{"doi":"10.1093/eurheartj/ehaf062","title":"Autophagy is required for the therapeutic effects of the NAD+ precursor nicotinamide in obesity-related heart failure with preserved ejection fraction","abstract":"Metabolic cardiomyopathy is a major complication of obesity that often progresses to clinically evident heart failure with preserved ejection fraction (HFpEF).1 This predominant cardiometabolic form of HFpEF is a burgeoning public health problem with limited evidence-based therapies.2 In this regard, we previously showed that clinical HFpEF is associated with low cardiac levels of the metabolic cofactor nicotinamide adenine dinucleotide (NAD+) and that oral supplementation of nicotinamide (NAM), an NAD+ precursor, improves preclinical HFpEF in several rodent models.3 However, NAD+ is a pleiotropic molecule and its mode of action in HFpEF remains elusive. Because autophagy is an NAD+-stimulated mechanism that is essential for maintaining cellular homeostasis and mitochondrial health, particularly in long-lived post-mitotic cardiomyocytes under metabolic stress,4 we speculated that an increase of autophagic flux might contribute to the efficacy of NAM supplementation against metabolic cardiomyopathy and associated HFpEF. To determine whether NAD+ supplementation stimulates cardiac autophagy in cardiometabolic HFpEF, we assessed autophagy markers at both the mRNA and protein levels in NAM-fed ZSF1 obese rats, a model of cardiometabolic syndrome and HFpEF. At variance with our previous report,3 we administered a 40% lower and, hence, a more clinically feasible dose of NAM (0.3% w/v in the drinking water), which increased cardiac NAD+ by 30 ± 11% (mean ± SD) in treated vs. control rats. Moderate elevation of NAD+ was not associated with a significant difference in ejection fraction (Figure 1A), but efficiently improved cardinal signs of HFpEF. Specifically, NAM reduced cardiac hypertrophy and diastolic dysfunction, as indicated by lower echocardiography-derived left ventricular (LV) mass, LV remodelling and functional indices as well as pulmonary congestion, as measured by tibia length-normalized lung weight (Figure 1A). These cardioprotective effects of NAM coincided with increased expression of several mRNA species relevant to the autophagic-lysosomal pathway in the heart (Figure 1B). Consistently, NAM stimulated the autophagy-associated lipidation of microtubule-associated protein 1A/1B-light chain 3B (LC3B), leading to an increase in LC3B-II, while reducing the abundance of the autophagic substrate sequestosome 1 (SQSTM1, commonly known as p62) to the levels of lean controls (Figure 1B). Collectively, these findings suggest that the beneficial effects of NAM in obesity-related HFpEF coincide with restored cardiac autophagy. Notably, NAM also increased selective degradation of cardiac mitochondria detectable in mice expressing the mitophagy biosensor Mito-Keima mice5 (Figure 1B), suggesting that NAM might ameliorate cardiac function, at least in part, by improved mitochondrial quality control. Nicotinamide improves cardiometabolic HFpEF through autophagy activation. (A) Representative echocardiography tracings: M-mode (top), pulsed-wave Doppler (middle), and tissue Doppler (bottom) from 20-week-old ZSF1 lean and obese rats, treated or not with 0.3% v/w nicotinamide (NAM) in the drinking water for 12 weeks (Ob + NAM vs. Obese, respectively). EF, ejection fraction. Left ventricular mass (LVmass) normalized to tibia length (TL). Ratio of peak early Doppler transmitral flow velocity (E) to myocardial tissue Doppler velocity (e′). Lung weight normalized to tibia length (LW/TL) (n = 8–9 rats/group). (B) Heatmap of cardiac expression levels (red = high, blue = low) of differentially regulated genes involved in the autolysosome-lysosome KEGG pathway (left), (n = 4 rats/group). Representative Western blots and quantification (middle) of autophagy markers, including LC3B-II expression, LC3B-II-to-LC3B-I ratio, and the autophagy substrate p62 (normalized to GAPDH) in the hearts of ZSF1 lean, obese, and NAM-treated obese rats (n = 8/9/9 rats, respectively). Representative confocal images of myocardial sections from adult Mito-Keima reporter","journal":"European Heart Journal","year":2025,"id":510161,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":22,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9501,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1365501,"name":"Francisco Vasques‐Nóvoa","orcid":"0000-0001-9701-8538","position":1,"is_corresponding":false},{"id":1365502,"name":"Viktoria Trummer-Herbst","orcid":"0000-0002-0079-239X","position":2,"is_corresponding":false},{"id":1330319,"name":"Sylvère Durand","orcid":"0000-0001-6356-1006","position":3,"is_corresponding":false},{"id":1165386,"name":"Franziska Koser","orcid":"0009-0008-9585-0935","position":4,"is_corresponding":false},{"id":393329,"name":"Moydul Islam","orcid":"0000-0002-3828-9562","position":5,"is_corresponding":false},{"id":350015,"name":"Jihoon Nah","orcid":"0000-0003-2254-2233","position":6,"is_corresponding":false},{"id":859504,"name":"Eun‐Ah Sung","orcid":"0000-0002-1843-0338","position":7,"is_corresponding":false},{"id":1365503,"name":"Ruli Feng","orcid":"0000-0001-6741-0870","position":8,"is_corresponding":false},{"id":1365504,"name":"Fanny Aprahamian","orcid":"0000-0002-2457-8435","position":9,"is_corresponding":false},{"id":516116,"name":"Andreas Prokesch","orcid":"0000-0002-8487-7103","position":10,"is_corresponding":false},{"id":1366248,"name":"Pablo Zardoya-Laguardia","orcid":null,"position":11,"is_corresponding":false},{"id":247599,"name":"Junichi Sadoshima","orcid":"0000-0003-3724-4132","position":12,"is_corresponding":false},{"id":238348,"name":"Abhinav Diwan","orcid":"0000-0001-7554-4772","position":13,"is_corresponding":false},{"id":318287,"name":"Wolfgang A. Linke","orcid":"0000-0003-0801-3773","position":14,"is_corresponding":false},{"id":228546,"name":"João Pedro Ferreira","orcid":"0000-0002-2304-6138","position":15,"is_corresponding":false},{"id":49720,"name":"Guido Kroemer","orcid":"0000-0002-9334-4405","position":16,"is_corresponding":false},{"id":322558,"name":"Simon Sedej","orcid":"0000-0002-4419-6821","position":17,"is_corresponding":false},{"id":322551,"name":"Mahmoud Abdellatif","orcid":"0000-0002-5042-9054","position":0,"is_corresponding":true}],"reference_count":10,"raw_metadata":null,"created_at":"2026-07-19T02:47:30.942539Z","pmid":"39995248","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}