Dual Effects of Nicotinamide on Aging‐Related Arrhythmia: Protective at Low Dose, Proarrhythmic at Higher Doses

Journal of the American Heart Association, Volume 15, Issue 11 , June 2, 2026. BackgroundCardiac arrhythmia and dysfunction increase with age and are closely associated with declining nicotinamide adenine dinucleotide levels.

Nicotinamide, a critical nicotinamide adenine dinucleotide precursor, has shown protective effects in experimental models of aging‐related cardiac diseases. However, its dose‐dependent cardiac‐specific adverse effects and underlying mechanisms warrant investigation.MethodsThe effects of nicotinamide (10–100 mmol/L) on the contractility and calcium transient of HL‐1 cardiomyocytes, lifespan, and cardiac function ofDrosophila, as well as arrhythmia susceptibility of ex vivo Langendorff mouse hearts were assessed.

SERCA2a (sarcoplasmic/endoplasmic reticulum Ca2+‐ATPase 2a) acetylation was analyzed by immunoprecipitation followed by Western blotting.ResultsAcute perfusion with 10 mmol/L nicotinamide had limited influence on aging‐related atrial fibrillation susceptibility in ex vivo mouse andDrosophilahearts. Short‐term dietary nicotinamide (10 mmol/L) in late life protected against aging‐induced arrhythmia and contractile dysfunction exclusively in maleDrosophila.

In contrast, lifelong exposure or doses >20 mmol/L caused dose‐dependent adverse cardiac effects, including impaired contractility and calcium transient amplitude and kinetics in HL‐1 cardiomyocyte and shortened lifespan inDrosophila, with impaired excitability and increased arrhythmia in both models.