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

Abstract

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.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40256-025-00764-7.

Key Points

This study confirmed that nicotinamide adenine dinucleotide (NAD+) supplementation can enhance cardiac function in patients with heart failure resulting from ischemic cardiomyopathy.

Clinical data indicated that NAD+ supplementation improved patients’ left ventricular ejection fraction and showed a tendency to improve N-terminal pro B-type natriuretic peptide levels, the incidence rates of composite events, and New York Heart Association functional classification.

Introduction

Ischemic cardiomyopathy (ICM) represents the most prevalent etiology of heart failure (HF) [1–3]. Approximately two-thirds of chronic HF cases are attributed to ICM, which is associated with a significantly poorer prognosis compared to patients with non-ICM [4]. Research indicates that the incidence of HF is approximately 10% within 2 years following myocardial infarction (MI) and exceeds 40% by 6.5 years post-event [5, 6]. Despite significant advancements in the treatment of HF, the overall prognosis for patients remains unfavorable, and substantial progress in halting disease progression is yet to be realized [7, 8]. This grim outlook is primarily attributed to myocardial damage and persistent mitochondrial dysfunction, which are characteristic features of ICM pathophysiology [9]. Consequently, it is imperative for researchers to identify new therapeutic targets and strategies for the investigation of HF [10].

Nicotinamide adenine dinucleotide (NAD+), an essential coenzyme involved in cellular energy metabolism and redox homeostasis, plays a pivotal role in regulating cardiac bioenergetics through sirtuin-dependent pathways (SIRT1/3/6) [11, 12]. Notably, NAD+ levels are markedly reduced in patients with HF [13]. The depletion of NAD+ adversely impacts mitochondrial biogenesis, adenosine triphosphate (ATP) synthesis, and antioxidant responses, thereby accelerating ventricular remodeling [14, 15]. In accordance with this mechanistic rationale, preclinical models of ischemic HF have demonstrated that exogenous NAD+ supplementation effectively restores myocardial NAD+ levels, rescues mitochondrial function, mitigates adverse remodeling—including hypertrophy and fibrosis—reduces infarct size, and significantly enhances cardiac performance [11, 16–19].

However, despite substantial preclinical evidence supporting these findings, there is a notable lack of conclusive data derived from rigorous and adequately powered randomized placebo-controlled trials specifically evaluating the efficacy of NAD+ supplementation in patients with HF secondary to ICM. This critical gap in the evidence impedes the clinical translation of NAD+ repletion as a targeted metabolic therapy for this high-risk HF population. Therefore, to assess the therapeutic potential of NAD+ in this context, we conducted a prospective randomized placebo-controlled trial aimed at evaluating the effects of adjunctive intravenous NAD+ in patients with HF due to ICM.

Methods

Study Design

This study was designed as a single-center, prospective, randomized, and placebo-controlled clinical trial. A total of 180 participants were randomly assigned in a 1:1 ratio to either the NAD+ group or the placebo group. All participants received standard treatment for HF resulting from ICM, which included basic therapies and medications recommended by HF guidelines [20–22], with timely dose adjustments made by the investigator based on individual patient conditions.

Patients in the NAD+ group received an intravenous infusion of 10 mg NAD+, dissolved in 100 ml of a 5% glucose solution (or normal saline for diabetic patients), administered once daily for 7 consecutive days. The dosing regimen of 10 mg NAD+ via intravenous administration was selected based on emerging clinical data synthesis [23–25]. Intravenous infusions were performed through the dorsal hand or forearm veins (preferably utilizing the median cubital, cephalic, or basilic veins), commencing with an initial infusion rate of 100–120 mL/h. This rate was titrated stepwise, increasing every 15–30 min in the absence of discernible adverse reactions. The maximum allowable infusion rate did not exceed 200 mL/h, resulting in a total administration duration of approximately 40–60 min. The NAD+ used (SFDA Approved No. H41024721) was supplied by Kaifeng Kangnuo Pharmaceutical Co., Ltd. In the control group, an equivalent volume (100 mL) of a 5% glucose solution (or normal saline for diabetic patients) was administered via intravenous drip under identical conditions as those applied to the experimental group.

All participants were recruited during hospitalization at the Department of Cardiology at the First Affiliated Hospital of the University of Science and Technology of China (USTC). All procedures conducted within this study received approval from the ethics committee of the hospital (2022KY053) on April 13, 2022. This study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki and its subsequent amendments. It was registered under registration number ChiCTR2200059169 in the Chinese Clinical Trial Registry on April 26, 2022.

Population

Eligible participants included patients diagnosed with ICM who were at least 18 years of age and had been identified as having HF (New York Heart Association [NYHA] grade II–III) with a reduced ejection fraction (left ventricular ejection fraction [LVEF] ≤ 45%) at the time of providing written informed consent for participation in our study.

ICM is diagnosed when patients meet specific criteria, which include:

• 1.1.
  Strong evidence of myocardial necrosis or ischemia, which may consist of:

  • Previous cardiac events
  • A history of revascularization
  • Objective evidence of myocardial ischemia either at rest or during exertion despite no known history of acute coronary syndromes, such as pathological Q-waves observed on an electrocardiogram (ECG) indicating myocardial necrosis or segmental ventricular wall motion abnormalities detected via echocardiography, along with severe coronary stenosis confirmed through computed tomography (CT) coronary angiography or other imaging modalities.
• 2.Significant cardiac enlargement was observed.
• 3.Clinical manifestations and/or laboratory findings indicative of cardiac insufficiency while excluding certain complications associated with coronary heart disease, including perforation of the interventricular septum, ventricular wall tumors, and papillary muscle dysfunction due to mitral valve insufficiency, as well as other forms of heart disease or alternative causes leading to cardiac enlargement and HF.

The primary exclusion criteria were as follows: (1) clinical conditions such as constrictive pericarditis, obstructive cardiomyopathy, acute coronary syndrome, malignant arrhythmias, pulmonary embolism, or other significant comorbidities; (2) treatment with NAD+ or other cardiac metabolic enhancement agents (e.g., trimetazidine, coenzyme Q10, leucovorin, creatine phosphate, and ranolazine) within 30 days prior to the trial’s commencement or during hospitalization; (3) a history of trauma within the past 2 months, including traumatic cardiopulmonary resuscitation or prolonged (≥ 10 min) cardiopulmonary resuscitation, a major surgical procedure, or a history of head trauma within the last 6 months; (4) patients with uncontrolled hypertension (systolic blood pressure ≥ 180 mmHg and/or diastolic blood pressure ≥110 mmHg); (5) a history of congenital or valvular heart disease; (6) a history of severe hepatic and renal dysfunction (aspartate aminotransferase [AST]/alanine aminotransferase [ALT] levels exceeding three times the upper limit of normal; creatinine level ≥ 225 μmol/L); (7) serious conditions such as malignant tumors, lymphoma, cirrhosis, human immunodeficiency virus (HIV) positivity, and other significant illnesses; (8) patients who underwent intra-aortic balloon counter pulsation and tracheal intubation during hospitalization.

Randomization

Randomization was conducted in accordance with a blinded randomization scheme developed by an independent statistician, ensuring an allocation ratio of 1:1 for each group. The randomization process strictly adhered to the blinded randomization scheme designed by the independent statistician. Each group received allocations at a 1:1 ratio, with random numbers produced through SPSS version 29.

Before medication administration, all participants underwent comprehensive transthoracic doppler echocardiography (transthoracic echocardiogram [TTE]), performed by the same experienced sonographer. Follow-up echocardiography to evaluate cardiac condition was scheduled after a 30-day period. TTE was executed by a single accredited sonographer utilizing a Philips IE33 system equipped with an S5-1 transducer. To ensure standardization, images were captured at end-expiration. The LVEF was calculated offline using Simpson's biplane method, incorporating apical four-chamber and two-chamber views while performing endocardial tracing at both end-diastole and end-systole phases. Measurements were averaged over three consecutive cardiac cycles for accuracy. Left ventricular dimensions (left ventricular end-diastolic diameter [LVEDD]), volumes (left ventricular end-diastolic volume [LVEDV]), and left atrial diameter (LAD) were measured following the guidelines set forth by the American Society of Echocardiography (ASE) [26]. N-terminal pro B-type natriuretic peptide (NT-proBNP) levels were assessed at baseline and again after seven days, with an additional measurement at 30 days, using a Getein 1600 Fluorescence Immunoassay Analyzer (Getein Biotech, China; model: GN1002).

Treatment

Physicians overseeing patient care were instructed to prescribe guideline-directed medications—including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), angiotensin receptor neprilysin inhibitors (ARNIs), beta-blockers, and mineralocorticoid receptor antagonists—unless contraindications or objections arose from patients or their family members.

Outcome

The primary outcome of this study was the comparison of LVEF at 1 month post-treatment between the two patient groups. Secondary outcomes included (1) a comparison of NT-proBNP levels at 7 and 30 days; (2) a composite measure of major adverse cardiac and cerebral events (MACCE), which encompasses cardiac death, nonfatal MI, stroke, and the first unplanned hospitalization for HF assessed over 6 months following randomization; and (3) NYHA assessments regarding improvements in cardiac function at 1 and 6 months. Safety evaluations were conducted through laboratory tests—including routine blood tests as well as assessments of hepatic and renal function—and monitoring for adverse events.

Sample Size

Based on findings from a previous similar study [23], we assumed that the mean LVEF value at 30 days post-treatment in the control group would be 46.8%, with a standard deviation of 8.5%, employing a two-sided significance level α= 0.05. We further estimated an 80% probability that the mean LVEF value in the NAD+ group would exceed that in the control group by 3.7%. To achieve this statistical power, we planned to enroll 83 patients per group (as determined using PASS version 15 software; see Supplementary Fig. 1 in the electronic supplementary material). Anticipating potential dropouts, we aimed for an enrollment target of 90 cases per group, resulting in a total sample size of 180 participants.

Statistical Analysis

The primary analysis adhered to the intention-to-treat principle. Missing data at endpoint were addressed using the last observation carried forward (LOCF) method. Baseline characteristics and demographic variables were compared across groups; continuous variables were statistically summarized using means, medians, standard deviations, and ranges, with non-normally distributed data (e.g., NT-proBNP levels) presented as median (interquartile range); while categorical variables—both nominal and ordinal—were described through frequency counts. In descriptive analyses, comparisons between groups and categorical variables were conducted using the chi-square test or Fisher’s exact probability method. For continuous variables, analysis of variance (ANOVA) was employed when the data exhibited a normal distribution and homogeneous residual variances; otherwise, the Wilcoxon rank sum test or Kruskal-Wallis test was utilized. The comparison of primary and secondary endpoints between the two groups was carried out through statistical analysis of survival data, employing the log-rank test for inter-group comparisons and Kaplan-Meier estimation for survival curves. All statistical tests were performed at a significance level of 5%, utilizing two-sided tests or expressed as 95% confidence intervals.

Results

Between April 2022 and December 2023, a total of 180 patients diagnosed with HF due to ICM were recruited for the study. The participants were randomly assigned to two treatment groups, each comprising 90 individuals (Fig. 1). The baseline characteristics of the participants are detailed in Table 1, revealing no significant differences in baseline parameters between the two groups.

Fig. 1.

Flow diagram of the study. NAD+ nicotinamide adenine dinucleotide

Table 1.

Baseline demographic and clinical characteristics

Variable	NAD+ (n = 90)	Placebo(n = 90)	P value
Demographics
Age	67.52 ± 11.39	66.10 ± 11.63	0.408
Male, n (%)	64 (71.1%)	71 (78.9%)	0.228
NYHA functional, n (%)			0.765
Grade II	42 (46.7%)	44 (48.9%)
Grade III	48 (53.3%)	46 (51.2%)
Clinical data
Heart rate	79.16 ± 13.89	80.60 ± 16.52	0.522
Blood pressure, mmHg
Systolic	124.97 ± 18.51	124.68 ± 22.15	0.924
Diastolic	75.83 ± 11.80	78.10 ± 14.67	0.255
Body mass index	24.20 ± 3.38	24.24 ± 3.15	0.935
Glycosylated hemoglobin A1c, %	6.50 (5.80–7.63)	6.30 (5.90–7.50)	0.827
cTnI (ng/mL)	0.06 (0.02–0.36)	0.07 (0.02–0.25)	0.863
CK (U/L)	75.00 (52.50–107.75)	94.00 (55.25–139.00)	0.293
CK-MB (U/L)	13.00 (9.00–17.00)	13.00 (10.75–17.25)	0.534
Blood lipids, mmol/L
Total cholesterol	4.03 ± 1.15	4.08 ± 1.40	0.797
Triglycerides	1.43 ± 0.65	1.45 ± 0.89	0.870
LDL-C	2.45 ± 0.87	2.42 ± 0.86	0.773
HDL-C	0.94 ± 0.23	1.13 ± 0.26	0.216
Hemoglobin, g/L	125.91 ± 19.29	127.89 ± 21.19	0.538
eGFR, mL/min/1.73 m2	84.09 ± 34.54	83.64 ± 36.99	0.933
Comorbid conditions, n (%)
Previous MI	15 (16.7%)	13 (14.4%)	0.681
Previous PCI	29 (32.2%)	35 (38.9%)	0.350
Hypertension	61 (67.8%)	58 (64.4%)	0.637
Diabetes	42 (46.7%)	33 (36.7%)	0.174
History of stroke	21 (23.3%)	17 (9.8%)	0.465
Atrial fibrillation	12 (13.3%)	14 (15.6%)	0.672
Anemia	27 (30.0%)	28 (31.1%)	0.871
Lifestyle, n (%)
Current smoking	36 (30.4%)	35 (29.2%)	0.540
Current drinking	38 (29.6%)	29 (27.7%)	0.340
In-hospital treatment, n (%)
PCI	67 (74.4%)	65 (72.2%)	0.736
CABG	2 (2.2%)	1 (1.1%)	1.000
Medications, n (%)
Aspirin	64 (71.1%)	60 (66.7%)	0.520
P2Y12 antagonists	49 (54.4%)	52 (57.8%)	0.652
Statins	81 (90.0%)	83 (92.2%)	0.600
SGLT2 inhibitors	43 (47.8)	48 (53.3)	0.456
ACEI/ARB/ARNI	59 (65.6)	57 (63.3)	0.755
MRA	81 (90.0)	79 (87.8)	0.635
Beta -blockers	70 (77.8)	65 (72.2)	0.389

Normally distributed continuous variables are expressed as mean ± standard deviation; non-normally distributed continuous variables are expressed as median (interquartile range); and categorical variables are expressed as n (%)

ACEI angiotensin-converting enzyme inhibitor, ARB angiotensin II receptor blocker, ARNI angiotensin receptor neprilysin inhibitor, CK creatine kinase, CK-MB creatine kinase–creatine kinase, cTnI cardiac troponin I, eGFR estimated glomerular filtration rate, HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, MI myocardial infarction, MRA mineralocorticoid receptor antagonist, NAD+ nicotinamide adenine dinucleotide, NYHA New York Heart Association, PCI percutaneous coronary intervention, CABG coronary artery bypass grafting, SGLT sodium glucose cotransporter

During the 6-month follow-up period, one patient from the NAD+ group and one from the placebo group were classified as dropouts. As illustrated in Table 2, there was a statistically significant improvement in LVEF within the NAD+ group at 1 month compared to the placebo group (45.44 ± 8.55% vs. 42.44 ± 9.09%, p = 0.024). While NAD+ supplementation resulted in a notable increase in LVEF (4.49 ± 5.35% vs. 2.25 ± 7.54%, p = 0.023), no significant intergroup differences were observed regarding structural parameters such as LVEDD, LVEDV, and LAD at 1 month (Table 2).

Table 2.

Primary outcome results: Changes in LVEF among participants at 1-month follow-up visit

Outcomes	NAD+ (n = 90)	Placebo(n = 90)	P value
LVEF, %
Baseline	40.96 ± 7.52	40.24 ± 8.09	0.542
1st month	45.44 ± 8.55	42.44 ± 9.09	0.024
LVEF Changes between 1st month and baseline, %	4.49 ± 5.35	2.25 ± 7.54	0.023
LVEDD, mm
Baseline	61.97 ± 7.51	62.64 ± 8.11	0.561
1st month	61.07 ± 8.08	62.25 ± 8.00	0.327
LVEDD Changes between 1st month and baseline, %	−0.90 ± 4.22	−0.35 ± 4.47	0.397
LAD, mm
Baseline	44.53 ± 5.19	44.90 ± 6.40	0.675
1st month	43.84 ± 5.38	44.60 ± 6.04	0.399
LAD Changes between 1st month and baseline, %	−0.92 ± 3.57	−0.27 ± 4.31	0.300
LVEDV, mL
Baseline	202.22 ± 59.71	208.84 ± 58.96	0.472
1st month	198.34 ± 61.02	202.75 ± 64.11	0.654
LVEDV Changes between 1st month and baseline, %	−8.32 ± 30.30	−3.52 ± 45.47	0.451

Normally distributed continuous variables are expressed as mean ± standard deviation, and categorical variables are expressed as n (%)

LAD left atrial diameter, LVEDD left ventricular end-diastolic diameter, LVEF left ventricular ejection fraction, LVEDV left ventricular end-diastolic volume, NAD+ nicotinamide adenine dinucleotide

As presented in Table 3, there was a trend towards reduced levels of NT-proBNP in the NAD+ group at 7 days (1471.00 [828.00–2950.00]pg/mL vs. 2317.50 [1155.00–4752.50]pg/mL, p = 0.102]. Additionally, incidence rates of composite events at 6 months appeared lower in the NAD+ group compared to those observed in the placebo cohort (14.6% vs. 24.7%, p = 0.089) (Fig. 2). Furthermore, rates of first unplanned HF hospitalizations tended to be lower among patients receiving NAD+ than those receiving placebo (13.5% vs. 23.6%, p = 0.078) (Fig. 3). However, no significant differences were noted concerning cardiac death rates (1.1% vs. 1.1%), MI occurrences (2.2% vs. 1.1%), or stroke incidents (1.1% vs. 0) between the groups (p > 0.05).

Table 3.

Secondary outcomes and safety evaluation

Outcomes	NAD+ (n = 90)	Placebo (n = 90)	P value
NT-proBNP, pg/mL
Baseline	1927.00 (1360.00-5996.75)	2761.00 (1244.00-6091.50)	0.576
7th day	1471.00 (828.00–2950.00)	2317.50 (1155.00–4752.50)	0.102
Changes between 7th day and baseline	−793.50 (−2283.50 to −150.25)	−502.00 (−2133.25 to 138.50)	0.124
1st month	1689.00 (561.00–3047.00)	2090.00 (754.50–5011.75)	0.203
Changes between 1st month and baseline	−980.00 (−2277.00 to −18.00)	−804.00 (−2747.00 to 567.00)	0.621
ALT, U/L
Baseline	21.00 (16.00–32.45)	19.50 (12.75–34.25)	0.914
7th day	18.75 (13.08–28.25)	18.00 (13.60–29.00)	0.731
AST, U/L
Baseline	22.00 (17.00–31.00)	21.00 (16.00–32.20)	0.764
7th day	21.80 (17.60–30.90)	20.00 (16.28–29.00)	0.338
Serum creatinine, μmol/L
Baseline	84.00 (69.00–102.00)	86.00 (70.00–111.00)	0.582
7th day	86.00 (72.00–103.50)	83.50 (71.00–109.00)	0.965
Blood glucose, mmol/L
Baseline	6.58 (5.50–9.54)	5.93 (5.17–8.70)	0.236
7th day	6.50 (5.20–8.30)	5.85 (4.98–7.12)	0.138
Clinical outcomes at 6 months, n (%)
MACCE	13 (14.6%)	22 (24.7%)	0.089
Cardiac death	1 (1.1%)	1 (1.1%)	0.997
MI	2 (2.2%)	1 (1.1%)	0.564
Stroke	1 (1.1%)	0	0.317
The first unplanned HF	12 (13.5%)	21 (23.6%)	0.078
Change in NYHA functional class
Changes between 1st month and baseline, n(%)			0.088
Improved (higher to lower class)	65 (73.0%)	51 (57.3%)
Remained the same	21 (23.6%)	33 (37.1%)
Deteriorated (lower to higher class)	3 (3.4%)	5 (5.6%)
Changes between 6st month and baseline, n(%)			0.115
Improved (higher to lower class)	48 (53.9%)	35 (39.3%)
Remained the same	35 (39.3%)	43 (48.3%)
Deteriorated (lower to higher class)	6 (6.7%)	11 (12.4%)

Non-normally distributed continuous variables are expressed as median (interquartile range), and categorical variables are expressed as n (%)

ALT alanine aminotransferase, AST aspartate aminotransferase, HF heart failure, MACCE major adverse cardiac and cerebral events, MI myocardial infarction, NAD+ nicotinamide adenine dinucleotide, NT-proBNP N-terminal pro B-type natriuretic peptide, NYHA New York Heart Association

Fig. 2.

Kaplan-Meier curve of major adverse cardiac and cerebral events (MACCE). NAD+ nicotinamide adenine dinucleotide

Fig. 3.

Kaplan-Meier curve of the first unplanned heart failure (HF) hospitalization. NAD+ nicotinamide adenine dinucleotide

The Changes in NYHA class from baseline to 1 month in the NAD+ group compared to the placebo group were as follows: improvement was observed in 73.0% of participants receiving NAD+ versus 57.3% in the placebo group, no Change occurred in 23.6% versus 37.1%, and deterioration was noted in 3.4% versus 5.6% (Table 3). When compared to the placebo, the improvement associated with NAD+ in NYHA class appeared to be more pronounced at 1 month (p = 0.088). This initial trend may continue for up to 6 months, with improvements reported at rates of 53.9% for NAD+ and 39.3% for placebo (p = 0.115).

Safety Outcome

Within the NAD+ group, there was a single report of minor dizziness that subsided after approximately 1 h; although we did not attribute this incident directly to NAD+, its use was subsequently discontinued as a precautionary measure. In contrast, one instance involving chest discomfort occurred within the placebo cohort. No notable adverse effects on laboratory parameters, including liver and kidney function and glucose levels, were observed (Table 3).

Discussion

In our prospective randomized controlled trial (RCT), we observed that treatment with NAD+ supplementation over a continuous 7-day period, in conjunction with guideline-directed [20–22] international medications for HF, was well tolerated by the patients. Furthermore, cardiac function exhibited significant improvement compared to the placebo group.

HF resulting from ICM is associated with a markedly poorer prognosis than that seen in patients with non-ICM. Myocardial NAD+ depletion in ICM arises through interconnected pathogenic cascades, including hyperactivation of poly (ADP-ribose) polymerase-1 (PARP-1) [27] and impairment of nicotinamide phosphoribosyltransferase (NAMPT)-mediated salvage pathways [28, 29]. This depletion results from a complex interplay of cellular stress responses; the overactive PARP-1 consumes excessive amounts of NAD+ to repair DNA damage, thereby exacerbating the energy crisis within cardiac muscle cells [27]. Concurrently, compromised NAMPT activity hinders the regeneration of NAD⁺ from nicotinamide, further depleting this essential coenzyme [28, 29].

NAD+ serves as an indispensable cofactor for sirtuin deacetylases (SIRT1, SIRT3, and SIRT6), which regulate mitochondrial homeostasis. Consequently, NAD+ deficiency impairs sirtuin activity and disrupts mitochondrial biogenesis (via peroxisome proliferator-activated receptor γ coactivator-1α, PGC-1α), ATP synthesis efficiency, antioxidant defenses (e.g., via SIRT3-FOXO3/SOD2), Ca²⁺ homeostasis, and mitophagy—collectively driving bioenergetic collapse alongside oxidative stress and inflammation while promoting adverse remodeling [14, 30].

Preclinical evidence [16] consistently demonstrated that restoring NAD+ levels in models of ischemic HF rescues mitochondrial function, attenuates remodeling effects, and enhances cardiac performance. However, despite the compelling rationale for intervention, conclusive evidence from adequately powered randomized placebo-controlled trials specifically evaluating the efficacy of NAD+ supplementation in patients with ICM-induced HF remained insufficient. This critical gap hindered clinical translation.

Our clinical findings provided substantial support for the translational potential of NAD+ replenishment. Exogenous NAD+ supplementation significantly improved LVEF within 1 month. This functional enhancement likely results from improved cardiac bioenergetics due to restored NAD+ levels and subsequent activation of sirtuins (SIRT), which enhance mitochondrial efficiency and improve contractility. A pilot RCT [25] administering intravenous exogenous NAD+ (50 mg/day for 7 days) to elderly HF patients classified as NYHA II–III reported significant improvements in markers of oxidative stress, evidenced by changes in SIRT1, SIRT3, SIRT6, and reactive oxygen species (ROS) levels. Additionally, endothelial integrity was reflected by alterations in endothelin levels as early as 2 weeks post-initiation.

However, this study had certain limitations. First, given the small absolute number of events at the 6-month follow-up, our study was not sufficiently powered to detect significant differences in clinical events. A large multicenter RCT program powered by clinical events is warranted. Second, while we demonstrated early functional improvement in LVEF, it may be inadequate to induce structural reverse remodeling (e.g., unchanged LVEDD/LVEDV). The 1-month duration of our study may be too short to identify structural changes via transthoracic echocardiography, especially with metabolic-targeted therapy. Future studies should consider longer treatment and follow-up periods. Additionally, future studies should focus on specific populations (e.g., by age, sex, diabetes severity, renal function, and revascularization status) to determine which patient groups are most likely to benefit from NAD+ therapy. Lastly, while there were no significant differences in the use of sodium glucose cotransporter 2 inhibitors (SGLT2i) between the two groups, the baseline usage of SGLT2i was relatively low due to the recommendation of SGLT2i for HF treatment in the Chinese guideline [31] during our study period.

Conclusion

In conclusion, this study has demonstrated that supplementation with exogenous NAD+ can significantly enhance cardiac function in patients with HF due to ICM. Further research is necessary to validate its efficacy and effectiveness through clinical trials. Such investigations will contribute to the development of effective and applicable treatments for affected patients.

Supplementary Information

Below is the link to the electronic supplementary material.

Funding

This study was supported by research funds of the Center for Leading Medicine and Advanced Technologies of IHIM (2023IHM01063), China Heart House-Chinese Cardiovascular Association HX fund (2022-CCA-HX-077), and a research grant and study drug supply from Kaifeng Knature Pharmaceutical Co. Ltd. The funders played no part in designing or executing the study, nor did they participate in the collection, management, analysis, or interpretation of the data. Additionally, they were not involved in the preparation, review, approval, or decision to submit the manuscript for publication.

Declarations

Conflict of Interest

Xiaofan Yu, Jie Xu, Jiaoyu Cao, Qizhi Xu, Hongwu Chen, Dongbiao Yu, Xunxia Yao, Kaibing Chen, and Likun Ma declare that they have no potential conflicts of interest that might be relevant to the contents of this manuscript.

Data Availability

The datasets used during the current study are available from the corresponding author on reasonable request. Further inquiries can be directed to the corresponding authors.

Author Contributions

X Yu and LM conceived and designed the study. HC, DY, QX, JX, X Yao, KC, and JC were involved in data collection, interpretation, and analysis. JX, X Yao, and JC were involved in telephone follow-up. X Yu wrote the manuscript. LM was involved in the editing of the manuscript.

Ethics Statement

The Ethics Committee of the First Affiliated Hospital of USTC approved this study (no. 2022KY053).

Consent to Participate

All the participants provided written informed consent to participate in this study.

Consent for Publication

All the authors agree to publish the article.

Code Availability

Not applicable.