Losing weight improves heart muscle contraction in people with obesity and heart failure

In a new research report, a team of scientists led by Johns Hopkins Medicine say people with severe obesity and a common type of heart failure experience weakened heart muscles, and that losing weight may reverse some of these effects.

In the National Institutes of Health-funded study, to be published April 23 in Science, the scientists analyzed heart muscle cells from people with heart failure and preserved ejection fraction (HFpEF), a common form of heart failure that disproportionately affects people with severe obesity. Their research identified abnormalities associated with the condition, including weakened force production in muscle cells obtained from the hearts of very obese people (those with a body mass index of greater than 40 kg/m2) with HFpEF.

In a subgroup of patients from the study who underwent weight loss therapy, those who lost the most weight had better contraction of their heart muscle cells, suggesting that contraction problems may be reversible. The Johns Hopkins Medicine team also identified a chemical change that causes weakened contraction on a muscle protein, troponin I. This change was more prominent in people with HFpEF and severe obesity, pointing to troponin I as a potential drug target for patients with this specific condition.

This is a major advance in understanding a common yet puzzling form of heart failure that disproportionately affects people with severe obesity." David Kass, M.D., study lead, the Abraham and Virginia Weiss Professor of Cardiology, Johns Hopkins University School of Medicine

About 6.6 million people in the United States have heart failure, and nearly half of these have HFpEF, which has a one-year mortality rate of 20%–29%, according to the American College of Cardiology.

In HFpEF, the heart's main pumping chamber appears to contract normally, but it has increased stiffness and relaxes slowly, so has difficulty filling, Kass says. Historically, HFpEF occurred in older people with long-standing high blood pressure, thick-walled hearts with fibrosis, diabetes and kidney disease. Newer research indicates patients with HFpEF are likely to have obesity (a body mass index over 30 kg/m2) or severe obesity (a body mass index of over 40 kg/m2), Kass says. Obesity with HFpEF is linked with worse outcomes, including greater weakness, fatigue, kidney disease and an increased likelihood of death.

Ejection fraction measures the percentage of blood a heart ejects each beat, and is typically around 65% in healthy people and in those with HFpEF. This measurement may not, however, tell you what the underlying muscle cells are doing, says first author Vivek Jani, an M.D./Ph.D. candidate at the Johns Hopkins University School of Medicine.

"That could be at the root of the fundamental paradox as to how patients with heart failure can have different ejection fractions and responses to drugs, yet present with similar symptoms," says Jani.

In their study, Kass and his team turned to Kavita Sharma, M.D., director of the Johns Hopkins Medicine Center for Heart Failure with Preserved Ejection Fraction, to collect biopsies of small pieces of heart muscle with permission from 80 patients with HFpEF. The researchers compared these samples to heart tissue from the Division of Cardiology at the University of Pennsylvania, which was obtained from human organ donors without heart failure and from people with advanced heart failure receiving a heart transplant.

The researchers first used a computer algorithm to sort patients with HFpEF using information about their heart muscle cell properties. The algorithm identified two subgroups based on body mass index, one group whose BMI was much greater, 43 kg/m2, and a second group whose BMI was 30 kg/m2. The scientists say the cells' ability to increase force with calcium or stretch, which are key to muscle contraction, was very reduced in the first group of patients with HFpEF and more severe obesity, as compared to the second, less obese HFpEF group, as well as non-failing heart tissue samples.

"Myocytes from people with HFpEF and severe obesity surprisingly resembled those from people with heart failure and a low ejection fraction who were receiving a heart transplant," says Kass.

Resting cell stiffness, thought to be a common feature of HFpEF, was more prevalent in the least obese HFpEF group, Kass says. However, both HFpEF groups had slower muscle cell relaxation, with the slowest measures in those with the most severe obesity.

The investigators also observed how myocytes malfunction depending on the severity of obesity. X-ray analysis revealed the crystal-like structure of motor proteins in the muscle cells, and cells from the most obese HFpEF group had abnormal structures, resulting in a lower active force that weakens the heart's ability to contract. In heart tissue samples from people with severe obesity without heart failure, the researchers say severe obesity alone did not appear to cause similar heart muscle cell problems.

Then, the scientists examined the underlying causes of weak active muscle contraction in people with severe obesity and HFpEF. Looking at the major proteins that form the muscle contraction unit, called a sarcomere, they found changes in the protein troponin-I. Troponin-I is critical to contraction and relaxation of muscle and has a sub-unit altered by a process called phosphorylation. The researchers found more phosphorylation in HFpEF patients who were more obese, and demonstrated that this chemical change alone could weaken active muscle cell force.

In a subset of the HFpEF group, 16 people with a starting BMI averaging 39 underwent weight loss therapy with primarily a GLP-1 inhibitor for a median time of 1.5 years. In this group of people who lost weight, scientists say their muscle cells regained contraction abilities. Those who lost 10% or more of their body weight had close to normal peak muscle cell force, Kass says.

"HFpEF has long been viewed as a stiffness problem," Kass says. "Our study shows a distinct picture in patients with severe obesity: The muscle itself can be weaker, driven by a specific chemical change in a contraction protein, opening possibilities for targeted treatment."

Given their findings, the scientists caution against prescribing certain drugs to severely obese people with HFpEF, including mavacamten and aficamten, which are used to treat hypertrophic cardiomyopathy, another form of heart disease with a "preserved" ejection fraction, Kass says.

"This work points to potential therapies," says Jani. "Supporting safe, sustained weight loss for patients, and developing drugs that reverse the molecular change we've identified in sarcomere proteins."

In addition to Kass, other researchers include Vivek Jani, Marcus Rhodehamel, Axel Fenwick, Eli Fisher, Maria Giannakopoulos, Sun Moon, Meaghan Barry, Virginia Hahn, Kavita Sharma and Anthony Cammarato from Johns Hopkins, Weikang Ma and Thomas Irving from Illinois Institute of Technology, Romi Castillo and Jil Tardiff from University of Arizona, Leslie Kennedy and Elizabeth Murphy from the National Heart, Lung, and Blood Institute, Raghothama Chaerkady and Qing Wang from Complete Omics, and Kenneth Margulies and Kenneth Bedi Jr. from the Perelman School of Medicine at the University of Pennsylvania.

The work was supported by the National Heart, Lung, and Blood Institute and National Institute of General Medical Sciences of the National Institutes of Health, the American Heart Association, the United States Department of Energy, the National Science Foundation, Amgen, and the Steven M. Gootter Foundation.

Jani, V. P., et al. (2026). Severe obesity in human HFpEF alters contractile protein function and organization. Science. DOI: 10.1126/science.adz7118. https://www.science.org/doi/10.1126/science.adz7118