Neuregulin-1β Is Associated with Cardiomyopathy Etiology, Disease Severity, and Adverse Outcomes in Chronic Heart Failure

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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 characterize circulating neuregulin-1β (NRG-1β) levels in chronic human heart failure and test the association with clinical outcomes. Methods: Serum NRG-1β was quantified in 899 outpatients in the Penn Heart Failure Study, a prospective referral cohort representing a broad spectrum of systolic heart failure. Linear regression analyses were used to define the relationships between NRG-1β and clinical factors, and Cox proportional hazard models were used to determine the multivariable associations between NRG-1β and the combined incidence of death or cardiac transplantation. Results: Circulating NRG-1β was significantly elevated in patients with worse disease severity (NYHA Class IV median 6.2 versus 4.4ng/ml for Class I, p=0.002), but decreased in those with chemotherapy-induced dysfunction (median 4.1ng/ml, p=0.02). In adjusted models, NRG-1β was independently associated with an increased risk of death or cardiac transplantation over a median follow-up of 2.4 years (adjusted HR 1.58 [95% CI 1.04-2.39, p=0.03] comparing 4^th versus 1^st NRG-1β quartile). Associations with outcome differed by heart failure etiology and symptom severity, with the strongest associations observed in patients with ischemic cardiomyopathy (interaction p=0.008) and NYHA Class III/IV symptoms (interaction p=0.01). These findings were all independent of BNP, and assessment of NRG-1β and BNP jointly provided better risk stratification than each biomarker individually in patients with ischemic or NYHA Class III/IV heart failure (p<0.001). Conclusions: Circulating NRG-1β is independently associated with cardiomyopathy etiology, 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-1β as a novel biomarker that may have important clinical applications in both common forms of heart failure and chemotherapy-related dysfunction.