Kardiologie Forschung

MINOTAUR

Metabolic Therapy for Managing Diastolic Heart Failure

Partners

  • Simon Sedej, University of Graz, Graz, Austria (Coordinator)
  • Wolfgang A. Linke, University of Münster, Münster, Germany
  • Adelino Leite-Moreira, Faculty of Medicine, University of Porto, Porto, Portugal
  • Guido Kroemer, French Institute of Health and Medical Research, INSERM, Paris, France
  • Jorge Alegre-Cebollada, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

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. Growing epidemiological and experimental 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 are 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.

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