David Kass, MD, is the Abraham and Virginia Weiss Professor of Cardiology at the Johns Hopkins University School of Medicine.

David Kass, MD

HFpEF Myocardial Dysfunction May Be Reversible With Weight Loss

Findings from a Johns Hopkins investigation suggest that cardiomyocyte dysfunction seen in heart failure with preserved ejection fraction (HFpEF) and severe obesity may not be permanent, with weight loss associated with measurable recovery in contractile function at the cellular level.

HCPLive spoke to senior study investigator, David Kass, MD, the Abraham and Virginia Weiss Professor of Cardiology at the Johns Hopkins University School of Medicine.

 to learn more about the findings of severe obesity linked to distinct myocardial dysfunction in HFpEF.

Weight loss linked to improved cardiomyocyte function

To determine whether obesity-associated myocardial dysfunction is fixed or modifiable, investigators examined cardiomyocyte function in a subgroup of patients with HFpEF who underwent weight loss therapy, primarily using GLP-1 receptor agonists, over a median of 1.5 years.

In 16 patients with a baseline BMI of approximately 39 kg/m², reductions in body weight were associated with improved cardiomyocyte contractile performance. Those who lost at least 10% of body weight demonstrated near-normal peak force generation in isolated myocardial cells.

Kass said the improvement was consistent at the cellular level.

“In a subgroup of patients who underwent weight loss, those changes in muscle contraction improved, suggesting that this may be reversible with weight reduction,” Kass explained.

These findings suggest that at least some of the contractile impairment observed in HFpEF with obesity is not fixed structural damage but may reflect dynamic, modifiable signaling changes within cardiomyocytes.

Mechanistic basis: phosphorylation of sarcomeric proteins

To understand the biological basis for reversibility, investigators focused on the sarcomere, the contractile unit of the cardiomyocyte responsible for generating force through coordinated actin–myosin interactions.

Rather than differences in protein abundance, the key distinction between groups appeared to involve post-translational modification—specifically phosphorylation, a process in which phosphate groups modify protein function by altering charge and protein–protein interactions.

Kass described phosphorylation as a key regulator of normal muscle function. Phosphorylation is a common modification where a phosphate group is added to a protein, altering its charge and, in turn, can affect how the protein function

In HFpEF patients with severe obesity, investigators identified increased phosphorylation of cardiac troponin I at a site not typically phosphorylated under normal conditions. Importantly, this modification increased progressively with BMI and was not present in non-failing controls or less-obese HFpEF patients.

“A molecule called troponin I—stands for inhibitory troponin—showed up, and it had a phosphorylation at a particular site that is normally not there,” Kass noted. “The higher the body mass index, the more of this phosphorylation.”

Functionally, experimental modeling showed that mimicking this phosphorylation state reduced cardiomyocyte contractility, while enzymatic removal of phosphate groups improved force generation, supporting a potentially reversible signaling mechanism.

A reversible signaling pathway rather than fixed structural damage

These findings suggest that at least part of the myocardial dysfunction in HFpEF with obesity may be driven by dynamic biochemical signaling rather than irreversible structural remodeling.

In this framework, weight loss may improve cardiomyocyte function by altering upstream metabolic and inflammatory pathways that regulate sarcomeric phosphorylation states, rather than directly modifying contractile proteins themselves.

Kass emphasized that identifying the upstream kinase responsible for troponin I phosphorylation is a key next step, noting that such enzymes are often druggable targets.

Implications for HFpEF treatment in obesity

The data raise the possibility that HFpEF associated with severe obesity may represent a partially reversible cardiomyopathy at the cellular level, with improvements in body weight translating into measurable improvements in myocardial contractile function.

While mechanistic uncertainty remains, the authors suggest that therapies targeting weight reduction—and potentially the signaling pathways regulating sarcomeric phosphorylation—may represent a future avenue for treatment in this HFpEF phenotype.

Editor’s Note: Kass reports no relevant disclosures.

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

Jani VP, Rhodehamel M, Fenwick AJ, et al. Severe obesity in human HFpEF alters contractile protein function and organization. 

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Kass explains recent findings from a study that suggest myocardial dysfunction in HFpEF may be reversible with weight loss. 

HFpEF Myocardial Dysfunction May Be Reversible With Weight Loss, With David Kass, MD

Severe Obesity Linked to Distinct Myocardial Dysfunction in HFpEF

 with preserved ejection fraction (HFpEF) includes two biologically distinct subgroups defined by body mass index (BMI).

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 

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.

“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.

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.

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.

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.

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. 

https://www.eurekalert.org/news-releases/1124709?

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. 

Kass explains 2 distinct biological subgroups discovered in HFpEF and how they relate to a paradigm shift. 

David Kass, MD

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