Abstract 10654: Enhancement of Gap Junctional Coupling During Acute Myocardial Infarction Reduces Inhomogeneity of Border Zone Scarring and Late Ventricular Arrhythmia Susceptibility
Introduction: Survivors of myocardial infarction (MI) are predisposed to ventricular arrhythmias as the healed infarct scar forms a substrate for re-entry, with increased inhomogeneity of scarring being associated with greater arrhythmia susceptibility. We hypothesized that enhancing gap junctional (GJ) intercellular communication during acute MI can produce a more homogeneous chronic infarct scar thus reducing late susceptibility to post-MI arrhythmias, and that this strategy was not pro-arrhythmic acutely.
Methods: For chronic MI studies, Sprague-Dawley rats underwent LAD ligation and were treated with rotigaptide (ZP123) to enhance GJ coupling (ROT, n=13) or saline control (CON, n=14) immediately pre-MI, and then for 7 days post-MI by osmotic minipump. At 4 weeks post-MI, rats had in vivo ECG-telemetry, and ex vivo programmed electrical stimulation (PES) with optical mapping. Heterogeneity of infarct border zone (IBZ) scarring was quantified by histomorphometry. For acute ischaemia-reperfusion (I-R) studies, rat hearts were treated with AAP10 to enhance GJ coupling or control (n=10 each) and subjected to 8 minutes LAD ischaemia then reperfusion ex vivo, with optical mapping and ECG monitoring.
Results: Chronic MI studies: ROT-animals had reduced arrhythmia susceptibility at PES (VT Inducibility score: ROT 2.4 ± 0.8, CON 5.0 ± 0.6, P<0.05). Infarct size was not different (ROT 25 ± 2%, CON 21 ± 5%, P=NS). ROT-hearts had less heterogeneous IBZ structural complexity than control (S.D. of IBZ Complexity Score: ROT 1.1 ± 0.1, CON 1.4 ± 0.1, P<0.05), associated with a non-significant improvement in IBZ conduction velocity (ROT 43.1 ± 3.4, CON 35.7 ± 1.7 cm/s). Acute I-R studies: AAP10 attenuated the conduction slowing that occurred during acute ischaemia and reduced reperfusion VF incidence (50% vs. CON 90%).
Conclusions: Enhancement of GJ coupling for a limited duration during acute MI produced more homogeneous scarring at the infarct border zone and reduced arrhythmia susceptibility at 4 weeks post-MI. Enhancing GJ coupling was also anti-arrhythmic in the acute I-R setting. Short-term GJ modulation at the time of MI may represent a novel therapeutic strategy to modify the morphology of the healed infarct scar and reduce late post-MI arrhythmic risk.
- © 2011 by American Heart Association, Inc.