NAD+ May Modulate Inflammation in End-Stage Heart Failure Patients
Raising NAD+ levels with the precursor Nicotinamide Riboside (NR) was found to reduce markers of inflammation in the blood from a small group of Stage D heart failure (HF) patients.
Unraveling Inflammation and Heart Failure
A pilot study just published in The Journal of Clinical Investigation found that NR supplementation decreased levels of proinflammatory cytokines, such as interleukin-6 (IL-6), as well as increased basal and maximal mitochondrial respiration in blood cells obtained from a small group of Stage D heart failure patients [1]. These preliminary findings represent an important step forward in unraveling the complex process of cardiovascular inflammation and heart failure progression.
Cardiovascular disease is the leading cause of death in the U.S. Congestive heart failure is a form of end-stage cardiovascular disease which has no curative treatments and portends a 5-year survival rate of 45%.
Cardiovascular disease is inextricably linked with inflammation. While inflammation is part of the body’s normal defensive response to cellular damage or pathogenic invasion, it can present with deleterious consequences if chronically and incorrectly aimed against normal tissue--running the gamut from autoimmune disorders like lupus to cardiovascular disease.
Inflammation of the endothelium (the lining of the blood vessels) may, over many years, result in atherosclerosis, or the buildup of fatty plaques in arteries. The irritation of the vessel lining allows for thrombi (or small clots) to form, activating an immune response that often increases the size of these thrombi.
Atherosclerosis may make blood vessels less compliant (stiffer), raising blood pressure (hypertension) and burdening the heart which in turn increases the risk of heart failure. More acutely, the thrombi can completely obstruct blood vessels leading to myocardial ischemia (heart attack), stroke, and heart failure--all of which are irreversible and often prove fatal.
Fortunately, scientists are beginning to better understand the underlying mechanisms of inflammation. One such potential target is NR, which has been clinically proven to raise levels of the cellular coenzyme NAD+. NAD+ in turn, is believed to play an important role in regulating the inflammatory response.
Playing with Fire: Cardiovascular Inflammation
Several preclinical studies have suggested a role for NR and NAD+ in helping reduce cardiovascular inflammation. A recent in vitro study found that raising NAD+ inhibited inflammation of the blood vessel lining in a direct, unique pathway, restoring normal smooth muscle function (i.e. making blood vessels less stiff, thus possibly preventing hypertension) [2]. In 2018, a clinical study published in Nature Communications found that NR reduced systolic blood pressure in pre-hypertensive patients relative to a placebo [3].
Now, this latest pilot study enrolled a small group of patients with the most severe form of heart failure (Stage D). These patients were supplemented with NR twice daily to determine whether increasing NAD+ levels could mitigate inflammation. Their blood was analyzed for levels of proinflammatory cytokines (e.g. IL-6) as well as the mitochondrial respiration rate of peripheral blood mononuclear cells (PBMCs) [1].
PBMCs are immune cells that have been implicated in the inflammatory response that leads to the decompensation and worsening of heart failure. Mitochondria are cellular organelles that produce the energy that immune cells use to regulate inflammation, and mitochondrial dysfunction may contribute to immune dysregulation and inflammation. The respiration rate of PBMCs, as measured in this study, served as a metric for mitochondrial function and health. NAD+ has previously been found to improve mitochondrial health and function such as in the ovaries of mice in order to maintain fertility with aging [4].
The study found that PBMCs extracted from heart failure patients had impaired mitochondrial respiratory capacity and increased proinflammatory cytokine gene expressions. Treating PBMCs isolated from heart failure patients with NR in vitro reduced proinflammatory cytokines and improved mitochondrial respiration. Similar effects were seen in a small group of heart failure patients following NR supplementation for 5-9 days. NR increased the mitochondrial respiration rate of the patients’ PBMCs, as well as reduced the production and gene expression of proinflammatory cytokines. In particular, expression of the NLRP3 inflammasome and the cytokine IL-6 were reduced in these patients [1].
The Potential of NAD+ in Cardiovascular Health
Research into the many roles of NAD+ in cardiovascular health is ongoing; however, unraveling its full potential in larger human trials will take time.
With a large and growing disease burden, supporting cardiovascular health is a top priority for U.S health officials. NR is currently being evaluated for its potential to improve function in peripheral artery disease, to improve the effects of exercise on hypertension, and to address high blood pressure in patients with chronic kidney disease.
This latest pilot study has found that increasing NAD+ holds potential in facilitating cardiovascular health as a modulator of inflammation, results which are being followed up with a slurry of additional clinical trials. NAD+ may usher in an exciting new age for cardiovascular research and innovation on a molecular level.