Universität zu Köln

Stoeckigt, Florian, Peche, Vivek Shahaji, Linharti, Markus, Nickenig, Georg, Noegel, Angelika Anna and Schrickel, Jan Wilko (2016). Deficiency of cyclase-associated protein 2 promotes arrhythmias associated with connexin43 maldistribution and fibrosis. Arch. Med. Sci., 12 (1). S. 188 - 199. POZNAN: TERMEDIA PUBLISHING HOUSE LTD. ISSN 1896-9151

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Abstract

Introduction: Cyclase-associated protein 2 (CAP2) plays a major role in regulating the actin cytoskeleton. Since inactivation of CAP2 in a mouse model by a gene trap approach (Cap2(gt/gt)) results in cardiomyopathy and increased mortality, we hypothesized that CAP2 has a major impact on arrhythmias and electrophysiological parameters. Material and methods: We performed long-term-ECG recordings in transgenic CAP2 deficient mice (C57BL/6) to detect spontaneous arrhythmias. In vivo electrophysiological studies by right heart catheterization and ex vivo epicardial mapping were used to analyze electrophysiological parameters, the inducibility of arrhythmias, and conduction velocities. Expression and distribution of cardiac connexins and the amount of cardiac fibrosis were evaluated. Results: Spontaneous ventricular arrhythmias could be detected in Cap2(gt/gt) during the long-term-ECG recording. Cap2(gt/gt) showed marked conduction delays at atrial and ventricular levels, including a reduced heart rate (421.0 +/- 40.6 bpm vs. 450.8 +/- 27.9 bpm; p < 0.01), and prolongations of PQ (46.3 +/- 4.1 ms vs. 38.6 +/- 6.5 ms; p < 0.01), QRS (16.2 +/- 2.6 ms vs. 12.6 +/- 1.4 ms; p < 0.01), and QTc interval (55.8 +/- 6.0 ms vs. 45.2 +/- 3.3 ms; p = 0.02) in comparison to wild type mice. The PQ prolongation was due to an infra-Hisian conduction delay (HV: 9.7 +/- 2.1 ms vs. 6.5 +/- 3.1 ms; p = 0.02). The inducibility of ventricular tachycardias during the electrophysiological studies was significantly elevated in the mutant mice (inducible animals: 88% vs. 33%; p = 0.04). Cap2(gt/gt) showed more abnormal distribution of connexin43 compared to WT (23.0 +/- 4.7% vs. 2.9 +/- 0.8%; p < 0.01). Myocardial fibrosis was elevated in Cap2(gt/gt) hearts (9.1 +/- 6.7% vs. 5.5 +/- 3.3%; p < 0.01). Conclusions: Loss of CAP2 results in marked electrophysiological disturbances including impaired sinus node function, conduction delays, and susceptibility to malignant arrhythmias. Structural changes in Cap2(gt/gt) are associated with alterations in myocardial connexins and fibrosis.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Stoeckigt, Florian UNSPECIFIED UNSPECIFIED UNSPECIFIED Peche, Vivek Shahaji UNSPECIFIED UNSPECIFIED UNSPECIFIED Linharti, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Nickenig, Georg UNSPECIFIED UNSPECIFIED UNSPECIFIED Noegel, Angelika Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Schrickel, Jan Wilko UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-285568
DOI:	10.5114/aoms.2015.54146
Journal or Publication Title:	Arch. Med. Sci.
Volume:	12
Number:	1
Page Range:	S. 188 - 199
Date:	2016
Publisher:	TERMEDIA PUBLISHING HOUSE LTD
Place of Publication:	POZNAN
ISSN:	1896-9151
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NONISCHEMIC DILATED CARDIOMYOPATHY; CONDUCTION; DEATH; CELLS; MICE; CYTOSKELETON; MECHANISMS; LOCALIZES; HOMOLOG; HEART Multiple languages Medicine, General & Internal Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/28556