Circulation Research. 2004
Published online before print September 2, 2004, doi: 10.1161/01.RES.0000144125.61927.1c
Published online before print September 2, 2004, doi: 10.1161/01.RES.0000144125.61927.1c
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Submitted on February 23, 2004
Revised on August 25, 2004
Accepted on August 26, 2004
Mechanisms Underlying Conduction Slowing and Arrhythmogenesis in Nonischemic Dilated Cardiomyopathy
Fadi G. Akar ;
From the Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Md.
* To whom correspondence should be addressed. E-mail: gtomasel{at}jhmi.edu.
Heart Failure (HF) is associated with an increased risk of sudden death caused by ventricular tachyarrhythmias. Recent studies have implicated repolarization abnormalities and, in particular, exaggerated heterogeneity of transmural repolarization in the genesis of polymorphic ventricular tachycardia in a canine model of nonischemic dilated cardiomyopathy. The presence and degree to which conduction abnormalities play a role in arrhythmogenesis in this model are uncertain. HF was produced in dogs by rapid RV-pacing for 3 to 4 weeks. High-resolution optical action potentials were recorded from epicardial and endocardial surfaces of arterially perfused canine wedge preparations isolated from LV and RV of normal and failing dogs. Cellular and molecular determinants of conduction were investigated using patch-clamp recordings, Western blot analysis, and immunocytochemistry. HF was associated with marked prolongation (by 33%) of the QRS duration of the volume conducted electrocardiogram and significant (>20%) slowing of epicardial and endocardial conduction velocities (CV) in both LV and RV. Cx43 expression was reduced by >40% in epicardial and endocardial layers of the LV, but was unchanged in the RV of failing hearts. Despite greater epicardial than endocardial Cx43 expression, epicardial CV was consistently slower (P<0.01). Immunocytochemical analysis revealed predominant colocalization of Cx43 with N-cadherin in normal versus failing samples, because Cx43 was redistributed from the intercalated disk to lateral cell borders in failing tissue. Moreover, a significant (P<0.05) increase in hypophosphorylated Cx43 was detected in the LV and RV of failing hearts. Action potential upstroke velocities in isolated ventricular myocytes from normal and failing hearts were not different (P=0.8, not significant), and Masson trichrome staining revealed no significant change in fibrosis content in HF. Nonischemic dilated cardiomyopathy is associated with significant slowing of CV that was not directly related to reduced Cx43 expression. Changes in phosphorylation and localization of Cx43 may contribute to gap-junction dysfunction, CV slowing, and arrhythmias in HF.
Key words: heart failure • arrhythmias • optical mapping • connexin • gap junctions
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|
|
|
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|
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|
|
|
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|
|
|
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