Following myocardial infarction (MI), the heart undergoes an extensive remodeling process causing fibrosis in both infarcted and non-infarcted cardiac tissues, which distorts tissue structure, increases tissue stiffness, and leads to heart failure, Such adverse remodeling is primarily regulated by locally generated factors in the heart including angiotensin (Ang) II and nitric oxide (NO). Previous studies indicate that post- MI exercise training improves cardiac function. The improved cardiac function is most likely due to the improved myocardial remodeling. Exercise training decreases resting plasma AngII and increases NO synthesis, both of which have positive effects on myocardial remodeling. Since following MI the heart experiences different phases in the remodeling process, such as inflammation, fibrosis, and scar formation, exercise at the right time may more efficiently attenuate myocardial fibrosis. Furthermore, exercise training together with pharmaceutical treatment, such as Ang converting enzyme, and L-arginine (the substrate for NO synthesis), may augment the beneficial effect on the remodeling. The overall objective of this project is to investigate the role and mechanism of exercise training, and the compounding effect of exercise and pharmaceutical treatment on myocardial remodeling and function following MI. By using a rat model of MI, we intend to fulfill the following specific aims:
Aim 1) To determine the optimal start time of post-MI exercise training to optimize myocardial remodeling and cardiac function;
Aim 2) To determine the potential regulation of exercise on cardiac AngII generation and the effect of combination of exercise training and AnglI receptor blockade on post-MI remodeling and cardiac function;
and Aim 3) To determine whether post-MI exercise training promotes nitric oxide synthesis in the inffacted heart and whether the combination of NO synthesis augmentation and exercise training has additive effect on myocardial remodeling and function. The significance of this project is to provide novel information regarding the post-MI exercise timing, the effect of post-MI exercise training, and the combination of exercise and pharmaceutical treatment on post-MI myocardial remodeling and function. The ultimate goal of our research is to provide clinically relevant information regarding the pathophysiology of post-MI recovery through exercise training or the combination of pharmaceutical treatment and exercise training.
