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

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.

Catch up with Part 1 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.

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. Jani VP, Rhodehamel M, Fenwick AJ, et al. Severe obesity in human HFpEF alters contractile protein function and organization. Science. Published online April 23, 2026. doi:https://doi.org/10.1126/science.adz7118