Mechano-Growth Factor in the Failing Heart

Abstract

Ischemic heart disease (IHD) is a leading cause of death in New Zealand, responsible for seventeen deaths each day. Many of these deaths are due to myocardial infarction (MI) secondary to acute coronary artery occlusion. Moreover, IHD is also the most common cause of heart failure (HF) a significant cause of morbidity and mortality in our community. In order to manage IHD-related illness more effectively, it is necessary to understand the underlying pathophysiological mechanisms. Animal models can help by providing novel insights into the cellular mechanisms involved in myocardial disease. Importantly the models may also point to potential clinical therapies. A clinical understanding of the disease process of interest, such as MI, combined with in-depth knowledge of the model is essential to enable translation of findings to human disease states. Large animal models play a crucial role in the development of both pharmacologic and surgical strategies intended toward improving morbidity and mortality in patients with heart disease. The specific advantages of large animal models include a high degree of physiological similarities to humans and the ability to perform complex technical procedures on. In this thesis I report the development of a large animal ovine MI model created by coronary artery occlusion using microembolisation techniques. The ovine MI model results in pathophysiological changes that are remarkably similar to those seen in man post MI. Extension of the single MI model with repetitive microembolisations results in significant impairment of myocardial function and HF. The ovine model was used to examine the effects of insulin-like growth factors post MI. An intriguing relationship between Insulin-Like Growth Factor–I (IGF-I) action and cardiac function has been noted for some time, with low IGF-I levels increasing the risk of HF suggesting that IGF-I has cardio-protective effects, but exactly how IGF-I modulates myocardial function has remained obscure. Recent research however provides novel insight into potential mechanisms of IGF-I actions in cardiac muscle. In this thesis, I report that following an MI, surviving cardiomyocytes at the infarct border show marked changes in IGF-I localization, production, and specific binding, indicating that the IGF axis is directly involved in post-infarct events. Using the ovine AMI model, I also demonstrated that exogenous administration of intrapericardial IGF-I improves myocardial function in the failing heart post MI. In contrast systemic administration of IGF-I has little effect. These findings, and other recent discoveries, have helped elucidate the role of IGF-I signaling in protecting cardiac muscle against injuries, and support potential therapeutic roles for IGF-I in the failing heart. IGF-I is a complex system expressed by most tissues, including the heart, which exists as different forms of splice variants, each of which has a somewhat different action. The splice variant Mechano–Growth Factor (MGF) is reported to be a potent growth factor for increasing skeletal muscle strength and appears to activate muscle stem cell proliferation after muscle damage. Furthermore the MGF splice variant of IGF-I, appears to be markedly up-regulated post MI in animal studies. These results coupled with my findings identifying marked expression of IGF-I in the peri-infarct region suggest that the MGF splice variant of IGF-I, specifically may be involved in the post MI response. The ovine MI model was used to compare the effects of the MGF E domain with those of full MGF and with the 70 amino acid mature IGF-I peptide on post-infarct cardiac function. The E domain of MGF was demonstrated to reduce the loss of cardiac function which occurs following MI, and that the mechanism of action is probably by the reduction of muscle loss due to apoptosis. These results indicate that local delivery of the IGF-I splice variant MGF, in preference to IGF-I, may be of therapeutic potential in the failing heart following an MI.