Abstract
Cardiac pathologies associated with arrhythmic activity are often accompanied by inflammation. The contribution of inflammatory cells to the electrophysiological properties of injured myocardium is unknown. Myocardial scar cell types and intercellular contacts were analyzed using a three-dimensional reconstruction from serial blockface scanning electron microscopy data. Three distinct cell populations were identified: inflammatory, fibroblastic and endocardial cells. While individual fibroblastic cells interface with a greater number of cells, inflammatory cells have the largest contact area suggesting a role in establishing intercellular electrical connections in scar tissue. Optical mapping was used to study the electrophysiological properties of scars in fetal liver chimeric mice generated using connexin43 knockout donors (bmpKO). Voltage changes were elicited in response to applied current pulses. Isopotential maps showed a steeper pattern of decay with distance from the electrode in scars compared with uninjured regions, suggesting reduced electrical coupling. The tissue decay constant, defined as the distance voltage reaches 37% of the amplitude at the edge of the scar, was 0.48 ± 0.04 mm (n = 11) in the scar of the bmpCTL group and decreased 37.5% in the bmpKO group (n = 10). Together these data demonstrate inflammatory cells significantly contribute to scar electrophysiology through coupling mediated at least partially by connexin43 expression.
Highlights
Many cardiac pathologies associated with arrhythmic activity are associated with a complex immune response[1]
Macrophages could contribute to arrhythmias via different mechanisms including cytokine release that directly affects myocyte function, crosstalk with fibroblasts leading to increased fibrosis, or by directly regulating electrical activity through intercellular coupling
Following studies continued to focus in the electrical interactions between myocytes and fibroblasts, partly because fibroblasts constitute the largest cell population in the heart in terms of numbers, and because of their important role in cardiac remodeling in disease states and following cardiac injury
Summary
Many cardiac pathologies associated with arrhythmic activity are associated with a complex immune response[1]. Macrophages could contribute to arrhythmias via different mechanisms including cytokine release that directly affects myocyte function, crosstalk with fibroblasts leading to increased fibrosis, or by directly regulating electrical activity through intercellular coupling. The organization of non-myocyte cell populations in scar tissue remains poorly characterized, in particular it is not known what cells establish intercellular contacts and to what extent. This void in knowledge is partly due to technical spatial resolution limitations, as well as long held views that minimized or even negated the contribution of the cardiac non-myocyte cell populations to the electrical function of the heart. The findings of this study provide important new information on the role of inflammatory cells in establishing the electrophysiological properties of scar tissue 30 days after cardiac injury
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