# Nicotinamide Riboside--The Current State of Research and Therapeutic Uses
## 3 Effects of NR on Metabolism and Age-Associated Pathophysiology
### Effects on Cardiovascular Diseases  
Disruption of NAD+ homeostasis due to mitochondrial dysfunction is central in the development of cardiac hypertrophy and heart failure (HF) and has been reported in several models of HF including pressure overload, myocardial infarction, and angiotensin II infusion [57; 58; 59; 60; 61; 62]. Furthermore, a shift from fatty acid oxidation and oxidative phosphorylation to other forms of substrate metabolism (glycolysis and ketone oxidation) often occurs in the development of HF [63; 64], while the NAD+/NADH ratio also decreases [64]. The change in oxidative-reductive capacity further increases cardiac susceptibility to stress. The level of protein hyperacetylation also increases, driven by decreasing NAD+-dependent deacetylation both in mouse models of hypertrophy and in human patients with ischemic HF or dilated cardiomyopathy (DCM) [64; 65]. NR supplementation normalizes the myocardial NAD+/NADH ratio and exhibits protective effects in adverse cardiac remodeling, while long-term supplementation increases nucleocytoplasmic protein acetylation by stimulating citrate and acetyl-CoA metabolism and antioxidant gene expression [66]. By improving NAD+ homeostasis and activating NMRK2, NR can further prevent the deterioration of cardiac function and adverse remodeling, which are both early and persistent events in a mouse model of DCM leading to HF. In several models of cardiac injuries, the NAMPT enzyme is repressed [62], while Nmrk2 expression is robustly upregulated [66]. A similar shift was observed in human failing heart in models of cardiomyopathy [66]. Hence, it was proposed that the activation of the NMRK2 pathway represents a common adaptive mechanism in the failing heart, while the Nmrk2 gene can be activated in response to NAMPT inhibition. Furthermore, the shift from NAMPT to NMRK2 for NAD+ synthesis is an energy-sparing mechanism that may be favored, since NMN synthesis from NR by NMRK enzymes requires a single ATP, while synthesis from NAM by NAMPT requires more than three ATP equivalents (Figure 2). Although the NMRK2 pathway is activated in the HF mice, the myocardial NAD+ level is depressed, which suggests that circulating and tissue levels of NAD+ precursors are insufficient to sustain cardiac NAD+ synthesis on a regular rodent diet. This supports the interest in NR supplementation to improve this condition. Moreover, a strong beneficial effect of NR was discovered in mouse models of HF with the preservation of cardiac function and a limitation of cardiac remodeling, that was associated with maintained NAD+ levels in the heart. This further suggests that oral NR supplementation is a powerful approach to preserve cardiac function and limit remodeling in DCM. NAD+ precursor supplementation also has the potential to protect against adverse cardiac remodeling by additional mechanisms of activating SIRTs (Table 2) and maintaining Ca2+ homeostasis [67]. Namely, in vivo activation of SIRT1 protects against cardiac hypertrophy, metabolic dysregulation, and cardiac inflammation in a mouse model of cardiac hypertrophy, and exhibitsprotective effects in other models of cardiac dysfunction [68; 69; 70; 71]. In addition, SIRT2 and SIRT6 have emerged as prominent cardioprotective SIRTs [72; 73], as deficiency of SIRT2 intensified cardiac hypertrophy in aged mice and mice stressed with angiotensin II [73], while a loss of SIRT6 in mice resulted in the development of cardiac hypertrophy and HF [74]. The activity of mitochondrial SIRTs is implicated in cardiac remodeling and the development of HF, including SIRT3 which appears to be required for maintaining cardiac function [75]. Data further suggests NR as a favored NAD\({}^{+}\) precursor in mitochondria [76], while in vivo NR effects have been interpreted as dependent on mitochondrial sirutin activities [37; 77]. However, the importance of nucleocytosolic targets should not be excluded [1; 78].