Dual effects of nicotinamide on aging-related arrhythmia: protective at low dose, proarrhythmic at high doses

Abstract

Background Cardiac arrhythmia and dysfunction progressively increase with age, both of which are closely associated with a decline in NAD+. Supplementation with nicotinamide (NAM), a critical NAD+ precursor, has shown protection in experimental models of aging-related cardiac diseases, including atrial fibrillation (AF) and heart failure, especially heart failure with preserved ejection fraction. With the potential rise of NAM in treatment of various cardiometabolic diseases, its dose-dependent cardiac-specific adverse effects and underlying mechanisms warrant investigation. Methods The effects of NAM on aging-related arrhythmia and cardiac dysfunction were assessed using ex vivo Langendorff mouse hearts and adult Drosophila heart preparations. Different doses of NAM (10-100 mM) were tested for their impact on the contractility of HL-1 cardiomyocytes, lifespan and cardiac function of Drosophila, as well as arrhythmia susceptibility of ex vivo mouse hearts. Acetylation of sarcoplasmic/endoplasmic reticulum Ca2+; ATPase 2a (SERCA2a) was measured by immunoprecipitation followed by Western blotting. Results Acute perfusion with 10mM NAM had limited influence on aging-related AF susceptibility in ex vivo mouse hearts. Short-term dietary intervention with 10 mM NAM in late-life protected against aging-induced cardiac arrhythmia and contractile dysfunction exclusively in male Drosophila. In contrast, life-long exposure or NAM concentrations above 20 mM led to dose-dependent adverse cardiac effects, including impaired contractility in HL-1 cardiomyocyte and shortened lifespan in Drosophila, with increased arrhythmia observed in both models. In ex vivo mouse hearts, 100 mM NAM increased SERCA2a acetylation, suggesting inhibition of sirtuin1 and impaired calcium handling, which likely underlies the observed effects of high-dose NAM on arrhythmia and cardiac dysfunction. Conclusions NAM exhibits a narrow therapeutic window in aging-related cardiac dysfunction and arrhythmia, with its efficacy highly dependent on dose, duration, and biological context. While a moderate dose in late-life may be protective, chronic or excessive intake of NAM can induce arrythmia and impair cardiac function, likely through disruption of the SERCA2a activity. These findings underscore the importance of cautious and context-specific application of NAM in clinical settings. Keywords: nicotinamide, arrhythmia, atrial fibrillation, cardiac dysfunction, aging, SERCA2a