Fibroblast Growth Factor-23 Explored As Biomarker for Coronary Heart Disease

Evaluating a possible role for FGF-23 in CHD, accounting for differences in race, sex, and chronic kidney disease status from a subset of the REGARDS data

With Orlando M. Gutierrez, MD, and Tamara L. Wexler, MD, PhD

Fibroblast growth factor-23 (FGF23), a bone-derived phosphatonin, has been established as a hormonal regulator of phosphate and vitamin D metabolism. More recent findings suggest a role for FGF23 in the risk of cardiovascular diseases in men and postmenopausal women,1 noting it may become a useful marker of cardiovascular disease in pregnant women with gestational diabetes mellitus.2

Could FGF-23 reflect differences in coronary heart disease development?

Evidence has consistently linked the levels of fibroblast growth factor-23 with an increased risk of heart failure-related events, possibly by promoting cardiomyocyte hypertrophy.3,4 However, the data regarding coronary heart disease is less clear, with some studies demonstrating an independent association of higher FGF23 concentrations with coronary heart disease (CHD) events and other studies showing no associations.5,6

Making use of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) population data,7 research led by Orlando M. Gutierrez, MD, associate professor of medicine at the University of Alabama at Birmingham, examined the association of FGF23 concentration with incident CHD, and whether the association was modified by race, sex, or CKD status.4

Could Fibroblast Growth Factor-23 Be a Marker for CHD?

The REGARDS study,7 which enrolled 30,239 Black and White adults, 45 years and older, between January 2003 and October 2007 and followed them through the end of 2011, aimed to study stroke incidence.

Trained interviewers obtained self-reported information over the phone about sociodemographic characteristics, cardiovascular risk factors, and use of medications for hypertension, diabetes, menopause (in women), or hypercholesterolemia from each participant. Follow-up was conducted by in-home visits by healthcare professionals during which blood and urine samples were collected, along with blood pressure and electrocardiography readings, height and weight parameters, and an inventory of current medications.4

For the FGF23 study,4  the researchers identified 829 REGARDS patients who developed incident coronary heart disease and randomly selected another 812 participants were chosen as case controls. FGF23 concentrations had been measured at baseline for the nearly 1650 study participants. The investigators defined incident CHD events as a “composite of definite or probable myocardial infarction or definite or probable CHD death.” The investigators stratified the cohorts into quartiles based on baseline FGF23 concentration levels.4

At baseline, higher FGF23 levels were associated with greater age, lower estimated glomerular filtration rate (eGFR), higher urine albumin to creatinine ratio (ACR), and female sex.4 In addition, individuals in the higher quartiles were more likely to be smokers, take renin-angiotensin-aldosterone system inhibitors, and have higher levels of: parathyroid hormone, triglycerides, and high-sensitivity c-reactive protein (CRP) concentrations.

After controlling for race, age, and sex, Dr. Gutiérrez reported the study found “higher FGF23 concentrations were associated with greater risk of coronary heart disease independently of CHD risk factors (and kidney function), although the strength and magnitude appeared to differ by sex.” 

Dr. Gutiérrez told EndocrineWeb “accounting for higher FGF23 levels in women or the use of hormone [replacement] therapy in women attenuated statistical differences in the associations by sex.” However, he acknowledged that the investigators did not have any information regarding the type of hormone therapy or the duration of its use among the women included in his study.

A Look at the Clinical Relevance of FGF-23 Levels

Since the data were collected in the early 2000s, when menopausal women might have been receiving higher doses and longer duration of hormone therapy than is currently recommended, this might have had an effect on the findings.

“There was no data recorded in the study on phosphate or calcium levels, which might have provided important additional information,” Tamara L. Wexler, MD, PhD, clinical assistant professor in the department of rehabilitation medicine at NYU Langone Health in New York City, said in reviewing the study for EndocrineWeb. Also, information on testosterone replacement therapy for men was not collected, so the impact of current hormone use might change the relevance of the findings for patients now.

Dr. Wexler also noted that there were no apparent differences found between the races, nor was there any subanalysis comparing the findings between individuals with definite versus probable CHD.  In effect, she noted, “it is still unclear as to whether FGF23 itself is a marker for something, or if it acts through another channel to exert effects.”

Both Dr. Gutiérrez and Dr. Wexler agree that “the clinical application of FGF23 is unclear at this time.” Dr. Gutiérrez suggested that if FGF23 eventually becomes a target of therapy to reduce CHD risk, results from his study suggest that the cut-off levels of FGF23 might differ by sex.

 There were no financial conflicts of interest regarding this study.

Continue Reading:
Hormone Therapy Found Protective Against Coronary Heart Disease When Used at or Near Menopause
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