• A new drug called MK-0159 was designed to block an enzyme (CD38) that degrades NAD+ — an essential molecule that declines with age.  
  • Boosting NAD+ with MK-0159 and/or the NAD+ precursor NR (nicotinamide riboside) reduces heart tissue death in mice modeling heart disease. 
  • MK-0159 also raises NAD+ levels in human blood vessel cells. 

When our coronary arteries (arteries that supply our heart) become clogged, often from fat deposits that have accumulated with age, a lack of oxygen causes portions of our heart to die. These portions of dead heart tissue called infarcts can lead to heart attacks, which account for most of the 18 million cardiovascular-related deaths that occur each year. 

Researchers from Mitobridge, a company owned by Astellas Pharma Inc. report in the  Journal of Medicinal Chemistry that boosting NAD+ (nicotinamide adenine dinucleotide) can minimize heart infarct size, suggesting that NAD+ could reduce the risk of death associated with heart damage. Lagu and colleagues induced heart infarctions in mice and found that MK-0159 and/or NR reduced the size of the infarction. It was also shown that MK-0159 raises NAD+ levels in the heart of these mice, as well as in human cells.

NAD+ Boosters Reduce Heart Tissue Death 

To simulate coronary artery occlusion, Lagu and colleagues restricted blood flow (ischemia) to the heart of mice by surgically tying off one of their coronary arteries. After 30 minutes, the artery was untied, allowing blood to flow again (reperfusion). Without blood, heart cells deprived of oxygen will quickly die off (necrosis) until blood flow and oxygen are restored. The infarct size (area of dead tissue) depends on the number of cells that die in the absence of oxygen. The Cambridge, Massachusetts-based researchers found that NR, MK-0159, or MK-0159 + NR treatment decreased infarct size. Moreover, they found that the combination of MK-0159 and NR (MK-0159 + NR) worked synergistically to generate the greatest reduction in infarct size compared to the other treatments.

(Lagu et al., 2022 | Journal of Medicinal Chemistry) NAD+ Boosters Reduce Cardiac Infarction Size. The diagram outlines the study’s design. Mice were pretreated orally with either 300 mg/kg of NR, 30 mg/kg of 78c, 30 mg/kg MK-0159, or both MK-0159 and NR four hours before ischemia. After 30 minutes of ischemia, blood was restored to the artery by reperfusion. The images show a representative heart from each group with the infarct size outlined with a white dotted line. The graph quantifies the average infarct size from each group, showing that NR and 78c reduce infarct size similarly. The combination of MK-0159 and NR reduces infarct size more than either MK-0159 or NR alone, suggesting additional NAD+ reduces infarct size further.

NAD+ levels decline with age, which is thought to underlie nearly all age-related diseases. CD38 is an enzyme helmed by immune cells that breaks down NAD+ and contributes to age-related NAD+ decline. CD38 positive immune cells (CD38+) increase in the heart in response to blood flow restriction and can damage heart tissue. Lagu and colleagues took an existing CD38+ inhibitor called 78c to design the more potent MK-0159. Both of these inhibitors raise NAD+ levels by stopping CD38+ from degrading NAD+. As a precursor to NAD+, NR also boosts NAD+ by direct synthesis.

To support the applicability of MK-0159 in humans, Lagu and colleagues treated human cells with the drug and measured NAD+ levels. They found that treating human blood vessel cells leads to an increase in NAD+ levels in a dose-dependent manner. This could mean that MK-0159 raises NAD+ levels in the blood vessels and heart of humans.

(Lagu et al., 2022 | Journal of Medicinal Chemistry) MK-0159 Raises NAD+ Levels in Human Cells. Human epithelial (A549) and cardiac microvascular endothelial cells (HMVEC) cells were cultured and treated with varying doses of MK-0159. MK-0159 raises NAD+ levels in both cell types in a dose-dependent manner.

Could Boosting NAD+ Prevent Damage Caused by Heart Attacks?

According to the Cleveland Clinic, there are six medications that doctors commonly prescribe to prevent heart attacks. Many of these medications work by lowering the risk of artery occlusion and include statins (lower LDL cholesterol), aspirin, clopidogrel, and warfarin (blood thinners). Beta-blockers and ACE inhibitors are used to lower blood pressure, making blood vessels less narrow and putting less strain on the heart. While these medications are used to prevent infarction, they do not treat the infarction itself.

There are other ways of reducing the risk of myocardial infarction, including cessation of smoking, limiting alcohol consumption, maintaining a healthy weight, exercising, reducing stress, and eating a diet rich in fruits and vegetables. Like the medications mentioned above, these lifestyle interventions can prevent artery occlusion which causes heart tissue death. In contrast, Lagu and colleagues show that boosting NAD+ reduces the damage once it has already occurred. Other studies have also shown that boosting NAD+, including with the NAD+ precursor NMN can limit heart damage. Therefore, it is possible that medical and lifestyle interventions in conjunction with boosting NAD+ can both reduce the probability of infarction and reduce infarction size if it happens to occur.