Author + information
- Received June 7, 2010
- Revision received August 24, 2010
- Accepted September 6, 2010
- Published online February 8, 2011.
- Larissa Fabritz, MD⁎,
- Mark G. Hoogendijk, MD†,
- Brendon P. Scicluna, MSc†,
- Shirley C.M. van Amersfoorth, MSc†,
- Lisa Fortmueller, DVM⁎,
- Susanne Wolf, DVM⁎,
- Sandra Laakmann, DVM⁎,
- Nina Kreienkamp⁎,
- Ilaria Piccini, PhD⁎,
- Günter Breithardt, MD⁎,
- Patricia Ruiz Noppinger, PhD‡,
- Henning Witt, PhD‡,
- Klaus Ebnet, PhD§,
- Thomas Wichter, MD∥,
- Bodo Levkau, MD¶,
- Werner W. Franke, PhD#,
- Sebastian Pieperhoff, PhD#,
- Jacques M.T. de Bakker, PhD†,⁎⁎,
- Ruben Coronel, MD, PhD† and
- Paulus Kirchhof, MD⁎,⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Paulus Kirchhof, Department of Cardiology and Angiology, University Hospital Münster, Albert-Schweitzer-Straβe 33, D-48149 Münster, Germany
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.
This work was supported by IZKF Münster (Core unit CarTel), DFG (Ki 731/1-1, Fa 413 3/1, SFB 656 projects A5 and A8), the Netherlands Heart Foundation Grant 2008B062, and the Fondation Leducq. All authors have reported that they have no relationships to disclose. Drs. Fabritz and Hoogendijk contributed equally to this work.
- Received June 7, 2010.
- Revision received August 24, 2010.
- Accepted September 6, 2010.
- American College of Cardiology Foundation