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[Figure: see text].

Background: Improved understanding of the mechanisms underlying infarct border zone electrogram fractionation may be helpful to identify arrhythmogenic regions in the postinfarction heart. We describe the generation of electrogram fractionation from changes in activation wavefront curvature in experimental canine infarction., Methods and Results: A model was developed to estimate the extracellular signal shape that would be generated by wavefront propagation parallel to versus perpendicular to the lateral boundary (LB) of the reentrant ventricular tachycardia (VT) isthmus or diastolic pathway. LBs are defined as locations where functional block forms during VT, and elsewhere they have been shown to coincide with sharp thin-to-thick transitions in infarct border zone thickness. To test the model, bipolar electrograms were acquired from infarct border zone sites in 10 canine heart experiments 3 to 5 days after experimental infarction. Activation maps were constructed during sinus rhythm and during VT. The characteristics of model-generated versus actual electrograms were compared. Quantitatively expressed VT fractionation (7.6±1.2 deflections; 16.3±8.9-ms intervals) was similar to model-generated values with wavefront propagation perpendicular to the LB (9.4±2.4 deflections; 14.4±5.2-ms intervals). Fractionation during sinus rhythm (5.9±1.8 deflections; 9.2±4.4-ms intervals) was similar to model-generated fractionation with wavefront propagation parallel to the LB (6.7±3.1 deflections; 7.1±3.8-ms intervals). VT and sinus rhythm fractionation sites were adjacent to LBs ≈80% of the time., Conclusions: The results suggest that in a subacute canine infarct model, the LBs are a source of activation wavefront discontinuity and electrogram fractionation, with the degree of fractionation being dependent on activation rate and wavefront orientation with respect to the LB.

Background: The border zone of healing myocardial infarcts is an arrhythmogenic substrate, partly the result of structural and functional remodeling of the ventricular gap junction protein, Connexin43 (Cx43). Cx43 in arrhythmogenic substrates is a potential target for antiarrhythmic therapy., Methods and Results: We characterized Cx43 remodeling in the epicardial border zone (EBZ) of healing canine infarcts 5 days after coronary occlusion and examined whether the gap junction-specific agent rotigaptide could reverse it. Cx43 remodeling in the EBZ was characterized by a decrease in Cx43 protein, lateralization, and increased Cx43 phosphorylation at serine (S) 368. Rotigaptide partially reversed the loss of Cx43 but did not affect the increase in S368 phosphorylation, nor did it reverse Cx43 lateralization. Rotigaptide did not prevent conduction slowing in the EBZ, nor did it decrease the induction of sustained ventricular tachycardia by programmed stimulation, although it did decrease the EBZ effective refractory period., Conclusions: We conclude that partial reversal of Cx43 remodeling in healing infarct border zone may not be sufficient to restore normal conduction or prevent arrhythmias.