In-hospital course of patients with heart failure with improved ejection fraction in the DELIVER trial.

AIMS: Patients with heart failure (HF) with improved ejection fraction (HFimpEF) may face residual risks of clinical events that are comparable to those experienced by patients with HF whose left ventricular ejection fraction (LVEF) has consistently been above 40%. However, little is known about the clinical course of patients with HFimpEF during hospitalization for HF. METHODS AND RESULTS: DELIVER randomized patients with HF and LVEF >40% to dapagliflozin or placebo, including HFimpEF (LVEF previously ≤40%). We evaluated all HF hospitalizations adjudicated by the clinical endpoints committee with available data for determination of in-hospital course. Complicated hospitalization was defined as any hospitalization requiring intensive care unit stay, intravenous vasopressors/inotropes/vasodilators, invasive or non-invasive ventilation, mechanical fluid removal, ultrafiltration, or mechanical circulatory support. LVEF changes were extracted using a validated GPT-3.5, a large language model, via a secure private endpoint. Of the 6263 patients enrolled in DELIVER, 1151 (18%) had HFimpEF. During a median follow-up of 2.3 years, there were 224 total HF hospitalizations in 144 patients with HFimpEF and 985 in 603 patients with LVEF consistently >40%. Patients with HFimpEF experienced higher rates of complicated HF hospitalization as compared with patients with LVEF consistently >40% (39% vs. 27%; p < 0.001). Among those who experienced a first HF hospitalization, there was no significant difference in length of stay or in-hospital mortality between patients with HFimpEF versus LVEF consistently >40%. In a subset of participants who had at least one LVEF measurement available during HF hospitalization, 66% of those with HFimpEF and 29% of patients with LVEF consistently >40% experienced a reduction in their LVEF to ≤40% from the time of enrolment (p < 0.001). In the entire DELIVER cohort, dapagliflozin reduced total uncomplicated and complicated HF hospitalizations, irrespective of HFimpEF status (pinteraction ≥0.30). CONCLUSIONS: Among patients hospitalized for HF in DELIVER, those with HFimpEF experienced a more adverse in-hospital clinical course, necessitating higher resource utilization beyond standard diuretic therapy compared with patients with HF and LVEF consistently >40%, but had similar in-hospital mortality. Treatment benefits of dapagliflozin were not modified by hospitalization type.

Heart failure with improved ejection fraction: patient characteristics, clinical outcomes and predictors for improvement.

Background: Heart failure with improved ejection fraction (HFimpEF) is a recently recognized entity presenting a diagnostic and therapeutic challenge. Our aim was to characterize the profile of HFimpEF patients and evaluate predictors for EF lack of improvement among heart failure with reduced ejection fraction (HFrEF) patients. Methods: We included ambulatory HFrEF patients (EF≤40%) between January 1, 2015, and September 1, 2022, with two consecutive echocardiography exams at least 6 months apart. HFimpEF was defined as improved EF from ≤40%->40% and by ≥10%. Results: A total of 567 HFrEF patients (72% male, 54.3 ± 14.4 years old) were analyzed. Patients without EF improvement were more likely to be male, had more comorbidities, ischemic cardiomyopathy (ICMP), markers of adverse cardiac remodeling (lower EF and higher left and right ventricular diameters) and presence of late gadolinium enhancement (LGE) in MRI (P < 0.05 for all). In a multivariate analysis, male sex, ICMP, lower EF, larger ventricular size and LGE remained independent predictors for lack of EF improvement. A prediction model for lack of EF improvement including LVEF, LV diameter, diastolic blood pressure and ischemic etiology exhibited an area under the ROC curve of 0.77 (95% CI 0.73-0.81; P < 0.001). HFimpEF patients had better prognosis with lower hospitalizations and mortality rates. Guideline directed medical therapy (GDMT) were associated with improved outcomes in both groups regardless of EF improvement. Conclusions: Lack of improvement in EF among HFrEF patients may be predicted by HF etiology and imaging parameters of adverse cardiac remodeling, and is associated with worse prognosis. GDMT were associated with improved outcomes in both HFimpEF and HFrEF patients.

Heart Failure With Improved Ejection Fraction: Prevalence, Predictors, and Guideline-Directed Medical Therapy.

Recently, a new category of heart failure with improved ejection fraction (HFimpEF) has emerged in the classification system. This is defined as the subgroup of patients with heart failure with reduced ejection fraction (HFrEF) whose left ventricular ejection fraction has recovered partially or completely, with no specific cut-off values established yet in the guidelines. In our review, we aim to provide an overview of prevalence, predictors, mechanism of remodeling, and management strategies regarding HFimpEF. These patients constitute a sizeable cohort among patients with reduced ejection fraction. Certain patient characteristics including younger age and female gender, absence of comorbid conditions, low levels of biomarkers, and non-ischemic etiology were identified as positive predictors. The heart undergoes significant maladaptive changes post failure leading to adverse remodeling influenced etiology and duration. Goal-directed medical therapy including beta-blockers, angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin II receptor blockers (ARBs) have notably improved cardiac function by inducing reverse remodeling. Despite a more favorable prognosis compared to HFrEF, patients with improved ejection fraction (EF) still face clinical events and reduced quality of life, and remain at risk of adverse outcomes. Although the evidence is scarce, it is advisable to continue treatment modalities despite improvement in EF, including device therapies, to prevent relapse and clinical deterioration. It is imperative to conduct further research to understand the mechanism leading to EF amelioration and establish guidelines to identify and direct management strategies.

Myocardial Recovery and Relapse in Heart Failure With Improved Ejection Fraction.

Purpose of review: The purpose of this review is to discuss myocardial recovery in heart failure with reduced ejection fraction (HFrEF) and to summarize the contemporary insights regarding heart failure with improved ejection fraction (HFimpEF). Recent findings: Improvement in left ventricular ejection fraction (LVEF ≥ 40%) with improved prognosis can be achieved in one out of three (10-40%) patients with HFrEF treated with guideline-directed medical therapy. Clinical predictors include non-ischemic etiology of HFrEF, less abnormal blood or imaging biomarkers, and lack of specific pathogenic genetic variants. However, a subset of patients may ultimately relapse, suggesting that many patients are merely in remission rather than having fully recovered. Summary: Patients with HFimpEF have improved prognosis but nonetheless remain at risk of relapse and long-term adverse events. Future studies will hopefully chart the natural history of HFimpEF and identify clinical predictors such as blood or novel imaging biomarkers that distinguish subgroups of patients based on differential trajectory and prognosis.

Clinical, Echocardiographic, and Longitudinal Characteristics Associated With Heart Failure With Improved Ejection Fraction.

Heart failure with improved ejection fraction (HFimpEF) has better outcomes than HF with reduced EF (HFrEF). However, factors contributing to HFimpEF remain unclear. This study aimed to evaluate clinical and longitudinal characteristics associated with subsequent HFimpEF. This was a single-center retrospective HFrEF cohort study. Data were collected from 2014 to 2022. Patients with HFrEF were identified using International Classification of Diseases codes, echocardiographic data, and natriuretic peptide levels. The main end points were HFimpEF (defined as EF >40% at ≥3 months with ≥10% increase) and mortality. Cox proportional hazards and mixed effects models were used for analyses. The study included 1,307 patients with HFrEF with a median follow-up of 16.3 months (interquartile range 8.0 to 30.6). The median age was 65 years; 68% were male whereas 57% were White. On follow-up, 38.7% (n = 506) developed HFimpEF, whereas 61.3% (n = 801) had persistent HFrEF. A multivariate Cox regression model identified gender, race, co-morbidities, echocardiographic, and natriuretic peptide as significant covariates of HFimpEF (p <0.05). The HFimpEF group had better survival compared with the persistent HFrEF group (p <0.001). Echocardiographic and laboratory trajectories differed between groups. In this HFrEF cohort, 38.7% transitioned to HFimpEF and approximately 50% met the definition within the first 12 months. In a HFimpEF model, gender, co-morbidities, echocardiographic parameters, and natriuretic peptide were associated with subsequent HFimpEF. The model has the potential to identify patients at risk of subsequent persistent or improved HFrEF, thus informing the design and implementation of targeted quality-of-care improvement interventions.

Factors Associated With Maintenance of an Improved Ejection Fraction: An Echocardiogram-Based Registry Study.

Background Heart failure with improved ejection fraction (EF) is increasingly recognized as a sizable and distinct entity. While the features associated with improvedEF have been explored and new guidelines have emerged, factors associated with sustaining an improved EF over time have not been defined. We aimed to assess factors associated with maintenance of an improved EF in a large real-world patient cohort. Methods and Results A total of 7070 participants with heart failure with improved EF and a subsequent echocardiogram performed after at least 9 months of follow-up were included in a retrospective cohort study conducted at the Cleveland Clinic in Cleveland, Ohio. Multiple logistic regression models, adjusted for demographics, comorbidities, and medications were built to identify characteristics and therapeutic interventions associated with maintaining an improved EF. Mean age (SD) was 64.9 (13.8) years, 62.7% were men, and 75.1% were White participants. White race and the use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or angiotensin receptor-neprilysin inhibitors were associated with maintaining the EF at least 9 months after EF improvement. In contrast, male sex or having atrial fibrillation/flutter, coronary artery disease, history of myocardial infarction, presence of an implanted cardioverter-defibrillator, and use of loop diuretics were associated with a decline in EF after previously documented improvement. Conclusions Continued use of renin-angiotensin-aldosterone system inhibitors was associated with maintaining the EF beyond the initial improvement phase.

Influence of background medical therapy on efficacy and safety of dapagliflozin in patients with heart failure with improved ejection fraction in the DELIVER trial.

AIMS: The Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial demonstrated the sodium-glucose cotransporter 2 inhibitor dapagliflozin to be beneficial in patients with symptomatic heart failure (HF) with improved ejection fraction (HFimpEF; those with prior left ventricular ejection fraction ≤40% that had improved to >40% by enrolment). Whether this benefit differs by background medical therapy is unclear. The current study aims to determine the efficacy and safety of dapagliflozin among patients with HFimpEF by background medical therapy. METHODS AND RESULTS: Treatment effects on the primary endpoint (worsening HF or cardiovascular death) were assessed by number of background HF medical therapies (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, evidence-based beta-blocker, and mineralocorticoid receptor antagonist). Among the 6263 patients randomized in DELIVER, 1151 (18%) had HFimpEF. Of those, 21% of patients were on 0-1 therapies, 44% were on two therapies, and 35% were on three therapies. During 2.3 years of median follow-up, the incidence rate of the primary outcome was 9.7, 8.8, and 8.4 per 100 person-years for patients on 0-1, 2 and 3 HF medications at baseline, respectively. Treatment effects with dapagliflozin on the primary outcome may be greater in patients with HFimpEF on 0-1 therapies at baseline (pinteraction = 0.09), driven mostly by a significant interaction for HF hospitalization (pinteraction = 0.023) with no evidence of effect modification for cardiovascular death (pinteraction = 0.65). Treatment effects of dapagliflozin on the primary outcome were, however, consistent when assessed across the modified Heart Failure Collaboratory Medical Therapy Score integrating both therapeutic use and dosing (pinteraction = 0.39). The use of dapagliflozin was not associated with changes in use or doses of background HF therapies, and among patients on three HF medications at baseline, the addition of dapagliflozin did not lead to higher adverse events. CONCLUSIONS: In patients with HFimpEF, the safety and efficacy of dapagliflozin were largely similar by background use and dosing of HF medical therapies. The benefit of dapagliflozin in reducing HF events tended to be greater in those patients on 0-1 medications at baseline. Among patients already on three HF medical therapies, the addition of dapagliflozin was safe without requiring de-escalation of other therapies.

Prognostic value of late-gadolinium enhancement on cardiac magnetic resonance in patients with cardiac sarcoidosis.

BACKGROUND: Late-gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) is a predictor of adverse events in patients with cardiac sarcoidosis (CS), but available studies had small sample sizes and did not consider all relevant endpoints. OBJECTIVE: To evaluate the association between LGE on CMR in patients with CS and mortality, ventricular arrhythmias (VA) and sudden cardiac death (SCD), and heart failure (HF) hospitalization. METHODS: A literature search was conducted for studies reporting the association between LGE in CS and the study endpoints. The endpoints were mortality, VA and SCD, and HF hospitalization. The search included the following databases: Ovid MEDLINE, EMBASE, Web of Science, and Google Scholar. The search was not restricted to time or publication status. The minimum follow-up duration was 1 year. RESULTS: A total of 17 studies and 1915 CS patients (595 with LGE vs. 1320 without LGE) were included; mean follow-up was 3.3 years (ranging between 17 and 84 months). LGE was associated with increased all-cause mortality (OR 6.05, 95% CI 3.16-11.58; p < .01), cardiovascular mortality (OR 5.83, 95% CI 2.89-11.77; p < .01), and VA and SCD (OR 16.48, 95% CI 8.29-32.73; p < .01). Biventricular LGE was associated with increased VA and SCD (OR 6.11, 95% CI 1.14-32.68; p = .035). LGE was associated with an increased HF hospitalization (OR 17.47, 95% CI 5.54-55.03; p < .01). Heterogeneity was low: df = 7 (p = .43), I2 = 0%. CONCLUSIONS: LGE in CS patients is associated with increased mortality, VA and SCD, and HF hospitalization. Biventricular LGE is associated with an increased risk of VA and SCD.

Heart Failure with Improved Ejection Fraction: Insight into the Variable Nature of Left Ventricular Systolic Function.

The progress of contemporary cardiovascular therapy has led to improved survival in patients with myocardial disease. However, the development of heart failure (HF) represents a common clinical challenge, regardless of the underlying myocardial pathology, due to the severely impaired quality of life and increased mortality comparable with malignant neoplasms. Left ventricular ejection fraction (LVEF) is the main index of systolic function and a key predictor of mortality among HF patients, hence its improvement represents the main indicator of response to instituted therapy. The introduction of complex pharmacotherapy for HF, increased availability of cardiac-implantable electronic devices and advances in the management of secondary causes of HF, including arrhythmia-induced cardiomyopathy, have led to significant increase in the proportion of patients with prominent improvement or even normalization of LVEF, paving the way for the identification of a new subgroup of HF with an improved ejection fraction (HFimpEF). Accumulating data has indicated that these patients share far better long-term prognoses than patients with stable or worsening LVEF. Due to diverse HF aetiology, the prevalence of HFimpEF ranges from roughly 10 to 40%, while the search for reliable predictors and genetic associations corresponding with this clinical presentation is under way. As contemporary guidelines focus mainly on the management of HF patients with clearly defined LVEF, the present review aimed to characterize the definition, epidemiology, predictors, clinical significance and principles of therapy of patients with HFimpEF.

Epicardial adipose tissue volume is an independent predictor of left ventricular reverse remodeling in patients with non-ischemic cardiomyopathy.

BACKGROUND: In some patients with non-ischemic cardiomyopathy, left ventricular (LV) contraction is improved by optimal medical therapy, leading to LV reverse remodeling (RR). Patients with heart failure with improved ejection fraction and LVRR have a good prognosis, but the factors that predict RR are not fully understood. The relationship between body composition and cardiovascular disease has been reported. The present study aimed to assess the clinical predictors of LVRR in association with body composition. METHODS: We recruited patients who were diagnosed with non-ischemic cardiomyopathy between September 2017 and January 2020. Finally, 89 patients with a reduced LV ejection fraction were enrolled in this prospective study. Body composition, including ectopic fat, was measured in all patients using computed tomography. Echocardiography was performed 6 months after enrollment to evaluate LVRR. RESULTS: LVRR was observed in 39 patients (43.8%) after 6 months. In terms of the demographic findings, epicardial adipose tissue volume was greater in the LVRR group than in the non-LVRR group (135.2 cm3 [SD 128.4 cm3] vs. 88.9 cm3 [SD 54.6 cm3]; p = 0.040). The Kaplan-Meier analysis demonstrated that adverse cardiac events were significantly less frequent in the LVRR group than in the non-LVRR group (log-rank test, p = 0.013). The multivariate logistic regression analysis identified epicardial adipose tissue volume as an independent predictor of LVRR (odds ratio [OR]: 1.010, 95% confidence interval [CI]: 1.001-1.01; p = 0.036). CONCLUSION: Epicardial adipose tissue volume is an independent predictor of LVRR in patients with non-ischemic cardiomyopathy.

The Prognostic Value of Anemia in Patients with Preserved, Mildly Reduced and Recovered Ejection Fraction.

Data on the relevance of anemia in heart failure (HF) patients with an ejection fraction (EF) > 40% by subgroup-preserved (HFpEF), mildly reduced (HFmrEF) and the newly defined recovered EF (HFrecEF)-are scarce. Patients with HF symptoms, elevated NT-proBNP, EF ≥ 40% and structural abnormalities were registered in the HFpEF-HFmrEF database. We described the outcome of our HFpEF-HFmrEF cohort by the presence of anemia. Additionally, HFrecEF patients were also selected from HFrEF patients who underwent resynchronization and, as responders, reached 40% EF. Using propensity score matching (PSM), 75 pairs from the HFpEF-HFmrEF and HFrecEF groups were matched by their clinical features. After PMS, we compared the survival of the HFpEF-HFmrEF and HFrecEF groups. Log-rank, uni-and multivariate regression analyses were performed. From 375 HFpEF-HFmrEF patients, 42 (11%) died during the median follow-up time of 1.4 years. Anemia (HR 2.77; 95%CI 1.47-5.23; p < 0.01) was one of the strongest mortality predictors, which was also confirmed by the multivariate analysis (aHR 2.33; 95%CI 1.21-4.52; p = 0.01). Through PSM, the outcomes for HFpEF-HFmrEF and HFrecEF patients with anemia were poor, exhibiting no significant difference. In HFpEF-HFmrEF, anemia was an independent mortality predictor. Its presence multiplied the mortality risk in those with EF ≥ 40%, regardless of HF etiology.