Improved Ejection Fraction in the Acute Heart Failure Setting: Cardiac Structure, Cardiac Function, or Extrinsic Factors?

Left ventricular ejection fraction (LVEF) remains central to the classification and management of heart failure (HF). It is closely linked to underlying pathogenesis, pathophysiology, natural history, and outcomes and continues to guide both therapeutic decision making and eligibility for clinical trials. ¹

HF with improved ejection fraction (HFimpEF) is defined as a baseline LVEF ≤40%, with subsequent improvement to >40% and an absolute increase ≥10%. ² HFimpEF is common and has been described in chronic HF ³ and in the present issue of the Journal of the American Heart Association (JAHA) also in acute HF (AHF). ⁴

What Are the Implications of HFimpEF?

Biology and Physiology

LVEF represents both cardiac structure and function. In HF with reduced ejection fraction (HFrEF), progressive adverse remodeling causes structural changes in the form of left ventricular (LV) dilatation, and increased LV end‐diastolic and end‐systolic volumes. This, in itself reduces LVEF, even if stroke volume may be maintained. Also, in HFrEF, the fundamental and intrinsic defect in cardiomyocyte contractility will manifest as a lower stroke volume and lower difference between LV end‐systolic volume and LV end‐diastolic volume, thus leading to lower LVEF, even if LV end‐diastolic volume remains normal. Simplistically, HFimpEF may thus represent both reverse remodeling and improved structure, which occurs usually with medical therapy over 3 to 12 months, or improved contractility and function, which can occur both immediately with changes in load and with, for example, treatment with inotropes, and over the long term reflecting reversal of maladaptive post‐translational modifications of proteins involved in, for example, β‐adrenergic signaling and the sarcomere.

Prognosis

In chronic HFrEF, HFimpEF has been well characterized. Because it reflects structural reverse remodeling over time, it is robust and strongly associated with a reduced risk of cardiovascular death and HF hospitalization (whereas worsening or persistently reduced LVEF identifies patients at higher risk), highlighting LVEF trajectory as a clinically meaningful risk marker beyond baseline assessment. ⁵ In AHF, it is more complex. Apart from being highly load dependent and a reflection of ventriculo‐vascular coupling (unlike intrinsic contractility), ejection fraction is increasingly recognized to be dependent on additional dynamic parameters such as adrenergic drive and inflammation as well as early or even immediate inotropic but also reverse remodeling treatment effects. ³ , ⁶ In this context, increasing attention has been directed toward the concept of LVEF trajectories rather than single‐time‐point assessments as a more informative marker of disease severity and treatment response. ³ , ⁵ However, the role of in‐hospital changes in acute HFrEF (as compared with longer‐term change in chronic HFrEF) is more complex and less well studied. Does it reflect durable structural and functional myocardial recovery or transient improvement in intrinsic (contractility) or extraneous (load) functional parameters?

In this issue of JAHA, Cocianni et al. ⁴ present data from a single‐center registry of 779 patients hospitalized with AHF and reduced LVEF (≤40%), specifically examining in‐hospital trajectories of LVEF. HFimpEF occurred in ≈15% of patients. The primary outcome was all‐cause death, and the authors assessed both predictors of LVEF improvement and its association with outcomes. Predictors of early LVEF improvement included valvular pathogenesis, smaller LV volumes, and absence of right ventricular dysfunction, together delineating a phenotype consistent with shorter duration of HF and more reversible functional changes. Valvular (likely primarily mitral) disease likely reflects predominantly load‐dependent impairment, enabling rapid improvement with decongestion and afterload reduction. In parallel, smaller ventricular volumes indicate less advanced remodeling, whereas the absence of right ventricular dysfunction suggests a shorter‐duration, less severe disease state with preserved cardiac reserve and a greater potential for recovery. The cohort was relatively young (mean age, 68 years) and predominantly men, reflecting a selected population compared with broader contemporary AHF registries. HFimpEF was independently associated with improved outcomes, consistent with prior observations in chronic HF. However, in the acute setting, this likely reflects not only true myocardial recovery but also effective decongestion and transient changes in loading conditions. Thus, HFimpEF may serve more as an integrated marker of treatment response and disease reversibility than a pure measure of myocardial recovery. Notably, HFimpEF was independently associated with a significantly lower risk of 1‐ and 5‐year death, whereas baseline LVEF at admission was not prognostic.

Does AHF HFimpEF Affect Therapy?

At any given time, whether in acute or chronic HF, initiation of therapy is guided by the prevailing LVEF; that is, initiation of guideline‐directed medical therapy is indicated in both chronic and acute HFrEF. Once guideline‐directed medical therapy has been established, it should be maintained even if ejection fraction improves, as supported by both randomized evidence (eg, TRED‐HF [Withdrawal of Pharmacological Treatment for Heart Failure in Patients With Recovered Dilated Cardiomyopathy] ⁷ ) and large observational studies, which demonstrate a high risk of relapse following treatment withdrawal. ⁸ In patients with AHF and reduced LVEF who have not yet received all guideline‐directed medical therapy, normalization of ejection fraction during hospitalization would have excluded patients from the pivotal randomized trials and removes the formal indication for initiating additional guideline‐directed medical therapy. Here, the understanding of AHF physiology and the dynamic nature of LVEF in the AHF setting remains poorly understood, due to the multiple confounding factors in the acute setting, such as excessive variations in load, infection and the systemic inflammatory response, and the multitude of potential in‐hospital complications. Unlike in chronic HFrEF, trials in AHF have been largely unsuccessful, and more studies such as the one by Cocianni et al. ⁴ are sorely needed.

Disclosures

L.H.L. has no disclosures related to the present manuscript. Unrelated to present manuscript, he reports grants and consulting and lecture honoraria to author's institution from AstraZeneca, Boerhinger Ingelheim, Bayer, Pharmacosmos, Novo Nordisk, Pfizer; and stock in AnaCardio. K.K. has no disclosures to report.