NAD⁺ precursors: a new remedy against heart failure with preserved ejection fraction?

Heart failure with preserved ejection fraction (HFpEF) is the most common diagnosis in hospitalized patients >65 years of age. Due to the increased stiffness of the left ventricle, patients with HFpEF suffer from shortness of breath, a drop in physical performance and a reduced quality of life. Despite the high mortality rate of 35% after the initial diagnosis, there are no treatment options for this prevalent form of heart failure. Intake of nicotinamide adenine dinucleotide (NAD⁺) precursors could represent a first evidence-based therapy against HFpEF.

Obesity and high blood pressure, in combination with aging, are among the greatest risk factors for HFpEF. Current HFpEF management guidelines do not include dietary regimes, and little is known about selected nutrients that may target metabolic risks and various intracellular processes. A recent preclinical study showed that an increase in nicotinamide adenine dinucleotide (NAD⁺) bioavailability through dietary intake of nicotinamide could represent a first evidence-based therapy against HFpEF. Future interventional clinical studies are necessary to test whether nicotinamide or other NAD⁺ precursors might be effective against HFpEF in patients.

HFpEF is an ever-growing disease without effective therapies

Heart failure with preserved ejection fraction (or shortly HFpEF) is the most common cause for hospitalization of the elderly. In Europe and the USA alone, around 6 million patients aged > 65 years currently suffer from HFpEF for which there are no evidence-based treatment options.¹

Global obesity epidemic and demographic aging of the population are the major culprits for the continuously increasing prevalence of the disease, which poses one of the greatest challenges in cardiovascular and geriatric medicine. HFpEF is characterized by the increased cardiac stiffness and reduced myocardial relaxation due to a limited or normal left ventricular function but at the expense of elevated filling pressure (so-called diastolic dysfunction). Although HFpEF could be asymptomatic at rest, the disease manifests during physical exertion owing to mounting left ventricular pressures, leading to blood accumulation in the lungs, shortness of breath and decline in performance. The quest for effective HFpEF pharmacotherapies has so far been particularly challenging because of the limited insight into the molecular mechanisms underlying this age-associated and systemic syndrome.²

The complexity of HFpEF is further characterized by gender-specific differences, because women have a poorer quality of life despite a higher overall survival than men with HFpEF.³ Since standard medication against heart failure with reduced ejection fraction (HFrEF), such as neurohormonal antagonists and nitrate derivatives, has proven inefficient in improving the quality of life and survival of patients with HFpEF, alternatives are urgently needed.

Calorie restriction against HFpEF?

Calorie restriction (or fasting without malnutrition) is the most effective life-prolonging intervention that also improves left ventricular hypertrophy and exercise capacity in obese men and women with HFpEF.⁴ However, the implementation of calorie restriction in humans is not sustainable, especially for the elderly due to poor adherence and adverse effects on bone health and the immune system. Growing evidence suggests that biochemical changes of calorie restriction can be reproduced by natural or pharmacological supplements or small molecules – called calorie restriction mimetics – which partially activate the health-promoting mechanisms of calorie restriction. These fast-mimicking molecules might thus be one of the most attractive and perhaps most practicable interventions for daily nutrition – probably also because they would maintain a balanced food composition and ensure the supply of all nutrients without reducing the amount of calorie intake.

Nicotinamide: a potential calorie restriction mimetic

A promising candidate for such a calorie restriction mimetic is nicotinamide, a naturally occurring precursor of the co-enzyme nicotinamide adenine dinucleotide (NAD⁺). NAD⁺ plays a vital role in redox homeostasis in mitochondria and is a central metabolite in the breakdown of carbohydrates (glycolysis) or fatty acids (β-oxidation), and the tricarboxylic acid cycle. NAD⁺ stimulates lipolysis and, thus, reduces the risk of obesity. Interestingly, NAD⁺ levels are typically reduced in aging and obesity,⁵ both of which are most common risk factors in HFpEF. Both calorie restriction and exercise can restore cellular NAD⁺, which can be also replenished by the supplementation of NAD⁺ precursors, such as nicotinamide.

Targeting NAD⁺ metabolism can reproduce the promising effects of calorie restriction on HFpEF

A recent study showed reduced cardiac NAD⁺ concentration in patients with HFpEF.⁶ The authors made similar observations also in obese rats with metabolic syndrome and diastolic dysfunction – the hallmark of HFpEF. Oral administration (as an additive in drinking water) of the natural NAD⁺ precursor, nicotinamide, promoted the synthesis of NAD⁺ and improved cardinal HFpEF symptoms in three different animal models with diastolic dysfunction (metabolic syndrome, hypertension or advanced aging). The increased oxidative breakdown of fatty acids and weight loss was associated with restored energy homeostasis in the myocardium and skeletal muscle upon nicotinamide treatment. Mechanistically, nicotinamide-induced deacetylation of the giant structural molecule, titin, directly reduced the passive stiffness of cardiomyocytes. Since nicotinamide has already been successfully used in humans for the treatment of skin cancers and kidney diseases,^7,8 these findings could also open up new ways to counteract the loss of cardiac elasticity in patients with HFpEF. Of note, the authors used two non-obese animal models to demonstrate a direct effect of nicotinamide on the heart. In old mice, the administration of nicotinamide attenuated cardiac hypertrophy and mitigated diastolic dysfunction ultimately leading to improved left ventricular relaxation and filling of the heart. In salt-sensitive rats, which develop hypertensive heart failure, the administration of nicotinamide improved the elasticity of the cardiac muscle and delayed the progression of heart failure. These findings are clinically relevant, since high blood pressure and hypertrophy are among the most common risk factors for the development of diastolic dysfunction, which can subsequently lead to HFpEF.

The effects of nicotinamide in humans

The bulk of cellular NAD⁺ is produced from vitamin B3 ingested with food in the form of nicotinamide and nicotinic acid, or alternatively from the essential amino acid tryptophan (NAD⁺ precursor). Upon analyzing the human data from the „Bruneck study“, the authors found that subjects consuming a diet rich in these precursors had significantly reduced risk for cardiovascular diseases. Increased intake of dietary niacin (consisting of nicotinamide and nicotinic acid) has been also associated with reduced hypertension and lower risk of death from heart disease. In this 20-years long study, a total of 815 probands in the Bruneck area in South Tyrol (Italy) has been comprehensively examined and their eating habits were documented with the help of questionnaires and under the guidance of nutritionists. In this way, the amount of vitamin B3 ingested with the food was calculated and then compared with the probands’ medical history.

Conclusions

In summary, this study demonstrates that boosting NAD⁺ metabolism by nicotinamide or other precursors might become the first evidence-based therapy for HFpEF, which is arguably one of the toughest challenges in cardiovascular medicine.