Endocrine crosstalk in cardiovascular-kidney-metabolic syndrome-related heart failure: the fibroblast growth factor 23-Klotho axis and cardiometabolic therapy.

Heart failure arising in cardiovascular-kidney-metabolic (CKM) syndrome, hereafter referred to as CKM-related heart failure (CKM-HF), is increasingly understood as the cardiac expression of multisystem endocrine and metabolic stress rather than as an isolated myocardial disorder. In this narrative review, we examine how kidney, bone, adipose tissue, gut, pancreas, vasculature, and myocardium communicate through maladaptive hormonal and metabolic signals, with particular emphasis on heart failure with preserved ejection fraction (HFpEF). We position the fibroblast growth factor 23 (FGF23)-Klotho axis as a candidate organizing framework for mineral endocrine stress in diabetic kidney disease and chronic kidney disease. Human observational studies associate higher circulating FGF23 and altered Klotho biology with adverse cardiovascular phenotypes, whereas preclinical studies provide mechanistic plausibility for links to cardiac hypertrophy and fibrosis. However, current evidence does not establish that elevated FGF23 directly causes cardiac remodeling in humans. We examine insulin resistance, adipose dysfunction, RAAS activation, anemia, and gut-derived metabolites selectively as modifiers, competing pathways, or confounders that shape the interpretation of FGF23-Klotho biology in CKM-related heart failure. Established cardiometabolic therapies are discussed according to their proven clinical effects and as modifiers of the context in which FGF23 and soluble Klotho are interpreted; their efficacy is not considered evidence of FGF23-Klotho pathway engagement or mediation. An FGF23-Klotho-centered CKM-HF framework may support research phenotyping, prospective biomarker validation, and mechanism-based trial design. However, the proposed phenotype remains unvalidated, circulating FGF23 and soluble Klotho are not established for routine clinical use, and their incremental value beyond conventional kidney, mineral, cardiac, and imaging markers remains unknown.