Nicotinamide for the treatment of heart failure with preserved ejection fraction

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent and intractable form of cardiac decompensation commonly associated with diastolic dysfunction. Here, we show that diastolic dysfunction in patients with HFpEF is associated with a cardiac deficit in nicotinamide adenine dinucleotide (NAD+). Elevating NAD+ by oral supplementation of its precursor, nicotinamide, improved diastolic dysfunction induced by aging (in 2-year-old C57BL/6J mice), hypertension (in Dahl salt-sensitive rats), or cardiometabolic syndrome (in ZSF1 obese rats). This effect was mediated partly through alleviated systemic comorbidities and enhanced myocardial bioenergetics. Simultaneously, nicotinamide directly improved cardiomyocyte passive stiffness and calcium-dependent active relaxation through increased deacetylation of titin and the sarcoplasmic reticulum calcium adenosine triphosphatase 2a, respectively. In a long-term human cohort study, high dietary intake of naturally occurring NAD+ precursors was associated with lower blood pressure and reduced risk of cardiac mortality. Collectively, these results suggest NAD+ precursors, and especially nicotinamide, as potential therapeutic agents to treat diastolic dysfunction and HFpEF in humans.

Heart Failure Syndrome With Preserved Ejection Fraction Is a Metabolic Cluster of Non-resolving Inflammation in Obesity

“…In addition, recent findings highlighted an improved endothelial function in Zucker spontaneously fatty hypertensive heart failure F1 hybrid (ZSF1) obese rats, a recent model qualifying for HFpEF studies including hypertension and diabetes. In this study, supplementation of the NAD + precursor nicotinamide (NAM) elicited an antihypertensive effect correlated with improved endothelial function, as indicated by an enhanced vasodilatory response to acetylcholine in isolated aortic rings ( 59 ) ( Table 1 ).…”

Caloric Restriction Mimetics in Nutrition and Clinical Trials

“…Interestingly, in the Bruneck study situated in northern Italy, recent analysis found relative high dietary NE intake of 28.9 mg (23.5 to 35.0) in men and 26.9 mg (21.9 to 33.0) in women per day ( 154 ), which is corroborated by similar observations made in the US (28 and 18 mg niacin/day for men and women, respectively) and Canada (41 and 28 mg niacin/day for men and women, respectively) ( 76 ).…”

Enhancing NAD+ Metabolome in Cardiovascular Diseases: Promises and Considerations

“…Moreover, a randomized controlled trial showed that NR administration for 6 weeks led to reduction in blood pressure and aortic stiffness in middle-aged and older adults (36). A recent study reported that diastolic heart failure in humans is associated with depleted NAD + content (37). Using three murine models of heart failure, (i) aging, (ii) hypertension, and (iii) ZSF1 obese rats, the study showed that NAM treatment prevented diastolic dysfunction by improving cardiometabolic function and bioenergetics (Figure 1).…”

“…Using three murine models of heart failure, (i) aging, (ii) hypertension, and (iii) ZSF1 obese rats, the study showed that NAM treatment prevented diastolic dysfunction by improving cardiometabolic function and bioenergetics (Figure 1). Moreover, they performed a long-term population-based analysis which suggested that supplementation of NA or its equivalent is capable of reducing blood pressure and, thereby it was associated with lower risks of cardiac mortality (37).…”