Obesity Linked to Distinct Heart Muscle Abnormalities in Patients With HFpEF, Study Finds

A recent study published in Nature Cardiovascular Research highlighted the significant impact of severe obesity on myocardial ultrastructure in patients with heart failure with preserved ejection fraction (HFpEF), revealing potential therapeutic targets.

The small study, led by Johns Hopkins Medicine researchers, examined the impact of obesity on muscle structure in patients with HFpEF. HFpEF accounts for over half of all heart failure cases globally, with over 3.5 million cases in the United States. Traditionally linked to high blood pressure and muscle hypertrophy, HFpEF is increasingly associated with severe obesity and diabetes. Despite high hospitalization and mortality rates (30%-40% over 5 years), effective therapies for HFpEF remain limited, partly due to the lack of studies on human heart tissue to pinpoint abnormalities.

Dr David Kass, the lead investigator, highlighted the complexity of HFpEF, noting that while heart contraction appears normal, heart failure symptoms persist. Although standard heart failure drugs have been ineffective, success has been found with diabetes and obesity treatments. Specifically, SGLT2 inhibitors have improved HFpEF symptoms and reduced rehospitalization and mortality rates. GLP1-receptor agonists, used for weight loss, also show promise in improving HFpEF symptoms, with ongoing studies exploring their potential to reduce mortality and hospitalizations.

In the study, researchers examined heart muscle tissue from 25 patients with HFpEF with diabetes and obesity, compared to tissue from 14 healthy organ donors. Using an electron microscope, the researchers identified significant ultrastructural abnormalities in the heart tissue of the most obese patients, including swollen and disrupted mitochondria, numerous fat droplets, and tattered sarcomeres. These abnormalities were less pronounced in less obese patients and unrelated to diabetes.

Myocardial proteomics revealed protein reductions associated with fatty acid uptake, processing, oxidation, and mitochondrial respiration, particularly in very obese patients with HFpEF. Dr Mariam Meddeb explained that the electron microscope's high magnification provides a detailed view of muscle cell ultrastructure, revealing critical abnormalities.

“These results will help those trying to develop animal models of HFpEF, since they show what one wants to generate at this microscopic level,” notes Dr Kass. “It also raises the key question of whether reducing obesity, as is now being done with several drug therapies, will reverse these ultrastructural abnormalities, and in turn improve HFpEF outcome.”

These insights enhance the understanding of HFpEF, highlighting obesity's impact on heart disease and suggesting potential targets for therapy to benefit millions of patients with HFpEF.

References

Hopkins Medicine. Study uncovers connections between obesity and feart failure. News release. Published August 1, 2024. Accessed August 5, 2024. https://www.hopkinsmedicine.org/news/newsroom/news-releases/2024/08/study-uncovers-connections-between-obesity-and-heart-failure

Meddeb, M, Koleini, N, Binek, A et al. Myocardial ultrastructure of human heart failure with preserved ejection fraction. Nat Cardiovasc Res. Published online July 25, 2024. doi:10.1038/s44161-024-00516-x