Circulating Angiokines Are Associated With Reverse Remodeling and Outcomes in Chronic Heart Failure

Abstract

Background: We sought to determine whether circulating modifiers of endothelial function are associated with cardiac structure and clinical outcomes in patients with heart failure with reduced ejection fraction (HFrEF).

Methods: We measured 25 proteins related to endothelial function in 99 patients from the GUIDE-IT study. Protein levels were evaluated for association with echocardiographic parameters and the incidence of all-cause death and hospitalization for heart failure (HHF).

Results: Higher concentrations of angiopoietin 2 (ANGPT2), vascular endothelial growth factor receptor 1 (VEGFR1) and hepatocyte growth factor (HGF) were significantly associated with worse function and larger ventricular volumes. Over time, decreases in ANGPT2 and, to a lesser extent, VEGFR1 and HGF, were associated with improvements in cardiac size and function. Individuals with higher concentrations of ANGPT2, VEGFR1 or HGF had increased risks for a composite of death and HHF in the following year (HR 2.76 (95% CI 1.73-4.40) per 2-fold change in ANGPT2; HR 1.76 (95% CI 1.11-2.79) for VEGFR1; and HR 4.04 (95% CI 2.19-7.44) for HGF).

Conclusions: Proteins related to endothelial function associate with cardiac size, cardiac function and clinical outcomes in patients with HFrEF. These results support the concept that endothelial function may be an important contributor to the progression to and the recovery from HFrEF.

Figure 1:. Consort Diagram.

Patients from GUIDE-IT included in this analysis were limited to those with both echo and plasma samples at 0 and 12 months from enrollment.

Figure 2:. Association of Circulating Modulators of Endothelial Function with Echocardiographic Markers of Cardiac Size and Function.

Point estimates and 95% confidence intervals depicting the effect of a 2-fold increase in each protein with echocardiographic parameters. A. Association of each protein with left ventricular ejection fraction (LVEF). B. Association of each protein with global longitudinal strain (GLS). C. Association of each protein with left ventricular end systolic volume index (LVESVi). D. Association of each protein with left ventricular end diastolic volume index (LVEDVi).

Figure 3:. Changes in ANGPT2, VEGFR1, and HGF Concentrations Based on the Presence of Reverse Remodeling Over the Study Period.

Mean biomarker concentrations across the study period are plotted based on the presence (orange line) or absence (blue line) of reverse modeling. Error bars indicate SEM. P values are the results of Wilcoxon rank-sum testing for a difference in change in biomarker concentrations between patients with and without reverse remodeling at time points 0 and 12 months. Panel A: ANGPT2 Panel B: VEGFR1 Panel C: HGF Left Ventricular end systolic volume index (LVESVi).

Figure 4:. Association of ANGPT2, VEGFR1, and HGF Concentrations with a Composite of Death and Hospitalization for Heart Failure.

P value is the result of log-rank testing. Note that this was a landmark analysis, and all patients necessarily survived for the 12 months prior to these events; patients may have been hospitalized during this initial 12 month period).