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Preliminary Clinical Trial Data Shows Elevated NAD+ Improves Inflammatory Response in Heart Failure in Human Patients

Preliminary Clinical Trial Data Shows Elevated NAD+ Improves Inflammatory Response in Heart Failure in Human Patients

NR supplementation improves mitochondrial function and affects inflammatory response in heart failure patients

Although inflammation is a way that the immune system tries to heal the body, it may be involved in the progression of heart failure. The cells that mediate this process, immune cells, are highly dependent on mitochondria, their power generators. Yet, whether the heightened inflammatory state in patients with heart failure is exacerbated by the malfunctioning mitochondria in certain circulating immune cells is unclear.

Zhou and colleagues published clinical trial (NCT03727646) results in the Journal of Clinical Investigation examining the connection between the mitochondria in immune cells, inflammation, and heart failure. The research team from the University of Washington show in their article that inflammation in patients’ hearts was linked to poor mitochondrial function in immune cells called peripheral blood mononuclear cells (PBMCs). Heart failure patients given nicotinamide riboside (NR) orally (1000 mg twice daily), a precursor to the essential mitochondrial molecule nicotinamide adenine dinucleotide (NAD+), had enhanced PBMC mitochondrial function and reduced inflammatory responses. Results from this study suggest that NAD+ augmentation may be protective against heart disease in humans.

NAD+ Helps Hearts Heal in Mice

Enhancing the levels of NAD+, which is essential to mitochondrial function, has been demonstrated to reduce inflammation and protect the hearts of mice. These observations raise the possibility that elevating levels of NAD+ might benefit patients with heart failure by modulating the inflammation associated with this dire medical condition. But, whether boosting NAD+ can help mitochondrial function in circulating immune cells to quell inflammation in heart failure patients is unclear.

Does NAD+ Protect Human Patients with Heart Disease?

Zhou and colleagues compared the function of mitochondria of PBMCs of 19 hospitalized heart failure patients with that of 19 healthy participants. PBMCs from patients with heart failure showed reduced mitochondrial function. These cells also had elevated levels of pro-inflammatory cytokines, small proteins that are crucial in controlling the growth and activity of immune system cells and blood cells.

Zhou and colleagues also examined the blood of heart failure patients before and after taking 5 to 9 days of oral nicotinamide riboside (NR), an NAD+ precursor. For experiments associated with oral NR administration, 5 hospitalized patients with heart failure were put on escalating doses of NR (250 mg twice a day for day 1, 500 mg twice a day for day 2, and 1,000 mg twice a day from day 3 on) for 5 to 9 days.

Increasing NAD+ levels with NR enhanced mitochondrial function in human heart failure patients. It also reduced proinflammatory cytokine production in these patients. The results suggest that the NR’s effect is what preserves mitochondrial function and reduces the production of harmful molecules to cells called reactive oxygen species in the presence of an inflammatory trigger.

This study demonstrates a critical role of mitochondrial function in the inflammatory activation of peripheral immune cells in patients with heart failure. It also suggests that increasing NAD+ levels may have the potential to improve mitochondrial function and attenuate inflammation caused by PBMCs in heart failure. Stopping systemic inflammation by blocking the pro-inflammatory activation of circulating immune cells allows the system to break from the vicious cycle perpetuating the disease.

More Clinical Trials on NAD+ and Heart Failure are Needed

However, the study is limited in several ways. For example, the small number and short treatment period (5 to 9 days) of the experiments involving NR administration to heart failure patients limit drawing conclusions regarding the efficacy or safety of NR. The results pose promising opportunities for future clinical trials to investigate NR’s potential anti-inflammatory effect.

“To our knowledge, this study is the first to examine whether NAD+ augmentation has anti-inflammatory effects in the context of human heart failure,” said the investigators in the article. “Although the human efficacy data are currently lacking, the collective actions of NAD+ repletion on preserving cardiac function and reducing systemic inflammation may provide a molecular basis for a novel heart failure therapy.”


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