Myocardial infarction (MI) leads to the formation of an infarct scar as well as adverse remodeling of the remote uninjured myocardium. Cellular engraftment is being evaluated in attempts to convert the infarct scar into contractile tissue and improve myocardial function. However, the scar is less than an ideal environment for cellular engraftment, and it is possible that resulting changes in the scar may not reverse the remodeling of non-infarcted myocardium. This remodeling is controlled by a balance among numerous deleterious and beneficial factors such as the kallikrein-kinin system, which has been suggested to play a protective role. The proposed project will attempt to improve upon existing approaches to cellular engraftment by testing the hypothesis that delivery of beneficial gene products to the myocardium using genetically engineered skeletal muscle myoblasts will: 1) improve cell engraftment into the infarct scar; and 2) limit remodeling.
Aim 1 will test the hypothesis that cellular engraftment into the scar, and thus its effects on cardiac function, can be enhanced by implanting myoblasts expressing elevated levels of collagenase.
Aim 2 will test the hypothesis that kallikrein gene transfer to the infarct scar and uninjured myocardium via genetically engineered myoblasts will result in sufficient kinin generation to favorably affect post-MI remodeling. Kallikrein over-expressing myoblasts will be delivered by intracardiac, intrapericardial and intracoronary injection to determine the most effective route of administration.
Aim 3 will determine if synergistic effects are observed when combining cellular engraftment with kallikrein and collagenase over-expressing myoblasts. Results from numerous labs including ours suggest that engraftment of pluripotent cells offers an exciting new approach to the treatment of post-MI heart failure. However, numerous questions need to be addressed before full scale clinical trials are reasonable, including concerns about the ability of implanted cells to assume a cardiac phenotype, the mitotic capacity of implanted cells, integration of engrafted cells into the electrical syncitium, and the need to reverse the remodeling process that occurs in non-infarcted tissue. Previous studies in our labs and others have shown that autologous myoblasts provide a beneficial effect when injected into the scar and that this treatment is not limited by rejection. Proposed studies will build upon this model to address some of the remaining issues.
