Abstract
The goal was to determine the feasibility of mapping the injured-but-not-infarcted myocardium usingTc-duramycin in the postischemic heart, with spatial information for its characterization as a pathophysiologically intermediate tissue, which is neither normal nor infarcted. Coronary occlusion was conducted in Sprague Dawley rats with preconditioning and 30-minute ligation. In vivo single-photon emission computed tomography was acquired after 3 hours (n=6) usingTc-duramycin, a phosphatidylethanolamine-specific radiopharmaceutical. TheTc-duramycinareas were compared with infarct and area-at-risk (n=8). Cardiomyocytes and endothelial cells were isolated for gene expression profiling. Cardiac function was measured with echocardiography (n=6) at 4 weeks. In vivo imaging withTc-duramycin identified the infarct (3.9±2.4% of the left ventricle and an extensive area 23.7±2.2% of the left ventricle) with diffuse signal outside the infarct, which is pathologically between normal and infarcted (apoptosis 1.8±1.6, 8.9±4.2, 13.6±3.8%; VCAM-1 [vascular cell adhesion molecule 1] 3.2±0.8, 9.8±4.1, 15.9±4.2/mm; tyrosine hydroxylase 14.9±2.8, 8.6±4.4, 5.6±2.2/mm), with heterogeneous changes including scattered micronecrosis, wavy myofibrils, hydropic change, and glycogen accumulation. TheTc-duramycintissue is quantitatively smaller than the area-at-risk (26.7% versus 34.4% of the left ventricle,=0.008). Compared with infarct, gene expression in theTc-duramycin-noninfarct tissue indicated a greater prosurvival ratio (BCL2/BAX [B-cell lymphoma 2/BCL2-associated X] 7.8 versus 5.7 [cardiomyocytes], 3.7 versus 3.2 [endothelial]), and an upregulation of ion channels in electrophysiology. There was decreased contractility at 4 weeks (regional fractional shortening -8.6%,<0.05; circumferential strain -52.9%,<0.05). The injured-but-not-infarcted tissue, being an intermediate zone between normal and infarct, is mapped in vivo using phosphatidylethanolamine-based imaging. The intermediate zone contributes significantly to cardiac dysfunction.
Overview
- The study aimed to determine the feasibility of mapping the injured-but-not-infarcted myocardium using Tc-duramycin in the postischemic heart, with spatial information for its characterization as a pathophysiologically intermediate tissue, which is neither normal nor infarcted. Coronary occlusion was conducted in Sprague Dawley rats with preconditioning and 30-minute ligation. In vivo single-photon emission computed tomography was acquired after 3 hours (n=6) using Tc-duramycin, a phosphatidylethanolamine-specific radiopharmaceutical. The Tc-duramycin areas were compared with infarct and area-at-risk (n=8). Cardiomyocytes and endothelial cells were isolated for gene expression profiling. Cardiac function was measured with echocardiography (n=6) at 4 weeks. In vivo imaging with Tc-duramycin identified the infarct (3.9±2.4% of the left ventricle and an extensive area 23.7±2.2% of the left ventricle) with diffuse signal outside the infarct, which is pathologically between normal and infarcted (apoptosis 1.8±1.6, 8.9±4.2, 13.6±3.8%; VCAM-1 [vascular cell adhesion molecule 1] 3.2±0.8, 9.8±4.1, 15.9±4.2/mm; tyrosine hydroxylase 14.9±2.8, 8.6±4.4, 5.6±2.2/mm), with heterogeneous changes including scattered micronecrosis, wavy myofibrils, hydropic change, and glycogen accumulation. The Tc-duramycin tissue is quantitatively smaller than the area-at-risk (26.7% versus 34.4% of the left ventricle,=0.008). Compared with infarct, gene expression in the Tc-duramycin-noninfarct tissue indicated a greater prosurvival ratio (BCL2/BAX [B-cell lymphoma 2/BCL2-associated X] 7.8 versus 5.7 [cardiomyocytes], 3.7 versus 3.2 [endothelial]), and an upregulation of ion channels in electrophysiology. There was decreased contractility at 4 weeks (regional fractional shortening -8.6%,<0.05; circumferential strain -52.9%,<0.05). The injured-but-not-infarcted tissue, being an intermediate zone between normal and infarct, is mapped in vivo using phosphatidylethanolamine-based imaging. The intermediate zone contributes significantly to cardiac dysfunction.
Comparative Analysis & Findings
- The study compared the outcomes observed under different experimental conditions or interventions detailed in the study. The infarct was identified using Tc-duramycin in vivo imaging, which showed a diffuse signal outside the infarct, indicating that the injured-but-not-infarcted tissue is pathologically between normal and infarcted. The Tc-duramycin tissue is quantitatively smaller than the area-at-risk, indicating that the injured-but-not-infarcted tissue contributes significantly to cardiac dysfunction. Compared with infarct, gene expression in the Tc-duramycin-noninfarct tissue indicated a greater prosurvival ratio and an upregulation of ion channels in electrophysiology, suggesting that the injured-but-not-infarcted tissue may have a different pathophysiology than the infarcted tissue. The study also identified heterogeneous changes in the Tc-duramycin tissue, including scattered micronecrosis, wavy myofibrils, hydropic change, and glycogen accumulation, which may contribute to the cardiac dysfunction observed in the intermediate zone.
Implications and Future Directions
- The study's findings have significant implications for the field of research or clinical practice. The identification of the injured-but-not-infarcted tissue using Tc-duramycin in vivo imaging may provide a new tool for the characterization of this tissue and its contribution to cardiac dysfunction. The study also identified heterogeneous changes in the Tc-duramycin tissue, which may have important implications for the development of new therapies for ischemic heart disease. Future research could explore the use of Tc-duramycin in vivo imaging for the diagnosis and treatment of ischemic heart disease, as well as the development of new therapies targeting the injured-but-not-infarcted tissue.