title: Exercise training improves cardiac function and attenuates arrhythmia in CPVT mice.
abstract: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal ventricular arrhythmia evoked by physical or emotional stress. Recessively inherited CPVT is caused by either missense or null-allele mutations in the cardiac calsequestrin (CASQ2) gene. It was suggested that defects in CASQ2 cause protein deficiency and impair Ca(2+) uptake to the sarcoplasmic reticulum and Ca(2+)-dependent inhibition of ryanodine channels, leading to diastolic Ca(2+) leak, after-depolarizations, and arrhythmia. To examine the effect of exercise training on left ventricular remodeling and arrhythmia, CASQ2 knockout (KO) mice and wild-type controls underwent echocardiography and heart rhythm telemetry before and after 6 wk of training by treadmill exercise. qRT-PCR and Western blotting were used to measure gene and protein expression. Left ventricular fractional shortening was impaired in KO (33 ± 5 vs. 51 ± 7% in controls, P < 0.05) and improved after training (43 ± 12 and 51 ± 9% in KO and control mice, respectively, P = nonsignificant). The exercise tolerance was low in KO mice (16 ± 1 vs. 29 ± 2 min in controls, P < 0.01), but improved in trained animals (26 ± 2 vs. 30 ± 3 min, P = nonsignificant). The hearts of KO mice had a higher basal expression of the brain natriuretic peptide gene. After training, the expression of natriuretic peptide genes markedly decreased, with no difference between KO and controls. Exercise training was not associated with a change in ventricular tachycardia prevalence, but appeared to reduce arrhythmia load, as manifested by a decrease in ventricular beats during stress. We conclude that, in KO mice, which recapitulate the phenotype of human CPVT2, exercise training is well tolerated and could offer a strategy for heart conditioning against stress-induced arrhythmia.
authors.affiliation: Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Efrat
authors.initials: E
authors.lastname: Kurtzwald-Josefson
authors.forename: Edith
authors.initials: E
authors.lastname: Hochhauser
authors.forename: Guy
authors.initials: G
authors.lastname: Katz
authors.forename: Eyal
authors.initials: E
authors.lastname: Porat
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Seidman
authors.forename: Christine E
authors.initials: CE
authors.lastname: Seidman
authors.forename: Yelena
authors.initials: Y
authors.lastname: Chepurko
authors.forename: Asher
authors.initials: A
authors.lastname: Shainberg
authors.forename: Michael
authors.initials: M
authors.lastname: Eldar
authors.forename: Michael
authors.initials: M
authors.lastname: Arad
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002155:Calsequestrin / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D005081:Exercise Therapy; D017079:Exercise Tolerance; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020127:Recovery of Function; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017180:Tachycardia, Ventricular / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D013997:Time Factors; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: D002155:Calsequestrin; D012333:RNA, Messenger; C514388:casq2 protein, mouse; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor