Impact of incretin-based therapeutic strategies for obesity and heart failure with preserved ejection fraction

• Applicants: Dr. Ulrich Dischinger; Dr. Vasco Sequeira
• Subject Area: Cardiology, Angiology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 530849567

Obesity and its associated comorbidities are a growing socioeconomic burden. There is a very strong association between obesity and heart failure with preserved ejection fraction (HFpEF). In HFpEF, left ventricular (LV) volumes are typically normal, whereas LV end-diastolic filling pressures are elevated due to increased LV stiffness with slow diastolic filling. Mechanical efficiency during exercise is decreased in patients with HFpEF, and obesity induces and exacerbates this condition. In addition to reducing mechanical efficiency, obesity aggravates LV hypertrophy, the exercise-induced increase of pulmonary artery- and wedge pressures, and the resulting right ventricular dilation in patients with HFpEF. The exact pathomechanism(s) of HFpEF are still incompletely resolved. Myocardial fibrosis, but also increased stiffness of cardiomyocytes due to tissue remodeling and post-translational modifications of sarcomeric proteins (titin) are part of the pathomechanism. Of high relevance, energy utilization in the hearts of patients with HFpEF is less effective and flexible, since defects in cardiac energetics are closely related to defects in systolic and diastolic function, particularly during physical exertion. Similarly to patients with heart failure with reduced ejection fraction, phosphocreatine (PCr)/ATP ratios are decreased in the hearts of patients with HFpEF at rest, which correlates closely with the reduced systolic and diastolic reserve as well as pulmonary congestion during exercise. The treatment options for both obesity and HFpEF are limited. Bariatric surgery is the most effective way to induce weight loss and improve comorbidities. Following RYGB, weight loss is primarily a result of consuming fewer energy-dense foods. The mechanisms behind this are not fully understood. Changes in incretin levels after RYGB are repeatedly documented and believed to be the most relevant factor for its remarkable efficiency. The identification of incretin based therapies for obesity is extremely appealing. Levels of anorectic hormones GLP-1 and PYY are elevated postprandial following RYGB and might therefore be relevant parts of an effective medical obesity treatment strategy. In rats with diet-induced obesity, we could show that the combination of the GLP-1 mimetic liraglutide and PYY was more efficient than liraglutide alone and, remarkably, as efficient as RYGB in reducing body weight and high fat diet preference. This approach might therefore be useful to treat obesity and HFpEF. We mainly aim to evaluate the cardiac effects of an incretin based treatment (semaglutide, semaglutide+PYY) in a rat model with diet induced obesity and hypertension (induced by L-NAME). We will analyze, if our incretin-mimetic therapy has beneficial effects on cardiac energy consumption and the metabolism in general and if this therapy will restore a healthy equilibrium between Ca2+ influx and efflux, hence enhancing cellular contractility and diastolic function.

• DFG Programme: Research Grants
• Co-Investigators: Professorin Nazha Hamdani, Ph.D.; Dr. Roland Hergenröder