title: Β-adrenergic blockade combined with subcutaneous B-type natriuretic peptide: a promising approach to reduce ventricular arrhythmia in heart failure?
abstract: OBJECTIVE
  Clinical studies failed to prove convincingly efficiency of intravenous infusion of neseritide during heart failure and evidence suggested a pro-adrenergic action of B-type natriuretic peptide (BNP). However, subcutaneous BNP therapy was recently proposed in heart failure, thus raising new perspectives over what was considered as a promising treatment. We tested the efficiency of a combination of oral β1-adrenergic receptor blocker metoprolol and subcutaneous BNP infusion in decompensated heart failure.
  
  
  RESULTS
  The effects of metoprolol or/and BNP were studied on cardiac remodelling, excitation-contraction coupling and arrhythmias in an experimental mouse model of ischaemic heart failure following postmyocardial infarction. We determined the cellular and molecular mechanisms involved in anti-remodelling and antiarrhythmic actions. As major findings, the combination was more effective than metoprolol alone in reversing cardiac remodelling and preventing ventricular arrhythmia. The association of the two molecules improved cardiac function, reduced hypertrophy and fibrosis, and corrected the heart rate, sympatho-vagal balance (low frequencies/high frequencies) and ECG parameters (P to R wave interval (PR), QRS duration, QTc intervals). It also improved altered Ca(2+) cycling by normalising Ca(2+)-handling protein levels (S100A1, SERCA2a, RyR2), and prevented pro-arrhythmogenic Ca(2+) waves derived from abnormal Ca(2+) sparks in ventricular cardiomyocytes. Altogether these effects accounted for decreased occurrence of ventricular arrhythmias.
  
  
  CONCLUSIONS
  Association of subcutaneous BNP and oral metoprolol appeared to be more effective than metoprolol alone. Breaking the deleterious loop linking BNP and sympathetic overdrive in heart failure could unmask the efficiency of BNP against deleterious damages in heart failure and bring a new potential approach against lethal arrhythmia during heart failure.
authors.affiliation: Inserm U1046, Physiologie & Médecine Expérimentale, Cœur et Muscles, Université Montpellier-1 & 2, , Montpellier, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Thireau
authors.forename: Sarah
authors.initials: S
authors.lastname: Karam
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Roberge
authors.forename: Julien
authors.initials: J
authors.lastname: Roussel
authors.forename: Franck
authors.initials: F
authors.lastname: Aimond
authors.forename: Cécile
authors.initials: C
authors.lastname: Cassan
authors.forename: Arnaud
authors.initials: A
authors.lastname: Gac
authors.forename: Dominique
authors.initials: D
authors.lastname: Babuty
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Le Guennec
authors.forename: Alain
authors.initials: A
authors.lastname: Lacampagne
authors.forename: Jérémy
authors.initials: J
authors.lastname: Fauconnier
authors.forename: Sylvain
authors.initials: S
authors.lastname: Richard
mesh_terms: D000284:Administration, Oral; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage*; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004562:Electrocardiography; D006333:Heart Failure / Q000150:complications* / Q000188:drug therapy / Q000503:physiopathology; D007279:Injections, Subcutaneous; D008297:Male; D008790:Metoprolol / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D045283:Natriuretic Agents / Q000008:administration & dosage; D020097:Natriuretic Peptide, Brain / Q000008:administration & dosage*; D017180:Tachycardia, Ventricular / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D016896:Treatment Outcome; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D000319:Adrenergic beta-Antagonists; D045283:Natriuretic Agents; D020097:Natriuretic Peptide, Brain; D008790:Metoprolol
keywords: ARRHYTHMIAS; AUTONOMIC NERVOUS SYSTEM; HEART FAILURE; PHARMACOLOGY