Background
Left atrial (LA) and left ventricular (LV) diastolic function analysis can yield new strategies to recognize early cardiac involvement and prognostic indicators in Chagas disease.
Methods
Patients with Chagas disease with the indeterminate ( n = 69) or with the cardiac form (32 with changes limited to electrocardiography [stage A], 25 with changes in LV systolic function but no heart failure [HF; stage B], and 26 with HF) underwent evaluation of LV diastolic function (mitral inflow, pulmonary vein flow, color M-mode echocardiography, and tissue Doppler analysis), and LA function by three-dimensional echocardiography and strain analysis and were prospectively followed for the occurrence of clinical events. Echocardiograms were also obtained from 32 controls.
Results
LV diastolic dysfunction was gradually more prevalent and severe across groups from patients with the indeterminate form of Chagas disease to patients with HF. Tissue Doppler was the best tool to demonstrate the worsening of LV diastolic function across the groups (E′ velocity: controls, 12.6 ± 2.3 cm/sec; patients with the indeterminate form, 12.1 ± 3.1 cm/sec; stage A, 10.3 ± 2.9 cm/sec; stage B, 8.3 ± 2.8 cm/sec; patients with HF, 5.6 ± 1.9; P < .0001). Although maximum LA volume was increased only in patients with HF, minimum LA volume (controls, 8 ± 2 mL/m 2 ; patients with the indeterminate form, 8 ± 2 mL/m 2 ; stage A, 9 ± 3 mL/m 2 ; stage B, 11 ± 4 mL/m 2 ; patients with HF, 27 ± 17 mL/m 2 ; P < .0001) and precontraction LA volume (controls, 11 ± 3 mL/m 2 ; patients with the indeterminate form, 12 ± 3 mL/m 2 ; stage A, 13 ± 4 mL/m 2 ; stage B, 16 ± 5 mL/m 2 ; patients with HF, 32 ± 19 mL/m 2 ; P < .0001) were increased in all cardiac form groups. LA conductive function was depressed in all cardiac form groups, while LA contractile function was depressed only in patients with HF. Cox proportional-hazards regression analysis revealed that end-systolic LV diameter (hazard ratio, 1.6; 95% confidence interval, 0.9–2.8; P = .09), E′ velocity (hazard ratio, 0.5; 95% confidence interval, 0.3–0.8; P = .001), and peak negative global LA strain (hazard ratio, 1.21; 95% confidence interval, 1.02–1.4; P = .03), were independent predictors of clinical events.
Conclusions
LV diastolic dysfunction was found in all forms of chronic Chagas disease, including those without LV systolic dysfunction. LV diastolic dysfunction may contribute to changes in LA volume and conductive function found in early stages of the cardiac form. Both LV diastolic function and LA contractile function were independent predictors of clinical events.
About 10 million people worldwide are chronically infected by Trypanosoma cruzi , mostly in Latin America. However, Chagas disease has been increasingly detected in other countries in the Americas, the western Pacific region, and Europe because of population migration.
The consequences of Chagas disease on left ventricular (LV) systolic function are well described, but studies regarding LV diastolic function and left atrial (LA) volume and function in Chagas disease are still limited. LA index is a recognized prognostic marker in many conditions, such as heart failure (HF), atrial fibrillation, and Chagas disease. Moreover, LA function was described as a prognostic indicator for atrial arrhythmias and for in-hospital mortality after myocardial infarction. LA function may emerge as an important component in the evaluation of Chagas disease because atrial arrhythmias and HF are common complications of Chagas heart disease. New technologies allow noninvasive measurement of the components of LA function (contractile, conduit, and reservoir). Those technologies include real-time three-dimensional echocardiography (RT3DE) and two-dimensional (2D) strain (ε) analysis by speckle-tracking echocardiography (STE). STE may allow a more direct assessment of LA myocardial contractility and passive deformation, and reference values have been already published.
There are few reports addressing LV diastolic function in Chagas disease. A large retrospective study evaluated only LV mitral inflow but identified LV diastolic dysfunction in the chronic indeterminate form and in all stages of Chagas heart disease. In another study, the severity of the LV diastolic dysfunction in Chagas disease was strongly correlated with LA dimension and LV dimensions and ejection fraction. Tissue Doppler–derived parameters were also described as survival predictors in Chagas disease. Moreover, LA function is closely related to LV diastolic function, and a thorough evaluation of LV diastolic function and LA function including patients with different forms of Chagas disease is still missing. Therefore, our aim was to evaluate LV diastolic function and LA function in patients with Chagas disease in different forms and at different stages to identify early changes in these parameters and their prognostic value.
Methods
Patients
Patients with chronic Chagas disease, diagnosed by two different serologic tests (enzyme-linked immunosorbent assay [ELISA] and immunofluorescence), between 18 and 60 years of age were prospectively and consecutively invited to participate in this study. The cutoffs used for ELISA were previously published. Results of immunofluorescence were considered positive whenever fluorescence was observed at dilutions > 1:40. The study was approved by the local ethics committees (no. 0059.0.009.000-09) and conformed to standards currently applied by the Brazilian National Committee for Research Ethics. All subjects gave written informed consent before their participation.
Control subjects were recruited among those referred to our institution for Chagas disease diagnosis who tested negative for Chagas disease on the two serologic tests; had no known diseases; had normal results on physical examination, electrocardiography, and echocardiography; had normal LV systolic function; and had no significant valvar disease.
The age limit of 60 years was arbitrarily chosen because of the association between age and diastolic dysfunction. Patients were classified at the time of their enrollment in the study according to the current Brazilian Chagas disease consensus as indeterminate (no evidence of cardiac involvement), stage A (no HF symptoms with isolated electrocardiographic changes), stage B (no HF symptoms with segmental or global LV systolic dysfunction), stage C (symptomatic HF), or stage D (end-stage HF). For study analysis, stage C and D patients were grouped together.
Echocardiography
Studies were performed using a phased-array ultrasound system (Vivid 7; GE Medical Systems, Milwaukee, WI) equipped with an M4S phased-array and a 2- to 4-MHz 4 matrix-array transducers. Echocardiograms were reviewed offline using EchoPAC PC version 108.1.12 (GE Medical Systems).
Cardiac dimensions and Doppler measurements were obtained in accordance with American Society of Echocardiography recommendations. M-mode echocardiography was used to measure LA diameter and LV end-diastolic and end-systolic diameters. Two-dimensional LV and LA volumes were determined using the modified Simpson’s rule, with images obtained from apical four-chamber 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, E-wave deceleration time, velocity-time integral (VTI) of the E wave (VTI E ), A-wave VTI (VTI A ), and LA filling fraction [VTI A /(VTI E + VTI A )] were obtained. From pulmonary vein velocities obtained at the right upper pulmonary vein, the following measurements were taken: peak S-wave inflow velocity during ventricular systole, peak D-wave inflow velocity during the early phase of ventricular diastole and the corresponding S/D ratio, and peak reversed atrial wave (Ar) velocity during LA contraction. Isovolumic relaxation time was measured from continuous-wave Doppler obtained in the apical long-axis view. Propagation velocity (Vp) of early LV inflow was measured using color M-mode echocardiography from the apical four-chamber view. Right ventricular (RV) systolic pressure was derived from continuous-wave Doppler interrogation of tricuspid regurgitation, in accordance with American Society of Echocardiography recommendations. RV systolic function was evaluated by measuring the peak systolic myocardial velocity (RV S′) of the lateral tricuspid annulus and the tricuspid annular plane systolic excursion, as recommended.
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 the septal and lateral positions.
Two-Dimensional ε Analysis
Two-dimensional speckle-tracking software (EchoPAC PC) was used to calculate LV longitudinal, circumferential, and radial ε; LV torsion and twist, RV longitudinal ε; and LA ε. All 2D clips analyzed were acquired at high frame rates (>60 frames/sec).
LA ε Analysis
LA ε was determined as previously described using images obtained in the apical four-chamber, two-chamber, and three-chamber views. Regarding the three-chamber view, we included only the inferoposterior wall, because the opposing wall includes the ascending aorta. The onset of the P wave was used as the reference point for LA ε calculation, which enabled the recognition of peak positive global LA ε (ε pos peak ), which corresponded to LA conduit function; peak negative global LA ε (ε neg peak ), which corresponded to LA contractile function; and the sum of those previous values (total global LA ε [ε tot ]), which corresponded to LA reservoir function. The final LA ε values were the averages of the values obtained for each apical view ( Figure 1 ).
Two-Dimensional LV and RV ε Analysis
LV longitudinal, circumferential, and radial ε were calculated as previously described. Electrocardiographic R-wave onset was used as the reference point. LV circumferential and radial ε was analyzed in short-axis views at the basal level, defined by visualization of the tips of the mitral valve; at the midlevel, defined by visualization of the papillary muscles; and at the apical level, defined as the LV cavity with no visible papillary muscles and a minimally visible right ventricle. LV longitudinal ε was analyzed in the four-chamber, two-chamber 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 values were the averages of the peak averages for global LV circumferential and radial ε obtained in each short-axis views. Peak global LV longitudinal ε was calculated similarly using long-axis views. In case tracking quality was not good in two segments of the same acoustic window, that view was excluded from global LV ε calculation. RV longitudinal ε was calculated similarly to LV longitudinal ε using four-chamber apical views.
LV Torsion Calculation
LV torsion and twist were calculated as previously described. LV twist was defined as the net difference of LV rotation between the apical and basal short-axis planes obtained from speckle-tracking echocardiographic analysis and LV torsion as LV twist divided by end-diastolic LV longitudinal length. LV rotation was defined as angular displacement of the LV about its central axis in the short-axis image. These values were expressed as degrees. Counterclockwise LV rotation as viewed from apex was expressed as a positive value. The same short-axis and apical views used for LV ε analysis were used to calculate LV rotation using the same approach.
LA and LV Volume and Function Analysis by RT3DE
RT3DE was performed in apical views. Three-dimensional LA images were taken using the full-volume method during end-expiration. Offline software (EchoPAC PC) was used for analyzing LA three-dimensional images, as previously described. Time-volume curves were obtained and used to determine maximum LA volume, minimum LA volume, and LA volume before LA contraction (precontraction LA volume). The following indexes of LA function were calculated, according to previous studies. Total LA emptying fraction was calculated as [(maximum LA volume − minimum LA volume)/maximum LA volume] × 100. Active LA emptying fraction was calculated as [(precontraction LA volume − minimum LA volume)/precontraction LA volume] × 100. Passive LA emptying fraction was calculated as [(maximum LA volume − precontraction LA volume)/maximum LA volume] × 100. LV volume was measured using a similar approach, as previously described. Time-volume curves were obtained and used to determine LV end-diastolic and end-systolic volumes and three-dimensional LV ejection fraction.
Survival Analysis
Patients were followed for the occurrence of a combined end point of all-cause mortality, stroke, heart transplantation, atrial fibrillation, or admission for worsening HF or cardiac arrhythmias. A multivariate Cox proportional-hazards regression analysis adjusted for age and sex was performed to identify independent predictors of the combined end point. Variables were entered in the model if their associated P values were <.05 and removed from the model if their associated P values were >.10.
Statistical Analysis
Calculations were done using MedCalc 12.5.0.0 (MedCalc Software, Mariakerke, Belgium). 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. Correlation between LA function and LV systolic and diastolic function parameters was analyzed using stepwise multiple regression analysis. Values obtained using two different techniques were compared using intraclass correlation coefficients. Interobserver and intraobserver agreement for global LA ε and LA volumes was determined after offline reanalysis of recorded clips of 14 randomly selected subjects and assessed by Bland-Altman analysis. P values ≤ .05 were considered significant.
Results
Subjects Characteristics
A total of 251 patients with Chagas disease were enrolled in the study between March 2010 and June 2012. Of these, 99 were excluded from analysis because of hypertension ( n = 55), diabetes ( n = 10), permanent pacemakers ( n = 14), coronary artery disease ( n = 6), atrial fibrillation ( n = 3), rheumatic heart disease ( n = 1), congenital heart disease ( n = 1), associated digestive form of Chagas disease ( n = 3), pregnancy ( n = 1), associated moderate to severe systemic disease ( n = 3), or inadequate imaging quality ( n = 2).
All patients tested positive on both ELISA and immunofluorescence. The reactive indexes obtained on ELISA ranged from 2.0 to 10.5, and immunofluorescence ranged from 1:80 to 1:2,560. All patient groups had similar ages. Body mass indexes were reduced in patients at stages C and D. There was a female predominance among stage A patients. Electrocardiographic changes were predominant among patients with the cardiac form, as expected ( Table 1 ).
| Variable | Controls ( n = 32) | Indeterminate ( n = 69) | Stage A ( n = 32) | Stage B ( n = 25) | Stages C and D ( n = 26) |
|---|---|---|---|---|---|
| Age (y) | 44 ± 7 | 45 ± 9 | 48 ± 8 | 48 ± 10 | 49 ± 8 |
| Men | 44% | 48% | 34% | 60% | 65% |
| BMI (kg/m 2 ) | 26 ± 4 | 26 ± 4 | 25 ± 4 | 26 ± 4 | 23 ± 4 ∗ , † , ‡ , § |
| ECG | |||||
| RBBB | 0% | 0% | 78.1% ∗ , † | 68% ∗ , † | 34.6% ∗ , † , ‡ , § |
| LBBB | 0% | 0% | 3.1% | 4% | 7.7% |
| LAHB | 0% | 4.3% | 50% ∗ , † | 52% ∗ , † | 65.4% ∗ , † |
| Primary repolarization changes | 0% | 0% | 37.5% ∗ , † | 52% ∗ , † | 42.3% ∗ , † |
| Medications | |||||
| Carvedilol | 0% | 0% | 0% | 24% | 88% |
| ACE inhibitor | 0% | 0% | 0% | 32% | 81% |
| ARB | 0% | 0% | 0% | 0% | 15% |
| Digoxin | 0% | 0% | 0% | 0% | 31% |
| Spironolactone | 0% | 0% | 0% | 4% | 92% |
| Furosemide | 0% | 0% | 0% | 0% | 88% |
| Amiodarone | 0% | 0% | 3% | 0% | 15% |
† P < .05 versus indeterminate.
Chamber Diameters and Systolic Function
LV and LA diameters were increased in patients with more advanced stages of the cardiac form. LV systolic function was decreased in patients at stages B, C, and D, as assessed by LV ejection fraction and LV S′. RV systolic dysfunction and pulmonary hypertension were present only in stage C and D patients, as assessed by RV S′, RV ε, and tricuspid annular plane systolic excursion ( Table 2 ). Mild functional mitral regurgitation was present in 25 patients (three indeterminate, five stage A, five stage B, 10 stage C, and two stage D), while functional mitral regurgitation was classified as moderate in four patients at stage C and two at stage D and as severe in two patients at stage D.
| Variable | Controls ( n = 32) | Indeterminate ( n = 69) | Stage A ( n = 32) | Stage B ( n = 25) | Stages C and D ( n = 26) |
|---|---|---|---|---|---|
| Left atrium (cm) | 3.4 ± 0.5 | 3.5 ± 0.4 | 3.6 ± 0.4 | 3.8 ± 0.4 ∗ , † , ‡ | 4.4 ± 0.8 ∗ , † , ‡ , § |
| LVd (cm) | 5.0 ± 0.4 | 5.0 ± 0.4 | 5.2 ± 0.5 | 5.7 ± 0.6 ∗ , † , ‡ | 6.7 ± 0.7 ∗ , † , ‡ , § |
| LVs (cm) | 3.1 ± 0.4 | 3.0 ± 0.4 | 3.2 ± 0.5 | 4.1 ± 0.8 ∗ , † , ‡ | 5.7 ± 0.9 ∗ , † , ‡ , § |
| LV ejection fraction (%) | 68 ± 6 | 68 ± 6 | 67 ± 7 | 55 ± 9 ∗ , † , ‡ | 34 ± 12 ∗ , † , ‡ , § |
| LV mass (g/m 2 ) | 59 ± 11 | 64 ± 17 | 67 ± 19 | 78 ± 19 ∗ , † , ‡ | 107 ± 29 ∗ , † , ‡ , § |
| LV S′ (cm/sec) | 9.2 ± 1.6 | 9.1 ± 1.6 | 9.0 ± 2.1 | 6.7 ± 1.2 ∗ , † , ‡ | 5.0 ± 1.3 ∗ , † , ‡ , § |
| RV S′ (cm/sec) | 14.3 ± 2.2 | 14.2 ± 2.1 | 13.7 ± 2.3 | 12.7 ± 2.1 ∗ , † | 10.7 ± 3.2 ∗ , † , ‡ , § |
| RV ε (%) | −22 ± 2 | −22 ± 4 | −22 ± 3 | −21 ± 3 | −15 ± 6 ∗ , † , ‡ , § |
| TAPSE (mm) | 24 ± 4 | 24 ± 3 | 25 ± 5 | 24 ± 5 | 19 ± 7 ∗ , † , ‡ , § |
| RVSP (mm Hg) | 28 ± 3 | 28 ± 4 | 28 ± 4 | 32 ± 7 | 44 ± 19 ∗ , † , ‡ , § |
† P < .05 versus indeterminate.
LV Diastolic Function
Mitral flow and tissue Doppler were obtained from all patients. Except for one indeterminate patient, two patients at stage A, one patient at stage C, and two patients at stage D, pulmonary vein flow was obtained from all patients. Except for three controls, one patient with the indeterminate form, and two patients at stages A, C, and D, Vp was obtained from all patients. LV diastolic dysfunction was present in all Chagas disease patient groups. However, it was gradually more prevalent and more advanced from patients with the indeterminate form to patients in the stages C and D of the cardiac form ( Table 3 ).
| Pattern | Controls ( n = 32) | Indeterminate ( n = 69) | Stage A ( n = 32) | Stage B ( n = 25) | Stages C and D ( n = 26) |
|---|---|---|---|---|---|
| Normal | 31 (97%) | 62 (89.8%) | 16 (50%) | 9 (36%) | 2 (7.7%) |
| Delayed relaxation | 1 (3%) | 6 (8.7%) | 11 (34.4%) | 9 (36%) | 5 (19.2%) |
| Pseudonormal | 0 | 1 (1.5%) | 5 (15.6%) | 5 (20%) | 12 (46.2%) |
| Restrictive | 0 | 0 | 0 | 2 (8%) | 7 (26.9%) |
Tissue Doppler was the best tool to demonstrate the gradual worsening in LV diastolic function across the groups. Although E/A ratio was significantly increased only in patients at stages C and D, E′ was progressively lower from patients at stage A to patients at stages C and D. E/E′ ratio was increased in indeterminate patients compared with controls and increased progressively across groups to patients at stages C and D ( Figure 2 ). E′/A′ ratio was decreased in patients at stages A and B but improved toward normal in patients at stages C and D because of the decrease in A′ observed in those patients. Isovolumic relaxation time was increased in patients at stage B and was further increased in those at stages C and D. Except for S and Ar velocities in stage A patients, average values for pulmonary vein parameters did not present significant differences across the groups. Although Vp was significantly depressed in patients at stages A, C, and D, E/Vp was increased in all Chagas disease groups and further increased in stage C and D patients. Untwist was decreased in stage B, C, and D patients compared with all other groups ( Table 4 ).
| Variable | Controls ( n = 32) | Indeterminate ( n = 69) | Stage A ( n = 32) | Stage B ( n = 25) | Stages C and D ( n = 26) |
|---|---|---|---|---|---|
| E/A ratio | 1.4 ± 0.3 | 1.5 ± 0.4 | 1.2 ± 0.3 ∗ , † | 1.4 ± 1.0 | 1.9 ± 1.3 † , ‡ |
| DT (msec) | 169 ± 33 | 170 ± 27 | 186 ± 50 | 186 ± 66 | 161 ± 60 |
| AFF (%) | 32 ± 6 | 33 ± 8 | 36 ± 8 | 36 ± 11 | 35 ± 11 |
| IVRT (msec) | 93 ± 16 | 96 ± 19 | 97 ± 22 | 108 ± 18 ∗ , † | 111 ± 36 ∗ , † , ‡ |
| E′ (cm/sec) | 12.6 ± 2.3 | 12.1 ± 3.1 | 10.3 ± 2.9 ∗ , † | 8.3 ± 2.8 ∗ , † , ‡ | 5.6 ± 1.9 ∗ , † , ‡ , § |
| A′ (cm/sec) | 9.4 ± 1.8 | 9.8 ± 2.0 | 10.5 ± 2.0 ∗ | 9.0 ± 2.2 ‡ | 5.7 ± 3.0 ∗ , † , ‡ , § |
| E/E′ ratio | 4.6 ± 1.7 | 6.7 ± 1.8 ∗ | 7.8 ± 2.9 ∗ , † | 9.6 ± 4.2 ∗ , † | 17.4 ± 8.5 ∗ , † , ‡ , § |
| E′/A′ ratio | 1.4 ± 0.3 | 1.3 ± 0.4 | 1.0 ± 0.3 ∗ , † | 1.0 ± 0.5 ∗ , † | 1.2 ± 0.7 |
| S (cm/sec) | 48 ± 10 | 54 ± 12 | 57 ± 10 ∗ | 52 ± 16 | 49 ± 19 |
| D (cm/sec) | 49 ± 10 | 52 ± 11 | 52 ± 11 | 49 ± 12 | 58 ± 21 |
| S/D ratio | 1.0 ± 0.2 | 1.1 ± 0.3 | 1.1 ± 0.3 | 1.1 ± 0.3 | 1.0 ± 0.5 |
| Ar (cm/sec) | 27 ± 4 | 29 ± 7 | 32 ± 9 ∗ | 30 ± 5 | 30 ± 7 |
| Vp (cm/sec) | 75 ± 23 | 68 ± 24 | 60 ± 25 ∗ | 62 ± 29 | 41 ± 12 ∗ , † , ‡ , § |
| E/Vp | 0.8 ± 0.3 | 1.2 ± 0.4 ∗ | 1.4 ± 0.4 ∗ | 1.5 ± 1.0 ∗ | 2.2 ± 1.1 ∗ , † , ‡ , § |
| Untwist (°/sec) | −102 ± 24 | −99 ± 36 | −97 ± 32 | −62 ± 29 ∗ , † , ‡ | −47 ± 25 ∗ , † , ‡ |
† P < .05 versus indeterminate.
LA Volume and Function by RT3DE and ε Analysis
Except for one control and one patient at stage A, real-time three-dimensional echocardiographic images of sufficient quality to determine LA volumes were obtained from all other patients. Although maximum LA volume was increased compared with other groups only in stage C and D patients, minimum and precontraction LA volumes were already increased compared with controls in stage A and B patients. Minimum and precontraction LA volumes were also progressively larger in stage B, C, and D patients compared with other groups of patients. Total LA emptying fraction was decreased in stage A and B patients compared with patients with the indeterminate form and in stage B patients compared with controls. Total LA emptying fractions were also decreased in the group of patients with HF compared with all other groups. Passive LA emptying fraction decreased progressively across the cardiac form stages of Chagas disease. Active LA emptying fraction was increased in patients at stage B compared with controls and stage A patients and was depressed in patients with HF ( Table 5 ).
| Variable | Controls ( n = 32) | Indeterminate ( n = 69) | Stage A ( n = 32) | Stage B ( n = 25) | Stages C and D ( n = 26) |
|---|---|---|---|---|---|
| RT3DE | |||||
| Maximum LA volume (mL/m 2 ) | 21.0 ± 5.3 | 21.7 ± 5.8 | 22.5 ± 5.4 | 23.6 ± 7.9 | 39.4 ± 17.6 ∗ , † , ‡ , § |
| Minimum LA volume (mL/m 2 ) | 7.6 ± 2.4 | 7.9 ± 2.4 | 9.2 ± 2.9 ∗ , † | 10.5 ± 3.8 ∗ , † | 26.7 ± 17.2 ∗ , † , ‡ , § |
| Pre-A LA volume (mL/m 2 ) | 10.7 ± 3.1 | 11.7 ± 3.4 | 12.9 ± 3.9 ∗ | 16.0 ± 5.4 ∗ , † , ‡ | 32.2 ± 18.6 ∗ , † , ‡ , § |
| Total LA EF (%) | 63 ± 7 | 63 ± 6 | 59 ± 8 † | 55 ± 9 ∗ , † | 37 ± 18 ∗ , † , ‡ , § |
| Active LA EF (%) | 29 ± 8 | 32 ± 9 | 29 ± 10 | 34 ± 11 ∗ , ‡ | 23 ± 12 ∗ , † , § |
| Passive LA EF (%) | 48 ± 9 | 46 ± 9 | 42 ± 12 ∗ | 31 ± 11 ∗ , † , ‡ | 22 ± 14 ∗ , † , ‡ , § |
| LA ε | |||||
| LA ε neg peak (%) | −12.7 ± 3.2 | −12.8 ± 2.5 | −13.1 ± 3.1 | −12.2 ± 2.8 | −7.3 ± 3.0 ∗ , † , ‡ , § |
| LA ε pos peak (%) | 17.2 ± 4.8 | 17.8 ± 4.6 | 14.8 ± 4.0 ∗ , † | 15.2 ± 7.0 † | 9.3 ± 4.7 ∗ , † , ‡ , § |
| LA ε tot (%) | 30.0 ± 6.2 | 30.6 ± 5.1 | 28.0 ± 5.5 † | 27.4 ± 8.0 † | 16.6 ± 7.0 ∗ , † , ‡ , § |
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