Heterogeneity of Repolarization and Cell-Cell Variability of Cardiomyocyte Remodeling Within the Myocardial Infarction Border Zone Contribute to Arrhythmia Susceptibility

Abstract

BACKGROUND: After myocardial infarction, the infarct border zone (BZ) is the dominant source of life-threatening arrhythmias, where fibrosis and abnormal repolarization create a substrate for reentry. We examined whether repolarization abnormalities are heterogeneous within the BZ in vivo and could be related to heterogeneous cardiomyocyte remodeling. METHODS: Myocardial infarction was induced in domestic pigs by 120-minute ischemia-reperfusion injury. After 1 month, remodeling was assessed by magnetic resonance imaging, and electroanatomical mapping was performed to determine the spatial distribution of activation-recovery intervals. Cardiomyocytes were isolated and tissue samples collected from the BZ and remote regions. Optical recording allowed assessment of action potential duration (di-8-Anepps, stimulation at 1 Hz, 37 °C) of large cardiomyocyte populations while gene expression in cardiomyocytes was determined by single nuclear RNA sequencing. RESULTS: In vivo, activation-recovery intervals in the BZ tended to be longer than in remote with increased spatial heterogeneity evidenced by a greater local SD (3.5±1.3 ms versus remote: 2.0±0.5 ms, P =0.036, n pigs =5). Increased activation-recovery interval heterogeneity correlated with enhanced arrhythmia susceptibility. Cellular population studies (n cells =635–862 cells per region) demonstrated greater heterogeneity of action potential duration in the BZ (SD, 105.9±17.0 ms versus remote: 73.9±8.6 ms; P =0.001; n pigs =6), which correlated with heterogeneity of activation-recovery interval in vivo. Cell-cell gene expression heterogeneity in the BZ was evidenced by increased Euclidean distances between nuclei of the BZ (12.1 [9.2–15.0] versus 10.6 [7.5–11.6] in remote; P <0.0001). Differentially expressed genes characterizing BZ cardiomyocyte remodeling included hypertrophy-related and ion channel–related genes with high cell-cell variability of expression. These gene expression changes were driven by stress-responsive TFs (transcription factors). In addition, heterogeneity of left ventricular wall thickness was greater in the BZ than in remote. CONCLUSIONS: Heterogeneous cardiomyocyte remodeling in the BZ is driven by uniquely altered gene expression, related to heterogeneity in the local microenvironment, and translates to heterogeneous repolarization and arrhythmia vulnerability in vivo.

Strain-controlled electrophysiological wave propagation alters in silico scar-based substrate for ventricular tachycardia

“…The elevated RTG caused the lines of conduction block to be longer, resulting in larger reentrant circuits. This, in combination with the lowered CV T in the remote part of reentrant pathways, can prolong reentrant cycle time and more easily result in sustained VT. Those effects might be even more pronounced if cardiomyocyte and APD heterogeneity after infarction is caused by mechanical load as well, as suggested in recent work ( Amoni et al, 2023 ).…”

“…Frontiers in Physiology frontiersin.org 10 sustained VT. Those effects might be even more pronounced if cardiomyocyte and APD heterogeneity after infarction is caused by mechanical load as well, as suggested in recent work (Amoni et al, 2023).…”

Effects of Mesenchymal Stem Cell Injection into Healed Myocardial Infarction Scar Border Zone on the Risk of Ventricular Tachycardia

“…MSC injections into the ventricular myocardium after MI have resulted in reverse-remodeling of the myocardium and improvement in ventricular function [ 9 ], however, its effect on ischemic ventricular arrhythmia has not been clearly demonstrated. The scar border zone is the main environment susceptible for post-MI VT, and the direct injection of stem cells into this area would be more effective for improving electrophysiologic properties than the stem cell implantation in infarcted myocardium with a non-viable scar [ 10 ]. However, results of experimental studies indicated that MSC therapy could be proarrhythmic due to altered electrophysiologic properties that can result in slowed conduction velocity and the changes in substrate refractoriness in MSC-survived heart tissue [ 11 ].…”