Abstract
Heart failure represents the terminal stage in the development of many cardiovascular diseases, and its pathological mechanisms are closely related to disturbances in energy metabolism and mitochondrial dysfunction in cardiomyocytes. In recent years, nicotinamide adenine dinucleotide (NAD(+)), a core coenzyme involved in cellular energy metabolism and redox homeostasis, has been shown to potentially ameliorate heart failure through the regulation of mitochondrial function. This review systematically investigates four core mechanisms of mitochondrial dysfunction in heart failure: imbalance of mitochondrial dynamics, excessive accumulation of reactive oxygen species (ROS) leading to oxidative stress injury, dysfunction of mitochondrial autophagy, and disturbance of Ca(2+) homeostasis. These abnormalities collectively exacerbate the progression of heart failure by disrupting ATP production and inducing apoptosis and myocardial fibrosis. NAD(+) has been shown to regulate mitochondrial biosynthesis and antioxidant defences through the activation of the deacetylase family (e.g., silent information regulator 2 homolog 1 (SIRT1) and SIRT3) and to increase mitochondrial autophagy to remove damaged mitochondria, thus restoring energy metabolism and redox balance in cardiomyocytes. In addition, the inhibition of NAD(+)-degrading enzymes (e.g., poly ADP-ribose polymerase (PARP), cluster of differentiation 38 (CD38), and selective androgen receptor modulators (SARMs)) increases the tissue intracellular NAD(+) content, and supplementation with NAD(+) precursors (e.g., β-nicotinamide mononucleotide (NMN), nicotinamide riboside, etc.) also significantly elevates myocardial NAD(+) levels to ameliorate heart failure. This study provides a theoretical basis for understanding the central role of NAD(+) in mitochondrial homeostasis and for the development of targeted therapies for heart failure.