Cardiac NAD depletion in mice promotes hypertrophic cardiomyopathy and arrhythmias prior to impaired bioenergetics.

Nicotinamide adenine dinucleotide (NAD) is an essential co-factor in metabolic reactions and co-substrate for signaling enzymes. Failing human hearts display decreased expression of the major NAD biosynthetic enzyme nicotinamide phosphoribosyltransferase (Nampt) and lower NAD levels, and supplementation with NAD precursors is protective in preclinical models. Here we show that Nampt loss in adult cardiomyocytes caused depletion of NAD along with marked metabolic derangements, hypertrophic remodeling and sudden cardiac deaths, despite unchanged ejection fraction, endurance and mitochondrial respiratory capacity. These effects were directly attributable to NAD loss as all were ameliorated by restoring cardiac NAD levels with the NAD precursor nicotinamide riboside (NR). Electrocardiograms revealed that loss of myocardial Nampt caused a shortening of QT intervals with spontaneous lethal arrhythmias causing sudden cardiac death. Thus, changes in NAD concentration can have a profound influence on cardiac physiology even at levels sufficient to maintain energetics.