Metabolic Therapy for Managing Diastolic Heart Failure - MINOTAUR

Cardiovascular disease remains the worldwide leading cause of death. Diastolic heart failure is one of the most rapidly increasing forms of cardiovascular disease characterized by a normal pump function with thickened and stiff heart muscle that does not relax properly (i.e. diastolic dysfunction). As a consequence, the heart cannot effectively fill with sufficient amount of blood to meet the body demands, resulting in typical symptoms of heart failure, such as fatigue, shortness of breath and body fluid retention (i.e. swollen legs). Every fifth person aged >65 years is at increased risk to develop heart failure essentially due to metabolic disorders, such as obesity or Type 2 Diabetes Mellitus. Despite of utmost public- health importance, the current treatment is ineffective, likely because our understanding of the fundamental mechanisms underlying diastolic heart failure is incomplete. Recent studies showed that caloric restriction has lifespan-extending and health-promoting effects in different organs, including the heart. Indeed, caloric restriction reduces the stiffness of heart muscle in healthy individuals and improves exercise capability in obese older patients with diastolic heart failure. However, stable weight loss due to prolonged caloric restriction, stringent diets and strenuous exercise may cause cardiovascular complications and are hard to enforce at the population level. A growing body of evidence suggests that cardioprotective effects of caloric restriction can be induced by natural or synthetic pharmacological agents known also as caloric restriction-like acting compounds (so-called caloric restriction mimetics). The research team headed by Prof. Dr. Simon Sedej from the Department of Cardiology at the Medical University of Graz coordinates an international project involving partners from 5 different EU countries. The team will test the hypotheses that (natural) caloric restriction mimetics prevent the development of diastolic dysfunction and improve diastolic function in a clinically relevant experimental model of diastolic heart failure, and taking into consideration gender aspect. The use of modern high-resolution imaging techniques and complementary cutting-edge methodology will enable the research team to explore - for the first time - the effects of caloric restriction mimetics underlying metabolic changes in diastolic heart failure and molecular details of stiffening heart muscle in order to discover novel therapeutic targets for the treatment of diastolic heart failure. The results of this project hold the promise to reveal important differences and similarities in the development of diastolic heart failure between men and women. A better understanding of the disease will pave the way for future clinical studies employing caloric restriction mimetics as a promising remedy for preventing and treating diastolic heart failure and potentially other cardiovascular disease. Unraveling the molecular details of the disease can lead to dietbased therapy as a novel and innovative therapeutic approach that will likely result in fewer hospitalizations and promote healthy (cardiac) aging.

Heart failure with preserved ejection fraction (HFpEF) is currently the predominant form of heart failure and the leading cause of hospitalization in the elderly. However, limited understanding of the underlying mechanisms of HFpEF has led to a longstanding absence of evidence-based therapies. That said, growing epidemiological and experiment al evidence indicate that excessive body fat and metabolic dysfunction might drive the pathogenesis of HFpEF. In fact, the majority of HFpEF patients are obese and/or diabetic, suggesting that metabolic therapies acting on the heart and peripheral organs a re worth considering. In this regard, nicotinamide adenine dinucleotide (NAD ) represents a master regulator of cellular energy metabolism, which can be targeted using available and safe -to-administer precursors in animals and humans. To this end, in our manuscript, published in Science Translational Medicine (2021), we showed for the first time that: 1) Cardiac NAD levels are significantly reduced in HFpEF patients and in rats with diastolic dysfunction. 2) In contrast, oral supplementation of the NAD precursor nicotinamide exerts cardiometabolic benefits, thereby improving cardinal signs of HFpEF in three different animal models of diastolic dysfunction, induced by metabolic syndrome, hypertension or advanced age. 3) Mechanistically, nicotinamide stimulated fatty acid oxidation, thereby restoring myocardial and skeletal muscle bioenergetics and attenuating adiposity. 4) Importantly, we uncovered that nicotinamide induces titin deacetylation, as a novel mechanism underlying improved passive stiffness of cardiac myocytes. 5) Finally, in a large prospective human cohort with 20 years of follow-up, we demonstrated that dietary intake of naturally-occurring NAD precursors is associated with lower blood pressure and a reduced risk of cardiac mortality. Collectively, our results demonstrate that boosting NAD metabolism by nicotinamide or other precursors might become the first evidence-based therapy for HFpEF, which is arguably one of the toughest challenges in cardiovascular medicine.