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. 2025 May 14;46(19):1863-1866.
doi: 10.1093/eurheartj/ehaf062.

Autophagy is required for the therapeutic effects of the NAD+ precursor nicotinamide in obesity-related heart failure with preserved ejection fraction

Mahmoud Abdellatif  1   2   3   4 , Francisco Vasques-Nóvoa  5   6 , Viktoria Trummer-Herbst  1 , Sylvère Durand  2   3 , Franziska Koser  7 , Moydul Islam  8 , Jihoon Nah  9   10 , Eun-Ah Sung  9 , Ruli Feng  1   11 , Fanny Aprahamian  2   3 , Andreas Prokesch  4   12 , Pablo Zardoya-Laguardia  13 , Junichi Sadoshima  9 , Abhinav Diwan  8   14 , Wolfgang A Linke  7 , João Pedro Ferreira  5   6 , Guido Kroemer  2   3   15 , Simon Sedej  1   4   16
Affiliations

Autophagy is required for the therapeutic effects of the NAD+ precursor nicotinamide in obesity-related heart failure with preserved ejection fraction

Mahmoud Abdellatif et al. Eur Heart J. .
No abstract available

Keywords: Autophagy; HFpEF; Metabolic cardiomyopathy; Mitophagy; NAD+ metabolism; Obesity.

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Figures

Figure 1
Figure 1
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 mice (3-month-old) treated with the mouse equivalent dose of NAM (0.5% v/w in the drinking water for two weeks), with quantitative assessment of the positive ratiometric area of Mito-Keima fluorescence (561 nm/467 nm excitation), indicating mitophagy (right). Values were obtained from 30 different pictures per sample (n = 3–4 mice/group). (C) Immunoblot-based quantification of autophagy proteins acetylation (normalized to GAPDH) in the hearts of ZSF1 lean, obese, and NAM-treated obese rats (n = 6 rats/group), along with a Volcano plot depiction of the relative difference in detectable autophagy-related protein acetylation in NAM-treated vs. control obese ZSF1 rats (top), (n = 4/3 rats, respectively). Representative Western blots and quantification of insulin-like growth factor-1 receptor (IGF-1R) expression (normalized to total protein content detected by Ponceau S staining), and Akt phosphorylation normalized to total Akt expression in the hearts of ZSF1 lean, obese, and NAM-treated obese rats (bottom), (n = 4/6/4 rats, respectively). (D) Representative confocal images of myocardial sections from adult CAG-RFP-GFP-LC3 transgenic mice (3-month-old) treated with NAM (0.5% v/w in the drinking water for two weeks) and IGF-1 (200 µg/kg i.p., 30 min before sacrifice) or vehicle, with quantitative assessment of the ratio of autolysosomes (punctate RFP signal) to autophagosomes (punctate RFP-GFP signal (n = 4–5 mice/group). (E) Schematic representation of NAM feeding protocol to 5-week-old cardiomyocyte-specific Atg5-deficient mice (Atg5−/−), generated by crossing Atg5flox/flox mice with knock-in mice expressing Cre+ recombinase driven by the cardiomyocyte-specific MLC2a gene encoding α-myosin light chain promoter (MLC2a-Cre+). Atg5−/− mice and their control littermates (Atg5+/+) were fed a standard diet (SD; Sniff, #V1534) or a combination of high-fat diet (HFD; 45% kcal from fat, lard; Sniff, cat. EF R/M #D12451 modified) and the nitric oxide synthase inhibitor L-NAME (0.5 g/L in the drinking water) in the presence or absence of NAM (0.5% v/w in the drinking water for 6 weeks). EF, E/e′ ratio, LVRI, LVmass/TL. (n = 5–9 mice/group) (F) NAM and methyl-NAM levels were measured in participants of the NETDiamond prospective HFpEF cohort (N = 88). Participants were stratified by the median of methyl-NAM/NAM ratio, a proxy of NAM depletion, and compared across demographic, analytical, and echocardiographic parameters; only statistically significant differences [sex and B-type natriuretic peptides (BNP)] are reported. Time-to-first-event analysis for the composite endpoint of cardiovascular death or HF progression (i.e. HF hospitalization, acute HF episodes, or diuretic intensification) was conducted using Kaplan–Meier curves and Cox proportional-hazards models. The analysis was stratified with split time at 1 year of follow-up due to a significant time-dependent interaction, indicating a violation of the proportional hazards assumption (P = 0.036). Hazard ratios (HR) with 95% confidence intervals (CI) for follow-up ≥1 year are presented for unadjusted and adjusted models, with covariates including age, sex, creatinine, and BNP levels. Data are presented as means ± SD with subject-level data superimposed as individual points. P values were calculated by ANOVA with Dunnett’s post hoc test (A–D), Student’s t-test (B, right), or two-way ANOVA with Dunnett’s post hoc test (E). In (F), P values were calculated by Mann–Whitney test, χ2 test, Log-Rank test, or Cox proportional-hazards model, respectively. Akt, Akt serine/threonine kinase 1; Hsp90, heat shock protein 90; Hspa8, heat shock cognate 71 kDa protein; LC3, microtubule-associated protein 1A/1B-light chain 3; p62, ubiquitin-binding protein p62; ns, non-significant; Vdac1, voltage-dependent anion-selective channel protein 1.
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