Highlights
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The authors evaluated LV ε in patients with no signs or in the early stage of Chagas heart disease.
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Patients had normal global and segmental LV systolic function by 2D echocardiography.
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Global and segmental LV ε were similar among the studied groups.
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Global LV ε was decreased in patients with cardiac fibrosis.
Background
Chagas heart disease has a high socioeconomic burden, and any strategy to detect early myocardial damage is welcome. Speckle-tracking echocardiography assesses global and segmental left ventricular (LV) systolic function, yielding values of two-dimensional strain (ε). The aim of this study was to determine if patients with chronic Chagas disease and normal LV ejection fractions present abnormalities in global and segmental LV ε.
Methods
In this prospective study, patients with Chagas disease with no evidence of cardiac involvement (group I; n = 83) or at stage A of the cardiac form (i.e., with changes limited to the electrocardiogram) (group A; n = 42) and 43 control subjects (group C) underwent evaluation of global and segmental LV ε by speckle-tracking echocardiography. A subset of randomly selected patients in group A underwent cardiac magnetic resonance imaging and repeated echocardiography 3.5 ± 0.8 years after the first evaluation.
Results
Mean age, chamber dimensions, and LV ejection fraction were similar among the groups. Global longitudinal (group C, −19 ± 2%; group I, −19 ± 2%; group A, −19 ± 2%), circumferential (group C, −19 ± 3%; group I, −20 ± 3%; group A, −19 ± 3%), and radial (group C, 46 ± 10%; group I, 45 ± 13%; group A, 42 ± 14%) LV ε were similar among the groups. Segmental longitudinal, circumferential, and radial LV ε were similar across the studied groups. Seven of 14 patients had areas of fibrosis on cardiac magnetic resonance imaging. Patients with fibrosis had lower global longitudinal (−15 ± 2% vs −18 ± 2%, P = .004), circumferential (−14 ± 2% vs −19 ± 2%, P = .002), and radial LV ε (36 ± 13% vs 54 ± 12%, P = .02) than those without cardiac fibrosis despite similar LV ejection fractions. Patients with fibrosis had lower radial LV ε in the basal inferoseptal wall than patients without cardiac fibrosis (27 ± 17% vs 60 ± 15%, P = .04).
Conclusions
Patients with chronic Chagas disease and normal global and segmental LV systolic function on two-dimensional echocardiography had global and segmental LV ε similar to that of control subjects. However, those in the early stages of the cardiac form and cardiac fibrosis had lower global longitudinal, circumferential, and radial LV ε.
Although Chagas disease is more prevalent in Latin America, intense migrant flow in recent decades has increased its prevalence in nonendemic countries. In the United States alone, ≥300,000 and as many as 1 million people are estimated to be infected by Trypanosoma cruzi . Most are unaware of their condition but are at risk for developing Chagas heart disease or transmitting the disease by blood or organ donation or during pregnancy. Because US blood banks began to screen donated blood for Chagas disease at large scale only after 2006, there is a risk for past disease transmission due to blood transfusion in the United States. In fact, one in every 13,292 donors in the United States was confirmed positive for T cruzi infection between 2007 and 2009. Therefore, Chagas disease has a high social, health, and economic burden not only in Latin America but in other parts of the world as well.
Chagas disease has two distinct phases: acute and chronic. In most cases, acute Chagas disease is not recognized, and the individual remains asymptomatic and without evidence of cardiac or digestive damage during the indeterminate form of the chronic phase. However, up to 20% to 30% of patients with the indeterminate form or no evidence of cardiac involvement will progress to a chronic form with heart disease and high prevalence of heart failure (HF), sudden death, and stroke. Global left ventricular (LV) systolic dysfunction is the most powerful echocardiographic predictor of an unfavorable outcome, but it is detected only in the late stages of Chagas disease.
Speckle-tracking echocardiography (STE) is a new technique that allows the measurement of myocardial strain (ε) and is used to noninvasively quantify global and segmental LV systolic function. Global LV ε is decreased in diseases associated with cardiomyocyte hypertrophy or changes in the extracellular matrix even before global LV systolic dysfunction ensues. Patients with hypertension, LV hypertrophy, and normal LV ejection fractions have decreased global longitudinal, circumferential, and radial LV ε. Patients with hypertrophic cardiomyopathy also have decreased global longitudinal, circumferential, and radial LV ε despite normal LV ejection fractions. Patients with diabetes and normal LV ejection fractions also have subclinical LV systolic dysfunction detected by decreased longitudinal LV ε and decreased basal radial and apical circumferential LV ε. Because the main pathologic finding in the hearts of patients with Chagas disease is chronic, progressive myocarditis with fibrosis, and focal myocarditis may be found even in patients with the indeterminate form, we sought to determine if subtle changes in cardiac contractility can be detected by ε analysis in patients with otherwise normal global and segmental LV systolic function as assessed by both M-mode and two-dimensional (2D) echocardiography.
Methods
Patients
This study is part of a prospective project evaluating the value of new echocardiographic tools in patients with Chagas disease approved by the local ethical committee (No. 0059.0.009.000-09). A previous report with other results of this project has been published. This project conforms to standards currently applied by the Brazilian National Committee for Research Ethics, and all subjects gave written informed consent before participation. All studies were performed after patient consent was obtained and followed the study protocol. Patients with chronic Chagas disease were consecutively invited to participate in this project between March 2010 and July 2013. From those, patients with chronic Chagas disease with no evidence of cardiac involvement (indeterminate form) or in stage A of the cardiac form, between 18 and 60 years of age, were considered for this study. Chagas disease was diagnosed by positive results on two different serologic tests using previously published criteria.
Control subjects who met previously published inclusion criteria were recruited among those referred to our institution for Chagas disease diagnosis.
The Chagas disease classification criteria used in this study followed the current Brazilian Chagas disease consensus : indeterminate (no evidence of cardiac involvement), stage A (no HF symptoms with isolated changes on the electrocardiogram), stage B (no HF symptoms with segmental or global LV systolic dysfunction), stage C (symptomatic HF), or stage D (end-stage HF).
Echocardiography
Studies were performed using phased-array ultrasound system (Vivid 7; GE Medical Systems, Milwaukee, WI) equipped with an M4S phased-array transducer. Echocardiograms were reviewed offline using EchoPAC PC workstation version 108.1.12 (GE Medical Systems).
Cardiac dimensions and Doppler measurements were obtained as recommended by the American Society of Echocardiography. M-mode echocardiography was used to measure left atrial diameter and LV end-diastolic and end-systolic diameters. Two-dimensional LV volumes were determined using the modified Simpson rule with images obtained from apical four- and two-chamber views. Pulsed-wave Doppler was performed in the apical four-chamber view. From transmitral recordings, the peak early (E) and late (A) diastolic filling velocities, E/A ratio, and E-wave deceleration time were obtained. Spectral pulsed tissue Doppler of the mitral annulus was obtained at the septal and lateral positions. Values shown for peak systolic myocardial velocity (S′) and peak early (E′) and late (A′) diastolic myocardial velocities are averages of the values obtained at septal and lateral positions.
Two-Dimensional LV ε Analysis
Two-dimensional speckle-tracking software (EchoPAC PC workstation) was used to calculate LV longitudinal, circumferential, and radial ε. All 2D clips analyzed were acquired at a high frame rate (>60 frames/sec). Global and segmental LV longitudinal, circumferential, and radial ε were calculated as previously described. Briefly, LV circumferential and radial ε were analyzed in basal, medial, and apical short-axis views, and LV longitudinal ε was analyzed in four-, two-, and three-chamber views. Global ε in each view was obtained by averaging the six regional ε curves obtained for each LV view. Peak global LV circumferential and radial ε were the average of the peak average for global LV circumferential and radial ε obtained in each short-axis view. Peak global LV longitudinal ε was calculated similarly using long-axis views. Any acoustic window with two or more segments without good tracking quality was excluded from global LV ε calculation.
Cardiac Magnetic Resonance Imaging
Cardiac magnetic resonance imaging (MRI) was performed in a randomly selected sample of patients with the stage A of the cardiac form to evaluate if changes found on STE would be associated with areas of cardiac fibrosis. Cardiac MRI was performed using a 1.5-T Siemens Avanto system (Siemens Healthcare, Erlangen, Germany) at Centro Estadual de Diagnóstico por Imagem (Rio de Janeiro, Brazil). LV images were obtained during a 15-sec breath-hold to minimize artifacts due to breathing movements. LV long-axis and short-axis images were obtained by two electrocardiographically triggered pulse sequences at the same locations to allow LV function and myocardial structure comparisons. LV function was analyzed using a gradient-echo (steady-state free precession) protocol. To evaluate myocardial fibrosis, images were acquired 10 to 20 min after an intravenous bolus of 0.2 mmol/kg of gadolinium-based contrast (Dotarem; Guerbet, Aulnay Sous Bois, France) using an inversion-recovery prepared gradient-echo for myocardial delayed enhancement protocol with the following parameters: repetition time, 7.2 msec; echo time, 3.2 msec; flip angle, 20°; matrix size, 256 × 192 pixels; slice thickness, 8 mm; gap between slices, 2 mm; field of view, 34 to 38 cm; receiver bandwidth, 125/31.2 kHz; inversion time, 150 to 300 msec; cardiac phases, 20/1; views per segment, 8/16 to 32; number of excitations, 1/2; and acquisition every heart beat for both.
Two observers blinded to the clinical characteristics and LV ε results of the studied patients analyzed cardiac magnetic resonance images. Segmental myocardial delayed enhancement was analyzed using the LV 17-segment model, and pattern of myocardial delayed enhancement was classified as subendocardial, midwall, subepicardial, or transmural.
Statistical Analysis
Calculations were done using MedCalc version 12.5.0.0 (MedCalc, Mariakerke, Belgium) and R (R Foundation for Statistical Computing, Vienna, Austria). Continuous variables are expressed as mean ± SD and discrete variables as percentages. All echocardiographic variables passed standard tests of normality (Kolmogorov-Smirnov test), allowing the use of parametric tests. Data between groups were compared using one-way analysis of variance followed by Student-Newman-Keuls post hoc analysis. Adjustment for multiple comparisons was performed using the Benjamini-Hochberg procedure in each table that describes segmental LV ε. The intra- and interobserver reliability coefficients for global and segmental LV ε were determined through a reliability index, as previously described, using 0.4 as the null hypothesis in a random-effects model. Offline reanalysis of recorded clips of 12 randomly selected subjects was performed twice by three different observers. P values < .05 were considered to indicate statistical significance.
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