HFimPEF: Breakthroughs in Ejection Fraction Improvement

Heart failure with improved ejection fraction (HFimEF) has emerged as a critical clinical entity, distinguishing patients who experience substantial recovery in left ventricular function from those with persistently reduced ejection fraction. This shift affects prognosis, management strategies, and long-term outcomes, making it a key area of research and clinical focus.

Advancements in targeted therapies and novel biomarkers have expanded understanding of ejection fraction improvement. As evidence grows, refining diagnostic criteria and optimizing treatment approaches remain essential challenges.

Clinical Identification

Recognizing HFimEF requires differentiating it from heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). HFimEF is defined by an increase in left ventricular ejection fraction (LVEF) of at least 10 percentage points from a baseline of ≤40%, reaching above 40%. However, this improvement does not always indicate full myocardial recovery, as structural and functional abnormalities often persist.

Serial echocardiographic assessments are the primary imaging tool for tracking LVEF changes, while cardiac magnetic resonance (CMR) imaging provides additional insights, particularly in detecting myocardial fibrosis. Studies using late gadolinium enhancement (LGE) on CMR have linked residual fibrosis to an increased risk of adverse cardiovascular events, highlighting the need for comprehensive imaging beyond LVEF measurement.

Beyond imaging, biomarkers such as brain natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) help distinguish HFimEF from other heart failure phenotypes. While these markers decline as ejection fraction improves, they often remain elevated compared to individuals without heart failure, reflecting ongoing myocardial stress. A study in Circulation found that BNP levels in HFimEF patients fall between those with HFrEF and HFpEF, reinforcing the role of biochemical markers in tracking disease progression.

The likelihood of ejection fraction recovery depends on the underlying cause of heart failure. Ischemic cardiomyopathy is less likely to show substantial LVEF improvement compared to non-ischemic causes such as myocarditis or tachycardia-induced cardiomyopathy. This distinction has therapeutic implications, as ischemic heart failure often requires more aggressive interventions like revascularization, while reversible causes may respond well to guideline-directed medical therapy alone.

Mechanisms of Ejection Fraction Recovery

LVEF restoration in HFimEF results from cellular, structural, and hemodynamic adaptations. Cardiomyocyte remodeling plays a key role, particularly through the reversal of pathological hypertrophy and improved contractile function. Studies indicate that maladaptive cardiomyocyte enlargement, common in HFrEF, can partially regress with effective therapy, enhancing systolic performance. Molecular signaling pathways such as the phosphoinositide 3-kinase (PI3K)/Akt axis promote cellular survival and myocardial regeneration, while enhanced mitochondrial biogenesis optimizes ATP production and reduces oxidative stress.

Extracellular matrix remodeling is another critical factor. Myocardial fibrosis, a hallmark of chronic heart failure, can partially regress with the downregulation of profibrotic pathways like transforming growth factor-beta (TGF-β) signaling. Guideline-directed medical therapy (GDMT), particularly agents targeting the renin-angiotensin-aldosterone system (RAAS), has been shown to reduce myocardial collagen deposition and improve ventricular compliance. CMR studies using LGE indicate that HFimEF patients often retain residual fibrosis, which may limit recovery and predispose them to recurrent dysfunction.

Hemodynamic improvements further support systolic function recovery by reducing ventricular afterload and optimizing preload. Beta-blockers and mineralocorticoid receptor antagonists lower systemic vascular resistance, easing the workload on the left ventricle and facilitating more efficient blood ejection. Reverse cardiac remodeling, marked by reductions in left ventricular end-diastolic and end-systolic volumes, reflects structural normalization and is associated with better survival and lower hospitalization rates.

SGLT2 Inhibition and HFimEF

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have reshaped heart failure management, offering benefits beyond glycemic control. Their role in HFimEF is gaining attention as emerging data suggest they promote myocardial recovery through multiple mechanisms. Unlike traditional heart failure therapies that target neurohormonal pathways, SGLT2 inhibitors exert systemic effects that enhance left ventricular function. By promoting glycosuria and natriuresis, they reduce plasma volume and lower cardiac preload, improving ventricular efficiency and facilitating reverse remodeling.

SGLT2 inhibitors also enhance myocardial energetics by shifting cardiac metabolism toward ketone utilization. In heart failure, impaired mitochondrial function and inefficient glucose oxidation contribute to energy deficits that weaken contractility. Studies show that SGLT2 inhibitors increase circulating ketone levels, providing a more oxygen-efficient fuel source for the failing myocardium. This metabolic shift has been linked to improved cardiac output and greater myocardial work efficiency, supporting sustained ejection fraction improvement. Additionally, SGLT2 inhibitors regulate intracellular sodium and calcium handling, preventing cytosolic sodium accumulation and calcium overload—key drivers of myocardial stiffness and diastolic dysfunction.

Their anti-inflammatory and antifibrotic effects further contribute to myocardial recovery. Chronic heart failure is often accompanied by low-grade systemic inflammation and excessive fibrosis, both of which impair contractility. Preclinical and clinical studies indicate that SGLT2 inhibition suppresses pro-inflammatory cytokines while attenuating fibrotic signaling pathways like TGF-β. These effects may promote structural remodeling in patients with previously reduced ejection fraction. The EMPEROR-Reduced and DAPA-HF trials, which evaluated SGLT2 inhibitors in heart failure populations, reported significant reductions in hospitalizations and mortality, suggesting these benefits extend to those experiencing ejection fraction improvement.

Assessing Biomarkers in HFimEF

Tracking biomarkers in HFimEF provides insight into disease progression, therapeutic response, and residual risk. While LVEF is the defining metric for HFimEF classification, circulating biomarkers offer a biochemical perspective on myocardial stress, neurohormonal activation, and remodeling. BNP and NT-proBNP remain central to this assessment. Although levels decline as LVEF improves, they often remain elevated compared to individuals without heart failure, reflecting ongoing myocardial strain. A study in JACC: Heart Failure found that BNP levels in HFimEF patients fall between those with HFrEF and HFpEF, reinforcing that biochemical recovery may lag behind functional improvement.

Beyond natriuretic peptides, emerging biomarkers such as soluble suppression of tumorigenicity 2 (sST2) and galectin-3 provide additional prognostic value. Both are associated with myocardial fibrosis and extracellular matrix remodeling, processes that may persist even after LVEF surpasses 40%. Elevated sST2 levels have been linked to a heightened risk of heart failure readmission and mortality in HFimEF patients, suggesting that persistent fibrosis contributes to residual cardiovascular vulnerability. Similarly, galectin-3, a macrophage-derived protein involved in fibrotic signaling, remains elevated in some patients despite optimized medical therapy, indicating that structural remodeling may not fully reverse with LVEF improvement alone.