Heart Failure With Mid-Range (Borderline) Ejection Fraction: Clinical Implications and Future Directions

Abstract

Heart failure (HF) with borderline ejection fraction was first defined in 2013 in the American College of Cardiology/American Heart Association guidelines as the presence of the typical symptoms of HF and a left ventricular ejection fraction (LVEF) of 41% to 49%. In 2016, the European Society of Cardiology specified HF with mid-range ejection fraction (HFmrEF) as LVEF of 40% to 49%. This range of LVEF is less well studied compared with HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF). Although there are effective, guideline-directed medical therapies for patients with HFrEF, no therapies thus far show measurable benefit in HFpEF. Patients with HFmrEF have a clinical profile and prognosis that are closer to those of patients with HFpEF than those of HFrEF, with certain distinctions. Whether these patients represent a unique and dynamic HF group that may benefit from targeted therapies known to be beneficial in patients with HFrEF, such as neurohormonal blockade, requires further study. This review summarizes what is known about the clinical epidemiology, pathophysiology, and prognosis for patients with HFmrEF and how these features compare with the more well-studied HF groups. Although recommended treatments currently focus on aggressive management of comorbidities, we summarize the studies that identify a potential signal for beneficial therapies. Future studies are needed to not only better characterize the HFmrEF population but to also determine effective management strategies to reduce the high cardiovascular morbidity and mortality burden on this phenotype of patients with HF.

Keywords: HFbEF; HFmrEF; HFpEF; epidemiology; heart failure with borderline ejection fraction; heart failure with mid-range ejection fraction; heart failure with preserved ejection fraction; outcomes.

FIGURE 1. Distribution of LVEF in the OPTIMIZE-HF Study

A modest bimodal distribution of Left ventricular ejection fraction (LVEF) was observed among patients hospitalized for heart failure. OPTIMIZE-HF = Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure. Reprinted with permission from Fonarow et al. (2).

FIGURE 2. Comparisons of the Outcomes in Patients With HFpEF, HFmrEF, and HFrEF in the GWTG-HF Registry

Cumulative incidence functions for all-cause mortality, all-cause rehospitalization, cardiovascular (CV) rehospitalization, and heart failure (HF) rehospitalization in the heart failure with preserved ejection fraction (HFpEF) (black lines), heart failure with mid-range ejection fraction (HFmrEF) (blue lines), and heart failure with reduced ejection fraction (HFrEF) (red lines) groups. GWTG-HF = Get With The Guidelines-HF Registry. Adapted with permission from Cheng et al. (8).

CENTRAL ILLUSTRATION. Characterization of HFpEF, HFmrEF, and HFrEF

General comparisons of the clinical characteristics, outcomes, and guideline-directed medical therapies for each heart failure group. Class of recommendation is denoted in parentheses, if applicable. ACEI = angiotensin-converting enzyme inhibitors; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor-neprilysin inhibitor; BB = beta-blockers; CAD = coronary artery disease; HFmrEF = heart failure with mid-range ejection fraction; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; MRA = mineralocorticoid receptor antagonist.