title: Cardiomyocyte-specific deletion of survivin causes global cardiac conduction defects.
abstract: Survivin (Surv) belongs to the inhibitor of apoptosis protein family. Its cardiac-specific deletion results in reduced cardiomyocyte number, increased cardiomyocyte size and ploidy, and development of heart failure. Its impact on cardiac electrophysiology is unknown. In vivo transvenous electrophysiological studies were carried out in adult male mice with a cardiac-specific deletion of survivin (Surv(-/-); n = 12) and wild-type controls (Surv(+/+); n = 12). Epicardial activation mapping (EAM) was performed in Langendorff-perfused hearts of 16 Surv(-/-) and 6 Surv(+/+) mice. Surface-ECG showed lower heart rates in Surv(-/-) mice (326 ± 66 bpm vs. 440.6 ± 39 ms; P = 0.0001), accompanied by significantly prolonged P waves (20.3 ± 5.8 vs. 14.6 ± 2.0 ms; P = 0.009), PQ-(47.4 ± 8.6 vs. 41.1 ± 3.7 ms; P = 0.043), QRS- (19.5 ± 4.8 vs. 14.0 ± 1.0 ms; P = 0.002) and QT-intervals (41.6 ± 4.4 vs. 36.2 ± 3.4 ms; P = 0.003). The HV-interval was prolonged in Surv(-/-) mice (12.1 ± 2.4 vs. 9.3 ± 1.4 ms; P = 0.0045). We found impaired sinus-nodal function (sinus node recovery times: 310.2 ± 76.6 vs. 207.8 ± 68.6 ms; P = 0.003) and AV-nodal conduction (Wenckebach-periodicity: 105.9 ± 15.9 vs. 79.6 ± 8.1 ms; P = 0.0002). EAM showed significant slowing and heterogeneity of conduction in the myocardium of Surv(-/-) mice. All Surv(-/-) mice showed spontaneous supraventricular and ventricular ectopic beats (P < 0.0001 vs. wildtype). Quantitative immunofluorescence staining for connexin43 (Cx43) revealed a decrease in both per cardiomyocyte and single gap junction. Surv(-/-) mice exhibit severe global conduction attenuations in atrial and ventricular myocardium as well as the specific conduction system, accompanied by lower connexin43 levels. Lack of susceptibility to AF and VT suggests that reduced cardiomyocyte number and increased size constitute determinants of electrical stableness in the heart and counteract potentially proarrhythmogenic connexin43 loss in Surv(-/-).
authors.affiliation: Department of Medicine-Cardiology, University of Bonn, Germany. jan.schrickel@ukb.uni-bonn.de
authors.forename: Jan Wilko
authors.initials: JW
authors.lastname: Schrickel
authors.forename: Lars
authors.initials: L
authors.lastname: Lickfett
authors.forename: Thorsten
authors.initials: T
authors.lastname: Lewalter
authors.forename: Klaus
authors.initials: K
authors.lastname: Tiemann
authors.forename: Georg
authors.initials: G
authors.lastname: Nickenig
authors.forename: Hideo
authors.initials: H
authors.lastname: Baba
authors.forename: Gerd
authors.initials: G
authors.lastname: Heusch
authors.forename: Rainer
authors.initials: R
authors.lastname: Schulz
authors.forename: Bodo
authors.initials: B
authors.lastname: Levkau
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism*; D001699:Biometry; D053840:Brugada Syndrome; D000075224:Cardiac Conduction System Disease; D018031:Connexin 43 / Q000378:metabolism*; D004562:Electrocardiography; D056149:Epicardial Mapping; D017629:Gap Junctions / Q000378:metabolism; D006329:Heart Conduction System / Q000002:abnormalities / Q000378:metabolism; D066298:In Vitro Techniques; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000378:metabolism; D012032:Refractory Period, Electrophysiological; D012097:Repressor Proteins / Q000378:metabolism*; D000077022:Survivin; D018879:Ventricular Premature Complexes / Q000209:etiology*
chemical_list: C117749:Birc5 protein, mouse; D018031:Connexin 43; C543076:GJA1 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D012097:Repressor Proteins; D000077022:Survivin; D018995:Myosin Heavy Chains