Heterogeneous Connexin43 distribution in heart failure is associated with dispersed conduction and enhanced susceptibility to ventricular arrhythmias.
OBJECTIVE
Sudden arrhythmogenic cardiac death is a major cause of mortality in patients with congestive heart failure (CHF). To investigate determinants of the increased arrhythmogenic susceptibility, we studied cardiac remodelling and arrhythmogenicity in CHF patients and in a mouse model of chronic pressure overload.


RESULTS
Clinical and (immuno)histological data of myocardial biopsies from CHF patients with (VT+) and without (VT-) documented ventricular arrhythmia were compared with controls. In CHF patients, ejection fraction was decreased and QRS duration was increased. Cell size and interstitial fibrosis were increased, but Connexin43 (Cx43) levels, the most abundant gap junction in ventricular myocardium, were unchanged. No differences were found between VT+ and VT- patients, except for the distribution pattern of Cx43, which was significantly more heterogeneous in VT+. Mice were subjected to transverse aortic constriction (TAC) or sham operated. At 16 weeks, cardiac function was determined by echocardiography and epicardial ventricular activation mapping was performed. Transverse aortic constriction mice had decreased fractional shortening and prolonged QRS duration. Right ventricular conduction velocity was reduced, and polymorphic VTs were induced in 44% TAC and 0% sham mice. Interstitial fibrosis was increased and Cx43 quantity was unchanged in TAC mice with and without arrhythmias. Similar to CHF patients, heterogeneous Cx43 distribution was significantly associated with arrhythmias in TAC mice and with spatial heterogeneity of impulse conduction.


CONCLUSIONS
Heterogeneous Cx43 expression during CHF is associated with dispersed impulse conduction and may underlie enhanced susceptibility to ventricular tachyarrhythmias.
Interuniversity Cardiology Institute of The Netherlands, Utrecht, The Netherlands.
Mohamed
M
Boulaksil
Stephan K G
SK
Winckels
Markus A
MA
Engelen
Mèra
M
Stein
Toon A B
TA
van Veen
John A
JA
Jansen
André C
AC
Linnenbank
Marti F A
MF
Bierhuizen
W Antoinette
WA
Groenewegen
Matthijs F M
MF
van Oosterhout
Johannes H
JH
Kirkels
Nicolaas
N
de Jonge
András
A
Varró
Marc A
MA
Vos
Jacques M T
JM
de Bakker
Harold V M
HV
van Rijen
D000818:Animals; D001706:Biopsy; D018031:Connexin 43 / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D004452:Echocardiography; D004562:Electrocardiography; D005260:Female; D006333:Heart Failure / Q000175:diagnosis / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D017180:Tachycardia, Ventricular / Q000175:diagnosis / Q000378:metabolism* / Q000503:physiopathology
D018031:Connexin 43