Functional evidence for an active role of B-type natriuretic peptide in cardiac remodelling and pro-arrhythmogenicity

• DOI: 10.1093/cvr/cvs167
• Publication Date: 2012-05-23T01:03:02Z
• Authors: Jérôme Thireau; Sarah Karam; Jérémy Fauconnier; Stéphanie Roberge; Cécile Cassan; Olivier Cazorla; Franck Aimond; Alain Lacampagne; Dominique Babuty; Sylvain Richard
• Keywords: Heart Failure; Male; Sympathetic Nervous System; Ventricular Remodeling; S100 Proteins; Arrhythmias, Cardiac; Vagus Nerve; [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system; Sarcoplasmic Reticulum Calcium-Transporting ATPases; 3. Good health; Mice, Inbred C57BL; Electrocardiography; Mice; 03 medical and health sciences; 0302 clinical medicine; [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system; [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie; Natriuretic Peptide, Brain; Animals; [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie; Calcium; Receptors, Adrenergic, beta-1; Metoprolol

During heart failure (HF), the left ventricle (LV) releases B-type natriuretic peptide (BNP), possibly contributing to adverse cardiovascular events including ventricular arrhythmias (VAs) and LV remodelling. We investigated the cardiac effects of chronic BNP elevation in healthy mice and compared the results with a model of HF after myocardial infarction (PMI mice).Healthy mice were exposed to circulating BNP levels (BNP-Sham) similar to those measured in PMI mice. Telemetric surface electrocardiograms showed that in contrast with fibrotic PMI mice, electrical conduction was not affected in BNP-Sham mice. VAs were observed in both BNP-Sham and PMI but not in Sham mice. Analysis of heart rate variability indicated that chronic BNP infusion increased cardiac sympathetic tone. At the cellular level, BNP reduced Ca(2+) transients and impaired Ca(2+) reuptake in the sarcoplasmic reticulum, in line with blunted SR Ca(2+) ATPase 2a and S100A1 expression. BNP increased Ca(2+) spark frequency, reflecting Ca(2+) leak through ryanodine receptors, elevated diastolic Ca(2+), and promoted spontaneous Ca(2+) waves. Similar effects were observed in PMI mice. Most of these effects were reduced in BNP-Sham and PMI mice by the selective β1-adrenergic blocker metoprolol.Elevated BNP levels, by inducing sympathetic overdrive and altering Ca(2+) handling, promote adverse cardiac remodelling and VAs, which could account in part for the progression of HF after MI. The early use of β-blockers to prevent the deleterious effects of chronic BNP exposure may be beneficial in HF.