15 * Early pharmacological enhancement of gap junction coupling with rotigaptide reduces arrhythmia vulnerability and modulates structural remodelling in reperfused myocardial infarction

Abstract

Introduction: Survivors of myocardial infarction (MI) are at increased risk of late ventricular arrhythmias and sudden cardiac death with infarct size and scar heterogeneity as key determinants of arrhythmic risk. Current preventative strategies are limited to few, select antiarrhythmic drugs or an implantable cardioverter-defibrillator. Cardiac gap junctions (GJ) have a key role in allowing the passage of small molecules between cells and may mediate the spread of acute myocardial infarction. We hypothesised that enhancing GJ coupling in the acute phase of MI may beneficially modify the extent and pattern of necrosis and infarction acutely, thus affording a protective effect against late arrhythmogenesis. Methods: A small-animal model of infarction-reperfusion, mimicking clinical reperfusion, was used to study the effects of Rotigaptide on arrhythmogenicity and structural remodelling in a four-week healed model of MI. Male Sprague-Dawley rats (250–300g) underwent infarction-reperfusion surgery with either Rotigaptide (n=15) or Saline (n=15) via minipump. The arrhythmia phenotype was characterised at four-weeks with in-vivo telemetry, 6-lead ECG, ex-vivo arrhythmia provocation studies and dual optical mapping. Structural changes post-MI were studied with diffusion-weighted MRI (DWI) and Masson's Trichrome histology. Results: Rotigaptide resulted in a significant reduction in arrhythmias induced by programmed stimulation (arrhythmia score ROT 3.2 vs. CON 1.4, p<0.05), driven by a reduction in sustained VT (20% vs. 53%, p<0.06). Rotigaptide had no effect on mortality or the incidence of spontaneous arrhythmias or ECG parameters. Remodelling of the optical action potential (AP) was similar between groups a reduction in conduction velocity at the border zone and slowing of the AP upstroke. DWI provided quantifiable measures of structural remodelling in the remote, IBZ and infarct. In control hearts, the infarct demonstrated a significant reduction in fractional anisotropy, and a significant increase in mean diffusivity, compared to remote, partially reversed by Rotigaptide (FA: CON -15% vs. ROT -5%, p<0.05, MD: 6% vs. 2%, p<0.05). The 3D laminar structure of the IBZ was remodelled by Rotigaptide, with a reduction in mean (ROT 16 degrees vs. CON 19 degrees, p<0.05) and dispersion (9 degrees vs. 12 degrees, p<0.05) of the transverse angle. There was no remodelling of helix or transverse angle in remote of either treatment group. Conclusions: Pharmacological GJ enhancement in the early healing phase in reperfused infarction modifies the infarct scar morphology to render myocardium less vulnerable to arrhythmias during programmed stimulation, without affecting the properties of the cardiac action potential or calcium transient. The effects of Rotigaptide were limited to at-risk regions with attenuation of remodelling in the infarct and reduced fibre dispersion in the IBZ offering potential mechanistic explanations for the reduced arrhythmic risk.