Altering ventricular activation remodels gap junction distribution in canine heart

Gap Junctional Remodeling in Paced Ventricle. Introduction: Prolonged arrhy thmic or paced ventricular activation causes persistent changes in myocardi al conduction and repolarization that may result from altered electrotonic current flow, for which gap junctional coupling is the principal determinan t. Remodeling of gap junctions and their constituent connexins modifies con duction and has been causally implicated in reentrant arrhythmogenesis. We hypothesized conversely that altering the pattern of ventricular activation causes gap junctional remodeling. Methods and Results: Seven dogs were paced from the left ventricular (LV) e picardium (VVO, similar to 120 beats/min) for 21 days before excision of tr ansmural 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 pacin g, 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 duratio n and repolarization were associated with a reduction in epimyocardial conn exin43 expression on quantitative Western blotting of LV myocardium from cl ose to, but not distant from, the pacing site (61.7 +/- 18.4 vs 100.9 +/- 3 4.0; P < 0.02) and a marked disruption in imnunolabeled connexin43 distribu tion in epimyocardium only. Conclusion: Spatially distinct transmural and regional gap junctional remod eling is a consequence of abnormal ventricular activation and is associated with consistent changes in activation that may alter patterns of repolariz ation and facilitate reentrant arrhythmogenesis.