Insulin-Like Growth Factor-Binding Protein-7 as a Biomarker of Diastolic Dysfunction and Functional Capacity in Heart Failure With Preserved Ejection Fraction: Results From the RELAX Trial

Abstract

Objectives: This study sought to investigate relationships between insulin-like growth factor-binding protein-7 (IGFBP7) and parameters of diastolic function or functional capacity in patients with heart failure and preserved ejection fraction (HFpEF) who were randomized to receive sildenafil or placebo.

Background: IGFBP7 was previously found to be associated with diastolic function in heart failure with reduced ejection fraction, but it is unclear whether these associations are present in HFpEF.

Methods: At baseline and 24 weeks, IGFBP7, imaging studies, and peak oxygen consumption (Vo_2max) were obtained and compared in 160 patients with HFpEF who were randomized to receive sildenafil or placebo.

Results: Patients with supramedian baseline IGFBP7 concentrations were older, had signs of systemic congestion and worse renal function, and had higher concentrations of prognostic heart failure biomarkers including amino-terminal pro-B-type natriuretic peptide (p < 0.05). Higher baseline IGFBP7 was modestly correlated with worse diastolic function: higher E velocity (Spearman correlation [ρ] = 0.40), E/E' (ρ = 0.40), left atrial volume index (ρ = 0.39), and estimated right ventricular systolic pressure (ρ = 0.41; all p < 0.001) and weakly correlated with transmitral E/A (ρ = 0.26; p = 0.006). Notably, change in IGFBP7 was significantly correlated with change in E, E/A, E/E', and right ventricular systolic pressure. Elevated baseline IGFBP7 was associated with lower baseline Vo_2max (13.2 vs. 11.1 ml/min/kg; p < 0.001), and change in IGFBP7 was weakly inversely correlated with change in Vo_2max (ρ = -0.19; p = 0.01). Subjects receiving sildenafil had a decrease in IGFBP7 over 24 weeks, in contrast to placebo-treated patients (median change in IGFBP7 -1.5 vs. +13.6 ng/ml; p < 0.001).

Conclusions: In patients with HFpEF, IGFBP7 may be a novel biomarker of diastolic function and exercise capacity.

Keywords: biomarkers; diastolic function; heart failure with preserved ejection fraction; insulin-like growth factor–binding protein 7.

Figure 1. Correlation between baseline IGFBP7 and baseline parameters of diastolic dysfunction

There were significant correlations between IGFBP7 and E/A, E/E’, left ventricular (LV) mass index, E’, left atrial (LA) volume index, and estimated right ventricular systolic pressure (RVSP).

Figure 2. Correlation between ΔIGFBP7 and ΔVO2max over 24 weeks

There was a significant inverse correlation over the study period. The P value comes from a linear regression model that adjusts for baseline IGFBP7 and VO_2max.