Age- and training-dependent development of arrhythmogenic right ventricular cardiomyopathy in heterozygous plakoglobin-deficient mice.
BACKGROUND
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disorder that causes sudden death and right ventricular heart failure in the young. Clinical data suggest that competitive sports may provoke ARVC in susceptible persons. Genetically, loss-of-function mutations in desmosomal proteins (plakophilin, desmoplakin, or plakoglobin) have been associated with ARVC. To test the hypothesis that reduced desmosomal protein expression causes ARVC, we studied the cardiac effects of heterozygous plakoglobin deficiency in mice.


RESULTS
Ten-month-old heterozygous plakoglobin-deficient mice (plakoglobin+/-) had increased right ventricular volume, reduced right ventricular function, and spontaneous ventricular ectopy (all P<0.05). Left ventricular size and function were not altered. Isolated, perfused plakoglobin+/- hearts had spontaneous ventricular tachycardia of right ventricular origin and prolonged right ventricular conduction times compared with wild-type hearts. Endurance training accelerated the development of right ventricular dysfunction and arrhythmias in plakoglobin+/- mice. Histology and electron microscopy did not identify right ventricular abnormalities in affected animals.


CONCLUSIONS
Heterozygous plakoglobin deficiency provokes ARVC. Manifestation of the phenotype is accelerated by endurance training. This suggests a functional role for plakoglobin and training in the development of ARVC.
Kirchhof
Paulus
P
Department of Cardiology and Angiology, Hospital of the University of Muenster, Germany. kirchhp@uni-muenster.de
Fabritz
Larissa
L
Zwiener
Melanie
M
Witt
Henning
H
Schäfers
Michael
M
Zellerhoff
Stephan
S
Paul
Matthias
M
Athai
Timur
T
Hiller
Karl-Heinz
KH
Baba
Hideo A
HA
Breithardt
Günter
G
Ruiz
Patricia
P
Wichter
Thomas
T
Levkau
Bodo
B
D000375:Aging / Q000502:physiology*; D000818:Animals; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D003896:Desmosomes / Q000473:pathology*; D004195:Disease Models, Animal; D004562:Electrocardiography; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D005947:Glucose / Q000378:metabolism; D006579:Heterozygote; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000235:genetics / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008955:Models, Cardiovascular; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure; D010641:Phenotype; D010805:Physical Conditioning, Animal / Q000009:adverse effects*; D013312:Stress, Physiological / Q000503:physiopathology; D013550:Swimming; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000235:genetics; D018497:Ventricular Dysfunction, Right / Q000209:etiology / Q000235:genetics; D018879:Ventricular Premature Complexes / Q000209:etiology / Q000235:genetics; D051185:gamma Catenin / Q000172:deficiency* / Q000235:genetics
D051185:gamma Catenin; D005947:Glucose