NAD+ Metabolism and Cardiovascular Disease: Mechanisms and Therapeutic Strategies
Can a single molecule in the human body become a key driver of heart health? Nicotinamide adenine dinucleotide (NAD+) is rapidly emerging as a major focus of scientific research. As a core participant in energy metabolism, NAD+ not only maintains vascular elasticity and myocardial vitality, but also influences cardiovascular health through multiple mechanisms, including regulation of redox balance, inflammation, autophagy, and mitochondrial function. At a time when cardiovascular disease (CVD) has become one of the leading causes of death worldwide, the importance of NAD+ is being increasingly supported by scientific evidence.
Figure 1. NAD+ metabolism and therapeutic strategies in cardiovascular disease
NAD+ homeostasis is maintained through synthesis, consumption, and regeneration via multiple pathways. These processes are regulated by specific NAD+-consuming enzymes, biosynthetic enzymes, and redox reactions.
NAD+ biosynthesis in organisms is regulated by three major pathways: the de novo biosynthesis pathway, the Preiss–Handler pathway, and the salvage pathway. The salvage pathway is the primary route, recycling nicotinamide (NAM), a byproduct of NAD+ consumption. In this pathway, nicotinamide phosphoribosyltransferase (NAMPT) converts NAM into nicotinamide mononucleotide (NMN), which is then converted into NAD+ by nicotinamide mononucleotide adenylyltransferase (NMNAT). Metabolically active organs such as the heart rely heavily on this pathway. In the Preiss–Handler pathway, nicotinic acid (NA) is converted into nicotinic acid mononucleotide (NAMN) by nicotinic acid phosphoribosyltransferase (NAPRT), and subsequently into NAD+. The liver and kidneys are the primary organs utilizing this pathway, while its contribution in the heart is relatively limited. In the de novo synthesis pathway, tryptophan (Trp) is converted into quinolinic acid (QA) via the kynurenine pathway and ultimately into NAD+. This pathway contributes minimally to NAD+ production in the heart.
NAD+ consumption occurs through redox reactions and NAD+-dependent enzymes:
Figure 2. NAD+ metabolic pathways
Figure 3. The relationship between NAD+ and vascular health
The heart is one of the most metabolically active organs in the human body, and mitochondrial dysfunction is a hallmark of heart failure. NAD+ deficiency exacerbates oxidative stress through the following mechanisms, causing endothelial oxidative damage and promoting atherosclerotic plaque formation:
CD38-mediated NAD+ depletion: During aging or metabolic disorders, CD38 is highly expressed in macrophages and endothelial cells, promoting the release of pro-inflammatory cytokines (such as IL-6 and TNF-α) while suppressing the anti-inflammatory effects of SIRT1.
Anti-inflammatory pathways of SIRT1 and SIRT6: SIRT1 suppresses inflammatory signaling by deacetylating NF-κB, while SIRT6 regulates glucose metabolism and genomic stability. Dysfunction of these pathways accelerates vascular disease progression.
SIRT1–FOXO pathway: NAD+ activates SIRT1 to promote the expression of autophagy-related genes (such as Atg7), thereby maintaining endothelial cell homeostasis.
NAM-induced autophagy inhibition: Excess NAM inhibits SIRT1, increases Atg7 acetylation, and blocks autophagosome formation.
Figure 4. NAD+ supplementation therapies and their effects on CVD
Figure 1. NAD+ metabolism and therapeutic strategies in cardiovascular disease
I. NAD+ Metabolic Pathways
NAD+ homeostasis is maintained through synthesis, consumption, and regeneration via multiple pathways. These processes are regulated by specific NAD+-consuming enzymes, biosynthetic enzymes, and redox reactions.
NAD+ biosynthesis in organisms is regulated by three major pathways: the de novo biosynthesis pathway, the Preiss–Handler pathway, and the salvage pathway. The salvage pathway is the primary route, recycling nicotinamide (NAM), a byproduct of NAD+ consumption. In this pathway, nicotinamide phosphoribosyltransferase (NAMPT) converts NAM into nicotinamide mononucleotide (NMN), which is then converted into NAD+ by nicotinamide mononucleotide adenylyltransferase (NMNAT). Metabolically active organs such as the heart rely heavily on this pathway. In the Preiss–Handler pathway, nicotinic acid (NA) is converted into nicotinic acid mononucleotide (NAMN) by nicotinic acid phosphoribosyltransferase (NAPRT), and subsequently into NAD+. The liver and kidneys are the primary organs utilizing this pathway, while its contribution in the heart is relatively limited. In the de novo synthesis pathway, tryptophan (Trp) is converted into quinolinic acid (QA) via the kynurenine pathway and ultimately into NAD+. This pathway contributes minimally to NAD+ production in the heart.
NAD+ consumption occurs through redox reactions and NAD+-dependent enzymes:
In redox reactions, NAD+ is reduced to NADH during glycolysis and mitochondrial respiration. The NAD+/NADH redox ratio directly affects metabolic pathway activity.
NAD+ serves as a co-substrate for various enzymes, including poly(ADP-ribose) polymerases (PARPs), sirtuins, CD38/CD157, and SARM1. These enzymes use NAD+ to regulate diverse biological processes. The sirtuin family (SIRT1–7) is involved in deacetylation and regulates mitochondrial function, stress responses, and aging. PARPs consume large amounts of NAD+ during DNA repair, and their overactivation can lead to NAD+ depletion. CD38/CD157 hydrolyze NAD+ to produce cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP); their overexpression is associated with aging and inflammation.
Figure 2. NAD+ metabolic pathways
II. Mechanisms Linking NAD+ Deficiency to Cardiovascular Disease
NAD+ plays multiple roles in maintaining vascular health. On one hand, reduced NAD+ levels impair mitochondrial function and autophagy, leading to the accumulation of damaged mitochondria, apoptotic cells, and damaged DNA. On the other hand, NAD+ deficiency enhances inflammatory responses, oxidative stress, and protein acetylation, thereby reducing blood flow and inhibiting endothelial cell migration and lipid homeostasis. Together, these factors further exacerbate the prevalence of cardiovascular disease (CVD).
Figure 3. The relationship between NAD+ and vascular health
1. Oxidative Stress and Mitochondrial Dysfunction
The heart is one of the most metabolically active organs in the human body, and mitochondrial dysfunction is a hallmark of heart failure. NAD+ deficiency exacerbates oxidative stress through the following mechanisms, causing endothelial oxidative damage and promoting atherosclerotic plaque formation:
Inhibition of SIRT3 activity: SIRT3 is an NAD+-dependent deacetylase of mitochondrial proteins (such as SOD2 and IDH2). Reduced SIRT3 activity decreases reactive oxygen species (ROS) scavenging capacity.
Imbalance of the NAD+/NADH ratio: Under chronic stress or ischemia–reperfusion injury, impaired mitochondrial complex I function leads to NADH accumulation, inhibiting fatty acid oxidation and pyruvate dehydrogenase activity, thereby worsening the energy crisis.
2. Inflammatory Responses
Chronic low-grade inflammation is a pathological basis of atherosclerosis, hypertension, and related diseases. NAD+ regulates inflammation through the following mechanisms:CD38-mediated NAD+ depletion: During aging or metabolic disorders, CD38 is highly expressed in macrophages and endothelial cells, promoting the release of pro-inflammatory cytokines (such as IL-6 and TNF-α) while suppressing the anti-inflammatory effects of SIRT1.
Anti-inflammatory pathways of SIRT1 and SIRT6: SIRT1 suppresses inflammatory signaling by deacetylating NF-κB, while SIRT6 regulates glucose metabolism and genomic stability. Dysfunction of these pathways accelerates vascular disease progression.
3. Impaired Autophagy
Autophagy is essential for removing damaged organelles and proteins, and its dysfunction is closely associated with myocardial hypertrophy and vascular stiffening:SIRT1–FOXO pathway: NAD+ activates SIRT1 to promote the expression of autophagy-related genes (such as Atg7), thereby maintaining endothelial cell homeostasis.
NAM-induced autophagy inhibition: Excess NAM inhibits SIRT1, increases Atg7 acetylation, and blocks autophagosome formation.
4. Overactivation of PARP and CD38
In ischemia–reperfusion injury or diabetic cardiomyopathy, DNA damage and oxidative stress lead to excessive PARP1 activation, consuming large amounts of NAD+. This suppresses glycolysis and mitochondrial respiration and accelerates cell death. Overexpression of CD38 further aggravates NAD+ depletion, creating a vicious cycle.III. Therapeutic Strategies for NAD+ Supplementation
Several strategies can increase NAD+ levels, including supplementation with NAD+ precursors and inhibition of NAD+-consuming enzymes. Studies suggest that combination strategies may yield improved cardiovascular outcomes. In atherosclerosis, elevated NAD+ levels reduce chronic inflammation and lower LDL cholesterol. NAD+ also enhances endothelial function and vasodilation. In coronary artery disease, increased NAD+ levels improve autophagy and mitochondrial function while reducing ROS production, inflammation, and tissue necrosis.
Figure 4. NAD+ supplementation therapies and their effects on CVD
1. Supplementation with NAD+ Precursors
NAD+ precursors directly or indirectly participate in NAD+ biosynthesis through different metabolic pathways and represent the most extensively studied intervention strategy. Dietary supplementation with NAD+ precursors—such as tryptophan, NA, NAM, nicotinamide riboside (NR), and NMN—effectively increases NAD+ levels in both animals and humans.2. Inhibition of NAD+-Consuming Enzymes
Inhibiting the excessive activation of NAD+-consuming enzymes reduces unnecessary NAD+ depletion and is particularly beneficial in diseases associated with oxidative stress or DNA damage.
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| NAD+ Supplement | Duration | Participants | Sample Size | Outcomes | Trial ID |
| NMN | 60 days | Healthy adults aged 40–65 | 66 | Changes in serum NAD+/NADH levels and blood pressure | NCT04228640 |
| NMN | 28 days | Healthy volunteers aged 30–60 | 20 | Changes in arterial blood pressure, heart rate, and blood lipids | NCT04862338 |
| NR | 6 weeks | Healthy middle-aged adults | 30 | Blood pressure changes | NCT02921659 |
| NR | 6 weeks | Elderly patients with hypertension | 49 | Changes in systolic blood pressure and arterial stiffness | NCT04112043 |
| NR | 3 months | Patients with moderate to severe chronic kidney disease | 118 | Changes in aortic stiffness and arterial blood pressure | NCT04040959 |
| NAM | 48 months | Women with early-onset preeclampsia | 25 | Changes in mean blood pressure | NCT03419364 |
