One Week of IV NAD+ Modestly Improves Heart Pumping in Ischemic Heart Failure Trial

Why this matters: Ischemic cardiomyopathy (ICM) is the most common cause of heart failure (HF), accounting for roughly two-thirds of chronic cases, and it carries a worse prognosis than non-ischemic HF. Failing hearts show mitochondrial dysfunction and reduced levels of NAD+, a coenzyme essential for energy metabolism and for sirtuin (SIRT1/3/6) signaling. Animal studies show that restoring NAD+ improves mitochondrial function, limits fibrosis and hypertrophy, and boosts cardiac performance. Rigorous human trials in ICM have been lacking.

What was studied: This single-center, prospective, randomized, placebo-controlled trial at the First Affiliated Hospital of USTC (Hefei, China) enrolled 180 hospitalized adults with ICM, LVEF ≤45%, and NYHA class II–III. Patients were randomized 1:1 to 10 mg intravenous NAD+ in 100 mL of 5% glucose (saline for diabetics) or an equal-volume placebo infusion once daily for 7 days. All patients also received guideline-directed HF therapy. Patients who had recently received other cardiac metabolic agents (trimetazidine, coenzyme Q10, ranolazine and similar) were excluded. The primary endpoint was LVEF at 1 month, measured by a single sonographer using Simpson's biplane method. Secondary endpoints were NT-proBNP at 7 and 30 days, 6-month MACCE (cardiac death, non-fatal MI, stroke, first unplanned HF hospitalization), and NYHA class improvement. Analysis was intention-to-treat with last-observation-carried-forward for missing data. The trial was powered at 83 per group to detect a 3.7-point LVEF difference.

Key results: At 1 month, LVEF was significantly higher with NAD+ than placebo (45.44 ± 8.55% vs 42.44 ± 9.09%, p=0.024). The other results were trends rather than statistically significant differences. Median NT-proBNP at day 7 was 1471 vs 2317.5 pg/mL (p=0.102). Six-month MACCE was 14.6% vs 24.7% (p=0.089), driven mainly by first unplanned HF hospitalization (13.5% vs 23.6%, p=0.078). NYHA improvement was 73.0% vs 57.3% at 1 month (p=0.088) and 53.9% vs 39.3% at 6 months (p=0.115). Structural measures (LVEDD, LVEDV, left atrial diameter) did not differ. The text available to us ended in the baseline table, so the detailed safety data and discussion were not reviewed. Baseline characteristics were reported as balanced.

Implications: The results suggest that short-course IV NAD+ repletion may modestly improve systolic function in ICM-related HF, consistent with the preclinical metabolic rationale. The authors call for larger multicenter trials focused on clinical endpoints.

Caveats: The authors' statement that the study 'confirmed' benefit overstates the evidence. Only the primary endpoint reached significance, with a modest p-value and no adjustment for multiple secondary endpoints. All clinical outcome signals were non-significant, and the trial was not powered for them. The control group's 1-month LVEF (42.4%) was lower than the 46.8% assumed in the sample-size calculation. Single-center design, 7-day treatment, and 6-month follow-up limit generalizability. The 10 mg IV dose is small, and the trial did not establish tissue NAD+ repletion or mechanism. These findings should not be extrapolated to oral NAD+ precursors.