Epidemiologic insights on the role of fibroblast growth factor 23 in cardiovascular disease

Abstract

Purpose of review: Fibroblast growth factor 23 (FGF23) regulates phosphate and vitamin D homeostasis and rises as kidney function declines. Animal studies have demonstrated direct and indirect effects of FGF23 that may promote heart disease. Herein, we review the recent epidemiologic literature evaluating the relationship between FGF23 and cardiovascular disease.

Recent findings: In observational prospective studies, higher FGF23 associates with a greater risk of incident cardiovascular disease including ischemic heart disease, stroke, heart failure, and atrial fibrillation. These studies establish a temporal sequence of events over long-term follow-up that suggest a possible role of FGF23 in cardiovascular disease pathogenesis. In most studies, risk is generally graded; however, in the largest study to date, higher FGF23 within the low-normal range was not associated with higher risk. In several recent studies higher FGF23 associated more strongly with the risk of congestive heart failure compared with atherosclerotic events, a finding consistent with surrogate endpoints and animal experiments. Currently, the utility of FGF23 as a predictive biomarker of cardiovascular risk is not established, and interventions to reduce FGF23 need to be studied to confirm its possible pathophysiologic role.

Summary: Higher FGF23 is associated with the subsequent development of cardiovascular disease, and perhaps most notably heart failure, in a growing number of studies. These findings bolster ongoing efforts to lower FGF23 using strategies to reduce phosphate intake and absorption.

Figure 1. Qualitative Summary of Major Prospective Studies Evaluating the Independent Relationship Between Fibroblast Growth Factor 23 and Clinical Cardiovascular Events Across Populations and Event Types

Significant independent associations between FGF23 and events are highlighted in red with a report of no independent association highlighted in green. Reporting of precise effect sizes across studies are limited by differences in scaling of FGF23 (additive vs. multiplicative). Where possible, results from multivariable models including adjustment for kidney function are emphasized. Some endpoints that are listed as negative (green) had limited power to detect associations. Global composites include some atherosclerotic endpoints and congestive heart failure, but exact atherosclerotic endpoints included differ by study. Atherosclerotic composites include some combination of myocardial infarction, peripheral arterial disease, cerebrovascular accident/transient ischemic attack, or cardiovascular cause specific mortality, but exact composition differs by study. In the PIVUS Study this endpoint included all cause-mortality. Some of the results summarized here emanate from different publications involving the same cohort as indicated by citations. Abbreviations include: MESA, Multi-Ethnic Study of Atherosclerosis; ARIC, Atherosclerosis Risk in Communities Study; HPFS, Health Professionals Follow-Up Study; NOMAS, Northern Manhattan Study; CHS, Cardiovascular Health Study; ULSAM, Uppsala Longitudinal Study of Adult Men; PIVUS, Prospective Investigation of the Vasculature in Uppsala Seniors; HOST, Homocysteine in Kidney and End-Stage Renal Disease Study; CRIC, Chronic Renal Insufficiency Cohort Study; OVIDS-CKD, Osaka Vitamin D Study in Patients with CKD; PEACE, Prevention of Events with Angiotensin-Converting Enzyme Trial; LURIC, Ludwigshafen Risk and Cardiovascular Health Study; Athero, atherosclerotic; IHD, ischemic heart disease; PAD, peripheral arterial disease; CVA, cerebrovascular accident (may include transient ischemic attack); CHF, congestive heart failure; CV death, cardiovascular death; A fib, atrial fibrillation

Figure 2. Moving “upstream” of fibroblast growth factor 23 (FGF23) to target dietary phosphate

Therapies with a central focus on lowering FGF23 may fail to consider its important physiologic functions in maintaining phosphate (green arrow) and vitamin D homeostasis (not pictured). Although challenging, a central therapeutic focus on dietary phosphate, as a root cause of total phosphate axis dysfunction (purple arrows), may yield better results by mitigating the potential cardiovascular toxicities of both FGF23 and phosphate (red arrows).