We identified an age ≥ 64 years, the presence of atrial fibrillation, diabetes mellitus, CKD stages 1–3 and dilated cardiomyopathy, an LAVI ≥ 39 mL/m2, and serum levels of hs-CRP ≥ 6.10 mg/L, irisin ≤ 7.2 ng/mL and visfatin ≤ 1.1 ng/mL as predictors of poor clinical outcome in HFpEF patients treated with guideline-based optimal therapy with target level of NT-proBNP less than 300 pmol/mL. This evidence concerns the gene NPPB and dilated cardiomyopathy.