A recent small-scale study conducted by researchers at Johns Hopkins Medicine, published on July 25th in the journal Nature Cardiovascular Research, has uncovered how obesity affects muscle structure in patients suffering from a type of heart failure known as heart failure with preserved ejection fraction (HFpEF).
According to the Journal of Cardiac Failure, HFpEF accounts for over half of all heart failure cases globally. In the U.S., it is responsible for more than 3.5 million heart failure diagnoses. This form of heart disease was initially linked to high blood pressure and resulted in increased muscle mass (hypertrophy) as a response to manage this pressure. Over the last two decades, however, HFpEF has become more common among individuals with severe obesity and diabetes, as noted in the Journal of the American College of Cardiology. Despite this, there is a lack of effective treatments for HFpEF, and a significant barrier to developing therapies has been the limited research on human heart tissue to identify specific abnormalities. With hospitalization and mortality rates in HFpEF patients being alarmingly high (30-40% over five years), it is crucial to understand the condition’s root causes.
“HFpEF is a complex syndrome that involves issues in several organs,” explains lead researcher David Kass, M.D., a Professor of Medicine at the Johns Hopkins University School of Medicine. “While we refer to it as heart failure (HF) due to its resemblance to symptoms seen in patients with weakened hearts, HFpEF patients often have normal heart contractions but still experience heart failure symptoms. Although many past treatments for HFpEF using standard heart failure medications have been ineffective, success has been found with drugs tailored for diabetes and obesity.”
Specifically, SGLT2 inhibitors (sodium glucose transporter 2 inhibitors), a class of diabetes medications, are currently the only drugs with evidence supporting their efficacy in improving symptoms and reducing long-term hospitalization and mortality rates in HFpEF. Furthermore, GLP1-receptor agonists, prescribed for weight loss, have demonstrated symptom improvement in HFpEF patients. Ongoing studies are investigating whether they can also positively affect critical outcomes, such as reducing mortality and hospitalization for HF.
In this study, researchers collected small muscle tissue samples from 25 patients diagnosed with varying levels of HFpEF attributed to diabetes and obesity, and compared these to heart tissue from 14 organ donors with normal hearts. The muscle samples were examined using an electron microscope, which provides high magnification to analyze muscle structure in detail.
Mariam Meddeb, M.D., MS, a cardiovascular disease expert at Johns Hopkins University School of Medicine and the study’s lead investigator, states, “Unlike traditional microscopy, the electron microscope allows us to magnify images up to 40,000 times, providing an exceptionally clear view inside muscle cells—what we refer to as ultrastructure—including mitochondria, which function as energy factories, and sarcomeres, the fundamental units of muscle fibers that generate force.”
The researchers discovered significant ultrastructural abnormalities, particularly in muscle tissue from the most obese patients with HFpEF. These included swollen, pale, and disrupted mitochondria, increased fat droplets, and damaged sarcomeres. These abnormalities were independent of the presence of diabetes and were less pronounced in patients with lower obesity levels.
“These findings will aid researchers in creating animal models of HFpEF, as they provide insights into what needs to be replicated at the microscopic level,” notes Dr. Kass. “It also raises an important question: will reducing obesity—something currently being targeted by several drug therapies—reverse these ultrastructural abnormalities and subsequently improve outcomes for HFpEF patients?”
This new research advances our comprehension of HFpEF and clarifies the role of obesity in heart disease, offering a focus for developing therapies that could benefit millions of HFpEF patients.
Additional researchers from Johns Hopkins who contributed to this study include Navid Koleini, Mohammad Keykhaei, Seoyoung Kwon, Celia Aboaf, Mohamed Lehar, Kavita Sharma, and Virginia S. Hahn.
