Fibroblast Growth Factor 23 and Risk of Heart Failure Subtype: The CRIC (Chronic Renal Insufficiency Cohort) Study.

Rationale & Objective: Heart failure (HF) is an important cause of morbidity and mortality among individuals with chronic kidney disease (CKD). A large body of evidence from preclinical and clinical studies implicates excess levels of fibroblast growth factor 23 (FGF23) in HF pathogenesis in CKD. It remains unclear whether the relationship between elevated FGF23 levels and HF risk among individuals with CKD varies by HF subtype. Study Design: Prospective cohort study. Settings & Participants: A total of 3,502 participants were selected in the Chronic Renal Insufficiency Cohort study. Exposure: Baseline plasma FGF23. Outcomes: Incident HF by subtype and total rate of HF hospitalization. HF was categorized as HF with preserved ejection fraction (HFpEF, ejection fraction [EF] ≥ 50%), HF with reduced EF (HFrEF, EF < 50%) and HF with unknown EF (HFuEF). Analytical Approach: Multivariable-adjusted cause-specific Cox proportional hazards models were used to investigate associations between FGF23 and incident hospitalizations for HF by subtype. The Lunn-McNeil method was used to compare hazard ratios across HF subtypes. Poisson regression models were used to evaluate the total rate of HF. Results: During a median follow-up time of 10.8 years, 295 HFpEF, 242 HFrEF, and 156 HFuEF hospitalizations occurred. In multivariable-adjusted cause-specific Cox proportional hazards models, FGF23 was significantly associated with the incidence of HFpEF (HR, 1.41; 95% CI, 1.21-1.64), HFrEF (HR, 1.27; 95% CI, 1.05-1.53), and HFuEF (HR, 1.40; 95% CI, 1.13-1.73) per 1 standard deviation (SD) increase in the natural log of FGF23. The Lunn-McNeil method determined that the risk association was consistent across all subtypes. The rate ratio of total HF events increased with FGF23 quartile. In multivariable-adjusted models, compared with quartile 1, FGF23 quartile 4 had a rate ratio of 1.81 (95% CI, 1.28-2.57) for total HF events. Limitations: Self-report of HF hospitalizations and possible lack of an echocardiogram at time of hospitalization. Conclusions: In this large multicenter prospective cohort study, elevated FGF23 levels were associated with increased risks for all HF subtypes. Plain-Language Summary: Heart failure (HF) is a prominent cause of morbidity and mortality in individuals with chronic kidney disease (CKD). Identifying potential pathways in the development of HF is essential in developing therapies to prevent and treat HF. In a large cohort of individuals with CKD, the Chronic Renal Insufficiency Cohort (N = 3,502), baseline fibroblast growth factor-23 (FGF23), a hormone that regulates phosphorous, was evaluated in relation to the development of incident and recurrent HF with reduced, preserved, and unknown ejection fraction. In this large multicenter prospective cohort study, elevated FGF23 levels were associated with increased risk of all HF subtypes. These findings demonstrate the need for further research into FGF23 as a target in preventing the development of HF in individuals with CKD.