Altered adrenergic response in myocytes bordering a chronic myocardial infarction underlies in vivo triggered activity and repolarization instability

• Published in: The Journal of physiology 2020-07, Vol.598 (14), p.2875-2895
• Main Authors: Dries, Eef, Amoni, Matthew, Vandenberk, Bert, Johnson, Daniel M., Gilbert, Guillaume, Nagaraju, Chandan K., Puertas, Rosa Doñate, Abdesselem, Mouna, Santiago, Demetrio J., Roderick, H. Llewelyn, Claus, Piet, Willems, Rik, Sipido, Karin R.
• Format: Article
• Language: English
• Subjects: Aberrant Calcium Signaling and Arrhythmia Mechanisms; Action Potentials; Adrenergic Agents; animal models of human disease; Animals; Arrhythmia; arrhythmias; Arrhythmias, Cardiac - etiology; autonomic nervous system; Ca2+/calmodulin-dependent protein kinase II; Calcium; calcium cycling; Cardiac arrhythmia; Heart attacks; Hypertrophy; Isoproterenol; Life Sciences; Myocardial Infarction; Myocytes; Myocytes, Cardiac; Research Paper; Swine; Ventricle
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/JP278839

Key points Ventricular arrhythmias are a major complication after myocardial infarction (MI), associated with sympathetic activation. The structurally heterogeneous peri‐infarct zone is a known substrate, but the functional role of the myocytes is less well known. Recordings of monophasic action potentials in vivo reveal that the peri‐infarct zone is a source of delayed afterdepolarizations (DADs) and has a high beat‐to‐beat variability of repolarization (BVR) during adrenergic stimulation (isoproterenol, ISO). Myocytes isolated from the peri‐infarct region have more DADs and spontaneous action potentials, with spontaneous Ca2+ release, under ISO. These myocytes also have reduced repolarization reserve and increased BVR. Other properties of post‐MI remodelling are present in both peri‐infarct and remote myocytes. These data highlight the importance of altered myocyte adrenergic responses in the peri‐infarct region as source and substrate of post‐MI arrhythmias. Ventricular arrhythmias are a major early complication after myocardial infarction (MI). The heterogeneous peri‐infarct zone forms a substrate for re‐entry while arrhythmia initiation is often associated with sympathetic activation. We studied the mechanisms triggering these post‐MI arrhythmias in vivo and their relation to regional myocyte remodelling. In pigs with chronic MI (6 weeks), in vivo monophasic action potentials were simultaneously recorded in the peri‐infarct and remote regions during adrenergic stimulation with isoproterenol (isoprenaline; ISO). Sham animals served as controls. During infusion of ISO in vivo, the incidence of delayed afterdepolarizations (DADs) and beat‐to‐beat variability of repolarization (BVR) was higher in the peri‐infarct than in the remote region. Myocytes isolated from the peri‐infarct region, in comparison to myocytes from the remote region, had more DADs, associated with spontaneous Ca2+ release, and a higher incidence of spontaneous action potentials (APs) when exposed to ISO (9.99 ± 4.2 vs. 0.16 ± 0.05 APs/min, p = 0.004); these were suppressed by CaMKII inhibition. Peri‐infarct myocytes also had reduced repolarization reserve and increased BVR (26 ± 10 ms vs. 9 ± 7 ms, P