Load-Reducing Therapy Prevents Development of Arrhythmogenic Right Ventricular Cardiomyopathy in Plakoglobin-Deficient Mice

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

卷:57

Article

Fabritz, Larissa¹  Hoogendijk, Mark G.²  Scicluna, Brendon P.²  van Amersfoorth, Shirley C. M.²  Fortmueller, Lisa¹  Wolf, Susanne¹  Laakmann, Sandra¹  Kreienkamp, Nina¹  Piccini, Ilaria¹  Breithardt, Guenter¹  Noppinger, Patricia Ruiz³  Witt, Henning³  Ebnet, Klaus⁴  Wichter, Thomas⁵  Levkau, Bodo⁶  Franke, Werner W.⁷  Pieperhoff, Sebastian⁷  de Bakker, Jacques M. T.^2,8  Coronel, Ruben²  Kirchhof, Paulus¹ 

[1] Univ Hosp Munster, Dept Cardiol & Angiol, D-48149 Munster, Germany

[2] Univ Amsterdam, Acad Med Ctr, Heart Failure Res Ctr, NL-1105 AZ Amsterdam, Netherlands

[3] Charite, Ctr Cardiovasc Res, Berlin, Germany

[4] WWU Muenster, Inst Med Biochem, Cell Adhes & Cell Polar Grp, ZMBE, Munster, Germany

[5] Klin Herzzentrum Osnabruck Bad Rothenfelde, Marienhosp Osnabruck, Osnabruck, Germany

[6] Univ Duisburg Essen, Univ Hosp Essen, Inst Pathophysiol, Essen, Germany

[7] German Canc Res Ctr, Helmholtz Grp Cell Biol, D-6900 Heidelberg, Germany

[8] Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands

关键词: arrhythmogenic right ventricular cardiomyopathy;    plakoglobin;    pre-load reduction;    transgenic mice;   

DOI  :  10.1016/j.jacc.2010.09.046

来源: Elsevier

【 摘 要 】

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 mu l; treated plako(+/-) 78 +/- 5 mu l; WT 81 +/- 5 mu l; 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 beta-catenin and N-cadherin concentration was not changed. Conclusions Load-reducing therapy prevents training-induced development of ARVC in plako(+/-) mice. (J Am Coll Cardiol 2011;57:740-50) (C) 2011 by the American College of Cardiology Foundation

【 授权许可】

Free