HFmrEF as a Unique Phenotype of Heart Failure, With Jane Wilcox, MD, MSc

The Heart Failure Society of America (HFSA) has released an official scientific statement covering the rapidly evolving phenotype of heart failure with mildly reduced ejection fraction (HFmrEF).1

In 2016, the European Society of Cardiology released a statement officially recognizing HFmrEF as a distinct category of heart failure (HF), separate from HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). The document defined HFmrEF as encompassing all patients with HF who have a left ventricular ejection fraction (LVEF) between 40% and 49%.2

“This is a really important diagnosis that people have more or less never heard of,” Jane Wilcox, MD, MSc, section chief of heart failure treatment and recovery at Northwestern Feinberg School of Medicine and lead author of the statement, told HCPLive in an exclusive interview. “We all see the patient who’s got the borderline reduced ejection fraction and evidence of heart failure, and they want to know what can be done for them. A lot of us in the community have been treating them akin to HFrEF, but we really wanted to summarize the available data out there and get the word out for clinicians.”

The present statement has determined that, rather than functioning as an intermediate between HFrEF and HFpEF, HFmrEF instead resembles a milder form of HFrEF, as cross-sectional data have revealed that the majority of patients with HFmrEF are more closely aligned with those with HFrEF than HFpEF. These patients are typically older, with a mean age of roughly 65-80 years, but younger than those with HFpEF, and have a high prevalence of ischemic heart disease, atrial fibrillation, and diabetes.1

Wilcox and colleagues also examined data from 4 community-based longitudinal studies to analyze potential predictors of HFmrEF – they ultimately determined that older age, male sex, a higher systolic blood pressure, diabetes mellitus, and previous myocardial infarction, among other factors, were independent predictors. Interim myocardial infarction carried over a 2-fold increased risk in HFmrEF compared to a 3-fold increase in HFrEF and a 34% increase in HFpEF. Conversely, the team noted a stronger association between body mass index and HFpEF rather than HFmrEF and HFrEF.1

The investigators also examined the Meta-analysis Global Group in Chronic Heart Failure (MAGGIC) study of roughly 42,000 patients with HF, collected from 31 separate studies. Based on these data, they concluded that all-cause mortality was worse among patients with lower EF and did not increase before EF fell below 40%. This allowed the team to determine that HFmrEF exhibits better survival than HFrEF. Hospitalization burdens, however, have been mixed, with some registries displaying substantially higher hospitalization rates compared to HFpEF and HFrEF while others showed comparatively similar rates.1

Ultimately, Wilcox and colleagues determined that the use of guideline-directed medical therapy consistent with the treatment of HFrEF is the optimal course of action for treating HFmrEF due to its phenotypic similarities. However, the team also emphasized the need for further research, as HFmrEF is still underrepresented in clinical trials.1

“We’re missing a fair number of infiltrative cardiomyopathies,” Wilcox said. “We’re missing early dilated cardiomyopathy in first-degree relatives of patients with heart failure with non-ischemic or dilated cardiomyopathy, we’re missing genetic testing, and so I think the take-home point is that you’re not done with ejection fraction. We still need to do the diagnostic workup and not miss those underlying disease pathologies.”

Editors’ Note: Wilcox reports disclosures with Abbott, Abiomed, Boehringer Ingelheim, Cytokinetics, IONIS, FIRE1Foundry, and others.

References

1. Wilcox J, Lund L, Cox Z, et al. Heart Failure With Mildly Reduced Ejection Fraction: A Heart Failure Society of America Scientific Statement. Journal of Cardiac Failure. Published online April 22, 2026. Accessed May 21, 2026. doi:10.1016/j.cardfail.2026.01.024

2. Andronic AA, Mihaila S, Cinteza M. Heart Failure with Mid-Range Ejection Fraction - a New Category of Heart Failure or Still a Gray Zone. Maedica (Bucur). 2016;11(4):320-324.