Noninvasive prognostic markers for cardiac death and ventricular arrhythmia in long-term follow-up

12 Pages·2007·0.65 MB·English

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ISSN 0100-879X
Noninvasive prognostic markers for
cardiac death and ventricular
arrhythmia in long-term follow-up of
subjects with chronic Chagas’ disease
P.R. Benchimol Barbosa1,2 1Seção de Arritmia e Eletrofisiologia, Hospital Universitário Pedro Ernesto,
Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brasil
2Serviço de Métodos Diagnósticos em Cardiologia, Hospital Central Aristarcho Pessoa,
Corpo de Bombeiros Militar do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brasil
Abstract
Correspondence The objective of the present study was to investigate clinical, echocar- Key words
P.R. Benchimol Barbosa diographic and electrocardiographic (12-lead resting ECG, 24-h am- •Chagas’ disease
Rua Pompeu Loureiro, 36/702 bulatory ECG monitoring and signal-averaged ECG (SAECG)) pa- •Cardiomyopathy
22061-000 Rio de Janeiro, RJ rameters in subjects with chronic Chagas’ disease in a long-term •Noninvasive prognostic
Brasil follow-up as prognostic markers for adverse outcomes. Fifty adult assessment
E-mail: [email protected] •Long-term follow-up study
outpatients (34 to 74 years old, 31 females) staged according to Los
•Echocardiography
Andes class I, II or III and complaining of palpitation were enrolled in
Research supported by Faculdade •Electrocardiography
de Ciências Médicas, UERJ (No. a longitudinal study. SAECG was analyzed in time and frequency
5152/2001), Rio de Janeiro, RJ, domains and the endpoint was a composite of cardiac death and
Brasil. ventricular tachycardia. During a follow-up of 84.2 ± 39.0 months,
34.0% of the patients developed adverse outcomes (9 cardiac deaths
and 11 episodes of ventricular tachycardia). After optimal dichotomi-
zation, in a stepwise multivariate Cox-hazard regression model, apical
Received April 28, 2006
aneurysm (HR = 3.7; 95% CI = 1.2-1.3; P = 0.02), left ventricular
Accepted October 9, 2006
ejection fraction <62% (HR = 4.60; 95% CI = 1.39-15.24; P = 0.01)
and incidence of ventricular premature contractions >614 per 24 h
(hazard ratio = 6.1; 95% CI = 1.7-22.6; P = 0.006) were independent
predictors of the composite endpoint. Although a high frequency
content in SAECG demonstrated association with the presence of left
ventricular dysfunction and myocardial fibrosis, its predictive value
for the composite endpoint was not significant. Apical aneurysms,
reduced left ventricular function and a high incidence of ventricular
ectopic beats over a 24-h period have a strong predictive value for a
composite endpoint of cardiac death and ventricular tachycardia in
subjects with chronic Chagas’ disease.
Introduction cause of chronic cardiomyopathy due to an
immune-mediated response in Latin Amer-
American trypanosomiasis (Chagas’ dis- ica. The disease affects over 18,000,000
ease) is an anthropozoonosis circumscribed people in South America (1) with a mortality
to the American continent and the major rate of 6000/year (2,3), potentially becom-
Braz J Med Biol Res 40(2) 2007
168 P.R. Benchimol Barbosa
ing a significant healthcare-related problem ELISA and indirect immunofluorescence.
in Europe and the United States due to mi- All subjects were referred to the arrhythmia
gration (4). Systemic infection is generally unit with a complaint of palpitations. At the
acquired at an early age (5,6), has an insidi- time of admission, due to the lack of benefi-
ous and asymptomatic course ranging from cial effects demonstrated thus far, none had
10 to 30 years and progresses to myocardial received nitroderivative therapy. According
dysfunction, which occurs in 20-25% of in- to the Los Andes classification (20), subjects
fected subjects, representing a marker of were staged into three groups: class I - 14
unfavorable prognosis for cardiac mortality subjects (group 1), class II - 24 subjects
(7-10). (group 2), and class III - 12 subjects (group
Electrical markers of abnormal ventricu- 3). Clinical and laboratory data were as-
lar activation (5,11,12) and repolarization sessed during a personal interview and by
(13,14) have been demonstrated to be im- review of medical records. At admission, all
portant predictors of mortality risk in both subjects were in New York Heart Associa-
the general population and in subjects with tion (NYHA) functional class I or II, had
Chagas’ disease. Particularly, the signal- normal sinus rhythm and normal PR inter-
averaged electrocardiogram (SAECG) is a val. Exclusion criteria at initial enrollment
noninvasive method applied to assess the were: any degree of atrioventricular block or
presence of abnormal electrical potentials non-sinus rhythm, previous documented
during ventricular activation (ventricular late acute coronary events (unstable angina or
potentials), which are considered to be mark- myocardial infarction), chronic obstructive
ers of myocardial fibrosis and arrhythmia pulmonary disease, rheumatic or nonrheu-
(15-17). However, information regarding matic valvular heart disease, alcohol addic-
the predictive value of SAECG in subjects tion, thyroid dysfunction, or abnormal se-
with chronic Chagas’ cardiomyopathy is lim- rum electrolytes. A treadmill stress test or a
ited (18,19). Thus, the objective of the pres- coronary artery angiogram was indicated in
ent study was to assess the prognostic value selected subjects to exclude concomitant
of clinical, echocardiographic, and 12-lead coronary artery disease. World Health Or-
resting ECG, 24-h ambulatory ECG moni- ganization and Helsinki Treaty regulations
toring, and SAECG parameters in subjects reviewed in Venice (1983) were followed.
with Chagas’ disease in a long-term follow- The study was approved by the local Ethics
up. Committee and all subjects provided written
informed consent.
Material and Methods
Clinical follow-up
In a longitudinal prospective study, a
cohort of 50 consecutive subjects (34 to 74 All subjects have been followed-up by
years old; 31 females) with Chagas’ disease the same team of physicians for the past 10
followed up for at least 10 years at the car- years. Medical visits have been scheduled at
diomyopathy outpatient clinic of Pedro the outpatient clinic at 6-month intervals and
Ernesto University Hospital, Rio de Janeiro, medications are prescribed at the discretion
RJ, Brazil, a tertiary care center, was en- of the physician who performed the primary
rolled from 1995 to 1999. Subjects had been evaluation. Body weight varied <2 kg dur-
born in endemic regions of the Minas Gerais ing follow-up, and serum potassium varied
and Bahia States of Brazil and Chagas’ dis- from 3.5 to 5 mEq/L. Mild systemic arterial
ease was diagnosed on the basis of positive hypertension was observed in 41% of the
serum tests, hemagglutination cruzipain- patients and was treated with converting
Braz J Med Biol Res 40(2) 2007
Noninvasive prognostic markers in Chagas’ heart disease 169
enzyme inhibitors, diuretics, vasodilators Resting surface ECG and corrected XYZ Frank
and/or ß-blockers at the discretion of the vectorcardiogram
physician who performed the primary evalu-
ation in order to reduce blood pressure levels For each subject, standard resting 12-
to less than 140/90 mmHg. The follow-up of lead ECGs were recorded in the supine posi-
the present study was abbreviated according tion (with simultaneous 3-lead acquisition)
to the endpoint, defined as a composite of with a Cardimax ECAPS 12 2000 Compliant
either cardiac death or documented episodes Electrocardiograph (Nihon-Kohden Co., To-
of ventricular tachycardia (VT). Subjects kyo, Japan) on the same day of blood sample
were excluded from follow-up after the first collection. Electrocardiographic abnormali-
documented VT endpoint. All causes of ad- ties were classified according to standard
verse events were ascertained by review of criteria for conduction disturbances (intra-
the medical records and by arrhythmic epi- ventricular and atrioventricular), chamber
sodes documented by 24-h ambulatory ECG overload, and pathologic Q waves. The vec-
monitoring or 12-lead resting ECG records. torcardiogram was recorded using corrected-
The difference between the last and the ini- XYZ Frank leads with 1507c Programmer
tial NYHA classes was used to assess pro- model Hewlett Packard equipment (Hewlett
gression of subjective symptoms during fol- Packard, Palo Alto, CA, USA) with the sub-
low-up. ject in the supine position, in a quiet environ-
ment, and used to assess the presence of
Echocardiogram intraventricular conduction disorders and to
confirm electrical markers of inactive areas
M-mode and two-dimensional echocar- (pathologic Q wave in a 12-lead resting
diograms were analyzed by a trained observer ECG). The electrocardiographic variables
blind to the study using an Apogee CX 200 assessed were: P-wave duration (on lead II),
apparatus (ATL, Bothell, WA, USA) with a PR interval (on lead II), QRS complex dura-
4-MHz broadband transducer. Echocardio- tion (the longest ventricular duration in pre-
graphic parameters were assessed according cordial leads), presence of bundle branch
to standard procedures of the Section of Echo- block and/or left hemi-block, presence of
cardiography of the Department of Cardiol- pathological Q waves (defined as the first
ogy, with special care taken to detect left QRS deflection >1-mm deep and >0.04-ms
ventricular apical aneurysms (21). The echo- wide), and left atrial overload (P-wave dura-
cardiographic parameters assessed were left tion in lead II >110 ms or Morris index in V1
ventricular ejection fraction (LVEF) calcu- >4 mV . ms). An independent observer blind
lated by the Theicholz method, M-mode left to the study analyzed the electrocardiographic
ventricular end diastolic diameter (LVEDD), (2N and 50 mm/s) and vectorcardiographic
left ventricular end systolic diameter (LVESD), records automatically obtained with the elec-
and left atrial diameter, interventricular sep- trocardiograph equipment. The ECG was
tal thickness and posterior wall thickness, recorded at each clinical visit in order to
and the presence of an apical aneurysm. assess cardiac rhythm and ventricular ar-
Serial echocardiograms were scheduled at rhythmia during follow-up.
the discretion of the physician who per-
formed the primary evaluation in order to Twenty-four-hour ambulatory ECG
monitor the progression of systolic function monitoring
during follow-up, which was assessed as the
difference between the last and initial esti- Twenty-four-hour ambulatory ECG mon-
mates of LVEF. itoring was performed using a three-channel
Braz J Med Biol Res 40(2) 2007
170 P.R. Benchimol Barbosa
DMS cassette-tape recorder and carefully µV, regardless of filtered QRS duration (24).
analyzed using the Del-Mar Avionics In the frequency domain, spectral turbu-
StrataScan System (Del Mar Avionics, Irvine, lence analysis was carried out using a previ-
CA, USA) by a trained observer blind to the ously reported technique on a vector magni-
study in order to assess the presence of ven- tude map (25). On the vector magnitude
tricular arrhythmia and atrioventricular con- time-frequency map, two-by-two neighbor
duction disturbances. Variables assessed in power spectral segment correlations were
the 24-h ambulatory ECG were: i) isolated deployed in a time series, and the mean and
premature ventricular contractions (PVC/24 standard deviation were calculated. For each
h), ii) coupled ventricular premature com- segment, the frequency corresponding to
plexes (couplets/24 h), iii) polymorphic PVC 80% of the area under the power density
(PVCs with more than one morphology), function was tracked over the ventricular
and iv) VT episodes (heart rate >100 bpm, activation and deployed into a time-series.
QRS duration >120 ms, and atrioventricular The mean and the standard deviation of the
dissociation. Sustained VT was defined as edge track time-series were analyzed. The
episodes of VT lasting 30 s or more, with correlation between successive power-spec-
non-sustained VT being characterized by tral estimates was limited to the range from 0
different values. During follow-up, 24-h to 300 Hz in order to avoid interference of
ambulatory ECG was scheduled from 2 to 5 noise. Using previously defined normality
years in order to assess cardiac rhythm and thresholds, identification of at least 2 abnor-
arrhythmia. All tape recordings were suc- mal parameters of 4 defined the presence of
cessfully analyzed, and both normal rhythm abnormal spectral turbulence.
and arrhythmia episodes were appropriately SAECG parameters were assessed as
assessed. markers of myocardial fibrosis in the time or
frequency domains (23).
Signal-averaged electrocardiogram
Treadmill stress test and coronary artery
SAECG was acquired with a Predictor angiography
IIc apparatus (ART Inc., Fitchburg, MA,
USA) using XYZ Frank orthogonal leads Subjects underwent a treadmill stress test
and coherent-averaged up to the noise level in order to evaluate the presence of coronary
of 0.3 µV. SAECGs were analyzed in both artery disease. Five subjects underwent cor-
time and frequency domains using a previ- onary angiography and ventriculography af-
ously reported technique (22,23) by an inde- ter an inconclusive test and all demonstrated
pendent observer blind to the study protocol. normal coronary artery anatomy. An apical
In the time domain, SAECG was analyzed aneurysm was demonstrated in three sub-
on the magnitude vector and parameters were: jects during ventriculography.
duration of the filtered ventricular activation Clinical, echocardiographic, electrocardio-
(ms), duration of the potentials at the termi- graphic, 24-h ambulatory ECG, and SAECG
nal region of ventricular activation below 40 variables grouped according to Los Andes
µV (ms), and root-mean-squared voltage of classification are presented in Table 1.
the terminal 40 ms of ventricular activation
(RMS40, µV). Identification of at least 2 Statistical analysis
abnormal parameters of 3 defined the pres-
ence of ventricular late potentials. In the Categorical variables are reported as ra-
presence of bundle branch block, ventricular tio or percentage, and continuous variables
late potentials were present if RMS40 <14 as mean ± SD. Univariate analysis was ap-
Braz J Med Biol Res 40(2) 2007
Noninvasive prognostic markers in Chagas’ heart disease 171
plied to categorical variables by the Yates- ate. Continuous variables were compared
corrected chi-square test for contingency after standard skewness normality assessment
tables or Fisher’s exact test when appropri- by the Student t-test or Mann-Whitney test,
Table 1. Clinical, electrocardiographic and echocardiographic parameters of the patients on admission.
Los Andes classification P
Class I Class II Class III
(group 1; N = 14) (group 2; N = 24) (group 3; N = 12)
Clinical variables
Age (years) 52.6 ± 7.8 51.5 ± 9.9 49.8 ± 10.6 >0.05
Gender (F/M) 9/5 19/5 7/5 >0.05
NYHA functional class >1 (%) 0% 0% 33.3% 0.001
Resting 12-lead electrocardiogram
P-wave duration (ms) 90.0 ± 17.1 91.3 ± 17.0 89.2 ± 22.7 >0.05
QRS duration (ms) 80.0 ± 7.8 127.5 ± 24.7 121.7 ± 31.6 <0.001
Left atrial overload (%) 7.1% 12.5% 16.7% >0.05
Left bundle branch block (%)a 0% 16.7% 16.7% >0.05
Right bundle branch block (%)a 0% 70.8% 41.7% 0.001
Left anterior hemi-block (%) 0% 41.7% 50.0% 0.009
Inactive area (%) 0% 25.0% 41.7% 0.03
M-mode and 2-D mode echocardiogram
LAD (mm) 3.5 ± 0.5 3.5 ± 0.6 3.9 ± 0.7 >0.05
LVESD (mm) 3.1 ± 0.7 2.8 ± 0.6 5.0 ± 0.9 <0.001
LVEDD (mm) 5.0 ± 0.7 4.8 ± 0.7 6.1 ± 0.9 0.001
LVEF (%) 71.7 ± 9.6 76.5 ± 9.1 36.3 ± 11.4 <0.001
Apical aneurysm (%) 7.7% 25.0% 18.2% >0.05
24-h ambulatory electrocardiogram
Isolated PVC (count/24 h) 2029 ± 4116 602 ± 1008 7505 ± 8246 0.002
Couplets (count/24 h) 16 ± 39 11 ± 25 457 ± 730 <0.001
Polymorphic PVC (%) 50.0% 50.0% 91.7% >0.05
NSVT (%) 14.3% 12.5% 58.3% 0.006
Signal-averaged electrocardiogram
Duration (ms) 92.6 ± 7.0 137.4 ± 23.0 140.7 ± 32.7 <0.001
RMS40 (µV) 51.1 ± 40.9 17.4 ± 8.9 27.4 ± 31.7 <0.001
LAS40 (ms) 29.0 ± 6.7 47.6 ± 20.1 46.3 ± 15.5 0.002
Time domain positive (%) 14.3% 45.8% 41.6% >0.05
MSC (%) 0.96 ± 0.01 0.95 ± 0.01 0.95 ± 0.02 0.01
SSC (%) 0.05 ± 0.02 0.07 ± 0.03 0.07 ± 0.03 >0.05
MET (Hz) 73.9 ± 4.2 85.0 ± 12.8 90.1 ± 14.2 0.001
SET (Hz) 27.1 ± 4.3 37.9 ± 16.9 40.2 ± 14.2 0.01
Frequency domain positive (%) 35.7% 70.8% 75.0% >0.05
Data are reported as mean ± SD or as percent. NYHA = New York Heart Association; LAD = left atrial
diameter; LVESD = left ventricular end systolic diameter; LVEDD = left ventricular end diastolic diameter;
LVEF = left ventricular ejection fraction; PVC = premature ventricular contraction; NSVT = nonsustained
ventricular tachycardia; Duration = duration of ventricular activation; RMS40 = root-mean-squared voltage of
the last 40 ms of ventricular activation; LAS40 = duration of the potentials below 40 µV in terminal region until
the offset of ventricular activation; MSC = mean of the spectral correlation series; SSC = standard deviation of
the spectral correlation series; MET = mean of the edge track series; SET = standard deviation of the edge
track series. aComplete bundle branch block - QRS duration >120 ms (see text for details).
Categorial variables (%) were analyzed statistically with the chi-square test and continuous variables (mean ±
SD) were analyzed with Kruskal-Wallis ANOVA.
Braz J Med Biol Res 40(2) 2007
172 P.R. Benchimol Barbosa
when appropriate. Kruskal-Wallis ANOVA 1 (3 nonfatal), 20.8% in group 2 (1 fatal and
was used for inter-group comparison. 4 nonfatal) and in 75.0% in group 3 (8 fatal
In univariate analyses, the relative risk and 4 nonfatal; P = 0.003). At the end of
(RR) for composite endpoint and respective follow-up, worsening in NYHA functional
95% confidence intervals (CI) were assessed class was observed in 42% of the subjects
for all significant variables. For continuous (overall average reduction of NYHA func-
variables, RR for adverse outcomes was es- tional class in 10 years: 1.71 ± 1.01; P < 0.001).
timated at an optimal dichotomization thresh- Subjects who experienced adverse events
old calculated by receiver operating charac- showed a significant deterioration of NYHA
teristic (ROC) curve analysis. In the latter, functional class as compared to those who
24-h isolated PVC and couplet counts were did not (2.4 ± 1.2 vs 1.3 ± 0.5; P = 0.005).
assessed as continuous variables. According to the Los Andes classification,
Variables found to be significant by uni- worsening in NYHA functional class was
variate analysis were entered into a stepwise observed in 33% of subjects in group 1, in
multivariate Cox proportional-hazards re- 23% in group 2, and in 92% in group 3 (P =
gression model to define independent pre- 0.0004).
dictors of the composite endpoint. The re- Reduction of LVEF was observed in
producibility of SAECG variables was as- 60.6% of subjects (overall average reduc-
sessed by κ inter-rate agreement in two con- tion of LVEF: 14.6 ± 10.4%; P < 0.001), rep-
secutive signal acquisitions in an independ- resenting an average reduction of 4.3 ± 4.6%
ent group of 32 control volunteers (age, per year (P < 0.001). The average annual
mean ± SD, 58.5 ± 11.0 years, 6 females). drop in ejection fraction in subjects who
Univariate α error level was set at 0.05. In experienced adverse events during follow-
Cox proportional-hazard regression only up was not significantly different from the
variables with P < 0.10 in univariate analy- annual drop of those who did not experience
sis were entered into the model. The soft- adverse events (2.8 ± 3.3 vs 2.6 ± 4.8%,
ware packages used for data analysis were respectively; P = 0.54). According to the Los
MS Excel 2000 (Microsoft Corporation, Andes classification, average annual reduc-
Redmond, WA, USA), Medcalc version 8 tion of LVEF was 1.3 ± 2.4% in group 1, 3.3
(Medcalc Sofware, Mariakerke, Belgium), ± 5.0% in group 2, and 2.0 ± 2.5% in group
Epi-Info 6.04 (Center of Disease Control, 3 (P = 0.30).
Atlanta, GA, USA), and Statgraphics ver- At the end of follow-up, 3.4 ± 0.6 echocar-
sion 5.1 Plus (Manugistic Inc., Rockville, diograms and 2.2 ± 0.6 24-h ambulatory
MD, USA). ECG monitoring per subject had been ana-
lyzed. The overall average time taken from
Results the first to the last exam assessed was re-
duced among subjects who experienced ad-
Clinical follow-up verse events (75.6 ± 34.8 months for sub-
jects with no adverse events vs 27.6 ± 27.6
The overall mean follow-up was 84.2 ± months for subjects with adverse events; P <
39.0 months, ranging from 6 to 120 months, 0.001). According to the Los Andes classifi-
and was abbreviated by adverse events. Com- cation upon admission, no significant differ-
posite endpoint was observed in 34.0% (9 ences were observed regarding requests of
cardiac deaths and 11 episodes of VT, all echocardiograms (group 1 = 3.5 ± 0.7,
nonsustained). According to the Los Andes group 2 = 3.5 ± 0.5, group 3 = 3.0 ± 0.6; P =
classification on admission, adverse events 0.10) or 24-h ambulatory ECG monitoring
were observed in 21.4% of subjects in group (group 1 = 2.2 ± 0.4, group 2 = 2.3 ± 0.6,
Braz J Med Biol Res 40(2) 2007
Noninvasive prognostic markers in Chagas’ heart disease 173
group 3 = 2.0 ± 0.6; P = 0.22) by primary
assistance during follow-up. According to Table 2. Clinical, electrocardiographic, and echocardiographic parameters on admis-
sion as a function of clinical outcomes during follow-up.
outcomes at the end of follow-up, no signifi-
cant differences were observed in requests
Adverse No adverse P
of echocardiograms (3.5 ± 0.6 in the ab- events (N = 17) events (N = 33)
sence of adverse events vs 3.2 ± 0.6 in the
Clinical variables
presence of adverse events; P = 0.11) or 24-
Age (years) 51.5 ± 11.1 51.3 ± 8.6 >0.05
h ambulatory ECG monitoring (2.3 ± 0.5 in
Gender (F/M) 8/9 25/6 0.03
the absence of adverse events vs 2.0 ± 0.6 in NYHA functional class >1 (%) 23.5% 0% 0.01
the presence of adverse event; P = 0.07) by
Resting 12-lead electrocardiogram
primary assistance.
P-wave duration (ms) 87.6 ± 21.9 91.8 ± 16.1 >0.05
QRS duration (ms) 116.5 ± 32.0 110.9 ± 30.8 >0.05
Left atrial overload (%) 17.7% 9.1% >0.05
Univariate analyses of clinical, resting
Left bundle branch block (%)a 17.7% 9.1% >0.05
12-lead ECG, echocardiogram,
Right bundle branch block (%)a 35.3% 48.5% >0.05
24-h ambulatory ECG monitoring, Left anterior hemi-block (%) 41.2% 27.3% >0.05
and signal-averaged ECG as predictors Inactive area (%) 41.2% 12.1% 0.03
of composite endpoint
M-mode and 2-D mode echocardiogram
LAD (mm) 3.8 ± 0.7 3.5 ± 0.5 >0.05
Univariate analyses of significant vari- LVESD (mm) 4.1 ± 1.1 3.0 ± 0.9 <0.001
ables of 12-lead resting ECG, echocardio- LVEDD (mm) 5.6 ± 0.8 4.9 ± 0.8 0.004
LVEF (%) 52.5 ± 20.8 73.8 ± 12.5 <0.001
gram, 24-h ambulatory ECG monitoring,
Apical aneurysm (%) 41.2% 6.5% 0.006
and SAECG parameters are summarized in
24-h ambulatory electrocardiogram
Table 2. The distribution of hypertensive
Isolated PVC (count/24 h) 5792 ± 6963 1043 ± 3316 <0.001
subjects did not differ significantly between
Couplets (count/24 h) 351 ± 653 11 ± 39 <0.001
those who experienced (33.3%) and did not Polymorphic PVC (%) 88.2% 51.5% 0.01
experience (45.2%; P = 0.71) adverse events NSVT (%) 52.9% 9.1% 0.001
during follow-up. Age was not a significant
Signal-averaged electrocardiogram
predictor of adverse outcome (P = 0.50). Duration (ms) 134.2 ± 31.9 121.0 ± 28.7 >0.05
Significant variables in univariate analy- RMS40 (µV) 23.6 ± 25.1 31.5 ± 31.8 >0.05
LAS40 (ms) 46.1 ± 18.6 40.1 ± 17.9 >0.05
sis for unfavorable outcome of composite
Time domain positive (%) 37.5% 35.3% >0.05
endpoint were: i) demographic and clinical
MSC (%) 0.95 ± 0.02 0.95 ± 0.01 >0.05
parameters: male gender (RR = 2.6; 95% CI SSC (%) 0.07 ± 0.03 0.06 ± 0.02 >0.05
= 1.3-5.5; P = 0.027), NYHA >1 (RR = 3.5; MET (Hz) 84.6 ± 16.2 82.0 ± 10.7 >0.05
SET (Hz) 35.9 ± 13.6 35.0 ± 15.4 >0.05
95% CI = 2.2-5.6; P = 0.01) and Los Andes
Frequency domain positive (%) 62.5% 61.8% >0.05
class III (RR = 3.6; 95% CI = 1.8-7.2; P =
0.003); ii) echocardiographic parameters: Data are reported as mean ± SD or as pecent. NYHA = New York Heart Association;
apical aneurysm (RR = 3.0; 95% CI = 1.6- LAD = left atrial diameter; LVESD = left ventricular end systolic diameter; LVEDD = left
5.7; P = 0.006), LVESD (P < 0.001), LVEDD ventricular end diastolic diameter; LVEF = left ventricular ejection fraction; PVC =
premature ventricular contraction; NSVT = nonsustained ventricular tachycardia; Dura-
(P < 0.004), and LVEF (P < 0.001), iii) 12-
tion = duration of the ventricular activation; RMS40 = root-mean-squared voltage of the
lead resting ECG parameters: pathologic Q last 40 ms of ventricular activation; LAS40 = duration of the potentials below 40 µV in the
wave in 12-lead surface ECG (RR = 2.5; terminal region until the offset of ventricular activation; MSC = mean of the spectral
95% CI = 1.2-5.0; P = 0.03); iv) 24-h ambu- correlation series; SSC = standard deviation of the spectral correlation series; MET =
mean of the edge track series; SET = standard deviation of the edge track series.
latory ECG parameters: isolated-PVC counts/
aComplete bundle branch block - QRS duration >120 ms (see text for details).
24 h (P < 0.001), couplet counts/24 h (P < The Student t-test or Mann-Whitney test was used to analyze continuous variables
0.001), polymorphic-PVC (RR = 4.1; 95% (mean ± SD) and the chi-square test or Fisher's exact test to analyze categorial
CI = 1.1-16.4; P = 0.01), and VT (RR = 3.6; variables (%), when appropriate.
95% CI = 1.8-7.2; P = 0.001); v) SAECG
Braz J Med Biol Res 40(2) 2007
174 P.R. Benchimol Barbosa
parameters: SAECG in time or frequency ard ratio (HR) = 3.7; 95% CI = 1.2-11.4; P =
domains demonstrated significant agreement 0.02), isolated-PVC count/24 h >614 (HR =
(κ = 0.92; 95% CI = 0.77-1.07, and κ = 0.80; 6.1; 95% CI = 1.7-22.6; P = 0.006), and
95% CI = 0.59-1.02, respectively), in two LVEF <62% (HR = 4.60; 95% CI = 1.4-
consecutive acquisitions. SAECG parameters 15.2; P = 0.01) were independent predictors
were nonsignificant predictors of composite of adverse outcomes. The Kaplan-Meier
endpoint or worsening of NYHA functional curves for independent predictors are illus-
class or systolic function during follow-up. trated in Figure 1A-C.
The optimal thresholds of significant pa-
rameters assessed by ROC curve analysis Discussion
were: LVESD >2.8 mm (100.0% sensitivity,
56.2% specificity; RR = 2.3; 95% CI = 1.5- The objective of the present study was to
3.4), LVEDD >4.9 mm (81.2% sensitivity, assess clinical, electrocardiographic and
62.5% specificity; RR = 2.2; 95% CI = 1.3- echocardiographic parameters as predictors
3.6), and LVEF <62% (56.2% sensitivity, of adverse outcome during long-term fol-
81.2% specificity; RR = 3.2; 95% CI = 1.4- low-up of subjects with Chagas’ disease
7.4), isolated-PVC counts/24 h >614 (82.4% staged according to the Los Andes classifi-
sensitivity, 84.8% specificity; RR = 7.0; cation upon admission. Among subjects with
95% CI = 2.3-21.3) and couplet counts/24 h Chagas’ disease assisted at our tertiary hos-
>6 (70.6% sensitivity, 90.9% specificity; pital outpatient clinics from 1995 and 1999,
RR = 5.1; 95% CI = 2.2-11.8). those with complaints of palpitations, corre-
sponding to 9.1%, and with normal atrial-
Multivariate analysis for composite endpoints ventricular conduction composed the cohort
of the present study. Palpitations have been
Multivariate analysis is summarized in considered a harbinger of adverse outcome
Table 3. In multivariate analysis, significant (26). On the other hand, conduction delay,
univariate predictors (Los Andes class III, reported in 5.8 to 20.2% of subjects with
apical aneurysm, LVESD >2.8 mm, LVEDD chronic Chagas’ cardiomyopathy (27,28), is
>4.9 mm, LVEF <62%, isolated-PVC counts/ a muscarinic-like immunoglobulin G-medi-
24 h >614, couplet counts/24 h >6 and VT) ated disturbance considered to be a key point
were entered in a stepwise Cox-hazard re- in the physiopathogenesis of intraventricu-
gression model. After adjustment, the model lar electrical abnormalities in Chagas’ dis-
converged (maximum likelihood ratio = 27.3; ease (29-32). The exclusion of subjects with
3 d.f.; P < 0.001), and the following vari- atrioventricular delay at enrollment elimi-
ables were significant: apical aneurysm (haz- nated those at a higher risk for adverse events
(11). Additionally, on admission, the use of
nitroderivatives in Chagas’ disease was not
Table 3. Multivariate Cox proportional-hazard analysis of adverse events during
follow-up. a consensus in our hospital due the lack of
proved beneficial effects of these compounds.
Variable ß coefficient SEM z value P HR 95% CI
In fact, nitroderivatives have demonstrated
conflicting results regarding eradication of
Apical aneurysm 1.32 0.57 2.32 0.020 3.74 1.23-11.37
Isolated PVC count/24 h >614 1.81 0.67 2.73 0.006 6.14 1.67-22.64 parasitemia or retardation of the progression
LVEF <62% 1.53 0.61 2.51 0.012 4.60 1.39-15.24 of Chagas’ cardiomyopathy (33,34). Re-
cently, however, in a large nonrandomized-
SEM = standard error of the mean estimate; HR = hazard ratio; 95% CI = confidence
interval at 95%; PVC = premature ventricular contraction; LVEF = left ventricular controlled trial, Viotti et al. (35) demon-
ejection fraction. Cut-off thresholds determined by receiver operating characteristic strated a beneficial effect of benzimidazole
analysis (see text for details).
in reducing the progression of Chagas’ dis-
Braz J Med Biol Res 40(2) 2007
Noninvasive prognostic markers in Chagas’ heart disease 175
ease in seropositive subjects in the indeter- A Kaplan-Meier event-free survival function Figure 1. A, Kaplan-Meier event-
minate phase. These results await confirma- free probability function for ad-
100
verse outcomes (composite
tion in large randomized controlled studies.
90 endpoint) in subjects grouped
At the end of follow-up, the overall num- according to left ventricular ejec-
80
ber of echocardiograms and 24-h ambula- %) tion fraction (LVEF) in the echo-
70
( cardiogram. LVEF threshold
tory ECG monitoring requested per subject y
at the discretion of primary assistance did abilit 60 wceaisv ears soepsesreadti nbgy acnhaalryasciste orfis rteic-
b 50
ntchooemt dLeeosm.s HoAnonswtdreaevtse e csrl,ia gasn stiirffeiicncadant itto odnwif afgerrrdoe unapncse i sno acrcr oeroaussts-- nt-free pro 4300 LVEF (c(wRHaaORnrtd)C )ifnt ohccreu re ravaldoesvswee. e rNsirn eo L theVoa uEtzthFcaeo r dm(sH iegrR ant tiofi=oi--
ing rate of request of exams for subjects who Eve 2100 <≥6622%% 40..6001;2 ,9 5C%o xC pI r=o p1o.3rt9io-1n5a.l-2h4a; zPa r=d
experienced more clinical complaints or
0 ‘z’ variable test). B, Kaplan-
worsening of clinical conditions during fol- <62%11 9 5 4 4 3 3 Meier event-free probability
low-up was observed, probably reflecting a ≥62% 39 37 35 33 31 31 29 function for adverse outcomes
0 20 40 60 80 100 120 (composite endpoint) in subjects
concern of primary assistance regarding ap-
Follow-up (month) grouped according to isolated
propriate medical care delivery to these sub-
premature ventricular contrac-
jects. B Kaplan-Meier event-free survival function tions (PVC) count in 24-h ambu-
In the present study, a composite end- 100 latory ECG ((isolated PVC
count/24 h <614 or ≥614) in am-
point of cardiac death and ventricular tachy- 90
bulatory electrocardiogram. Iso-
cardia was observed in 34.0% of subjects 80 lated PVC threshold was as-
during follow-up, with an 18.0% total car- (%) 70 sessed by analysis of ROC
y curves. Note the increased HR
diac mortality rate (either sudden death or bilit 60 for adverse outcome toward the
a
end-stage congestive heart failure). Adverse b 50 higher isolated PVC count (HR
o
events were significantly more prevalent in pr 40 = 6.1; 95% CI = 1.7-22.6; P =
ee 0.006, Cox proportional-hazard
ggrroouupp 32 ((7250%.8)% th, aPn =in 0 g.0ro0u3p), 1c l(e2a1r.l4y% r)e parned- vent-fr 3200 Isolat<e6d1 P4VC count/24 h M‘z’e ivearr iaebvleen tt-efrset)e. Cpr, oKbaapblialinty-
senting the impact of the severity of cardiac E 10 ≥614 function for adverse outcomes
(composite endpoint) in subjects
involvement on prognosis at initial evalua-
0
grouped according to presence
tion. Although the mortality rate in long- <614 30 30 29 29 27 27 24
≥614 20 16 11 9 7 6 6 of apical aneurysm. Note a sig-
term follow-up studies varies in the litera- 0 20 40 60 80 100 120 nificant increase in HR for ad-
ture, several factors seem to influence out- Follow-up (month) verse outcome toward the
higher isolated PVC count (HR
come, including the severity of systolic dys-
C Kaplan-Meier event-free survival function = 3.74; 95% CI = 1.23-11.37; P
function and intraventricular conduction dis- 100 = 0.020, Cox proportional-haz-
turbances. In this context, studies by Espinosa ard ‘z’ variable test).
90
et al. (7), Pimenta et al. (11), Hagar and
80
Rahimtoola (31), and Bestetti and Muccillo %)
( 70
(36) have reported 42, 36.6, 78, and 23% y
mortality rates after 10 years of follow-up, abilit 60
b 50
respectively. Viotti et al. (34) assessed dur- pro
ing a 10-year follow-up a large cohort of ee 40
subjects with Chagas’ disease who had been nt-fr 30 Apical aneurysm
classified at admission according to the se- Eve 20 No
Yes
verity of cardiac involvement. The authors 10
reported a 13% mortality rate in subjects 0
No 41 39 34 34 31 31 31
with systolic dysfunction, and less than 1% Yes 9 8 6 4 3 3 2
0 20 40 60 80 100 120
in subjects with mild or no overt cardiac
Follow-up (month)
involvement.
Braz J Med Biol Res 40(2) 2007
176 P.R. Benchimol Barbosa
An important finding in the present study classification. Dopico et al. (38) have previ-
was that although LVEF on admission was ously reported similar findings limited to
an independent prognostic marker for ad- time domain analysis (Table 1). In other
verse events, paradoxically, progression of words, in Chagas’ disease, electrical mark-
left ventricular function (regardless of the ers of myocardial fibrosis are directly asso-
Los Andes group or left ventricular function ciated with the severity of cardiac involve-
on admission), as assessed by LVEF during ment (39). Presently, an inactive area in 12-
follow-up, did not differ between those who lead ECG was associated with longer late
experienced adverse events and those who potentials (duration of the potentials below
did not, assessed as composite endpoint. On 40 µV in terminal region until the offset of
the other hand, subjects who experienced ventricular activation: 53.3 ± 18.5 ms, inac-
adverse events developed a more rapid tive areas, vs 39.0 ± 17.0 ms, no inactive
worsening of NYHA functional class when areas; P = 0.02) and higher turbulence (mean
compared to those who did not experience of the edge track time-series: 90.4 ± 12.3
adverse events. Thus, progression of ven- Hz, inactive areas, vs 80.8 ± 12.2 Hz, no
tricular dysfunction seems to be relentless inactive areas; P = 0.03). Nevertheless,
and occupies a core position in Chagas’ SAECG failed to demonstrate statistically
pathophysiology, although, by itself, it may significant prognostic value for composite
not necessarily represent unfavorable evolu- endpoint during follow-up. Although a very
tion in a 10-year follow-up. Rather, worsen- small number of long-term follow-up stud-
ing of NYHA function class faithfully re- ies have been conducted to assess SAECG
flected the evolution of the disease. Thus, it as a predictor of cardiac mortality in Chagas’
is attractive to speculate that, once installed, disease, conflicting results still arise from
Chagas’ heart disease inexorably progresses, studies assessing the role of SAECG in pre-
but it is the cardiovascular status determined dicting arrhythmic events (24,40). In the
in turn by the immune response at early present study, SAECG parameters did show
stages of infection that actually influences a significant predictive value for arrhythmic
prognosis. events during follow-up (data not shown).
In the present study, after optimal di- The explanations for these findings are still
chotomization, male gender, NYHA >1, api- elusive. One can speculate that autonomic
cal aneurysm, LVESD >2.8 mm, LVEDD dysfunction and inflammation (34) when
>4.9 mm, LVEF <62%, isolated-PVC counts/ superimposed to myocardial fibrosis play
24 h >614, couplet counts/24 h >6, and key roles in the mechanism of cardiac death.
previous documented episodes of nonsus- Finally, in the present study, apical aneu-
tained VT assessed on admission were uni- rysm, LVEF and PVC/24 h were independ-
variate prognostic markers of a composite of ent predictors of a composite of cardiac death
cardiac mortality and ventricular tachycar- and ventricular arrhythmia. Accordingly,
dia endpoints (Table 2). These findings as echocardiography and 24-ambulatory ECG
predictors of cardiac mortality and arrhyth- monitoring are germane in the admission
mic events agree with reports by other inves- workup of subjects with Chagas’ disease.
tigators (7-10,14,37).
In particular, concerning SAECG analy- Limitations of the study
sis in the time and frequency domains, the
diagnostic results showed appropriate re- A potential limitation of this investiga-
producibility, and abnormal values were di- tion is that it was performed on a hospital-
rectly associated with growing complexity derived cohort, perhaps restricting the ex-
of heart disease according to the Los Andes tension of the present findings to a general,
Braz J Med Biol Res 40(2) 2007