Altering ventricular activation remodels gap junction distribution in canine heart.
BACKGROUND
Prolonged arrhythmic or paced ventricular activation causes persistent changes in myocardial conduction and repolarization that may result from altered electrotonic current flow, for which gap junctional coupling is the principal determinant. Remodeling of gap junctions and their constituent connexins modifies conduction and has been causally implicated in reentrant arrhythmogenesis. We hypothesized conversely that altering the pattern of ventricular activation causes gap junctional remodeling.


RESULTS
Seven dogs were paced from the left ventricular (LV) epicardium (VVO, approximately 120 beats/min) for 21 days before excision of transmural LV samples that were divided into endomyocardial, mid-myocardial, and epimyocardial layers. Another five paced dogs had recording electrodes attached to multiple LV sites. All 12 dogs developed characteristic pacing-induced persistent T wave changes of cardiac memory. After 21 days of pacing, the ventricularly paced QRS duration prolonged by a mean of 4 msec over baseline (P < 0.05), a change that was associated with significant slowing of intraventricular conduction to local sites. These changes in QRS duration and repolarization were associated with a reduction in epimyocardial connexin43 expression on quantitative Western blotting of LV myocardium from close to, but not distant from, the pacing site (61.7+/-18.4 vs 100.9+/-34.0; P < 0.02) and a marked disruption in immunolabeled connexin43 distribution in epimyocardium only.


CONCLUSIONS
Spatially distinct transmural and regional gap junctional remodeling is a consequence of abnormal ventricular activation and is associated with consistent changes in activation that may alter patterns of repolarization and facilitate reentrant arrhythmogenesis.
Patel
P M
PM
Imperial College School of Medicine at St. Mary's Hospital, London, United Kingdom.
Plotnikov
A
A
Kanagaratnam
P
P
Shvilkin
A
A
Sheehan
C T
CT
Xiong
W
W
Danilo
P
P
Rosen
M R
MR
Peters
N S
NS
D000201:Activation Analysis; D000818:Animals; D015153:Blotting, Western; D018031:Connexin 43 / Q000032:analysis; D004285:Dogs; D004562:Electrocardiography; D004594:Electrophysiology; D005260:Female; D017629:Gap Junctions / Q000502:physiology*; D006321:Heart / Q000502:physiology*; D006329:Heart Conduction System / Q000502:physiology; D007150:Immunohistochemistry; D008297:Male; D008955:Models, Cardiovascular; D009206:Myocardium / Q000473:pathology; D013997:Time Factors; D020257:Ventricular Remodeling / Q000502:physiology*
D018031:Connexin 43