
since the event) optimally managed using current standard
pharmacologic regimens and potentially: a) mechanical or
chemical reperfusion and/or b) CABG surgery (6 months to
3 years post-surgery) and 2) preserved left ventricular function
with an ejection fraction > 50%. Inclusion criteria for CG
were: 1) apparently healthy based on clinical examination and
2) no use of prescription medications. The exclusion criteria
for both groups were: 1) body mass index (BMI) ≥ 30 kg/m2,
2) use of tobacco, 3) habitual drinking or illegal drug
use, 4) orthopedic limitations, 5) neurological disease,
6) diabetes, 7) uncontrolled systemic arterial hypertension,
8) functional capacity ≤ 4 metabolic equivalents, 9) lung
diseases, 10) inappropriate behavior of BP to exertion,
11) malignant ventricular arrhythmia, 12) atrial fibrillation,
13) complex ectopic ventricular beats, 14) supraventricular
or sinus tachycardia, 15) 2º and 3º atrioventricular block,
16) fixed frequency pacemaker, and 17) participation in a
regular exercise program in the last 6 months. This study
was approved by the local Ethics Committee and conducted
in accordance with the Declaration of Helsinki (1975).
Written informed consent was obtained from each individual
before the initiation of the study.
Clinical examination
Prior to study initiation, all subjects underwent a
clinical evaluation to characterize their clinical status.
The evaluation comprised: 1) clinical cardiac examination;
2) resting ECG (Ecafix TC 500, São Paulo, São Paulo,
Brazil); 3) maximal standard exercise test on a treadmill
(DIGISTRESS Vega, Digitronica, Belo Horizonte, Minas
Gerais, Brazil); and 4) laboratory measurements: glycemia,
hemoglobin, lipid profile, urea, creatinine, and uric acid.
Subjects discontinued pharmacological prior to the exercise
test, which was conducted by a physician using the Bruce
protocol17 in accordance with the American Thoracic Society
recommendations1, Symptoms of dyspnea and leg fatigue were
assessed using the modified Borg scale18 and all subjects were
asked about the occurrence of angina at each stage of the
exercise protocol.. After a minimum resting period of 48 h,
all eligible subjects performed CPX.
Cardiopulmonary exercise testing (CPX)
On the same day as CPX, the maximal walking velocity on
a treadmill (Master ATL, Inbramed, Porto Alegre, Rio Grande
do Sul, Brazil) was determined for all subjects. The starting
treadmill speed was set at 3.0 km/h without elevation, with
subsequent 0.5 km/h increases in speed every 30 s. At this
point, the speed was increased or decreased by 0.1 km/h
until the subjects reached a maximal comfortable walking
cadence without running19. After determining the maximal
walking velocity, symptom-limited CPX was performed using
a calibrated ventilatory expired gas unit (CPX-D, Medical
Graphics, Saint Paul, Minnesota, United States) according to
a ramping protocol: 1) 1 min at rest; 2) an incremental phase,
beginning at an initial speed of 0.8 km/h until maximal walking
velocity was reached; 3) 0.5% increase in incline grade every
15 s; 4) 1 min of active recovery at 3.0 km/h; and 5) 5 min
of passive recovery. Ventilatory expired gases were collected
breath-by-breath and calculated as moving means after every
eight respiratory cycles (Breeze Suite 6.4.1, Medical Graphics,
Saint Paul, Minnesota, United States)19,20. The criteria for test
termination were based on current exercise guidelines21,22.
Throughout CPX, ECG (12 simultaneous leads) and
heart rate (HR) were monitored and registered (WinCardio,
Micromed, Brasilia, Distrito Federal, Brazil). Delta of HR was
expressed as peak HR minus HR at rest and the predicted
maximum HR was calculated as 220 minus age in years.
The BP was measured at rest, every 2 min during the test
and throughout recovery (BD, São Paulo, São Paulo, Brazil).
Perceived exertion (symptoms of dyspnea and leg fatigue)
was assessed using the modified Borg scale18 and all subjects
were asked about the occurrence of angina and symptoms
at each stage of the exercise protocol, according to current
exercise guidelines21,22.
Peak VO2 and peak respiratory exchange ratio (RER)
(defined as the ratio between VCO2 and VO2) were expressed
as the highest averaged values observed during the last 30 s of
exercise19,23. The VE/VCO2 slope and the OUES were calculated
from the initiation of exercise to peak16,22. The VE/VCO2
slope was obtained by analyzing the linear relationship
between VE and VCO2, with VE on the y-axis and VCO2 on
the x-axis2. The OUES was obtained by analyzing the linear
relationship between VO2 and VE, with VO2 on the y-axis and
the log‑transformation of VE on the x-axis3,4. Other variables
were calculated: 1) peak rate-pressure product (RPP) = product
of peak systolic BP and peak HR; 2) peak oxygen pulse = peak
VO2 divided by the peak HR; 3) CP = product of peak VO2
and peak systolic BP12 and 4) VP = peak systolic BP divided
by the VE/VCO2 slope16.
Statistical analysis
Based on a pilot study using VP and CP as endpoints
(CAD-G = 5 individuals; CG = 5 individuals), a sample size for
the current study that would provide sufficient statistical power
(β = 0.8) to detect an important difference (α = 0.05) was
estimated to be 12 and 21 subjects (VP and CP, respectively)
in each group (GPower software package, version 3.1.6, Kiel,
Schleswig–Holstein, Germany). The Kolmogorov–Smirnov
test was used to investigate the data distribution. Continuous
Arq Bras Cardiol. 2015; 104(6):476-486
477
Castello-Simões et al.
Circulatory and ventilatory power
Original Article
quantitative variables were expressed as mean ± standard
deviation (SD) and categorical variables as absolute values
and percentages. Subjective data (dyspnea and leg fatigue)
were expressed as median ± [minimum − maximum].
The unpaired Student’s t-test was used to compare the
continuous quantitative variables between CAD-G and
CG. Fisher’s exact test was used to compare the categorical
variables between groups and the situations after versus
before treatment. Stepwise regression analysis was performed
to determine the possible influence of group, medications,
risk factors (hypertension and dyslipidemia) and number
of vessels with stenosis after treatment on the main studied
variables (HR, BP, VO2, VE/VCO2 slope, CP and VP). One-way
ANOVA (followed by Tukey’s post-hoc test) was performed
after subdividing CAD-G according to the type of event and
treatment to assess possible differences between subgroups.
Pearson correlation analysis was applied to determine the
relationships between CP or VP and peak VO2, OUES, RPP
and oxygen pulse. The probability of type 1 error occurrence
was established at 5% for all tests (p < 0.05). SPSS (version
17.0, SPSS Inc., Chicago, Illinois, United States) was used to
perform the statistical analysis.
Results
Of a total of 97 apparently healthy subjects, we excluded
52 subjects aged < 40 or > 65 years. Forty-five subjects
were contacted and recruited for CG. In relation to CAD-G,
54 subjects were recruited; however, 12 were excluded after
clinical examination because of BMI ≥ 30 kg/m2 (n = 2),
use of tobacco (n = 2), chronic obstructive pulmonary
disease (n = 2), presence of cardiac arrhythmias (n = 2),
uncontrolled systemic arterial hypertension (n = 1), restenosis
after mechanical reperfusion (n = 2), and inability to perform
the maximal standard exercise test (n = 1). Thus, our sample
consisted of 87 men (45 in CG and 42 in CAD-G). It is
important to emphasize that a preliminary analysis (one-way
ANOVA) was performed by dividing CAD-G into subgroups
according to the type event and treatment. There were no
significant differences between subgroups pertinent to any of
the studied variables; thus, we pooled the data of all patients
in CAD-G.
The characteristics of CAD-G and CG are presented in
Table 1. No significant difference was found between groups
with regard to age (p = 0.087), height (p = 0.318), weight
(p = 0.165), and BMI (p = 0.222). In relation to the clinical
data of CAD-G before treatment, most patients had two vessels
with stenosis (33%), and considering only the 41 subjects with
stenosis, the vessel most affected was the anterior descending
artery (78%). After treatment, most patients had one-vessel
stenosis (48%), and considering only the 29 subjects with
stenosis, the vessel most affected was the left circumflex artery
(45%). Most subjects in CAD-G (76%) previously suffered a
myocardial infarction and had been managed in the following
ways: 1) only with standard medication (2%), 2) angioplasty
(60%), and 3) CABG (14%). The remaining subjects in the
experimental group had CAD with no previous myocardial
infarction (24%) and had been managed with: 1) medication
only (5%), 2) angioplasty (7%), and 3) CABG (12%) (Table 1).
Of the 42 subjects in CAD-G, 15 had a past smoking history and
478
Arq Bras Cardiol. 2015; 104(6):476-486
none was diabetic; furthermore, 38 subjects were diagnosed
with systemic arterial hypertension and 39 with dyslipidemia;
both risk factors were managed pharmacologically. Of the
45 subjects in CG, three had a past smoking history and none
had a diagnosis of diabetes, systemic arterial hypertension or
dyslipidemia. None of the CG subjects used any prescribed
medication (Table 1).
Table 2 shows the comparison between groups in relation to
peak variables obtained during the maximal standard exercise
test that preceded CPX. CAD-G had significantly lower values
for HR (p < 0.001) and systolic BP (p = 0.012) compared
with CG. In addition, CAD-G had significantly higher values
for diastolic BP (p = 0.016) and symptoms of dyspnea
and leg fatigue (p < 0.001 and p = 0.008, respectively)
compared with CG. Furthermore, the occurrence of angina
(reported by the patients) was present in only 5% of CAD-G
(n = 2), whereas it was not present in any subjects in CG.
ECG recordings revealed that 7% of CAD-G (n = 3) presented
ST segment depression < 2 mm and 5% (n = 2) presented
ST segment depression ≥ 2 mm; there was no abnormality
in ECG in CG (Table 2).
During CPX, the maximum walking velocity obtained
was significantly lower in CAD-G (6.2 ± 0.4 km/h, range:
5–7 km/h) than CG (7.1 ± 0.7 km/h, range: 6–8 km/h in CG)
(p < 0.001); however, there were no significant differences
with respect to maximum grade obtained between groups:
12.8 ± 4.9 % (range: 3.5–22 %) in CAD-G and 11.6 ± 5.6%
(range: 1.5–21 %) in CG (p = 0.311). Key CPX variables
and aerobic functional classification according to American
Heart Association (AHA) guidelines24 for CAD-G and CG are
presented in Table 3. There were no significant differences in
HR and BP between groups during rest. During peak effort,
CAD-G had significantly lower values for VO2 (p < 0.001),
HR (p < 0.001), % of predicted maximum HR (p < 0.001),
delta of HR (p < 0.001), systolic BP (p < 0.001), RPP
(p < 0.001), oxygen pulse (p = 0.008), OUES (p < 0.001),
CP (p < 0.001), and VP (p < 0.001) compared with CG.
In addition, during peak effort, CAD-G had significantly
higher values for diastolic BP (p < 0.001), the VE/VCO2 slope
(p = 0.004), symptoms of dyspnea and leg fatigue (p = 0.008
and p < 0.001, respectively) compared with CG. Furthermore,
angina (reported by the patients) occurred only in 2% of
CAD-G (n = 1) and was not present in any subjects in CG.
There were no ECG abnormalities in either group (CAD-G and
CG) during CPX (Table 3). With regard to the aerobic functional
classification according to AHA guidelines24, Table 3 shows
that the majority of patients of CAD-G had a weak aerobic
classification (53%), while in CG slightly more than half of
subjects had a regular level of aerobic classification (53%).
Stepwise regression analysis was performed to determine
the possible influence of group, medications, risk factors
(hypertension and dyslipidemia), and number of vessels
with stenosis after treatment on CPX variables of interest.
We found that none of the variables were affected by risk factors.
However, the following influences were determined: 1) peak
VO2 was influenced by group and medications (interaction
effects: R2 = 0.46, β of group = 0.95 and β of medications
= −0.35, p < 0.001); 2) peak systolic BP was influenced
only by medications (R2 = 0.11, β = 0.34, p < 0.001); 3) the
Castello-Simões et al.
Circulatory and ventilatory power
Original Article
Table 1 – Characteristics of CAD-G and CG
CAD-G (n = 42)
CG (n = 45)
p value
54.3 ± 6.6
53.9 ± 6.4
0.087
Height, m
1.70 ± 0.07
1.73 ± 0.13
0.318
Weight, kg
79.0 ± 12.3
76.9 ± 9.9
0.165
27 ± 3.9
26 ± 5.9
0.222
63.9 ± 7.1
-
-
Age, years
Anthropometry
Body mass index, kg/m2
Cardiac function
LVEF, %
Vessels with stenosis, n (%)
Before treatment (n = 42)
After treatment (n = 42)
1 (2)
13 (31)
-
< 0.001
One diseased vessel
10 (24)
20 (48)
-
0.039
Two diseased vessels
14 (33)
6 (14)
-
0.071
Three diseased vessels
8 (19)
3 (7)
-
0.194
Multivessel (> 3 diseased vessels)
9 (22)
0
-
0.002
Before treatment (n = 41)
After treatment (n = 29)
Without stenosis
Location of stenosis (> 50%), n (%)
Anterior descending artery
32 (78)
8 (28)
-
< 0.001
Left circumflex artery
26 (63)
13 (45)
-
0.147
Right coronary artery
24 (58)
10 (34)
-
0.056
Diagonal arteries
8 (19)
6 (21)
-
1.000
Marginal arteries
4 (10)
1 (3)
-
0.394
CAD characteristics, n (%)
With myocardial infarction
Treated only with medication
1 (2)
-
-
Treated with angioplasty
25 (60)
-
-
Treated with CABG
6 (14)
-
-
2 (5)
-
-
Treated with angioplasty
3 (7)
-
-
Treated with CABG
5 (12)
-
-
15 (36)
3 (7)
< 0.001
0
0
-
Arterial hypertension
38 (90)
0
< 0.001
Dyslipidemia
39 (93)
0
< 0.001
Without myocardial infarction
Treated only with medication
Risk factors, n (%)
History of smoking
Diabetes
Medications, n (%)
Beta-blocker
37 (88)
-
-
ACE inhibitor
24 (57)
-
-
Diuretic
12 (29)
-
-
Lipid-lowering
39 (93)
-
-
Antiplatelet/ anticoagulant
42 (100)
-
-
Data are presented as mean ± SD or absolute values (%).
CAD-G: coronary arterial disease group; CG: control group, n: number of individuals; LVEF: left ventricular ejection fraction; CABG: coronary artery bypass grafting;
(-): not applicable; ACE: angiotensin converting enzyme. Unpaired Student’s t-test and Fisher’s exact test.
Arq Bras Cardiol. 2015; 104(6):476-486
479
Castello-Simões et al.
Circulatory and ventilatory power
Original Article
Table 2 – Peak variables obtained during maximal standard exercise testing for clinical evaluation in CAD-G and CG
CAD-G (n = 42)
CG (n = 45)
p value
HR, bpm
144.9 ± 20.0
169.9 ± 19.1
< 0.001
Systolic BP, mmHg
175.7 ± 26.5
189.5 ± 22.3
0.012
Diastolic BP, mmHg
91.3 ± 11.8
85.0 ± 11.2
0.016
Symptoms of dyspnea (0–10)
7.0 [2 - 10]
4.0 [2 - 6]
< 0.001
Leg fatigue (0–10)
6.0 [0 - 10]
4.5 [2 - 5]
0.008
Angina, n (%)
2 (5)
0
0.230
ST segment depression < 2 mm, n (%)
3 (7)
0
0.108
ST segment depression ≥ 2 mm, n (%)
2 (5)
0
0.230
Data are presented as mean ± SD, median [minimum - maximum] or absolute values (%).
CAD-G: coronary artery disease group; CG: control group; n: number of subjects; HR: heart rate; BP: blood pressure. Unpaired Student’s t-test and Fisher’s exact test.
VE/VCO2 slope was influenced only by group (R2 = 0.08,
β = 0.30, p < 0.001); 4) CP was influenced only by group
(R2 = 0.44, β = 0.67, p < 0.001); and 5) VP was influenced
by group and number of vessels with stenosis after treatment
(interaction effects: R2 = 0.46, β of group = 0.62 and β of number
of vessels with stenosis after treatment = −0.30, p < 0.001).
Figure 1 illustrates a significant correlation between both
CP and VP and peak VO2, considering the subjects by aerobic
functional classification according to AHA guidelines24. For better
visualization of Figure 1, only those with a weak (n = 22) and
regular level of classification (n = 14) in CAD-G and only those
with regular (n = 24) and good level of classification (n = 15)
in CG were included in the statistical analysis and presented
in this figure. With respect to CP, there was a strong positive
correlation with peak VO2 (Figure 1A, r = 0.91, p < 0.001),
while VP showed a moderate positive correlation with peak VO2
(Figure 1B, r = 0.43, p < 0.001). Figure 2 illustrates the significant
correlations between CP and VP and other CPX indices (OUES,
RPP, and oxygen pulse), considering the entire study cohort.
CP exhibited a strong positive correlation with OUES (Figure 2A,
r = 0.75, p < 0.001) and peak RPP (Figure 2C, r = 0.74,
p < 0.001) and moderate positive correlation with peak oxygen
pulse (Figure 2E, r = 0.59, p < 0.001); with regard to VP there
was a moderate positive correlation with OUES (Figure 2B,
r = 0.55, p < 0.001), peak RPP (Figure 2D, r = 0.58, p < 0.001)
and peak oxygen pulse (Figure 2F, r = 0.55, p < 0.001).
Discussion
The main findings from this study were: 1) CAD patients
without heart failure under current standard pharmacologic
regimens, angioplasty, or surgical management had lower CP
and VP values compared with CG; 2) the indices CP and VP
correlated positively with VO2 according to aerobic functional
classification as per AHA guidelines24; and 3) the response of
CPX and the metabolic, ventilator, and cardiovascular variables
demonstrated lower functional capacity and poorer exercise
response in subjects with CAD.
To the best of our knowledge, this is the first study to
introduce CP and VP indices in the functional evaluation
of subjects with CAD without heart failure compared with
480
Arq Bras Cardiol. 2015; 104(6):476-486
apparently healthy controls. Thus, our findings have a potential
clinical relevance given that these indices may be used to
assess the functional significance of the disease process.
The potential advantage of CP and VP indices is that both are
simple and noninvasive and synergistically combine singular
indices related to cardiopulmonary integrity and health.
Sample characteristics
As listed in Table 1, the groups did not differ in terms of age;
this is an important consideration as it is known that aging affects
peak VO2 25,26. In addition, we did not include obese individuals
because they present with abnormal exercise responses
unique to body habitus, which could have confounded our
results27,28. We included patients with controlled systemic
arterial hypertension and controlled dyslipidemia in CAD-G;
however, we observed (using stepwise regression analysis) that
these factors did not influence the CPX response.
Cardiopulmonary exercise testing (CPX)
CP and VP were lower in CAD-G than in CG; the same
observation was applicable to the following peak variables
obtained during CPX: VO2, HR, % of predicted maximum
HR, delta of HR, systolic BP, RPP, oxygen pulse, and
OUES. Moreover, higher values of peak diastolic BP and
the VE/VCO2 slope were found in CAD-G. Pharmacologic
management, such as angiotensin-converting enzyme
inhibitors, diuretics, and particularly beta-blockers, may
contribute to the exercise response because CAD-G
presented with lower values of peak systolic BP, peak HR,
and peak VO2 in relation to CG during CPX. In addition,
during the maximal standard exercise test performed with
suspended pharmacological therapy, CAD-G presented
with a higher peak HR (approximately 7%) than CPX,
in which the subjects were undergoing pharmacological
therapy. Although these medications may have influenced
our results, they are considered standard of care therapy
for these patients29,30, and beta-blocker withdrawal can
increase the risk of heart events31. Because VO2 is present
in the formula of CP and BP is present in the formula of
CP and VP, it is important to consider that medications
Castello-Simões et al.
Circulatory and ventilatory power
Original Article
Table 3 – Variables obtained during cardiopulmonary exercise testing and aerobic functional classification according to AHA guidelines in
CAD-G and CG
CAD-G (n = 42)
CG (n = 45)
p value
65.9 ± 11
69.7 ± 11
0.110
Systolic BP, mmHg
120.7 ± 10.7
117.4 ± 18.7
0.298
Diastolic BP, mmHg
82.6 ± 7.6
79.7 ± 9.6
0.103
Rest
HR, bpm
Peak
VO2, ml.kg−1 min−1
22.9 ± 4.8
32.7 ± 6.6
< 0.001
RER
1.11 ± 0.07
1.12 ± 0.08
0.738
HR, bpm
135.4 ± 22.2
165.0 ± 18.7
< 0.001
% of predicted maximum HR
81.8 ± 13.4
97.7 ± 9.9
< 0.001
Delta of HR, bpm
52.7 ± 23.1
85.2 ± 20.7
< 0.001
Systolic BP, mmHg
169.8 ± 24.6
186.1 ± 19.8
< 0.001
Diastolic BP, mmHg
88.3 ± 9.9
80.1 ± 10.7
< 0.001
23052 ± 4889
30713 ± 4800
< 0.001
Oxygen pulse, mL/beat
13.5 ± 2.9
15.4 ± 3.8
0.008
VE/VCO2 slope
31.6 ± 5.2
28.6 ± 4.4
0.004
RPP, mmHg.bpm
OUES
1963 ± 449.7
2555 ± 552
< 0.001
CP, mmHg.ml.kg−1 min−1
3902 ± 1016
6099 ± 1403
< 0.001
VP, mmHg
5.5 ± 1.2
6.6 ± 1.3
< 0.001
Symptoms of dyspnea (0–10)
6.0 [4 - 8]
4.5 [2 - 5]
0.008
Leg fatigue (0–10)
7.0 [4 - 9]
4.5 [2 - 6]
< 0.001
1 (2)
0
0.230
ST segment depression < 2 mm, n (%)
0
0
-
ST segment depression ≥ 2 mm, n (%)
0
0
-
Very weak
6 (14)
1 (2)
0.052
Weak
22 (53)
3 (7)
< 0.001
Regular
14 (33)
24 (53)
0.083
Good
0
15 (33)
< 0.001
Excellent
0
2 (5)
0.494
Angina, n (%)
Aerobic functional classification, n (%)
Data are presented as mean ± SD, median [minimum - maximum] or absolute values (%).
CPX: cardiopulmonary exercise testing; AHA: American Heart Association; CAD-G: coronary artery disease group; CG: control group; n: number of subjects;
HR: heart rate; BP: blood pressure; VO : oxygen uptake; RER: respiratory exchange ratio; % of predicted maximum HR: % of 220 minus age; Delta of HR peak HR
minus HR at rest; RPP: rate-pressure product; VE/VCO2 slope: linear relation between minute ventilation, and carbon dioxide production; OUES: linear relationship
between oxygen uptake and minute ventilation, CP: circulatory power; VP: ventilatory power. Unpaired Student’s t-test and Fisher’s exact test.
2
influenced peak VO2 and peak systolic BP (as indicated
by stepwise regression analysis), but did not influence CP
and VP. Furthermore, the group influenced peak VO2, the
VE/VCO2 slope, CP, and VP, while the number of vessels
with stenosis after treatment influenced the VP. Thus, we
believe that the lower values of CP and VP observed during
CPX in CAD-G are related to standard medications, level
of aerobic capacity and characteristics of CAD and that the
reduction of VP in this population may also be related to
number of vessels with stenosis after treatment.
One way to quantify exercise performance is by
measuring peak VO2. In the present study the lower values
of this variable observed in CAD-G reinforce the role of
CAD in a worse CPX response10, which was also directly
related to the ventilatory inefficiency observed in this group
(higher VE/VCO2 slope and lower OUES). High values of the
VE/VCO2 slope are often related to a worsening pulmonary
hemodynamic profile and increased chemoreceptor and
ergoreceptor activation, as well as decreased autonomic
modulation and cardiovascular function7. Lower OUES
Arq Bras Cardiol. 2015; 104(6):476-486
481
Castello-Simões et al.
Circulatory and ventilatory power
Original Article
Figure 1 – Circulatory power (CP) and ventilatory power (VP) correlated with oxygen uptake (VO2) by aerobic functional classification according to American Heart
Association guidelines. Legend: (ο) coronary artery disease group (CAD-G) with weak functional classification, (•) CAD-G with regular functional classification, (∆) control
group (CG) with regular functional classification and (▲) CG with good functional classification. Pearson correlation analysis.
values indicate that the extraction and utilization of oxygen
is impaired because this variable is strongly correlated
to VO 2 3,4,10. Furthermore, we observed in the present
study that RPP and oxygen pulse were lower in CAD-G at
peak CPX. RPP has been used as a relevant parameter in
evaluating ventricular function, and high values at peak
exercise are most likely related to good ventricular function
and no ischemia32,33. In addition, the oxygen pulse indicates
the amount of oxygen consumed per heart beat, which
reflects the efficiency of the cardiovascular system and may
provide prognostic information in patients with CAD34,35.
Another interesting and novel finding of this study was
that subjects with a lower peak VO2 presented with lower
indices CP and VP that correlated with the aerobic functional
classification according to AHA guidelines 24. A recent
prospective study36 that evaluated the associations between
exercise test parameters and all-cause mortality in patients
without previous cardiovascular disease showed that poor
exercise tolerance (determined by the observed duration of
exercise in relation to the predicted duration) is associated with
greater mortality risk. In our cross-sectional comparative study
we observed that CP and VP positively correlated (strong and
moderate correlation, respectively) with aerobic functional
classification evaluated by peak VO2.
Cohen-Solal et al. (2002)12 longitudinally evaluated (mean
follow-up 25 ± 10 months) 175 heart failure patients who were
subjected to an incremental CPX. Their study showed that CP
was predictive of prognosis and that the combination of VO2 and
systolic BP (through the CP index) strengthens the prognostic
value of CPX, particularly in subjects with low peak VO2 and
peak BP. Similar to the previous report, Forman et al. (2012)16
evaluated the prognostic use of VP in a longitudinal study (mean
follow-up 4 years) with 875 heart failure patients submitted
to CPX. The authors showed that VP was independently
predictive of cardiac events compared with standard CPX
482
Arq Bras Cardiol. 2015; 104(6):476-486
indices (i.e., peak VO2 and the VE/VCO2 slope); furthermore,
in a multivariate analysis, combined CP and VP provided even
better prognostic discrimination. Although traditional variables
obtained by CPX, such as VO2, systolic BP, and the VE/VCO2
slope, reflect the aerobic capacity, hemodynamic control and
carbon dioxide production eficiency efficiency, respectively, CP
and VP are indices that combine these variables. VP, as an index
that combines systemic hemodynamics with carbon dioxide
production efficiency during exercise, and CP as an index that
combines central and peripheral components of cardiac stroke
work, appear to both portend important information regarding
disease severity and prognosis12,16,37.
Recently, Borghi-Silva el al (2014)37 assessed the relationship
between VP and key measures obtained using Doppler
echocardiography in patients with heart failure and reduced
ejection fraction; their results showed that lower values of VP
translate into a very unfavorable phenotype characterized by
a lower peak VO2 and cardiac output response. The current
study is a cross-sectional analysis with the goal of characterizing
these indices in a CAD cohort under current standard
pharmacologic regimens, angioplasty, or surgical management
without heart failure. Our findings demonstrate that CP and
VP are abnormal in CAD patients compared with healthy
controls, and are related not only to standard medication
but also to the level of aerobic capacity and characteristics of
CAD; moreover, VP is related to the number of vessels with
stenosis after treatment. Future work is needed to determine
the prognostic utility of CP and VP in patients with CAD and
establish whether both indices perform similarly to what has
been found in patients with heart failure12,14,16.
Study limitations
This investigation is characterized by an initial exploration
of CP and VP indices in males with CAD; however, it
has some limitations. First, although the literature 12,16,37
Castello-Simões et al.
Circulatory and ventilatory power
Original Article
Figure 2 – Circulatory power (CP) and ventilatory power (VP) correlated with OUES, RPP and oxygen pulse. Legend: (ο) coronary arterial disease group (CAD-G), (•) control group
(CG), OUES linear relationship between oxygen uptake and minute ventilation, RPP rate-pressure product. Pearson correlation analysis.
indicates that CP and VP appear to be important prognostic
markers in patients with heart failure, the cross-sectional
nature and relatively small sample size of the current
study did not allow us to expand upon prognostic utility.
Therefore, additional prospective evaluations in this
population are needed to determine the usefulness of
these indices as prognostic markers. In relation to cardiac
function, the CAD group was characterized only by left
ventricular ejection fraction because 50% of patients were
evaluated by ventriculography and 50% by echocardiogram.
Women were not included in this study because the selected
age could include both women with regular menstrual cycle
(with and without use of contraceptives) and women in the
postmenopausal stage (with and without use of hormone
replacement therapy) and these differences could influence
our results38,39. Although the pharmacologic management
of systemic arterial hypertension by angiotensin converting
enzyme inhibitors, diuretics, and particularly beta-blockers
may have influenced the behavior of CP and VP (as well as
of other indices obtained from CPX), medication cessation
is not possible because it is mandatory therapy for some
patients. Future studies including a control group of systemic
Arq Bras Cardiol. 2015; 104(6):476-486
483
Castello-Simões et al.
Circulatory and ventilatory power
Original Article
arterial hypertension patients without CAD (with similar
pharmacologic management to our study) could eliminate
the possible influence of medications on studied variables.
Conclusions
The CP and VP indices were lower in men with
CAD, without heart failure, and under current standard
pharmacologic regimens, angioplasty, or surgical management
than healthy controls, demonstrating a poorer cardiopulmonary
function in this population. Our results suggest that both CP
and VP may hold value as screening tools in assessing the
functional significance of disease, exercise tolerance, and
may consequently assist in the prescription of physical
training in this population when used individually or
complementarily to other indices currently attained by CPX.
In fact, a multivariate approach including indices related to
both central and peripheral function would likely provide
a more comprehensive evaluation of exertional physiology.
Future investigations are needed to evaluate if lower CP and
VP values are due only to the CAD or to the use of standard
pharmacologic regimens, as well as to verify the prognostic
value of these indices in this patient population.
Acknowledgments
The authors would like to thank the patients for their effort
and enthusiastic cooperation throughout the study and the
physicians Sérgio Luiz Berti and João Orávio de Freitas Jr. for
support with the hemodynamic section patients.
Author contributions
Conception and design of the research:Castello-Simões V, Catai
AM. Acquisition of data:Castello-Simões V, Minatel V, Karsten M,
Simões RP, Perseguini NM, Milan JC, Neves LMT. Analysis and
interpretation of the data: Castello-Simões V, Minatel V, Karsten
M, Simões RP, Perseguini NM, Milan JC, Arena R, Neves LMT,
Catai AM. Statistical analysis: Castello-Simões V, Minatel V, Karsten
M, Simões RP, Neves LMT, Borghi-Silva A. Obtaining financing:
Castello-Simões V, Karsten M, Perseguini NM, Catai AM. Writing
of the manuscript:Castello-Simões V, Karsten M, Simões RP, Catai
AM. Critical revision of the manuscript for intellectual content:
Castello-Simões V, Simões RP, Arena R, Borghi-Silva A, Catai AM.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Sources of Funding
This study was funded by Fundação de Amparo à Pesquisa
do Estado de São Paulo (FAPESP), São Paulo/SP/Brasil (processo:
2010/52070-4); Coordenação de Aperfeiçoamento de Pessoal
de Nível Superior (CAPES), Brasília/DF/Brasil; Conselho
Nacional de Desenvolvimento Científico e Tenológico (CNPq),
Brasília/DF/Brasil (processo: 483945/2007-2).
Study Association
This article is part of the thesis of Doctoral submitted by Viviane
Castello Simões, from Universidade Federal de São Carlos.
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Back to the Cover
Original Article
Blood Pressure and Hemodynamic Adaptations after a Training
Program in Young Individuals with Down Syndrome
Bruna Barboza Seron, Karla Fabiana Goessler, Everaldo Lambert Modesto, Eloise Werle Almeida, Márcia Greguol
Universidade Estadual de Londrina, Londrina, PR – Brazil
Abstract
Background: Cardiovascular diseases affect people worldwide. Individuals with Down Syndrome (DS) have an up to
sixteen-time greater risk of mortality from cardiovascular diseases.
Objective: To evaluate the effects of aerobic and resistance exercises on blood pressure and hemodynamic variables of
young individuals with DS.
Methods: A total of 29 young individuals with DS participated in the study. They were divided into two groups: aerobic
training (AT) (n = 14), and resistance training (TR) (n = 15). Their mean age was 15.7 ± 2.82 years. The training program
lasted 12 weeks, and had a frequency of three times a week for AT and twice a week for RT. AT was performed in treadmill/
bicycle ergometer, at an intensity between 50%-70% of the HR reserve. RT comprised nine exercises with three sets
of 12 repetition-maximum. Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP)
and hemodynamic variables were assessed beat-to-beat using the Finometer device before/after the training program.
Descriptive analysis, the Shapiro-Wilk test to check the normality of data, and the two-way ANOVA for repeated measures
were used to compare pre- and post-training variables. The Pearson’s correlation coefficient was calculated to correlate
hemodynamic variables. The SPSS version 18.0 was used with the significance level set at p < 0.05.
Results: After twelve weeks of aerobic and/or resistance training, significant reductions in variables SBP, DBP and MBP
were observed.
Conclusion: This study suggests a chronic hypotensive effect of moderate aerobic and resistance exercises on young
individuals with DS. (Arq Bras Cardiol. 2015; 104(6):487-492)
Keywords: Arterial Pressure / physiology; Hemodynamic / physiology; Heart Defects / congenital; Down Syndrome;
Adolescent; Resistance Training.
Introduction
Cardiovascular disease is the major cause of mortality
worldwide and although cardiovascular events are more
frequent after the fifth decade of life, there is evidence that
their precursors have origin in childhood1. Individuals with
Down syndrome (DS) show an up to sixteen-time higher risk
of mortality for cardiovascular diseases2. While the incidence
of congenital heart defects in the general population is
of 0.8%, approximately 40%-65% of individuals with DS
develop the disease3. The development of congenital heart
defects is multifactorial and under the interference of
molecular and morphological signaling. Additionally, the
incidence of atrioventricular and ventricular septal defects
is of 45% and 35% in patients with DS 3, respectively.
Mailing Address: Márcia Greguol •
Universidade Estadual de Londrina - Rodovia Celso Garcia Cid - Pr 445 Km
380, s/n - Campus Universitário, Postal Code 86057-970, Londrina, PR – Brazil
E-mail: [email protected]
Manuscript received September 11, 2014; revised manuscript received
January 21, 2015; accepted January 22, 2015.
DOI: 10.5935/abc.20150033
487
Also, the risk of persistent pulmonary hypertension in
neonates is 5.2% higher for children with DS in comparison
to the general population3,4.
Among the major cardiovascular risk factors, we should
point out high blood pressure (BP) and sedentary lifestyle.
Some studies have proven that both risk factors show
strong tracking from childhood to adulthood5-8 and this
suggests that there should be incentives for their reduction
from early ages.
BP control is related to lifestyle changes including
increasing physical activity 9. Few studies correlating the
effect of physical training on the cardiovascular response of
individuals with DS are available; therefore, the specificities
of physical exercises should be carefully verified for this
population. Kelley et al 10 conducted a meta-analysis
involving non-disabled children and adolescents and
demonstrated that short-term physical exercises did not
lead to reductions in resting SBP and DBP.
Nonetheless, McDonnell et al 11 showed that regular
physical exercise is associated with a beneficial vascular
profile, which is explained by lower large artery stiffness in
older individuals, but lower peripheral vascular resistance in
young individuals.
Seron et al.
Blood Pressure and Young Individuals with Down Syndrome
Original Article
The literature points to the benefits of an active lifestyle
for the general population. However, the population with
DS has a less active lifestyle than do individuals without
DS. This may be harmful to the health and autonomy of
this population12,13.
The increase in life expectancy of this population
makes the prevention of secondary diseases increasingly
more important. Therefore, we hypothesized that physical
training (aerobic and resistance) could reduce blood
pressure levels and thus improve and/or prevent the
development of cardiovascular diseases in individuals with
DS. For this reason, knowing the importance of a physically
active lifestyle for BP control and for the prevention of
cardiovascular diseases, the objective of this study was to
investigate the effects of aerobic and resistance training on
BP values and hemodynamic variables in young individuals
with DS after the training period.
Methods
Participants
Twenty nine young individuals of both genders (20 boys
and 9 girls) with Down syndrome and a mean age of
15.7 ± 2.82 years participated in the study. Subject selection
was made by inviting all young individuals with DS aged
between 12 and 20 years from 3 institutions in the city of
Londrina/State of Parana/ Brazil, which provide care for
intellectually disabled individuals. Those presenting with
orthopedic or cardiac problems; using medications that
could affect the heart rate; and those presenting with severe
or profound intellectual disability that could affect their
understanding and/or ability to perform the procedures
were excluded from the study. After receiving explanations
on the terms of the research, their parents and/or guardians
gave written informed consent. The study was approved by
the Research on Humans Ethics Committee, Universidade
Estadual de Londrina, under opinion number 93.680/2012.
The participants were divided into two groups, according
to their availability to attend the physical exercise program:
aerobic training group (n = 14, of which 4 were girls and
10 were boys); and resistance training group (n = 15, of which
5 were girls and 10 were boys).
Initially, there was a control group; however, the
individuals from this group did not attend the second
assessment visit, and therefore the control group was
excluded from the analysis.
Training programs
The aerobic and resistance training programs consisted of
12 weeks with 50-minute-duration sessions.
The aerobic training was performed three times a week
in a treadmill and bicycle ergometer (15 minutes each), at
an intensity between 50% and 70% of the HR reserve for
30 minutes, preceded by a 10-minute warm- up (articulations
and stretching) and followed by 10 more minutes of recovery
(stretching). The intensity was monitored by a Polar FT2 heart
rate monitor. The HRmax used for the calculation of HR reserve
was obtained by means of a maximal exercise test validated
for individuals with DS14. This test started at a 4 km/h speed
and 0% inclination for two minutes. Every two minutes the
treadmill inclination was increased by 2.5% up to 12.5%.
Thereafter, the speed was raised by 1.6 km/h at every minute
until volitional fatigue. The test was performed on a treadmill
(INBRAMED, model 10.200) with the use of a portable
metabolic measurement system (Cosmed k4b², Italy).
The resistance training consisted of 9 exercises performed
in three sets of 12 repetition-maximum, with a 1-minute
interval between the sets and 3-minute intervals between
exercises. The following series of exercises was proposed:
chest press machine; leg extension machine; lat pull down;
biceps cable curl; standing leg curl with ankle weights;
cable triceps extension; calf raises with ankle weights;
dumbbell front raise and abdominal exercises. The two first
sessions were for adaptation to the exercise training with
low loads and, subsequently, the load used was estimated
by observing the participant’s ability to perform the exercise
in 12 repetitions. Load progression was spontaneous, with
increases made whenever the participant was able to perform
the three sets of twelve complete repetitions15.
To participate in the study, the individuals showed a
medical clearance certificate for the practice of physical
exercises. Additionally, the attendance rate was of at least
75% of the program for all participants, and therefore,
none was lost to follow-up. All attended the two assessment
visits proposed.
Blood pressure
Blood pressure was monitored by a Finometer™
(Finapres Medical System, BV, The Netherlands) device
before and after the training program. Continuous
digital electrocardiographic monitoring and noninvasive
cardiovascular hemodynamic monitoring by digital infrared
photoplethysmography were performed for 15 minutes with
the individual in the sitting position.
For the acquisition of pressure curves, a small sensor
was placed around the middle phalanx of the left index
finger, taking into consideration the participant’s age, body
mass, height and gender. Body mass (BM) was expressed
in kilograms and measured in a digital scale to the
nearest 100 grams; height, in meters, was measured in a
stadiometer to the nearest 0.1 centimeter; a 2-m flexible tape
measure was used for the measurement of the abdominal
circumference (AC). The following hemodynamic variables
were considered for the analyses: systolic blood pressure
(SBP), diastolic blood pressure (DBP), heart rate (HR), cardiac
output (CO), peripheral vascular resistance (PVR) and stroke
volume (SV); the latter was obtained using the formula
SV = CO/HR. A researcher blind to the groups performed
the assessments and analysis of variables.
Statistical analyses
Data are presented as means and standard deviation of the
mean. The Shapiro-Wilk test was used to check the normality
of data. The two-way ANOVA for repeated measures was
used for the comparison of hemodynamic variables pre- and
Arq Bras Cardiol. 2015; 104(6):487-492
488
Seron et al.
Blood Pressure and Young Individuals with Down Syndrome
Original Article
post-aerobic or resistance training. The Pearson’s correlation
coefficient was used to correlate the hemodynamic variables
with age, body mass and height. Data were analyzed by the
SPSS version 18.0 software; in all analyses, the significance
level was set at 5%.
Results
Anthropometric data of the groups obtained before
the intervention are shown in Table 1. No BP variables
or hemodynamic variables showed statistically significant
differences (p > 0.05) between the groups at the
pre‑training timepoint.
Data presented in Table 2 show a significant reduction
(p < 0.05) of systolic, diastolic and mean blood pressure
after aerobic and resistance training. No interaction was
observed between the factor time and group for variables
SBP (p = 0.20), DBP (p = 0.53) and MBP (p = 0.58).
Data regarding heart rate, stroke volume, cardiac output
and peripheral vascular resistance are shown in Table 3.
No statistically significant differences were found for these
variables between timepoints pre- and post-exercise in
both groups.
Finally, the Pearson’s correlation test between anthropometric,
hemodynamic and blood pressure variables did not show
significant values for any of the two groups studied.
Discussion
The major finding of the present study suggests a chronic
hypotensive effect of aerobic and resistance exercise on
young individuals with DS. Nonetheless, the findings of the
present study corroborate those of several trials investigating
the effects of exercise on blood pressure of non-disabled
individuals, which usually show BP reduction after physical
– especially aerobic, training. For resistance exercises, the
few studies conducted also point to a BP reduction effect15-18
albeit less consistently in comparison to aerobic exercises.
Despite the paucity of studies investigating the effect
of exercises on blood pressure of individuals with DS, the
literature shows some that address aspects of blood pressure
and the vascular system in this population. According to
Rodrigues et al19, although individuals with DS show early
aging in several organ systems, no difference was observed
regarding aortic artery stiffness, which is related to several
risk factors for CVD, including high BP, in individuals with DS
in comparison to individuals without this condition.
Some studies have found that individuals with DS
have chronic hypotension, i.e., blood pressure levels
lower than those of normotensive individuals without the
syndrome19-21. However, there is evidence that deaths related
to cardiovascular diseases are more common in individuals
with DS than in the general population2,22.
Although BP levels of individuals with and without DS have
not been compared in this study, the mean SBP and DBP found
for the participants were considered within normal limits23.
Additionally, the baseline levels of SBP, DBP and MBP were
similar for both groups.
The guidelines suggest that increasing physical activities
contributes to the primary and secondary prevention of
arterial hypertension15. However, according to Cornelissen
and Smart18, the effect of training on the magnitude of BP
reduction may vary according to the modality of exercise
(aerobic or resistance), duration, intensity, and frequency
of training . Our findings corroborate these authors’
recommendation of physical exercises for BP control18 based
on the finding that aerobic exercises are effective in BP
reduction, as are resistance exercises, which, albeit providing
lower reductions in comparison to aerobic exercises, still play
Table 1 – Anthropometric data of participants
Aerobic training (n = 14)
Resistance training (n = 15)
61.43 ± 11.6
52.7 ± 10.0
Height (cm)
151.7 ± 8.11
150.4 ± 7.0
BMI (kg/m²)
26.61 ± 4.36
23.3 ± 4.3
Abdominal circumference (cm)
86.8 ± 11.1
77.5 ± 9.2¥
Body mass (kg)
¥ Significant difference between groups – p < 0.05.
Table 2 – Blood pressure values before and after training
Variables
SBP (mmHg)
GrType of Training A Aerobic
Training Group Resistance
Pre
Post
Δ
Pre
Pós
Δ
Time p
Time x group p
Group p
119.6 ± 11.46
110.4 ± 11.7*
-9.3 ± 8.8
113.19 ± 13.04
107.04 ± 10.41*
-6.2 ± 12.0
0.001
0.05
0.03
DBP (mmHg)
77.27 ± 4.73
72.66 ± 6.69*
-4.6 ± 6.9
76.98 ± 8.10
72.23 ± 8.30*
-4.8 ± 10.2
0.03
0.53
0.98
MBP (mmHg)
92.58 ± 5.40
88.35 ± 7.37*
-4.2 ± 7.3
91.74 ± 8.74
86.75 ± 8.38*
-5.0 ± 9.7
0.01
0.58
0.74
SBP: systolic blood pressure; DBP: diastolic blood pressure; MBP: mean blood pressure. * significant difference between pre-training and post-training timepoints – p < 0.05.
489
Arq Bras Cardiol. 2015; 104(6):487-492
Seron et al.
Blood Pressure and Young Individuals with Down Syndrome
Original Article
Table 3 – Values of hemodynamic variables before and after training
Variables
Training Group Aerobic
Pre
Post
Training Group Resistance
Pre
Post
Time p
Time x group p
Group p
CO
2.97 ± 0.71
3.80 ± 0.81
2.76 ± 1.02
3.32 ± 1.05
0.60
0.98
0.20
PVR (mmHg.min.l)
32.91 ± 8.54
24.07 ± 4.48
36.62 ± 10.92
28.56 ± 9.64
0.22
0.93
0.07
HR (bpm/min)
SV (ml)
81 ± 11
82 ± 11
84 ± 10.04
84 ± 9.34
0.93
0.58
0.31
0.037 ± 0.00
0.047 ± 0.01
0.032 ± 0.01
0.040 ± 0.01
0.43
0.77
0.17
CO: cardiac output; PVR: peripheral vascular resistance; HR: heart rate; SV: stroke volume.
an important role in BP control. Thus, for this population,
resistance training showed significant reductions in blood
pressure levels (SBP = -6.2 mmHg; DBP = -4.8 mmHg;
MBP = -4.2 mmHg). However, in addition to bringing
benefits to blood pressure responses, resistance training
has been considered safe for individuals with DS because it
improves strength, balance and body composition24.
As regards the chronic antihypertensive mechanisms of
exercise, Pescatello et al25 found a reduction in peripheral
vascular resistance as the major mechanism, which is possibly
mediated by neuro-humoral and structural adaptations.
Reduction in vasoconstrictors such as endothelin-1, and
elevation in vasodilators such as nitric oxide have been pointed
as neurohumoral adaptations to physical exercises26,27.
Although several mechanisms and hemodynamic
adaptations have been pointed in response to the chronic
effects of aerobic and resistance training on BP, Cornelissen
and Fagard28 conducted a meta-analysis and showed that the
hemodynamic mechanisms in response to aerobic training
resulted from a significant reduction of peripheral vascular
resistance (PVR), with no changes in the cardiac output
(CO). This can be explained by the increased SV, which is
counterbalanced by decreased HR.
In the present study, no significant changes were observed
for peripheral vascular resistance in any of the groups (aerobic
and resistance training) after the 12-week training.
The adaptations in BP found in the present study may
be important for individuals with DS, because, as Hu et al29
suggest, these individuals may have a higher incidence of
cardiovascular risk factors such as a low cardiorespiratory
capacity and obesity. In this context, many studies have
advanced in relation to the influence of exercise on the
physical fitness of young individuals with DS, and usually
show positive results regarding their cardiopulmonary capacity,
strength and body composition24,30-34. Therefore, the findings of
the present study in relation to the chronic reduction of blood
pressure after an intervention program contribute with more
information on the potential benefits of physical exercises
for this population.
Although the physical training program has provided
significant adaptations of blood pressure, some limitations
should be pointed out. First, the number of individuals in each
group was small, and this may have hindered some analyses.
Additionally, the non-randomized division of intervention
groups may have interfered in the results. Nonetheless, our
findings may contribute to a better understanding of the
physiological adaptations to physical exercises in young
individuals with DS, in addition to stressing the importance
of this practice for the health of this population.
Conclusion
By means of the interventions performed, the present study
demonstrated that 12 weeks of either aerobic or resistance
training provided significant reductions in SBP, DBP and MBP
of young individuals with DS. The adaptations found are
believed to significantly help control BP and prevent the risk
of developing cardiovascular diseases.
Therefore, the implementation of either aerobic or
resistance training programs and practice of physical exercises
is suggested for young individuals with DS as a means
of preventing cardiovascular risks. For these individuals,
maintaining a physically active lifestyle should be seen as a
strategy that can contribute significantly to improve a sedentary
lifestyle and obtain several health benefits.
Author contributions
Conception and design of the research:Seron BB, Goessler
KF, Modesto EL, Greguol M. Acquisition of data: Seron BB,
Goessler KF, Modesto EL, Almeida EW, Greguol M. Analysis
and interpretation of the data: Seron BB, Goessler KF,
Modesto EL, Almeida EW, Greguol M. Statistical analysis:
Goessler KF. Writing of the manuscript: Seron BB. Critical
revision of the manuscript for intellectual content: Seron BB,
Goessler KF, Greguol M.
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 Bruna
Barboza Seron, from Universidade Estadual de Londrina.
Arq Bras Cardiol. 2015; 104(6):487-492
490
Seron et al.
Blood Pressure and Young Individuals with Down Syndrome
Original Article
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Original Article
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Back to the Cover
Original Article
Heart Rate Variability Correlates to Functional Aerobic Impairment in
Hemodialysis Patients
Maria Angela Magalhães de Queiroz Carreira1, André Barros Nogueira1, Felipe Montes Pena1, Marcio Galindo Kiuchi1,
Ronaldo Campos Rodrigues1, Rodrigo da Rocha Rodrigues1, Jorge Paulo Strogoff de Matos2, Jocemir Ronaldo Lugon2
Universidade Federal Fluminense, Department of Cardiology1; Universidade Federal Fluminense, Department of Nephrology2, Rio de Janeiro, RJ - Brazil
Abstract
Background: Autonomic dysfunction (AD) is highly prevalent in hemodialysis (HD) patients and has been implicated
in their increased risk of cardiovascular mortality.
Objective: To correlate heart rate variability (HRV) during exercise treadmill test (ETT) with the values obtained when
measuring functional aerobic impairment (FAI) in HD patients and controls.
Methods: Cross-sectional study involving HD patients and a control group. Clinical examination, blood sampling,
transthoracic echocardiogram, 24-hour Holter, and ETT were performed. A symptom-limited ramp treadmill protocol
with active recovery was employed. Heart rate variability was evaluated in time domain at exercise and recovery periods.
Results: Forty-one HD patients and 41 controls concluded the study. HD patients had higher FAI and lower HRV
than controls (p < 0.001 for both). A correlation was found between exercise HRV (SDNN) and FAI in both groups.
This association was independent of age, sex, smoking, body mass index, diabetes, and clonidine or beta-blocker
use, but not of hemoglobin levels.
Conclusion: No association was found between FAI and HRV on 24-hour Holter or at the recovery period of ETT.
Of note, exercise HRV was inversely correlated with FAI in HD patients and controls. (Arq Bras Cardiol. 2015;
104(6):493-501)
Keywords: Sympathetic Nervous System / physiopathology; Exercise Test; Renal Dialysis; Mortality; Exercise.
Introduction
The treatment offered to end-stage renal disease (ESRD)
patients on hemodialysis (HD) has improved over the past
decades resulting in increased survival and better quality of
life1. However, cardiovascular morbidity and mortality remain
exceptionally high in this group of patients2.
The prevalence of autonomic dysfunction (AD) is high in
patients undergoing current standard HD treatment1 and this
has been associated with an increased risk of sudden death2.
In the general population, cardiorespiratory fitness (CRF)
is an independent predictor of all-cause and cardiovascular
mortality3. In normal subjects, maximal functional aerobic
capacity was inversely associated with the risk of all-cause
and cardiovascular death. The risk was 2.50 times higher
for all-cause death, and 2.04 times higher for cardiovascular
death in men with a low exercise capacity than in men with
Mailing Address: Maria Angela Magalhães de Queiroz Carreira •
Rua Arroio Fundo, 230, Anil. Postal Code 22765-260, Rio de Janeiro, RJ – Brazil
E-mail: [email protected]
Manuscript received September 12, 2014; revised manuscript January 14, 2015;
accepted January 19, 2015.
DOI: 10.5935/abc.20150039
493
a high exercise capacity, after adjustment for risk factors and
ischemic ST changes during exercise4. Cardiorespiratory fitness
is also a predictor of sudden cardiac death in normal subjects.
As a continuous variable, one metabolic equivalent (MET)
increment in CRF was associated with a 22% decrease in the
risk of sudden cardiac death in normal men4.
Exercise treadmill test (ETT) has been used in the assessment
of autonomic function by analyzing changes in heart rate (HR)
under physical stress.
The aim of this study was to assess the autonomic function
of HD patients and controls by assessing HR variability (HRV)
during an ETT and to correlate the results with functional
aerobic impairment (FAI).
Methods
Study population
We conducted a cross-sectional study with ESRD patients
on HD three times a week (4-hour duration sessions) for at
least three months and a control group matched by sex and
age without overt kidney disease. Hemodialysis patients were
recruited from a single dialysis center and the control group
consisted of individuals referred for exercise testing at the
University Hospital. Informed consent was obtained, and the
study protocol was approved by the Medical School ethical
Carreira et al.
RR variability and functional aerobic impairment
Original Article
committee. Chronic medications, including those for blood
pressure control, were not discontinued during the study.
Exclusion criteria were as follows: impaired gait that
prevented walking on the treadmill, arrhythmias preventing
proper HR assessment, and presence of symptomatic heart
disease. Cardiac evaluation was always accomplished in a
middle-of-week non-dialytic day and consisted of clinical
examination, transthoracic echocardiogram, 24-h Holter,
and ETT.
Echocardiography
A two-dimensional transthoracic echocardiography was
performed with GE VIVID 7 System (General Electric, USA)
to assess left ventricle wall motion and systolic and diastolic
ventricular function.
24-h Holter
Patients underwent a 24-h Holter (Galix Biomedical
Instrumentation, Florida, USA). A 3-channel recorder was
used to record the electrocardiographic tracings. A time
domain analysis of HRV was performed, and the following
parameters were obtained: a) SDNN, standard deviation
(SD) of all normal RR intervals (NN); b) SDANN, SD of the
averages of 5-min NN intervals over 24h; c) rMSSD, the
square root of the mean of the square of successive NN
intervals; and d) triangular index (TI), integral of the density
distribution (that is, the number of all NN intervals) divided
by the maximal density distribution.
Exercise treadmill test
Patients underwent ETT with a treadmill ramp protocol
using the Ergo13 program (Heart Ware Co., Minas Gerais,
Brazil). The test was symptom limited, with 2-minute
active recovery under 40% of the speed and incline of
peak effort. Automatic ECG recordings were obtained on
13 simultaneous leads before exercise in the supine and
standing positions, at peak exercise, and at every recovery
minute. The following HRV parameters were analyzed:
SDNN and rMSSD during exercise and recovery. For the
ramp protocol, the predicted maximal VO2 was reduced by
20% in HD patients. The maximal VO2 peak exercise was
obtained by the Foster formula backed with hands. The FAI
was calculated using the formula: FAI= [(maximal predicted
VO2–VO2 peak) /maximal predicted VO2] x 100. In ETT, HRV
was obtained with a software specially designed for the study,
conveying electrocardiographic data findings from Ergo13
to Cardio Smart (Cardios, São Paulo, Brazil) during exercise
and recovery separately.
Statistics
Results were expressed as mean and SD, for normal
distribution, and median and range, otherwise. Categorical
variables were expressed as frequencies and compared
using the Chi-square test. Comparisons between two
continuous variables were accomplished by the t test
(for normal distribution) or its nonparametric equivalent
(Mann‑Whitney test). Correlation was assessed using
the Pearson test. Logistic regression was used to analyze
associations. Variables with p values < 0.10 were included
in the multivariate model, and p < 0.05 was considered
significant. Analyses were performed using SPSS for
Windows version 18.0 (SPSS Inc., Chicago, IL, USA).
Results
A total of 125 patients from a single dialysis center
were initially evaluated. Nine were promptly excluded
due to gait impairment. Of the 116 remaining, 59 agreed
to participate and signed the consent form. Eighteen
patients were excluded: 10 did not show up for the exams,
4 had a past myocardial infarction, 2 had arrhythmia,
1 had artery-venous fistulas in both arms, and 1 had
current pulmonary infection. At the end, 41 HD patients
concluded the study. The most common renal disease
etiologies were: hypertensive nephrosclerosis (56%),
chronic glomerulonephritis (17%), adult polycystic kidney
disease (10%), and diabetic nephropathy (7%). Table 1
shows the general features of patients and controls. Use of
antihypertensive drugs and physical inactivity were more
frequent among patients on HD. Use of beta‑blockers
tended to be higher in HD patients, but statistical
significance was not found. Diuretic use was more common
in the control group.
Left ventricular systolic function, analyzed by the ejection
fraction on echocardiogram, was similar between groups
(66.1 ± 10.1% vs. 68.6 ± 5.4% for HD patients and controls,
respectively, p = 0.167), but diastolic dysfunction was more
prevalent in HD patients (77% vs. 42%, p = 0.004).
Table 2 shows the cardiovascular parameters on ETT.
There was no difference between groups in relation
to pre‑exercise test parameters. Functional aerobic
impairment was found higher in HD patients (Figure 1).
Reasons for stopping the exercise were as follows: general
exhaustion, 80.5%; exhaustion of the muscles of lower
limbs, 4.9%; left bundle branch block of high‑grade,
2.4%; arrhythmia, 2.4%; and hypertension, 2.4%.
No complications occurred during ETT in any group.
When analyzing the 24-h Holter, HD patients showed less
HRV than controls. Differences were observed regarding the
mean HRV values during exercise and recovery (Table 3).
SDNN was significantly lower in HD patients than in controls
on 24-h Holter, and during exercise and recovery (Figure 2).
Exercise SDNN correlated with FAI in HD patients and controls
(Figure 3). On 24-h Holter, there was no correlation between
HRV and FAI (Table 4). An exercise SDNN < 40 ms (median)
was used as the dependent variable to test associations with
FAI. In every multivariate logistic regression model tested,
exercise SDNN < 40 ms was independently associated
with FAI, regardless of age, sex, body mass index, smoking,
diabetes, and beta‑blocker or clonidine use. However, the
association was found to be dependent on serum levels of
hemoglobin (Table 5).
Arq Bras Cardiol. 2015; 104(6):493-501
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Table 1 – General features of HD patients and controls
HD patients
Age, years
50 ± 14
Male, %
21 (51.2)b
a
Controls
p value
50 ± 13
0.975
21 (51.2)
1.000
Race, non-white %
27 (65.9)
21 (51.2)
0.391
Body mass index, kg/m2
25.1 ± 5.1
27.3 ± 4.1
0.030
HD vintage, months
67.2 ± 47.3
n.a.
4 (9.8)
5 (12.2)
0.724
Diabetes, %
Smoking, %
3 (9.1)
8 (20.5)
0.180
Familial CAD,%
15 (36.6)
17 (41.5)
0.520
Familial hypertension, %
26 (63.4)
21 (51.2)
0.525
Sedentary lifestyle, %
33 (80.5)
24 (58.5)
0.031
Anti-hypertensive drugs, %
Beta-blocker
33 (80.5)
20 (48.8)
0.003
14 (34.1)
7 (17.1)
0.077
Diuretic
2 (4.9)
8 (19.5)
0.043
Calcium channel blocker
5 (12.2)
2 (4.9)
0.236
ACE inhibitor/ARB
12 (29.3)
16 (39.0)
0.352
Clonidine
8 (19.5)
-
0.003
Alfa-blocker
Hemoglobin, g/dL
eGFR (MDRD study), ml/min/1.73m2
6 (14.6)
-
0.011
11.5 ± 1.4
13.8 ± 1.2
< 0.001
n.a.
87.5 ± 23.1
HD: hemodialysis; CAD: coronary artery disease; ACE: angiotensin-converting-enzyme; ARB: AT1-receptor blocker; n.a.: not applicable; eGFR: estimated
glomerular filtration rate; MDRD: modification of diet in renal disease. a Mean ± SD; b n (%).
Table 2 – Baseline and peak values of heart rate, blood pressure and functional capacity on ETT in HD patients and controls
HD patients
Controls
p value
pre-exercise HR, bpm
77 ± 12a
76 ± 13
0.705
pre-exercise SBP, mmHg
131 ± 39
130 ± 31
0.860
pre-exercise DBP, mmHg
82 ± 11
83 ± 9
0.135
peak HR, bpm
130 ± 25
160 ± 19
< 0.001
peak SBP, mmHg
193 ± 26
199 ± 21
0.273
peak DBP, mmHg
99 ± 11
93 ± 11
0.040
Exercise time, min
8.5 ± 1.9
10.1 ± 2.4
0.002
29.5 ± 12.0
2.8 ± 20.1
< 0.001
FAI, %
HD: hemodialysis; HR: heart rate; SBP: systolic blood pressure; DBP: diastolic blood pressure. FAI: functional aerobic impairment. a Mean ± SD
Discussion
In ESRD patients, AD is a frequent abnormality and
a marker of cardiovascular events and death5-8. Exercise
treadmill test, a valuable tool to assess AD, is hardly used
in HD patients.
We studied autonomic parameters related to HRV during
ETT in HD patients as compared to a control group, and the
ETT results were correlated with FAI.
495
Arq Bras Cardiol. 2015; 104(6):493-501
In our sample, the body mass index was in the
upper limit of normality (borderline overweight) in HD
patients, and clearly above that limit in the control group.
This is not unexpected considering that malnutrition
was common in HD patients in the past9, but not in the
present, and that obesity is a recognized risk factor for
cardiovascular disease 10,11. The proportion of diabetes
mellitus in our sample was lower than that reported in
international series12,13, and even lower than that reported
Carreira et al.
RR variability and functional aerobic impairment
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Figure 1 – Functional aerobic impairment in hemodialysis (HD) patients and controls.
Table 3 – Heart rate variability parameters during 24-h Holter and exercise treadmill test in HD patients and controls
HD patients
Controls
p value
SDNN, msec
82.6 ± 27.6
119.1 ± 47.6
< 0.001
SDANN, msec
74.3 ± 26.8
113.1 ± 43.2
< 0.001
rMSSD, msec
17.4 ± 7.7
27.6 ± 11.1
< 0.001
Triangular index, msec
23.3 ± 8.4
34.4 ± 9.3
< 0.001
exercise SDNN, msec
33.7 ± 14.2
50.0 ± 21.8
< 0.001
exercise rMSSD, msec
11.0 ± 5.5
15.3 ± 14.7
0.092
recovery SDNN, msec
20.1 ± 9.8
27.3 ± 17.4
0.024
recovery rMSSD, msec
11.5 ± 7.8
15.4 ± 17.3
0.196
24-h Holter
Exercise treadmill test
HD: hemodialysis; SDNN: standard deviation (SD) of all normal RR intervals (NN); SDANN: SD of the averages of 5-min NN intervals over 24h; rMSSD: the square
root of the mean of the square of successive NN intervals. Values shown as mean ± SD.
for the Brazilian dialysis population14, probably as a result
of the inclusion and exclusion criteria adopted in the study.
In support to the majority of reported series1,12-14, a substantial
number of HD patients used anti-hypertensive drugs.
Consistent with the concept that sympathetic hyperactivity
may play an important role in the hypertension of CKD
patients, drugs mainly affecting this pathway were more
frequently prescribed for HD patients 15. In agreement
with previous reports 16,17, left diastolic dysfunction on
echocardiogram was more frequent in HD patients.
In contrast, left ventricular systolic function was similar in
both groups, perhaps due to our enrollment criteria, which
excluded patients with overt heart failure.
When analyzing cardiovascular parameters in ETT,
no difference was found between groups regarding systolic
(SBP) or diastolic blood pressure (DBP) either at rest or
exercise peak. Similarly, the HR at rest did not differ
between groups, but the HR at peak exercise was lower in
Arq Bras Cardiol. 2015; 104(6):493-501
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Carreira et al.
RR variability and functional aerobic impairment
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Figure 2 – Heart rate variability (SDNN) during 24-h Holter, exercise, and recovery in hemodialysis (HD) patients and controls.
Figure 3 – Correlation between functional aerobic impairment and heart rate variability (SDNN) during exercise in hemodialysis patients (left) and controls (right).
HD patients. An attenuated HR response to exercise has
been shown to predict adverse cardiac events in subjects
without overt cardiovascular disease. Reduced HR response
to exercise also predicts major adverse cardiac events
among individuals with overt or suspected cardiovascular
disease even after adjusting for left ventricular function and
the severity of exercise-induced myocardial ischemia18.
Our population comprised individuals of different ages.
For this reason, to analyze functional aerobic capacity we
resort to the use of FAI, which compares the obtained VO2
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Arq Bras Cardiol. 2015; 104(6):493-501
with that expected for age and sex. In our results, FAI was
higher in HD patients, a well-documented finding in HD
patients 3,19. In the general population, the functional
aerobic capacity is a factor independently associated with
cardiovascular and overall mortality. Our results found
a mean FAI of 30% in the HD group and of 3% in the
control group. In this population, the FAI may reach 65%
of that predicted for sex and age as compared to controls20.
Many factors may be involved with this reduction, some
relating to the pathophysiology of the disease and others
Carreira et al.
RR variability and functional aerobic impairment
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Table 4 – Correlation coefficients between functional aerobic impairment and heart rate variability during 24-h Holter and exercise treadmill
test in hemodialysis (HD) patients and controls
HD patients
Controls
r
p
r
p
-0.046
0.780
-0.183
0.260
24-h Holter
SDNN
SDANN
-0.044
0.792
-0.274
0.087
rMSSD
-0.090
0.585
0.248
0.123
Triangular index
-0.072
0.661
-0.123
0.451
-0.633
< 0.001
-0.752
< 0.001
Exercise treadmill test
exercise SDNN
exercise rMSSD
0.300
0.858
0.023
0.887
recovery SDNN
-0.017
0.917
0.038
0.813
recovery SDNN
0.080
0.622
-0.028
0.864
r: Correlation coefficient; SDNN: standard deviation (SD) of all normal RR intervals (NN); SDANN: SD of the averages of 5-min NN intervals over 24h; rMSSD: the square
root of the mean of the square of successive NN intervals.
Table 5 – Crude and adjusted OR and 95% CI in different models of multivariate logistic regression to test for associations of exercise
SDNN <40 msec with functional aerobic impairment in hemodialysis patients
OR
95% CI
p value
Crude
1.145
1.033-1.270
0.010
Model 1
1.213
1.059-1.390
0.005
Model 2
1.160
1.022-1.318
0.022
Model 3
1.141
1.010-1.288
0.034
Model 4
1.149
1.007-1.312
0.039
Model 5
1.153
0.979-1.357
0.088
The models consisted of the progressive inclusion of the following confounding factors: age and sex (model 1); smoking and body mass index (model 2); diabetes
(model 3); clonidine and beta-blocker use (model 4); and hemoglobin (model 5).
to age and environment. 3 During exercise, there is an
increased oxygen demand to supply muscle activity.
The provision of this increase depends on many factors:
peripherally, increased blood flow and increment of the
arteriovenous oxygen extraction; and centrally, increased
cardiac output. The raise in cardiac output during exercise
depends mainly on HR increase. However, in HD patients,
the chronotropic reserve is often reduced and this has
been attributed to AD, admittedly present in uremia.3
Autonomic tests are frequently abnormal in HD
patients. Heart rate variability during a 24-h Holter has
been considered a good marker of dysautonomia in those
patients7,8. Reduced HRV in the time or frequency domain
has been associated with reduced survival in individuals on
HD6,7,21. In consonance with previous studies, the HRV during
24-h Holter was lower in our HD patients demonstrating an
altered autonomic function5-7,21,22.
During ETT, HRV in the time domain decreases in
the supine position and during exercise, and increases
very slowly in the recovery period after exercise.
Sympathetic hyperactivity persists for at least 45 minutes after
exercise, being accompanied by a reduction in HRV20. In our
results, SDNN during ETT was significantly lower in HD patients
during exercise and recovery. These findings again may reflect
the hyperadrenergic state characteristic of HD patients, because
SDNN represents a general evaluation of the autonomic
nervous system balance, which depends on modulation by
sympathetic and parasympathetic branches6. In contrast, the
variable predominantly affected by the parasympathetic branch,
rMSSD, was not different between groups.
Our results showed a significant correlation between FAI
and SDNN during exercise in both HD patients and controls.
This finding reinforces the hypothesis that the reduction in
functional aerobic capacity is strongly associated with the
presence and severity of dysautonomia.23 The stress resulting
from exercise requires substantial changes of the autonomic
nervous system, facilitating recognition of disturbances that
otherwise could remain undetectable.
Arq Bras Cardiol. 2015; 104(6):493-501
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Our HD patients had reduced serum levels of hemoglobin,
a finding not uncommon in ESRD. To control for anemia and
other confounding factors regarding the association of HRV
during exercise with FAI, we resort to a variety of logistic
regression models in which smoking and diabetes (associated
with lower HRV), and anemia and use of beta-blocker or
clonidine (associated with increased FAI) were included as
explanatory variables. Exercise SDNN was independently
associated with FAI in all models tested, except for the
one in which serum levels of hemoglobin were included.
Several authors23-27 have reported that the reduction of
serum levels of hemoglobin causes a significant reduction
in CRF and that the higher the reduction, the greater the
FAI.23 Furthermore, red cell transfusion23,24 or administration
of erythropoietin 25-27 was associated with a significant
improvement in functional aerobic capacity, with a 6%-18%
increase in VO2 peak in different series and protocols.
The clinical relevance of our findings is prominent. Both
AD and FAI are important predictors of mortality, justifying
that efforts be made to find ways to reduce the risk of affected
patients. From the pharmacological point of view, in addition to
the treatment of anemia with erythropoietin, which effectively
increases the functional capacity of those patients, alternatives
are sparse.3,26,,27 In this regard, the use of inhibitors of hepcidin,
a peptide involved in the pathogenesis of anemia of chronic/
inflammatory diseases28,29, looks promising. On the other
hand, it is well established that training improves functional
capacity and reduces the rate of overall and cardiovascular
mortality of those patients30,31. The mechanisms by which
this occurs are multiple and certainly involve improvement
in autonomic function and inflammation31,32.
The reduced number of patients recruited from a single dialysis
center is a limitation of our study. It should also be pointed that
the maximal VO2 during peak exercise was obtained by using
the Foster formula, backed with hands, and not by using direct
measurement of gas exchange during exercise. This should be
especially considered, because we could not find validation
studies of the cited formula for HD patients. In view of that,
additional studies are needed to confirm our findings.
Conclusion
Functional aerobic impairment showed a strong
correlation with HRV during exercise. This association
was independent of age, sex, body mass index, smoking,
diabetes, use of beta-blockers or clonidine, but not of serum
levels of hemoglobin.
Author contributions
Conception and design of the research:Carreira MAMQ,
Nogueira AB, Pena FM, Kiuchi MG, Rodrigues RC, Rodrigues
RR, Matos JPS, Lugon JR. Acquisition of data:Carreira MAMQ,
Nogueira AB, Pena FM, Kiuchi MG, Rodrigues RC, Rodrigues
RR, Matos JPS, Lugon JR. Analysis and interpretation of
the data: Carreira MAMQ, Nogueira AB, Pena FM, Kiuchi
MG, Rodrigues RC, Rodrigues RR, Matos JPS, Lugon JR.
Statistical analysis: Carreira MAMQ, Nogueira AB, Pena
FM, Kiuchi MG, Rodrigues RC, Rodrigues RR, Matos JPS,
Lugon JR. Obtaining financing: Carreira MAMQ, Matos JPS,
Lugon JR. Writing of the manuscript:Carreira MAMQ, Pena
FM, Rodrigues RC, Matos JPS, Lugon JR. Critical revision of
the manuscript for intellectual content: Carreira MAMQ,
Nogueira AB, Pena FM, Kiuchi MG, Rodrigues RC, Rodrigues
RR, Matos JPS, Lugon JR.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Sources of Funding
This study was partially funded by FAPERJ.
Study Association
This article is part of the thesis of Doctoral submitted
byMaria Angela M. Q. Carreira, from Universidade Federal
Fluminense.
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Back to the Cover
Review Article
Reverse Cardiac Remodeling: A Marker of Better Prognosis in
Heart Failure
José Rosino de Araújo Rocha Reis Filho1, Juliano Novaes Cardoso1, Cristina Martins dos Reis Cardoso1, Antonio
Carlos Pereira-Barretto1,2
Serviço de Cardiologia do Hospital Santa Marcelina1; Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina, Universidade de
São Paulo (USP)2, São Paulo, SP – Brazil
Abstract
In heart failure syndrome, myocardial dysfunction causes
an increase in neurohormonal activity, which is an adaptive
and compensatory mechanism in response to the reduction in
cardiac output. Neurohormonal activity is initially stimulated
in an attempt to maintain compensation; however, when it
remains increased, it contributes to the intensification of clinical
manifestations and myocardial damage. Cardiac remodeling
comprises changes in ventricular volume as well as the thickness
and shape of the myocardial wall. With optimized treatment,
such remodeling can be reversed, causing gradual improvement
in cardiac function and consequently improved prognosis.
Introduction
When cardiac function reduces, neurohormonal activity
increases. This important compensatory mechanism is a
response to reduced cardiac output and also the main
component in syndrome progression and in cardiac remodeling
process. Neurohormonal activity is initially stimulated in an
attempt to maintain compensation in patients; however, when
it remains increased, it contributes to the worsening of clinical
manifestations and myocardial damage. Similar to cardiac
remodeling, the pathophysiological Frank-Starling mechanism
is initially activated in an attempt to maintain compensation;
nonetheless, when dilation is persistent, this mechanism
results in the progression of myocardial damage and clinical
manifestations of heart failure (HF) syndrome1-5.
Ventricular remodeling is the process by which ventricular
size, shape, and function are regulated by mechanical,
neurohormonal, and genetic factors. It can be defined by
molecular, cellular, and interstitial changes in the myocardium,
resulting in alterations in the size, mass, geometry, and function
of the heart as a result of a myocardial injury5.
Its pathophysiological importance was well-demonstrated
in the experimental studies with rats, conducted by the Pfeffer
Keywords
Heart Failure / therapy; Ventricular Remodeling; Stroke
Volume / physiology; Prognosis.
Mailing Address: José Rosino de Araújo Rocha Reis Filho •
Hospital Santa Marcelina. Rua Santa Marcelina, 177, Itaquera.
Postal Code 08270-070, São Paulo, SP – Brazil
E-mail: [email protected], [email protected]
Manuscript received October 18, 2014; revised manuscript January 5, 2015;
accepted January 7, 2015.
DOI: 10.5935/abc.20150025
502
and Pfeffer (initially, Marc and Janice). In the myocardial
infarction model, they demonstrated that mortality in rats was
strongly associated with the degree of cardiac dilation and
reduced ejection fraction6,7. Infarcted rats with greater cardiac
dilation and lower ejection fraction had poorer outcomes
than those with less involvement6,7. The postinfarction period
is conventionally divided into two phases: early (up to 72 h)
and late (after 72 h)8. Initial remodeling involves the expansion
of the infarcted area, which can result in ventricular rupture
or aneurysm formation8. In the early stage, after a moderate
to large infarction, the ventricular cavity increases in size due
to expansion or to stretching and thinning of the infarcted
segment8,9. Late remodeling comprises the ventricle as a whole
and is associated with time-dependent dilation, ventricle shape
distortion, and ventricular wall hypertrophy, which can continue
for months to years8,9. Pfeffer and Pfeffer6 observed that rats with
small infarctions (infarcted area < 20%) did not develop cardiac
dilation and rats with moderate infarction (between 20% and
40% of infarcted area) presented progressive dilatation occurring
in the noninfarcted area. The pathophysiological importance
of cardiac remodeling and its role in HF prognosis have been
expanded with the results of studies on ACE inhibitors in the
treatment of infarcted rats. These studies have demonstrated
that these drugs prevent cardiac remodeling and, in some cases,
promote its reversal7. Rats treated with ACE inhibitors presenting
dilation prevention or reverse remodeling had better prognosis
than those that did not6,7. It was observed that the benefit of
treatment was more significant in rats with moderate infarction7.
In a subsequent study, Pfeffer et al.10 coordinated the SAVE
study; they demonstrated that the concept of remodeling also
applied to humans and that treatment with ACE inhibitors
modified the natural course of myocardial infarction
and myocardial infarction-associated HF. Patients with
myocardial infarction and ejection fraction of < 40% treated
with captopril exhibited approximately 40% reduction in
cardiovascular events10.
Other studies have demonstrated that this knowledge
regarding cardiac remodeling could also be applied to patients
with cardiac dilatation without myocardial infarction. Data from
the Framingham study clearly documented that cardiac dilation
was associated with HF11. Patients with cardiac dilation had a
1.47-fold risk of developing heart failure compared with those
without dilation11.
The role of cardiac remodeling has been highlighted in
studies on HF, confirming these findings. In this context, the
Val-HeFT study demonstrated that patients with the highest
ventricular volumes and lowest baseline left ventricular ejection
fractions presented higher mortality12.
Cardoso et al.
Reverse Cardiac Remodeling in HF
Review Article
Reverse ventricular remodeling
Cardiac dilation is identified as an important marker of poor
prognosis. Conversely, its reversal is associated with improved
prognosis. Several studies have demonstrated that drugs or
procedures, which modify ventricular remodeling, preventing
or delaying cardiac dilation, are associated with improved
outcomes. Not all drugs used in the treatment of HF influence
cardiac remodeling. Animal studies in the postinfarction period
have shown that beta-blockers, aldosterone blockers, and
renin–angiotensin system inhibitors prevented cardiac dilation,
whereas hydralazine and digitalis did not. Thus, clinical and
experimental evidence suggests that the renin–angiotensin–
aldosterone system and sympathetic nervous system play an
important role in the process.
ACE inhibitors, as demonstrated in the SOLVD studies,
reduced the rate of cardiac dilation and, in initial forms,
promoted regression in cardiac dilation10,13,14.
Studies on angiotensin II receptor blockers demonstrated
that these drugs also have a beneficial effect on ventricular
remodeling. In the ELITE study, both patients receiving
ACE inhibitors and those receiving angiotensin II AT1
receptor‑antagonists (ARB) presented the same trend regarding
ventricular remodeling, with prevention of cardiac dilation.
There were no differences in response between the ACE
inhibitor and ARB treatments analyzed in that study14.
Cardiac dilation is not reversed in all patients with HF and
ventricular dysfunction. In patients with lesser involvement,
reversal is not generally observed; it is more frequently
identified in cases of moderate to intense involvement, with
greater magnitude in the former7,10,12,14. Studies have shown
reversal of cardiac dilation in approximately 30%–60% of the
cases treated with neurohormonal blockers.
In a study of outpatients over 70 years of age, Cioffi et al.15
observed an improvement in the ejection fraction in 36%
during a mean follow-up of 17 months. Predictors for this
improvement were absence of diabetes, history of hypertension,
and treatment with beta-blockers; treatment with beta-blockers
increased the chance of reversal by 3.4 times15. In the V-HeFT
I and II studies, reverse remodeling was also observed both in
the group treated with hydralazine and nitrate and that treated
with enalapril16. A 5-unit increase in ejection fraction was
the best predictor of mortality among the studied variables16.
Approximately 30% of the patients had an increase in ejection
fraction greater than 5 units; 50% of these presented an increase
of more than 10 units.
The improvement in cardiac remodeling has also been
observed. In the IMPROVE-HF registry, which examined
3,994 patients hospitalized for compensation, ejection fraction
increased over 10% in 28.6% of patients17.
Increased adrenergic activity appears to have a greater role
in ventricular remodeling. Studies have demonstrated that
beta-blockers promoted a more intense reversal of cardiac
dilation than ACE inhibitors (Figure 1). ACE inhibitors prevent
ventricular dilation and promote small increases in ejection
Figure 1 – ACE inhibitors prevent cardiac dilation and beta-blockers reverse it. Coh JN et al JACC 2000; 35: 569-82.
Arq Bras Cardiol. 2015; 104(6):502-506
503
Cardoso et al.
Reverse Cardiac Remodeling in HF
Review Article
fraction, but reduction in ventricular diameter and increase in
ejection fraction are more significant with beta-blockers13,18.
The current literature documents that adrenergic activity
actually plays an important role in ventricular remodeling, greater
than that of the renin–angiotensin system, at least in the most
symptomatic forms of the disease. Conversely, the adrenergic
system may not be greatly stimulated in the initial phases of
ventricular dysfunction because blockage of this system in
asymptomatic forms of ventricular dysfunction does not result
in a very significant reduction in mortality, as demonstrated in
the CAPRICORN study19.
Prognosis and remodeling
There is a growing body of evidence on the importance
of reverse ventricular remodeling in HF prognosis 19-23.
Patients who present regression of ventricular dilation or
increased ejection fraction after treatment have better
quality of life.
At follow-up, Cioffi et al.15 demonstrated that patients
with reverse cardiac remodeling had lower mortality (3%)
compared with those who did not present reversal (22%).
In the V-HeFT I study, mortality in the first year of follow-up
for patients who had a reduction in ejection fraction greater
than 6 units, an alteration in ejection fraction ranging
between −5 and 5 units, and those who had an increase
in ejection fraction greater than five units was 29%, 16%,
and 6%, respectively16.
Hoshikawa et al.18 observed that prognosis is related
to the reversal of cardiac dilation. They divided their
patients into three groups: those with full reverse cardiac
remodeling, with LV diameter < 55 mm and Delta D
fraction > 25%; those with partial reversal; and those
who did not present reversal. The authors observed
that all patients with no reversal of cardiac dilation died
during the follow-up, which lasted an average of 5 years18.
All patients who presented some reversal survived.
In that study population, all patients were treated with
neurohormonal blockers; 78% showed a reversal of cardiac
dilatation and, of these, 57% showed complete reversal18.
This same group reassessed their patients. Furthermore,
Matsumura et al. 24 demonstrated the role of reverse
remodeling in long-term prognosis. This study revealed that
in 12 years of follow-up, all patients who had regression
of cardiac dilation survived; however, those presenting
increased dilation died or required transplantation. In this
population of patients with dilated cardiomyopathy, it was
observed that 35.6% of patients had some reversal; 37% of
these presented normal diameters and ejection fractions24.
All patients with some reversal remained alive at the end of
12 years, demonstrating that even small reversals indicate
a good response to treatment24.
In addition to the analysis of clinical trials and small
group studies, reverse cardiac remodeling was assessed in
504
Arq Bras Cardiol. 2015; 104(6):502-506
a meta‑analysis involving 69,766 patients in 30 randomized
trials25, which showed a strong relationship between improved
ejection fraction and reduced mortality. Overall, mortality
significantly decreased by 49% in patients presenting improved
ejection fraction compared with those who did not25. Based on
the regression analysis, a 5% increase in mean ejection fraction
corresponded to a relative reduction of 14% in mortality (OR,
0.86; 95% CI, 0.77–0.96; p = 0.013). For each 5% absolute
increase in ejection fraction, patients who presented reversals
had a 4.9-fold higher chance of not dying compared with
those showing no reversal. Similar results were described for
the change in left ventricular volume25.
Treatment and reverse remodeling
Because prognosis is better in patients with reversed cardiac
dysfunction, at least partially, reversal should be considered a
primary treatment goal. Patients not presenting this reversal
should have their treatment regimen reassessed. In the absence
of reversal, they should be more carefully followed up because
they are at risk for a poorer outcome. Effective treatment should
reverse cardiac remodeling26-28. Notably, all effective drugs and
procedures, such as cardiac resynchronization, promote the
reversal of cardiac dilation18,29-32. Nonreversal may be a sign that
the doses of prescribed medications are inadequate or that the
disease severity is high, resulting in a failure to obtain desired
response to a proposed treatment.
In the treatment of HF, dosage is extremely important.
Reverse remodeling is often not observed because the
treatment drugs are administered at low doses. The importance
of dosage can be observed in the FAST–Carvedilol study33.
In this study, half of patients were discharged after using this
drug at a dose of 3.125 mg or 6.25 mg twice daily, whereas
the dosage for the remaining was rapidly increased during
hospitalization and was the highest tolerated dose during
discharge. At the outpatient clinic, dosage of carvedilol was not
increased by the physicians for various reasons; this was most
frequently because of borderline blood pressure. Thus, the
average carvedilol dose was 6.99 mg/day in the control group
and 16.19 mg/day in the intervention group. At follow-up, the
intervention group presented a reversal of cardiac dilation;
this reduction was already evident at 3 months of treatment
(Figure 2)33. The group treated with low doses did not present
reversal. At follow-up, in the first year, the survival rate was
43.5% in the control group versus 65.2% in the intervention
group. The data draw attention to the importance of dosage
both in reversing cardiac dilatation and reducing mortality and
show that both are probably interconnected33.
The authors of the present study have used these guidelines
in clinical practice, increasing the dosage (particularly for
beta-blockers) in patients who did not present reverse cardiac
remodeling, thereby achieving a reversal of the dilation not
obtained with the usual dosage. In patients whose heart rate
is consistently above 70 bpm during optimized treatment,
ivabradine has been effective in reversing cardiac dilation34.
Cardoso et al.
Reverse Cardiac Remodeling in HF
Review Article
Figure 2 - Beta-blockers used at the correct dosage reverses cardiac dilation; this reduction is already evident at 3 months of treatment. Melo D et al. JACC 2011; 57 (supl A): 17.
Conclusion
Cardiac dilation is a marker of poorer prognosis in
patients with HF. The drugs used to treat HF, particularly
beta-blockers, ACE inhibitors, and ARBs, promote reverse
remodeling. Patients who present reverse remodeling during
treatment have better outcomes and lower mortality than
those who do not present it.
Filho JRAR, Cardoso JN, Cardoso CMR, Barretto AC. Critical
revision of the manuscript for intellectual content: Reis Filho
JRAR, Cardoso JN, Cardoso CMR, Barretto AC.
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: Reis Filho JRAR,
Cardoso JN, Cardoso CMR, Pereira-Barretto, AC. Acquisition of
data: Reis Filho JRAR, Cardoso JN, Cardoso CMR, Barretto AC.
Analysis and interpretation of the data: Reis Filho JRAR, Cardoso
JN, Cardoso CMR, Barretto AC. Writing of the manuscript: Reis
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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Arq Bras Cardiol. 2015; 104(6):502-506
Back to the Cover
Letter to the Editor
An Issue Waiting to be Clarified: Effects of the QT Prolonging Drugs
on Tp-e Interval
Omer Yiginer, Mehmet Dogan, Emrah Erdal
Gulhane Military Medical Academy, Haydarpasa Training Hospital, Department of Cardiology, Selimiye – Istanbul
We read the article ‘Impact of Psychotropic Drugs on QT
Interval Dispersion in Adult Patients’ by Claudio et al. with
great interest1. They investigated in this study the effects
of psychotropic drugs on QT interval (QTI), corrected QT
interval (QTc), and QT dispersion (QTd). They concluded that
psychotropic drugs increased QTd and QTc interval.
QTd is the most frequently used non-invasive method
to quantify electrical myocardial heterogeneity. However,
there are variable results in studies related to QTI due to
the technical limitations in measurements2. It is well-known
that the reproducibility of QTI measurements is low both
in manual and automatic measurements2. In this study, the
measurements were performed digitally by four cardiologists
using the Preview software with a magnification of 300%.
We appreciated the method used in this study in order
to obtain more accurate data. It is recommended that
measurements be done digitally at least by two cardiologists2.
Quantifying electrical myocardial heterogeneity
and transmural dispersion of repolarization (TDR) was
introduced in the beginning of 2000’s3. The myocardium
Keywords
Psychotropic /drugs therapeutic; Electrocardiography;
Cardiovascular Diseases; Torsades de Pointes; Ventricular
Fibrillation; Death, Sudden.
comprises 3 distinct myocyte types - namely, endocardial,
epicardial, and midmyocardial M cells3. Although these
myocytes are morphologically similar, they exhibit different
electrophysiological characteristics. M cells have typically the
longest action potential. Furthermore, when myocardium is
exposed to conditions prolonging the repolarization phase,
such as bradycardia or agents, the action potential duration
of the M cells are more prolonged than in the other cells3.
While repolarization of the epicardial region ends at the peak
of T-wave, repolarization phase of M cells ends at the end of T
wave3. Therefore, the time between the peak and end of the
T wave is called Tp-e interval, as an index of TDR.
The role of the TDR in the prediction of possible
life‑threatening arrhythmic events has been demonstrated in
the Brugada, short-QT and long-QT syndromes and coronary
artery disease3. Previously, we showed that TDR was increased
in patients with obstructive sleep apnea and chronic arsenic
exposure4,5. However, there is no study investigating the effects
of QT prolonging drugs on TDR. The repolarization phase of
myocytes in midmyocardial and endocardial layers may be
more influenced by the drugs. In this context, psychotropic
drugs may be increasing QT interval duration via Tp-e
interval prolongation. In conclusion, it seems that adding the
data related to Tp-e interval to the study results might have
completely illuminated the effects of psychotropic drugs on
electrical heterogeneity of myocardium in many respects.
Mailing Address: Mehmet Drogan •
Gulhane Military MEdical Academy. Selimiye Uskudar. Postal Code 34688,
Selimiye – Istanbul
E-mail: [email protected]
Manuscript received November 11, 2014; revised manuscript November 11,
2014; accepted January 19, 2015.
DOI: 10.5935/abc.20150037
References
1. Claudio B de Q, Costa MA, Penna F, Konder MT, Celoria BM, Souza LL, et
al. Impact of psychotropic drugs on QT interval dispersion in adult patients.
Arq Bras Cardiol. 2014;102(5):465-72.
2.
Malik M, Batchvarov VN. Measurement, interpretation and clinical potential
of QT dispersion [Review]. J Am Coll Cardiol. 2000;36(6):1749-66.
3. Gupta P, Patel C, Patel H, Narayanaswamy S, Malhotra B, Green JT, et
al. T(p-e)/QT ratio as an index of arrhythmogenesis. J Electrocardiol.
2008;41(6):567-74.
507
4. Kilicaslan F, Tokatli A, Ozdag F, Uzun M, Uz O, Isilak Z, et al. Tp-e interval,
Tp-e/QT ratio, and Tp-e/QTc ratio are prolonged in patients with moderate
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35(8):966-72.
5. Yildiz A, Karaca M, Biceroglu S, Nalbantcilar MT, Coskun U, Arik F, et
al. Effect of chronic arsenic exposure from drinking waters on the QT
interval and transmural dispersion of repolarization. J Int Med Res.
2008;36(3):471-8.
Yiginer et al.
Effects of the QT prolonging drugs on Tp-e interval
Letter to the Editor
Answer to Letter to Editor
We appreciate the authors’ interest in our study and the
valuable contributions on the subject.
The spatial dispersion of ventricular repolarization can occur
in the transmural, trans-septal or apical-basal direction.1,2.
A large number of publications has been dedicated to the study
of cell diversity of the human myocardium and its heterogenic
response to pharmacological agents.
Researchers such as Antzelevitch et al.3 and Luo e Rudy4
have tested several models in normal hearts and individuals
with congenital long-QT syndrome, concluding that the
properties of the M cell action potential critically participate
on QT interval dispersion, mainly in the presence of drugs
with binding capacity in the IKr and IKs channels1,5.
artery disease model, Karaman et al.6 found an association
between increased QT dispersion and the Tp-e interval with
slowed coronary flow in coronary angiography (TIMI 1) in
patients with acute coronary syndrome, when compared to
the control group (TIMI 3)6.
In our study, we chose to measure the QT dispersion, as
it is a powerful tool that can be fully incorporated by general
practitioners that prescribes psychotropic drugs in the routine
monitoring of a potentially fatal complication of their patients7.
However, we expect the Tp-e interval, considering its solid
results in the literature, also to become a routine tool in the
increasingly frequent use of these drugs.
Under this idea, in fact, the measurement of Tp-e is
conceptually an electrocardiographic correlation truthful to the
abovementioned concepts. In a recent article, in the coronary
Sincerely,
Bruno de Queiroz Claudio
References
1. Antzelevitch C. The role of spatial dispersion of repolarization in inherited
and acquired sudden cardiac death syndromes. Am J Physiol Heart Circ
Physiol. 2007;293(4):H2024-38.
4.
2. Restivo M, Caref EB, Kozhevnikov DO, El-Sherif N. Spatial dispersion of
repolarization is a key factor in the arrythmogenicity of long QT syndrome.
J Cardiovasc Electrophysiol. 2004;15(3):323-31.
5. Antzelevitch C, Shimizu W. Cellular mechanisms underlying the long QT
syndrome. Curr Opin Cardiol. 2002;17(1):43-51.
3.
Antzelevitch C, Shimizu W, Yan GX, Sicouri S, Weissenburger J, Nesterenko VV, et
al. The M cell: its contribution to the ECG and to normal and abnormal electrical
function of the heart. J Cardiovasc Electrophysiol. 1999;10(8):1124-52.
Luo CH, Rudy Y. A dynamic model of the cardiac ventricular action potential.
I. Simulations of ionic currents and concentration changes. Circ Res.
1994;74(6):1071-96.
6. Karaman K1, Altunkaş F, Cetin M, Karayakali M, Arısoy A, Akar I, Zencir C,
Aygüç B, Celik A. New Markers for Ventricular Repolarization in Coronary
Slow Flow: Tp-e Interval, Tp-e/QT Ratio, and Tp-e/QTc Ratio. Ann
Noninvasive Electrocardiol. 2014 Sep 30. [Epub ahead of print]
Arq Bras Cardiol. 2015; 104(6):507-508
508
Back to the Cover
Clinicoradiological Session
Case 5/2015 – Late Outcome of Corrected Aortopulmonary Window
in A 23-Year-Old Female Patient Who Underwent Surgery in Childhood
Edmar Atik
Clínica Privada Dr. Edmar Atik, São Paulo, SP – Brazil
Clinical data: At 10 months of age, the patient underwent
correction of a large aortopulmonary window and mitral valve
regurgitation secondary to volume overload, which caused
severe heart failure. The post-operative clinical outcome was
favorable. Prior to operation, her clinical picture was of concern
because of severe malnutrition (weight of 5,500 g), congestive
heart failure (tachypnea of 60 bpm), hepatomegaly (liver
palpable at 4 cm of the right costal margin), severe cardiomegaly,
and increased pulmonary vasculature. Cardiovascular
examination showed left ventricular (LV) enlargement; thrill
and systolic murmur in the mitral area; accentuated S2; marked
LV overload on electrocardiogram (ECG); mitral regurgitation
due to incomplete leaflet coaptation; and pulmonary systolic
pressure of 60 mmHg. At surgery, the 2-cm-diameter window
between the pulmonary trunk and ascending aorta (Ao) was
closed, and plication of the posterior ring of the mitral valve
was performed. There was an immediate clinical response with
hemodynamic stabilization, resolution of the heart murmur and
heart failure, and subsequent normal weight gain. Medication
for congestive heart failure was discontinued at 4 years of age,
when the cardiac silhouette had returned to normal. To date,
the patient tolerates routine exercises well and does not report
any symptoms.
Physical examination: good general state of health,
normal breathing, acyanotic, normal pulses. Weight: 53 kg;
height: 165 cm; blood pressure on right arm (BPRA):
105/75 mmHg; heart rate (HR): 76 bpm. Aorta not palpable
on the suprasternal notch.
The apical impulse was not palpable in the precordium,
and there were no systolic impulses. Normal heart sounds,
no heart murmurs. Liver not palpable.
Laboratory tests
ECG (Figure 1) at 22 years of age showed normal sinus
rhythm with no signs of overload, and normal ventricular
repolarization. PA = +10o, QRSA = +50o, TA = +50o (lower
tracing). ECG prior to operation, at 10 months of age (upper
Keywords
Aortopulmonary Window/surgery; Heart Defects,
Congenital/surgery; Infant.
Mailing Address: Edmar Atik •
Rua Dona Adma Jafet, 74, conj. 73, Bela Vista. Postal Code 01308-050.
São Paulo, SP – Brazil
E-mail: [email protected] ; [email protected]
Manuscript received July 24, 2014; revised manuscript October 06, 2014;
accepted October 06, 2014.
DOI: 10.5935/abc.20150062
e55
tracing), showed marked left ventricular overload, with
QRSA = +70o, PA = +20o and TA = +80o; RS morphology
(amplitudes of 24 and 30 mm) from V1 to V3 and QRs
(amplitudes of 10, 50 and 3 mm) from V4 to V6; Sokolow
index of 90 mm; no ventricular repolarization abnormalities.
Chest radiograph showed normal cardiac silhouette
(cardiothoracic ratio = 0.46) and pulmonary vasculature
(Figure 2). In the image prior to surgery, these parameters were
markedly increased, with a cardiothoracic ratio of 0.85 (Figure 2).
Echocardiogram showed normal size cardiac chambers
(Ao = 34; left atrium − LA = 36, right ventricle − RV = 13,
LV = 49; ejection fraction − EF = 61%, septum = posterior
wall = 8 mm); no mitral regurgitation. Echocardiogram prior
to surgery showed enlargement of left chambers (LA = 37,
Ao = 17 and LV = 42; RV = 10, septum = posterior wall
= 5 mm; EF = 82%), with marked mitral regurgitation.
Clinical diagnosis: Aortopulmonary window with mitral
regurgitation secondary to volume overload and severe heart
failure resolved after surgical correction and favorable late
outcome until adulthood.
Clinical reasoning: The postoperative clinical elements
were consistent with normal cardiovascular parameters, unlike
in the preoperative period, in which the overt manifestations of
heart failure suggested the diagnosis of congenital heart defect
expressed by signs of mitral regurgitation. On that occasion,
the aortopulmonary window was diagnosed during surgery,
and mitral regurgitation was secondary to and resulted from
the volume overload caused by the defect. LV overload on
ECG confirmed the magnitude of the volume overload, which
predominated over the RV pressure overload.
Differential diagnosis: other defects accompanied by
severe arterial left-to-right shunt, such as ductus arteriosus and
arteriovenous fistulas, should be remembered in this context.
Management: In view of the marked consequences of
the arterial shunt, the surgery for closure of the interarterial
defect not only repaired the secondary dilatation of the mitral
annulus, but also resulted in cure, thus surpassing the concern
about pulmonary arterial hypertension at the time.
Commentaries: aortopulmonary window usually has
important manifestations early in the first months of life, and
cardiac surgery corrects the signs and symptoms of heart
failure and associated defects such as those of secondary
mitral regurgitation, which was present in the case reported1-3.
Generally, pulmonary arterial hypertension also subsides, and so
does the secondary dilatation of the different correlate cardiac
structures. This is encouraging, given the important implications
of this defect, which should be corrected right after diagnosis.
The return of anatomical and functional parameters to normal,
in this case, becomes of great value as an example of outcome
for similar cases in an early period of life.
Edmar Atik
Late Outcome of Surgically Corrected Aortopulmonary Window
Clinicoradiological Session
Figure 1 – Electrocardiograms at two timepoints: in the preoperative period, at 10 months of age (upper tracing), and at late postoperative period at 22 years of age
(lower tracing). These electrocardiograms show resolution of the left ventricular overload initially observed.
Figure 2 – Chest radiographs in the preoperative period and later at 23 years of age, after surgical correction performed at 10 months of age, showing markedly enlarged
and normal cardiac silhouette, respectively.
Arq Bras Cardiol. 2015; 104(6):e55-e57
e56
Edmar Atik
Late Outcome of Surgically Corrected Aortopulmonary Window
Clinicoradiological Session
References
1.
Soares AM, Atik E, Cortêz TM, Albuquerque AM, Castro CP, Barbero-Marcial
M, et al. Aortopulmonary window. Clinical and surgical assessment of 18
cases. Arq Bras Cardiol.1999;73(1):59-74.
2. Barnes ME, Mitchell ME, Tweddell JS Aortopulmonary window. Semin
Thorac Cardiovasc Surg Pediatr Card Surg Annu. 2011;14(1):67-74.
e57
Arq Bras Cardiol. 2015; 104(6):e55-e57
3.
Atik E, Barbero-Marcial M, Andrade JL, Baucia JA, Iwahashi E, Aiello V, et al.
[Clinical manifestation of aortopulmonary window as mitral regurgitation
caused by secondary dilatation of the valvar anulus]. Arq Bras Cardiol.
1994;63(6):493-5.
Back to the Cover
Case Report
Acute Myocardial Infarction and Severe Prosthetic Dysfunction after
Bentall Procedure
Viviane Tiemi Hotta, Pedro Gabriel de Melo Barros, Paulo Sampaio Gutierrez, Angela Cristina Pasiani Bolonhez,
Wilson Mathias, Ricardo Ribeiro Dias
InCor / Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP - Brazil
Introduction
Coronary artery anastomotic dehiscence is a rare
complication following aortic procedures. A 59-year-old male
previously underwent replacement of the ascending aorta
and aortic valve because of ascending aorta aneurysm and
severe aortic regurgitation. Eight years after the procedure, he
presented with acute myocardial infarction. Transesophageal
echocardiography (TEE) and coronary angiography revealed
coronary artery dehiscence. This finding rarely occurs after
a Bentall procedure; however, if it does, it usually occurs
in the early postoperative period and is associated with
an infectious etiology. In this case, coronary dehiscence
presented with myocardial infarction years after the
procedure and was first suspected after TEE.
Case Report
A 59-year-old male presented with chest pain and
breathlessness of three days’ duration, which was rapidly
deteriorating. Eight years ago, he had undergone a classical
Bentall procedure because of ascending aorta aneurysm and
severe aortic regurgitation. He had been treated with beta
blockers, angiotensin-converting enzyme inhibitors, statin
for systemic arterial hypertension and dyslipidemia control,
and oral anticoagulants.
On physical examination, blood pressure was
130/40 mmHg and heart rate was 74 beats/minute.
On cardiac auscultation, a mechanical click with a systolic
murmur and a high-pitched aortic diastolic murmur at the
left sternal border radiating toward the apex was noted.
Electrocardiogram revealed left bundle branch block.
Chest X-ray showed mild pulmonary congestion, enlarged
mediastinum, and aortic mechanical prosthesis. There was
an increase in myocardial necrosis markers. A thoracic
computed tomography (CT) angiogram was performed to
evaluate aortic dissection, which was inconclusive, and a
TEE was performed.
Keywords
Myocardial Infarction; coronary ostium dehiscence, Bentall
procedure, prosthetic aortic valve disfunction
Mailing Address: Viviane Tiemi Hotta •
Unidade Clínica de Miocardiopatias do InCor/FMUSP. Avenida Doutor Enéas
Carvalho de Aguiar, 44. São Paulo, Postal Code 05403-000. São Paulo, SP - Brazil.
Email: [email protected], [email protected]
Manuscript received June 26, 2014; revised manuscript July, 23, 2014;
accepted July, 28, 2014.
DOI: 10.5935/abc.20140199
e58
Transthoracic echocardiogram showed moderate left
ventricular systolic dysfunction due to anterior and apical
akinesia and severe dysfunction of the aortic mechanical
prosthesis (severe aortic regurgitation). TEE evaluation
evidenced solutions of continuity causing turbulent
leakage flow between the Dacron graft on the ascending
aorta and the aneurismal native aorta (Figure 1) was also
observed. Moreover, severe aortic central and periprosthetic
regurgitation was noted.
The oral anticoagulant therapy was withdrawn, and
low‑molecular-weight heparin (enoxaparine) therapy
was initiated. After normalization of the international
normalized ratio, coronary angiography was performed
and showed no significant lesions on the coronary arteries.
On the 12 th day after acute myocardial infarction, the
patient underwent a Cabrol procedure (Figure 2A);
intraoperative findings revealed disconnection of both
the left and right coronary ostium from the graft and a
periprosthetic leak.
The patient was discharged on the 14th postoperative day
without complications.
Discussion
Coronary ostial anastomoses dehiscence is a rare
complication following aortic procedures1-6. Regarding the
etiologies related to this unusual finding, infection of
aortocoronary vein graft suture lines is the most common
cause of this condition and some cases may be associated
with early postoperative Staphylococcus aureus superficial
wound infection. In this case, the patient presented
with late clinical features several years after the surgical
procedure; and the anatomopathological examination7,8
revealed no signs of infection in the aorta specimen and
Dacron prosthesis (Figure 2B).
Dehiscence of the coronary ostial anastomoses may also
occur more frequently in patients with connective tissue
diseases or other genetically defined aortopathies like Marfan
syndrome. In these patients, recurrence of life‑threatening
cardiovascular manifestations is not uncommom. Other aspects
related to dehiscence of the coronary graft concern to technical
details during the Bentall procedure like increased bleeding
or difficulties of hemostasis, limiting the reestablishment of
coronary flow, a crucial aim of the composite graft-valve
procedures like Bentall De Bono technique.
In this case, the patient had an unremarkable evolution
after the Bentall procedure. Subclinical manifestations of
early infection after the first procedure may have passed
unnoticed and may have been associated with periprosthetic
Hotta et al.
Cardiac complications after bentall procedure
Case Report
Figure 1 – TTE images showing severe regurgitation of the aortic prosthesis on continuous (A) and pulsed wave Doppler (B) mappings in the apical five-chamber
view. TEE images of the color M-mode of the left ventricular outflow tract (LVOT; C) and color Doppler study (D) evidencing severe aortic prosthetic regurgitation.
TEE transverse plane imaging showing the solutions of continuity between the Dacron prosthesis and native aorta (E and F, arrows). TEE imaging, at 145º, depicting
the LVOT and color Doppler study (G and H). TTE: transthoracic echocardiography; TEE: transesophageal echocardiography; LA: left atrium; LV: left ventricle; RV: right
ventricle; RA: right atrium; AO: Aorta; LVOT: left ventricle outflow tract; AR: Aortic regurgitation.
leaks. Moreover, technical problems may have contributed to
dehiscence formation. Small leaks can progress along the years
and evolve late after surgery into pseudoaneurysms and other
variable clinical features depending on the site of the aortic
dehiscence and involvement of the surrounding structures.
In this patient, dehiscence of the coronary ostium was
diagnosed due to an acute myocardial infarction secondary
to inadequate coronary flow resulting from graft dehiscence
since atherosclerotic coronary artery disease was excluded
by coronary angiography. Late postoperative aortic graft
dehiscence may occur rarely after Bentall procedure and in
this case, it was first suspected after TEE evaluation.
Advantages of the classical Bentall technique are graft
cover up using the remaining aortic tissue and immediate
protection against bleeding during the perioperative period;
disadvantages include pseudoaneurysm formation. This is
why the modified Bentall procedure is currently the most used
operation for aortic root reconstruction using a valved graft.
CT aortography can be helpful in the diagnosis of this
complication9, but in this case, it was inconclusive. TEE showed
solutions of continuity on the Dacron graft in the ascending
aorta and the native aorta, raising the suspicion of coronary
ostium dehiscence that was further confirmed by intraoperative
examination. The patient underwent a Cabrol procedure with
no complications (Figure 2A).
Complete coronary artery dehiscence is an exceptional cause
of pseudoaneurysm after a Bentall procedure. So far, there are
very few case reports with this disorder presenting as acute
myocardial infarction. Additionally, in our case, there was no
evidence of infection and diagnosis was possible by means of TEE.
Arq Bras Cardiol. 2015; 104(6):e58-e60
e59
Hotta et al.
Cardiac complications after bentall procedure
Case Report
Figure 2 – A) Post operatory aspect after Cabrol procedure. B) Histological section of a fragment of the aorta removed during surgery, showing fibrosis at the adventitia
(indicated by arrows) and very mild mononuclear inflammatory infiltrate (hematoxylin & eosin staining).
References
1.
Haddy SM. Aortic pseudoaneurysm after Bentall procedure. J Cardiothorac
Vasc Anesth. 1999;13(2):203-6.
2. Shinohara K, Ishikura F, Tanaka N, Asaoka N, Nakasone I, Masuda Y, et
al. Diagnosis of coronary artery dehiscence and pseudoaneurysm after
modified Bentall operation by Doppler color flow imaging: a case report. J
Cardiol. 1994; 24(6):475-9.
3. Barbetseas J, Crawford ES, Safi HJ, Coselli JS, Quinones MA, Zoghbi WA.
Doppler echocardiographic evaluation of pseudoaneurysms complicating
composite grafts of the ascending aorta. Circulation. 1992; 85(1):212-22.
e60
4.
Cujec B, Bharadwaj B, Chait P, Hayton R.Dehiscence of the proximal
anastomosis of aortocoronary bypass graft. Am Heart J. 1990; 120(5): 1217-20.
5.
Rice MJ, McDonald RW, Reller MD. Diagnosis of coronary artery dehiscence
and pseudoaneurysm formation in postoperative Marfan patient by color
flow Doppler echocardiography. J Clin Ultrasound . 1989; 17(5):359-65.
Arq Bras Cardiol. 2015; 104(6):e58-e60
6.
Monney P, Pellaton C, Qanadli SD, Jeanrenaud X. Aortic pseudo-aneurysm
caused by complete dehiscence of the left coronary artery 7 years after a
composite mechanical-valved conduit aortic root replacement (Bentall
operation). Eur Heart J. 2012; 33(1):60.
7.
Smith P, Qureshi S, Yacoub MH. Dehiscence of infected aortocoronary vein
graft suture lines. Cause of late pseudoaneurysm of ascending aorta. Br Heart
J.1983;50(2):193-5.
8. Douglas BP, Bulkley BH, Hutchins GM. Infected saphenous vein coronary
artery bypass graft with mycotic aneurysm. Fatal dehiscence of the proximal
anastomosis. Chest. 1979;75(1):76-7.
9.
Ceviz M, Becit N, Gündogdu F, Unlü Y, Kantarci M. Pseudoaneurysm of the
left coronary ostial anastomoses as a complication of the modified Bentall
procedure diagnosed by echocardiography and multislice computed
tomography. Heart Surg Forum. 2007;10(3):E191-2.
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