Intrinsic Myocyte Dysfunction and Tyrosine Kinase Pathway Activation Underlie the Impaired Wall Thickening of Adjacent Regions During Postinfarct Left Ventricular Remodeling

Abstract

Left ventricular remodeling after infarction is accompanied by dysfunction of regions adjacent to the infarct. We hypothesized that myocyte contractile abnormalities and elongation greater than in remote regions underlie adjacent-region dysfunction in the remodeled ventricle. The activation of the tyrosine kinase pathway, which mediates in vitro hypertrophy by stretch and/or angiotensin, was also assessed in myocytes separately isolated from adjacent and remote regions. ECG-gated magnetic resonance imaging short-axis images were acquired 2 weeks after coronary ligation in rats. After the rats were killed, myocytes were isolated from animals with large (n = 7) and small (n = 7) infarcts and from 4 sham-operated controls. Regional wall thickening was correlated with local myocyte function and morphology. Cytochemistry for tyrosine-phosphorylated proteins was performed in myocytes from the same regions. Remodeled ventricles were dilated relative to controls by 93.7%, and wall thickening in adjacent regions was less than in remote regions (27.8 +/- 6.11% versus 54.0 +/- 10.1%, P < .01). In large infarcts, cell extent and velocity of shortening were reduced in adjacent cells versus controls by 47% and 44%, respectively (P < .05). Myocyte shortening was reduced in adjacent versus remote regions (P < .06), and cell dysfunction correlated with impaired wall thickening (r = .72, P < .05). Myocytes in adjacent regions were longer than in remote regions (150.3 +/- 1.89 versus 143.1 +/- 1.76 microns, P < .05) and also showed 88% more membrane-related phosphotyrosine clusters (P < .05). After infarction, impaired wall thickening in adjacent regions is accompanied by greater myocyte dysfunction and elongation than in remote regions. These abnormalities are associated with regional differences in the tyrosine kinase pathway activation, indicating a potential intracellular mechanism for postinfarct myocardial remodeling.