The Efficacy of Risk Factor Modification Compared to NAD+ Repletion in Diastolic Heart Failure

[Display omitted] •The feasibility of NAD+ repletion in human myocardial tissue using the NAD precursor NR is demonstrated in our study.•In a preclinical model, it is demonstrated that both prophylactic and therapeutic NAD+ repletion is equally effective in addressing HFpEF.•Despite favorable effects on cardiac metabolism, the HFpEF phenotype is not rescued by dietary intervention and weight loss. In contrast, the findings in our preclinical study suggest that NAD+ repletion emerges as a promising strategy for phenotype rescue. Heart failure (HF) with left ventricular diastolic dysfunction is a growing global concern. This study evaluated myocardial oxidized nicotinamide adenine dinucleotide (NAD+) levels in human systolic and diastolic HF and in a murine model of HF with preserved ejection fraction, exploring NAD+ repletion as therapy. We quantified myocardial NAD+ and nicotinamide phosphoribosyltransferase levels, assessing restoration with nicotinamide riboside (NR). Findings show significant NAD+ and nicotinamide phosphoribosyltransferase depletion in human diastolic HF myocardium, but NR successfully restored NAD+ levels. In murine HF with preserved ejection fraction, NR as preventive and therapeutic intervention improved metabolic and antioxidant profiles. This study underscores NAD+ repletion’s potential in diastolic HF management.