Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized, Placebo-Controlled Trial.

Background: Nicotinamide adenine dinucleotide (NAD+) is a fundamental coenzyme that plays a crucial role in cellular energy metabolism and redox homeostasis. A deficiency in NAD+ has been associated with heart failure (HF), which often occurs in the advanced stages of cardiovascular diseases. While numerous studies have indicated that NAD+ supplementation may enhance cardiac bioenergetics and function in animal models, there is limited research investigating this potential effect in human patients. Therefore, this study aims to evaluate whether NAD+ treatment can lead to improved clinical outcomes for patients with HF due to ischemic cardiomyopathy (ICM).

Methods: This single-center, prospective, randomized, placebo-controlled trial enrolled 180 adults diagnosed with ICM whose left ventricular ejection fraction (LVEF) was ≤ 45% and whose New York Heart Association (NYHA) grade was II-III. Participants were randomly assigned to receive either intravenous NAD⁺ (10 mg/day) or an equivalent placebo (5% glucose/normal saline) for a duration of 7 days, alongside guideline-directed medical therapy. The primary endpoint was the Change in LVEF at 1 month. Secondary endpoints included changes in N-terminal pro B-type natriuretic peptide (NT-proBNP) at 7 and 30 days; a composite of major adverse cardiac and cerebrovascular events (MACCE), which encompassed cardiac death, non-fatal myocardial infarction, stroke, and the first unplanned HF hospitalization within 6 months; and improvements in NYHA functional class.

Results: At 1 month, the NAD+ group demonstrated a significantly greater improvement in LVEF compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). A trend towards decreased NT-proBNP levels was observed in the NAD+ group at day 7 (1471.00 [828.00-2950.00]pg/mL vs. 2317.50 [1155.00-4752.50]pg/mL, p = 0.102). The 6-month composite MACCE rate appeared lower among those receiving NAD+ treatment compared to the placebo group (14.6% vs. 24.7%, p = 0.089), primarily driven by a trend toward fewer first unplanned HF hospitalizations (13.5% vs. 23.6%, p = 0.078). Additionally, a greater proportion of patients in the NAD+ group demonstrated improvement in NYHA functional class at both 1 month (73.0% vs. 57.3%, p = 0.088) and 6 months (53.9% vs. 39.3%, p = 0.115). No significant differences were observed in structural parameters (left ventricular end-diastolic diameter, left ventricular end-diastolic volume, left atrial diameter).

Conclusions: This study has confirmed that supplementation with NAD+ can enhance cardiac function in patients with from HF due to ICM, thereby affirming its beneficial impact on cardiac performance. Trends indicating reductions in NT-proBNP levels and composite clinical events (particularly HF hospitalization) and improvements in NYHA functional class were noted, suggesting potential broader clinical benefits. These findings advocate for NAD+ repletion as a promising therapeutic strategy that warrants further validation through more extensive multicenter trials focused on clinical endpoints.

Registration: Chinese Clinical Trial Registry identifier number ChiCTR2200059169.