Neuregulin-1β 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-1␤ is associated with disease severity and clinical outcomes in chronic heart failure. Methods and Results-Serum NRG-1␤ was quantified in 899 outpatients in the Penn Heart Failure Study, a referral cohort representing a broad spectrum of systolic heart failure. Circulating NRG-1␤ 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; Pϭ0.002). In adjusted models, NRG-1␤ 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; Pϭ0.03 comparing fourth versus first NRG-1␤ quartile). Associations with outcome differed by heart failure cause and symptom severity, with the strongest associations observed in patients with ischemic cardiomyopathy (interaction Pϭ0.008) and New York Heart Association class III/IV symptoms (interaction Pϭ0.01). These findings were all independent of brain natriuretic peptide, and assessment of NRG-1␤ 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-1␤ 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-1␤ as a novel biomarker that may have clinical applications. (Circulation. 2009;120:310-317.)

Loss-of-function DNA sequence variant in the CLCNKA chloride channel implicates the cardio-renal axis in interindividual heart failure risk variation

“…To validate the association between rs10927887 and heart failure, we resequenced CLCNKA exon 3 in an independent cohort of 857 Caucasian heart failure cases and 311 unaffected Caucasian controls from the Penn Heart Failure Study (20). Again, rs10927887 was overrepresented in heart failure (≈0.56 vs. ≈0.48 in controls; P = 4.4 × 10 −4…”

“…dinal studies of heart failure genomics (P50 HL77101 and R01 HL88577) from patients presenting to the heart failure referral program at the University of Cincinnati (16,19) or the University of Pennsylvania (20), according to prespecified criteria. The same infrastructure was used to recruit nonaffected controls.…”

Troponin I and C-Reactive Protein Are Commonly Detected in Patients with Breast Cancer Treated with Dose-Dense Chemotherapy Incorporating Trastuzumab and Lapatinib

“…Brain natriuretic peptide (BNP) has been extensively tested as a prognostic marker of CHF and has been examined for chemotherapy-related cardiotoxicity along with other biomarkers such as glycogen phosphorylase BB and heart-type fatty acid-binding protein (24,37,38). The epidermal growth factor neuregulin-1 (NRG-1) plays a critical role in the growth and survival of cardiac myocytes and is of particular interest since NRG-1 is a target of T (38). In CHF, NRG-1 correlates with disease severity and risk of death independently of BNP, although the combination of NRG-1 and BNP provides better risk stratification than either biomarker individually (38).…”

“…The epidermal growth factor neuregulin-1 (NRG-1) plays a critical role in the growth and survival of cardiac myocytes and is of particular interest since NRG-1 is a target of T (38). In CHF, NRG-1 correlates with disease severity and risk of death independently of BNP, although the combination of NRG-1 and BNP provides better risk stratification than either biomarker individually (38). This study adds weight to the argument that a single biomarker (such as cTnI) should not be used in isolation to stratify risk of cardiotoxicity and guide preventative strategies (such as ACE inhibitor use).…”

The Vulnerability of the Heart As a Pluricellular Paracrine Organ

“…60 In chronic heart failure of ischemic but not of nonischemic etiology, circulating NRG-1 levels are increased. 61 This suggests that ischemia may also be an important trigger for endothelial NRG-1 synthesis and release.…”