www.arquivosonline.com.br
Sociedade Brasileira de Cardiologia • ISSN-0066-782X • Volume 104, Nº 4, April 2015
Figure 1 – Schematic representation of quantitative coronary analysis by 64-slice MDCT (above)
and IVUS (below). The upper images show the longitudinal reconstruction for both methods. The lower
images show illustrative vessel cross-sections with the outer vessel and lumen (inner) boundaries
tracings. page 317
Original Articles
Letter to the Editor
Infant Mortality in Novo Hamburgo: Associated Factors and
Left Atrial Volume Index as Predictor of Events in Acute Coronary
Cardiovascular Causes
Syndrome
Insulin Resistance, Dyslipidemia and Cardiovascular Changes in a
Group of Obese Children
Eletronic Pages
Subclinical Ventricular Dysfunction Detected by Speckle Tracking Two
Years after Use of Anthracycline
Clinicoradiological Session
Blood Pressure Variation Throughout Pregnancy According to Early
Case 4/2015 A 48-year-old Male Patient with Coarctation of the
Gestational BMI: A Brazilian Cohort
Aorta, Bicuspid Aortic Valve and Normal Ascending Aorta
Progression of Blood Pressure and Cardiovascular Outcomes in
Case Report
Hypertensive Patients in a Reference Center
Sickle-cell Anemia and Latent Diastolic Dysfunction:
Quality of Life on Arterial Hypertension: Validity of Known Groups of
MINICHAL
Influence of Spironolactone on Matrix Metalloproteinase-2 in Acute
Decompensated Heart Failure
Comparison between MDCT and Grayscale IVUS in a Quantitative
Analysis of Coronary Lumen in Segments with or without
Atherosclerotic Plaques
Review Article
Treatment of Dyslipidemia with Statins and Physical Exercises: Recent
Findings of Skeletal Muscle Responses
Echocardiographic Alterations
Viewpoint
Correct Anatomical Orientation of the Heart and Reflections on the
Nomenclature Used in Daily Practice
Image
Incremental Value Of 3D Transesophageal Echocardiography for The
Assessment of Mitral Valve Prolapse
A JOURNAL OF SOCIEDADE BRASILEIRA DE CARDIOLOGIA - Published since 1948
Contents
Original Articles
Pediatric Cardiology
Infant Mortality in Novo Hamburgo: Associated Factors and Cardiovascular Causes
Camila de Andrade Brum, Airton Tetelbom Stein, Lucia Campos Pellanda
.....................................................................................................................................................................page 257
Insulin Resistance, Dyslipidemia and Cardiovascular Changes in a Group of Obese Children
António Pires, Paula Martins, Ana Margarida Pereira, Patricia Vaz Silva, Joana Marinho, Margarida Marques,
Eduardo Castela, Cristina Sena, Raquel Seiça
.....................................................................................................................................................................page 266
Echocardiography - Adults
Subclinical Ventricular Dysfunction Detected by Speckle Tracking Two Years after Use of Anthracycline
André Luiz Cerqueira de Almeida, Viviane Almeida Silva, Alberto Teófilo de Souza Filho, Vinicius Guedes Rios,
João Ricardo Pinto Lopes, Samuel Oliveira de Afonseca, Daniel de Castro Araújo Cunha1, Murilo Oliveira da
Cunha Mendes, Danilo Leal Miranda, Edval Gomes dos Santos Júnior
.....................................................................................................................................................................page 274
Epidemiology
Blood Pressure Variation Throughout Pregnancy According to Early Gestational BMI: A Brazilian Cohort
Fernanda Rebelo, Dayana Rodrigues Farias, Roberta Hack Mendes, Michael Maia Schlüssel, Gilberto Kac
.....................................................................................................................................................................page 284
Hypertension
Progression of Blood Pressure and Cardiovascular Outcomes in Hypertensive Patients in a
Reference Center
Gilberto Campos Guimarães Filho, Ana Luiza Lima Sousa, Thiago de Souza Veiga Jardim, Weimar Sebba Barroso
Souza, Paulo César Brandão Veiga Jardim
.....................................................................................................................................................................page 292
Systemic Arterial Hypertension
Quality of Life on Arterial Hypertension: Validity of Known Groups of MINICHAL
Ana Lúcia Soares Soutello, Roberta Cunha Matheus Rodrigues, Fernanda Freire Jannuzzi, Thaís Moreira São-João,
Gabriela Giordano Martini, Wilson Nadruz Jr., Maria-Cecília Bueno Jayme Gallani
.....................................................................................................................................................................page 299
Heart Failure
Influence of Spironolactone on Matrix Metalloproteinase-2 in Acute Decompensated Heart Failure
João Pedro Ferreira, Mário Santos, José Carlos Oliveira, Irene Marques, Paulo Bettencourt, Henrique Carvalho
.....................................................................................................................................................................page 308
Arquivos Brasileiros de Cardiologia - Volume 104, Nº 4, April 2015
Cardiovascular Computed Tomography
Comparison between MDCT and Grayscale IVUS in a Quantitative Analysis of Coronary Lumen
in Segments with or without Atherosclerotic Plaques
João L. A. A. Falcão, Breno A. A. Falcão, Swaminatha V. Gurudevan, Carlos M. Campos, Expedito R. Silva,
Roberto Kalil-Filho, Carlos E. Rochitte, Afonso A. Shiozaki, Otavio R. Coelho-Filho, Pedro A. Lemos
.....................................................................................................................................................................page 315
Review Article
Treatment of Dyslipidemia with Statins and Physical Exercises: Recent Findings of Skeletal
Muscle Responses
Mariana Rotta Bonfim, Acary Souza Bulle Oliveira, Sandra Lia do Amaral, Henrique Luiz Monteiro
.....................................................................................................................................................................page 324
Letter to the Editor
Left Atrial Volume Index as Predictor of Events in Acute Coronary Syndrome
Luciano Barros Pires e Rodrigo Pires dos Santos
.....................................................................................................................................................................page 333
Arquivos Brasileiros de Cardiologia - Volume 104, Nº 4, April 2015
Arquivos Brasileiros de Cardiologia - Eletronic Pages
Clinicoradiological Session
Case 4/2015 A 48-year-old Male Patient with Coarctation of the Aorta, Bicuspid Aortic Valve and
Normal Ascending Aorta
Edmar Atik, Raul Arrieta, Otávio Rizzi Coelho
.................................................................................................................................................................. page e27
Case Report
Sickle-cell Anemia and Latent Diastolic Dysfunction: Echocardiographic Alterations
André Fattori, Daniela Camargo Oliveira, Roger Frigério Castilho, Otávio Rizzi Coelho
.................................................................................................................................................................. page e30
Viewpoint
Correct Anatomical Orientation of the Heart and Reflections on the Nomenclature Used in Daily Practice
Viviane Tiemi Hotta e Vera Demarchi Aiello
.................................................................................................................................................................. page e34
Image
Incremental Value Of 3D Transesophageal Echocardiography for The Assessment of Mitral Valve Prolapse
Viviane Tiemi Hotta, Mirian Magalhães Pardi, Valdir Ambrósio Moisés
.................................................................................................................................................................. page e37
* Indicate manuscripts only in the electronic version. To view them, visit: http://www.arquivosonline.com.br/2014/english/10404/edicaoatual.asp
Arquivos Brasileiros de Cardiologia - Volume 104, Nº 4, April 2015
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A JOURNAL OF SOCIEDADE BRASILEIRA DE CARDIOLOGIA - Published since 1948
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SUPPORT
Back to the Cover
Original Article
Infant Mortality in Novo Hamburgo: Associated Factors and
Cardiovascular Causes
Camila de Andrade Brum1, Airton Tetelbom Stein2,3,4, Lucia Campos Pellanda1,2
Instituto de Cardiologia/Fundação Universitária de Cardiologia (IC/FUC)1; Universidade Federal de Ciências da Saúde de Porto Alegre
(UFCSPA)2; Grupo Hospitalar Conceição (GHC)3; Universidade Luterana do Brasil (ULBRA)4; Porto Alegre, RS - Brazil
Abstract
Background: Infant mortality has decreased in Brazil, but remains high as compared to that of other developing
countries. In 2010, the Rio Grande do Sul state had the lowest infant mortality rate in Brazil. However, the municipality
of Novo Hamburgo had the highest infant mortality rate in the Porto Alegre metropolitan region.
Objectives: To describe the causes of infant mortality in the municipality of Novo Hamburgo from 2007 to 2010,
identifying which causes were related to heart diseases and if they were diagnosed in the prenatal period, and to assess
the access to healthcare services.
Methods: This study assessed infants of the municipality of Novo Hamburgo, who died, and whose data were collected
from the infant death investigation records.
Results: Of the 157 deaths in that period, 35.3% were reducible through diagnosis and early treatment, 25% were
reducible through partnership with other sectors, 19.2% were non-preventable, 11.5% were reducible by means of
appropriate pregnancy monitoring, 5.1% were reducible through appropriate delivery care, and 3.8% were ill defined.
The major cause of death related to heart disease (13.4%), which was significantly associated with the variables ‘age at
death’, ‘gestational age’ and ‘birth weight’. Regarding access to healthcare services, 60.9% of the pregnant women had
a maximum of six prenatal visits.
Conclusion: It is mandatory to enhance prenatal care and newborn care at hospitals and basic healthcare units to
prevent infant mortality. (Arq Bras Cardiol. 2015; 104(4):257-265)
Keywords: Infant Mortality; Perinatal Mortality / epidemiology; Fetal Death / epidemiology; Heart Diseases /
epidemiology; Midwifery; Maternal and Child Health.
Introduction
Infant mortality in Brazil has decreased over the past
few decades, but remains high as compared to that
of other developing countries 1. In 2010, that rate was
19.88/1000 live births. In that same year, the Rio Grande
do Sul state had the lowest infant mortality rate in Brazil
(11.2 deaths/1000 live births) 2, while the municipality
of Novo Hamburgo, in the Porto Alegre metropolitan
region, had the highest infant mortality rate in that region
(14.2 deaths/1000 live births)3,4 (Figure 1).
The major causes of neonatal mortality in Brazil are
intrauterine and intrapartum asphyxia and low birth weight/
prematurity. Conversely, in developed countries, those causes
are extreme prematurity and congenital malformation 5.
Mailing Address: Lucia Campos Pellanda •
Av. Princesa Isabel, 370, Santana. Postal Code 90.620-000, Porto Alegre,
RS - Brazil
E-mail: [email protected]
Manuscript received May 29, 2014; revised manuscript September 05,
2014; accepted September 16, 2014
DOI: 10.5935/abc.20140203
257
Similar to early neonatal mortality, high late neonatal
mortality relates to poor maternal health conditions and
unsatisfactory prenatal, delivery and newborn care6.
Because of the reduction in preventable causes, which
result from social determinants, there is an increasing need
to study congenital malformations, of which, heart diseases
have the greatest impact.
This study was aimed at: describing the causes of infant
mortality in the municipality of Novo Hamburgo, Rio Garnde
do Sul state, from 2007 to 2010; identifying the causes of
death related to heart diseases and if they were diagnosed in
the prenatal period; and assessing the access to healthcare
services of the cases of infant death in the municipality of
Novo Hamburgo.
Methods
This is a population-based case study (deaths).
From 2010 to 2011, data of the municipality of Novo
Hamburgo were collected from the 2007-2010 infant
death investigation records and from the Infant Mortality
System by the same highly skilled researcher. This study
sample comprised 157 infant deaths.
Brum et al.
Infant mortality and heart diseases
Original Article
Municipalities of the Porte Alegre Metropolitan Region
Series 1;
Novo Hamburgo; 14.2
Series 1;
Viamão; 12.7
Series 1;
Cachoeirinha; 12.6
Series 1;
Alvorada; 11.5
Series 1;
São Leopoldo; 11.2
Series 1;
Gravataí; 11
Series 1;
Porto Alegre; 10.5
Series 1;
Canoas; 8.3
Infant Mortality Rate (per 1000 live births)
Figure 1 – Comparison of infant mortality in the Porto Alegre metropolitan region in 2010. Source: Health Secretariat of Rio Grande do Sul State.
This study included data of infants in the municipality of
Novo Hamburgo, who died. Variables not found in the infant
death investigation records were excluded.
The number of live births was obtained from the Live Birth
Information System of the Health Secretariat of Rio Grande
do Sul State (Sinasc). Birth and death dates and causes of
death were collected from death certificates by the researcher
responsible for the infant death investigation, as were the
variables ‘gestational age’, ‘birth weight’ and ‘number of
prenatal visits’, obtained from the hospital medical records of
the newborn or from the maternal medical records.
The infant death investigation records are completed
by a health professional (nurse or doctor), who investigates
death based on the infant’s medical records, the maternal
medical records and interviews with family members during
home visits.
The causes of death were classified according to the
Classification of the São Paulo State Data Analysis System
(Seade) Foundation, which is used by the Brazilian Ministry
of Health to classify the causes de death aiming at prevention.
Heart diseases are classified as preventable causes, which can
be reduced through early management interventions.
For categorical variables, descriptive analysis (percentage)
was used, and, for continuous variables, mean and standard
deviation. The chi-square test and analysis of residues were
used. The 5% significance level was adopted. The SPSS
software, version 19, was used for data analysis.
This study used secondary data, was approved by the
Committee on Ethics and Research of the Institute of
Cardiology of Rio Grande do Sul, and no written informed
consent was required.
Results
Of the 157 deaths in the 2007-2010 period, 44.6% occurred
in the early neonatal period, 22.3% in the late neonatal period,
and 33.1% in the postneonatal period. According to the Seade
Foundation Classification, the major causes of infant death in
Novo Hamburgo (35.3%) could be reduced through actions of
diagnosis, prevention and early treatment; 25% were reducible
by use of partnership with other sectors; and 19.2% were
non‑preventable (Figure 2). Regarding birth sites, 77.4% of the
births occurred at hospitals of the Novo Hamburgo municipality,
and 21.3% at hospitals of other municipalities. Regarding the
infants who died, 57.2% were males and 64.1% had a birth
weight lower than 2,500 g.
Regarding maternal characteristics, most women whose
infants died were younger than 35 years (84.6%), and 39.7% of
them had a gestational age higher than 36 weeks. Considering
access to healthcare services, 39.2% of the pregnant women
had at least six prenatal visits (Table 1).
Heart diseases were the major cause of infant death
(13.4%), followed by respiratory distress syndrome of the
newborn (8.9%) and unspecified bacterial septicemia of the
newborn (8.3%). The causes of mortality related to heart
Arq Bras Cardiol. 2015; 104(4):257-265
258
Brum et al.
Infant mortality and heart diseases
Classification of Death According to the Seade Foundation
Original Article
55 (35.3%)
39 (25.0%)
30 (19.2%)
18 (11.5%)
8 (5.1%)
6 (3.8%)
Number of children
Figure 2 – Causes of infant mortality in the municipality of Novo Hamburgo in 2007-2010 according to the Seade Foundation.
diseases in death certificates were: unspecified cardiac
malformations (7.6%); malformations related to Edwards
syndrome (1.3%); unspecified malformation of the chambers
and septal defects (0.6%); unspecified malformation of the
great vein (0.6%); coarctation of the aorta (0.6%); congenital
mitral stenosis (0.6%); common arterial trunk (0.6%);
pulmonary valve atresia (0.6%); and hypoplastic left heart
syndrome (0.6%). Most of the deaths related to heart diseases
occurred in the postneonatal period (61.9%).
There was a statistically significant association between
heart disease and the variables ‘age at death’, ‘gestational
age’ and ‘birth weight’. A statistically significant association
was observed between the cause of death and the following
variables studied: ‘age at death’ (p = 0.043), with 23.1% of
the postneonatal deaths related to cardiovascular causes; and
‘gestational age’ (p = 0.013), 24.2% of those born after the
36th gestational week had a cardiovascular cause of death.
Regarding the variable ‘birth weight’ (p = 0.015), 96.2% of
the extremely low birth weight infants (<1,000 g) showed
an association with death due to other causes, and 26.7% of
those with birth weight between 1,500 and 2,499 g showed
an association with death due to heart diseases (Table 2).
No heart disease was diagnosed prior to delivery, and no
pregnant woman underwent echocardiography.
Discussion
Reducing infant mortality is a major challenge in Brazil for
health managers and professionals and the whole society7.
259
Arq Bras Cardiol. 2015; 104(4):257-265
Although the number of deaths significantly decreased in
the past decade, because of the reduction in postneonatal
mortality in Brazil, most deaths occurred in the poorest
regions, reflecting social inequities. That situation is even worse
considering that most of those early deaths could have been
prevented with timely access to quality healthcare services8.
According to The Lancet – University of Oslo Commission
on Global Governance for Health, the objective of the policy
for equity and health is not to eliminate all health differences
so that everybody has the same health level and quality,
but to reduce or eliminate those differences resulting from
preventable and unfair factors9.
In the early neonatal period, the most common risk factors
are prematurity, intrapartum asphyxia, neonatal infections and
low birth weight10. The World Health Organization estimates
that, in developed countries, approximately two thirds of
low-birth-weight newborns are premature, while one third
is small for gestational age11. That relationship is inverse in
poor countries, where approximately 75% of low-birth-weight
newborns are small for gestational age, and low birth weight
is almost always strongly associated with conditions of poverty
and maternal chronic poor nutrition and insufficient food
consumption12.
This is the first study to assess the causes of infant death in
a developed municipality of Rio Grande do Sul state, Novo
Hamburgo, whose per capita Gross Domestic Product (GDP)
in 2011 was R$ 23,009.67, and whose Human Development
Index (HDI) in 2010 was 0.7472. In the years 2007 to
Brum et al.
Infant mortality and heart diseases
Original Article
Table 1 – Characteristics of the sample
Variables
n = 157
Classification of age at death – n (%)
Early neonatal
70 (44.6)
Late neonatal
35 (22.3)
Postneonatal
52 (33.1)
Infant sex – n (%)
Male
90 (57.3)
Female
67 (42.7)
Birth site* – n (%)
Hospital of the NH municipality
120 (77.4)
Hospital of another municipality
33 (21.3)
Other (outside hospital)
2 (1.3)
Gestation** – n (%)
Single
135 (87.7)
Double
19 (12.3)
Delivery** – n (%)
Vaginal
81 (52.6)
Cesarean
73 (47.4)
Maternal age*** – n (%)
< 35 years
132 (84.6)
≥ 35 years
24 (15.4)
Income – n (%)
#
None/up to 1 minimum wage
17 (18.9)
1-3 minimum wages
53 (58.9)
> 3 minimum wages
20 (22.2)
Maternal schooling – n (%)
##
Illiterate/1-3 years
15 (10.1)
4-8 years
86 (58.1)
> 8 years
47 (31.8)
Gestational age*** (weeks) – n (%)
22-27
39 (25.0)
28-31
27 (17.3)
32-36
28 (17.9)
> 36
62 (39.7)
Birth weight*** (grams) – n (%)
< 1,000 – extreme low weight
53 (34.0)
1,000-1,499 – very low weight
17 (10.9)
1,500-2,499  low weight
30 (19.2)
≥ 2,500 – eutrophic
56 (35.9)
Number of prenatal visits – n (%)
9 (6.3)
None
1-3
19 (13.3)
4-6
59 (41.3)
>6
56 (39.2)
NH: Novo Hamburgo. * Two infants (1.3%) without birth site registration; ** Three infants (1.9%) lacked that information; *** One mother (0.6%) lacked that information;
#
67 registries (42.7%) lacked that information. ## Nine registries (5.7%) lacked that information.
Arq Bras Cardiol. 2015; 104(4):257-265
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Brum et al.
Infant mortality and heart diseases
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Table 2 – Association between cause of death and the variables studied
Variables
n
Death due to CV causes
Death due to NCV causes
n (%)
n (%)
Classification of death
0.043
Early neonatal
70
6 (8.6)
64 (91.4)
Late neonatal
35
3 (8.6)
32 (91.4)
Postneonatal
52
12 (23.1)**
40 (76.9)
Male
90
13 (14.4)
77 (85.6)
Female
67
8 (11.9)
59 (88.1)
Hospital of the NH municipality
120
15 (12.5)
105 (87.5)
Hospital of another municipality
33
6 (18.2)
27 (81.8)
Other (outside hospital)
2
0 (0.0)
2 (100)
Single
135
19 (14.1)
116 (85.9)
Double
19
1 (5.3)
18 (94.7)
Infant sex
0.827
Birth site
0.597
Gestation
0.470
Delivery
0.625
Vaginal
81
9 (11.1)
72 (88.9)
Cesarean
73
11 (15.1)
62 (84.9)
< 35 years
132
17 (12.9)
115 (87.1)
≥ 35 years
24
4 (16.7)
20 (83.3)
17
1 (5.9)
16 (94.1)
Maternal age
0.744
Income
None/up to 1 minimum wage
0.235
1-3 minimum wages
53
4 (7.5)
49 (92.5)
> 3 minimum wages
20
4 (20.0)
16 (80.0)
15
1 (6.7)
14 (93.3)
4-8 years
86
12 (14.0)
74 (86.0)
> 8 years
47
6 (12.8)
41 (87.2)
22-27
39
2 (5.1)
37 (94.9)
28-31
27
1 (3.7)
26 (96.3)
Maternal schooling
Illiterate/1-3 years
0.738
Gestational age (weeks)
0.013
32-36
28
3 (10.7)
25 (89.3)
> 36
62
15 (24.2)**
47 (75.8)
53
2 (3.8)
51 (96.2)**
16 (94.1)
Birth weight
< 1,000 – extreme low-weight
0.015
1,000-1,499 – very low weight
17
1 (5.9)
1,500-2,499 – low weight
30
8 (26.7)**
22 (73.3)
≥ 2,500 – eutrophic
56
10 (17.9)
46 (82.1)
9
0 (0.0)
9 (100)
Number of prenatal visits
None
p*
0.235
1-3
19
1 (5.3)
18 (94.7)
4-6
59
6 (10.2)
53 (89.8)
>6
56
10 (17.9)
46 (82.1)
CV: cardiovascular; NCV: non-cardiovascular; NH: Novo Hamburgo. * Chi-square test. ** Statistically significant association according to the analysis of residues
adjusted to 5% significance.
261
Arq Bras Cardiol. 2015; 104(4):257-265
Brum et al.
Infant mortality and heart diseases
Original Article
2010, 157 infants died, the infant mortality rate being 13.1
deaths/1000 live births. The present study found that the major
cause of infant mortality was heart disease (13.4%), and almost
half of the pregnant women had at least six prenatal visits.
The infant mortality rate in the municipality of Novo
Hamburgo was 14.2/1000 live births in 2010, which is higher
than the mean rate for the Rio Grande do Sul state, whose
rates have decreased (Figure 3) due to the implementation
of public health policies in the most needy municipalities13.
In 2010, that state registered 11.2 deaths/1000 live births
and a mean of 12 deaths/1000 live births in the period
studied. The infant mortality in the municipality of Novo
Hamburgo is low as compared to that of the municipalities
of the Brazilian Northern and Northeastern regions, but, as
compared to other similar municipalities of the Porto Alegre
metropolitan region, it is high, indicating insufficiently
organized primary healthcare and poor quality prenatal
care. The interface between primary and secondary
healthcare is inadequate, and many patients go to the
municipality of Novo Hamburgo, because it is a reference
center with neonatal intensive care units of the Brazilian
Unified Healthcare System (SUS). In 2010, that municipality
was changing its healthcare provision system, leaving the
population with an insufficient number of basic healthcare
units. From that year on, teams of Family Healthcare
Strategy were implemented according to the needs of
each neighborhood, and more healthcare units were built.
The model of healthcare provided exclusively through
basic healthcare units might not ensure the coverage of all
pregnant women regarding prenatal visits, which can be
facilitated in the presence of a family healthcare strategy.
The family healthcare approach widens healthcare access
and improves user’s adherence, increasing the capacity to
solve problems and the quality of the healthcare provided.
In Brazil, neonatal mortality has stabilized at elevated levels,
with a small change in its early neonatal component, playing
an important role in infant mortality14. This reflects the care
provided to pregnant women and fetuses during the antepartum
and delivery periods, and the immediate care provided to
newborns at birth14. Novo Hamburgo follows that trend, with
66.9% of deaths in the neonatal period. In a study conducted in
Porto Alegre between 2000 and 2003, Jobim and Aerts15 have
reported 56.9% of the deaths occurring in the neonatal period.
Most infant deaths in the period studied (35.3%) could
have been reduced through prevention, diagnosis and early
treatment actions. That is, they were caused by treatable
diseases, such as diseases of the circulatory, respiratory,
nervous and endocrine systems, whose treatment could
be highly complex. Twenty-five percent of deaths were
classified as reducible by means of partnerships with other
sectors and could have been prevented by expanding
basic sanitation, educational measures (related to AIDS),
and prevention of accidents, violence and malnutrition.
Non-preventable deaths corresponded to 19.2% of the
total and were related to either congenital malformations
incompatible with life or birth weight lower than 1,000 g.
Adequate pregnancy monitoring could have reduced 11.5%
of the deaths, and adequate delivery care, 5.1%16,17. In a
study performed in the Brazilian Federal District in 1999
and 2000, classifying death according to preventability,
Monteiro and Schmitz18 have reported a similar result, with
35.5% of deaths being reducible by means of prevention,
diagnosis and early treatment actions18. In a study carried
out from 2000 to 2003 in the city of Porto Alegre, where
1,139 deaths occurred, Jobim and Aerts15 reported that
76.6% were classified as preventable.
The present study found that 77% of the deaths were
considered preventable. A study conducted in the city of
Londrina, Paraná state, has assessed two birth cohorts and
found that 71.6% of the infant deaths of the 2000-2001
cohort and 65.5% of those of the 2007-2008 cohort were
considered preventable19. Another study, carried out in
the city of Recife, Pernambuco state, has reported that,
from 2000 to 2009, 76.4% of the infant deaths could have
been prevented20. Preventable deaths are those that can
be reduced through effective actions of health services.
They are also considered sentinel events of healthcare
quality, their presence indicating a flaw in healthcare.
The classification of deaths as preventable is aimed at:
monitoring and assessing healthcare services; analyzing
temporal trends; comparing indicators between regions;
and planning measures for their reduction20.
This study showed that 60.9% of pregnant women had a
maximum of six prenatal visits, only 39.2% had more than
six prenatal visits, and the infants who died due to heart
diseases had not been prenatally diagnosed. It is worth noting
that, even with prenatal care and obstetrical echography, the
prenatal detection rate of heart disease is very low21.
In the study by Soares and Menezes7, the number of
prenatal visits had a protective effect against early infant
mortality. The newborn, whose mother had none or only
one to three prenatal visits, had a four-fold increased risk
of dying than that whose mother had at least six prenatal
visits. In the present study, 60.9% of the pregnant women
had a maximum of six prenatal visits, and most of them
(41.3%) had four to six visits. Several studies have shown
the importance of prenatal care to prevent neonatal
morbidity and mortality22,23. Although infant mortality in
Brazil has significantly decreased in past decades, the
velocity of neonatal death reduction is lower than desired.
A significant number of deaths is still part of the Brazilian
social and sanitary reality, being due to preventable causes,
mainly related to healthcare actions, such as prenatal,
delivery and newborn care. The Brazilian Ministry of Health
recommends at least six prenatal visits24.
The present study identified that 13.4% of the deaths
were due to cardiovascular causes, corresponding to an
incidence of 1.8 death/1000 live births. There is agreement
between that and the incidence reported by several
studies with specific populations (2-10/1000 live births)25.
However, a study conducted in the Rio Grande do Sul state,
screening 3,980 fetuses by use of echography at a reference service
from 1996 to 2000, has reported an incidence of 25.8/100026.
Another study, performed at a maternity in the Minas Gerais
state from 1990 to 2003, has analyzed a data bank with
29,770 deaths and found a heart disease prevalence of 37.2%
of live newborns and of 18.7% of stillbirths27.
Arq Bras Cardiol. 2015; 104(4):257-265
262
Brum et al.
Infant mortality and heart diseases
Original Article
18
16.4
16
Infant Mortality Rate (per 1000 live births)
14
13.3
14.2
12.8
12.8
12.7
12
11.2
10
8.9
NH
8
RS
6
4
2
0
2007
2008
2009
2010
Year of assessment
Figure 3 – Comparison of infant mortality in the Rio Grande do Sul state (RS) and municipality of Novo Hamburgo (NH) in 2007-2010. Source: Health Secretariat of Rio
Grande do Sul State.
When analyzing data regarding deaths due to heart
diseases and the variables studied, 23.1% of the infants
died in the postneonatal period, which might represent a
low diagnosis rate of those diseases, which were neither
detected during prenatal care nor diagnosed and treated at
birth. The gestation of 24.2% of the infants dying due to heart
diseases lasted more than 36 weeks, and the birth weight of
26.7% of them was 1500-2499 g. These data evidence that
they had neither extremely low birth weight nor extreme
prematurity. If diagnosed at an early phase, they could have
been referred to a specialized service and properly treated,
preventing some deaths.
Regarding the limitations of this study, it is worth noting
the lack of information in the infant death investigation
records (incomplete medical records, family not found) of
some cases. For infants born in other municipalities, not
all information on death could be obtained, because the
Mortality Information System is centralized in the Brazilian
Ministry of Health and not provided to the municipalities.
Regarding prenatal care, the infant death investigation
records provided the number of prenatal visits, but not the
gestational trimester of the visit, which limits prenatal care
assessment. In addition, infant death investigation records
classified the number of prenatal visits as ‘four to six’ or ‘more
than six’, hindering the description of the exact number of
visits. Such limitations do not invalidate the results of this
study, which are in accordance with the literature.
263
Arq Bras Cardiol. 2015; 104(4):257-265
Conclusion
Heart diseases were the major cause of infant mortality in
this study. The risk factors related to infant mortality and the
circumstances under which the deaths occur need to be known.
Thus, better planning of healthcare actions specific for local realities
will be possible, resulting in a decrease in childhood mortality
rates. By reducing preventable deaths, the early identification of
complex situations, such as heart diseases, is increasingly needed.
Although the Brazilian Ministry of Health recommends at
least six prenatal visits, 60.9% of the pregnant women in this
study had a maximum of six visits, which did not prevent infant
death. Auditing is thus required to assess the quality of prenatal
care at basic healthcare units, as well as planning strategies to
facilitate the access of pregnant women to healthcare services.
Based on the fact that the major causes of infant death
in the municipality of Novo Hamburgo could have been
reduced by means of actions of diagnosis, prevention and
early treatment, it is mandatory to enhance prenatal care,
newborn care at hospitals and at basic healthcare units, and
to ensure the availability of tests to assess the fetal heart at
prenatal visits to avoid deaths due to cardiovascular diseases.
Acknowledgements
We thank the Health Secretariat of Novo Hamburgo for
providing data for this study.
Brum et al.
Infant mortality and heart diseases
Original Article
Author contributions
Sources of Funding
Conception and design of the research:Pellanda LC, Stein AT.
Acquisition of data: Brum CA. Analysis and interpretation of the
data:Brum CA, Pellanda LC, Stein AT. Statistical analysis: Brum
CA, Pellanda LC, Stein AT. Writing of the manuscript: Brum CA,
Pellanda LC, Stein AT. Critical revision of the manuscript for
intellectual content: Brum CA, Pellanda LC, Stein AT.
Study Association
There were no external funding sources for this study.
This article is part of the dissertation of master submitted
by Camila de Andrade Brum, from Instituto de Cardiologia
do Rio Grande do Sul/ Fundação Universitária de Cardiologia.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
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Back to the Cover
Original Article
Insulin Resistance, Dyslipidemia and Cardiovascular Changes in a
Group of Obese Children
António Pires1, Paula Martins1, Ana Margarida Pereira2, Patricia Vaz Silva1, Joana Marinho1, Margarida Marques3,
Eduardo Castela1, Cristina Sena2, Raquel Seiça2
Centro Hospitalar e Universitário de Coimbra1; Laboratório de Fisiologia - Instituto Biomédico de Investigação da Luz e Imagem da Faculdade de
Medicina da Universidade de Coimbra2; Laboratório de Estatística da Faculdade de Medicina da Universidade de Coimbra - Instituto Biomédico
de Investigação da Luz e Imagem3, Coimbra - Portugal
Abstract
Background: Obesity-related comorbidities are present in young obese children, providing a platform for early adult
cardiovascular disorders.
Objectives: To compare and correlate markers of adiposity to metabolic disturbances, vascular and cardiac morphology
in a European pediatric obese cohort.
Methods: We carried out an observational and transversal analysis in a cohort consisting of 121 obese children of both
sexes, between the ages of 6 and 17 years. The control group consisted of 40 children with normal body mass index
within the same age range. Markers of adiposity, plasma lipids and lipoproteins, homeostasis model assessment-insulin
resistance, common carotid artery intima-media thickness and left ventricular diameters were analyzed.
Results: There were statistically significant differences between the control and obese groups for the variables analyzed,
all higher in the obese group, except for age, high-density lipoprotein cholesterol and adiponectin, higher in the control
group. In the obese group, body mass index was directly correlated to left ventricular mass (r = 0.542; p = 0.001), the
homeostasis model assessment-insulin resistance (r = 0.378; p ≤ 0.001) and mean common carotid artery intima‑media
thickness (r = 0.378; p ≤ 0.001). In that same group, insulin resistance was present in 38.1%, 12.5% had a combined
dyslipidemic pattern, and eccentric hypertrophy was the most common left ventricular geometric pattern.
Conclusions: These results suggest that these markers may be used in clinical practice to stratify cardiovascular risk,
as well as to assess the impact of weight control programs. (Arq Bras Cardiol. 2015; 104(4):266-273)
Keywords: Pediatric Obesity; Insulin Resistance; Dyslipidemias; Cardiovascular Diseases.
Introduction
The growing prevalence of childhood obesity has led to
an increased risk of diabetes and cardiovascular diseases in
adulthood1,2.
One of the most concerning complications of childhood
obesity is insulin resistance, considered a precursor of type 2
diabetes mellitus3. In clinical practice, the homeostasis model
assessment-insulin resistance (HOMA-IR) is used to diagnose
insulin resistance and it is an independent predictor of cardiac
pathology in adulthood4. Clinically acanthosis nigricans, a
hyperpigmented, brownish velvety lesion, usually found in
skin folds, has been related to obesity and insulin resistance5.
Mailing Address: Antonio Manuel Pires •
Rua Nova do Rossio, 20, Bairo Novo do Rossio, Anca. Postal Code 3060-011,
Coimbra – Portugal
Email: [email protected]
Manuscript received June 13, 2014; revised manuscript September 24, 2014;
accepted October 01, 2014
DOI: 10.5935/abc.20140206
266
In adults, common carotid artery intima-media thickness
(cIMT) correlates with the incidence of cardiovascular events,
and, as such, is considered a useful tool for cardiovascular
risk stratification6. Several studies have shown that cIMT
is increased in children with cardiovascular risk factors,
possibly making it a useful tool for assessing cardiovascular
risk in children7,8.
Another cardiovascular risk factor is left ventricular mass
(LVM)9. As shown by the Bogalusa Heart Study, childhood
adiposity is related to LVM in adults, and left ventricular
hypertrophy is strongly and independently related to
cardiovascular morbidity and mortality10,11. Although left
ventricular hypertrophy is rare in obese children, cardiac
remodeling might be present, which in adults has also
been found to predict adverse cardiovascular outcomes,
particularly in hypertensive patients12-15.
Dyslipidemia is another cardiovascular risk factor related to
obesity. It is estimated that about 42% of obese children have lipid
abnormalities, particularly those with visceral obesity16. In these,
the most common lipid abnormality pattern consists of elevated
triglycerides, decreased high-density lipoprotein cholesterol and
normal to mildly elevated low-density lipoprotein cholesterol.
Pires et al.
Childhood obesity and related comorbidities
Original Article
Plasma lipoproteins also seem to be of particular
importance in the assessment of dyslipidemic patients.
Apolipoprotein B reflects the entire spectrum of atherogenic
particles. In contrast, apolipoprotein A-I is considered to have
anti-atherogenic properties17. Lipoprotein (a) consists of a
cholesterol-rich low-density lipoprotein cholesterol particle.
In adults, several studies have identified lipoprotein (a) as a
risk factor for premature atherosclerotic disease18. In children,
it is a potential marker of cardiovascular risk, and, in this
context, some authors have found it to be more sensitive than
anthropometric measures19.
Methods
Subjects
We carried out an observational and transversal
analysis, in a cohort of obese children, recruited randomly
from the Cardiovascular Risk Clinic of the Department
of Pediatric Cardiology of Coimbra’s Pediatric Hospital,
Portugal. This study complied with the Declaration of
Helsinki. All parents gave their informed consent, which
had been approved by the local Ethics Committee.
The inclusion criteria for the study group was primary
obesity [body mass index (BMI) above the 95th percentile
(P95) for sex and age] in children aged 6 to 17 years, without
recent or chronic illnesses. The control group included
healthy children within the same age range with normal BMI.
All children had undergone a 12-hour fast prior to clinical
evaluation and blood sampling.
The study group comprised 121 children and the control
group, 40 children, of both sexes.
The variables analyzed were age, pubertal age, sex, BMI,
waist circumference (WC), percentage fat mass (%FM),
acanthosis nigricans, cIMT, leptin, adiponectin, insulin,
glucose, HOMA-IR, total cholesterol, high-density lipoprotein
cholesterol, low-density lipoprotein cholesterol, triglycerides,
apolipoprotein A-I, apolipoprotein B, lipoprotein (a), left
ventricular end-diastolic diameter (LVED), left ventricular
end-systolic diameter (LVSD), interventricular septum
diameter (IVS), left ventricular posterior wall diameter
(LVPW), left ventricular mass index (LVMI) and LVM, left
ventricular relative wall thickness (RWT).
Anthropometric and clinical evaluation
Acanthosis nigricans was documented as zero (0) if not
present and as one (1) if present. Pubertal stage was based
on Tanner’s classification and divided into prepubertal
(Tanner stage 1) and pubertal (Tanner stage 2-5). Weight
(in kilograms to the nearest 100g) was determined using
a SECA 220 digital weight scale (Medical Scales and
Measuring Systems, Germany) and, for standing height
(in centimeters to the nearest 0.1cm), a stadiometer was
used, with the children wearing only underwear. BMI was
calculated based on the formula: BMI = (weight/height 2)20.
Waist circumference (to the nearest 0.1cm) was measured
using a plastic flexible tape placed midway between the
last rib and the iliac crest. Its percentile was based on
published WC charts21. Percentage fat mass was determined
by bioelectric impedance using the BIA 101 Anniversary
analyzer (AKERN SRL, Italy), and defined according to %FM
charts published by McCarthy22.
Blood collection and biochemical analysis
Serum and plasma were prepared from collected venous
blood samples (15 mL) and then frozen (-80°C) for storage
until analysis.
Insulin levels were determined by chemiluminescence
and processed in the IMMULITE 2000 (Siemens Healthcare
Diagnostics Products Ltd) analyzer, and glucose levels were
analyzed in the VITROS 5.1 FS system (Ortho Clinical
Diagnostics, Johnson & Johnson) with Micro Slide TM
technology. HOMA-IR was calculated based on the formula:
HOMA-IR = insulin (mU/L) x glucose (mmol/L)/22.5, taking
3 as the cutoff value for the diagnosis of insulin resistance.
Total cholesterol, high-density lipoprotein cholesterol,
low-density lipoprotein cholesterol and triglyceride levels
were measured using an automated biochemical VITROS 5.1
FS analyzer (Ortho Clinical Diagnostics, Johnson & Johnson).
Apolipoprotein A-I, B and lipoprotein (a) levels were
determined by immunonephelometry and processed in the BN
ProSpec® System (Siemens Healthcare Diagnostics Inc.) analyzer.
Leptin (eBioscience, San Diego, CA, USA) and adiponectin
(BioVendor, Brno, Czech Republic) were evaluated using
commercially available enzyme-linked immunosorbent assay
kits, and the absorbances were measured at 450 nm (BIO-RAD
Microplate Reader Model 680, Hercules, CA, USA).
Ultrasonography
To determine cIMT, we used a General Electric
Vivid 7 Dimension (GE, USA) ultrasound system and a
linear, high resolution 12-mHz probe and the technique
recommended by Mannheim23.
In the same ultrasound system, left ventricular
diameters were assessed by 2D M-mode echocardiography
in the parasternal long axis view with the patient in the
left lateral decubitus position, using a high-resolution
3.5-mHz transducer.
Left ventricular mass was calculated using Devereux’s
formula: 0.8{1.04[LVED+LVPW+IVS) 3- LVED 3]}+0.6.
Left ventricular geometry was assessed based on the
LVMI (increased if > P95 for sex and age) and the RWT
(increased if > 0.41), and classified as follows: normal,
if both parameters were within the normal range;
concentric remodeling, if RWT was increased and LVMI
was normal; concentric hypertrophy, if both parameters
were increased; and eccentric hypertrophy, if LVMI was
increased and RWT was normal.
Statistical analysis
Data were analyzed using the IBM SPSS 20 software.
To calculate the case and control population sample size,
we used the G*Power 3.1.5 program. Based on a 0.05 level of
significance, a 0.80 power, a 0.52 effect size, and a control to
study group ratio of 3, our study group and our control group
had to include 118 and 40 individuals, respectively.
Arq Bras Cardiol. 2015; 104(4):266-273
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Pires et al.
Childhood obesity and related comorbidities
Original Article
Based on the sample size of the variables included in this
study, normality was tested using the Kolmogorov-Smirnov or
the Shapiro-Wilk analysis.
Results
To compare the quantitative variables in both groups,
Student t test was used, if the distribution was normal, and
Mann-Whitney U test, if not. Chi-square test was used for
categorical variables.
One hundred and twenty-one obese children, 61 boys
and 59 girls, with ages between 6 and 17 years (mean
age, 11.65 ± 0.432 years) were included in this study.
The control group was made up of 40 healthy, non-obese
children, 29 boys and 12 girls, within the same age group
(mean age, 12.73 ± 0.270 years).
To verify the association between quantitative parameters,
we used Pearson’s correlation if their distribution was normal,
and Spearman’s correlation, if not.
Quantitative variables are expressed as mean and respective
standard error of the mean, and qualitative variables, as N(%).
For multivariate analysis between the two groups, logistic
regression was used.
The results were considered statistically significant
at p < 0.05.
Comparative analysis between the two groups
We firstly compared the two groups regarding
anthropometric, clinical, analytical and ultrasonographic
parameters, whose results are shown in Table 1.
As age (p = 0.038) and sex (p = 0.027) showed significant
statistical differences between the two groups, with higher
age in the control group, the analysis was repeated using
logistic regression, but adjusted for these parameters.
Table 1 – Anthropometric, analytical and ultrasonographic parameters of the obese and non-obese groups
Obese
Variable
Age (years)
Non-obese
N
Mean ± SEM
N
Mean ± SEM
p-value
121
11.65 ± 0.432
40
12.73 ± 0.270
0.038**
BMI
121
28.465 ± 0.438
40
18.933 ± 0.429
< 0.001*
WC (cm)
121
93.15 ± 1.197
40
68.16 ± 0.861
< 0.001**
%FM (%)
121
36.840 ± 0.647
40
18.544 ± 0.526
< 0.001*
Leptin (ng/mL)
118
28.973 ± 1.627
40
4.845 ± 0.706
< 0.001
Adiponectin (µg/mL)
95
3.597 ± 0.140
32
5.173 ± 0.413
0.001
HOMA-IR
118
2.81 ± 0.165
33
1.54 ± 0.151
< 0.001**
LVED (mm)
121
45.92 ± 0.54
40
44.28 ± 0.97
NS
LVSD (mm)
121
29.29 ± 0.43
40
27.34 ± 0.74
< 0.023*
IVS (mm)
121
7.21 ± 0.16
40
7.11 ± 0.22
NS
PWD (mm)
121
7.51 ± 0.17
40
6.92 ± 0.24
0.045*
LVM (g)
121
108.27 ± 3.75
40
95.80 ± 5.46
NS
LVMI
121
34.30 ± 0.79
40
28.80 ± 0.99
< 0.001*
RWT
121
0.33 ± 0.080
40
0.32 ± 0.012
NS
cIMT (mm)
119
0.49 ± 0.005
40
0.44 ± 0.055
0.001**
TC (mg/dL)
121
166.86 ± 2.522
40
163.83 ± 5.394
NS
LDL-C (mg/dL)
121
96.45 ± 2.44
40
82.71±3.74
0.003*
HDL-C (mg/dL)
121
47.33 ± 0.90
40
59.17 ± 2.04
< 0.001**
TG (mg/dL)
121
92.33 ± 4.94
40
59.15 ± 4.28
< 0.001**
Apo A-I (g/L)
114
1.34 ± 0.018
33
1.47 ± 0.043
0.001*
Apo B (g/L)
114
0.74 ± 0.016
33
0.66 ± 0.032
0.016*
Lp (a) (mg/dL)
114
27.42 ± 2.56
33
17.6 ± 2.92
0.014*
Male N(%)
121
61 (50.8%)
40
29 (70.7%)
0.027*
N: sample number; SEM: standard error of the mean; p-value: level of significance; BMI: body mass index; WC: waist circumference; %FM: percent fat mass;
HOMA-IR: homeostasis model assessment for insulin resistance; LVED: left ventricular end-diastolic diameter; LVSD: left ventricular end-systolic diameter;
IVS: interventricular septum diastolic diameter; PWD: left ventricular diastolic posterior wall diameter; LVM: left ventricular mass; LVMI : left ventricular mass
index; RWT: relative wall thickness; cIMT: common carotid artery intima-media thickness; TC: total cholesterol; LDL-C: low-density lipoprotein cholesterol;
HDL-C: high-density lipoprotein cholesterol; TG: triglycerides; Apo A-I: apolipoprotein A-I; Apo B: apolipoprotein B; Lp (a): lipoprotein (a); *Student t test;
**Mann-Whitney U test.
268
Arq Bras Cardiol. 2015; 104(4):266-273
Pires et al.
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Original Article
Left ventricular mass index above the P95 and RWT > 0.41
were seen in 31.7% and 18.3 % of the sample, respectively. Based
on these findings we then subdivided left ventricular geometry
into three patterns: eccentric hypertrophy (21.7%); concentric
hypertrophy (10%); and concentric remodeling (8.3%).
On adjusting, the statistical differences remained, but
LVED (p < 0.001) and LVM, both higher in the obese
group, (p < 0.001) became significant.
Analysis of the obese group
Concerning the plasma lipids and lipoproteins profile,
high-density lipoprotein cholesterol was the only variable
that was inversely, but weakly correlated to BMI (r= -0.30;
p < 0.01) and WC (r = -0.26; p < 0.01). Percentage fat mass
did not show any significant correlation to plasma lipid and
lipoprotein levels.
In the obese group, we firstly analyzed the influence of sex and
age group (pre- and adolescence) on these variables. Regarding sex,
leptin (p = 0.001) and adiponectin (p = 0.04) were significantly
higher in girls, and LVED (p = 0.023), LVM (p = 0.011) and LVMI
(p = 0.044) were significantly higher in boys. Analysis by age group
showed statistically significant differences for LVED (p < 0.001),
LVSD (p < 0.001), IVS (p = 0.008) and LVPW (p < 0.001),
higher in the pre‑adolescent group, and BMI (p < 0.001), WC
(p < 0.001), triglycerides (p = 0.014) and adiponectin (p = 0.010),
higher in the adolescent group.
Body mass index was directly, but weakly correlated to leptin
(r = 0.39; p < 0.001), cIMT (r = 0.21; p = 0.026) and HOMA‑IR
(r = 0.38; p < 0.001). Waist circumference was directly, but
weakly correlated to leptin (r = 0.34; p < 0.001), cIMT (r = 0.19;
p = 0.047) and HOMA-IR (r = 0.36; p < 0.001). Percent fat
mass was directly, but weakly correlated to leptin (r = 0.29;
p = 0.002) and HOMA-IR (r = 0.36; p < 0.001).
Acanthosis nigricans was found in 62% of the obese
population (0% in the non-obese group). In the pre-adolescent
group, males were more affected (53.7% vs 48.5% in females)
and, in the adolescent group, females predominated (51.5%
vs 46.3% in males).
The HOMA-IR was inversely correlated to high-density
lipoprotein cholesterol (r = -0.2999; p = 0.002) and directly,
but weakly, correlated to triglyceride levels (r = 0.25;
p = 0.006).
We then used Pearson’s correlation to establish the
association between the indices of adiposity and insulin
resistance, dyslipidemia, cIMT and LVMI.
In this study, 38.1% of our population was considered
insulin resistant, 68.9% had acanthosis nigricans, higher
than the non-insulin resistant group (31.1%), although
this difference was not statistically significant (p = 0.515).
Girls and adolescents represented 60% and 62.2% of the
insulin resistant group, the statistical differences being
non‑significant (p = 0.088 and p = 0.221, respectively).
Regarding the echocardiographic data, as demonstrated in
Table 2, BMI was directly and moderately correlated to LVED
(r = 0.54; p < 0.001) and LVSD (r = 0.46; p < 0.001), as
well as to LVM (r = 0.54; p < 0.001), and less so to LVPW
(r = 0.34; p < 0.001), IVS (r = 0.19; p = 0.034) and LVMI
(r = 0.26; p < 0.001). Waist circumference showed a similar
pattern, whereas %FM was not correlated to any of these
parameters. The RWT was not correlated to these indices.
The cIMT was directly correlated to LVM (r = 0.21; p = 0.019),
LVED (r = 0.30; p = 0.001) and LVSD (r = 0.30; p = 0.001).
Table 2 – Correlations between body mass index, waist circumference and percentage fat mass with the echocardiographic parameters,
leptin, common carotid artery intima-media thickness and insulin resistance in the obese group
BMI (Kg/m2)
Variable
WC (cm)
%FM (%)
Pearson correlation
p-value
Pearson correlation
p-value
Pearson correlation
p-value
LVED (mm)
0,54**
< 0.001
0.53**
< 0.001
-0.05
0.593
LVSD (mm)
0.46**
< 0.001
0.47**
< 0.001
-0.06
0.497
IVS (mm)
0.20*
0.034
0.16
0.103
0.16
0.082
PWD (mm)
0.34**
< 0.001
0.32**
0.001
0.14
0.124
LVM (g)
0,54**
< 0.001
0,52**
< 0.001
0.09
0.324
LVMI
0.26**
< 0.001
0.10
0.298
0.09
0.311
RWT
0.06
0.508
0.05
0.578
0.17
0.064
cIMT (mm)
0.21*
0.025
0.19*
0.047
0.03
0.725
Leptin (ng/mL)
0.34**
< 0.001
0.34**
< 0.001
0.29**
0.002
Adiponectin (µg/mL)
0.18*
0.046
0.27**
0.004
0.22**
0.016
HOMA-IR
0.38**
< 0.001
0.36**
< 0.001
0.35**
< 0.001
BMI: body mass index; WC: waist circumference; %FM: percent fat mass LVED: left ventricular end-diastolic diameter; LVSD: left ventricular end-systolic diameter;
IVS: interventricular septum diameter; PWD: left ventricular posterior wall diameter; LVM: left ventricular mass; LVMI:left ventricular mass index; RWT: relative wall
thickness; cIMT: common carotid artery intima-media thickness; HOMA-IR: homeostasis model assessment for insulin resistance; correlation is significant at the *0.05
level and at the ** 0.01 level (2-tailed).
Arq Bras Cardiol. 2015; 104(4):266-273
269
Pires et al.
Childhood obesity and related comorbidities
Original Article
Discussion
We have demonstrated that there are statistically
significant differences between the obese and control groups
for the variables analyzed and that adiposity has a clear
impact on insulin resistance, dyslipidemia, cIMT and LVM
in obese children.
Insulin resistance in childhood is predictive of insulin resistance
in adult life. It is the most common metabolic abnormality
related to obesity and is strongly linked to type 2 diabetes and
cardiovascular disorders24,25. Based on the HOMA-IR results,
38% of the obese group individuals were considered insulin
resistant. None had type 2 diabetes. In our study the prevalence
of insulin resistance is lower than that published (50%-70%)26.
This discrepancy may be due to the different HOMA-IR cutoff
values used in the various reports to diagnose insulin resistance,
as standardized cutoff value has not been put forward27.
The association between obesity and acanthosis nigricans
has been well documented. The overall prevalence is 62%,
similar to that found in our group of obese children (65%),
mainly in boys (70.5%). As insulin is related to acanthosis
nigricans, some authors have proposed it as a reliable marker of
hyperinsulinemia, and hence, insulin resistance28. As expected,
we found insulin to be significantly correlated to acanthosis
nigricans; however, we failed to establish an association
between acanthosis nigricans and insulin resistance, as one
third of our obese children with insulin resistance had no
evidence of acanthosis nigricans. This observation is consistent
with some results published29. Clearly, in our experience,
acanthosis nigricans was not a reliable marker of insulin
resistance, and, thus, should not be used as a screening
marker for type 2 diabetes in obese children, as proposed
by some authors5. Nevertheless, as a clinical sign in the
context of obesity, it ought to alert clinicians to the underlying
pathophysiological mechanisms of insulin resistance and act
accordingly. In fact, our observations led to the conclusion
that insulin resistance was mostly related to %FM, BMI, WC
and leptin, and inversely related to high-density lipoprotein
cholesterol. These findings mirror the most important factors
related to insulin resistance, namely the interplay between
adiposity, adipokines and dyslipidemia.
Dyslipidemia was also a prominent cardiovascular risk
factor found in our study population, particularly when
compared to our control group. Considering the values
proposed by the National Cholesterol Education Program
Expert Panel on Cholesterol Levels in Children30, 45% had
intermediate-high to high levels of triglycerides, 42.5% had
intermediate-low to low levels of high-density lipoprotein
cholesterol and 31% had intermediate-low to low levels
of low‑density lipoprotein cholesterol. As a combined
dyslipidemia, it represented 12.5% of our sample.
This pattern is different from that found in non‑obese
children, namely high total and low-density lipoprotein
cholesterol levels, and is considered particularly atherogenic
as small dense low-density lipoprotein particles are
inefficiently cleared by low-density lipoprotein receptors,
elevated total low-density lipoprotein levels increase
the risk of entrapment in the subendothelial matrix, and
decreased levels of high-density lipoprotein particles limit
270
Arq Bras Cardiol. 2015; 104(4):266-273
reverse cholesterol transport. As observed in our study,
insulin resistance was inversely correlated to high-density
lipoprotein cholesterol but not to low-density lipoprotein
cholesterol, potentially contributing to the mechanisms
that trigger early onset atherosclerosis and, hence,
cardiovascular disease in young adults. Research shows
that this combined dyslipidemia pattern is increasing in
prevalence and predicts vascular dysfunction in young
adults and early clinical events in adult life.
We also compared apolipoprotein A-I, B and lipoprotein
(a) between the two groups. Although the obese group
undoubtedly had a more atherogenic profile [higher
apolipoprotein B and lipoprotein (a) and lower apolipoprotein
A-I], none of these variables correlated to insulin resistance.
Individually, apolipoprotein B was weakly correlated to leptin
(r = 0.33; p < 0.001), apolipoprotein A-I was inversely,
but weakly, correlated to BMI (r = -0.19; p = 0.042), and
lipoprotein (a) to BMI (r = 0.22; p = 0.019) and leptin
(r = 0.21; p = 0.029). Unlike Cunnigham et al19, which found
lipoprotein (a) to be a useful cardiovascular risk marker in
children, we did not come to the same conclusion, possibly
due to differences in population ethnicity. In fact, based on
these findings, it appears that plasma lipoproteins do not offer
an advantage over lipoprotein cholesterol measures in the
management of dyslipidemias and risk stratification during
childhood, at least in our population. Along the same lines,
studies in obese adults with insulin resistance have concluded
that plasma lipoproteins do not provide further prognostic
information when compared to the standard lipoprotein
cholesterol profile.
The atherogenicity induced by insulin resistance and
lipid abnormalities during childhood result in structural
vascular changes that can be assessed non-invasively by
ultrasonography of the cIMT. This variable has been validated
as a cardiovascular risk marker in children and adults,
although in obese children, observations have not always
been consensual31. We sought to correlate cIMT with other
cardiovascular risk markers and its usefulness as a surrogate of
preclinical atherosclerosis. Contrary to the findings by Tounian
et al32, in our analysis, cIMT was significantly higher (p<0.001)
in the obese group. In this group, multivariate analysis
demonstrated that the most significant correlations were with
age (r= 0.26; p= 0.004), BMI (r=0.21; p=0.025) and WC
(r= 0.19; p=0.047), suggesting a direct link between adiposity
and cIMT, whereas lipids and lipoproteins were not related.
The latter finding does not concur with the observations
published by Magnussen et al33, a far larger study, where
childhood dyslipidemia was related to an increase in cIMT in
adulthood. Most likely our smaller sample size accounts for
these differences.
We also investigated whether LVM and LVMI were linked
to adiposity. Left ventricular mass index was above the P95
in 32% of our obese group. Through multivariate analysis,
we were able to show a direct correlation to age, BMI and
WC, but, when indexed to height2,7, only BMI remained
significantly correlated. This confirms previous observations,
and highlights the impact of adiposity on left ventricular
dimensions, whose adverse effects are already present
in our young obese population, and which are known to
Pires et al.
Childhood obesity and related comorbidities
Original Article
track into adulthood. In adults, a LVMI > 51g/m2,7 carries
prognostic significance as these individuals are known to
be more susceptible to cardiovascular events34,35. We also
aimed at addressing the relationship between adiposity and
abnormal ventricular geometric patterns. Overall, 40% of our
population presented abnormal geometric patterns, the most
common being eccentric left ventricular hypertrophy (21.7%).
Considering that obesity is characterized by chronic volume
overload, this would be the expected pattern; however, several
adult studies have shown that, in fact, concentric hypertrophy
is the most common ventricular geometric abnormality,
even in the absence of arterial hypertension, implying
that mechanisms other than volume overload play a role.
Based on these results we postulate that volume overload is an
important contributing factor, as we found no other relevant
associations. Nevertheless, 10% of our population had left
ventricular concentric hypertrophy, followed by 8% with
concentric left ventricular remodeling. The latter condition,
although not related to increased LVMI, has also been shown
to be associated with adverse cardiac events and provides
another marker for assessing cardiovascular risk in children36.
This study has a few limitations, our sample size, particularly
the control group, being one. Due to our local population
characteristics, our sample included Caucasian children only.
Implicitly, these factors may represent a bias.
Conclusions
In conclusion, we have highlighted indices of adiposity as
a common link to adverse metabolic and structural changes
patent in obese children. As these track into adulthood,
efforts should continue to be made to reverse these changes,
aiming at lifestyle modifications, and potentially decreasing the
socioeconomic burden of cardiovascular disease in adulthood.
Author contributions
Conception and design of the research:Pires A, Matins P.
Acquisition of data: Pires A, Pereira AM, Silva PV, Marinho J.
Analysis and interpretation of the data: Pires A, Sena C, Seiça
R. Statistical analysis: Pires A, Marques M, Sena C. Writing
of the manuscript: Pires A, Matins P. Critical revision of the
manuscript for intellectual content: Pires A, Matins P, Silva PV,
Marinho J, Castela E, Sena C, Seiça R. Analysis Procedure:
Pereira AM.
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
António Pires , from Faculdade de Medicina da Universidade
de Coimbra, Portugal.
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al; American Society of Echocardiography’s Nomenclature and Standards
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Childhood obesity and related comorbidities
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273
Back to the Cover
Original Article
Subclinical Ventricular Dysfunction Detected by Speckle Tracking
Two Years after Use of Anthracycline
André Luiz Cerqueira de Almeida1,2, Viviane Almeida Silva2, Alberto Teófilo de Souza Filho2, Vinicius Guedes Rios2,
João Ricardo Pinto Lopes2, Samuel Oliveira de Afonseca3, Daniel de Castro Araújo Cunha1, Murilo Oliveira da
Cunha Mendes1, Danilo Leal Miranda1, Edval Gomes dos Santos Júnior1,2
Universidade Estadual de Feira de Santana1; Hospital Dom Pedro de Alcântara da Santa Casa de Misericórdia de Feira de Santana2; Unidade
de Alta Complexidade em Oncologia (UNACON)3, Feira de Santana, BA - Brazil
Abstract
Background: Heart failure is a severe complication associated with doxorubicin (DOX) use. Strain, assessed by two-dimensional
speckle tracking (2D-STE), has been shown to be useful in identifying subclinical ventricular dysfunction.
Objectives: a) To investigate the role of strain in the identification of subclinical ventricular dysfunction in patients who
used DOX; b) to investigate determinants of strain response in these patients.
Methods: Cross-sectional study with 81 participants: 40 patients who used DOX ±2 years before the study and
41 controls. All participants had left ventricular ejection fraction (LVEF) ≥55%. Total dose of DOX was 396mg (242mg/m²).
The systolic function of the LV was evaluated by LVEF (Simpson), as well as by longitudinal (εLL), circumferential (εCC), and
radial (εRR) strains. Multivariate linear regression (MLR) analysis was performed using εLL (model 1) and εCC (model 2) as
dependent variables.
Results: Systolic and diastolic blood pressure values were higher in the control group (p < 0.05). εLL was lower in the
DOX group (-12.4 ±2.6%) versus controls (-13.4 ± 1.7%; p = 0.044). The same occurred with εCC: -12.1 ± 2.7% (DOX)
versus -16.7 ± 3.6% (controls; p < 0.001). The S’ wave was shorter in the DOX group (p = 0.035). On MLR, DOX was
an independent predictor of reduced εCC (B = -4.429, p < 0.001). DOX (B = -1.289, p = 0.012) and age (B = -0.057,
p = 0.029) were independent markers of reduced εLL.
Conclusions: a) εLL, εCC and the S’ wave are reduced in patients who used DOX ±2 years prior to the study despite normal
LVEF, suggesting the presence of subclinical ventricular dysfunction; b) DOX was an independent predictor of reduced εCC;
c) prior use of DOX and age were independent markers of reduced εLL. (Arq Bras Cardiol. 2015; 104(4):274-283)
Keywords: Heart Failure; Ventricular Dysfunction Left / chemically induced; Echocardiography; Anthracyclines / adverse
effects.
Introduction
Cardiovascular and oncologic disorders are the most
prevalent diseases and the main global causes of morbidity and
mortality. Together they are associated with more than 70% of
the death causes worldwide1. Treatment of cancer has been
conducted with a combination of chemotherapy, radiotherapy
and surgery in an attempt, often successful, to benefit the
patient. In recent years, it has been observed a marked
increase in average survival in patients with cancer due to,
among other causes, a greater effectiveness of antineoplastic
drugs, in particular the anthracyclines 2. However, this
Mailing Address: André Luiz Cerqueira de Almeida •
Rua Alto do Paraguai, 280, S.I.M. Postal Code 44085-232, Feira de Santana,
BA – Brazil
E-mail: [email protected]; [email protected]
Manuscript received June 19, 2014; revised manuscript August 21, 2014;
accepted October 08, 2014.
DOI: 10.5935/abc.20140209
274
greater effectiveness occurs at the expense of side effects.
Both chemotherapy and radiotherapy are associated with
cardiotoxic effects and their cardiovascular complications,
which manifest as heart failure, myocardial ischemia,
myocardial infarction, hypertension, thromboembolism,
pericarditis and cardiac arrhythmias3.
The combination of increased survival and consequent
aging of the population, associated with the cardiotoxicity
of the antineoplastic treatment, has led to increased
cardiovascular morbidity and mortality in individuals
with cancer4.
In clinical practice, cardiotoxicity has been identified
by symptomatic or asymptomatic left ventricular (LV)
dysfunction. The LV ejection fraction (LVEF), estimated by
echocardiography or myocardial scintigraphy, is generally
used to evaluate the LV function5. This method presents some
limitations, including low sensitivity for detection of initial LV
injury. Moreover, the failure to detect changes in LVEF does
not exclude subclinical cardiac injury, nor the possibility of
cardiac deterioration at a later stage6.
Almeida et al.
Subclinical LV Dysfunction After Use of Anthracycline
Original Article
Strain, assessed by two-dimensional speckle tracking
(2D-STE), is useful in identifying subclinical heart disease
in several pathologies7,8, with the ability to identify early
(subclinical) cardiac injury during chemotherapy9.
The study was approved by the Ethics Committee for
Research Involving Human Subjects of our university and all
participants signed an Informed Consent Form.
The aims of this study are: a) To investigate the role of strain,
evaluated by 2D-STE, in identifying subclinical ventricular
dysfunction in patients treated with doxorubicin (DOX); b) to
investigate determinants of strain response in cancer survivors.
Conventional Doppler Echocardiography
Methods
Research Subjects
Patients who completed treatment with DOX in the
oncology unit of our hospital between February 2010
and June 2011 and who lived in our city were invited
to participate in this cross-sectional study. Through chart
review, we collected demographic data, previous medical
history, information about use of adjuvant radiation therapy,
doses of anthracycline used (total and indexed to body
surface area), as well as the dates of beginning and end
of treatment. Members of the administrative staff of the
hospital without previous history of neoplasia were invited
to participate in the study and composed the control
group. In these individuals, we collected demographic
data and prior medical history. All participants underwent
transthoracic echocardiogram with 2D-STE, as well as
clinical evaluation with detailed history and physical
examination when the following parameters were obtained:
weight, height, heart rate, abdominal circumference
(AC), body mass index (BMI), and systolic and diastolic
blood pressure (BP). Exclusion criteria were presence of
heart failure (HF) by Framingham criteria, history of prior
cardiovascular disease (except hypertension), any valvular
lesion greater than mild, change in segmental contractile
function in transthoracic echocardiogram, LVEF < 55% and/
or prior chemotherapy.
The AC was measured at the navel level with a standard
tape measure. BMI was obtained by the ratio of the
weight to the height squared (Kg/m2). BP was measured
three times with participants in the sitting position.
The average of the two last measurements was included in
the analysis. All participants had LVEF ≥ 55% and showed
no clinical manifestations of HF by Framingham criteria.
Patients with at least two serum glucose levels > 126mg/dL
or in use of oral hypoglycemic drugs and/or insulin were
classified as diabetics. Hypertensive were participants
in use of antihypertensive medication or who presented
systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg
on at least two occasions. Patients with dyslipidemia had
total cholesterol > 200 mg/dL and/or LDL cholesterol
> 130 mg/dL. Smokers were individuals who continued
smoking or had left the habit less than 10 years before.
Alcohol consumption was categorized in absent, eventual,
weekly, or daily. The race of the participants was classified
according to self-reported information as white, brown,
yellow or black. Physical activity was defined as the
practice of exercises at least three times a week, with a
minimum duration of 30 minutes per session.
Echocardiographic images were obtained by experienced
echocardiographers (ALCA, VAS, ATSF and VGR) and were
interpreted by a single examiner (ALCA). The tests were
carried out on the equipment Artida (Toshiba Medical
Systems Corp., Tochigi, Japan). All images were digitalized
and stored for later analysis. Doppler echocardiographic
images were acquired following the recommendations of
the American Society of Echocardiography10. The LV mass
was determined by the diastolic thickening of the septum,
the LV posterior wall, and the LV end-diastolic diameter, and
indexed to body surface area, generating the variable LV
mass index (LVMI)11. LVEF was calculated using the modified
(biplane) Simpson's rule. The transmitral early diastolic flow
velocity (E wave) and late diastolic flow velocity (A wave),
as well as the deceleration time were measured using
conventional pulsed Doppler. Tissue Doppler evaluates
the longitudinal excursion of the mitral ring during systole
and diastole. Tissue Doppler velocities were assessed in the
four basal segments of the LV in the apical 4-chamber and
2-chamber views, with an angle smaller than 200 between
the ultrasound beam and the plane of cardiac motion.
We measured the peak systolic (S' wave), early diastolic
(E' wave) and late diastolic (A´ wave) velocities. The final
result of each of these variables consisted on the average of
the values found in the four analyzed segments. The volume
of the left atrium (LA) was measured by two-dimensional
planimetry using the biplane Simpson's rule in the frame
that preceded the opening of the mitral valve, and was
indexed to body surface generating the variable left atrial
volume index (LAVI)10.
Two-Dimensional Speckle Tracking Echocardiography
The two-dimensional images were acquired in the short
axis of the LV, at the level of the insertion of the papillary
muscles, and in the apical 4-chamber and 2-chamber views.
They were recorded using a sectorial transducer (frequency
range 1.7 to 3.5 MHz) with harmonic imaging, pulse
repetition frequency between 40 and 80 cycles/second,
maintaining a single focus in the central region of the LV,
regulating the sector width (narrowest possible), depth
(minimum possible) and the gain to optimize the quality of
the two-dimensional image.
Longitudinal (ε LL ), circumferential (ε CC ) and radial
(ε RR) strains were analyzed with the two-dimensional
speckle tracking software by Toshiba (Toshiba 2D Wall
Motion Tracking software, Toshiba Medical Systems).
Manual delineation of the endocardial border of the LV at
end-systole (determined anti-clockwise) was followed by
automatic tracing of the epicardial border (which could be
manually adjusted) and of a line in the middle region of
the LV wall12. A similar approach was made on the apical
4-chamber image, starting the trace on the lateral corner
of the mitral valve ring at end-diastole, and in the apical
Arq Bras Cardiol. 2015; 104(4):274-283
275
Almeida et al.
Subclinical LV Dysfunction After Use of Anthracycline
Original Article
2-chamber image (beginning the trace at the junction
of the inferior wall with the mitral ring at end-diastole).
The software 2D-STE uses the sum of the differences of
the squares to find the dot pattern (speckles) most similar
to the one obtained in the two-dimensional model in two
subsequent cycles (frames)13. Strain (ε, %) was calculated
as the change in regional length relative to the length at
end-diastole: ε = (L(t) – L0) x 100/0L, in which L(t) is the
length at time t and L0 is the length of the segment at the
beginning of the QRS segment. Global εLL (Figure 1), global
εCC (Figure 2) and global εRR were represented by the peak
of the strain averages, and the values of the longitudinal
and circumferential strains were those representative of
the middle region of the myocardium. Since εLL and εCC
reflect shortening of the myocardial segment analyzed, the
more negative its value, the greater will be the myocardial
deformation relative to the state observed at end-diastole.
The regions of the LV short axis and the projections in 4 and 2
chambers were divided according to the recommendations
by the American Society of Echocardiography14. Segments
of the LV with inadequate image quality were excluded
from the analysis due to the presence of acoustic shadows,
image artifacts, reverberations or poor quality in the trace
of the points by manual evaluation.
Figure 1 – Representation of longitudinal strain.
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Arq Bras Cardiol. 2015; 104(4):274-283
Reproducibility
All echocardiographic measurements were performed
offline by a single blinded examiner (ALCA). The intraobserver
reproducibility for εLL and εCC was evaluated by repeating the
measurements in 20 randomly selected participants, with a
minimum interval of 30 days from the first test.
Statistical Analysis
Quantitative variables were expressed as mean ± standard
deviation and compared by Student's t test or Wilcoxon signedrank test, whereas qualitative variables were expressed by their
frequencies and percentages, and compared by the chi-square
test or Fisher's exact test. Univariate analysis was used to evaluate
the relationship between εCC and εLL with the variables of interest.
Two stepwise multivariate linear regression (MLR) models were
created. The dependent variables in models 1 and 2 were εLL and
εCC, respectively. We considered as independent those variables
with p < 0.20 in the univariate analysis and those with biological
plausibility of interference with the strain. Intraobserver variability
was assessed by the intraclass correlation coefficient. The level
of significance was defined as p < 0.05. The statistical analyses
were processed with the software Statistical Package for the Social
Sciences, version 17.0 (SPSS Inc., Chicago, Illinois).
Almeida et al.
Subclinical LV Dysfunction After Use of Anthracycline
Original Article
Figure 2 – Representation of circumferential strain.
Results
Cohort Characteristics
The main clinical characteristics of the study population
are shown in Table 1.
Only female patients accepted to participate in the
study and reported to the unit for evaluation. Fifty-one
women who had used DOX 25.5 ± 4.7 months before
the study (median: 24 months; interquartile range [IQR]:
22 to 28 months) comprised the group of patients. Eleven
were excluded from the analysis: six due to LVEF < 55%,
three had previously undergone chemotherapy and two
had echocardiography with inadequate technical quality
for analysis. The average age of the patients included in
the analysis was 52 ± 11 years. One had history of nonHodgkin lymphoma and 39 of breast neoplasm. The control
group was composed of 42 women from the administrative
staff of the hospital, without previous history of neoplasia.
One was excluded due to LVEF < 55%. The average age
of the patients in the control group was 56 ± 10 years.
There was no difference between the two groups regarding
the percentage of patients with hypertension, diabetes,
blacks, smokers and alcohol consumption. Age, AC,
BMI and LVMI were similar (p > 0.05 for all). Systolic
and diastolic BP values were higher in the control group
(p = 0.028 and 0.027, respectively).
The average total dose of DOX received was 396 ± 85 mg,
which corresponded to 242 ± 43 mg/m². None of the patients
received trastuzumab. Fifteen patients (37.5%) also used
5-fluorouracil and 31 (77.5%) received cyclophosphamide.
Twenty-one patients (52.5%) underwent adjuvant radiation
therapy, which was applied to the right side in 13 (32.5%)
patients and to the left side in 8 (20%) patients.
Conventional Doppler Echocardiographic Variables
The LVEF was normal and showed no difference between the
groups: 65.3 ± 4.8% (patients) versus 66.7 ± 4.3% (controls;
p = 0.18). The same occurred with LVMI: 75 ± 15 g/m2
(patients) versus 71 ± 16 g/m2 (controls; p=0.34). The absolute
diameter of the LA was greater in the control group (p = 0.006).
However, there was no difference when LA was indexed to
body surface area (p = 0.11), nor when we assessed the LAVI
(p = 0.58). The average S' wave velocity on tissue Doppler
was higher in controls (6.6 ± 0.9cm/s) when compared with
patients (6.1 ± 1.0cm/s; p = 0.035). This was mainly due to
the increased velocity of the S' wave side corner of the mitral
ring (7.1 ± 1.0cm/s versus 6.3cm/s; p = 0.004). The velocity
of the E and E' waves, the mitral flow deceleration time, as
well as the relationships E/A and E/E´ were similar between
the groups, without difference regarding the results of the LV
diastolic function. All other conventional echocardiographic
variables were similar between groups (Table 2).
Arq Bras Cardiol. 2015; 104(4):274-283
277
Almeida et al.
Subclinical LV Dysfunction After Use of Anthracycline
Original Article
Table 1 – Characteristics of the study cohort
Variable
Doxorubicin (N = 40)
Controls (N = 41)
p value
Total dose of doxorubicin
396 mg (242 mg/m²).
-
-
52 ± 11
56±9
0.11
35
39
0.71
10.0
9.8
1
33
41
0.40
Age (years)
Hypertension (%)
Diabetes (%)
Dyslipidemia (%)
Race - black (%)
77.5
82.1
0.76
Smoking (%)
22.5
29.3
0.22
Alcohol consumption (%)
Abdominal circumference (cm)
27.5
19.5
0.34
93 ± 14
95 ± 9
0.35
BMI (Kg/m²)
25.8 ± 5.3
27.3 ± 3.8
0.15
Body surface area (m2)
1.70 ± 0.21
1.75 ± 0.20
0.30
Systolic BP (mmHg)
130 ± 21
141 ± 22
0.028
Diastolic BP (mmHg)
80 ± 14
87 ± 12
0.027
BMI: body mass index; BP: blood pressure.
Table 2 – Characteristics of conventional Doppler echocardiography
Variable
Aortic root (mm)
LA (mm)
LA/BSA (mm/m2)
Doxorubicin (N = 40)
Controls (N = 41)
p value
30 ± 3
31 ± 3
0.34
33 ± 3
35 ± 4
0.006
19.3 ± 2.2
20.1 ± 2.1
0.11
LVDD (mm)
46 ± 4
47 ± 4
0.87
LVSD (mm)
30 ± 3
30 ± 3
0.94
Septum (mm)
8±1
8±1
0.44
LVPW (mm)
8±1
8±1
0.36
LVEF (%, Simpson)
65 ± 5
67 ± 4
0.18
LVMI (g/m²)
75 ± 15
71 ± 16
0.34
LAVI (mm)
22 ± 5
21 ± 6
0.58
Mitral E wave (cm/s)
67 ± 15
73 ± 14
0.06
Mitral A wave (cm/s)
71 ± 19
73 ± 18
0.52
E/A Ratio
1.0 ± 0.3
1.0 ± 0.3
0.68
DT
181 ± 41
176 ± 31
0.56
Mitral E' wave (cm/s)
8.9 ± 2.5
9.5 ± 2.3
0.30
Mean S' wave (cm/s)
6.1 ± 1.0
6.6 ± 0.9
0.035
E/E' Ratio
8.0 ± 2.7
8.2 ± 2.5
0.78
LA: left atrium; BSA: body surface area; LVDD: left ventricular diastolic diameter; LVSD: left ventricular systolic diameter; LVPW: left ventricular posterior wall;
LVEF: left ventricular ejection fraction; LVMI: left ventricular mass index; LAVI: left atrial volume index; DT: deceleration time.
εLL, εCC and εRR Obtained by Two-Dimensional Speckle
Tracking
Even though the LVEF was normal and showed no
difference between groups, the εLL in the patients' group
was -12.4 ± 2.6%, representing values 7.5% lower than
278
Arq Bras Cardiol. 2015; 104(4):274-283
the corresponding values for the controls (-13.4 ± 1.7%;
p = 0.04; Table 3). εCC was -12.1 ± 2.7% in patients,
representing a reduction of 27.5% compared with controls
(-16.7 ± 3.6%; p < 0.001). There was no difference between
the groups with respect to εRR (p = 0.89).
Almeida et al.
Subclinical LV Dysfunction After Use of Anthracycline
Original Article
There was no correlation between the dose of DOX and the
strain (DOX versus εLL: p = 0.89; DOX versus εCC: p = 0.95).
Intraobserver intraclass correlation coefficient was 0.89
(p < 0.01) for εLL and 0.83 (p = 0.01) for εCC.
Determinants of Longitudinal Strain
In model 1 of the MLR analysis, previous use of DOX
(B = -1.289; 95% confidence interval [CI]: -2.282 to
-0.296; p = 0.012) and the age in years (B = -0.057;
95% CI: -0.108 to -0.006; p = 0.029) were the only
independent predictors of ε LL (Table 4).
Determinants of Circumferential Strain
In model 2 of the MLR, previous use of DOX was
the only independent predictor of reduction in εCC after
adjustments for LVMI, presence of dyslipidemia, age, prior
radiotherapy and systolic BP (B = -4.429; 95% CI: -5.907
to -2.952; p < 0.001; Table 5).
Discussion
The results of this study show that εLL and εCC, evaluated
by 2D-STE, are reduced in patients who used DOX 2 years
before when compared with healthy controls. This occurred
even though the LVEF was normal and did not differ
between the groups, suggesting the presence of subclinical
ventricular dysfunction in a group considered at high risk for
cardiovascular events. Our results also showed that previous
use of DOX was an independent predictor of reduction of εCC
in cancer survivors, and that previous use of DOX and age
were independent markers of reduced εLL in this population.
The S' wave, another echocardiographic variable able to
identify preclinical changes in LV systolic function, was also
reduced in patients who used the anthracycline.
With the global trend of population aging, the risk factors
for cardiovascular disease will become more prevalent.
It is therefore expected that there will be an increase in the
occurrence of heart disease. Likewise, there is an increase
Table 3 – Strain results in the study population
Variable
Doxorubicin (N = 40)
Controls (N = 41)
p value
εLL (%)
-12.4 ± 2.6
-13.4 ± 1.7
0.04
εCC (%)
-12.1 ± 2.7
-16.7 ± 3.6
< 0.001
εRR (%)
30.9 ± 10.4
31.2 ± 10.4
0.89
εLL: longitudinal strain; εCC: circumferential strain; εRR: radial strain
Table 4 – Determinants of longitudinal strain
Dependent Variable: εLL
Independent Variables
Univariate Analysis
Multivariate Analysis (p = 0.011)
B Coef (%)
95% CI
p value
B Coef (%)
95% CI
p value
Doxorubicin (Yes)
-1.02
(-2.006;-0.038)
0.042
-1.289
(-2.282;-0.296)
0.012
Age (years)
-0.052
(-0.102;0.002)
0.044
-0.057
(-0.108;-0.006)
0.029
LV mass index (g/m²)
-0.008
(-0.041;0.025)
0.616
-
-
0.867
Diabetes (Yes)
-0.561
(-2.232;1.110)
0.506
-
-
0.65
Obesity (Yes)
-0.775
(-1.945;0.395)
0.191
-
-
0.246
Systolic BP (mmHg)
0.004
(-0.019;0.028)
0.716
-
-
0.842
Prior radiotherapy (Yes)
-0.401
(-1.560;0.758)
0.493
-
-
0.953
Alcohol (Yes)
0.424
(-0.662;1.512)
0.440
-
-
-
Smoking (Yes)
0.350
(-0.599;1.298)
0.465
-
-
-
Race (Black)
0.583
(-0.827;1.994)
0.412
-
-
-
Physical activity (Yes)
0.230
(-0.914;1.373)
0.690
-
-
-
Abdominal circumference (cm)
-0.021
(-0.064;0.022)
0.340
-
-
-
BMI (Kg/m²)
-0.051
(-0.159;0.057)
0.347
-
-
-
Hypertension (Yes)
-0.501
(-1.552;0.550)
0.345
-
-
-
LV: left ventricle; BP: blood pressure; BMI: body mass index; Coef: coefficient; CI: confidence interval.
Arq Bras Cardiol. 2015; 104(4):274-283
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Almeida et al.
Subclinical LV Dysfunction After Use of Anthracycline
Original Article
Table 5 – Determinants of circumferential strain
Dependent Variable: εCC
Independent Variables
Univariate Analysis
Multivariate Analysis (p < 0.001)
B Coef (%)
95% CI
p value
B Coef (%)
95% CI
p value
Doxorubicin (Yes)
-4.539
(-6.010;-3.067)
< 0.001
-4.429
(-5.907;-2.952)
< 0.001
Dyslipidemia (Yes)
-1.077
(-2.921;0.767)
0.248
-
-
0.065
LV mass index (g/m²)
0.012
(-0.047;0.071)
0.688
-
-
0.206
Prior radiotherapy (Yes)
-3.237
(-5.119;-1.354)
0.001
-
-
0.851
-
-
Age (years)
0.04
(-0.05;0.14)
0.349
BMI (Kg/m²)
-0.056
(-0.265;0.152)
0.591
0.928
Systolic BP (mmHg)
0.026
(-0.017;0.069)
0.235
-
-
0.651
Diabetes (Yes)
0.703
(-2.247;3.653)
0.636
-
-
-
Smoking (Yes)
0.157
(-1.510;1.823)
0.852
-
-
-
0.124
Alcohol (Yes)
-0.168
(-2.126;1.790)
0.865
-
-
-
Physical activity (Yes)
0.464
(-1.558;2.485)
0.649
-
-
-
Abdominal circumference (cm)
-0.011
(-0.095;0.072)
0.787
-
-
-
Race (Black)
0.958
(-1.412;3.327)
0.422
-
-
-
Hypertension (Yes)
0.0412
(-1.46;2.248)
0.662
-
-
-
LV: left ventricle; BP: blood pressure; BMI: body mass index; Coef: coefficient; CI: confidence interval.
in cancer incidence in older populations15. The effectiveness
of antineoplastic treatment has significantly reduced the
mortality due to cancer2. These same drugs, however, are
associated with increased morbidity and mortality due
to cardiovascular causes. Patients treated with DOX who
develop signs of HF have a mortality rate at 2 years of 60%,
a 3.5 times higher risk than those with idiopathic dilated
cardiomyopathy16. Monitoring of myocardial function in
patients using chemotherapeutic agents is usually based on
clinical findings and on LVEF. These parameters, however,
only change in the later stages of cardiovascular disease,
usually when there is already structural apoptosis of
myocytes and therefore, little likelihood of reversion of the
clinical picture3,4. The identification of cardiac injury in the
early stages has proven beneficial in patients undergoing
cancer treatment17, and the reduction in εLL emerging as an
independent predictor of late reduction in LVEF in patients
treated with anthracyclines justify early therapy with drugs
with cardioprotective effect in these patients18.
Sawaya et al18 showed that unlike the longitudinal strain,
LVEF and information from LV diastolic function are unable
to predict cardiotoxicity, and that LVEF is not sensitive
enough to detect early LV injury19. In other words, when the
dysfunction is detected, heart injury has already occurred
for some time, preventing use of prophylactic strategies.
Moreover, the failure to detect changes in LVEF does not
exclude subclinical cardiac damage, nor the possibility of
later cardiac deterioration6,20. Our results showed that more
sensitive markers related to subclinical myocardial injury,
such as εLL, εCC and S' wave, are reduced in patients who used
the anthracycline, despite normal LVEF which did not differ
280
Arq Bras Cardiol. 2015; 104(4):274-283
between groups. Similar results were obtained by other
authors, signaling that the use of these new technologies
can be useful in the evaluation of cardiotoxicity in patients
undergoing chemotherapy17,21-23.
The differences observed in the absolute value of the strain
tend to be small when we deal with subclinical ventricular
dysfunction8,17. In our study, the relative difference observed
in εLL was 7.5% and in εCC of 27.5%, similar to the results
obtained in other studies21,24.
Even though the qualitative analysis (DOX: yes versus no)
have influenced the results of the εCC and the εLL, the variation
in DOX dose used in our study was very low (median =
240 mg/m²; IQR: 231-286 mg/m²), justifying the absence of
correlation observed between the dose of DOX and the strain.
The participants in the control group in this study cannot be
considered normal. Although they were included as controls,
none of them underwent a stress test and, therefore, did not
have potential incipient heart diseases excluded. Additionally,
the prevalences of dyslipidemia, diabetes, hypertension,
smoking and alcohol consumption in both groups bring our
cohort very close to the "real world", which, in our view,
reinforce even more the results of the study. In an article
from the MESA (Multi-Ethnic Study of Atherosclerosis) trial8,
the characteristics of the control group were very similar to
those in our control group, and the software used for the
analysis of strain was the same used in our study. In that
article, longitudinal strain between controls was -13.9 ± 2.3%,
a result close to that found in our study (-13.4 ± 1.7%). It is
also possible that these values may be slightly lower when
compared with truly normal individuals.
Almeida et al.
Subclinical LV Dysfunction After Use of Anthracycline
Original Article
The algorithm used by Toshiba's equipment allows
measurement of circumferential and longitudinal strain in
the endocardial, mid-myocardial and epicardial regions.
In the absence of ischemia, strain is greater in the endocardium
than in the epicardium, with intermediate values in the middle
region of the myocardium12. Experimental data validated by
sonomicrometry show that while the circumferential strain
in the mid-myocardial region was -13.3 ± 4.7%, the results
in the endocardium and epicardium were -25.2 ± 8.7%
and -9.4 ± 9.3%, respectively12. In our study, the results
of longitudinal and circumferential strains were those
representing the middle region of the myocardium, as
described in the methodology.
According to Feigenbaum et al25, one of the limitations
for propagation of the method of strain analysis by speckle
tracking is the fact that many manufacturers have not yet
presented interchangeable results between different software
applications for strain analysis. That is, the results obtained with
the Toshiba software, used in our study, are unlikely to be the
same results obtained by another manufacturer.
Participants in the control group had levels of systolic
and diastolic BP higher in the initial clinical evaluation,
although there was no difference between groups in the
percentage of participants labeled hypertensive. This finding
seems contradictory, but it was probably due to greater
adherence to antihypertensive therapy among patients who
were undergoing medical follow-up after chemotherapy.
The increase in BP levels tend to influence the results of
εLL and εCC . Marwick et al26 showed that the higher the
diastolic BP, the greater will be the impact on the strain.
Our results showed that patients who underwent
chemotherapy presented lower ε LL and ε CC , despite
presenting lower levels of systolic and diastolic BP when
compared with healthy controls. Although this contradicts
the results reported by Marwick et al26, this information
can reinforce the importance of prior use of DOX as an
independent predictor of reduced εLL and εCC in our patients.
Although the absolute dimension of the LA was higher in
controls, there was no difference when it was indexed to body
surface area. Similarly, there was no difference in the values of
LAVI, which is a more robust index to represent the dimensions of
the LA and has a higher correlation with cardiovascular disease10,27.
Side effects of mediastinal radiotherapy on the heart can
be expressed in the form of cardiomyopathy, valvular injury,
coronary artery disease (CAD), and mainly pericardial disease3,28.
Pericardial effusion has been reported in earlier phases after
radiation. However, constrictive pericarditis, CAD, valvular
heart disease and cardiomyopathy usually appear after longer
follow-up3, with higher incidence when the radiation is directed
towards the left side of the chest29. In our sample, 52.5% of the
patients received adjuvant radiotherapy. However, only 20%
had it performed on the left side of the chest. In addition, the
average time after chemotherapy was only two years, which may
justify the absence of signs of pericardial disease in our sample.
Cyclophosphamide and 5-fluorouracil were used by
77.5% and 37.5% of our patients, respectively. Both are also
associated with cardiotoxicity, but with a frequency much
lower than that associated with use of anthracyclines3.
Limitations
This is a cross-sectional study and as such, is unable
to establish a precise causal relationship between the use
of anthracyclines and the findings of reduced εLL and εCC.
However, the reduction in the values of εLL and εCC in patients
who used DOX was observed even in the absence of HF by
Framingham's criteria, history of illness, prior cardiovascular
disease, valvular lesion greater than mild, change in segmental
contractile function in the transthoracic echocardiogram and
LVEF <55%. In addition, the participants were examined
under stable conditions to prevent changes secondary to
the effects of hemodynamic instability. However, larger
prospective studies will be necessary to assess the possible
effects of confounding variables. Even though the patients
had no prior angina or myocardial infarction, they did not
undergo stress test. The sample was composed only by
women, therefore these results cannot be extrapolated to
male patients. The analysis of the echocardiographic findings
variables was performed by only one examiner.
Conclusions
εLL, the εCC and the S' wave are reduced in patients who
used DOX ± 2 years prior to the study, despite normal LVEF,
suggesting the presence of subclinical ventricular dysfunction
in a group considered at high risk of cardiovascular events.
Previous use of DOX was an independent predictor of εCC
reduction in cancer survivors. Previous use of DOX and age
were independent markers of εLL reduction.
Author contributions
Conception and design of the research: Almeida ALC,
Silva VA, Souza Filho AT, Rios VG, Lopes JRP, Afonseca SO,
Santos Júnior EG; Acquisition of data and Critical revision of
the manuscript for intellectual content: Almeida ALC, Silva
VA, Souza Filho AT, Rios VG, Lopes JRP, Afonseca SO, Cunha
DCA, Mendes MOC, Miranda DL, Santos Júnior EG; Analysis
and interpretation of the data: Almeida ALC, Santos Júnior
EG; Statistical analysis and Obtaining financing: Almeida ALC;
Writing of the manuscript: Almeida ALC, Santos Júnior EG.
Potential Conflict of Interest
Dr. André Luiz Cerqueira de Almeida has served as a speaker
in activities sponsored by Toshiba Medical Systems. He has also
received support from Toshiba Medical Systems in the form of
equipment and for participation in meetings. Drs. Viviane Almeida
Silva, Alberto Teófilo de Souza Filho, Vinicius Guedes Rios, João
Ricardo Pinto Lopes, Samuel Oliveira de Afonseca, Daniel de
Castro Araújo Cunha, Murilo Oliveira da Cunha Mendes, Danilo
Leal Miranda, Edval Gomes dos Santos Júnior have received
support from Toshiba Medical Systems in the form of equipment.
Sources of Funding
This study was partially funded by Toshiba Medical Systems.
Study Association
This study is not associated with any thesis or dissertation work.
Arq Bras Cardiol. 2015; 104(4):274-283
281
Almeida et al.
Subclinical LV Dysfunction After Use of Anthracycline
Original Article
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283
Back to the Cover
Original Article
Blood Pressure Variation Throughout Pregnancy According to Early
Gestational BMI: A Brazilian Cohort
Fernanda Rebelo1,3, Dayana Rodrigues Farias1,2, Roberta Hack Mendes1, Michael Maia Schlüssel4, Gilberto Kac1
Observatório de Epidemiologia Nutricional1, Departamento de Nutrição Social e Aplicada, Instituto de Nutrição Josué de Castro, Universidade
Federal do Rio de Janeiro; Programa de Pós-Graduação em Nutrição2, Instituto de Nutrição Josué de Castro, Universidade Federal do Rio de
Janeiro; Programa de Pós-Graduação em Epidemiologia em Saúde Pública3, Escola Nacional de Saúde Pública, Fundação Oswaldo Cruz, Rio de
Janeiro - Brazil; Oxford Clinical Trials Research Unit, Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology
and Musculoskeletal Sciences, University of Oxford4, Oxford - United Kingdom
Abstract
Background: The maternal cardiovascular system undergoes progressive adaptations throughout pregnancy, causing blood
pressure fluctuations. However, no consensus has been established on its normal variation in uncomplicated pregnancies.
Objective: To describe the variation in systolic blood pressure (SBP) and diastolic blood pressure (DBP) levels during pregnancy
according to early pregnancy body mass index (BMI).
Methods: SBP and DBP were measured during the first, second and third trimesters and at 30-45 days postpartum in a
prospective cohort of 189 women aged 20-40 years. BMI (kg/m²) was measured up to the 13th gestational week and classified
as normal-weight (<25.0) or excessive weight (≥25.0). Longitudinal linear mixed-effects models were used for statistical
analysis.
Results: A decrease in SBP and DBP was observed from the first to the second trimester (βSBP=-0.394; 95%CI: -0.600- -0.188
and βDBP=-0.617; 95%CI: -0.780- -0.454), as was an increase in SBP and DBP up to 30-45 postpartum days (βSBP=0.010;
95%CI: 0.006-0.014 and βDBP=0.015; 95%CI: 0.012-0.018). Women with excessive weight at early pregnancy showed higher
mean SBP in all gestational trimesters, and higher mean DBP in the first and third trimesters. Excessive early pregnancy BMI
was positively associated with prospective changes in SBP (βSBP=7.055; 95%CI: 4.499-9.610) and in DBP (βDBP=3.201; 95%CI:
1.136-5.266).
Conclusion: SBP and DBP decreased from the first to the second trimester and then increased up to the postpartum period.
Women with excessive early pregnancy BMI had higher SBP and DBP than their normal-weight counterparts throughout
pregnancy, but not in the postpartum period. (Arq Bras Cardiol. 2015; 104(4):284-291)
Keywords: Arterial Pressure; Pregnant Women; Pregnancy; Body Mass Index; Cohort Studies.
Introduction
The maternal cardiovascular system undergoes progressive
adaptations throughout pregnancy, including decreased
vascular resistance, increased blood volume, and other
metabolic changes¹. Although the effects of these changes
on systemic blood pressure (BP) have been described in
many studies, there is no consensus on its normal variation in
uncomplicated pregnancies2,3.
Hypertensive disorders of pregnancy (HDP) represent
a major obstetric complication that affects 5%-10% of
pregnancies, depending on characteristics of the study
population, and are one of the leading causes of maternal and
neonatal morbidity and mortality worldwide4. HDP include
chronic hypertension, gestational hypertension, preeclampsia
Mailing Address: Gilberto Kac •
Rua Viúva Lacerda, 249 bloco 3, ap. 302, Humaitá - Postal code 22260-050
Rio de Janeiro, RJ – Brazil.
Email: [email protected]; [email protected].
Manuscript received July 09, 2014; revised manuscript October 07, 2014;
accepted December 02, 2014.
DOI: 10.5935/abc.20150007
284
and eclampsia, being considered the second most common
cause of direct maternal death in developed countries5.
The etiology of HDP is not clear; however, there are several
risk factors associated with their occurrence, such as body mass
index (BMI)6. As the prevalence of obesity increases in women
of reproductive age7, BMI [weight (kg)/stature2 (m2)] and its
associated complications represent a relevant public health
matter. Maternal obesity is a significant risk factor for morbidity
and mortality for both mother and fetus8. A systematic review
has demonstrated that an increase of approximately 5-7 kg/m²
units in BMI was associated with a two-fold increased risk
of preeclampsia9.
Given these previous findings, this study aims to describe
the variation in systolic blood pressure (SBP) and diastolic
blood pressure (DBP) levels during uncomplicated pregnancy,
according to BMI.
Methods
This prospective cohort study was conducted at a prenatal
care unit in Rio de Janeiro, Brazil. The enrollment of pregnant
women occurred freely and continuously between November
2009 and October 2011. The follow-up period lasted until
July 2012. A total of 258 women were recruited according
Rebelo et al.
Blood pressure throughout pregnancy
Original Article
to the following criteria: being less than 13-week pregnant
at enrollment, being 20 to 40 years old and being free from
any infectious or chronic diseases (except obesity). The study
comprised four follow-up waves: 4th-13th week (first trimester),
14th-27th week (second trimester), 28th-40th week (third
trimester), and 30-45 postpartum days. The first follow-up
wave included two visits on different days; BP and BMI data
were obtained during the first visit, and all other covariates
used for adjustment in the analysis were collected during the
second visit. Women who underwent the first follow-up visit
but quit before the second visit (n=6) were excluded from
the analysis, as were those with the following characteristics:
twin pregnancies (n=4); diagnosis of an infectious or noncommunicable disease (n=17); miscarriage (n=25); and BP
not measured in the specified interval (n=17). The final sample
was composed of 189 pregnant women (Figure 1).
Systolic and diastolic BP were measured using an automated
oscillometric BP monitoring system (HEM-742, OMRON, São
Paulo, Brazil) validated according to the international protocol
of the European Society of Hypertension10. Blood pressure was
measured after the women had rested for at least five minutes
and were seated comfortably with their back supported, their
legs uncrossed and their feet flat on the floor. Clothing was
removed from the arm in which the cuff was placed. The arm
was supported at heart level, with the palm facing up and the
elbow slightly flexed. The women were advised not to speak
during the procedure. Different cuff sizes, based on the upper
arm circumference at the time of each measurement, were
used. Blood pressure was measured twice at the first trimester
(in two distinct days) to determine if the women had chronic
hypertension (values of SBP ≥ 140 or DBP ≥ 90 mm Hg,
before the 20th gestational week). Each measurement of BP
was performed in duplicate, for all follow-up waves, with an
approximate 30-minute interval between measurements. The
mean values of the duplicate measurements from each timepoint were used for analysis11.
The women were weighed with a digital scale (Filizola Ltd.,
São Paulo, Brazil), and their stature was measured in duplicate
with a Seca Portable Stadiometer (Seca Ltd., Hamburg,
Germany). The mean of the duplicate standing height
values was used to calculate BMI. Early pregnancy BMI was
obtained prior to the 13th gestational week. Anthropometric
measurements were standardized and performed by trained
interviewers12. The BMI was classified into two categories,
934 Pregnant women responded to the study recruitment questionnaire
541 were not eligible: 241 were adolescents; 157 were beyond the 13th gestational week; 81
lived outside of the study programmatic area; 42 had chronic diseases; 10 were > 40 years old;
8 had infectious disease; 2 intended to receive prenatal care in another public health center
393 Potentially eligible to participate in the study
54 signed the term of consent, but did not initiate the protocol: 20 were beyond the 13th
gestational week; 16 received prenatal care in another public health center; 10 declined to
participate; 8 had spontaneous abortion before the first visit
40 Refused to participate
299 Attended the 1st interview
41 excluded: participated in a nested clinical trial regarding
supplementation of n-3 fatty acids
258 participants of the cohort
69 excluded: 6 underwent the first follow-up visit but quit before the second visit; 4 had twin
pregnancies; 17 were diagnosed with an infectious or non-communicable disease; 25 had a
miscarriage; 17 did not have BP measured in the specified interval
Final sample = 189
Figure 1 - Flowchart illustrating the process of recruitment of women attending the prenatal care at a Public Health Center. Rio de Janeiro, 2009 – 2011
Arq Bras Cardiol. 2015; 104(4):284-291
285
Rebelo et al.
Blood pressure throughout pregnancy
Original Article
using the cutoff points proposed by the World Health
Organization13 (normal weight, 18.5–24.9 kg/m2; excessive
weight, ≥25.0 kg/m2). The two BMI categories were created
by joining underweight with normal-weight women and
overweight with obese women; only seven women were
underweight, and the sensitivity analysis showed no difference
in terms of magnitude or significance in the results whether
underweight women were included or excluded.
values for the first, second and third trimesters and postpartum
were 66.7 (65.6 – 67.8), 64.4 (63.3 – 65.4), 67.0 (65.8 –
68.1), and 73.3 (72.0 – 74.7), respectively. The longitudinal
regression coefficients for SBP and DBP decreased from the
first to the second trimester [βSBP=-0.394 (-0.600 – -0.188),
βDBP=-0.617 (-0.780 – -0.454)] and then increased from the
second trimester to the postpartum period [βSBP=0.010 (0.006
– 0.014), βDBP=-0.015 (-0.767 – -0.442)] (Figure 2).
The gestational age (in weeks) was estimated using,
preferably, ultrasound performed before the 26th week of
pregnancy or, alternatively, the last menstrual period reported.
The following variables were also considered in the analysis:
maternal age (years); self-reported skin color (white/black/
brown); parity (nulliparous/multiparous); current smoking
status (yes/no); marital status (lives with a partner/does not
live with a partner); education (<8/≥8 years) and practice
of leisure time physical activity (LTPA) before pregnancy (yes/
no). The dependent variables were tested for normality using
the Shapiro-Wilk test. Possible differences in the distributions
of the confounders, according to the BMI categories, were
assessed using the chi-square test for proportions. The pattern
in BP change was assessed using longitudinal linear regression
models, which used SBP and DBP as dependent variables
and gestational age and quadratic gestational age as time
independent variables. In order to improve model adequacy,
a quadratic term for gestational age was used. Prospective
changes in SBP and DBP, according to early pregnancy
BMI, were assessed with longitudinal linear regression
after adjustment for confounders, including parity, current
smoking status, marital status, years of education and LTPA.
Comparisons between eligible women lost during the followup and the final sample were performed with chi-square test
for proportions.
The mean SBP significantly differed among the BMI groups
in all gestational trimesters. The mean DBP was significantly
higher among overweight/obese women in the first and third
trimesters only. Neither SBP nor DBP differed between BMI
groups at postpartum. The longitudinal linear regression model
showed that BMI was positively associated with prospective
changes in SBP and DBP [β=7.055 (4.499 – 9.610)
and β=3.201 (1.136 – 5.266), respectively] throughout
pregnancy (Figure 3).
The statistical analyses were performed using Stata Data
Analysis and Statistical Software (STATA) version 12.0 (Stata
Corp., College Station, Texas, USA). Differences were
considered statistically significant when the p-value < 0.05.
The study protocol was approved by the research ethics
committee of the Municipal Secretary of Health of the city
of Rio de Janeiro (registration number: 0139.0.314.000-09).
All participants signed a two-way term of consent, which
was obtained freely and spontaneously after all necessary
explanations had been provided.
Results
The sample characteristics did not differ according to early
pregnancy BMI categories (p>0.05). The majority of women
were younger than 30 years (73.5%), brown or black (73.5%),
multiparous (58.2%), lived with a partner (78.8%), had at
least eight years of education (71.4%) and did not participate
in LTPA prior to pregnancy (74.3%) (Table 1). None of these
variables significantly differed between eligible women lost
to follow-up and the final sample, indicating a non-selective
loss (data not shown).
For the overall sample, the mean SBP values for the first,
second and third trimesters and postpartum (95% CI) were
109.7 (108.4 – 111.1), 107.8 (106.4 – 109.2), 111.0 (109.5 –
112.5) and 114.6 (112.9 – 116.3), respectively. The mean DBP
286
Arq Bras Cardiol. 2015; 104(4):284-291
Discussion
The main findings of this study corroborate the known
BP pattern during healthy pregnancy. The study women
experienced a mid-trimester drop, followed by a progressive
increase in SBP and DBP up to 30-45 postpartum days.
Furthermore, our results indicated a strong association
between early pregnancy BMI and SBP/DBP. Women who
began pregnancy with a BMI in the overweight or obese
categories presented higher values of SBP and DBP in all
gestational trimesters.
Although many studies have shown this same BP pattern
during pregnancy14-17, some authors have found different
results, such as a mid-trimester BP rise instead of a drop18-20.
For this reason, the publication of new findings is still necessary.
The description of usual values and

variations of SBP and DBP
in healthy pregnancies is important for prenatal practitioners to
detect abnormal variations that may be related to the onset of a
disorder. Studies to elucidate this issue should be encouraged.
Grindheim et al.17 have followed a cohort with four visits
during pregnancy to evaluate BP variation. Their sample was
very similar to ours in terms of age, parity, BMI, and gestational
age at BP measurements. The main finding of this study was
the statistically significant drop in SBP and DBP up to midpregnancy (22-24 weeks), followed by a progressive increase
until delivery, which corroborates our results. However, their
sample was smaller (n = 63) and comprised only Norwegian
women, which is a very homogeneous population.17
Nama et al.20 have found a progressive increase in SBP
and DBP in a sample of primiparous, healthy, white pregnant
women residing in London. The authors have discussed the
importance of conducting similar studies with heterogeneous
populations, considering factors such as BMI. Other studies
have also found progressive increases in SBP in homogeneous
populations18-19. However, there are no studies that have
monitored BP in healthy, adult, pregnant women from Brazil,
a country composed of a very heterogeneous population.
Another point to be considered is the mean SBP and DBP
valuesin our study. Other similar investigations have found
markedly higher values in all pregnancy trimesters19,21-23,
similar to the highest BMI group in our sample. In a recent
Rebelo et al.
Blood pressure throughout pregnancy
Original Article
Table 1 – General characteristics of the study sample, according to early pregnancy Body Mass Index (BMI) of women followed at a public
health center in the city of Rio de Janeiro, Brazil, 2009 - 2012
BMI‡ categories
Total
n (%)
Normal-weight
n (%)
Excessive weight
n (%)
< 30
139 (73.5)
78 (72.9)
61 (74.4)
≥ 30
50 (26.5)
29 (27.1)
21 (25.6)
White
50 (26.5)
27 (25.2)
23 (28.0)
Brown or black
139 (73.5)
80 (74.8)
59 (72.0)
0
79 (41.8)
43 (40.2)
36 (43.9)
≥1
110 (58.2)
64 (59.8)
46 (56.1)
Yes
15 (92.1)
7 (6.5)
8 (9.8)
No
174 (7.9)
100 (93.5)
74 (90.2)
Characteristics
p-value*
Maternal age (years)
0.818
Self-reported skin color
0.664
Parity
0.608
Current smoking
0.418
Marital status
Lives with a partner
149 (78.8)
87 (81.3)
62 (75.6)
Do not live with a partner
40 (21.2)
20 (18.7)
20 (24.4)
<8
54 (28.6)
31 (29.0)
23 (28.0)
≥8
135 (71.4)
76 (71.0)
59 (72.0)
Yes
48 (25.7)
28 (26.4)
20 (24.7)
No
139 (74.3)
78 (73.6)
61 (75.3)
0.342
Education (years)
0.889
Practice of LTPA† before pregnancy
0.789
*
p-value refers to a chi-square test for proportions; †LTPA: leisure time physical activity; ‡BMI: body mass index (normal-weight < 25 kg/m2; excessive weight
≥ 25 kg/m2).
study, MacDonald-Wallis et al.23, in an attempt to establish BP
reference values during pregnancy, have found higher mean
SBP and DBP values at 12 and 37 weeks of normal pregnancies
as compared to our results. Given that the possibility of
changing the cutoff points for the diagnosis of HDP has been
discussed, it is important to consider the differences in BP
values for different populations and BMI categories24.
Although a similar pattern of variability in normal-weight
and excessive-weight women was observed, those who began
pregnancy as overweight or obese showed significantly higher
values of SBP in all trimesters and of DBP in the first and third
trimesters of pregnancy. Similar results have been observed in
other populations16,19. This indicates that the normal variation
of BP is different between BMI categories. If a woman with a
normal BMI has a SBP or DBP level below 140 or 90 mm Hg,
respectively, but above the mean for her BMI, it may indicate
an increased risk for adverse outcomes when compared with
a woman who initiated pregnancy obese and has similar
absolute BP values.
Some authors consider postpartum BP as the normal BP of
nonpregnant women; postpartum BP is sometimes used as
a pre-pregnancy measure17. Extrapolating for our results, it
can be said that there is no BP variability outside pregnancy
between BMI groups. Putting together, the significant
difference of BP between groups in the first trimester
indicates that the BP drop in early pregnancy is probably
higher among those with a lower BMI.
Some strengths and limitations of this study should be
highlighted. This is the first study to assess longitudinal BP
data in a group of Brazilian pregnant women. Furthermore,
we used a robust statistical analysis, considering the data
as repeated measures, not merely comparing means. As
limitations, the evaluation of additional points during
pregnancy would provide a more complete pattern of
variability. Moreover, the use of ambulatory blood pressure
monitoring to measure variations throughout the day would
be important. Another potential limitation is the loss to
follow-up of 11.3% of study participants. However, the
Arq Bras Cardiol. 2015; 104(4):284-291
287
Rebelo et al.
Blood pressure throughout pregnancy
ß1=-0.394* (95% CI: -0.600 – -0.188)
ß2=0.010* (95% CI: 0.006 – 0.014)
116.3
114.6
114
Mean systolic blood pressure (mmHg)
116
Original Article
112.9
111.1
111.0
109.7
109.5
109.2
108.4
107.8
106.4
106
108
110
112
112.5
10
20
30
40
50
Time elapsed since conception (weeks)
ß1=-0.617* (95% CI: -0.780 – -0.454)
ß2=0.015* (95% CI: 0.012 – 0.018)
74.7
73.3
72
Mean diastolic blood pressure (mmHg)
74
95% Confidence Interval
68.1
67.8
66.7
67.0
65.6
65.8
65.4
64.4
64
66
68
70
72.0
63.3
10
20
30
40
50
Time elapsed since conception (weeks)
95% Confidence Interval
Figure 2 - Mean systolic and diastolic blood pressure changes during pregnancy and 30-45 days post-partum of women followed at a public health center in the city
of Rio de Janeiro, Brazil, 2009 - 2012
Note: β1,2: the longitudinal linear regression coefficients for gestational age and quadratic gestational age, respectively; CI: Confidence interval. *p-value < 0.001
refers to maximum likelihood estimator. Mean (95% CI) gestational weeks or days postpartum and number of participants (n) in each follow-up evaluation: 1st
trimester: 9.7 (9.4 – 10.0) weeks, n = 189; 2nd trimester = 23.7 (23.4 – 24.0) weeks, n=157; 3rd trimester: 32.4 (32.0 – 32.8) weeks, n = 162; postpartum: 36.4
(34.9 – 37.9) days, n = 153.
288
Arq Bras Cardiol. 2015; 104(4):284-291
Rebelo et al.
Blood pressure throughout pregnancy
119.5
ß1=7.055* (95% CI: 4.499 – 9.610)
105
117.1
117.1
114.9
114.7
114.8
115.8
113.7
112.6
112.7
110.4
110.2
112.5
111.6
110
115
Mean systolic blood pressure (mmHg)
120
Original Article
108.2
108.3
108.3
107.5
106.7
106.4
105.8
105.2
110.3
104.1
10
20
30
40
50
Time elapsed since conception (weeks)
normal weight
excessive weight
95% Confidence Interval
74.6
74.1
ß1=3.201** (95% CI:1.136 – 5.266)
72.7
72.1
71.5
70.5
70.8
70.0
68.8
68.6
67.1
67.5
66.4
65.1
66.0
66.2
64.5
64.7
63.1
63.3
63.8
61.8
60
65
70
Mean diastolic blood pressure (mmHg)
75
76.0
10
20
30
40
50
Time elapsed since conception (weeks)
normal weight
excessive weight
95% Confidence Interval
Figure 3 - Mean systolic and diastolic blood pressure changes during pregnancy according to BMI categories of women followed at a public health center in the city of
Rio de Janeiro, Brazil, 2009 - 2012
Note: β1: longitudinal linear regression coefficient for body mass index category excessive weight (reference category: normal weight) adjusted for gestational age,
quadratic gestational age, parity, current smoking status, marital status, education, practice of leisure time physical activity before pregnancy. CI: confidence interval;
normal-weight <25 kg/m2; excessive weight ≥ 25 kg/m2. *p-value <0.001 and **p-value: 0.002 refers to maximum likelihood estimator. Mean (95% CI) gestational weeks
or days post-partum and number of participants (n) in each follow-up evaluation: 1st trimester: 9.7 (9.4 – 10.0) weeks, n = 189; 2nd trimester: 23.7 (23.4 – 24.0) weeks,
n = 157; 3rd trimester: 32.4 (32.0 – 32.8) weeks, n = 162; postpartum: 36.4 (34.9 – 37.9) days, n = 153.
Arq Bras Cardiol. 2015; 104(4):284-291
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Rebelo et al.
Blood pressure throughout pregnancy
Original Article
statistical technique employed to investigate the influence
of BMI on BP is efficient even when there are some values
missing from the study sample25.
Conclusions
This study provides new data about the pattern of BP
variability throughout pregnancy, an issue that has been
of great interest in recent years. We found that SBP and
DBP decreased from early to mid-pregnancy and then
increased up to 30-45 postpartum days. The findings also
reinforced the role of BMI on SBP and DBP, highlighting the
importance of considering this variable in studies assessing
BP in pregnancy, as well as during prenatal care monitoring.
Acknowledgments
We would like to thank our funding sources: National Council
for Scientific and Technological Development (CNPq) and Carlos
Chagas Filho Foundation for Research Support of Rio de Janeiro
State (FAPERJ). Kac G is research fellow from CNPq. Rebelo F
has received a scholarship from National School of Public Health
(Oswaldo Cruz Foundation), and Farias DR and Mendes RH
have received scholarships from CAPES during the development
of the study.
Author contributions
Conception and design of the research:Rebelo F, Schlüssel
MM, Kac G. Acquisition of data: Rebelo F, Farias DR. Analysis
and interpretation of the data: Rebelo F, Farias DR, Schlüssel
MM, Kac G. Statistical analysis: Rebelo F, Farias DR, Schlüssel
MM, Kac G. Obtaining financing:Schlüssel MM, Kac G.
Writing of the manuscript: Rebelo F, Farias DR, Mendes RH,
Schlüssel MM, Kac G. Critical revision of the manuscript
for intellectual content: Rebelo F, Farias DR, Mendes RH,
Schlüssel MM, Kac G.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Sources of Funding
This study was funded by CNPq and FAPERJ.
Study Association
This study is not associated with any thesis or dissertation
work.
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Back to the Cover
Original Article
Progression of Blood Pressure and Cardiovascular Outcomes in
Hypertensive Patients in a Reference Center
Gilberto Campos Guimarães Filho, Ana Luiza Lima Sousa, Thiago de Souza Veiga Jardim, Weimar Sebba Barroso
Souza, Paulo César Brandão Veiga Jardim
Liga de Hipertensão da Faculdade de Medicina da Universidade Federal de Goiânia, Goiás, GO - Brazil
Abstract
Background: Hypertension is a public health problem, considering its high prevalence, low control rate and cardiovascular
complications.
Objective: Evaluate the control of blood pressure (BP) and cardiovascular outcomes in patients enrolled at the Reference
Center for Hypertension and Diabetes, located in a medium-sized city in the Midwest Region of Brazil.
Methods: Population-based study comparing patients enrolled in the service at the time of their admission and after
an average follow-up of five years. Participants were aged ≥ 18 years and were regularly monitored at the Center
up to 6 months before data collection. We assessed demographic variables, BP, body mass index, risk factors, and
cardiovascular outcomes.
Results: We studied 1,298 individuals, predominantly women (60.9%), and with mean age of 56.7 ± 13.1 years. Over time,
there was a significant increase in physical inactivity, alcohol consumption, diabetes, dyslipidemia, and excessive weight.
As for cardiovascular outcomes, we observed an increase in stroke and myocardial revascularization, and a lower frequency
of chronic renal failure. During follow-up, there was significant improvement in the rate of BP control (from 29.6% to 39.6%;
p = 0.001) and 72 deaths, 91.7% of which were due to cardiovascular diseases.
Conclusion: Despite considerable improvements in the rate of BP control during follow-up, risk factors worsened and
cardiovascular outcomes increased. (Arq Bras Cardiol. 2015; 104(4):292-298)
Keywords: Hypertension / complications; Arterial Pressure / physiopathology; Cardiovascular Diseases; Risk Factors;
Indicators of Morbidity and Mortality.
Introduction
High blood pressure (BP) is one of the most important
modifiable causes of cardiovascular (CV) morbidity and
mortality in the adult population worldwide, and an
independent risk factor for CV diseases 1,2.
The increased prevalence of high BP, associated with
the large number of undiagnosed and inadequately treated
hypertensive individuals, promotes hypertension to a serious
public health problem3.
The efficacy of the services responsible for care of
hypertensive patients, with identification of the strengths
of their operations, may represent an important tool for
management and planning.
The fact that hypertension is also the most frequent CV
disease has contributed significantly to make it the third most
important cause of disability worldwide and the leading risk
factor for CV complications such as stroke, acute myocardial
infarction (AMI), and terminal renal chronic disease1,4.
Considering this background, the present study aimed
at evaluating the rate of BP control, and frequency of risk
factors and CV outcomes in hypertensive patients undergoing
treatment at the Reference Center for Hypertension and
Diabetes (Centro de Referência em Hipertensão e Diabetes,
CRHD), located in a medium-sized city in the Midwest
Region of Brazil.
This fact explains 54% of the deaths from stroke and 47%
of those due to ischemic heart disease, with little variation
Methods
Mailing Address: Gilberto Campos Guimaraes Filho •
Rua Villa 05, Lote 83, Qd 07 Condomínio Miafiori, Bairro Residencial
Miafiori. Postal Code 75900-000, Rio Verde, GO - Brazil
E-mail: [email protected]; [email protected]
Manuscript received July 28, 2014; revised manuscript August 11,2014;
accepted October 20, 2014.
DOI: 10.5935/abc.20150001
292
between genders5,6. This reality shows that effective, safe
and focused treatment goals are essential, leading to a better
prognosis of hypertensive individuals by reducing CV events7.
The research project number 128/11 was evaluated and
approved by the Ethics Committee of the Hospital das Clínicas,
Universidade Federal de Goiás (UFG) and all participants signed
an informed consent form.
This was a quasi-experimental study including a representative
sample of the population of hypertensive patients undergoing
follow-up at the CRHD.
Guimarães Filho et al.
Progression Of Pressure And Outcomes In Hypertensive Individuals
Original Article
The CRHD was created with the primary purpose of building
a system to reorganize the services offered to carriers of these
diseases. In its structure, the Center seeks to monitor continually,
by a multidisciplinary team, the care through consultations, use
of medication, control of risk factors and CV outcomes.
The sample size was calculated assuming a significance
level of 5%, at a confidence interval of 95%, with an absolute
accuracy of 2.5% and an estimated frequency of concurrence
of other risk factors associated with hypertension of 73.47%
(Lessa et al., 2004) with an estimated frequency of 25% of
the patients with controlled BP, according to Burt et al., 1995.
Based on these parameters, we obtained 1,298 individuals.
From an initial database of 14,000 patients enrolled in the
CRHD, we randomly selected the participants for the study.
We included individuals of both genders (18 to 95 years),
diagnosed with hypertension and undergoing regular treatment,
registered at the CRHD between 2003 and 2012 until six months
before starting data collection. Exclusion criteria included
inability or refusal to sign the consent form, participation in other
research protocols, presence of type 1 diabetes mellitus (DM),
inability to locate the subject in two home visits, and incomplete
initial consultation form.
We analyzed data from medical records pertaining the
admission to the Center, and then followed up the individuals
with new data collection during home visits. The instruments
used on the admission to the CRHD and during home visit
contained information related to anthropometric parameters,
personal data, BP measurements, sedentary lifestyle, smoking,
alcohol consumption, DM, dyslipidemia, stroke, AMI, chronic
renal failure (CRF), and coronary artery bypass grafting (CABG).
We considered individuals as smokers if they consumed at
least one cigarette a day8. Alcohol intake was reported by the
patient as present or not, without amount quantification. We
defined as physically active those individuals who reported
engaging in any physical activity at least 3 times a week for at
least 30 minutes each time.
The investigation of the diet was simplified and the
individuals were asked if they were in a low-sodium,
low-calorie, low-carbohydrate or low-fat diet. The use of
medication was assessed during home visits through medical
prescription and/or visual confirmation of the medications.
The presence of DM and dyslipidemia was determined
by evaluating existing biochemical tests which confirmed
the disorder, or use of specific medications. In the absence
of both, we performed a rapid test of blood glucose with a
glucometer (ACTIVE®, model Accu-Chek), and a lipid profile
with biochemical analysis performed in a laboratory of the
public health system (SUS).
Cardiovascular outcomes considered in the study were
AMI, CABG, stroke, CRF and death. The investigation of these
outcomes was performed based on report by the participant,
a family member or a companion, by complementary tests,
medical records or death certificate.
We calculated the body mass index (BMI) using the
Quetelet index9. The weight was measured with the participant
without shoes, using a calibrated electronic scale (Toledo®),
with an accuracy of 100 g. The height was measured with
an inextensible tape measure 150 inches long, set 50 inches
above the ground.
The BP measurement on admission was performed with
a calibrated aneroid sphygmomanometer (Preminum®).
During home visits, the BP was measured with a digital,
calibrated and validated automated sphygmomanometer
(OMRON 710 CP). We performed two measurements
with 1 minute interval between each and considered for
analysis the average between them. Both measurements
were performed according to the VI Brazilian Guidelines
on Hypertension (2010).
Statistical Analysis
The statistical analysis was performed with the software
SPSS v.20.0®. To verify the normality of the data distribution
we used the Kolmogorov-Smirnov test. For correlation between
variables, we calculated the correlation coefficient of Pearson
or Spearman. To compare means between related groups, we
used the Wilcoxon test, Student’s t test or ANOVA and the
McNemar’s test to compare categorical variables at different
moments. To compare proportions, we used the chi-square test
(χ2). For all tests, we considered a significance level of 5% and
a confidence interval of 95%.
Results
The initial sample (admission phase) consisted of
1,299 participants. Of these, 123 were not found for the 2nd
phase in two contact attempts and/or refused to participate
in the study and were replaced by other participants of the
initial database. The final sample (home visit) consisted of
1,227 individuals, with 72 deaths recorded.
The mean age was 56.7±13.1 years (minimum of 18 years
and maximum of 95 years), 60.9% were females and 45.3%
were in the age range above 60 years.
The frequency of elderly individuals at the admission to the
CRHD was 45.3% (n = 588), of which 63.0% (n = 320) were males.
Regarding risk factors for CV disease, besides hypertension,
we observed at the beginning of the study that 59.4%
(n = 772) were sedentary, 21.2% (n = 275) were smokers,
1.3% (n = 17) consumed alcohol, 25.3% (n = 329) were
diabetics, 1.5% (n = 20) reported dyslipidemia and 66.8%
(n = 858) were overweight.
In the beginning of the study, 9.9% (n = 128) of the cohort
reported a history of stroke, the same number of participants
reported AMI, 12.7% (n = 165) reported CRF and 1.1%
(n = 14) reported CABG.
The risk factors for CV diseases were also observed equally
between men and women, except for excess weight, which was
significantly higher among women. As for initial CV outcomes,
we observed among men significantly higher frequencies of
stroke and CRF.
Analysis of the risk factors and CV outcomes relative to the
age range (< 60 years and > 60 years) showed no significant
differences.
Upon admission, 914 patients (70.4%) had a BP outside
the control targets. Among diabetics, it was also elevated the
Arq Bras Cardiol. 2015; 104(4):292-298
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Guimarães Filho et al.
Progression Of Pressure And Outcomes In Hypertensive Individuals
Original Article
number of individuals (n = 295) without adequate BP control,
corresponding to 89.7% of those.
Of 1,299 participants initially analyzed, 1,227 were
reevaluated at home visits. The mean follow-up was
4.5 ± 2.2 years (median 5 years), with a maximum of 9 years
and a minimum of 1 year.
Over time, there was a significant increase in the presence
of CV risk factors among the participants, with the exception of
smoking for which there were no changes (Table 1).
As for CV outcomes, we observed during the home visit a
significantly higher frequency of stroke and CABG, and a lower
frequency of CRF (Table 2).
In both phases of the study, there was a predominance of
hypertensive and overweight individuals from both genders,
which showed significant increase during follow-up (Table 3).
From admission to home visits, there was a significantly
greater percentage of patients with controlled BP (Table 4).
Of the deaths that occurred during follow-up, 87.5%
(n = 63) were due to CV diseases. There was no statistically
significant difference in the frequency of deaths according to
the age range (< 60 years and > 60 years).
Discussion
In the study cohort, there was a predominance of
women (p < 0.01), which was probably related, among
other reasons, to an inability of men to attend appointments
during the available hours of operation of the health services.
Similar results were also shown by Nascente et al, 201010 and
during the last phase of the National Health and Nutrition
Examination Survey (NHANES VI)11.
The present study showed a large number of overweight
participants, which were most frequently women. Similar
results were also observed in Goiânia7, Cuiabá12, Nobres13,
and São Luiz14. This fact shows the importance of excessive
weight as a risk factor and additional obstacle for improved
hypertension control.
The investigation showed an increased rate of sedentary
lifestyle (p < 0.01) during follow-up, which affected 76.3%
of the participants. This result is similar to that reported by
Duncan et al.15 who found only 30% of the subjects practicing
regular physical activity. This is another factor which prevents
a more effective implementation, since evidence indicates
that a regular routine of exercise lowers BP and reduces CV
mortality by 30%16.
The possibility of association between hypertension and DM
is 50%, which not infrequently requires management of both
diseases in the same individual. This is compounded by the fact
that this association enhances microvascular and macrovascular
damages arising from both diseases, causing high cardiovascular
and cerebrovascular morbidity1. Effective treatment for these
patients with high CV risk is crucial17. This study also showed
Table 1 – Presence of cardiovascular (CV) risk factors at baseline and at follow-up (Rio Verde - GO, 2012)
Admission
(n = 1,299)
Variables
Follow-up
(n = 1,227)
n
%
n
%
p*
Yes
772
59.4
936
76.3
0.00
No
527
40.6
291
23.7
Yes
275
21.2
268
21.8
No
1,024
78.8
959
78.2
Yes
17
1.3
157
12.8
No
1,282
98.7
1,070
87.2
Yes
329
25.3
415
31.9
No
970
74.7
812
66.2
Sedentarism
Smoking
0.73
Alcoholism
0.00
Diabetes mellitus
0.00
Dyslipidemias
Yes
20
1.5
367
29.9
No
1,279
98.5
860
70.1
Yes
858
66.1
875
71.3
No
427
32.9
352
28.7
0.00
Excessive weight
(*) McNemar’s test.
294
Arq Bras Cardiol. 2015; 104(4):292-298
0.00
Guimarães Filho et al.
Progression Of Pressure And Outcomes In Hypertensive Individuals
Original Article
Table 2 – Distribution of cardiovascular (CV) outcomes at admission and at follow-up (Rio Verde - GO, 2012)
Admission
(n = 1,299)
Variables
Follow-up
(n = 1,227)
n
%
n
%
p*
0.003
Stroke
Yes
128
9.9
152
12.4
No
1,171
90.1
1,075
87.6
Yes
128
9.9
129
10.5
No
1,171
90.1
1,098
89.5
Yes
165
12.7
129
10.5
No
1,134
87.3
1,098
89.5
AMI
0.372
CRF
0.00
CABG
Yes
14
1.1
79
6.4
No
1,285
98.9
1,148
93.6
0.00
(*) McNemar test.
AMI: Acute myocardial infarction; CRF: Chronic renal failure; CABG: Coronary artery bypass grafting.
Table 3 – Changes in body mass index (BMI) at admission and at follow-up according to gender (Rio Verde - GO, 2012)
BMI
Admission
Follow-up
(n = 1,299)
(n = 1,227)
Mean ± SD
Mean ± SD
p*
Male
27.2 ± 5.1
27.6 ± 5.2
0.00
Female
28.9 ± 6.6
29.3 ± 6.6
0.00
(*) Wilcoxon sign test.
SD: Standard deviation.
Table 4 – Progression of the rate of blood pressure (BP) control at baseline and at follow-up (Rio Verde - GO, 2012)
Admission
Uncontrolled BP
Controlled BP
Total
Follow-up
n
%
n
%
p*
RR
CI
914
70.4
741
60.4
0.00
1.2
1.1-1.4
385
29.6
486
39.6
1,299
100.0
1,227
100.0
(*) McNemar’s test.
CI: confidence interval; RR: Risk ratio.
higher presence of DM during follow-up (p < 0.01) which can
also be a limiting factor for better control of hypertension and
CV outcomes.
The complications associated with higher frequency of
hypertension and/or DM were stroke and AMI. Similar results
were observed by Moreira and Santos in Fortaleza in 201218.
Regarding stroke, which is closely related to BP values, it has
been occurring at an increasingly earlier age in Brazil19. A study in a
northeastern region of the country in 2012 also demonstrated that
this complication was the most frequent in 6.2% of the hypertensive
patients registered in the records analyzed18. Brescacin et al.20, in a
study published in 2010, showed that long-standing hypertension is
Arq Bras Cardiol. 2015; 104(4):292-298
295
Guimarães Filho et al.
Progression Of Pressure And Outcomes In Hypertensive Individuals
Original Article
one of the main reasons for a reduction in life expectancy in subjects
with stroke. The present study showed that such complication was
more frequent among hypertensive individuals, both at admission
and during follow-up, even in those with better BP control.
The explanation may be the low effectiveness of BP control
achieved by the program, and eventually by a greater association
with other comorbidities, such as the increased presence of
excessive weight and even, age progression.
There is a clear need for a critical reassessment of these
projects, but it is fundamental to reorganize all primary care.
This should be based on a better working relationship with
valorization of health professionals (creation of a formal career
in health care), in the restructuring of multidisciplinary teams
with defined responsibilities, and reorganization of the service
itself, with decentralized installations, operation on alternative
schedules, valorization of health promotion, and home visits.
Coronary heart disease, including AMI, is one of the most
common CV outcomes of hypertension21,22. In this study, AMI
was the second most frequent complication (10.5%) , similar to
that observed in another study, but with an incidence of 4.4%.
Among these, half were hypertensive, whereas the other half
had hypertension and DM, confirming the significant association
with such complication6.
Within this line of reasoning, special attention should be paid
to care regarding medication adherence to changes in lifestyle
habits, with the implementation of continuing education in real
hopes of lowering cardiovascular outcomes26,28.
The INTERHEART study, which was a multicentric
international study planned to systematically assess the
importance of risk factors for coronary heart disease in the
world, has confirmed that the traditional risk factors explained
more than 90% of the risk attributable to AMI23. The study
AFIRMAR24, performed in 104 hospitals in 51 Brazilian cities,
presented virtually identical findings.
Hypertension is closely related to CRF, and may be the cause
or the consequence of the renal disease25. A study conducted
in the northeast area of Brazil showed 4.4% of CRF, in which
half of these subjects were hypertensive and the other half
had association of hypertension and DM18. In the present
study, surprisingly, we observed a significant decrease in the
percentage of individuals with CRF, from 12.7% to 10.5%.
The fact that the collection of this variable has been recounted
by the patient at the stage of admission in detriment of
biomedical criteria for diagnosis of the disease was a major
limitation of the study and may explain this result.
A significant increase in risk factors and CV complications
evidenced in this investigation over five years may be explained
by the aging of the population itself, since age is a major
risk factor for hypertension and consequently, for their CV
outcomes. However, one must consider that the collection of
retrospective data (on the admission to the Center) may have
represented a bias, which led to some of the results found26,27.
The results obtained are far from ideal , since only 39.6%
of the patients obtained BP control in the final evaluation and,
as incredible as it may seem, this percentage is among the best
reported in the literature26,28-30.
Similar results were observed in the American study NHANES
(2003 -2004), which showed BP controlled in 36.8%11.
Similarly in Brazil, among hypertensive patients registered
in the program HIPERDIA in the city of Novo Hamburgo, Rio
Grande do Sul, the control of hypertension reached 33.7%31.
Also in the State of Rio Grande do Sul, a recent investigation32
found that only 10.4% of the individuals undergoing antihypertensive
treatment had adequately controlled BP levels, whereas the
CARMELA study33 showed a rate of BP control of 24%.
If we take into account the philosophy and the objectives for
which the CRHD medical unit was created, an alert message
should be recorded with the results found. Clearly, there have
been significant advances in the structure and form of care, but
the results are still not ideal.
296
Arq Bras Cardiol. 2015; 104(4):292-298
This study has the limitations of studies that use in part
retrospectively collected data. An important example is the
possibility of an underestimation of metabolic changes that were
mentioned in the first assessment and which were information
effectively obtained from measurements at follow-up visits, which
can simulate falsely higher values in the second stage. Despite these
limitations, the sample size, and the fact that the final data collection
was conducted during home visits, this study offers security for
those who consider the provided information sufficiently consistent,
to indicate paths in search of an improvement in the primary care
population in one of the areas of greatest need and importance.
Conclusions
The results of this study show that, despite the improvement in
the rates of BP control, there was a significant increase in risk factors
and CV outcomes in the participants undergoing intervention by
the CRHD compared with their stage of admission to the unit. It is
noteworthy, therefore, the importance of evaluating mechanisms
from the earliest stages, so that over time there is an adequate
assessment of the developments of the quality of care.
Author contributions
Conception and design of the research:Guimarães Filho
GC, Sousa ANL, Jardim PCBV. Acquisition of data: Guimarães
Filho GC, Sousa ANL, Jardim PCBV. Analysis and interpretation
of the data: Guimarães Filho GC, Sousa ANL, Jardim PCBV.
Statistical analysis: Guimarães Filho GC, Sousa ANL. Obtaining
financing: Guimarães Filho GC. Writing of the manuscript:
Guimarães Filho GC, Sousa ANL, Jardim PCBV. Critical revision
of the manuscript for intellectual content: Guimarães Filho GC,
Sousa ANL, Jardim TSV, Souza WSB, Jardim PCBV.
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
Gilberto Campos Guimarães, from Liga de Hipertensão da
Universidade Federal de Goiânia (UFG - Goiás).
Guimarães Filho et al.
Progression Of Pressure And Outcomes In Hypertensive Individuals
Original Article
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Back to the Cover
Original Article
Quality of Life on Arterial Hypertension: Validity of Known Groups of
MINICHAL
Ana Lúcia Soares Soutello1, Roberta Cunha Matheus Rodrigues1, Fernanda Freire Jannuzzi1, Thaís Moreira São-João1,
Gabriela Giordano Martini1, Wilson Nadruz Jr.1, Maria-Cecília Bueno Jayme Gallani2
Universidade Estadual de Campinas (Unicamp)1, Campinas, SP - Brazil; Université Laval2 – Canadá
Abstract
Background: In the care of hypertension, it is important that health professionals possess available tools that allow
evaluating the impairment of the health-related quality of life, according to the severity of hypertension and the risk for
cardiovascular events. Among the instruments developed for the assessment of health-related quality of life, there is the
Mini-Cuestionario of Calidad de Vida en la Hipertensión Arterial (MINICHAL) recently adapted to the Brazilian culture.
Objective: To estimate the validity of known groups of the Brazilian version of the MINICHAL regarding the classification
of risk for cardiovascular events, symptoms, severity of dyspnea and target-organ damage.
Methods: Data of 200 hypertensive outpatients concerning sociodemographic and clinical information and health-related
quality of life were gathered by consulting the medical charts and the application of the Brazilian version of MINICHAL.
The Mann-Whitney test was used to compare health-related quality of life in relation to symptoms and target-organ
damage. The Kruskal-Wallis test and ANOVA with ranks transformation were used to compare health-related quality of
life in relation to the classification of risk for cardiovascular events and intensity of dyspnea, respectively.
Results: The MINICHAL was able to discriminate health-related quality of life in relation to symptoms and kidney damage,
but did not discriminate health-related quality of life in relation to the classification of risk for cardiovascular events.
Conclusion: The Brazilian version of the MINICHAL is a questionnaire capable of discriminating differences on the
health‑related quality of life regarding dyspnea, chest pain, palpitation, lipothymy, cephalea and renal damage. (Arq Bras
Cardiol. 2015; 104(4):299-307)
Keywords: Hypertension; Quality of Life; Validation Studies; Clinical Trial; Psychometry; Questionnaires.
Introduction
Arterial hypertension (AH) is a highly prevalent disease
worldwide. It is a major condition for an increased risk
of cardiovascular morbidity and mortality 1-3. Studies 4,5
have demonstrated that hypertensive patients with target
organ damage (TOD) have a worse prognosis than patients
with non‑complicated AH, because of the high risk for
cardiovascular events among those with vascular damage6,7.
Although common, high-risk AH is underdiagnosed or
undertreated, and this has prompted the foreign guidelines
to recommend that its management be based on the
assessment of blood pressure levels and of the overall
cardiovascular risk6-9.
Early detection of hypertensive damage enables the
introduction of drug therapy, thus contributing for the
Mailing address: Thaís Moreira São-João •
Faculdade de Enfermagem – Unicamp
Rua Tessália Vieira de Camargo, 126, Cidade Universitária “Zeferino Vaz”.
Postal Code 13.083-887, Campinas, SP – Brazil.
E-mail: [email protected]
Manuscript received May 27, 2014; revised manuscript October 13, 2014;
accepted November 05, 2014.
DOI: 10.5935/abc.20150009
299
reduction of AH-related cardiovascular events and for
a better prognosis10, as well as for the improvement of
health‑related quality of life (HRQoL).
An adequate measurement of HRQoL is a challenge for
health professionals, researchers and health policy makers11,
and this has encouraged the construction and validation
of HRQoL measurement instruments. Among the types of
validity, that of known groups, which tests the difference
of characteristics measured among two or more groups
of subjects12, is of great interest in the clinical practice
because it permits the verification of the instrument’s ability
to discriminate groups with distinct characteristics such as
different levels of severity of disease.
In the care of hypertensive patients, it is important for
health professionals to have tools to enable them to assess
the impact on HRQoL13 according to the severity of AH and
the risk for cardiovascular events; this should contribute for
the design of specific interventions14.
Among the instruments created to assess HRQoL, we
point out the Mini-Cuestionario de Calidade de Vida em la
Hipertensión Arterial (MINICHAL)15-18, recently adapted for
Brazil19. The Brazilian version showed evidences of reliability
and validity19-21, and proved to be able to discriminate
normotensive from hypertensive individuals19.
Soutello et al.
Performance of MINICHAL on Arterial Hypertension
Original Article
Since the severity of AH can be assessed according to
different clinical criteria, the objective of this study was to
estimate the validity of known groups of the Brazilian version of
MINICHAL among hypertensive individuals, in relation to the
classification or risk for cardiovascular events, the occurrence
of TOD, the presence of symptoms and severity of dyspnea.
Methods
Research centers
This research was carried out in an AH outpatient service of
a university hospital and in a Basic Health Unit (UBS – Unidade
Básica de Saúde), both located in the State of Sao Paulo.
Subjects
A total of 200 hypertensive patients with ages 18 years
and above, and being followed up on an outpatient basis for
at least 6 months were enrolled in this study. Patients with
secondary AH, comorbidities of great impact on HRQoL
(such as neoplasia and dialytic kidney failure), chronic lung
diseases not related to AH (to exclude patients with dyspnea
not related to AH), and those unable to comprehend and
communicate verbally.
Sampling process
The sample size was calculated based on the difference
between the means of MINICHAL domains observed in a pilot
study (n = 27). Considering alpha of 0.05 and a test power
of 80% (beta of 0.20), a total of 200 subjects was estimated.
In order to achieve the minimum estimated sample size,
patients who met the inclusion criteria and did not meet any
of the exclusion criteria were enrolled sequentially until the
established n was reached.
Data collection
Data were collected by the principal investigator in the
research centers previously mentioned, from May to December
2009, after the participants had given written informed consent
(WIC). The method of available data recording was used
to obtain sociodemographic data from the medical records
(gender, skin color, age and marital status). To determine the
overall cardiovascular risk according to international guidelines7,
the following clinical variables were obtained: family history of
early cardiovascular disease (in women with less than 65 years of
age and men with less than 55); history of previous and current
cigarette smoking; dyslipidemias; diabetes mellitus (DM) and/
or glucose intolerance (plasma glucose levels between 102
and 125 mg/dL); hyperuricemia (uric acid > 7 mg/dL for men
and > 6.5 mg/dL for women); obesity (body mass index – BMI
> 30 kg/m2); and abdominal obesity (waist circunference – WC
> 102 cm for men and > 88 cm for women7).
Definition of target organ damage
In the present study, TOD was considered as kidney
function abnormalities (microalbuminuria, decreased
creatinine clearance and increased serum creatinine), cardiac
abnormalities (echocardiographic evidence of left ventricular
hypertrophy – LVH, and diastolic dysfunction), vascular
diseases, and hypertensive retinopathy. LVH was defined
by the ratio left ventricular mass / body surface ≥ 125 g/m2
for men and ≥ 110 g/m2 for women22. Diagnosis of diastolic
dysfunction was retrieved from Doppler echocardiography
reports. The presence of at least one atherosclerotic plaque
(defined as focal thickening > 1.3 mm in any segment of the
carotid arteries23 and/or presence of diffuse wall thickening,
with mean common carotid artery thickness > 0.9 mm)
was considered evidence of vascular abnormalities 7 .
Hypertensive retinopathy was diagnosed by the presence
of the following abnormalities on fundoscopy, as performed
by an ophthalmologist: arteriolar narrowing and light reflex
changes (grade 1); arteriolar narrowing, more marked
reflex changes and arteriovenous nicking (grade 2); grade 2
abnormalities, retinal hemorrhage and exudates (grade 3); or
grade 3 abnormalities and papilledema (grade 4), according
to the Keith-Wagener-Barker classification24.
After data collection from the medical records, the
patients were submitted to interview for collection of
sociodemographic data (years of schooling, employment
status, and monthly personal and family income) and clinical
data, such as the presence of symptoms (dyspnea, chest pain,
fatigue, headache, palpitations, and presyncope), measured
as dichotomous variables (yes/no). The purpose of interview
was also to obtain information regarding HRQoL by means
of the administration of the Brazilian version of MINICHAL.
For hypertensive patients reporting dyspnea, severity of
symptom was assessed by means of the Brazilian version of
the instrument Medical Research Council (MRC)25.
Instruments
MINICHAL consists of the short version18 of Calidad de
Vida em la Hipertensión Arterial (CHAL), developed and
validated in Spain14-16. This is a self-administered instrument
comprised of 16 items divided into the Mental Status (1 to
10) and Somatic Manifestations (11 to 16) dimensions, in
addition to one general question on quality of life, which
is not included in any of the dimensions. The items address
the past 7 days, by means of a Likert scale with the following
four possible answers: zero (absolutely not); 1 (yes, a little);
2 (yes, enough); and 3 (yes, a lot). The total score is obtained
by the sum of the items, and ranges from zero to 30 for the
Mental Status dimension, and from zero to 18 for the Somatic
Manifestations dimension; the closer to zero, the better the
quality of health. The question on general perception of health
is scored with the same possible answers, but is not considered
in the total score sum.
In the present study, the Brazilian version of MINICHAL
was used. However, for the total score sum, the composition
of dimensions of the original instrument18 was considered,
since in the validation study for the Brazilian context19, item 10
was excluded from the Mental Status dimension and included
in the Somatic Manifestations dimension, and the question
regarding the overall perception of health was included as the
17th question. The total score was calculated when the number
of missing questions did not exceed 25% of the total items
administered, i.e., when the number of valid items was equal
Arq Bras Cardiol. 2015; 104(4):299-307
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Soutello et al.
Performance of MINICHAL on Arterial Hypertension
Original Article
to 8 and 5 in the Mental Status and Somatic Manifestations
dimensions, respectively21. The question on general perception
of health was not considered in the total score sum, like in
the validation study18. Although the instrument had been
originally developed to be self-administered, given the low level
of education of participants, it was decided that it would be
administered by means of an interview. MINICHAL reliability
was evaluated as for its internal consistency by means of the
calculation of Cronbach’s alpha (α) coefficient. α values of 0.85,
0.84 and 0.59 were verified for the total score sum, Mental Status
dimension, and Somatic Manifestations dimension, respectively.
MRC is an instrument developed and validated in England
to measure the severity of dyspnea in patients with obstructive
pulmonary diseases 26, and comprises five items, with
answer scores ranging from 1 to 5. Grade 1 corresponds to
breathlessness on strenuous exercise; grade 2, to breathlessness
hurrying on the level or up a slight hill; grade 3, when walking
slower than people of the same age because of breathlessness or
having to stop for breath even when walking at their own pace;
grade 4, when having to stop after walking less than 100 m or
after a few minutes; and grade 5, when breathlessness prevents
from leaving the house or when dressing. The version adapted
for the Brazilian context was used25.
hypertensive patients with different levels of dyspnea25, followed
by the Tukey’s test to locate differences. The Kruskal-Wallis test
was used to compare HRQoL scores among hypertensive patients
stratified according to their risk for cardiovascular events7, as
follows: low, if stage-1 AH, with no risk factor (RF); moderate,
if stage-1 AH, with one to two RF and stage-2 AH, with no RF
or with one to two RF; high, if stages 1 or 2 AH, with three or
more RF or TOD or DM; and very high, if stages 1 or 2 AH and
cardiovascular disease and stage-3 AH, with one to two RF and/or
with three or more RF or TOD or DM or cardiovascular disease.
Findings were considered significant when p value < 0.05.
Ethical aspects
The study was approved by the local Research Ethics
Committees (report 1083/2008), according to the Declaration
of Helsinki.
Results
Data analysis
The sample (n = 200) was mostly comprised of women
(58%);with a mean age of 57 (11.3) years; Caucasians (64.5%);
living with a partner (61.5%); economically active (59.0%);
with a mean schooltime of 6.0 (4.1) years; and mean personal
and family income of 1.6 (1.5) and 3.2 (2.1) minimum wages
per month, respectively (Table 1).
Data were entered into the Excel for Windows 2003
software and transported to the Statistical Analysis System (SAS)
for Windows version 9.02 software for descriptive analyses (of
frequency for categorical variables; mean, median, standard
deviation and variation for continuous variables) and comparison
(between means of psycosocial variables). Since the variable of
interest was non-normally distributed, non-parametric tests were
used. The Mann-Whitney test was used to compare the HRQoL
scores in relation to symptoms, and the Analysis of Variance
(ANOVA) with rank transformation, to compare HRQoL among
The group was characterized by a mean time of 12.6
(10.5) years of AH, with a mean of 3.1 (1.7) associated
clinical conditions and/or RF. Half the group showed more
than two associated symptoms; 42.5% had TOD, especially
LVH and mean use of 3.6 (2.4) medications/day. Half the
sample showed high and/or very high risk for the occurrence
of cardiovascular events (50.5%); 16.5% of the subjects
were considered with no risk for cardiovascular events,
since their blood pressure levels fit the optimal/normal/
borderline stage (Table 2).
Table 1 – Sociodemographic characteristics of the hypertensive individuals (n = 200) being followed up on an outpatient basis in a university
hospital and Basic Health Unit, Campinas, 2009, 2010
Sociodemographic variables
Age (years)
n
%
200
Female gender
116
58.0
Caucasian
129
64.5
Level of education (years)
Marital status with partner
123
61.5
Inactive
81
40.5
Active
76
38.0
Housewife
42
21.0
Mean (SD)
Median
Variation
57 (11.3)
57
21-82
6 (4.1)
4
0-16
Employment status (n = 198)
Income, MW*
Monthly Personal income
199
1.6 (1.5)
1.29
0.0-8.6
Monthly family income
197
3.2 (2.1)
2.58
0.0-12.9
*
301
MW in the period of data collection was R$465.00 (US$265.71). MW: minimum wage; SD: standard deviation.
Arq Bras Cardiol. 2015; 104(4):299-307
Soutello et al.
Performance of MINICHAL on Arterial Hypertension
Original Article
Table 2 – Clinical characteristics of the hypertensive patients (n = 200) being followed up on an outpatient basis in a university hospital and
Basic Health Unit, Campinas, 2009, 2010
Clinical variables
n
Mean (SD)
Median
Variation
12.6 (10.5)
10
1-53
3.1 (1.7)
3
0-7
Number of associated symptoms
2.1 (1.6)
2
0-6
Number of medications used
3.6 (2.4)
3
0-11
Time of arterial hypertension (years)
%
198
Associated risk factors/clinical conditions
Dyslipidemia
133
66.5
Abdominal obesity (WC*)
132
66.0
Family history of cardiovascular disease
117
58.5
Obesity (BMI†)
90
45.0
Metabolic syndrome
82
41.0
Glucose intolerance¶
55
27.5
Diabetes mellitus
32
16.2
Hyperuricemia§
31
15.5
Current cigarette smoking
21
10.5
Number of associated clinical conditions
Acute coronary syndrome and/or myocardial revascularization
26
13.0
Heart failure
12
6.0
Stroke/transient ischemia
10
5.0
Peripheral artery disease
6
3.0
LVH‡
85
42.5
Diastolic dysfunction
80
40.0
Target organ damage
21
10.5
Hypertensive retinopathy¶¶
21
10.5
Carotid thickening
6
3.0
Headache
94
47.0
Palpitations
71
35.5
Lipotimia
57
28.5
Dyspnea
57
28.5
Chest pain
54
27.0
Hypertensive renal damage
††
§§
Symptoms
Risk stratification for cardiovascular events‡‡
No risk
33
16.5
Low risk
29
14.5
Moderate risk
37
18.5
High risk
65
32.5
Very high risk
36
18.0
* WC > 102 cm for men and > 88 cm for women; BMI > 30 kg/m ; blood glucose between 102-125 mg/dL; § uric acid > 7 mg/dL for men and > 6.5 mg/dL for women;
LVH ≥ 125 g/m2 ffor men and ≥ 110 g/m2 for women; †† hypertensive renal damage: creatinine clearance ≤ 60 mL/minute and/or serum creatinine > 1.5 mg/dL for men
and > 1.4 mg/dL for women and/or microalbuminuria > 300 mg/24 hours; ¶¶ hypertensive retinopathy: arteriolar narrowing and light reflex changes (grade 1); arteriolar
narrowing and more marked reflex changes and arteriovenous nicking (grade 2); grade 2 changes, retinal hemorrhages and exudates (grade 3); or grade 3 changes
and papilledema (grade 4) on fundoscopy; §§ intima-media > 0.9 mm; ‡‡ according to the European Society of Hypertension/European Society of Cardiology Guidelines7.
SD: standard deviation; WC: waist circumference; BMI: body mass index; LVH: left ventricular hypertrophy.
†
2 ¶
‡
Arq Bras Cardiol. 2015; 104(4):299-307
302
Soutello et al.
Performance of MINICHAL on Arterial Hypertension
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Construct validity: assessment of known groups
The construct validity of the Brazilian version of MINICHAL
was verified by means of the assessment of known groups.
It has been hypothesized that hypertensive patients with
symptoms (dyspnea, chest pain, presyncope, palpitations
and headache), TOD and high risk for cardiovascular
events would have a significantly higher HRQoL score than
hypertensive patients with no complications, i.e., with no
symptoms, no TOD, and at a low risk for cardiovascular
events, according to international guidelines.
Significantly higher HRQoL scores were observed among
those with renal damage in comparison to hypertensive
patients with preserved renal function, as regards the
Somatic Manifestations dimension and total MINICHAL
score. However, no significant difference was observed in
the comparison of HRQoL scores between patients with or
without LVH, as well as between those with and without
diastolic dysfunction and/or hypertensive retinopathy (Table 3).
We verified that hypertensive patients reporting symptoms
showed significantly higher scores (worse HRQoL) in both
dimensions and total score of the Brazilian version of
MINICHAL when compared to those without symptoms.
In addition, the Brazilian version of MINICHAL was proven
to be able to discriminate HRQoL among hypertensive patients
without and with different levels of dyspnea (Table 4).
However, no dimension of the Brazilian version of
MINICHAL was able to discriminate HRQoL between patients
classified as without and/or at a low/moderate risk and those
at a high/very high risk for cardiovascular events (Table 5).
Discussion
The objective of this study was to broaden the assessment
of the validity of known groups of the Brazilian version of
MINICHAL. Thus, the ability of this instrument to discriminate
hypertensive patients in relation to the severity of AH was
investigated, according to criteria for the classification of risk for
cardiovascular events and the occurrence of TOD, as well as in
relation to the presence of symptoms and severity of dyspnea.
Our findings showed that the Brazilian version of
MINICHAL was not able to discriminate hypertensive
patients according to the criteria used for the classification
of severity of AH. No significant difference was observed
in HRQoL measurement in the different stages of risk for
cardiovascular events, or among patients with and without
TOD, except for renal dysfunction.
However, the instrument was sensitive to show differences
in HRQoL according to the presence of all the symptoms
analyzed. In this regard, our findings are important and point
to a significant perspective to be considered in the follow-up
of hypertensive patients. Classically, AH is described as an
asymptomatic condition. Nonetheless, in clinical practice,
AH is associated with the presence of cardiovascular
symptoms, probably because of the presence of other
comorbidities14. In the present study, 50% of patients had
more than two associated symptoms, and this corroborates
the importance of the assessment of cardiovascular symptoms
throughout the clinical follow-up of hypertensive patients.
303
Arq Bras Cardiol. 2015; 104(4):299-307
In the validation study of the original version of MINICHAL
in the Spanish population18, significant differences were
observed in the Somatic Manifestations score among
hypertensive patients classified according to the stages of
severity of AH proposed by the World Health Organization
(stage I, with no signs of TOD; stage II, with one sign or
symptom of TOD; or stage III, ≥ 1 sign and symptom of
TOD)27. However, it is important to emphasize that the HRQoL
measurement was different only regarding the comparison
between stage-I patients (no signs of TOD and probably with
no symptoms) and those of clustered stages II and III, in which
the presence of symptoms was expected.
In a previous study assessing HRQoL of hypertensive
patients using a generic instrument, correlation between
echocardiographic changes resulting from AH and HRQoL
was verified only for the group presenting with dyspnea.
For the group without this symptom, there was no
correlation between variables. Thus, the findings point to
dyspnea as an important moderator in the relation between
HRQoL and one of the indicators of severity of disease,
because of the echocardiographic abnormalities14.
Another Brazilian study28 used the Medical Outcomes
Study 36 – Item Short – Form Health Survey (SF-36) to
evaluate HRQoL of 100 hypertensive patients participating in
an interdisciplinary experimental study based on educational
activities. No changes in the quality of life were detected among
the intervention and control groups, and this was attributed to
the characteristic of systemic AH of being asymptomatic.
It is possible that the relatively small case series of the
present study has contributed to the absence of significant
findings as regards the ability of the Brazilian version of
MINICHAL to discriminate different stages of severity of
AH. However, the low variability of scores in the different
stages weakens this hypothesis. It is hypothesized that the
severity of AH, when assessed according to the presence
or absence of cardiovascular symptoms, is an indicator
of changes in HRQoL. This assumption corroborates the
importance of the assessment of symptoms throughout
the follow-up of hypertensive patients so that the
pharmacological and non-pharmacological approaches be
adjusted also as a function of HRQoL, which is affected
by the manifestation of symptoms.
In the present study, the fact that the Brazilian version
of MINICHAL was not able to discriminate HRQoL
between hypertensive patients with and without LVH may
be explained by the inclusion of hypertensive patients
with structural cardiac changes, whether symptomatic or
asymptomatic. In the Spanish study18, the hypertensive
patients were grouped according to the presence of signs
and symptoms of TOD, which may have contributed to
the discrimination of HRQoL, since MINICHAL seems
to be sensitive in the detection of differences in HRQoL
in the presence of symptoms. The Brazilian version of
MINICHAL was also not able to discriminate HRQoL among
patients allocated at the extremes of the classification of
risk for cardiovascular events, which considers AH stages,
coexistence of RF, cardiovascular disease, and TOD.
The small number of patients distributed in the different strata
of the classification may have contributed to this finding.
Soutello et al.
Performance of MINICHAL on Arterial Hypertension
Original Article
Table 3 – Scores of the Brazilian version of MINICHAL, according to clinical variables of hypertensive patients followed up on an outpatient
basis (n = 200), Campinas, 2009, 2010
Domains of the Brazilian version of MINICHAL
LVH
†
Mental Status
Somatic Manifestations
Total score
n
Mean (SD)
Mean (SD)
Mean (SD)
Yes
85
6.3 (5.3)
3.3 (2.6)
9.6 (6.8)
No
115
7.0 (5.5)
3.5 (2.7)
10.5 (7.2)
NS
NS
NS
P value*
Hypertensive retinopathy ¶
Yes
21
6.2 (4.3)
3.9 (3.1)
10.1 (6.9)
No
179
6.8 (5.6)
3.4 (2.6)
10.1 (7.0)
NS
NS
NS
Yes
21
7.7 (4.5)
4.8 (3.2)
12.5 (5.9)
No
179
6.6 (5.5)
3.3 (2.5)
9.9 (7.1)
NS
< 0.05
< 0.05
P value
*
Renal damage§
P value*
Diastolic function‡
Yes
80
6.7 (5.9)
3.4 (2.7)
10.1 (7.5)
No
83
6.9 (4.7)
3.7 (2.6)
10.7 (6.2)
NS
NS
NS
Yes
57
8.9(6.9)
4.9 (2.9)
13.9 (8.6)
No
143
5.8 (4.5)
2.8 (2.3)
8.7 (5.7)
< 0.01
< 0.001
< 0.001
P value
*
Dyspnea
P value*
Chest pain
Yes
54
9.2 (6.7)
5.3 (3.0 )
14.5 (7.9)
No
146
5.8 (4.6)
2.7 (2.1)
8.5(5.9)
< 0.001
< 0.001
< 0.001
Yes
57
8.0 (5.9)
4.0 (2.5)
12 (7.3)
No
143
6.2 (5.2)
3.2 (2.7)
9.4 (6.8)
< 0.05
< 0.05
< 0.05
P value
*
Presyncope
P value*
Palpitations
Yes
71
9.0 (6.6)
4.9 (3.0)
13.9 (8.1)
No
129
5.4 (4.2)
2.6 (2.0)
8.1 (5.4)
< 0.001
< 0.001
< 0.001
Yes
94
8.2 (5.7)
4.0 (2.7)
12.2 (7.2)
No
106
5.4 (4.9)
2.9 (2.5)
8.3 (6.4)
< 0.001
< 0.01
< 0.001
P value
Headache
*
P value*
* Mann-Whitney test; left ventricular hypertrophy: ventricular mass/body surface ≥ 125 g/m for men and ≥ 110 g/m for women; hypertensive retinopathy: presence
of arteriolar narrowing and venous dilatation (type 1); arteries with spasms and pathological arteriovenous nicking (type 2); obvious arterial narrowing and irregularities,
flame-shaped hemorrhage or cotton-wool spots (type 3); or papilledema associated with types 1, 2 and 3 (type 4) on fundoscopy; § renal damage: creatinine clearance
≤ 60mL/minute or serum creatinine > 1.5 mg/dL for men and > 1.4 mg/dL for women or microalbuminúria > 300 mg/24 hours; ‡ diastolic dysfunction: retrieved from
Doppler echocardiogram report. SD: standard deviation; NS: not significant; LVH: left ventricular hypertrophy.
†
Conclusion
The findings of this study permit the conclusion that the
Brazilian version of MINICHAL is an instrument able to
discriminate differences in the health-related quality of life in
relation to the symptoms of dyspnea, chest pain, palpitations,
presyncope and headache, as well as to the presence
of renal damage (target organ damage). However, the
Brazilian version of MINICHAL was not able to discriminate
health-related quality of life among hypertensive patients
allocated at the extremes of the classification of risk for
2
2
¶
cardiovascular events. Further studies with larger sample sizes
are recommended to elucidate the ability of the Brazilian
version of MINICHAL to discriminate health-related quality
of life in hypertensive patients with different degrees of
severity of the disease.
Financial disclosure: This studied was financed by the
National Council of Scientific and Technological Development
(Conselho Nacional de Desenvolvimento Científico e
Tecnológico – CNPq), by means of a research grant (PQ) 2010
– 2012, process 308824/2009-1.
Arq Bras Cardiol. 2015; 104(4):299-307
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Performance of MINICHAL on Arterial Hypertension
Original Article
Table 4 – Scores of the Brazilian version of MINICHAL, according to the severity of dyspnea in outpatient hypertensive patients (n = 200),
Campinas, 2009, 2010
Domains of the Brazilian version of MINICHAL
Mental Status
Somatic manifestations
Total score
n
Mean (SD)
p value*
Mean (SD)
p value
Mean (SD)
p value
145
5.8 (4.6)
< 0.01†
2.8 (2.3)
< 0.001¶
8.7 (5.8)
< 0.001§
Grade 1 – breathlessness on strenuous exercise
9
8.3 (10.0)
2.9 (2.5)
11.2 (12.3)
Grade 2 – breathlessness hurrying on the level
or up a light hill
18
7.9 (5.7)
4.5 (2.8)
12.4 (7.0)
Grade 3 – Walks slower than people of the same
age because of breathlessness or has to stop for
breath even when walking at his/her own pace
6
10.0 (5.3)
6.7 (3.0)
16.7 (7.4)
Grade 4 – Has to stop for breath after walkin less
than 100 m or after a few minutes
12
9.9 (7.3)
5.7 (3.0)
15.6 (9.4)
Grade 5 – Breathlessness prevents from leaving
the house or when dressing
10
10.3 (5.7)
6.0 (2.7)
16.3 (15.2)
Grade 0 – no dyspnea
* ANOVA with rank transformation, followed by Tukey test: † degree 0 ≠ degree 5; ¶ degrees 3, 4, 5 ≠ 0; § degrees 4, 5 ≠ 0.
Table 5 – Scores of the Brazilian version of MINICHAL, according to the risk for cardiovascular events of hypertensive patients followed up on
an outpatient basis (n = 200), Campinas, 2009, 2010
Domains of the Brazilian version of MINICHAL
Mental Status
Somatic manifestations
Total score
n
Mean (SD)
p value*
Mean (SD)
p value
Mean (SD)
p value
No additional risk
33
7.3 (6.8)
NS
3.4 (2.5)
NS
10.7 (8.5)
NS
Low risk
29
6.1 (5.0)
Cardiovascular risk stratification
†
2.9 (2.5)
9.0 (6.6)
Moderate risk
37
7.1 (6.0)
3.3 (2.1)
10.4 (7.5)
High risk
65
6.8 (5.1)
3.6 (2.8)
10.3 (6.6)
Very high risk
36
6.1 (4.5)
3.9 (3.0)
10.0 (6.4)
No/ low and/ or moderate risk
99
6.9 (6.0)
High/ very high risk
101
6.5 (4.9)
Cardiovascular risk stratification¶
NS
3.2 (2.4)
NS
3.7 (2.9)
10.1 (7.6)
NS
10.2 (6.5)
*
Kruskal-Wallis test; † European Society of Hypertension/European Society of Cardiology Guidelines7; ¶ Clustered cardiovascular risk stratification. SD: standard
deviation; NS: not significant.
Author contributions
Conception and design of the research:Soutello AL,
Rodrigues R, Gallani MCBJ. Acquisition of data: Soutello
AL, Jannuzzi FF, Martini GG, Nadruz Jr. W. Analysis and
interpretation of the data: Soutello AL, Rodrigues R, SãoJoão TM, Gallani MCBJ. Statistical analysis: Soutello AL,
Rodrigues R, São-João TM. Obtaining financing:Soutello
AL, Rodrigues R, São-João TM. Writing of the manuscript:
Soutello AL, Rodrigues R, Nadruz Jr. W. Critical revision
of the manuscript for intellectual content: Soutello AL,
Rodrigues R, Jannuzzi FF, São-João TM, Martini GG,
Nadruz Jr. W, Gallani MCBJ.
305
Arq Bras Cardiol. 2015; 104(4):299-307
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Study Association
This article is part of the dissertation of master submitted by Ana
Lúcia Soares Soutello, from Universidade Estadual de Campinas.
Sources of Funding
This study was funded by CNPq (process: 308824/2009-1)
e FAEPEX - Unicamp (165/09).
Soutello et al.
Performance of MINICHAL on Arterial Hypertension
Original Article
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Back to the Cover
Original Article
Influence of Spironolactone on Matrix Metalloproteinase-2 in Acute
Decompensated Heart Failure
João Pedro Ferreira1, Mário Santos1, José Carlos Oliveira1, Irene Marques1, Paulo Bettencourt2, Henrique Carvalho1
Centro Hospitalar do Porto1; Centro Hospitalar São João2, Porto – Portugal
Abstract
Background: Matrix metalloproteinases (MMPs) are a family of enzymes important for the resorption of extracellular
matrices, control of vascular remodeling and repair. Increased activity of MMP2 has been demonstrated in heart failure,
and in acutely decompensated heart failure (ADHF) a decrease in circulating MMPs has been demonstrated along with
successful treatment.
Objective: Our aim was to test the influence of spironolactone in MMP2 levels.
Methods: Secondary analysis of a prospective, interventional study including 100 patients with ADHF. Fifty patients were
non-randomly assigned to spironolactone (100 mg/day) plus standard ADHF therapy (spironolactone group) or standard
ADHF therapy alone (control group).
Results: Spironolactone group patients were younger and had lower creatinine and urea levels (all p < 0.05). Baseline
MMP2, NT-pro BNP and weight did not differ between spironolactone and control groups. A trend towards a more
pronounced decrease in MMP2 from baseline to day 3 was observed in the spironolactone group (-21 [-50 to 19] vs
1.5 [-26 to 38] ng/mL, p = 0.06). NT-pro BNP and weight also had a greater decrease in the spironolactone group.
The proportion of patients with a decrease in MMP2 levels from baseline to day 3 was also likely to be greater in the
spironolactone group (50% vs 66.7%), but without statistical significance. Correlations between MMP2, NT-pro BNP and
weight variation were not statistically significant.
Conclusion: MMP2 levels are increased in ADHF. Patients treated with spironolactone may have a greater reduction in
MMP2 levels. (Arq Bras Cardiol. 2015; 104(4):308-314)
Keywords: Heart Failure; Spironolactona/therapeutic use; Matrix Metalloproteinase 2/ therapeutic use.
Introduction
Matrix metalloproteinases (MMPs) are a family of zincdependent interstitial enzymes important for the resorption
of extracellular matrices (ECM) in both health and disease1.
Extracellular matrices are a dynamic structure central to the
control of vascular remodeling and repair1, mostly due to the
ability of MMPs to reabsorb and digest excessive amounts of
ECM responsible for structural disruption2,3.
Elevated MMPs promote loss of cardiac contractility via cell
proteolysis and alterations in the ECM, contributing to cardiac
and extra-cardiac remodeling processes4. In fact, clinical and
experimental heart failure (HF) models of dilated and ischemic
cardiomyopathy have demonstrated an increased activity of
matrix metalloproteinase-2 (MMP2)2,5-7. In patients with HF,
increased levels of MMP2 were associated with all-cause
mortality8. Concordantly, in the acutely decompensated heart
Mailing Address: João Pedro Ferreira •
Rua Dr. José Oliveira e Silva, nº 52, Salreu-Estarreja. Postal Code 3865-209,
Porto – Portugal
Email: [email protected]
Manuscript received June 26, 2014; revised manuscript September 27,
2014; accepted September 30, 2014.
DOI: 10.5935/abc.20140205
308
failure (ADHF) setting a decrease of circulating MMPs has
been demonstrated along with successful ADHF treatment3,9.
Previous studies have suggested a therapeutic benefit of
spironolactone in ADHF setting10. But no studies had looked
to the effect of spironolactone in the ECM remodeling.
In the present study, we aimed to examine the influence
of spironolactone on the ECM remodeling in ADHF patients.
We hypothesized that MMP-2 plasma levels of ADHF patients
will have a steeper decrease if spironolactone is added to
standard treatment.
Methods
Study Design
We analyzed data from a previous pilot, prospective,
interventional, clinical trial that we performed between February
2012 and February 2013. During that period, we enrolled 100
consecutive patients who presented at a Portuguese tertiary
hospital with ADHF. Patients were eligible for enrollment if they
had decompensation of chronic HF with symptoms leading
to hospitalization. ADHF was diagnosed based on a history
of chronic HF and at least one acute symptom (dyspnea,
orthopnea, or edema) and one sign (rales, peripheral edema,
ascites, or pulmonary vascular congestion on chest radiography).
Ferreira et al.
Spironolactone and Matrix Metalloproteinases
Original Article
Patients were non-randomly assigned in a sequential 1:1 ratio to
spironolactone plus standard ADHF therapy or standard ADHF
therapy alone, 50 patients in each arm. Patients were alternately
assigned to the spironolactone arm or the standard ADHF therapy
arm in a sequential manner - the first patient to one arm and
the next to the other arm. This sequence was repeated until we
reached 100 patients, 50 in the spironolactone group and 50
in the control group. Patients were blinded to the allocation,
but the clinicians were not. The recommended spironolactone
dose was 100 mg/day. However, the attending physician could
decrease that dose to 50 mg/day after 48h upon admission.
Furosemide dose and route of administration were clinically
adjusted according to the patients’ hydration status.
Exclusion criteria were: chronic use of mineralocorticoid
receptor antagonists; cardiac surgery within 60 days of enrollment;
cardiac mechanical support; cardiac resynchronization-therapy
within the last 60 days; comorbid conditions with an expected
survival of less than 6 months; acute myocardial infarction at
time of hospitalization; uncorrected hemodynamically significant
primary cardiac valvular disease; patients requiring intravenous
vasodilators or inotropic agents; supine systolic arterial blood
pressure < 90 mmHg; plasma creatinine level > 1.5 mg/dL;
serum potassium level > 5.0 mmol/L; hemoglobin level < 9 g/dL;
and sepsis.
Institutional review board or ethics committee approval was
obtained. All patients provided written informed consent to
participate in the study.
Clinical assessment of participants
Patients’ clinical status, including physical examination,
was prospectively recorded by the same attending physician
on day 1 and day 3. Medications and respective dosages were
prospectively recorded by the investigators according to the
attending physician prescriptions.
Blood samples were collected in the first 24 hours after
the patient’s admission (baseline) to the hospital, and
day-3 samples were collected between 72 and 96 hours
of hospitalization. Samples were analyzed at a central
core laboratory, and included plasma creatinine and urea,
electrolytes, NT-pro BNP and MMP2. Clinical assessment and
routine analyses were performed daily during hospital stay.
Estimated glomerular filtration rate (eGFR) was determined
using the Chronic Kidney Disease Epidemiology Collaboration
(CKD-EPI) equation11. All patients performed a transthoracic
echocardiography within 72 hours from admission.
Left ventricular ejection fraction (LVEF) was calculated
according to biplane Simpson method.
MMP2 was measured by using enzyme -linked
immunosorbent assays (ELISA) - Quantikine Elisa Human
MMP-2 Immunoassay (R&D Systems, Inc®). The normal range
of MMP2 values published by the manufacturer, expressed as
median [interquartile range25-75, IQR25-75], is 199 [161 – 301]
ng/mL. The assay sensitivity is 0.047 ng/mL.
Of the 100 studied patients we analyzed baseline (day 1)
and day 3 blood samples from 87. Thirteen samples were not
analyzed due to transport and/or sampling processing errors.
Samples were collected in the morning with patients supine.
Serum was separated and stored at -80 °C until sample analysis.
Variable definitions
We classified patients according to spironolactone use
and their response to diuretic therapy.
We studied the relationships between baseline
characteristics, day 3 and changes (Δ, difference between
day 3 and baseline values) in MMP2, NT-proBNP and weight
regarding the spironolactone use and diuretic response.
Statistical Analysis
Normally distributed continuous variables are expressed
as mean ± standard deviation (SD), and skewed distributions
are presented as median [IQR25-75].
Categorical variables are expressed in proportions (%).
Comparison between groups was performed using
parametric (independent samples t-test), non-parametric
(Mann-Whitney test), or Chi-square tests, as appropriate.
Correlations of MMP2 were examined by single variable
linear regression and presented as correlation coefficient and
95% confidence interval (95% CI).
A p value < 0.05 was considered statistically significant.
Statistical analysis was performed using SPSS software,
version 19 (Chicago, IL, USA).
Results
Baseline Characteristics in Control and Spironolactone
Groups
Control group patients were older (78.8 ± 9.3 versus [vs.]
73.2 ± 11.7 years, p = 0.01), and had higher creatinine
and urea levels (1.15 ± 0.27 vs. 1.03 ± 0.30 mg/dL,
p = 0.026 and 59.32 ± 22.27 vs. 51.10 ± 18.63 mg/dL,
p = 0.048). No differences between groups were found
regarding the following variables: sex; diabetes mellitus;
chronic obstructive pulmonary disease; dementia; sleep
apnea; non-invasive ventilation; ischemic heart disease;
atrial fibrillation; LVEF; weight; systolic blood pressure;
potassium; sodium; hemoglobin; albumin; NT-pro BNP;
MMP2; furosemide dose; hospital length of stay; and the
proportion of patients on angiotensin converting enzyme
inhibitors and beta-blockers (Table 1).
Spironolactone Influence on MMP2, NT-pro BNP and
Weight Dynamic Changes
No differences between control and spironolactone
groups were observed regarding baseline and day 3 MMP2
levels (Table 2). However, MMP2 decreased from baseline to
day 3 in the spironolactone group, while, in control group,
MMP2 levels increased, leading to a tendency towards a
reduction in MMP2 levels in the spironolactone group (1.5
[-26 to 38] vs. -21 [-50 to 19] ng/mL, p = 0.06) (Table 2 and
Figure 1). The proportion of patients showing a decrease in
MMP2 levels from baseline to day 3 was also greater in the
spironolactone group. That difference, however, did not
reach statistical significance: 21 control patients (50%) vs. 30
spironolactone group patients (66.7%), p = 0.115.
Arq Bras Cardiol. 2015; 104(4):308-314
309
Ferreira et al.
Spironolactone and Matrix Metalloproteinases
Original Article
Table 1 - Baseline population characteristics, laboratory results, medications, and hospital length of stay in treatment and control groups
Control Group
(n = 50)
Spironolactone Group
(n = 50)
p Value
78.8 ± 9.3
73.2 ± 11.7
0.010
Male Sex – %
34
44
0.31**
Diabetes Mellitus - %
50
40
0.31**
Chronic Obstructive Pulmonary Disease - %
10
26
0.32**
Dementia - %
16
8
0.22**
Sleep Apnea - %
10
26
0.32**
Non-Invasive Ventilation - %
14
20
0.42**
Ischemic Heart Disease -%
48
52
0.69**
Atrial Fibrillation - %
68
50
0.07**
Left Ventricular Ejection Fraction < 40% - %
56
68
0.22**
Weight (Kg)
75.6 ± 16.3
76.1 ± 16.4
0.89
Systolic Blood Pressure (mmHg)
140.5 ± 23.9
139 ± 27.9
0.80
Plasma Creatinine (mg/dL)
1.15 ± 0.27
1.03 ± 0.30
0.03
eGFR (mL/min/1,73 m2)
54.5 ± 16.5
68.3 ± 23.6
0.001
Plasma Urea (mg/dL)
59.3 ± 22.3
51.1 ± 18.6
0.05
4.1 ± 0.4
4.0 ± 0.6
0.33
Serum Sodium (mmol/L)
140.5 ± 5.0
140.6 ± 3.7
0.96
Hemoglobin (g/dL)
12.2 ± 1.8
12.7 ± 2.3
0.22
Age (yrs)
Serum Potassium (mmol/L)
Albumin (mg/dL)
NT-pro BNP (pg/mL)
MMP2 (ng/mL)
Intravenous Furosemide Dose (mg/d)
3.7 ± 0.4
3.6 ± 0.4
0.63
3102 [1797 – 8204]
2701 [1463 – 5004]
0.17*
260 [226 – 299]
268 [207 – 336]
0.52*
75.6 ± 20.7
76.0 ± 25.5
0.93
ACEi/ARB – %
38
50
0.20**
Beta-Blocker - %
42
32
0.30**
-
100
-
-
94.5 ± 23.3
-
9.0 ± 3.7
8.7 ± 3.0
0.59
Spironolactone - %
Spironolactone Dose (mg/d)
Hospital Length of Stay (days)
Continuous variables are presented as mean ± standard deviation [SD], p value or median [interquartile range, IQR], p value. Categorical variables are presented
as absolute number (%), p value.
*Non-parametric paired sample test; ** Chi-square test.
eGFR: estimated glomerular filtration rate; NT-pro BNP: N-terminal pro brain natriuretic peptide; MMP2: matrix metalloproteinase -2; ACEi/ARB: angiotensinconverting enzyme inhibitors/angiotensin receptor blockers.
No differences were observed in NT-pro BNP levels at
baseline. However, on day 3, the spironolactone group
patients showed lower levels of NT-pro BNP (248 [923 – 5502]
vs. 1555 [722 – 2554] pg/mL, p = 0.05). No differences
between groups were observed in the variation of NT-pro
BNP levels probably due to the lower levels (although
not significantly lower) of NT-pro BNP at baseline in the
spironolactone group, leading to a smaller amplitude of
variation in this group (Table 2).
A greater weight decrease was also observed in the
spironolactone-treated patients (-2.9 ± 2.4 vs. -4.8 ± 2.8 kg,
p < 0.001) (Table 2).
310
Arq Bras Cardiol. 2015; 104(4):308-314
Δ MMP2, Δ NT-pro BNP and Δ Weight Correlations
No significant correlations were observed between Δ in
MMP2, NT-pro BNP and weight (Table 3).
Discussion
In the present study we observed increased baseline
levels of MMP2 in patients with ADHF. The patients
treated with spironolactone showed a tendency towards
a greater reduction in MMP2 levels. These results are
consistent with previous findings demonstrating the
impact of mineralocorticoid receptor antagonists on the
ECM remodeling and highlight the potential interest about
Ferreira et al.
Spironolactone and Matrix Metalloproteinases
Original Article
Table 2 - Comparison of MMP2, NT-pro BNP and weight at baseline, day 3, and change (Delta, Δ) between the study groups
Control Group
Spironolactone Group
p Value
MMP2
Baseline
Day 3
Δ (day 3 – baseline)
260 [226 – 299]
266 [227 – 298]
1.5 [-26 to 38]
268 [207 – 336]
261 [212 – 307]
-21 [-50 to 19]
0.52*
0.49*
0.06*
NT-pro BNP
Baseline
Day 3
Δ (day 3 – baseline)
3102 [1792 – 8204]
2488 [923 – 5502]
-945 [-2249 to -62]
2701 [1463 – 5004]
1555 [722 – 2554]
-816 [-1833 to -106]
0.17*
0.05*
0.75*
Weight
Baseline
Day 3
Δ (day 3 – baseline)
75.6 ± 16.3
72.8 ± 16.3
-2.9 ± 2.4
76.1 ± 16.4
71.3 ± 16.2
-4.8 ± 2.8
0.89
0.66
< 0.001
Continuous variables are presented as mean ± standard deviation [SD], p value or median [interquartile range, IQR], p value, and independent sample t-test or
independent sample non-parametric test were used, respectively.
*non-parametric test.
NT-pro BNP: N-terminal pro brain natriuretic peptide; MMP2: matrix metalloproteinase -2; Δ: delta or difference between day 3 and baseline values.
200.00
MMP2 Change from Baseline to Day 3
83
19
17
100.00
.00
66
p = 0.06
-100.00
44
93
-200.00
No Spíronolactone
Spironolactone
Figure 1 - Comparison of Δ MMP2 Levels from baseline to day 3 between control and spironolactone groups.
A trend towards a more pronounced reduction in MMP2 levels was observed in spironolactone group.
Analysis was performed comparing the variation (Δ, day 3 - baseline) of MMP2 levels between control and spironolactone groups using non-parametric independent
sample tests (1.5 [-26 to 38] versus -21 [-50 to 19], p = 0.06).
Legend: MMP2 = matrix metalloproteinase-2.
Table 3 - Correlation coefficients and 95% confidence intervals (CI) between delta (Δ) MMP2, Δ NT-pro BNP, and Δ weight
Δ MMP2 Correlation Coefficient
95%CI
p Value
Δ NT-pro BNP
0.11
-0.003 to 0.01
0.33
Δ Weight
0.12
-1.97 to 7.05
0.27
MMP2: matrix metalloproteinase-2; NT-pro BNP: N-terminal pro-brain natriuretic peptide; Δ: delta or difference between day 3 and baseline values.
Arq Bras Cardiol. 2015; 104(4):308-314
311
Ferreira et al.
Spironolactone and Matrix Metalloproteinases
Original Article
spironolactone for the treatment of ADHF, where those
mechanisms are strongly exacerbated.
Increased serum levels of MMP2 have been demonstrated
in the ADHF setting3,9. In our study, the median [IQR] MMP2
levels at admission were 260 [225 - 312] ng/mL. These values
are above the normal range defined by the manufacturer,
199 [161 – 301] ng/mL, and are in accordance with previous
reports on patients with HF decompensation. A previous
study by Shirakabe A. et al3 has also shown increased serum
MMP2 levels in ADHF, with a rapid decrease along with
HF compensation. Furthermore, an interventional placebocontrolled trial performed by Tziakas DN. et al9 has shown a
significant reduction in MMP2 levels in the group of patients
treated with levosimendan. In animal models, exacerbated
neurohormonal activation leads to an increase in the levels of
several myocardial MMP subtypes12-14. MMPs are important for
the proteolysis that can affect the composition of ECM and,
consequently, myocardial remodeling. Additionally, increased
ECM turnover may be associated with pathological myocardial
remodeling, which may be accelerated in decompensated
HF 3,15. Consequently, a reduction in markers of ECM
turnover may serve as a surrogate marker for deceleration of
myocardial turnover and remodeling. Our study showed a
greater decrease of MMP2 in the group of patients submitted
to spironolactone treatment. Mineralocorticoid receptor
antagonists improve survival and reduce morbidity in patients
with HF and reduced ejection fraction and mild-to-severe
symptoms, and in patients with left ventricular systolic
dysfunction and HF after acute myocardial infarction16-18.
Additionally, used in natriuretic doses, mineralocorticoid
receptor antagonists are likely to improve congestion in
ADHF with good tolerability and few side effects19. Several
proposed mechanisms explain how mineralocorticoid receptor
antagonists improve HF outcomes, and these pathways include
a reduction in myocardial remodeling20. Our study provides
important information on a better understanding of ECM
turnover processes. The steeper MMP2 reduction observed in
patients submitted to spironolactone treatment provides a real
demonstration of potential mitigation of harmful remodeling
through spironolactone use. Interestingly, patients without
MMP2 reduction or increase, after an acute HF episode, had
poorer prognosis3. Therefore, changes in MMP2 levels are
a potentially useful prognostic marker in patients admitted
due to ADHF.
NT-pro BNP is a well-validated, widely used, and very
accurate biomarker for the diagnosis and risk stratification
of HF21. Patients submitted to spironolactone treatment had
lower levels of NT-pro BNP on day 3, and a more pronounced
weight reduction when compared to controls, while patients
with slower diuretic response had higher NT-pro BNP levels
on day 3 of hospitalization, a tendency towards lower NT-pro
BNP reduction, and less weight loss. However, the changes in
MMP2 values did not correlate with the variation in NT-pro BNP
or weight. The small sample size, the NT-pro BNP and MMP2
elevated variance, and the different mechanisms influencing
those biomarkers may all explain the lack of correlation.
312
Arq Bras Cardiol. 2015; 104(4):308-314
Several limitations in our study should be noted. First,
this was a single-centre, non-randomized trial with a
small number of patients with mixed HF etiologies and
treatments. Second, this post-hoc analysis has limitations
inherent to observational studies. Third, the decision
to withdraw diuretic therapy was based on subjective
assessment of congestive signs and symptoms, so we
cannot rule out the inter-observer variability. However, in
real life, the decision to step down diuretic therapy is also
based on subjective clinical evaluation. Fourth, our study
excluded HF patients with significant renal impairment,
since plasma creatinine level lower than 1.5 mg/dL was
an inclusion criterion, leading to a potential selection of a
subset of low-risk patients, which can affect the external
validity of our results. Fifth, the spironolactone group
patients were younger and had lower plasma creatinine
and urea levels, which can positively affect the response
to that drug. Finally, only MMP2 was evaluated, and other
forms of MMPs may have different effects and responses
in ADHF patients.
Conclusion
The present study showed that MMP2 levels can
be increased in ADHF, and that patients treated with
spironolactone may have a greater reduction in MMP2 levels.
Whether these findings have prognostic significance requires
further investigation.
Acknowledgements
The authors acknowledge the lab technicians, especially Mr.
Fernando Santos, for technical assistance, and all physicians
collaborating in the study.
Author contributions
Conception and design of the research, Acquisition of
data, Statistical analysis and Writing of the manuscript:
Ferreira JP; Analysis and interpretation of the data: Ferreira
JP, Santos M, Oliveira JC, Bettencourt P; Obtaining financing:
Carvalho H; Critical revision of the manuscript for intellectual
content: Ferreira JP, Santos M, Marques I, Bettencourt P,
Carvalho H.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Sources of Funding
This study was partially funded by Johnson & Johnson.
Study Association
This article is part of the thesis of Doctoral submitted by
João Pedro Ferreira, from Centro Hospitalar do Porto.
Ferreira et al.
Spironolactone and Matrix Metalloproteinases
Original Article
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Spironolactone and Matrix Metalloproteinases
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Back to the Cover
Original Article
Comparison between MDCT and Grayscale IVUS in a Quantitative
Analysis of Coronary Lumen in Segments with or without
Atherosclerotic Plaques
João L. A. A. Falcão1, Breno A. A. Falcão1, Swaminatha V. Gurudevan2, Carlos M. Campos1, Expedito R. Silva1,
Roberto Kalil-Filho1, Carlos E. Rochitte1, Afonso A. Shiozaki1, Otavio R. Coelho-Filho1, Pedro A. Lemos1
Heart Institute (InCor), University of São Paulo Medical School (USP)1, São Paulo, SP - Brazil; Cedars-Sinai Heart Institute2, Los Angeles,
California, USA –United States
Abstract
Background: The diagnostic accuracy of 64-slice MDCT in comparison with IVUS has been poorly described and is
mainly restricted to reports analyzing segments with documented atherosclerotic plaques.
Objectives: We compared 64-slice multidetector computed tomography (MDCT) with gray scale intravascular
ultrasound (IVUS) for the evaluation of coronary lumen dimensions in the context of a comprehensive analysis,
including segments with absent or mild disease.
Methods: The 64-slice MDCT was performed within 72 h before the IVUS imaging, which was obtained for at least
one coronary, regardless of the presence of luminal stenosis at angiography. A total of 21 patients were included,
with 70 imaged vessels (total length 114.6 ± 38.3 mm per patient). A coronary plaque was diagnosed in segments
with plaque burden > 40%.
Results: At patient, vessel, and segment levels, average lumen area, minimal lumen area, and minimal lumen diameter
were highly correlated between IVUS and 64-slice MDCT (p < 0.01). However, 64-slice MDCT tended to underestimate
the lumen size with a relatively wide dispersion of the differences. The comparison between 64-slice MDCT and IVUS
lumen measurements was not substantially affected by the presence or absence of an underlying plaque. In addition,
64-slice MDCT showed good global accuracy for the detection of IVUS parameters associated with flow-limiting lesions.
Conclusions: In a comprehensive, multi-territory, and whole-artery analysis, the assessment of coronary lumen by
64-slice MDCT compared with coronary IVUS showed a good overall diagnostic ability, regardless of the presence or
absence of underlying atherosclerotic plaques. (Arq Bras Cardiol. 2015; 104(4):315-323)
Keywords: Coronary Artery Disease, Plaque, Atherosclerotic / diagnosis; Multidetector Computed Tomography / utilization;
Ultrasonography / utilization.
Condensed Abstract
A total of 21 patients (70 vessels; total length
114.6 ± 38.3 mm per patient) underwent 64-slice MDCT
and IVUS imaging. At patient, vessel, and segment levels,
average lumen area, minimal lumen area, and minimal lumen
diameter were highly correlated between IVUS and 64-slice
MDCT. The comparison between 64-slice MDCT and IVUS
lumen measurements was not substantially affected by the
presence or absence of an underlying plaque (defined as
Mailing Address: Ricardo João Westphal •
Rua dos Escultores 200, City Boaçava. Postal Code 05469-010.
São Paulo, SP - Brazil.
E-mail: [email protected]; [email protected]
Manuscript received June 03, 2014; revised manuscript July 13, 2014;
accepted October 13, 2014.
DOI: 10.5935/abc.20140211
315
IVUS plaque burden > 40%). In addition, 64-slice MDCT
showed good global accuracy for the detection of IVUS
parameters associated with flow‑limiting lesions.
List of Abbreviations
EEL
External elastic lamina
HU
Hounsfield units
IVUS
Intravascular ultrasound
MDCT
Multidetector computed
ROC
Receiver operating characteristic
CTA
Computed tomography angiography
Introduction
Multidetector computed tomography (MDCT) is a reliable
noninvasive method for the detection of coronary luminal
stenosis. However, most validation studies have compared
Lemos et al.
MDCT versus IVUS for coronary lumen analysis
Original Article
MDCT with catheter-based angiography, a method that
is known to have limitations1,2. Intravascular ultrasound
(IVUS) is currently considered the gold standard for the in
vivo assessment of coronary luminal dimensions. Compared
with quantitative angiography, morphologic data from IVUS
imaging have shown a better correlation with coronary flow
measurements and noninvasive detection of ischemia3.
Moreover, IVUS is a valuable prognostic parameter for patients
deferred from coronary angioplasty4.
A number of studies have previously compared MDCT
with intravascular ultrasound, indicating a good conformity
between these two methods5,6. Recent meta-analysis data
showed that, compared with IVUS, coronary computed
tomography angiography (CTA) appears to be highly
accurate for the estimation of luminal area, percentage
of area stenosis, plaque volume, and plaque area and for
the detection of plaque7. However, most studies evaluated
specific regions of interest within the coronary tree,
restricting the analysis to segments with atherosclerotic
plaques by IVUS5,6,7. It is important to note that, in clinical
practice, MDCT images are commonly analyzed following
an all-segment scheme without the aid of a coronary map
to focus the assessment on specific regions of interest.
It is important to evaluate the diagnostic performance of
MDCT in a comprehensive manner, including both coronary
segments with atherosclerosis as well as portions without
significant disease. Therefore, the present study compared
64-slice MDCT with IVUS for the quantitative assessment
of coronary luminal dimensions following an inclusive,
whole-artery analytic strategy.
Methods
Overall Protocol Design and Study Population
The study included patients with known coronary artery
disease who were scheduled for elective coronary stent
implantation. Intravascular ultrasound examination was
performed at the time of the percutaneous procedure, before
any therapeutic intervention. At least one major epicardial
vessel without previous angioplasty or surgical treatment was
examined with IVUS, but operators were strongly encouraged
to acquire IVUS images from all three coronary territories.
MDCT was performed 72 h prior to the IVUS procedure as
part of the study protocol. The study protocol was approved
by the local ethics committee, and written informed consent
was obtained from each patient.
Ivus Imaging and Analysis
The IVUS examination was carried out after the
administration of intracoronary nitrate, utilizing a 20 MHz
electronic multi-array 2.9F catheter (Eagle Eye®, Volcano
Corporation Inc., San Diego, CA, USA) connected to a
dedicated console (InVision Gold®, Volcano Corporation
Inc., San Diego, CA, USA). Acquisition was performed during
motorized pullback at a constant speed of 0.5 mm/s (R-100®
pullback device, Volcano Corporation Inc., San Diego, Ca,
USA). Off-line IVUS analyses were performed by operators
blinded to other patients’ characteristics, using a dedicated
software (pcVH 2.2 ®; Volcano Corporation Inc., San Diego,
CA, USA) for the measurement of vessels. The luminal
and external elastic lamina (EEL) boundaries were traced
semi‑automatically to obtain area measurements. Total plaque
plus media area was calculated as EEL area minus lumen area.
Plaque burden was calculated as the plaque plus media area
divided by the EEL area, multiplied by 100. A coronary plaque
was diagnosed to be present in all segments with plaque
burden > 40%. A coronary segment was considered to be free
of atherosclerosis or having only mild atherosclerotic plaque
when the plaque burden was ≤ 40%.
Multidetector Computer Tomography
Patients with a heart rate greater than 65 bpm received
up to 15 mg of intravenous metoprolol before the acquisition
of MDCT images, unless contraindicated. Sublingual nitrate
was given to all patients prior to the acquisition of MDCT
images8. All scans were performed utilizing a 64-slice MDCT
scanner (Aquillion 64TM, Toshiba Medical Systems, Japan).
Acquisition protocols were applied as previously described9.
Patients first underwent calcium scanning performed with
prospective electrocardiogram gating and a detector collimation
of 64 x 3.0 mm. The trigger delay for prospective gating was
adjusted to the heart rate in order to obtain the images during
the rest period of the coronary arteries. Only patients with a total
calcium score < 600 were included. After calcium scanning,
the CT coronary angiography protocol was performed using
a 64 x 0.5 mm detector collimation and a minimum gantry
rotation time of 400 ms, and the scanner settings including
pitch were adjusted according to patient’s sex and weight9.
After the intravenous injection of contrast medium (Iopamidol,
370 mg iodine/ml, Bracco) and after reaching a threshold of
180 Hounsfield units (HU), at the descending aorta, the helical
scan for CT coronary angiography was performed.
Quantitative coronary analysis was performed with a
dedicated workstation (Vitrea2, v3.9 loaded with the Coronary
Vessel Probe and SURE Plaque software; all by Vital Images
Inc, Plymouth, MN, USA). All analyses were performed by
operators blinded to clinical and IVUS characteristics, following
a predefined analytic plan. First, the average lumen attenuation
was measured in the ascending aorta (at the level of the coronary
ostia) and used as the parameter to set the threshold for the
detection of the coronary lumen borders. Then, the lumen and
the vessel borders were semiautomatically reconstructed for
the measurement of their areas (Figure 1); thus, permitting the
calculation of the plaque plus media area (vessel area minus
lumen area) and the percent of plaque burden (plaque plus
media area divided by the vessel area, multiplied by 100).
IVUS and MDCT Imaging Coregistration and Segment
Analysis
Intravascular ultrasound and 64-slice MDCT images
were matched by using reproducible vessel landmarks (e.g.,
aorto-ostial junction, side branches, etc.) as anatomical
axial references. Visible landmarks through the target vessel
length were annotated for both IVUS and 64-slice MDCT,
and all vessel portions were carefully scrutinized to match
the exact counterpart (Figure 1). The left main coronary
Arq Bras Cardiol. 2015; 104(4):315-323
316
Back to the Cover
Lemos et al.
MDCT versus IVUS for coronary lumen analysis
Original Article
was computed as a separate vessel for analysis. Repeated
measurements by the same operators were performed
for 27 segments, randomly selected, and correlation
coefficients were used to determine intra-observer and
inter-observer variability.
Statistical Analysis
The present study is an exploratory analysis without
a prior formal sample size calculation. Nevertheless, the
chosen sample size of 20 patients would be sufficient
to demonstrate a significant correlation of any given
continuous parameter with a Pearson coefficient of 0.65at
an alfa of 0.05 and a power of 0.9. Statistical analyses were
performed with software SPSS 21 (IBM Corp. Released
2012, IBM SPSS Statistics for Windows, Version 21.0.
Armonk, NY, USA). Categorical variables are presented
as percentages and continuous variables as means and
standard deviations. Continuous variables were analyzed
for correlation using the Pearson’s correlation test.
The method proposed by Bland and Altman10,11 was utilized
to evaluate the differences between the measurements of
64-slice MDCT and IVUS for mean lumen area, minimal
lumen area, and minimal lumen diameter. In Bland and
Altman’s method, the average of the two measurements
(64-slice MDCT and IVUS) is plotted against the difference
between them (64-slice MDCT minus IVUS) with 95% limits
of agreement calculated to evaluate the measurement
concordance. For all comparison tests, p < 0.05 was
considered significant.
Results
The study population consisted of 21 patients with
70 imaged vessels (3.3 vessels per patient) and a final
total length of 114.6 ± 38.3 mm per patient (ranging from
39.5 mm to 181.0 mm) (Table 1). All patients had coronary
artery disease with percutaneous coronary intervention
indication. Men were 71% of the study population, and mean
Figure 1 – Schematic representation of quantitative coronary analysis by 64-slice MDCT (above) and IVUS (below). The upper images show the longitudinal reconstruction
for both methods. The lower images show illustrative vessel cross-sections with the outer vessel and lumen (inner) boundaries tracings.
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Arq Bras Cardiol. 2015; 104(4):315-323
Lemos et al.
MDCT versus IVUS for coronary lumen analysis
Original Article
age was 56 years. There was a high prevalence of diabetes
mellitus (48%) and hypertension (71%) (Table 1).
All CT scans were considered of diagnostic quality and all
vessel segments > 2 mm were considered for analysis (there
were no unevaluable segments). A total of 72 plaques were
identified by IVUS (plaque burden > 40%) with 95 remaining
coronary segments without plaque or with mild atherosclerotic
disease (plaque burden ≤ 40%).
At patient and vessel levels, the measurements of
average lumen area and minimal lumen area were highly
correlated between IVUS and 64-slice MDCT (correlation
coefficient: patient level 0.75 and 0.78, vessel level 0.91
and 0.93, p < 0.01 for all comparisons) (Table 2). At the
patient level there was a moderate correlation between
minimal lumen diameter measured by IVUS and by
64-slice MDCT (correlation coefficient: 0.64, p = 0.002)
(Table 2). At the segment level, the correlation between
64-slice MDCT and IVUS was similar in segments with or
without a plaque burden > 40% (Table 2). However, the
average absolute difference in measurements tended to be
larger among coronary segments without atherosclerotic
plaque (Table 2 and Figure 3). Overall, 64-slice MDCT
underestimated the lumen size with a relatively wide
dispersion of the differences (Table 2 and Figure 2).
The correlation coefficients for repeated IVUS and
Table 1 – Patients characteristics (n = 21)
Age, years
56.6 ± 9.5
Male
71.4
Weight, kg
69.2 ± 9.9
Height, cm
161.2 ± 7.3
Diabetes
47.6
Hypertension
71.4
Previous myocardial infarction
38.1
Multivessel disease
38.1
Stable coronary disease
52.3
Total length of analyzed
vessels, mm
114.6 ± 38.3
Imaged vessel (n = 70)
Left main
24.3
Left anterior descending
25.7
Diagonal
1.4
Left circumflex
22.9
Obtuse marginal
1.4
Right coronary
24.3
Numbers are mean ± standard deviation or percentage.
Table 2 – Quantitative coronary lumen parameters by IVUS and by 64-slice MDCT at patient, vessel, and segment levels
IVUS
64-slice MDCT
Difference
Correlation coefficient
p-value for correlation
Mean lumen area, mm2
8.6 ± 2.1
7.8 ± 2.3
-0.7 ± 1.6
0.75
< 0.001
Minimal lumen area, mm2
3.3 ± 1.3
1.8 ± 1.9
-1.5 ± 1.2
0.78
< 0.001
Minimal lumen diameter, mm
1.8 ± 0.3
1.0 ± 0.6
-0.8 ± 0.5
0.64
0.002
Mean lumen area, mm2
10.1 ± 5.3
9.1 ± 4.8
-1.0 ± 2.2
0.91
< 0.001
Minimal lumen area, mm2
6.9 ± 5.3
5.3 ± 4.9
-1.5 ± 1.9
0.93
< 0.001
Minimal lumen diameter, mm
2.5 ± 0.9
1.9 ± 1.0
-0.6 ± 0.5
0.87
< 0.001
Mean lumen area, mm2
10.2 ± 5.2
9.1 ± 4.5
-1.1 ± 2.3
0.89
< 0.001
Minimal lumen area, mm2
8.1 ± 4.6
6.8 ± 4.1
-1.4 ± 2.3
0.87
< 0.001
Minimal lumen diameter, mm
2.8 ± 0.8
2.4 ± 0.8
-0.5 ± 0.5
0.78
< 0.001
7.1 ± 2.9
7.0 ± 3.3
-0.1 ± 1.8
0.84
< 0.001
5.1 ± 2.8
4.3 ± 3.3
-0.9 ± 1.9
0.82
< 0.001
2.2 ± 0.5
1.7 ± 0.8
-0.5 ± 0.5
0.76
< 0.001
Per-patient analysis (n = 21)
Per-vessel analysis (n = 70)
Per-segment analysis (n = 167)
Segments with IVUS-PB ≤ 40%
(n = 95)
Segments with IVUS-PB > 40%
(n = 72)
Mean lumen area, mm2
Minimal lumen area, mm
2
Minimal lumen diameter, mm
Numbers are mean ± standard deviation.
IVUS: intravascular ultrasound; MDCT: multidetector computed tomography; PB: plaque burden
Arq Bras Cardiol. 2015; 104(4):315-323
318
Lemos et al.
MDCT versus IVUS for coronary lumen analysis
Original Article
Per- Patient
Per-Vessel
5
5
Difference in mean
luminal area (mm2)
10
Difference in mean
luminal area (mm2)
10
0
–5
–10
3
6
9
12
15
Average mean luminal area (mm2)
0
0
–5
–10
5
5
Difference in minimal
luminal area (mm2)
10
Difference in minimal
luminal area (mm2)
10
0
–5
–10
30
0
–5
2
3
4
5
6
7
8
Average minimal luminal area (mm2)
0
5
10
15
20
25
30
Average minimal luminal area (mm2)
0
1
2
3
4
5
6
Average minimal luminal diameter (mm)
4
Difference in minimal
luminal diameter (mm)
4
Difference in minimal
luminal diameter (mm)
5
10
15
20
25
Average mean luminal area (mm2)
–10
1
2
0
–2
–4
0
0.5
1.0
1.5
2.0
2.5
3.0
Average minimal luminal diameter (mm)
2
0
–2
–4
Figure 2 –Bland-Altman graphs for 64-slice MDCT and IVUS measurements at patient and vessel levels. Mean lumen area (A), minimal lumen area (B), and minimal
lumen diameter (C) in per-patient (left) and per-vessel analyses (right). The solid lines represent the mean difference in measurements, and the traced lines represent
the upper and lower 95% confidence intervals for the difference in measurements.
64-slice MDCT lumen area tracings were 0.90 and 0.91,
respectively Table 3 shows the diagnostic performance of
64-slice MDCT for detecting luminal areas < 4.0 mm²
and lumen diameters < 1.8 mm by IVUS, cutoff values
previously shown to be markers of flow-restrictive coronary
lesions3. Interestingly, the accuracy to detect these IVUS
luminal cutoffs was not notably affected by the presence
or absence of atherosclerotic plaques (Table 3).
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Arq Bras Cardiol. 2015; 104(4):315-323
Discussion
Currently, the primary clinical role of 64-slice MDCT is
the evaluation of coronary luminal obstructions. This study
reports that the assessment of coronary lumen by 64-slice
MDCT shows excellent correlation with IVUS, with a good
overall diagnostic ability to quantify coronary luminal
dimensions regardless of the presence or absence of underlying
atherosclerotic plaques.
Lemos et al.
MDCT versus IVUS for coronary lumen analysis
Original Article
IVUS plaque burden<=40%
IVUS plaque burden >40%
10
Difference in mean luminal
area (mm2)
Difference in mean luminal
area (mm2)
10
5
0
–5
–10
5
10
15
20
25
Average mean luminal area (mm2)
–5
30
10
10
5
5
Difference in minimal
luminal area (mm2)
Difference in minimal
luminal area (mm2)
0
–10
0
0
–5
–10
0
5
10
15
Average mean luminal area (mm2)
20
0
5
10
Average minimal luminal area (mm2)
15
0
1
2
3
Average minimal luminal diameter (mm)
0
–5
–10
0
5
10
15
20
25
Average minimal luminal area (mm2)
30
4
4
2
2
Difference in minimal
luminal diameter (mm)
Difference in minimal
luminal diameter (mm)
5
0
–2
–4
0
–2
–4
1
2
3
4
Average minimal luminal diameter (mm)
5
4
Figure 3 – Bland-Altman graphs for 64-slice MDCT and IVUS measurements at segment level. Mean lumen area (A), minimal lumen area (B), and minimal lumen diameter (C) for
segments without significant plaques (IVUS plaque burden ≤ 40%; left) and for segments with atherosclerotic plaque (IVUS plaque burden > 40%; right). The solid lines represent
the mean difference in measurements, and the traced lines represent the upper and lower 95% confidence intervals for the difference in measurements.
A l t h o u g h s i g n i f i c a n t l y c o r r e l a t e d w i t h I V U S,
the measurements by 64-slice MDCT slightly underestimate
the lumen area and the minimal lumen diameter with
a relatively wide margin of error. In a previous study,
Cademartiri et al. showed that lumen attenuation measured
by CTA significantly affected the measured plaque
attenuation12. The higher the lumen attenuation, the higher
the plaque attenuation is. In contrast, calcium attenuation
and surrounding fat attenuation were not significantly
affected. On the basis of this finding, a semiautomatic tool
for tracing coronary lumen and plaque borders based on
aortic lumen attenuation could underestimate the luminal
area of segments with plaque and reduce the specificity
of CTA to identify non-significantly diseased segments by
IVUS. Nevertheless, 64-slice MDCT showed a good global
predictive accuracy for the detection of an IVUS luminal
area < 4.0 mm² and an IVUS minimal lumen diameter
< 1.8 mm, parameters previously shown to be markers of
Arq Bras Cardiol. 2015; 104(4):315-323
320
Lemos et al.
MDCT versus IVUS for coronary lumen analysis
Original Article
Table 3 – 64-slice MDCT sensitivity, specificity, negative predictive value, positive predictive value, and global predictive accuracy* for the
detection of luminal area < 4.0 mm2 and luminal diameter < 1.8 mm by IVUS†
Luminal area < 4.0 mm2
Luminal diameter < 1.8 mm
Prevalence
86%
67%
Per-patient analysis (n = 21)
Sensitivity
100%
100%
Specificity
33%
29%
Negative predictive value
100%
100%
Positive predictive value
90%
73%
Global predictive accuracy
0.82
0.74
Prevalence
44%
24%
Sensitivity
90%
94%
Specificity
69%
27%
Negative predictive value
70%
97%
Positive predictive value
70%
41%
Global predictive accuracy
0.90
0.90
Per-vessel analysis (n = 70)
Per-segment analysis (n = 167)
Segments with IVUS-PB ≤ 40% (n = 95)
Prevalence
14%
6%
Sensitivity
93%
100%
Specificity
83%
77%
Negative predictive value
99%
100%
Positive predictive value
48%
22%
Global predictive accuracy
0.92
0.89
Prevalence
49%
21%
Sensitivity
83%
93%
Specificity
69%
49%
Negative predictive value
81%
97%
Positive predictive value
73%
33%
Global predictive accuracy
0.87
0.89
Segments with IVUS-PB > 40% (n = 72)
IVUS: intravascular ultrasound; MDCT: multidetector computed tomography; PB: percent plaque burden
* Global predictive accuracy calculated as the area under the receiver operating characteristic curve (C-index)
†
IVUS parameters previously shown to be associated with flow-limiting lesions.(3)
flow-limiting coronary lesions3. In particular, 64-slice MDCT
showed excellent sensitivity and negative predictive value
for the identification of patients or vessels with the above
characteristics at the expense of poor specificity and positive
predictive value. These findings reinforce the primary clinical
role of 64-slice MDCT for screening and ruling out, rather
than ruling in, coronary luminal obstruction.
Our findings were obtained in the context of a blinded
whole-artery 64-slice MDCT assessment, with no previous
indication for focusing on a specific plaque-containing
segment. It is important to highlight that this analytic approach
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Arq Bras Cardiol. 2015; 104(4):315-323
emulates the way 64-slice MDCT is interpreted in clinical
practice. The fact that the diagnostic performance of 64-slice
MDCT for lumen assessment was not substantially different
for segments with or without plaques when using IVUS is
reassuring and strengthens the value of 64-slice MDCT as
a clinical tool. It must be emphasized that the assessment
of segments with minimal coronary disease is of clinical
relevance, because of the potential impact on future disease
progression and acute events and because of the importance
of analyzing segments beyond the stenosis site when planning
the therapeutic strategy.
Lemos et al.
MDCT versus IVUS for coronary lumen analysis
Original Article
Limitations
Author contributions
It must be emphasized that the present study is mainly
a methodological analysis with limited immediate clinical
application. The main limitation of our study is the relatively
small sample size included in the analysis. The patient
population analyzed had a relatively high risk profile, which
may limit our ability to extrapolate the results of this study to
other clinical scenarios. Exclusion of patients with coronary
calcium score > 600 could have overestimated the correlation
between IVUS and CTA for measurements of coronary
lumen area. In a previous study, the presence of calcification
was found to be independently correlated to coronary CTA
inaccuracy in evaluating coronary lumen area13. Each patient
contributed with multiple measurements; thus, affecting data
independence. Nonetheless, such limitation is a drawback
potentially found in every study aiming to evaluate the imaging
of coronary atherosclerotic disease.
Conception and design of the research: Falcão JLAA, Silva
ER, Rochitte CE, Lemos PA. Acquisition of data: Falcão JLAA,
Falcão BAA, Gurudevan SV, Campos CM, Silva ER, Shiozaki
AA, Coelho-Filho OR, Lemos PA. Analysis and interpretation
of the data: Falcão JLAA, Falcão BAA, Gurudevan SV, Campos
CM, Rochitte CE, Shiozaki AA, Coelho-Filho OR, Lemos
PA. Statistical analysis: Falcão JLAA, Rochitte CE, Lemos PA.
Obtaining financing: Falcão JLAA, Rochitte CE, Lemos PA.
Writing of the manuscript: Falcão JLAA, Kalil Filho R, Lemos
PA. Critical revision of the manuscript for intellectual content:
Falcão JLAA, Kalil Filho R, Rochitte CE, Lemos PA.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Conclusion
This study demonstrates that 64-slice MDCT has a good
correlation with IVUS for the evaluation of the coronary
artery lumen in segments with significant plaques as well as
in segments without plaques. Our data suggest that 64-slice
MDCT can be used by the clinician to comprehensively
define coronary artery anatomy in patients with coronary
artery disease, thereby improving clinical risk stratification and
facilitating effective clinical care.
Sources of Funding
This study was funded by Fundação de Amparo à Pesquisa
do Estado de São Paulo (FAPESP) and Technological
Development (CNPq).
Study Association
This article is part of the doctoral thesis of João Luiz de
Alencar Araripe Falcão by Universidade de São Paulo.
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Long-term follow-up after percutaneous transluminal coronary angioplasty
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Springer I, Dewey M. Comparison of multislice computed tomography with
intravascular ultrasound for detection and characterization of coronary
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Original Article
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Back to the Cover
Review Article
Treatment of Dyslipidemia with Statins and Physical Exercises:
Recent Findings of Skeletal Muscle Responses
Mariana Rotta Bonfim1, Acary Souza Bulle Oliveira2, Sandra Lia do Amaral3, Henrique Luiz Monteiro3
Programa de Pós-Graduação em Ciências da Motricidade, Instituto de Biociências, Universidade Estadual Paulista “Júlio de Mesquita Filho”
(UNESP)1, Rio Claro, SP; Setor de Doenças Neuromusculares, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP)2,
São Paulo, SP; Departamento de Educação Física, Faculdade de Ciências, UNESP3, Bauru, SP – Brazil
Abstract
Statin treatment in association with physical exercise
practice can substantially reduce cardiovascular mortality
risk of dyslipidemic individuals, but this practice is associated
with myopathic event exacerbation. This study aimed to
present the most recent results of specific literature about
the effects of statins and its association with physical exercise
on skeletal musculature. Thus, a literature review was
performed using PubMed and SciELO databases, through
the combination of the keywords “statin” AND “exercise”
AND “muscle”, restricting the selection to original studies
published between January 1990 and November 2013.
Sixteen studies evaluating the effects of statins in association
with acute or chronic exercises on skeletal muscle were
analyzed. Study results indicate that athletes using statins
can experience deleterious effects on skeletal muscle, as the
exacerbation of skeletal muscle injuries are more frequent
with intense training or acute eccentric and strenuous
exercises. Moderate physical training , in turn, when
associated to statins does not increase creatine kinase levels
or pain reports, but improves muscle and metabolic functions
as a consequence of training. Therefore, it is suggested that
dyslipidemic patients undergoing statin treatment should
be exposed to moderate aerobic training in combination to
resistance exercises three times a week, and the provision
of physical training prior to drug administration is desirable,
whenever possible.
Introduction
High serum lipoprotein levels are recognized as one of the
most significant risk factors for cardiovascular diseases. Alone,
lipid abnormalities are accountable for 56% of heart disease and
18% of cases of infarction, being also associated to one third of
deaths worldwide 1. Due to the magnitude of its effects, great
efforts have been made by the medical community to prevent
Keywords
Hydroxymethylglutaryl-CoA reductase inhibitors; Exercise;
Muscle, skeletal; Dyslipidemia.
Mailling Address: Mariana Rotta Bonfim •
Avenida Engenheiro Luiz Edmundo Carrijo Coube, 14-01, Vargem Limpa.
Postal Code 17033-360, Bauru, SP – Brazil.
E-mail: [email protected]
Manuscript received April 30, 2014; revised manuscript October 10, 2014;
accepted October 13, 2014.
DOI: 10.5935/abc.20150005
324
and control this metabolic condition, with the therapeutic
strategies recommended by the Brazilian Society of Cardiology
(SBC) and adopted by area specialists being such as encouraging
the adoption of healthy eating, increased physical exercise and
drug prescription2,3.
Specifically on the drug therapy, inhibitors of 3-hydroxy-3methylglutaryl coenzyme A reductase, (HMG-CoA reductase),
also known as statins, are most effective class of drugs for the
treatment of lipid disorders2-4. Recent evidence indicates that
the combination of medical treatment and physical exercise
can substantially reduce the risk of cardiovascular mortality
in dyslipidemic patients when compared to both treatments
separately, suggesting that treatment with statins associated
with moderate to high physical fitness level provides additional
protection against premature cardiovascular death5.
However, the use of statins is associated with the
occurrence of undesirable muscle effects such as muscular
pain, cramps, and/or stiffness6-8, as well as reduced muscle
strength in elderly individuals9. The practice of physical
exercises, in turn, is related to the exacerbation of these
discomforts, being directly associated with the intensity
of the physical effort performed7,8. Evidently, this situation
presents as a paradox, as it is not desirable that lack of
physical activity be a prerequisite for treatment with statins
without complications. It is thus necessary to further
assess the evidence of this association, as well as clarify
the mechanisms by which these effects are mediated.
Considering these facts, the aim of this study was to
review recent data from specific technical literature on
the effects of statins and physical exercise combination
on skeletal muscle.
Methods
The survey was carried out in the databases PubMed
and Scientific Electronic Library Online (SciELO), using
the combination of the terms "statin / statins" AND
"exercise" AND "muscle" (as well as the equivalent terms in
Portuguese), Only original articles in English or Portuguese,
published between January 1990 and November 2013 that
aimed to evaluate the effect of the association of statins
with acute or chronic exercise on skeletal muscle were
selected for this update. Review studies, editorials, letters
and consensuses were not included. A total of 109 articles
were found in the PubMed search, of which 15 were
original articles that comprised the established criteria;
the search in SciELO, in turn, resulted in a single original
article, totaling 16 articles analyzed.
Bonfim et al.
Muscle Responses to Statins and Exercises
Review Article
Data on the sample (sample size, gender, age and study
groups), on the specific characteristics of the drug therapy
(statin type and dose), the physical exercise protocol (type
and intensity of exercise, and time of intervention) were
extracted from the articles, as well as the results and the
conclusions of the studies.
Results and Discussion
The results of the present study are described in the text and
systematized in Chart 1. As the understanding of the effect of
statins on skeletal muscle is critical to understand the effects
of its association with exercise, it was considered important
to contextualize the reader about such aspects and, therefore,
the results are shown as two topics.
Statins and skeletal muscle
Statins work by inhibiting the activity of HMG-CoA reductase
enzyme, preventing the formation of mevalonate (Figure 1),
which leads to a reduction in the liver synthesis of cholesterol
and, consequently, increased synthesis of low-density
lipoprotein (LDL) receptors in hepatocytes, thereby increasing
its uptake from circulation to restore intracellular cholesterol10.
Although well tolerated by most patients, statins are associated
with the occurrence of muscle toxicity11,12, which may be mild
or severe, ranging from myalgia to rhabdomyolysis, and affecting
5 to 10% of patients6-8,12.
According to Parker and Thompson13, identifying the actual
incidence of muscle alterations caused by the use of statins may
be considered practically impossible, as these problems are
usually not evaluated in clinical trials funded by pharmaceutical
industries. They point out, however, that clinical reports have
confirmed the suspicion that muscle injuries produced by
statins are much more frequent. In fact, retrospective studies
in medical records have indicated that musculoskeletal injuries
and pain are more common among statin users when compared
to non-users14, with a high number of reports associated with
statins as primary suspects15.
A randomized clinical trial on the use of atorvastatin
(80 mg/day) or placebo for 6 months using a double-blind16
design found a higher incidence of myalgia among treated
individuals and only the symptomatic ones had decreased
muscle strength/resistance values17, with no association being
observed between creatine kinase (CK) increases and muscle
function, indicating that the levels of this injury marker are
not predictive of muscle symptoms associated with statins18.
This evidence indicates that statins can cause muscle damage
to its users; however, the discrepancy on how to identify such
alterations limits the identification of their incidence7,12.
The most prevalent theories about the mechanisms of
muscle damage by statins are related to the inhibition of
mevalonate formation by the drug, which, in turn, limits
the formation of several intermediates in cholesterol
biosynthesis (Figure 1), such as ubiquinone (coenzyme
Q10), one of the intermediates in the mitochondrial
electron transport chain19-21. Although there is evidence
regarding mitochondrial dysfunction due to coenzyme
Q10 deficiency (CoQ10) 22, this mechanism of muscle
injury by statins is quite controversial in the literature, as
ubiquinone supplementation has not shown to improve
muscle function23, suggesting possible direct effects of the
drug on muscle.
A study of the extensor digitorum longus (EDL) muscle of
rats (n = 32) indicated that drug treatment with lipid‑lowering
drugs alters the expression of proteins involved in cellular
defense against oxidative stress, also being observed a
significant reduction in the expression of oxidative and
glycolytic enzymes, and showing a therapy trend of modifying
proteins associated with energy supply systems24.
Similarly, Bouitbir et al.25,26 found that low doses of
atorvastatin may increase the production and concentration
of Reactive Oxygen Species (ROS) and reduce the maximum
mitochondrial respiration, muscle glycogen content and
mitochondrial DNA content in skeletal muscle of mice,
indicating that the statins may induce oxidative stress in skeletal
muscle and, consequently, cause mitochondrial dysfunction
due to reduction of its biogenesis.
Similar results have been found in research with
humans. In the study by Stringer et al.27, it was found that
the skeletal muscles of symptomatic patients had lower
content of mitochondrial DNA than that of asymptomatic
ones, suggesting that statins can induce mitochondrial
DNA depletion. Moreover, Larsen et al. 28 found that
individuals treated with simvastatin had reduced CoQ10
content, antioxidant proteins, compounds of complex IV
of the mitochondrial electron transport chain and type 1
fibers, when compared to their peers without medication,
suggesting that exposure to statins may limit the maximum
capacity of mitochondrial phosphorylation of skeletal
muscle. However, the mitochondrial alterations seem to
represent the early stage of the cascade of deleterious
mechanisms induced by statins. According to Sirvent
et al. 19,29,30, alterations in the mitochondrial respiratory
chain result in depolarization of the mitochondrial
inner membrane, causing calcium extrusion, which in
turn would increase its sarcoplasmic concentrations
and overload the sarcoplasmic reticulum, resulting
in the so‑called "calcium waves" and the consequent
statin‑induced myotoxicity. Although isolated effects of
statins on calcium homeostasis have been reported in rat
muscles31 and in both symptomatic32 and asymptomatic33
individuals, apparently its dysregulation is, in fact, a
consequence of mitochondrial lesions.
In fact, in a recent study, Sirvent et al.34 observed that
the skeletal musculature of patients treated with statins,
symptomatic or not, showed alterations in complex I of
the electron transport chain, which modified mitochondrial
function and deregulated calcium homeostasis, confirming
their previous results observed in in vitro experiments.
Similar results were found in a double-blind randomized
clinical trial developed by Galtier et al.35, who found that
atorvastatin-induced muscle toxicity was associated with
a physiopathological mechanism, of which changes in
mitochondrial respiration caused by the drug resulted in
irregular calcium homeostasis .
Analyzed together, this evidence explains, in large part, statininduced myotoxicity: mitochondrial and calcium homeostasis
Arq Bras Cardiol. 2015; 104(4):324-332
325
Bonfim et al.
Muscle Responses to Statins and Exercises
Review Article
Chart 1 – Description of the studies investigating the effect of statins and physical exercise on skeletal muscle
Reference
Sample
Drug therapy
Physical exercise protocol
Results
n = 80 individuals (59♂ and 21♀)
Different statin types and doses
(n = 37)
Running a marathon
Increase in CK after 24
horas in the statin group
n = 59 men (18-65 years)
Double-blind randomized trial
Lovastatin (40 mg/day; n = 22) or
placebo (n = 27) for 5 weeks
Treadmill (45’; 15% incline; 65%
HRmax)
Elbow flexion (4x10 repetitions;
50% MF)
Increase in CK 24 and 48
hours after the walk in the
lovastatin group
Reust et al.39
n = 10 men (27-28 years)
Double-blind crossover randomized
trial
Lovastatin (40 mg/day; n = 5) or
placebo (n = 5) for 30 days
Treadmill (60’; 14% incline; 3
km/h)
Maintenance of CK after
lovastatin compared with
placebo
Kearns et al.40
n = 79 men
Randomized trial
Atorvastatin (10 mg/day, n = 42; or
80 mg/day, n = 37) for 5 weeks
Treadmill (3x15’; 15% incline;
65% HRmax)
↑ total CK, CK-MB and
muscular pain after
exercise
Panayiotou et al.41
n = 28 sedentary men (> 65 years)
Atorvastatin (10-80 mg/day; n = 14)
for ≥ 1 year
Knee extension (5x8 maximum
EC; 2 sessions)
Similar muscular function
between groups
Urso et al.42
n = 8 sedentary men (18-30 years)
Randomized double-blind trial
Atorvastatin (80 mg/day; n = 4) or
placebo (n = 4) for 4 weeks
Knee extension (300 EC) before
and after treatment
Different expression of
genes from the PSU
pathway of catabolism and
of apoptosis
n = 80 male rats (hyperlipidic diet,
n = 60; standard diet, n = 20) in
8 groups
Simvastatin (20 mg, n = 20),
Fluvastatin (10 mg, n = 20) or
placebo (n = 20)
Treadmill (60’; 9.75 m/min)
5x/week for 8 weeks
Higher frequency of
morphological alterations
after statin, with or without
exercise
Seachrist et al.44
n = 48 female rats divided into
8 groups
Cerivastatin (0.1; 0.5; 1.0 mg/kg/day)
or placebo for 14 days
Treadmill (25’; 20 m/minute; 15º
of incline angle) 5x/week for
2 weeks
Exacerbation of
muscular degeneration;
mitochondrial involvement
Meex et al.45
n = 38 sedentary elderly men
Different types and doses of statins
(n = 14)
Cycloergometer (30’; 55%
ML) 2x/week and 8 resistance
exercises (3x8 repetitions; 55
and 75%) 1x/week, 12 weeks
Increase in ML, muscular
strength, muscular density
and mitochondrial function
in both groups
Mikus et al.46
n = 37 sedentary individuals with
risk factor for MS (13♂ and 24♀;
25-59 years)
Simvastatin (40 mg/day) (n = 19)
Treadmill (45’; 60-75% rHR) 5x/
week for 12 weeks
Increase in LM and
decrease in muscular
citrate synthase activity
Coen et al.47
n = 31 sedentary individuals (15♂
and 16♀; 40-65 years)
Randomized trial
Rosuvastatin (10 mg/day) for 20
weeks
Treadmill (20’; 60-70% rHR) and
8 resistance exercises (70-80%
1MR), 3x/weeks for 10 weeks
Increase in CK 48 hours
after the 1st session;
absence of reports of pain/
fatigue
Use of statins in athletes
Parker et al.37
Statins and acute physical exercises
Thompson et al.38
Statins and chronic physical exercises
Accioly et al.43
Mechanisms of muscular responses to statins and to physical exercises
Bouitbir et al.26
n = 34 male rats divided into 4
groups
Atorvastatin (10 mg/kg/day; n = 18)
or placebo for 2 weeks
Treadmill (40’; 40 cm/s with
increase of 5 cm/s up to
exhaustion; 1 session)
Increase in ROS and
decrease in mitochondrial
respiration
Wu et al.48
n = 10 subjects (5♂ and 5♀;
35‑69 years)
Different types and doses of statins
for 4 weeks
Plantar flexion (40% ML) for 7’ or
up to exhaustion
Increase in time of
metabolic recovery and CK
maintenance
n = 14 users of statins (n = 9
symptomatic; n = 6 asymptomatic)
Simvastatin or Atorvastatin (10-80
mg) up to myalgia onset (2 weeks to
4 months)
Sitting down and getting up
from a chair 300 times or up to
exhaustion
Decrease in the
expression of oxidative
phosphorylation genes and
of mitochondrial proteins in
symptomatic individuals
Meador and Huey50
n = 59 mice divided in 6 groups
Cerivastatin (1 mg/kg/day) or saline
solution (days 15-28)
Running wheels (adapted: days
1-28; non-adapted: days 15-28)
Adaptation to exercise
prevented loss of strength
and increased fatigue
associated with statin
Bouitbir et al.
n = 20 male rats (trained, n = 10;
sedentary, n = 10)
Atorvastatin application (4, 10,
40, 100, 200 and 400 µM) to the
plantaris muscle
Treadmill (30’; 40 cm/s; 15%
incline) for 10 days
Increased mitochondrial
tolerance to the drug and
decrease in production of
free radicals
Hubal et al.49
25
CK: creatine kinase; HRmax: Maximum heart rate; MF: maximum force; CK-MB: cardiac creatine kinase; EC: eccentric contractions; UPS ubiquitin proteasome; ML: maximum
load; MS: metabolic syndrome; rHR: resting heart rate; LM: lean mass; MR: maximal repetition; ROS: Reactive Oxygen Species.
326
Arq Bras Cardiol. 2015; 104(4):324-332
Bonfim et al.
Muscle Responses to Statins and Exercises
Review Article
Statins
HMG-CoA
Reductase
Acetyl-CoA
HMG-CoA
Mevalonate
Geranyl-PP
Cholesterol
Farnesyl-PP
Geranyl-Geranyl-PP
Prenylated
proteins
Dolichols
Ubiquinone
Figure 1 – Cholesterol biosynthesis stages and statin action. The enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase catalyzes the conversion of
HMG-CoA into mevalonate; the action of inhibiting this enzyme by statins results in the reduction of cholesterol synthesis, as well as other intermediates (prenylated
proteins, dolichols and ubiquinone), which can contribute to muscle injury resulting from statin use. CoA: Coenzyme A; PP: pyrophosphate.
alterations are related to modifications in the production of proteins
activated by calcium, such as calpains and caspases, which in turn,
are directly related to the apoptotic processes, protein degradation
and muscle remodeling; in addition, this condition can modify the
excitation-contraction coupling of muscular fibers, causing episodes
of muscle weakness, pain and cramps19,33.
Effect of statins and exercise on skeletal muscle
The negative effects of statins on skeletal muscle, as well
as the reported reduction in exercise capacity caused by the
drug, culminate in the increasing dissemination of the theory
of lesion exacerbation caused by the association of statins
and exercise, which can be characterized as a limiting factor
for the recommendation of physical activity in dyslipidemic
patients. In an attempt to clarify these associations, the
literature search information is shown as subtopics, which
include the effects of statins in athletes and response to acute
and chronic exercises, as well as the mechanisms responsible
for muscle responses to this interaction.
Use of statins in athletes
Regarding physical exercises, it is important to understand
what the effects of statins are on athletes’ musculature. In this
regard, Sinzinger and O'Grade36 evaluated 22 professional
athletes of different modalities, all diagnosed with familial
hypercholesterolemia, which were followed for 8 years and
who received different classes of statins. Of the assessed athletes,
78% did not tolerate any of the administered compounds; the
experienced symptoms were similar between athletes and types
of statins administered to them and consisted of muscle pain,
cramps and weakness. After drug use cessation, symptoms
disappeared in all athletes after approximately 3 weeks.
In a more recent study, Parker et al.37 evaluated 37 athletes
that used statins for over 6 months and 43 control subjects,
before and after a marathon race. The results showed that
marathon runners that used statins had more significant
increases in CK levels 24 hours after the marathon completion
when compared to non-users. It is concluded that athletes may
experience deleterious effects on skeletal muscle when using
statins, as these may exacerbate muscle injury associated with
intense and strenuous exercise, both performed acutely or as
part of training (Chart 1).
Statins and acute physical exercises
The pioneering studies that aimed to identify the
exacerbation of muscle injury by exercise were double-blind
clinical trials randomized for the use of lovastatin (40 mg/day)
or placebo, carried out in adult men (n = 59, 18-65 years)38
or young individuals (n = 10, 27-28 years)39, which found that
acute provision of eccentric and strenuous effort by walking
downhill after a 4-week treatment with lovastatin (40 mg/day),
could increase38 or not39 serum CK levels. A more recent study
reproduced the abovementioned research protocol, in which
adult males (n = 79, age > 40 years) were randomly exposed
to doses of 10 or 80 mg of atorvastatin for 4 weeks, and
then submitted to an acute eccentric and strenuous exercise
session by walking downhill. It was observed that exposure
to physical effort after the drug use increased CK levels and
reports of pain in both groups, with no significant differences
being identified between treatments with low or high dose40.
Together, the results a possible exacerbating effect of muscle
injury in response to these associations.
In contrast, a cross-sectional study that investigated the effects
of acute sessions of isokinetic eccentric exercises of the knee
Arq Bras Cardiol. 2015; 104(4):324-332
327
Bonfim et al.
Muscle Responses to Statins and Exercises
Review Article
extensors (five series of eight maximal voluntary repetitions) on
muscle function of elderly men (n = 28, age > 65 years) treated
with atorvastatin (10-80 mg / day) for more than one year, found
no differences in muscle function, in both moments, pre and
post-exercise, when compared to control patients. These results
indicated that the proposed eccentric exercise did not have a
negative impact on torque, range of motion and pain sensation
during squatting exercises and walking in statin users41.
Similarly, the double-blind trial randomized for the use of
atorvastatin (80 mg/day) or placebo for 4 weeks in healthy men
(n = 8, age 18 to 30), in which Bear et al.42 provided acute
strenuous exercise, characterized by 300 eccentric contractions
of the lower limbs before and after drug treatment, showed no
significant increases in CK levels with the combination of the
drug and the physical effort. However, it was observed that
this interaction increased the expression of genes involved
in protein catabolism and the ubiquitin proteasome (UPS)
pathway, changing the balance between protein breakdown
and muscle repair, indicating that the absence of changes in
CK may not reflect muscle tissue responses.
In general, the studies seem to indicate that men using
different statin classes, at low or high doses, show changes
in muscle function and injury markers when exposed to
acute sessions of eccentric and strenuous exercises walking
downhill, but not with lower-limb eccentric exercises alone.
However, they warn that this reality does not rule out the
occurrence of possible structural and metabolic changes in
muscle tissue. It is also noteworthy that the heterogeneity
of methodological protocols, as well as the absence of
women in the studies significantly limits these conclusions,
indicating the need for further studies to satisfactorily
establish this association.
When comparing previously sedentary adults with risk
factors for metabolic syndrome (n = 37, aged 25-59 years),
exposed to 12 weeks of moderate exercise on a treadmill,
performed five days a week, alone (n = 19 ) or associated
with the use of simvastatin (40 mg / day, n = 18), Mikus et al.46
found that, although the association caused more significant
reductions in total cholesterol (TC) and LDL-cholesterol levels,
the increases in cardiorespiratory fitness and citrate synthase
enzyme activity of the vastus lateralis muscle, in response to
exercise, were attenuated in subjects treated with statins,
indicating that the drug may inhibit some of the body’s
adaptive responses to exercise. Despite their significance,
these results were obtained in the absence of a group treated
with statins only, which considerably limits the advance of
knowledge about the exacerbation of the deleterious effects
of statins by physical exercise.
Considering the body’s adaptation to training, it can
be assumed that muscle responses to chronic exercises
are different from those observed in acute exercises.
An experimental study with an animal model, which
evaluated the effects of 60 minutes of moderate aerobic
physical activity (9.75 m/min) on a treadmill, performed five
times a week for two months, concomitant with simvastatin
(20 mg/kg) and fluvastatin (20 mg/kg) treatment in rats
showed that the drug use caused mild to severe muscle
changes in the soleus muscle, which were more frequent
when the drug was associated with exercise43.
In this regard, the present literature review found only
one study that assessed the effect of adding moderate
chronic exercise to regular treatment with rosuvastatin
(10 mg/day) in dyslipidemic adults of both sexes (n = 31,
aged 40-65 years). In this randomized clinical trial, it was
observed that both drug treatment and its association with
12 weeks of aerobic training on a treadmill and resistance
exercises, performed three times a week, led to significant
decreases in the participants’ lipid profile, with the reduction
in oxidized LDL more effective in individuals submitted to
exercises47. Statin users that practiced physical exercises had
an increase in maximum oxygen consumption compared to
their sedentary peers, with a similar effect observed for the
muscle strength variables, with no increase in CK levels or
the reports of pain, which demonstrates that this combination
results in health variable improvements with no additional
damage to the musculature of practitioners47.
Similarly, in the study carried out with guinea pigs
performed by Seachrist et al.44, high doses of cerivastatin
were concomitantly administered to the practice of intense
physical exercise on a treadmill for 14 days. Results showed
that this association increased CK levels and exacerbated
degeneration of mitochondria and other organelles of
skeletal muscles. Evidence from animal studies indicated
that physical training, of both high and moderate intensity,
when associated with statin treatment at low or potentially
harmful doses, results in muscle damage. However, studies
performed in humans have shown different results.
In summary, it can be observed that treatment with statins,
both in elderly men and the general adult population, when
combined with 12 weeks of aerobic training with aerobic
and resistance exercises, does not increase reports of pain
or CK levels, in addition to leading to gains in muscle and
metabolic functions resulting from the training. Despite the
little evidence and the need for longer studies, with different
exercise modalities and training intensities, and the assessment
of alterations in muscle tissue, these results show that performing
moderate exercise during statin use is safe and more beneficial
than remaining sedentary.
Statins and chronic physical exercises
328
In the study performed by Meex et al.45, elderly men, users
or not of statins, were exposed to a 12-week training protocol,
characterized by the practice of moderate aerobic exercise
on a cycle ergometer and resistance exercises three times a
week, with the following parameters being evaluated: substrate
oxidation, phosphocreatine (PCr) recovery and expression
of proteins from the skeletal muscle mitochondrial electron
transport chain complex. The results of this study showed that
treatment with statins (atorvastatin, rosuvastatin, pravastatin
and simvastatin) at different doses did not limit the practice of
physical exercise or training-induced gains in muscle mass and
mitochondrial quality of those practicing exercises, indicating
that the proposed associations were safe.
Arq Bras Cardiol. 2015; 104(4):324-332
Bonfim et al.
Muscle Responses to Statins and Exercises
Review Article
Mechanisms of muscle responses to statins and physical
exercises
To date, evidence from research indicates that the intense
training performed by athletes, as well as the practice of
eccentric and strenuous exercise may exacerbate muscle
injury caused by statin administration. In this regard,
Meador and Huey21 proposed, in their review study, some
of the mechanisms by which exercise exacerbates muscle
injury caused by statins. According to the authors, the
mitochondrial damage caused by statins, associated with
increased energy flow and glycogen depletion due to the
exercise, could be an exacerbation factor; however, they
add other possibilities, such as the activation of the protein
kinase pathway signaled by isoprenoids and stimulated by
muscle contraction, as well as increases in the UPS pathway
activity mediated by both statins and exercise.
In spite of this theoretical explanatory model of possible
muscle injury exacerbation mechanisms, the scientific
evidence to support these hypotheses is still scarce.
The increased expression of genes involved in protein
catabolism and UPS pathway was identified only in the
research Urso et al.42, while mitochondrial damages and
energy supply disorders have been further explored, having
been verified in both the studies by Seachrist et al.44, as in
more recent studies.
In this regard, Bouitbir et al.26 reported that rats treated with
atorvastatin (10 mg / kg / day) showed mitochondrial function
loss in the plantar muscle. The exposure of these animals to an
exhaustive exercise test on a treadmill produced 226% more
ROS than in the placebo group, with a reduction in maximum
mitochondrial respiration (-39%) also being observed, which
was significantly associated with the shortest distance walked
in the test (r = 0.62; p <0.01). ROS are generated in the
mitochondria as a result of energy metabolism and their
increased production can cause damage to lipids, proteins and
cellular DNA, altering mitochondrial function and triggering
deleterious effects to muscle. These results indicate that
exhaustive exercise, associated with mitochondrial damage
resulting from treatment with statins, actually exacerbate
metabolic disorders in skeletal muscle, resulting in a more
oxidant status in this structure and, consequently, reducing
the effort capacity of the animals.
This disorder in the muscle energy supply system caused
by the use of statins has also been found in humans, as shown
in the work by Wu et al.48, which characterized the kinetics
of PCr recovery after calf effort in individuals of both sexes
(n = 10, 35 to 69 years) treated with statins for 4 weeks.
The muscle PCr metabolic recovery rate is a parameter used
as an index of muscle oxidative capacity in vivo, with a longer
recovery time reflecting impaired oxidative phosphorylation
and/or mitochondrial ATP synthesis. The results showed that
exposure to statins did not alter CK levels, but resulted in a
significant increase in metabolic recovery time after effort
(from 28.1 to 55.4 seconds; p = 0.02), suggesting that this
drug may impair mitochondrial oxidative function, which
could explain the possible muscle involvement caused by its
association with physical exercise.
Despite evidence indicating non-selective mitochondrial
damage in the muscles of statin users, symptomatic individuals
are apparently more predisposed to lesions and show more
marked injury. In this regard, Hubal et al.49 assessed the global
pattern of gene expression on skeletal muscle of patients of
both sexes that used myalgia-inducing statins (n = 9) or not
(n = 5) in response to eccentric exercise. After 4 months of
drug treatment, it was found that patients who had classic signs
and symptoms of myalgia had decreased NADH expression of
complex I of the electron transport chain, as well as decreased
succinate dehydrogenase in complex II, cytochrome c oxidase
in complex IV and ATP4B in complex V, indicating that preexisting deficiencies in energy production could contribute
to the development of symptoms caused by physical effort
during statin therapy49.
However, information about the association of statins to
moderate chronic exercise suggests that other responses may
occur, in addition to muscle injury exacerbation. According to
Meador and Huey21, muscle adaptations caused by training,
such as increased heat shock protein protection (related to the
reduction in oxidative stress, apoptosis inhibition and muscle
injury attenuation), direct suppression of apoptotic factors
and increased mitochondrial biogenesis may result in muscle
injury attenuation. To test this hypothesis, the same authors
submitted mice to 14 days of combined treatment consisting
of physical exercise and statins, after a previous adaptation
of 14 days to exercise or physical inactivity and found that
the drug reduced muscle strength and fatigue resistance in
sedentary and non-adapted animals, when compared to
adapted ones, indicating that adaptation to exercise protects
the skeletal muscles against the deleterious effects of statins50.
Similarly, Bouitbir et al.25 found that training for 10 days on
a treadmill improved the oxidative and antioxidant capacity
of the plantar muscle in Wistar rats compared to sedentary
animals, and that in vitro exposure of the muscles of sedentary
animals to atorvastatin reduced the oxidative capacity in a
dose-dependent manner. However, they demonstrated that the
impaired mitochondrial function caused by drug exposure was
lower in the muscles of trained animals, indicating a protective
effect of physical exercise related to the improvement of
mitochondrial respiration and antioxidant capacity, aimed at
attenuating statin-induced oxidative stress.
The extrapolation of these results to humans seems to
suggest that physically active individuals prior to treatment
with statins may be protected from the deleterious drug effects,
indicating that the prescription of exercise training prior to
drug therapy with statins might be a preventive measure to
muscle effects. Despite the evidence, Bonfim et al.51 recently
found that many patients with dyslipidemia undergoing
treatment with statins are sedentary and, therefore, would
not be previously protected if they chose to carry out changes
in their lifestyle.
Practical contributions
In a recent review study, Opie52 briefly explored the
controversies between beneficial heart effects and myopathic
side effects of the statin and exercise association, outlining
Arq Bras Cardiol. 2015; 104(4):324-332
329
Bonfim et al.
Muscle Responses to Statins and Exercises
Review Article
some practical guidelines for this situation. Based on the
findings of Kokkinos et al.5, who found that statin therapy
associated with a moderate-to-high physical fitness level
offers additional protection against premature cardiovascular
death, and a meta-analysis of prospective studies that assessed
the association of dose-response between exercise intensity
and cardiovascular protection, the author recommends
the practice of brisk walking for at least 3 hours a week to
maintain cardiovascular protection, but does not provide more
specifications regarding the intensity.
Considering the side effects on musculature, the author
proposes that dyslipidemic individuals using statins that have
their running capacity limited due to isolated muscle pain,
choose carrying out shorter or slower runs; however, he
emphasizes that the lack of evidence in the literature to deal
with cases where the pain is accompanied by an increase in
CK levels allows both the cessation or reduction in medication
dose, as well as reducing the intensity of exercise as possible
therapeutic measures, stressing the urgent need to perform
further research to find the balance between muscle symptoms
and cardiovascular protection levels52.
In summary, considering the current state-of-the-art, it is
observed that the situations of muscle injury caused by statins
may be exacerbated by high-intensity physical training and
acute eccentric and strenuous exercises, while the chronic
practice of exercises at moderate intensity, both before and
concomitantly to treatment with statins, can attenuate the
injuries and even improve muscle function of the practitioners
(Figure 2). In this sense, it is suggested that dyslipidemic
patients on statins be exposed to aerobic exercises combined
with resistance exercises of moderate intensity, three days
a week. The provision of physical training prior to the
administration of drug treatment is desirable; however, in cases
when this is not feasible, we suggest caution in prescribing
physical activity during the first weeks, when strenuous and
eccentric exercises should be avoided.
Conclusion
The research evidence shows that intense training performed
by athletes, as well as the practice of eccentric and strenuous
exercises may exacerbate muscle injury resulting from the
administration of statins. On the other hand, chronic exercises
of moderate intensity, performed both before and concurrently
to treatment with statins, can attenuate the harmful effects and
improve muscle function in its practitioners.
Author contributions
Conception and design of the research:Bonfim MR.
Acquisition of data: Bonfim MR. Analysis and interpretation of the
data: Bonfim MR. Writing of the manuscript: Bonfim MR, Oliveira
ASB, Amaral SL, Monteiro HL. Critical revision of the manuscript
for intellectual content: Oliveira ASB, Amaral SL, Monteiro HL.
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
Mariana Rotta Bonfim, from Programa de Pós-Graduação em
Ciências da Motricidade of Universidade Estadual Paulista UNESP, Campus de Rio Claro.
Dysfunction in calcium homeostasis
Statins
Mitochondrial dysfunction
↑ Reactive oxygen species
Strenuous exercise
↑ In up pathway activity
Myopathy
Mitochondrial function improvement
Moderate exercise
↑ Antioxidant capacity
↑ Muscle strength and resistance
Figure 2 – Muscle responses of the association of statins with physical exercise. Strenuous exercises are characterized by acute eccentric exercises, maximum capacity
tests and/or competitive activities; moderate exercises are characterized by aerobic training, with or without resistance training, usually performed three times a week
for 12 weeks. UP: ubiquitin proteasome.
330
Arq Bras Cardiol. 2015; 104(4):324-332
Bonfim et al.
Muscle Responses to Statins and Exercises
Review Article
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Back to the Cover
Letter to the Editor
Left Atrial Volume Index as Predictor of Events in Acute Coronary
Syndrome
Luciano Barros Pires and Rodrigo Pires dos Santos
Instituto de Cardiologia do Rio Grande do Sul, Porto Alegre, RS – Brazil
Dear Editor,
The Left Atrial Volume Index (LAVi) is a measurement
that has gained importance in daily clinical practice due
to evidence of its capacity to predict mortality, in patients
followed after an Acute Myocardial Infarction (AMI), as well
as in the general population1.
The study by Secundo Junior et al. sought to evaluate
the role of LAVi as a predictor of late events in patients
with acute coronary syndrome2. This study was able to
corroborate previous findings in patients with AMI and
demonstrated that increased LAVi may also be able to predict
major cardiovascular events in patients with unstable angina.
Correspondingly, it showed that patients with increased
LAVi were those with higher prevalence of systemic arterial
hypertension (SAH), previous AMI and angioplasty, of older
age, with higher body mass index (BMI), lower left ventricular
(LV) ejection fraction and more severe diastolic dysfunction,
showing that the index may be a marker related to a higher
occurrence of cardiovascular diseases and comorbidities.
In cohort studies, a significant problem is the presence of
non-controlled variables, which are potential confounding
factors that can possibly interfere with the results. The degree
of reperfusion success (assessed by TIMI flow, myocardial
blush or ST-segment recovery), which maintains significant
correlation with better survival, can be one of those factors
not measured in this study3. Another confounding factor could
be the incidence of atrial fibrillation (AF) in the extra-hospital
period. The causal association between AF and ischemic
cerebrovascular accident (CVA) has been documented,
regardless of echocardiographic findings. It is associated with
a four to five-fold increase in the risk of ischemic CVA4 and it
is responsible for more than 15% of these events in individuals
in all age ranges and 30% in individuals older than 80 years5.
Thus, it is not clear, in the results of Secundo Junior et
al., whether the high incidence of CVA in the non-hospital
follow-up was due only to the increase in LAVi or the possible
occurrence of this arrhythmia, and one cannot say that
there was no influence of better or worse reperfusion on the
incidence of events in either group.
Keywords
Organ Size; Heart Atria; Myocardial reperfusion; Atrial
Fibrillation; Acute Coronary Syndrome/mortality.
Mailing Address: Luciano Barros Pires •
Rua Pinheiro Machado, 467, Centro. Postal Code 96180000, Camaquã,
RS – Brazil
E-mail: [email protected], [email protected]
Manuscript received December 09, 2014; revised manuscript January 07,
2015; accepted January 12, 2015
DOI: 10.5935/abc.20150030
References
1.
Moller JE, Hillis GS, Oh JK, Seward JB, ReederGS, Wright RS, et al Left atrial
volume: a powerful predictor of survival after acute myocardial infarction.
Circulation, 2003;107(17):2207-12.
2. Santos MA, Faro GB, Soares CB, Silva AM, Secundo PF Jr,et al. Indice de
volume atrial esquerdo e predição de eventos em síndrome coronária
aguda: registro solar. Arq Bras Cardiol. 2014; 103(4): 282-91
3. Sattur S, Sarwar B, Sacchi TJ, Brener SJ. Correlation between markers of
reperfusion and mortality in ST-elevation myocardial infarction: a systematic
review. J Invasive Cardiol. 2014; 26(11):587-95.
333
4. Wolf PA, Abbolt RD, Kannel WB. Atrial fibrillation as an independente risk
factor for stroke: the Framinghan Study. Stroke. 1991;22(8):983-8.
5. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation: a major contributor
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Pires & Santos
LAVi and Cardiovascular Events
Letter to the Editor
Answer to Letter to the Editor
Thank you for your comments and interest in our research
and the SOLAR registry. Regarding the potential influence
of atrial fibrillation on the higher incidence of ischemic
cerebrovascular accident (CVA) in patients with high Left
Atrial Volume Index (LAVi), we believe it has not occurred
in a significant manner in our study. As shown in Table 3, no
significant difference was found regarding atrial fibrillation
as a late event between the groups (p = 0.14). As for the
possible inclusion of the degree of reperfusion success, we
consider it unlikely the presence of any influence of this
factor, as the aforementioned table showed no difference
regarding hospital treatment between the high LAVi and low
LAVi groups, for both clinical treatment alone (p = 0.42)
and for angioplasty (p = 0.56), as well as for myocardial
revascularization (p = 0.68).
Additionally, we believe that the chosen model was the
most adequate to the study design and statistical analysis. This
was demonstrated by the number of factors (eight) considering
the sample size, avoiding overfitting and remaining within a
prudent association between predictors and achieved number
of events. Several post hoc tests were used, such as landmark
analysis, proportional hazards assumption test and obtaining
Schoenfeld residuals.
These tests showed absence of violations, robust estimates
and satisfactory fit of the final model which, incidentally,
included factors of extreme clinical relevance and that are
easy to acquire, such as the age, gender, presence of diabetes
or hypertension acute coronary syndrome type and ejection
fraction, then adjusted to LAVi. Finally, because this is a
registry, it is indeed necessary to consider the virtual presence
of confounding factors and interactions, which was duly
explained in the midst of the article, when we describe the
potential limitations of this study.
Sincerely,
Marcos Antônio Almeida Santos
Antônio Carlos Sobral Sousa
José Alves Secundo Júnior
Arq Bras Cardiol. 2015; 104(4):333-334
334
Back to the Cover
Clinicoradiological Session
Case 4/2015 A 48-year-old Male Patient with Coarctation of the
Aorta, Bicuspid Aortic Valve and Normal Ascending Aorta
Edmar Atik, Raul Arrieta, Otávio Rizzi Coelho
Instituto do Coração, Faculdade de Medicina, Universidade de São Paulo – USP, São Paulo, SP - Brazil
Clinical data: The patient reported that, at the age of
23 years, he had been diagnosed with hypertension, which
was controlled with five antihypertensive medications.
An ultrasound study performed one month ago detected
low blood flow through the abdominal aorta. Coarctation
of the aorta was suspected, and further confirmed
by angiographic CT scan. He had no cardiovascular
complaints, but had a sedentary lifestyle.
Physical examination: normal breathing; acyanotic; brisk
pulses in upper limbs, absent in lower limbs. Weight: 77 kg;
height: 168 cm; Blood pressure − BP = right arm = left
arm = 125/75 mmHg; BP legs = 75 mmHg; heart rate −
HR: 86 bpm. Aorta clearly palpable on the suprasternal notch.
Mild grade 1/4 systolic murmur on the suprasternal notch.
Apical impulse not palpable in the precordium; absence
of systolic impulses on the left sternal border. Normal heart
sounds; grade 1/4 coarse systolic murmur in the aortic area,
with no irradiation. No murmurs in the back. Liver not palpable.
Laboratory tests
Electrocardiogram: Normal sinus rhythm, no chamber
overload. Sokoloff index = 20 mm; mild ventricular
repolarization abnormality. Left anterior hemiblock and septal
fibrosis. PA: +60o; QRSA: -45o; TA: +100o (Figure 1).
Chest radiograph: Normal cardiac silhouette (cardiothoracic
ratio: 0.48). Normal pulmonary vascular network and concave
arch of pulmonary artery. The posterior aortic arch was not
bulged; hyperdensity in some rib borders (Figure 1).
Echocardiogram: Bicuspid aortic valve with maximum
and mean pressure gradient of 14 and 7 mmHg, respectively.
The ascending aorta (AscAo) was not dilated (35 mm); aortic
arch = 37 mm; narrowing in the isthmic region (3 mm), with
pressure gradient of 51 mmHg. Cardiac chambers of normal
size. No myocardial hypertrophy; septum and posterior wall
with 9-mm thickness. Normal left ventricular function (69%).
CT angiography of the aorta: AscAo = 40 mm;
aortic crossing and descending aorta (DescAo) = 32 mm;
Keywords
Coarctation of Aorta, Bicuspid Aortic Stenosis; Percutaneous;
Aortic Treatment.
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 23, 2014; revised manuscript August 08, 2014; accepted
August 08, 2014.
DOI: 10.5935/abc.20140215
e27
narrowing at isthmus = 3 mm and at diaphragm = 25 mm.
Marked collateral circulation, corresponding to the intercostal,
bronchial and mammary arteries.
Cardiac catheterization: (Figure 2). Pressure levels were
as follows: left ventricle − LV = 160/12, AscAo = 130/80
and DescAo = 90/80 mmHg. Angiography showed clear
narrowing at the aortic isthmus of approximately 2.5 cm past
the left subclavian artery, with no AscAo or DescAo dilatation
distal to the obstruction.
Clinical diagnosis: Severe coarctation of the aorta at the
isthmic region and mild aortic valve stenosis in bicuspid valve
with no AscAo dilatation or hypertrophy, in natural course.
Clinical reasoning: The clinical elements of coarctation
of the aorta are clear and easy to identify, and are mainly
represented by contrasting pulses and BP between the upper
and lower limbs, as occurred in this case, although detected
late by indirect means of abdominal ultrasound. Noteworthy,
despite the long-standing heart disease with pressure overload,
no myocardial hypertrophy, signs of electric overload or
symptoms are observed. This results from the fact that, in this
obstructive anomaly, there is formation of collateral vessels
that deviate blood in order to nourish the general circulation.
Chest radiograph with normal cardiac silhouette expresses
preserved ventricular function, and surprisingly there is no
AscAo dilatation despite the presence of bicuspid aortic valve
and coarctation of the aorta.
Differential diagnosis: Aortic obstructions in adulthood
usually result from previous aortitis, as occurs in Takayasu
and Kawasaki disease, as well as in connective tissue and
infectious diseases.
Management: In view of the long-standing systolic impact,
even without myocardial hypertrophy and with increased
pressures in the proximal aorta circuit, operation is mandatory
aiming at relieving the arterial obstruction, which would imply
a greater possibility of development of myocardial fibrosis,
heart failure, arrhythmias and earlier death. Dilatation of
the isthmic region was chosen using therapeutic cardiac
catheterization from the right femoral artery with placement
of a 40 x 18-mm stent just past the origin of the left subclavian
artery. Systolic BP immediately decreased to 100 mmHg
even without the use of antihypertensive drugs. Adequate
enlargement of the region was achieved (Figure 2) with
equalization of pressures between limbs. The mild systolic
murmur of aortic valve stenosis remained unchanged.
Commentaries: Cardiac compensation with maintained
antegrade flow, in coarctation of the aorta, is achieved by
the myocardial hypertrophy and/or development of collateral
circulation, which alleviates the aortic obstruction and
satisfactorily nourishes the circulation. In this case, the marked
aortic obstruction detected in adulthood and manifested
Edmar Atik
Coarctation of the Aorta and Bicuspid Aortic Valve
Clinicoradiological Session
Figure 1 – Chest radiography showing normal cardiac silhouette. 40 x 18-mm stent positioned in the beginning of the descending aorta, corresponding to the arch of the
pulmonary artery. Hyperdensity can be observed in the lower border of some ribs. On electrocardiogram, left anterior hemiblock, septal fibrosis and upper lateral ischemia.
by hypertension, was compensated by exuberant collateral
circulation. Hence the favorable outcome until the fifth
decade of life. Left anterior hemiblock and septal fibrosis on
the electrocardiogram are difficult to explain in the absence
of myocardial hypertrophy. Even when hemodynamically
compensated, this obstructive anomaly should be treated
early so as to prevent an unfavorable outcome in relation to
the development of myocardial fibrosis, arrhythmias and heart
failure. In the course of bicuspid aortic valve, unfavorable
elements such as AscAo dilatation arise, and these invariably
should be treated surgically in a timely manner. However, in
this patient, the expected aortic dilatation was not observed,
and this makes a good outcome possible even for a longer
term. Aortic dilatation seems to be more related to inherent
factors of the arterial wall (adequate morphology of the parietal
muscle) than to hemodynamic aspects1.
Arq Bras Cardiol. 2015; 104(4):e27-e29
e28
Edmar Atik
Coarctation of the Aorta and Bicuspid Aortic Valve
Clinicoradiological Session
Figure 2 – Upper angiographic images (A and B) show marked isthmic coarctation of the aorta with normal ascending aorta, and exuberant collateral circulation; C and
D show images of the descending aorta after placement of a 40 x 18-mm stent, with uniform diameters and no post-stenotic dilatation.
Reference
1. Jackson V, Petrini J, Caidahl K, Eriksson MJ, Liska J, Eriksson P, et al. Bicuspid
aortic valve leaflet morphology in relation to aortic root morphology: a study
of 300 patients undergoing open-heart surgery. Eur J Cardiothorac Surg.
2011;40(3):e118-24. Erratum in: Eur J Cardiothorac Surg. 2012;41(2):471.
e29
Arq Bras Cardiol. 2015; 104(4):e27-e29
Back to the Cover
Case Report
Sickle-cell Anemia and Latent Diastolic Dysfunction:
Echocardiographic Alterations
André Fattori, Daniela Camargo Oliveira, Roger Frigério Castilho, Otávio Rizzi Coelho
Faculdade de Ciências Médicas da Universidade Estadual de Campinas – Unicamp, São Paulo, SP - Brazil
Introduction
Sickle-cell anemia (SCA) is a disease that can cause
systemic complications, such as multiple organ dysfunction
due to vaso - occlusion and endothelial activation.
The genetic cause of the disease is a substitution of the
amino acid glutamic acid for valine in the position 6
of the beta globin chain1. Stress factors in the vascular
microenvironment (cellular dehydration, hypoxemia,
increased corpuscular hemoglobin concentration,
decreased red blood cell transit time in the microcirculation,
and decreased blood pH) trigger intracellular hemoglobin
polymerization, forming paracrystalline structures that
cause sickling of erythrocytes and increased blood viscosity,
hemolysis, and vaso-occlusion 1,2. Simultaneously, free
hemoglobin in the plasma sequesters nitric oxide (NO),
leading to decreased NO bioavailability and increased
endothelial adhesion (in physiological conditions, NO
inhibits of platelet aggregation, platelet activation,
transcription of platelet adhesion proteins)1.
The increase in cardiac output (CO), the afterload
reduction due to the peripheral vasodilation as a response to
hypoxemia, the increase in blood viscosity secondary to the
morphological alterations, and the loss of the deformability
of the sickle red blood cells are factors involved with the
systolic ventricular overload and progressive enlargement
of the cardiac chambers3-5.
Case Report
In the present paper, we report the adverse effects
after volume expansion observed in a single patient with
SCA. Initial examination showed borderline left ventricular
systolic function, without evident diastolic dysfunction on
echocardiography, which was performed as part of a study
protocol for cardiac complications in adults with SCA and was
previously approved by the local ethics committee.
We present the details of the case below. The patient
was a 40-year-old male SCA patient without history
Keywords
Ventricular Dysfunction; Heart Rate; Anemia, Sickle Cell;
Echocardiography, Doppler
Mailing Address: André Fattori •
Rua Joaquim de Paula Souza, 52, Proença. Postal Code: 13026-210,
Campinas – SP, Brazil
E-mail: [email protected]; [email protected]
Manuscript received, March 6, 2014, revised August 16, 2014,
accepted August 26, 2014.
DOI: 10.5935/abc.20150027
e30
of symptoms except for the complaint of sporadic
palpitations related to moderate physical effort at
presentation. Cardiac function was evaluated using
two-dimensional echocardiography in M-mode, pulsed
wave Doppler, continuous wave Doppler, color Doppler,
and tissue Doppler6,7. Baseline laboratory examinations
showed serum hemoglobin levels of 10.1 mg/dL, lactate
dehydrogenase (LD) levels of 1,002 U/L, ferritin levels
of 280.9 ng/mL, NT-pro-BNP levels of 250.0 pg/ml; the
electrophoretic profile of hemoglobin determined by
high‑performance liquid chromatography showed 82.6%
HBS and 3.8%, HA2, with the remainder being HBF.
After the initial examination, the patient underwent normal
saline infusion. After 12 min of infusion (400 ml), he complained
of palpitation and dyspnea. Physical examination showed an
elevated jugular venous column and pulmonary crepitations.
Echocardiography was repeated and isolated periods of
supraventricular bigeminy and supraventricular extrasystoles
were observed (Table 1); these findings persisted for up to
10 min after the infusion was stopped. When echocardiography
was repeated again after restarting intravenous normal saline
infusion, important variations were observed in chamber sizes
and parameters indicating diastolic function compared with
the values obtained at baseline. The left atrium (LA), which
initially showed a small increase in volume (34.0 ml/m²),
showed marked dilatation (56.0 ml/m²); the ejection fraction
was normal, as assessed by the Teicholtz (60%) and Simpson
(54%) methods (Figures 1 and 2).
Discussion
With regard to the parameters of diastolic function
analyzed in the present case, a progression to an abnormal
diastolic filling pattern was observed in the second
echocardiographic examination, as shown in Table 1.
The E/A ratio showed a marked increase, compatible with
an abnormal diastolic filling pattern, as observed in type II
diastolic dysfunction. These findings were corroborated by
the appearance of the L wave and the inversion of the S/D
flow in the pulmonary vein7. Other characteristic indicators of
diastolic dysfunction, such as increased isovolumic relaxation
time and E wave deceleration time, were compatible with
myocardial overload.
The expected change in diastolic function during pressure
overload of LA would be a reduction of E and mitral E velocities
and the maintenance of an elevated E/E’ ratio proportional
to the degree of diastolic dysfunction. In the present case,
mitral flow velocities were paradoxically decreased; however,
E’ velocity increased. Thus, mitral flow velocities were not
considered to be a reliable marker of diastolic dysfunction for
this patient. The pulmonary venous flow was a more accurate
Fattori et al.
Diastolic dysfunction in sickle-cell anemia
Case Report
Table 1 – Echocardiographic measures at baseline and after the volume load (400 mL of 0.9% saline solution)
Parameter
Aortic root diameter (cm)
Baseline
Value at overload
3.1
3.3
Left atrial diameter (cm)
4.4
4.4
Left atrial volume (end of the ventricular systole), ml/m2
34.0
56.0
Maximum right atrial volume (ml)
44.0
47.0
LV end-diastolic diameter (cm)
5.5
5.5
LV end-systolic diameter (cm)
3.8
3.7
Thickness of the interventricular septum (cm)
0.80
0.90
Thickness of LV posterior wall (cm)
0.80
0.80
RV end-diastolic diameter (cm)
2.4
2.3
Left ventricular mass (g)
122
142
LEV mass/volume ratio
0.80
0.90
Teichholz ejection fraction
58%
60%
Simpson ejection fraction
50%
54%
Mitral E/A ratio
1.27
2.67
Deceleration time (ms)
0.150
0.217
Isovolumic relaxation time (ms)
0.046
0.096
E wave (cm/s)
86.8
80.8
A wave (cm/s)
68.5
30.2
Mitral/Septal S’ wave (cm/s)
8.70
8.70
Mitral/Septal E’ wave (cm/s)
12.80
13.40
Septal/mitral E/E’ ratio
6.78
6.03
Septal/mitral E’/A’ ratio
1.47
2.4
TEI index
0.23
0.34
Acceleration time/ejection time
0.48
0.47
Mitral gradient
28.0
25.0
>1
<1
Systolic flow/diastolic flow of the pulmonary vein
marker of the alteration from the normal pattern to an abnormal
diastolic filling pattern. It is possible that this phenomenon is
related to a hyperdynamic cardiac state secondary to anemia,
probably because of increased recruitment of cardiac muscle
fibers during volume overload (evidenced by the increased E’
velocity and increased ejection fraction).
An important characteristic that was also evaluated
was the rate of global ventricular performance, or the Tei
index, a parameter indicated for the standardization and
comparison of results obtained by different studies. In this
patient, the Tei index increased from 0.23 to 0.34 after
normal saline infusion. This worsening of performance can
be explained by the increase in the duration of isovolumic
contraction and relaxation, combined with decreased
ventricular compliance. It is interesting to note that the
heart rate did not change in the observation period.
The echocardiographic follow-up used independent
measures of volume load because the hemodynamic
characteristics of SCA, such as increased CO, may mask
diastolic dysfunction, thus leading to the underdiagnosis of
the condition. The patient described in this case showed two
biochemical markers associated with unfavorable outcomes.
Elevated LD values are indicators of marked hemolysis
and predictors of clinical complications in SCA, mainly
those associated with endothelial activation and chronic
inflammation.8-10 Another characteristic was the elevation in
NT-pro-BNP levels, which were at 250.0 pg/ml at baseline in
the present case; this may suggest the subclinical impairment
of cardiac function. NT-pro‑BNP levels > 160.0 pg/mL
have been associated with the diagnosis of pulmonary
hypertension, and they are considered an independent risk
factor for high mortality.8-10
The importance of this case lies in the fact that
cardiopulmonary complications are the main cause of death
in SCA patients. In particular, in the present case, a normal
echocardiographic pattern was observed before volume
stress. This suggests that some SCA patients can present with
potentially fatal complications even if few abnormalities are
observed at examination. Additional studies are needed
to better understand the alterations in ventricular/atrial
Arq Bras Cardiol. 2015; 104(4):e30-e33
e31
Fattori et al.
Diastolic dysfunction in sickle-cell anemia
Case Report
Figure 1 – (A) Parasternal view in M-mode showing the aorta and the left atrium. (B) The same view as figure A, with ECG showing isolated ventricular extrasystoles.
(C) Baseline spectral Doppler recording of the mitral flow. (D) Postinfusion spectral Doppler recording, showing mitral reflux and the development of the L wave.
Figure 2 – Apical views of the four chambers before (A) and after (B) volume expansion, showing left atrial volumes of 34 mL/m2 and 56 mL/m2, respectively.
e32
Arq Bras Cardiol. 2015; 104(4):e30-e33
Fattori et al.
Diastolic dysfunction in sickle-cell anemia
Case Report
compliance and diastolic function as well as to identify
patients at risk of hemodynamic decompensation and
adverse outcomes.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Author contributions
Conception and design of the research: Fattori A, Oliveira
DC, Coelho OR; Acquisition of data and Writing of the
manuscript: Fattori A, Oliveira DC; Analysis and interpretation
of the data and Critical revision of the manuscript for
intellectual content: Fattori A, Oliveira DC, Castilho RF, Coelho
OR; Statistical analysis and Obtaining financing: Fattori A;
Fattori A, Oliveira DC, Castilho RF, Coelho OR.
Sources of Funding
This study was funded by FAPESP.
Study Association
This article is part of the thesis of Doctoral submitted
by Daniela Camargo Oliveira, from Faculdade de Ciências
Médicas - UNICAMP.
References
1. Kato GJ, Gladwin MT, Steinberg MH. Deconstructing sickle cell disease:
reappraisal of the role of hemolysis in the development of clinical
subphenotypes. Blood. 2007; 21(1):37-47.
2.
Eaton WA, Hofrichter J. Sickle cell hemoglobin polymerization. Adv Protein
Chem.1990;40:63-279.
3.
Covitz W, Espeland M, Gallagher D, Hellenbrand W, Leff S, Talner N. The heart
in sickle cell anemia. The Cooperative Study of Sickle Cell Disease (CSSCD).
Chest. 1995; 108(5):1214-9.
4. Eddine AC, Alvarez O, Lipshultz SE, Kardon R, Arheart K, Swaminathan S.
Ventricular structure and function in children with sickle cell disease
using conventional and tissue Doppler echocardiography.Am J
Cardiol.2012;109(9):1358-64.
5. Martins WA, Mesquita ET, Cunha DM, Ferrari AH, Pinheiro LAF, Filho
LJ.et al. Alterações cardiovasculares na anemia falciforme. Arq Bras
Cardiol.1998;70(5):365-70.
6.
Cheitlin MD, Alpert JS, Armstrong WF, Aurigemma GP, Beller GA, Bierman FZ
et al. ACC/AHA guidelines for the clinical application of echocardiography.
A report of the American College of Cardiology/American Heart Association
Task Force on Practice Guidelines (Committee on Clinical Application of
Echocardiography). Developed in collaboration with the American Society
of Echocardiography. Circulation. 1997;95(6):1686-744.
7.
Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA et al.
Recommendations for the evaluation of left ventricular diastolic function by
echocardiography. J Am Soc Echocardiogr. 2009;22(2):107-33.
8. Voskaridou E, Tsetsos G, Tsoutsias A, Spyropoulou E, Christoulas D, Terpos
E. Pulmonary hypertension in patients with sickle cell/beta thalassemia:
incidence and correlation with serum N-terminal pro-br92(6):738-43.ain
natriuretic peptide concentrations. Haematologica. 2007;92(6):73-43.
9.
Takatsuki S, Ivy DD, Nuss R. Correlation of N-terminal fragment of B-type
natriuretic peptide levels with clinical, laboratory, and echocardiographic
abnormalities in children with sickle cell disease. J Pediatr. 2012;160(3):428-33.
10. Aliyu ZY, Suleiman A, Attah E, Mamman AI, Babadoko A, Nouraie M et al.
NT-proBNP as a marker of cardiopulmonary status in sickle cell anaemia in
Africa. Br J Haematol.2010;150(1):102-7.
Arq Bras Cardiol. 2015; 104(4):e30-e33
e33
Back to the Cover
Viewpoint
Correct Anatomical Orientation of the Heart and Reflections on the
Nomenclature Used in Daily Practice
Viviane Tiemi Hotta1,2 and Vera Demarchi Aiello1
Instituto do Coração/Faculdade de Medicina da Universidade de São Paulo1; Fleury Medicina e Saúde2, São Paulo, SP – Brazil
In daily clinical practice and during the preparation of a
scientific publication, it is important to use the appropriate
nomenclature for an enhanced understanding of the
descriptions provided. The correct use of anatomical
terminology is the basis for universal communication in the
field of health, and it is based on the Latin nomenclature
originally published in 1895 (Basel Nomina Anatomica).
In addition, it allows the standardization of reports,
manuscripts, and scientific communication between
different specialties and imaging techniques.
The first Brazilian edition of the Anatomical Terminology
was published in 2001 and was used as reference for
this report. This study is the result of a joint effort of the
Federative Committee on Anatomical Terminology (FCAT) and
56 associations composed of members of the International
Federation of Associations of Anatomists (IFAA). The Brazilian
edition was translated by the Anatomical Terminology
Commission of the Brazilian Society of Anatomy1.
With regard to cardiac nomenclature, some terms
suggested by FCAT are not the most commonly used;
therefore, terms incorporated by usage may be employed
more frequently but do not necessarily represent the correct
way to designate anatomical structures. In particular, some
terms deserve special attention because of their frequency
of use. In addition, some of the terms present in the
Basel Nomina Anatomica have been questioned for not
representing the appropriate description of the anatomical
position or even the shape of the structure2-4.
A term that is usually used imprecisely in cardiology refers to
the heart valves: mitral, tricuspid, aortic, and pulmonary, often
referred to as “valvules.” As a matter of fact, the components or
functional units of the heart valves that are designated by the
Terminology Commission as valvules, which are defined as “small
valves.” This same committee has long attempted to modify the
term cuspid—which is defined as apex, acute end, peak, vertex—
by another term considered more appropriate: valvules or
leaflets, which are the subdivisions of the atrioventricular valves.
Anatomically, the FCAT considers that the description of the valve
Keywords
Terminology as Topic; Systematized Nomenclature of
Medicine; Cardiology/classification.
Mailing Address: Viviane Tiemi Hotta •
Unidade Clínica de Miocardiopatias do InCor/FMUSP. Avenida Doutor Enéas
Carvalho de Aguiar, 44. Postal Code 05403-000, São Paulo, SP – Brazil
E-mail: viviane.hotta@grupofleury,com,br; [email protected]
Manuscript received August 27, 2014; revised manuscript January 10, 2015;
accepted January 12, 2015.
DOI: 10.5935/abc.20150029
e34
shape as cusp or peak is not appropriate for the functional units
(or valvules) of the atrioventricular valves1.
In addition to the use of inappropriate terms with regard
to the shape of the cardiac structures, another relevant
concern is the failure to describe their location relative to the
conventional anatomical position.
In 2002, Cerqueira et al.5 published recommendations
from the Cardiac Imaging Committee of the American Heart
Association in an attempt to standardize the nomenclature
of different cardiac imaging techniques, including nuclear
medicine, magnetic resonance, computed tomography,
echocardiography, and coronary angiography5. Despite the
technical differences between these techniques, all of them
aim to describe the heart and adjacent structures as accurately
as possible. However, each of these techniques have evolved
independently with respect to the description of cardiac
orientation, number and classification of the myocardial
segments, and distribution of coronary arteries, considering
the inherent capabilities and limitations of each technique.
Therefore, to facilitate communication and the correlation
between the cardiac imaging techniques, the authors suggested
that all techniques should guide and show the heart along its
longitudinal axis, and the remaining planes should be oriented
orthogonally with respect to the longitudinal axis of the heart.
A simple Internet search (October 2014) indicates that this
study has been cited in the literature more than 2000 times;
therefore, it became an important reference in cardiovascular
nomenclature. In this study, the authors—who belong to
a committee of the American Heart Association that met
specifically to discuss nomenclature—corrected a clear failure
in the nomenclature of the inferior cardiac wall, formerly and
incorrectly designated as “posterior.” However, they continued
naming the wall opposite the inferior (diaphragmatic) wall as
“anterior.” The simple observation of Figure 1, showing the
heart on a CT scan, leaves no doubt that the wall opposite
the inferior wall is located superiorly. In addition, Figure 1
shows that the anterior portion of the left ventricular wall is
in fact the ventricular septum. This inconsistency should be
taken into consideration by those who examine the heart in
its natural position within the chest.
A similar inconsistency is related to the current
designation of the papillary muscles of the left ventricle.
The group known as “anterior-lateral” is in fact located
posteriorly in relation to the group usually designated as
“posterior-medial” (Figure 1).
In addition, in the anatomical position, the heart chambers
designated “right” are in reality located superoranteriorly to
the chambers referred to as “left” (Figure 1). This standard
nomenclature facilitates the description of right-left shunts, or
vice versa, but does not reflect the true anatomical position.
Hotta & Aiello
Correct Anatomical Orientation: Will We Adapt To It?
Viewpoint
Figure 1 – Left, schematic representation of the location of the heart in relation to its anatomical position within the thorax, showing the cardiac longitudinal axis (above).
View of the heart when the cardiac longitudinal axis is positioned with the heart in the anatomical position (middle) and according to the vertical orientation used in the
conventional nomenclature that is currently employed (below), considering the heart removed from the chest and resting on its apex. Right (above), computed tomography
images showing the position of the heart in relation to the spinal cord and the sternum (A). B, CT scan image of the ventricular mass in short (transverse) axis at the
level of the papillary muscles shows the anterior location of the “posterior-medial” muscle group (orange arrow) in relation to the “anterior-lateral” papillary muscle group.
The location of the myocardial walls in relation to the anatomical position is evidenced (correlate with Table 1).
A: anterior; H: head-cranial or superior; F: foot-caudal or inferior; RV: right ventricle; LV: left ventricle.
In another example, the coronary artery known as the posterior
descending artery is located on the diaphragmatic surface of
the heart and has an interventricular and inferior trajectory (not
descending and posterior)6,7. Its occlusion leads to an infarction
designated by cardiologists as “infarction of the inferior wall,”
despite the name of the coronary artery involved.
The issue of the use of nomenclature considering the
anatomical position of the heart has been treated with
great attention and care by electrophysiologists to facilitate
the teaching and understanding of the diagnostic and
interventionist catheterization performed by doctors in
training2. During the insertion of a catheter into the inferior
vena cava towards the apex of Koch’s triangle, where the
atrioventricular node is located, the direction of movement
was, in a not too distant past, described as “anterior,” in view
of the incorrect habit of describing the heart out of the chest
and supported vertically on its apex. However, the apex of
Koch’s triangle is located superiorly in relation to the vena
cava orifice, when considering the anatomical position of the
heart. These old habits of nomenclature can lead to errors
in learning and even iatrogenic errors.
Cosio et al.2 suggested a nomenclature of the cardiac walls
taking into consideration the correct anatomical orientation
of the heart (Table 1).
Closing remarks
This study does not intend to exhaust the subject
nor recommend an immediate change in the current
nomenclature. It aims to acknowledge and educate
the reader about the frequent use of terms that are
not completely adequate in describing the cardiac
morphology evaluated with different imaging techniques.
The nomenclature based on the correct anatomical
orientation significantly facilitates the spatial location of the
cardiac structures and the relationship of the heart with the
other organs. It also allows the exchange and comparison
of information between different imaging techniques and
guides diagnostic and therapeutic procedures, e.g., in
electrophysiology or multimodal examination.
However, the adoption of changes in nomenclature
already established by usage will require increased user
awareness and recognition of the need for change and
efforts towards the implementation and acceptance of
these changes.
Acknowledgments
We thank Dr José Rodrigues Parga Filho for the cardiac
computed tomographic images that illustrate this article.
Arq Bras Cardiol. 2015; 104(4):e34-e36
e35
Hotta & Aiello
Correct Anatomical Orientation: Will We Adapt To It?
Viewpoint
Author contributions
Sources of Funding
Conception and design of the research: Hotta VT, Aiello VD.
Writing of the manuscript: Hotta VT, Aiello VD. Critical revision
of the manuscript for intellectual content: Hotta VT, Aiello VD.
Study Association
Potential Conflict of Interest
There were no external funding sources for this study.
This study is not associated with any thesis or
dissertation work.
No potential conflict of interest relevant to this article
was reported.
Table 1 – Conventional nomenclature vs. nomenclature that considers the anatomical position
Myocardial wall (Conventional nomenclature)
Myocardial wall (Nomenclature that considers the anatomical position)
1. Inferior-septal
Inferior-septal (maintained)
2. Anterior-septal
Superior-septal
3. Anterior
Superior
4. Anterior lateral
Posterior superior
5. Inferior lateral or posterior
Posterior inferior
6. Inferior
Inferior (maintained)
Source: Adapted from Cosío et al.2
References
1.
Sociedade Brasileira de Anatomia. Terminologia anatômica. São Paulo: Ed.
Manole Ltda.; 2001.
4.
Message MA, Anderson RH. Towards a new terminology for clinical anatomy,
with special reference to the heart. Clin Anat. 1996;9(5):317-29.
2. Cosío FG, Anderson RH, Kuck KH, Becker A, Borggrefe M, Campbell
RW, et al. Living anatomy of the atrioventricular junctions. A guide to
electrophysiologic mapping. A Consensus Statement from the Cardiac
Nomenclature Study Group, Working Group of Arrhythmias, European
Society of Cardiology, and the Task Force on Cardiac Nomenclature from
NASPE. Circulation. 1999;100(5):e31-7.
5.
Cerqueira MD, Weissman NJ, Dilsizian V, Jacobs AK, Kaul S, Laskey WK, et al.
Standardized myocardial segmentation and nomenclature for tomographic
imaging of the heart. A statement for healthcare professionals from the
Cardiac Imaging Committee of the Council on Clinical Cardiology of the
American Heart Association. Circulation. 2002;105(4):539-42.
3. Selvester RH. Nomina anatomica contradicta revisited: especially as it
relates to cardiac imaging and electrocardiology. J Electrocardiol. 2008;
41(5):421-2.
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Arq Bras Cardiol. 2015; 104(4):e34-e36
6. Anderson RH, Loukas M. The importance of attitudinally appropriate
description of cardiac anatomy. Clin Anat. 2009; 22(1):47-51.
7. Cook AC, Anderson RH. Attitudinally correct nomenclature. Heart. 2002;
87(6):503-6.
Back to the Cover
Image
Incremental Value Of 3D Transesophageal Echocardiography for The
Assessment of Mitral Valve Prolapse
Viviane Tiemi Hotta1,2, Mirian Magalhães Pardi1,2, Valdir Ambrósio Moisés1,3
Fleury Medicina e Saúde1; Instituto do Coração da Faculdade Medicina da Universidade de São Paulo (USP)2, São Paulo, SP; Escola Paulista de
Medicina, Universidade Federal de São Paulo (Unifesp)3, São Paulo, SP – Brazil
A 90-year-old asymptomatic patient with atrial fibrillation
underwent a transesophageal echocardiography (TEE) for the
assessment of thrombus. The TEE examination evidenced
mitral valve anterior leaflet prolapse with moderate to severe
eccentric regurgitation. Three-dimensional (3D)-TEE was
performed and showed chordal rupture (A2) related to the
anterior scallop of the mitral valve (Figure 1 e video 1). In this
case, 3D-TEE provided additional anatomical information
regarding the mitral valve, allowing the diagnosis of flail leaflet
and chordal rupture, not assessed by the 2D evaluation.
B
A
LA
LA
RA
RV
LV
LV
C
LA
D
LA
AO
RV
LV
LV
E
F
Figure 1 – 2D-TEE, four-chamber view showing mitral valve prolapse at 0° (A) e 34° (B) rotation of imaging array. C and D. 2D TEE color flow mapping evidencing
eccentric mitral regurgitation, directed posteriorly at 0° (C) and 138° (D) rotation of imaging array. E and F. 3D-TEE images showing the mitral valve prolapse of the
anterior leaflet (A2) (E, arrow), in a surgical view (from the left atrium, LA) and chordal rupture (F, arrow). TEE: transesophageal echocardiography; RA: right atrium;
RV: right ventricule; LV: left ventricule; AO: aorta.
Keywords
Echocardiography, Transesophageal / utilization; Echocardiography, Three Dimensional / utilization; Mitral Valve Prolapse.
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.
E-mail: [email protected], [email protected]
Manuscript received September 1, 2014; revised manuscript Sptember 8, 2014; accepted September 8, 2014.
DOI: 10.5935/abc.20140200
37
Hotta et al.
Incremental Value Obtained By 3D-TE For Mitral Prolapse
Image
Video 1 – Additional Supporting Information: Real time 3D TEE cine loops evidence chordal rupture (A2) associated with mitral valve prolapse.
Arq Bras Cardiol. 2015; 104(4):e37-e38
38

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