Rotigaptide Infusion for the First 7 Days After Myocardial Infarction–Reperfusion Reduced Late Complexity of Myocardial Architecture of the Healing Border‐Zone and Arrhythmia Inducibility

Abstract

Background Survivors of myocardial infarction are at increased risk of late ventricular arrhythmias, with infarct size and scar heterogeneity being key determinants of arrhythmic risk. Gap junctions facilitate the passage of small ions and morphogenic cell signaling between myocytes. We hypothesized that gap junctions enhancement during infarction–reperfusion modulates structural and electrophysiological remodeling and reduces late arrhythmogenesis. Methods and Results Infarction–reperfusion surgery was carried out in male Sprague‐Dawley rats followed by 7 days of rotigaptide or saline administration. The in vivo and ex vivo arrhythmogenicity was characterized by programmed electrical stimulation 3 weeks later, followed by diffusion‐weighted magnetic resonance imaging and Masson's trichrome histology. Three weeks after 7‐day postinfarction administration of rotigaptide, ventricular tachycardia/ventricular fibrillation was induced on programmed electrical stimulation in 20% and 53% of rats, respectively (rotigaptide versus control), resulting in reduction of arrhythmia score (3.2 versus 1.4, P =0.018), associated with the reduced magnetic resonance imaging parameters fractional anisotropy (fractional anisotropy: −5% versus −15%; P =0.062) and mean diffusivity (mean diffusivity: 2% versus 6%, P =0.042), and remodeling of the 3‐dimensional laminar structure of the infarct border zone with reduction of the mean (16° versus 19°, P =0.013) and the dispersion (9° versus 12°, P =0.015) of the myofiber transverse angle. There was no change in ECG features, spontaneous arrhythmias, or mortality. Conclusions Enhancement of gap junctions function by rotigaptide administered during the early healing phase in reperfused infarction reduces later complexity of infarct scar morphology and programmed electrical stimulation–induced arrhythmias, and merits further exploration as a feasible and practicable intervention in the acute myocardial infarction management to reduce late arrhythmic risk.

Sodium–Glucose cotransporter 2 inhibitor empagliflozin decreases ventricular arrhythmia susceptibility by alleviating electrophysiological remodeling post-myocardial-infarction in mice

“…Ventricular arrhythmias are the main cause of mortality in patients suffering from myocardial infarction (MI) (Behnes et al, 2018;Frontera et al, 2020). Myocardial infarction is associated with significant electrophysiological remodeling including aberrant cardiac conduction and altered action potential duration (APD) in post-MI hearts (Jiang et al, 2007;Mendonca Costa et al, 2018;Chowdhury et al, 2021). The inhomogeneous prolongation of APD and slowing of cardiac conduction velocity in the infarct zone (IZ), bordering zone (BZ), and remote zone (RZ) are prone to induce arrhythmias in infarcted hearts (Mendonca Costa et al, 2018;Wen et al, 2018).…”

The potential roles of stress‐induced phosphoprotein 1 and connexin 43 in rats with reperfusion arrhythmia

“…Electrophysiological remodeling during I/R‐related arrhythmia is, in part, owing to cardiac gap junction (GJ) (fluorescence) uncoupling, and the eventual cellular injury can be determined by the acute effects of the passage of cell‐survival or apoptotic signals through open GJ channels between contiguous myocytes. 5 Connexin 43 (Cx43), a member of the connexins, is a special GJ protein that is most abundant on the cell membrane of mammalian ventricular cardiomyocytes. 6 Hemichannels are often regarded as “pathologic pores” that open abnormally in response to cellular stress.…”