title: Load-reducing therapy prevents development of arrhythmogenic right ventricular cardiomyopathy in plakoglobin-deficient mice.
abstract: OBJECTIVE
  We used a murine model of arrhythmogenic right ventricular cardiomyopathy (ARVC) to test whether reducing ventricular load prevents or slows development of this cardiomyopathy.
  
  
  BACKGROUND
  At present, no therapy exists to slow progression of ARVC. Genetically conferred dysfunction of the mechanical cell-cell connections, often associated with reduced expression of plakoglobin, is thought to cause ARVC.
  
  
  METHODS
  Littermate pairs of heterozygous plakoglobin-deficient mice (plako(+/-)) and wild-type (WT) littermates underwent 7 weeks of endurance training (daily swimming). Mice were randomized to blinded load-reducing therapy (furosemide and nitrates) or placebo.
  
  
  RESULTS
  Therapy prevented training-induced right ventricular (RV) enlargement in plako(+/-) mice (RV volume: untreated plako(+/-) 136 ± 5 μl; treated plako(+/-) 78 ± 5 μl; WT 81 ± 5 μl; p < 0.01 for untreated vs. WT and untreated vs. treated; mean ± SEM). In isolated, Langendorff-perfused hearts, ventricular tachycardias (VTs) were more often induced in untreated plako(+/-) hearts (15 of 25), than in treated plako(+/-) hearts (5 of 19) or in WT hearts (6 of 21, both p < 0.05). Epicardial mapping of the RV identified macro-re-entry as the mechanism of ventricular tachycardia. The RV longitudinal conduction velocity was reduced in untreated but not in treated plako(+/-) mice (p < 0.01 for untreated vs. WT and untreated vs. treated). Myocardial concentration of phosphorylated connexin43 was lower in plako(+/-) hearts with VTs compared with hearts without VTs and was reduced in untreated plako(+/-) compared with WT (both p < 0.05). Plako(+/-) hearts showed reduced myocardial plakoglobin concentration, whereas β-catenin and N-cadherin concentration was not changed.
  
  
  CONCLUSIONS
  Load-reducing therapy prevents training-induced development of ARVC in plako(+/-) mice.
authors.affiliation: Department of Cardiology and Angiology, Hospital of the University of Muenster, Germany.
authors.forename: Larissa
authors.initials: L
authors.lastname: Fabritz
authors.forename: Mark G
authors.initials: MG
authors.lastname: Hoogendijk
authors.forename: Brendon P
authors.initials: BP
authors.lastname: Scicluna
authors.forename: Shirley C M
authors.initials: SC
authors.lastname: van Amersfoorth
authors.forename: Lisa
authors.initials: L
authors.lastname: Fortmueller
authors.forename: Susanne
authors.initials: S
authors.lastname: Wolf
authors.forename: Sandra
authors.initials: S
authors.lastname: Laakmann
authors.forename: Nina
authors.initials: N
authors.lastname: Kreienkamp
authors.forename: Ilaria
authors.initials: I
authors.lastname: Piccini
authors.forename: Günter
authors.initials: G
authors.lastname: Breithardt
authors.forename: Patricia Ruiz
authors.initials: PR
authors.lastname: Noppinger
authors.forename: Henning
authors.initials: H
authors.lastname: Witt
authors.forename: Klaus
authors.initials: K
authors.lastname: Ebnet
authors.forename: Thomas
authors.initials: T
authors.lastname: Wichter
authors.forename: Bodo
authors.initials: B
authors.lastname: Levkau
authors.forename: Werner W
authors.initials: WW
authors.lastname: Franke
authors.forename: Sebastian
authors.initials: S
authors.lastname: Pieperhoff
authors.forename: Jacques M T
authors.initials: JM
authors.lastname: de Bakker
authors.forename: Ruben
authors.initials: R
authors.lastname: Coronel
authors.forename: Paulus
authors.initials: P
authors.lastname: Kirchhof
mesh_terms: D000818:Animals; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000209:etiology / Q000517:prevention & control*; D002306:Cardiac Volume / Q000187:drug effects*; D018031:Connexin 43 / Q000378:metabolism; D004195:Disease Models, Animal; D004232:Diuretics / Q000494:pharmacology / Q000627:therapeutic use*; D005665:Furosemide / Q000494:pharmacology / Q000627:therapeutic use*; D017380:Hypertrophy, Right Ventricular / Q000517:prevention & control; D066298:In Vitro Techniques; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D009566:Nitrates / Q000494:pharmacology / Q000627:therapeutic use*; D010766:Phosphorylation; D010805:Physical Conditioning, Animal / Q000009:adverse effects; D011897:Random Allocation; D017180:Tachycardia, Ventricular / Q000517:prevention & control; D017725:Ventricular Pressure / Q000187:drug effects*; D051185:gamma Catenin / Q000172:deficiency / Q000235:genetics
chemical_list: D018031:Connexin 43; D004232:Diuretics; D009566:Nitrates; D051185:gamma Catenin; D005665:Furosemide