Nicotinamide for the treatment of heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent and intractable form of cardiac decompensation commonly associated with diastolic dysfunction. Here, we show that diastolic dysfunction in patients with HFpEF is associated with a cardiac deficit in nicotinamide adenine dinucleotide (NAD+). Elevating NAD+ by oral supplementation of its precursor, nicotinamide, improved diastolic dysfunction induced by aging (in 2-year-old C57BL/6J mice), hypertension (in Dahl salt-sensitive rats) or cardiometabolic syndrome (in ZSF1 obese rats). Mechanistically, this effect was mediated partly through alleviated systemic comorbidities and enhanced myocardial bioenergetics, as evidenced by cardiac trasncriptome and metabolome analyses. Simultaneously, nicotinamide directly improved cardiomyocyte passive stiffness and calcium-dependent active relaxation through increased deacetylation of titin and the sarcoplasmic reticulum calcium ATPase 2a, respectively. In a long-term human cohort study, high dietary intake of naturally occurring NAD+ precursors was associated with lower blood pressure and reduced risk of cardiac mortality. Collectively, these results suggest NAD+ precursors, and especially nicotinamide, as potential therapeutic agents to treat diastolic dysfunction and HFpEF in humans. The aim of this study was to investigate the role of NAD+ in diastolic dysfunction and HFpEF. We quantified cardiac NAD+ in clinical and experimental HFpEF and evaluated the association between dietary intake of naturally occurring NAD+ precursors and cardiac mortality in a long-term human cohort. To examine the effect of increasing cellular NAD+ abundance on diastolic dysfunction in vivo, the NAD+ precursor NAM was orally supplemented to ZSF1 obese rats, which model key risk factors for HFpEF, namely hypertension, obesity and metabolic syndrome. We applied a multitude of in vivo and in vitro assays, including invasive hemodynamics, echocardiography, exercise tolerance testing with indirect calorimetry, RNA sequencing, metabolome profiling, and myocardial bioenergetics. For RNA sequencing, 4 myocardial rat samples per group were used, including lean ZSF1 rats as non-failing controls.