Neuregulin-1 beta is associated with disease severity and adverse outcomes in chronic heart failure

Abstract

Background: Neuregulin-1 (NRG-1) is a paracrine factor released by microvascular endothelial cells that has cardioprotective effects in animal models of heart failure. However, circulating NRG-1 has not been studied in human heart disease. We used a novel immunoassay to test whether circulating NRG-1beta is associated with disease severity and clinical outcomes in chronic heart failure.

Methods and results: Serum NRG-1beta was quantified in 899 outpatients in the Penn Heart Failure Study, a referral cohort representing a broad spectrum of systolic heart failure. Circulating NRG-1beta was significantly elevated in patients with worse disease severity (median, 6.2 ng/mL for New York Heart Association class IV versus 4.4 ng/mL for class I; P=0.002). In adjusted models, NRG-1beta was independently associated with an increased risk of death or cardiac transplantation over a median follow-up of 2.4 years (adjusted hazard ratio, 1.58; 95% confidence interval, 1.04 to 2.39; P=0.03 comparing fourth versus first NRG-1beta quartile). Associations with outcome differed by heart failure cause and symptom severity, with the strongest associations observed in patients with ischemic cardiomyopathy (interaction P=0.008) and New York Heart Association class III/IV symptoms (interaction P=0.01). These findings were all independent of brain natriuretic peptide, and assessment of NRG-1beta and brain natriuretic peptide jointly provided better risk stratification than each biomarker individually in patients with ischemic or New York Heart Association class III/IV heart failure.

Conclusions: Circulating NRG-1beta is independently associated with heart failure severity and risk of death or cardiac transplantation. These findings support a role for NRG-1/ErbB signaling in human heart failure and identify serum NRG-1beta as a novel biomarker that may have clinical applications.

Figure 1

Median NRG-1β according to NYHA class. Bars represent 25^th and 75^th percentiles. ^†p<0.01 for NYHA Class IV compared to I (p=0.01 overall). ^§Numbers in each class displayed in parentheses.

Figure 2

Transplant-free survival by NRG-1β quartiles (4^th versus 1^st). p=0.03 by the log-rank test.

Figure 3

Combined effects of NRG-1β and BNP on transplant-free survival in ischemic heart failure (n=245). p<0.001 by the log-rank test.

Figure 4

Combined Effects of NRG-1β and BNP on transplant-free survival in NYHA III/IV heart failure (n=309). p<0.001 by the log-rank test.