Subgroup analyses revealed significant associations observed in older patients (≥65 years; HR 1.35, 95% CI 1.02-1.79, P = 0.036), those with diabetes (HR 1.50, 95% CI 1.05-2.14, P = 0.026), CKD (HR 1.55, 95% CI 1.10-2.18, P = 0.013), and higher NT-proBNP levels (> median; HR 1.58, 95% CI 1.12-2.23, P = 0.010).<h4>Conclusions</h4>In middle-aged and older adults with HFpEF, concomitant cancer confers a sustained and clinically meaningful increase in mortality, HF hospitalization, and major cardiovascular events independent of traditional risk factors and biomarkers. This evidence concerns the gene NPPB and hydrops fetalis.