Introduction
Over time, advancements in the treatment of heart failure (HF) have been made, leading to improvements in symptoms, survival and quality of life. These improvements are often accompanied by an increase in the left ventricular ejection fraction (EF) (LVEF), which is associated with a better prognosis.1,2
This improvement in the LVEF, characterized as reverse remodelling (RR), has been outlined in recent guidelines. However, variations in the criteria adopted for RR have been observed among different studies and societies.3–6 The prevalence of RR ranges from 26% to 46%, and it is influenced by both the aetiology of the condition and the definition of RR used.7 Patients who achieve RR experience improved clinical outcomes, including lower mortality rates, reduced hospitalizations and a decreased need for heart transplantation.8–11
However, normalization of the LVEF does not mean a cure, as there is a risk of deterioration, especially if treatment is withdrawn.12 For this reason, some authors classify LVEF improvement as remission, acknowledging the potential for relapse over time.13–16 Therefore, HF is currently recognized as a dynamic disease.17 The management of patients who achieve RR is uncertain, and it is suggested that even after LVEF recovery, therapy should be maintained.4,6
Some features have been associated with RR, including female sex, non-ischaemic aetiology, less severe HF, elevated blood pressure, a shorter duration of disease and preserved renal function.7,18 However, there are limited data on the predictors of sustained RR (SRR).
To enhance the understanding of RR over time, the aim of this study was to identify predictors of SRR in patients with HF with reduced EF (HFrEF) following an increase in the LVEF.
Methods
Study design
This retrospective observational study included patients with HFrEF (initial LVEF < 40%) who had undergone at least two additional echocardiograms (echoes) between 2006 and 2019, with a minimum interval of 6 months. Patients were divided into three groups according to the LVEF trajectory: no RR (NRR), consisting of patients with all three LVEF values < 40%; non-SRR (NSRR), consisting of patients with first LVEF < 40%, second LVEF ≥ 40% and third LVEF < 40%; and SRR, consisting of patients with first LVEF < 40% and second and third LVEF ≥ 40%. The study was approved by the institutional ethics committee.
Study population and data collection
Data were collected from the electronic medical records of patients with HF at the Heart Institute of the University of São Paulo. Computerized data were provided by the institutional medical information department, whereas non-computerized clinical data were analysed by HF specialists (Lira MTSS, Marchi DC, Maciel PC and Furquim SR). Patients were excluded if they had less than 6 months between exams, insufficient records, loss to follow-up, congenital heart disease or residency in another state. Mortality data were obtained from the São Paulo Health Department and the patients' medical records.
Statistical analysis
Demographic data were analysed via Student's t test for continuous variables and the χ2 test for categorical variables. Continuous variables are expressed as the mean ± standard deviation (SD). To assess the associations of variables with SRR, logistic regression analysis was applied to variables in the NSRR and SRR groups. Survival analysis was conducted via the Kaplan–Meier method, with group comparisons performed via the log-rank test. A sensitivity analysis was performed using simple data imputation. All analyses were performed via Stata version 18.
Results
Between 2006 and 2019, a total of 28 497 patients were initially identified with first LVEF < 40%. Among them, 9418 patients underwent a second echo, with a minimal interval of 6 months. Following the evaluation of their medical records, 1346 patients were excluded. Among the remaining 8072 patients, 3628 had a third echo. These patients were divided into three groups on the basis of their LVEF trajectory: 2286 patients with NRR, 310 patients with NSRR and 1032 patients with SRR (Figure 1).
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Baseline characteristics
The baseline characteristics revealed that 2286 (63%) patients did not achieve RR, whereas 1342 (37%) did. Among those who achieved RR, 310 (23%) patients did not sustain it, whereas 1032 (77%) patients did. There were substantial differences observed among the groups (Table 1). Compared with those in the NRR group, the patients in the SRR group had an older age at diagnosis; a lower prevalence of male sex, Chagas disease and ischaemic aetiology; and a greater prevalence of valvular and tachycardia-induced cardiomyopathy.
Table 1 Baseline characteristics of patients with sustained reverse remodelling, non-sustained reverse remodelling and no reverse remodelling.
| SRR (1032) | NSRR (310) | NRR (2286) | Missing (%) | |||
| Age | 58 (48–67) | 58 (49–68) | 56 (48–64) | <0.001 | 0 | |
| Sex | Male | 623 (60.4) | 199 (64.2) | 1516 (66.3) | 0.004 | 0 |
| Female | 409 (35.6) | 111 (35.8) | 770 (33.7) | |||
| Aetiology | Ischaemic | 274 (26.5) | 110 (35.5) | 822 (35.9) | <0.001 | 0 |
| Hypertensive | 167 (16.18) | 42 (13.55) | 283 (12.38) | 0.012 | ||
| Valvular | 191 (18.51) | 43 (13.87) | 184 (8.05) | <0.001 | ||
| Chagas disease | 72 (6.98) | 39 (12.58) | 397 (17.37) | <0.001 | ||
| Tachycardia-induced | 40 (3.88) | 4 (1.29) | 9 (0.39) | <0.001 | ||
| Alcoholic | 33 (3.2) | 9 (2.9) | 93 (4.07) | 0.341 | ||
| Idiopathic | 185 (17.93) | 60 (19.35) | 442 (19.34) | 0.622 | ||
| Other | 65 (6.3) | 12 (3.9) | 110 (4.8) | 0.112 | ||
| NYHA | I–II | 872 (88.9) | 227 (77.2) | 1607 (72.8) | <0.001 | 0 |
| III–IV | 109 (11.1) | 67 (22.8) | 601 (27.2) | |||
| Systolic blood pressure (mmHg) | 121.3 (0.8) | 115.4 (1.5) | 110.6 (0.5) | <0.001 | 0 | |
| Diastolic blood pressure (mmHg) | 73.9 (0.5) | 71.2 (0.9) | 70.2 (0.3) | 0.044 | 0 | |
| Heart rate (bpm) | 70 (62–78) | 68 (60–76) | 70 (63–78) | 0.212 | 0 | |
| Medical history | ||||||
| Hypertension | 655 (63.53) | 204 (65.81) | 1297 (56.81) | <0.001 | 0 | |
| Diabetes mellitus | 314 (30.46) | 108 (34.84) | 716 (31.36) | 0.345 | ||
| Dyslipidaemia | 390 (37.83) | 116 (37.42) | 850 (37.23) | 0.947 | ||
| Atrial fibrillation/flutter | 311 (30.16) | 102 (32.9) | 607 (26.59) | 0.016 | ||
| Alcoholism | 81 (7.86) | 32 (10.32) | 260 (11.39) | 0.007 | ||
| Smoking | 284 (27.55) | 101 (32.58) | 770 (33.73) | 0.002 | ||
| COPD/asthma | 73 (7.08) | 31 (10) | 149 (6.53) | 0.076 | ||
| Hypothyroidism | 133 (12.9) | 46 (14.84) | 401 (17.56) | 0.003 | ||
| Myocardial infarction | 166 (16.1) | 66 (21.29) | 582 (25.49) | <0.001 | ||
| PCI | 128 (12.42) | 48 (15.48) | 317 (13.89) | 0.318 | ||
| CABG | 104 (10.09) | 44 (14.19) | 309 (13.53) | 0.015 | ||
| No comorbidities | 78 (7.57) | 12 (3.87) | 163 (7.14) | 0.072 | ||
| Laboratory | ||||||
| Haemoglobin (g/dL) | 13.5 (0.1) | 13.6 (0.1) | 13.6 (0.04) | 0.084 | 3 | |
| Sodium (mg/dL) | 140 (138–141) | 140 (138–141) | 140 (138–141) | 0.073 | 3 | |
| Potassium (mg/dL) | 4.4 (0.02) | 4.5 (0.03) | 4.5 (0.01) | 0.16 | 3 | |
| Urea (mg/dL) | 45.4 (0.8) | 47.7 (1.2) | 49.7 (0.5) | <0.001 | 4 | |
| Serum creatinine (mg/dL) | 1.31 (0.04) | 1.31 (0.06) | 1.27 (0.02) | 0.018 | 3 | |
| BNP (pg/mL) | 113 (39–314) | 106 (39–292) | 275 (110–621) | <0.001 | 48 | |
| Treatment | 1 | |||||
| Thiazide | 231 (22.56) | 71 (23.2) | 453 (19.94) | 0.136 | ||
| Daily doses (mg/day) | 25 (25–25) | 25 (25–25) | 25 (25–25) | 0.191 | ||
| Furosemide | 449 (43.85) | 194 (62.99) | 1589 (69.85) | <0.001 | ||
| Daily doses (mg/day) | 48.7 (1.4) | 56.1 (2.6) | 60.9 (1.0) | <0.001 | ||
| ACEi/RAS antagonist | 832 (81.33) | 250 (81.17) | 1896 (83.3) | 0.296 | ||
| Target dose percentage | 1.0 (0.5–1.0) | 0.5 (0.5–1.0) | 0.5 (0.3–1.0) | 0.072 | ||
| Beta-blocker | 872 (84.5) | 274 (88.4) | 2129 (93.2) | <0.001 | ||
| Target dose percentage | 0.5 (0.3–0.5) | 0.5 (0.3–0.5) | 0.5 (0.3–0.6) | 0.022 | ||
| Spironolactone | 403 (39.36) | 159 (51.62) | 1493 (65.68) | <0.001 | ||
| Daily doses (mg/day) | 25 (25–25) | 25 (25–25) | 25 (25–25) | 0.058 | ||
| Hydralazine | 124 (12.1) | 52 (16.94) | 572 (25.18) | <0.001 | ||
| Daily doses (mg/day) | 100 (75–150) | 75 (69–150) | 75 (75–150) | 0.507 | ||
| Nitrate | 94 (9.17) | 44 (14.29) | 515 (22.64) | <0.001 | ||
| Daily doses (mg/day) | 80 (40–120) | 60 (40–120) | 60 (40–120) | 0.274 | ||
| Digoxin | 141 (13.8) | 68 (22.08) | 612 (26.94) | <0.001 | ||
| Daily doses (mg/day) | 0.12 (0.12–0.25) | 0.12 (0.12–0.25) | 0.12 (0.12–0.25) | 0.514 | ||
| Amiodarone | 113 (11.06) | 48 (15.58) | 464 (20.42) | <0.001 | ||
| Daily doses (mg/day) | 200 (200–200) | 200 (200–200) | 200 (200–200) | 0.092 | ||
| Ivabradine | 21 (2.05) | 3 (0.97) | 44 (1.94) | 0.501 | ||
| Daily doses (mg/day) | 10 (10–15) | 5 (3.8–10) | 10 (5–15) | 0.33 | ||
| Implantable cardioverter-defibrillation | 30 (2.91) | 21 (6.77) | 311 (13.6) | <0.001 | ||
| Cardiac resynchronization therapy | 42 (4.07) | 19 (6.13) | 425 (18.59) | <0.001 | ||
| Echocardiography | ||||||
| LVEF (%) | 32 (0.2) | 32 (0.3) | 28 (0.1) | <0.001 | 0 | |
| LVEDD (mm) | 60 (54–64) | 60 (56–65) | 65 (60–70) | <0.001 | 0 | |
| LVESD (mm) | 49 (44–54) | 50 (46–55) | 56 (50–61) | <0.001 | 6 | |
| Left atrium diameter (mm) | 44 (40–49) | 44 (41–49) | 45 (41–50) | <0.001 | 1 | |
| IV septum thickness (mm) | 10 (9–11) | 9 (8–10) | 9 (8–10) | <0.001 | 0 | |
| Posterior wall thickness (mm) | 9 (8–10) | 9 (8–10) | 9 (8–10) | 0.01 | 0 | |
| RV dysfunction | 0.123 | 1 | ||||
| 0 | 700 (68.43) | 217 (70.92) | 1534 (68) | |||
| 1 | 163 (15.93) | 45 (14.71) | 306 (13.56) | |||
| 2 | 110 (10.75) | 29 (9.48) | 259 (11.48) | |||
| 3 | 50 (4.89) | 15 (4.9) | 157 (6.96) | |||
| Mitral regurgitation | <0.001 | 11 | ||||
| Mild | 632 (71.98) | 192 (71.91) | 1312 (63.14) | |||
| Moderate | 166 (18.91) | 50 (18.73) | 475 (22.86) | |||
| Severe | 80 (9.11) | 25 (9.36) | 291 (14) |
Compared with the other aetiologies, hypertensive aetiology was more strongly associated with SRR. There were differences in functional class between the SRR and NRR groups, with the SRR group having a greater prevalence of New York Heart Association (NYHA) classes I–II and a lower prevalence of NYHA classes III–IV. Systolic blood pressure (SBP) was greater in the SRR group than in the NSRR and NRR groups. Similarly, diastolic blood pressure was greater in the SRR group. Compared with the NRR group, the SRR group presented a greater prevalence of hypertension and a lower prevalence of hypothyroidism. Additionally, the SRR group had a lower prevalence of alcoholism, smoking and coronary artery bypass graft than the other groups did.
The NRR group had a lower frequency of atrial fibrillation/atrial flutter and higher serum creatinine levels. Furthermore, the SRR group received furosemide less often and at lower doses than the NRR group did. The prescription rates of beta-blockers were high overall but lower in the SRR group, with associated lower doses than those in the NRR group. Additionally, the SRR group had lower usage of spironolactone, hydralazine, nitrate, amiodarone and digoxin than the NRR group did, and fewer implantable cardioverter defibrillators and cardiac resynchronization therapy devices were used in the SRR group than in the other groups. Compared with those in the NRR group, patients in the SRR group presented lower levels of urea, BNP and serum creatinine.
The baseline echo exhibited a lower LVEF in the NRR group than in the other groups. Left ventricular end-diastolic diameter varied significantly across all groups, whereas Left ventricular end-systolic diameter (LVESD) was greater in the NRR group. Moreover, the left atrial (LA) diameter was greater in the NRR group, whereas the interventricular (IV) septum and posterior wall thickness were smaller. Moderate and severe mitral regurgitation were less prevalent in the SRR group than in the NRR group. The missing data are presented in Table 1. Furthermore, a demographic analysis comparing patients with two or three echoes was performed to identify potential selection bias (Table S1). The predictors for RR are described in the supplementary materials (Tables S2 and S3).
LVEF trajectory
Although both the SRR and NSRR groups showed improvement in the second LVEF measurement, the percentage increase differed significantly among all groups (49 ± 0.3, 44 ± 0.3 and 28 ± 0.1 in the SRR, NSRR and NRR groups, respectively; P < 0.001). This difference persisted in the third LVEF measurements (51 ± 0.3, 33 ± 0.3 and 28 ± 0.1 in the SRR, NSRR and NRR groups, respectively; P < 0.001). The average time between the first and second echoes was 2.5 ± 0.03 years and that between the second and third echoes was 2.6 ± 0.03 years (Figure 2).
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Survival
The mean (±SE) survival after the second echo was 10.6 (±0.2) years. There was significant between-group heterogeneity in survival rates, with the highest survival observed in patients with SRR (12.2 ± 0.3 years), followed by those with NSRR (10.6 ± 0.5) and the lowest survival in NRR patients (9.8 ± 0.2 years) (P < 0.001; Figure 3).
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Predictors of sustained reverse remodelling
Demographic, clinical and echocardiographic variables associated with SRR (Table 2) were identified through univariate analysis. Variables with a statistically significant association (P < 0.05) were included in the multivariate regression analysis model.
Table 2 Associations between predictors for sustained reverse remodelling (univariate analysis).
| Odds ratio | Confidence interval (95%) | |||
| Age (years) | 0.99 | 0.98–1.006 | 0.59 | |
| Sex | 1.17 | 0.90–1.53 | 0.22 | |
| Aetiology | Ischaemic | 0.65 | 0.5–0.86 | 0.002 |
| Hypertensive | 1.23 | 0.85–1.77 | 0.26 | |
| Valvular | 1.41 | 0.98–2.01 | 0.06 | |
| Chagas disease | 0.52 | 0.34–0.78 | 0.002 | |
| Tachycardia-induced | 3.08 | 1.09–8.7 | 0.03 | |
| Alcoholic | 1.1 | 0.52–2.3 | 0.8 | |
| Idiopathic | 0.91 | 0.65–1.25 | 0.57 | |
| Other | 1.67 | 0.89–3.13 | 0.11 | |
| NYHA | I–II | 2.36 | 1.7–3.3 | <0.001 |
| III–IV | 0.42 | 0.3–0.6 | <0.001 | |
| Systolic blood pressure (mmHg) | 1.007 | 1.003–1.01 | 0.001 | |
| Diastolic blood pressure (mmHg) | 1.01 | 1.002–1.017 | 0.008 | |
| Heart rate (bpm) | 0.997 | 0.99–1.004 | 0.5 | |
| Hypertension | 0.90 | 0.69–1.18 | 0.46 | |
| Diabetes mellitus | 0.82 | 0.62–1.07 | 0.15 | |
| Dyslipidaemia | 1.02 | 0.8–1.3 | 0.9 | |
| Atrial fibrillation/flutter | 0.88 | 0.67–1.15 | 0.36 | |
| Alcoholism | 0.74 | 0.48–1.13 | 0.17 | |
| Smoking | 0.78 | 0.6–1.04 | 0.08 | |
| COPD/asthma | 0.68 | 0.44–1.06 | 0.09 | |
| Hypothyroidism | 0.85 | 0.59–1.22 | 0.38 | |
| Myocardial infarction | 0.71 | 0.51–0.98 | 0.03 | |
| PCI | 0.77 | 0.54–1.1 | 0.16 | |
| CABG before 2nd echo | 0.786 | 0.42–1.47 | 0.453 | |
| No comorbidities | 2.03 | 1.1–3.8 | 0.025 | |
| Haemoglobin (g/dL) | 0.95 | 0.89–1.02 | 0.2 | |
| Sodium (mg/dL) | 0.998 | 0.95–1.05 | 0.96 | |
| Potassium (mg/dL) | 0.97 | 0.74–1.2 | 0.8 | |
| Urea (mg/dL) | 0.995 | 0.98–1.001 | 0.1 | |
| Serum creatinine (mg/dL) | 0.98 | 0.86–1.12 | 0.75 | |
| BNP (pg/mL) | 1.00 | 0.99–1.0005 | 0.5 | |
| Thiazide | 1.03 | 0.76–1.4 | 0.8 | |
| Furosemide use | 0.46 | 0.3–0.6 | <0.001 | |
| Furosemide daily dose (<40 mg) | 2.24 | 1.60–3.14 | <0.001 | |
| ACEi/RAS antagonist | 0.98 | 0.71–1.3 | 0.95 | |
| Target dose percentage | 1.23 | 0.81–1.85 | 0.32 | |
| Beta blocker | 0.72 | 0.5–1.1 | 0.09 | |
| Target dose percentage | 1.0 | 0.99–1.01 | 0.25 | |
| Spironolactone | 0.61 | 0.47–0.79 | <0.001 | |
| Hydralazine | 0.67 | 0.47–0.96 | 0.03 | |
| Nitrate | 0.61 | 0.41–0.89 | 0.01 | |
| Digoxin | 0.56 | 0.41–0.78 | 0.001 | |
| Ivabradine | 0.47 | 0.14–1.6 | 0.22 | |
| Amiodarone | 0.67 | 0.47–0.97 | 0.03 | |
| CRT before 2nd echo | 1.00 | 0.399–2.52 | 0.998 | |
| 1st LVEF (%) | 1.01 | 0.99–1.04 | 0.295 | |
| 1st LVEDD (mm) | 0.98 | 0.96–0.99 | 0.007 | |
| 1st LVESD (mm) | 0.98 | 0.96–0.99 | 0.013 | |
| 1st LA diameter (mm) | 0.99 | 0.98–1.01 | 0.426 | |
| 1st IV septum thickness (mm) | 1.09 | 1.01–1.18 | 0.020 | |
| 1st posterior wall thickness (mm) | 1.09 | 1.01–1.19 | 0.041 | |
| 1st RV dysfunction | ||||
| 1 | 0.97 | 0.53–1.76 | 0.914 | |
| 2 | 1.09 | 0.56–2.11 | 0.087 | |
| 3 | 1.14 | 0.56–2.30 | 0.720 | |
| 1st mitral regurgitation | ||||
| Moderate | 1.03 | 0.64–1.66 | 0.908 | |
| Severe | 1.04 | 0.59–1.79 | 0.895 | |
| 2nd LVEF (%) | 1.1 | 1.08–1.13 | <0.001 | |
| 2nd LVEDD (mm) | 0.91 | 0.89–0.93 | <0.001 | |
| 2nd LVESD (mm) | 0.89 | 0.87–0.91 | <0.001 | |
| 2nd LA diameter (mm) | 0.98 | 0.96–0.99 | 0.033 | |
| 2nd IV septum thickness (mm) | 1.11 | 1.03–1.20 | 0.004 | |
| 2nd posterior wall thickness (mm) | 1.06 | 0.97–1.16 | 0.17 | |
| 2nd RV dysfunction | ||||
| 1 | 0.90 | 0.52–1.56 | 0.72 | |
| 2 | 0.67 | 0.27–1.66 | 0.4 | |
| 3 | 0.88 | 0.09–8.50 | 0.9 | |
| 2nd mitral regurgitation | ||||
| Moderate | 2.43 | 0.39–15.2 | 0.34 | |
| Severe | 1.83 | 0.27–12.4 | 0.53 |
The multivariate regression model identified variables that were independently associated with SRR (Table 3) and were included in the final model, which demonstrated an area under the curve of 0.75 (Figure 4). In a sensitivity analysis using simple imputation, the selected variables and magnitude of effect remained consistent with primary findings (Table S4).
Table 3 Associations between predictors for sustained reverse remodelling (stepwise multivariate analysis,
| Coef. (B) | Wald | Odds ratio | CI (95%) | ||
| 2nd LV ejection fraction (%) | 0.057 | 16.92 | 1.06 | 1.03–1.90 | <0.001 |
| 2nd LVESD (mm) | −.0.074 | 25.59 | 0.93 | 0.90–0.96 | <0.001 |
| 2nd IV septum thickness (mm) | 0.097 | 4.28 | 1.12 | 1.03–1.23 | 0.012 |
| Systolic blood pressure (mmHg) | 0.010 | 6.02 | 1.01 | 1.00–1.02 | 0.014 |
| NYHA I–II | 0.575 | 8.10 | 1.86 | 1.27–2.74 | 0.001 |
| Non-use of furosemide | 0.568 | 13.00 | 1.87 | 1.29–2.40 | <0.001 |
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Discussion
Our study followed a cohort of patients with HFrEF, observing the trajectory of LVEF over time in individuals with three serial examinations with an average interval of 2 years between them. We were able to observe the behaviour of three different groups (SRR, NSRR and NRR) and determine the predictors of SRR. To our knowledge, this is the first study in which predictors of SRR were identified in a large cohort. The analysis revealed an RR rate of 37%, which is comparable with the prevalence described in the literature, with variations ranging from 26% to 46%, depending on the definition adopted.5,7,9,19–21 Similar predictors to those described in the literature were identified for RR, including non-ischaemic aetiology, notably valvular and tachycardiomyopathy; elevated blood pressure; less severe initial remodelling with lower LVSD and higher EF18; and other parameters indicative of less severe HF, such as lower doses of diuretics and fewer symptoms.
In the TREAD-HF study, where the recurrence rate was 40%, the decrease in the LVEF preceded the increase in natriuretic peptides, suggesting that this is not just an echo variation but also a recurrence of HF. Our findings reinforce this hypothesis by verifying worse survival in patients without SRR. Despite maintaining their use of beta-blockers, angiotensin-converting enzyme inhibitors and mineralocorticoid antagonists, our patients experienced a decrease in the LVEF at a rate of 23%. This rate was lower than that reported in the TREAD-HF study, where treatment suspension resulted in signs of HF recurrence in the majority of patients within just 8 weeks.12 These findings suggest that while maintaining medication may not entirely prevent LVEF deterioration, it can potentially decelerate this process. Evaluating the influence of SGLT2 and neprilysin inhibitors in maintaining RR in the long term would be extremely interesting. Contemporary cohorts will be able to provide more information.
Merlo et al. reported that approximately 37% of patients who experienced an initial improvement in the LVEF subsequently experienced a decline. Interestingly, their cohort did not identify predictors of what they termed ‘apparent persistent long-term cure’.22 Despite achieving RR, patients remain at risk of further worsening of LVEF and new HF.12 These findings corroborate the opinions of some authors, who view RR not as a recovery or cure but rather as a remission in some cases.13,14 Lupon et al. evaluated the long-term trajectory of LVEF among patients with HFrEF and HF with mildly reduced EF (HFmrEF) and reported an initial improvement in the LVEF during the first year, followed by a subsequent decline over time, characterized by an inverted U-shaped pattern. This pattern was found to be influenced by factors such as HF aetiology and duration, LVEF classification and sex.17 Our study additionally identified other clinical and echocardiographic predictors that may contribute to understanding these differences, such as the NYHA functional classification, SBP and non-use of furosemide.
There is evidence that changes caused by cardiac remodelling are maintained even after RR, suggesting incomplete improvement.4 The absence of these residual changes can be a good prognostic factor. In our analysis, NYHA I–II and the non-necessity of using furosemide, which are indirect indicators of better ventricular function, were associated with a greater chance of SRR.
Imaging techniques can also be used to predict RR and patient prognosis.23 LVEF is associated with prognosis and outcomes, but it is not considered a therapeutic target.7 Patients who achieved RR had lower LVEDD and LVESD, higher initial LVEF and increased posterior wall thickness at baseline,24 in agreement with our findings of a lower LVESD and a larger IV septum. Additionally, our study revealed a relationship between the second LVEF and SRR, suggesting that the greater the magnitude of LVEF recovery is, the greater the chance of LVEF maintenance. Structural parameters are potential biomarkers of prognosis and therapeutic response, but studies evaluating the value of using serial echocardiographic measurements are still limited.25 Patients with NSRR have a lower survival rate than patients with SRR, but they still have a better prognosis than patients who do not achieve RR. This information suggests that NSRR group patients warrant special attention throughout their follow-up and are candidates for the evaluation of new therapeutic and strategic approaches.
We hypothesized that the answer for myocardial recovery identification does not rely on an isolated biomarker or an assessment at isolated moments but rather on an assessment that incorporates different clinical, laboratory and imaging biomarkers, evaluating their trajectories throughout the follow-up.24
Limitations
This study has some limitations. First, it is based on data from a single centre. Second, the data analysis was performed retrospectively, resulting in some missing data. Third, the timing and indications for echocardiography were determined by the attending physician. Finally, this cohort had limited access to SGLT2 or neprilysin inhibitors.
Conclusions
In our study, we demonstrated that patients with HFrEF who achieved SRR had better long-term survival. In addition, we identified a greater LVEF and IV septum thickness, lower LVESD after RR, NYHA I–II status, higher blood pressure and furosemide non-use status as predictors of SRR. These results have the potential to enhance our comprehension of the phenotype associated with improved ventricular function, elucidate the mechanisms underlying remission and myocardial recovery and aid in the assessment of prognosis while identifying groups suitable for new therapeutic strategies.
Acknowledgements
We extend our gratitude to the Department of Health of the State of São Paulo and to the Department of Medical and Hospital Information at the Heart Institute within the School of Medicine at the University of São Paulo.
Conflict of interest statement
Dr Edimar Bocchi received consulting fees from Servier, AstraZeneca, Boehringer Ingelheim; subsidized travel/registration fees/hotel fees from Servier; membership in steering committees from Servier, Novartis, Boehringer Ingelheim; research grant support through Heart Institute from: Jansen, Bayer/Merck, AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, Cardiol Therapeutics, Eurofarma; and honoraria form Servier, Novartis, AstraZeneca and Boehringer Ingelheim. Dr Silvia Moreira Ayub-Ferreira received honoraria from Abbott, Novartis and CSL Vifor. Dr Felix Jose Alvarez Ramires received honoraria from Novartis, AstraZeneca, Bristol Myers Squibb and Amgen. Dr Maria Tereza Sampaio de Sousa Lira received honoraria from AstraZeneca. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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Abstract
Background
Patients with heart failure with reduced ejection fraction (HFrEF) who achieve reverse remodelling (RR) can experience a new decrease in ejection fraction (EF), and the predictors of sustained RR (SRR) are not completely understood.
Objectives
The study aims to identify predictors of SRR in patients with HFrEF after an increase in EF and evaluate SRR prognosis.
Methods
In this retrospective, observational study, we evaluated a real‐life cohort of patients with HFrEF and ≥2 consecutive echocardiograms, divided according to left ventricular EF (LVEF) trajectory: no RR (NRR: 3/3 LVEF measurements < 40%), non‐SRR (NSRR: second LVEF ≥ 40%, third LVEF < 40%), and SRR (SRR: second and third LVEF ≥ 40%).
Results
We included 3628 of 8072 assessed HF patients in the analysis, with mean age 56.2 (±13.4) years, 64.4% male and 77.7% New York Heart Association (NYHA) I–II. Improved EF was observed for 1342 (37%) patients. Among those who achieved RR, 310 (23%) were NSRR, and 1032 (77%) were SRR. The mean (±SE) survival after the second echocardiogram was 10.6 (±0.2) years. The SRR group had the longest survival (12.2 ± 0.3 years), followed by the NSRR (10.6 ± 0.5) and NRR (9.8 ± 0.2 years) groups (P < 0.001). According to logistic multivariable regression, second LVEF [odds ratio (OR) = 1.06, confidence interval (CI) = 1.03–1.90, P < 0.001], second left ventricular end‐systolic diameter (LVESD) (OR = 0.93, CI = 0.90–0.96, P < 0.001), second IV septum thickness (OR = 1.12, CI = 1.03–1.23, P = 0.012), systolic blood pressure (OR = 1.01, CI = 1.00–1.02, P = 0.014), NYHA I–II (OR = 1.86, CI = 1.27–2.74, P = 0.001) and furosemide non‐use (OR = 1.87, CI = 1.27–2.74, P < 0.001) independently predicted SRR.
Conclusions
Patients with greater EF increases and LVESD reductions at EF recovery, greater septum thickness, higher blood pressure, no need for diuretics and NYHA I/II maintenance had the best chance of maintaining recovered ventricular function.
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Details
; Bocchi, Edimar Alcides 1 ; Lira, Maria Tereza Sampaio de Sousa 1 ; Wanderley, Mauro Rogerio de Barros 2 ; Marchi, Daniel Catto 1 ; Maciel, Pamela Camara 1 ; Zimerman, Andre 3 ; Ramires, Felix Jose Alvarez 1 ; Nastari, Luciano 1 ; Biselli, Bruno 1 ; Chizzola, Paulo Roberto 1 ; Munhoz, Robinson Tadeu 1 ; Fernandes, Fábio 1 ; Ayub‐Ferreira, Silvia Moreira 1 1 Instituto do Coracao (InCor), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, SP, Brazil
2 Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, EUA, Boston, Massachusetts, USA
3 Clinical Trials Unit, Hospital Moinhos de Vento, Moinhos de Vento College of Health Sciences, Porto Alegre, Brazil