Recovery of cardiac pump function after myocaridial infarction will depend on the size and mechanical properties if the healed scar. The purpose of this proposal is to study the healing of experimental myocardial infarcts using a model of coronary artery ligation in the rabbit under normal conditions and after pharmacological interventions which may impair or improve infarct healing. Healing of myocardial infarct scars will be assessed by measurements of hydroxyproline content to evaluate collagen deposition, scar thickness and circumference, and passive elastic properties of scar stripes. These measurements will be related to the mechanical properties of the whole heart determined from left ventricular function curves and compliance curves generated in the isolated perfused heart. The measurements will be made in normal hearts and in hearts one day, one week, and three weeks after coronary occlusion. Other experiments will examine how scar geometry, scar elastic properties and ventricular functions are altered when healing is impaired by treatment with an anti-inflammatory glucocorticoid steroid. The role of ascorbic acid during infarct healing will be studied in experiments in which ascorbic acid and hydroxyproline content are measured in healing scars and in surrounding normal myocardium with and without dietary supplementation with ascorbic acid. These studies will dertermine whether dietary supplementation can increase the ammount of ascorbic acid which is normally concentrated in healing tissue, and whether such an increase would accelerate collagen deposition and improve scar mechanics. The role of histamine during infarct healing will be evaluated in experiments in which histamine and hydroxyproline content are measured during the normal course of healing and when histamine is depleted by treatment with a mast cell histamine releasing agent (compound 48/80) and a selective histidine decarboxylase inhibitor (alpha-fluoromdthylhistidine). These experiments will determine whether histamine content is altered during normal infarct healing and whether the presence of this autocoid is required for normal healing as seems to be the case for skin wounds. This research project should produce new information which describes how alterations in scar composition, geometry, and mechanics ultimately affect cardiac pump function. It is hoped that such information will eventually lead to therapies which will improve the recovery of cardiac function after myocardial infarction.
| Connelly, C M; McLaughlin, R J; Vogel, W M et al. (1991) Reversible and irreversible elongation of ischemic, infarcted, and healed myocardium in response to increases in preload and afterload. Circulation 84:387-99 |
