New findings suggest heart failure with preserved ejection fraction (HFpEF) includes two biologically distinct subgroups defined by body mass index (BMI).1

Given the known disproportionate impact of obesity on HFpEF, a National Institutes of Health-funded study identified reduced cardiomyocyte contraction despite preserved ejection fraction in patients with severe obesity defined as having a BMI ≥ 40 kg/m².1,2

Understanding HFpEF: Clinical Burden and Remaining Gaps

Approximately 75 million people worldwide live with heart failure, including about 7 million in the United States. HFpEF accounts for more than 50% of these cases.1

“Some hearts in heart failure are very big and dilated, like a giant measuring cup. I could pour out just a little of what’s inside, but that could still fill a glass,” study investigator David Kass, MD, the Abraham and Virginia Weiss Professor of Cardiology at the Johns Hopkins University School of Medicine, said. “The percent coming out is not very much because it’s a very large volume to start with—that’s what we call ejection fraction.”

Obesity has been identified as a major driver of HFpEF, with excess adipose tissue contributing to systemic inflammation, metabolic dysfunction, and mechanical cardiac strain, ultimately leading to increased ventricular stiffness, elevated filling pressures, and reduced functional capacity.2

Many therapies effective in heart failure with reduced ejection fraction (HFrEF) have not shown consistent benefit in HFpEF, with multiple large clinical trials yielding neutral or modest results, Kass explained. One of the first therapies to demonstrate clear outcome benefits in HFpEF was sodium-glucose cotransporter-2 (SGLT2) inhibitors, originally developed for diabetes before showing cardiovascular benefit.

How Did Kass and Colleagues Conduct Their Research?

Researchers at Johns Hopkins conducted a biopsy-based investigation of myocardial tissue from patients with HFpEF, using millimeter-scale samples obtained through an established clinical research program.

From these samples, investigators isolated individual cardiomyocytes and conducted approximately 30 functional measurements assessing key aspects of myocardial performance, including calcium responsiveness, cellular stiffness, and structural properties.

To analyze patterns across the dataset, researchers applied a machine learning–based clustering approach to identify potential subgroups within HFpEF based on cellular characteristics.

Identification of two HFpEF subgroups

The algorithm identified two clearly distinct groups within the HFpEF population divided by BMI

One group demonstrated severe obesity, while the comparison group had an average BMI of approximately 30 kg/m².

Notably, traditional clinical measures commonly used to characterize heart failure—including blood pressure, cardiac output, and filling pressures—did not differ between the groups.

Impaired Cardiomyocyte Function in Severe Obesity–Associated HFpEF

In patients with HFpEF and severe obesity, cardiomyocyte contraction was significantly reduced compared with less obese patients, despite similar clinical hemodynamic profiles.

These cells demonstrated reduced calcium responsiveness and diminished force generation, both of which are essential for increasing cardiac output during physical activity.

“In the very obese group, contraction… was not preserved… it was actually quite reduced,” Kass said.

These cellular abnormalities were also reflected in clinical performance. Patients whose cardiomyocytes showed worse function had reduced exercise capacity and higher intracardiac pressures during physiological stress testing.

HFpEF Is Not a Uniform Disease

The findings challenge the traditional view of HFpEF as a single disease defined primarily by impaired relaxation and preserved systolic function.

Instead, HFpEF appears to include biologically distinct subgroups that are not captured by standard clinical metrics such as ejection fraction.

“Even though all these patients look like HFpEF clinically, at the cellular level they are quite different,” the investigator said.

Implications for Therapy

The results raise questions about whether current HFpEF treatment strategies adequately reflect underlying biological differences between patient subgroups.

Many existing and investigational therapies assume preserved or even enhanced myocardial contraction in HFpEF. However, these assumptions may not apply uniformly, particularly in patients with severe obesity–associated disease.

The findings suggest a potential mismatch between therapeutic mechanisms and disease biology in certain HFpEF phenotypes, highlighting the need for more stratified approaches to treatment.

Editor’s Note: Kass reports no relevant disclosures.
References

1. Scientists find people with severe obesity and heart failure have weakened heart muscle contractions. Weight loss may reverse this condition. EurekAlert! Published April 23, 2026. Accessed April 24, 2026. https://www.eurekalert.org/news-releases/1124709?
2. Borlaug BA, Jensen MC, Kitzman DW, Carolyn S.P. Lam, Masaru Obokata, Rider OJ. Obesity and heart failure with preserved ejection fraction: new insights and pathophysiological targets. Cardiovascular Research. 2022;118(18):3434-3450. doi:https://doi.org/10.1093/cvr/cvac120