title: Functional evidence for an active role of B-type natriuretic peptide in cardiac remodelling and pro-arrhythmogenicity.
abstract: OBJECTIVE
  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).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: INSERM U1046, Physiologie and Médecine Expérimentale du Cœur et des Muscles, Université Montpellier-1, Université Montpellier-2, CHU Arnaud de Villeneuve, 371 Rue du doyen G. Giraud, Montpellier, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Thireau
authors.forename: Sarah
authors.initials: S
authors.lastname: Karam
authors.forename: Jérémy
authors.initials: J
authors.lastname: Fauconnier
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Roberge
authors.forename: Cécile
authors.initials: C
authors.lastname: Cassan
authors.forename: Olivier
authors.initials: O
authors.lastname: Cazorla
authors.forename: Franck
authors.initials: F
authors.lastname: Aimond
authors.forename: Alain
authors.initials: A
authors.lastname: Lacampagne
authors.forename: Dominique
authors.initials: D
authors.lastname: Babuty
authors.forename: Sylvain
authors.initials: S
authors.lastname: Richard
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology*; D002118:Calcium / Q000378:metabolism; D004562:Electrocardiography; D006333:Heart Failure / Q000209:etiology; D008297:Male; D008790:Metoprolol / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D020097:Natriuretic Peptide, Brain / Q000097:blood / Q000502:physiology*; D018342:Receptors, Adrenergic, beta-1 / Q000502:physiology; D009418:S100 Proteins / Q000502:physiology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000502:physiology; D013564:Sympathetic Nervous System / Q000502:physiology; D014630:Vagus Nerve / Q000502:physiology; D020257:Ventricular Remodeling
chemical_list: D018342:Receptors, Adrenergic, beta-1; D009418:S100 Proteins; C110294:S100A1 protein; D020097:Natriuretic Peptide, Brain; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D008790:Metoprolol; D002118:Calcium