Fibroblast Growth Factor-23, Cardiovascular Prognosis, and Benefit of Angiotensin-Converting Enzyme Inhibition in Stable Ischemic Heart Disease

Study Questions:

What is the prognostic impact of fibroblast growth factor (FGF)-23 in identifying patients with stable ischemic heart disease (SIHD) at high risk of cardiovascular events, and does FGF-23 identify patients who derive greater clinical benefit from angiotensin-converting enzyme (ACE) inhibitor therapy?

Methods:

FGF-23 levels were measured in 3,627 SIHD patients randomized to trandolapril or placebo within the PEACE (Prevention of Events With Angiotensin-Converting Enzyme) trial and followed for a median of 5.2 years. Cumulative event rates were calculated across quartiles of FGF-23 with the Kaplan-Meier method and compared by use of a trend test.

Results:

After adjustment for clinical risk predictors, left ventricular ejection fraction, markers of renal function, and established cardiovascular biomarkers, the top quartile FGF-23 concentration was independently associated with an increased risk of cardiovascular death or heart failure among patients allocated to placebo (hazard ratio [HR], 1.73; 95% confidence interval [CI], 1.09-2.74; p = 0.02) and significantly improved metrics of discrimination. Furthermore, among patients in the top quartile of FGF-23 levels, trandolapril significantly reduced cardiovascular death or incident heart failure (HR, 0.45; 95% CI, 0.28-0.72), whereas there was no clinical benefit in the remaining patients (HR, 1.07; 95% CI, 0.75-1.52; p-interaction = 0.0039). This interaction was independent of and additive to stratification based on renal function.

Conclusions:

The authors concluded that elevated levels of FGF-23 are associated with cardiovascular death and incident heart failure in SIHD patients, and identify patients who derive significant clinical benefit from ACE inhibitor therapy regardless of renal function.

Perspective:

This study reports that higher levels of FGF-23 are associated with cardiovascular mortality and incident heart failure in patients with SIHD, and this association was seen with plasma FGF-23 levels well within the observed range in the general population without known cardiovascular disease or renal impairment. Furthermore, it appears that FGF-23 provides incremental prognostic information even after adjusting for clinical risk factors, renal function, and cardiovascular biomarkers. Finally, the data also suggest that patients with higher levels of FGF-23 received clinical benefit from ACE inhibitor therapy, independent of renal function. These observations imply that this novel biomarker may be helpful in estimating future cardiovascular risk, and help to predict the response to ACE inhibitor therapy in SIHD patients.

Clinical Topics: Heart Failure and Cardiomyopathies, Statins, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Myocardial Ischemia, Indoles, Heart Failure, Cardiovascular Diseases, Stroke Volume, Risk Factors, Fibroblast Growth Factors, Peptidyl-Dipeptidase A


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