Circulating CD38 shows stronger association with incident heart failure in women despite lower levels: sex differences and kidney-function context.

内容摘要

CD38, an NADase implicated in aging and metabolic stress, promotes cardiac dysfunction via NAD⁺ depletion. Whether circulating CD38 is associated with incident heart failure (HF), whether this association differs by sex, and how it relates to kidney-function context remain unclear. We measured plasma CD38 in 42,584 UK Biobank participants (1,659 incident HF events) and evaluated its association with HF using sequential Cox models, attenuation analyses, competing-risk models, and incremental prediction metrics. Complementary mouse studies employed chronic β-adrenergic stress (isoproterenol) to investigate sex-specific responses and test the effects of CD38 inhibition (78c), TGF-β1 inhibition (SB431542), and their combination. CD38 was associated with incident HF in models adjusting for traditional risk factors (M1: HR per SD 1.25, 95% CI 1.18-1.32), with complete attenuation after eGFR adjustment. Despite higher CD38 levels in men, the association was stronger in women (M1: HR 1.39 vs. 1.17 per SD; sex interaction P = 0.004). After eGFR adjustment, the association remained positive in women (M3: HR 1.17) but became inverse in men (M3: HR 0.90). The CD38-HF association showed substantial attenuation after adjustment for NT-proBNP, ANGPT2, and IL-6, consistent with shared statistical variance with downstream biomarker burden rather than causal mediation. Fine-Gray competing-risk models (3,212 deaths without HF) produced similar results. In mice, isoproterenol induced cardiac remodeling and systolic impairment in both sexes and elicited greater metabolic and renal stress responses in females despite their higher baseline cardiac NAD⁺/ATP levels. CD38 inhibition restored cardiac NAD⁺/ATP and reduced renal stress markers, with numerically greater reductions in females, while TGF-β1 inhibition reduced fibrotic signaling. Combined inhibition produced complementary effects across metabolic and fibrotic readouts. Circulating CD38 is not an independent predictor of HF after accounting for kidney function and downstream biomarker burden, but appears to reflect a broader cardiometabolic-renal stress context. Despite lower circulating levels, CD38 showed a stronger association with HF in women than in men. Proof-of-concept mouse experiments showed that CD38 inhibition preserved cardiac NAD⁺/ATP and reduced renal stress markers, while TGF-β pathway inhibition reduced fibrotic signaling, providing mechanistic support for further sex-aware HF research. Women and men can develop heart failure through different biological pathways. CD38 is a protein in blood that breaks down NAD⁺, a molecule that cells use to make energy. We asked whether blood CD38 levels are linked to future heart failure, and whether this link differs by sex and kidney function. We studied 42,584 UK Biobank participants without heart failure at baseline and followed them for new-onset heart failure (1,659 events). We tested whether CD38 predicted heart failure risk and whether the association differed between women and men and across levels of kidney function. We also used a mouse model of long-term stress on the heart to examine sex-specific responses and to test whether blocking CD38 could protect the heart and kidney-related stress signals. Higher CD38 levels were associated with a higher risk of developing heart failure. Even though men had higher CD38 levels overall, the relationship between CD38 and heart failure risk was stronger in women. Kidney function also mattered: in women, higher CD38 was more strongly linked to risk as kidney function declined, while in men, the pattern differed when kidney function was very good. In mice, heart stress reduced heart energy molecules and triggered stronger kidney-stress responses in females. Blocking CD38 restored cardiac energy molecules in both sexes and reduced kidney-stress signals more in females. These findings suggest CD38-related energy pathways may contribute to heart failure risk differently in women and men, and that kidney function should be considered when evaluating NAD⁺-preserving strategies.