Disruption of Myocardial NAD⁺ Balance in Heart Failure: Mechanisms and Therapeutic Opportunities

Cardiac function depends on a delicate NAD⁺ homeostasis that integrates oxidative metabolism with genome maintenance mechanisms and cellular stress response pathways. In the failing heart, ischemic, mechanical, metabolic, and inflammatory insults induce DNA and chromatin damage, leading to hyperactivation of nuclear ADP-ribosyltransferases, most prominently of PARP1. This creates a high-flux NAD⁺ sink that depletes nucleocytoplasmic NAD⁺ pools, suppresses sirtuin-dependent signaling, disrupts mitochondrial function, and accelerates adverse myocardial remodeling. Additional NAD⁺ consumers, including sirtuins, CD38, and SARM1, further modulate NAD⁺ depletion and contribute to cell-type-specific vulnerabilities as fibroblast, macrophage, and endothelial cell populations expand during myocardial disease progression. Preclinical data suggest that limiting PARP1-dependent NAD⁺ consumption or replenishing NAD⁺ availability can restore metabolic function and attenuate cardiac injury; however, optimal dosing parameters and patient selection criteria remain to be defined. This review examines the interplay between NAD⁺ biosynthesis, compartmental distribution, and enzymatic NAD + consumption during cardiac stress and highlights emerging therapeutic strategies to rebalance the myocardial NAD⁺ landscape. • Myocardial NAD⁺ homeostasis couples metabolic stress to cellular signaling. • Excessive NAD⁺ consumption is a pathological driver of cardiac remodeling. • Cardiac remodeling expands fibroblast/immune niches, altering NAD+ flux. • NAD⁺-augmenting interventions can raise systemic NAD⁺ in heart failure. • Increased NAD + can dampen fibrosis, improving post-injury remodeling.