Load-reducing therapy prevents development of arrhythmogenic right ventricular cardiomyopathy in plakoglobin-deficient mice

J Am Coll Cardiol. 2011 Feb 8;57(6):740-50. doi: 10.1016/j.jacc.2010.09.046.


Objectives: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arrhythmogenic Right Ventricular Dysplasia / etiology
  • Arrhythmogenic Right Ventricular Dysplasia / prevention & control*
  • Cardiac Volume / drug effects*
  • Connexin 43 / metabolism
  • Disease Models, Animal
  • Diuretics / pharmacology
  • Diuretics / therapeutic use*
  • Furosemide / pharmacology
  • Furosemide / therapeutic use*
  • Hypertrophy, Right Ventricular / prevention & control
  • In Vitro Techniques
  • Mice
  • Myocardium / metabolism
  • Nitrates / pharmacology
  • Nitrates / therapeutic use*
  • Phosphorylation
  • Physical Conditioning, Animal / adverse effects
  • Random Allocation
  • Tachycardia, Ventricular / prevention & control
  • Ventricular Pressure / drug effects*
  • gamma Catenin / deficiency
  • gamma Catenin / genetics


  • Connexin 43
  • Diuretics
  • Nitrates
  • gamma Catenin
  • Furosemide