Nicotinamide for the treatment of heart failure with preserved ejection fraction

The NAD+ precursor nicotinamide improves diastolic dysfunction caused by aging, hypertension, or metabolic syndrome in rodents. Diet and diastolic dysfunction Increasing nicotinamide adenine dinucleotide (NAD+) can mimic some of the benefits of caloric restriction, which improves cardiac hypertrophy, metabolic dysfunction, and exercise capacity. Abdellatif et al. investigated whether nicotinamide, the NAD+ precursor, could alleviate diastolic dysfunction associated with heart failure with preserved ejection fraction (HFpEF). Rodent models of aging, metabolic syndrome, and hypertension (risk factors of HFpEF) showed improvements with NAM supplementation, which the authors linked to increased deacetylation of proteins involved in cardiac myocyte stiffness and relaxation. Greater dietary intake of NAD+ precursors was associated with lower cardiac mortality risk and decreased blood pressure in humans. Thus, NAD+ precursors may be a potential therapeutic strategy for HFpEF. 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). This effect was mediated partly through alleviated systemic comorbidities and enhanced myocardial bioenergetics. Simultaneously, nicotinamide directly improved cardiomyocyte passive stiffness and calcium-dependent active relaxation through increased deacetylation of titin and the sarcoplasmic reticulum calcium adenosine triphosphatase 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.