Abstract:
Cardiac muscle has very limited ability to regenerate following injury. Loss of muscle due to myocardial infarction (MI) is therefore compensated for by hypertrophy of the surviving cardiac muscle. Deposition of inflexible scar tissue in the infarct zone leads to subsequent dysfunction of the heart, often culminating in chronic morbidity and eventual death due to heart failure.
Insulin-like growth factor I (IGF-I) and insulin-like growth factor II (IGF-II) are members of a family of insulin-related peptides involved in tissue development, repair and replacement. Their involvement in these roles has been clearly demonstrated in skeletal muscle, but remains unclear in cardiac muscle. The aim of this thesis, therefore, was to undertake a comprehensive evaluation of the insulin-like growth factor axis following induced MI in sheep, in order to determine the relationship between time-based changes in the myocardium and insulin-like growth factor levels, and subsequently to determine the therapeutic effect of GH or IGF-I treatment on cardiac function following MI.
To achieve the aims of the thesis, a model of MI was developed from the existing cardiology technique of percutaneous transluminal coronary angioplasty. Using this model, MI was induced in adult ewes by selected coronary artery occlusion under fluoroscopic guidance. Subsequently, the model was further developed into one of stable heart failure, utilising serial microembolisations targeted by echocardiography.
Results showed that, in the cardiomyocytes bordering the infarct, IGF-I mRNA, protein and receptor binding increased, whereas IGF-II mRNA and protein levels did not vary, although IGF-II receptor binding increased.
Following these findings, IGF-I levels were manipulated by subcutaneous injections of either growth hormone or IGF-I, and by intra-pericardial IGF-I delivery via catheter.
Results showed that neither growth hormone nor subcutaneous IGF-I were able to effect an improvement in cardiac function, although there were indications that a longer duration of treatment with subcutaneous IGF-I might have done so. Intra-pericardial IGF-I, however, resulted in a significant and sustained improvement in cardiac function.
In conclusion, surviving cardiomyocytes at the infarct border show marked changes in IGF-I localisation, production and specific binding, indicating that IGF-I is directly involved in post-infarct events, possibly in the maintenance of cardiac function by the induction of hypertrophy. Delivery of IGF-I directly into the pericardium results in a significant improvement in left ventricular ejection fraction which is sustained after cessation of treatment. Such a result indicates that IGF-I may have a role as a therapy in the failing heart.