Study Finds Potential Biomarker for HFpEF

Serum fatty acid–binding protein 4 (FABP4) levels were increased in patients with heart failure with preserved ejection fraction (HFpEF), associated with cardiac remodeling and dysfunction, and linked to poor outcomes, according to study results published in ESC Heart Failure. The findings indicate that “FABP4 could be a potential biomarker in the complex pathophysiology of HFpEF,” the authors wrote.

Around 50% of patients with HF have preserved left ventricular (LV) ejection fraction, and prevalence is increasing in developed countries. However, the underlying mechanisms of HFpEF are unclear, and there is currently no proven treatment to improve outcomes in these patients.

FABP4 is secreted from adipocytes, and circulating FABP4 levels increase during bouts of exercise. In addition, cardiopulmonary exercise test results have shown that an induction of FABP4 is highly correlated with that of norepinephrine and workload. Mice studies have also found that FABP4 induces inflammatory cytokines, reduces myocardial contraction, and induces lipid accumulation in cardiomyocytes.

To determine whether circulating FABP4 levels are elevated in patients with HFpEF, and to see if the magnitude of elevation correlates with cardiac structural and functional abnormalities and clinical outcomes, researchers conducted a prospective study of 112 patients.

A total of 92 patients with HFpEF (EF ≥ 45%) admitted to a university hospital in Japan between 2015 and 2018 were included in the study. “Patients free of HF who were referred for coronary angiography for angina pectoris evaluation (n = 9) or follow‐up after percutaneous coronary intervention (n = 11) were included as a comparator group (coronary artery disease [CAD] group, n= 20),” researchers explained.

Investigators measured serum FABP4, lipid profiles, glucose, and other metrics and performed echocardiography in all patients. The lower limit of detection for FABP4 was 0.05 ng/mL, and intraassay and interassay coefficients of variation were 3.7% to 6.4% and 2.6% to 5.3%, respectively.

Participants were then followed up with to determine a composite end point of all-cause mortality or hospitalization for HF, defined as dyspnea and pulmonary edema on chest radiographs requiring intravenous diuretic treatment.

Although age was similar between the HFpEF and CAD groups, those with HFpEF were mostly female, anemic, and had a higher prevalence of atrial fibrillation (AF).

Analyses revealed:

• Compared with patients with CAD, those with HFpEF had higher FABP4 levels (median 12.5 [interquartile range (IQR), 9.1-21.0] vs 43.5 [24.6-77.4] ng/mL; P < .0001).
• During a median follow‐up of 9.1 months, there were 28 primary end points in the HFpEF cohort.
• Event‐free survival was significantly decreased in patients with FABP4 levels of at least 43.5 ng/mL compared with in those with FABP4 levels less than 43.5 ng/mL (P = .003).
• After adjusting for sex, AF, and renal function, FABP4 levels remained higher in patients with HFpEF than in those with CAD.

Overall FABP4 levels were associated with:

• cardiac remodeling (LV mass index: r = 0.29, P = .002; left atrial volume index: r = 0.40, P < .0001)
• LV systolic and diastolic dysfunction (global longitudinal strain: r = −0.24, P = .01; E/e′ ratio: r = 0.29, P = .002; and N‐terminal pro‐B‐type natriuretic peptide: r = 0.62, P < .0001)
• right ventricular dysfunction (tricuspid annular plane systolic excursion: r = −0.43, P < .0001)

“Given that FABP4 secretion from adipocytes is profoundly stimulated through lipolysis pathways, the results of our study indicate that serum FABP4 may be a potential biomarker for excessive lipolysis, which may be linked to the specific pathophysiology of HFpEF,” the researchers concluded.

However, obesity prevalence in this study cohort was much lower than that in Western populations. As such, further study is needed to confirm results in Western populations and determine the exact mechanisms of the increase in FABP4 levels.

The study’s small sample size could have also biased results, and the limited number of events did not allow researchers to perform multivariable Cox hazard models. Results should be confirmed in a larger external cohort.

Reference

Harada T, Sunaga H, Sorimachi H, et al. Pathophysiological role of fatty acid-binding protein 4 in Asian patients with heart failure and preserved ejection fraction. ESC Heart Fail. Published online November 2, 2020. doi:10.1002/ehf2.13071