title: SERCA2a gene transfer decreases sarcoplasmic reticulum calcium leak and reduces ventricular arrhythmias in a model of chronic heart failure.
abstract: BACKGROUND
  Sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) gene therapy improves mechanical function in heart failure and is under evaluation in a clinical trial. A critical question is whether SERCA2a gene therapy predisposes to increased sarcoplasmic reticulum calcium (SR Ca(2+)) leak, cellular triggered activity, and ventricular arrhythmias in the failing heart.
  
  
  RESULTS
  We studied the influence of SERCA2a gene therapy on ventricular arrhythmogenesis in a rat chronic heart failure model. ECG telemetry studies revealed a significant antiarrhythmic effect of SERCA2a gene therapy with reduction of both spontaneous and catecholamine-induced arrhythmias in vivo. SERCA2a gene therapy also reduced susceptibility to reentry arrhythmias in ex vivo programmed electrical stimulation studies. Subcellular Ca(2+) homeostasis and spontaneous SR Ca(2+) leak characteristics were measured in failing cardiomyocytes transfected in vivo with a novel AAV9.SERCA2a vector. SR Ca(2+) leak was reduced after SERCA2a gene therapy, with reversal of the greater spark mass observed in the failing myocytes, despite normalization of SR Ca(2+) load. SERCA2a reduced ryanodine receptor phosphorylation, thereby resetting SR Ca(2+) leak threshold, leading to reduced triggered activity in vitro. Both indirect effects of reverse remodeling and direct SERCA2a effects appear to underlie the antiarrhythmic action.
  
  
  CONCLUSIONS
  SERCA2a gene therapy stabilizes SR Ca(2+) load, reduces ryanodine receptor phosphorylation and decreases SR Ca(2+) leak, and reduces cellular triggered activity in vitro and spontaneous and catecholamine-induced ventricular arrhythmias in vivo in failing hearts. SERCA2a gene therapy did not therefore predispose to arrhythmias and may represent a novel antiarrhythmic strategy in heart failure.
authors.affiliation: National Heart and Lung Institute, Imperial College, London, United Kingdom. a.lyon@ic.ac.uk
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Lyon
authors.forename: Mark L
authors.initials: ML
authors.lastname: Bannister
authors.forename: Tom
authors.initials: T
authors.lastname: Collins
authors.forename: Emma
authors.initials: E
authors.lastname: Pearce
authors.forename: Amir H
authors.initials: AH
authors.lastname: Sepehripour
authors.forename: Sukhpreet S
authors.initials: SS
authors.lastname: Dubb
authors.forename: Edwin
authors.initials: E
authors.lastname: Garcia
authors.forename: Peter
authors.initials: P
authors.lastname: O'Gara
authors.forename: Lifan
authors.initials: L
authors.lastname: Liang
authors.forename: Erik
authors.initials: E
authors.lastname: Kohlbrenner
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Peters
authors.forename: Philip A
authors.initials: PA
authors.lastname: Poole-Wilson
authors.forename: Ken T
authors.initials: KT
authors.lastname: Macleod
authors.forename: Sian E
authors.initials: SE
authors.lastname: Harding
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D015316:Genetic Therapy / Q000379:methods*; D006333:Heart Failure / Q000150:complications / Q000235:genetics / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000627:therapeutic use*; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000235:genetics / Q000628:therapy*; D016896:Treatment Outcome; D016277:Ventricular Function, Left / Q000502:physiology
chemical_list: D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium