Cardiovascular disease remains a leading cause of morbidity and mortality in our society. The change in cardiovascular structure, or cardiovascular remodelling (CR) as left ventricular hypertrophy (LVH) and fibrosis is modified by endurance exercise and conditions such as diabetes, obesity, growth hormone deficiency, hypertension and heart failure (HP). The quality of hypertrophy has been demonstrated to be physiological and adaptive following exercise and progressively maladaptive if induced by cardiovascular disease states. LVH has been shown to be an important predictor of cardiovascular morbidity and mortality and to potentiate the development of coronary artery disease, myocardial infarction, stroke, arrhythmias and HP independently of elevated blood pressure. Following a maladaptive hypertrophic response, excess collagen deposition and cross-linking occur resulting in ventricular and vascular fibrosis.
Significant understanding of the underlying mechanisms of cardiovascular dysfunction in humans has come from the development of animal models of hypertension, HP, diabetes, obesity and growth hormone deficiency. This thesis has characterised several rat models of human cardiovascular disease by defining the development of CR. Cardiovascular structure and function was assessed by in vivo serial echocardiography and ex vivo isolated Langendorff heart preparations, histological determination of collagen, electrophysiological recordings from isolated left ventricular papillary muscles, terminal organ weights and vascular responses in isolated thoracic aortic rings.
Endurance exercise training induced physiological LVH. This was demonstrated by increased LV weight, increased LV internal diameter, increased cardiac output and increased LV metabolic reserves without an increase in LV collagen deposition or diastolic stiffness. Growth hormone deficient Lewis dwarf rats were moderately hypertensive and showed evidence of significant left ventricular hypertrophy which contributed to increasing left ventricular dysfunction from 15 to 18 months of age. There was no loss in LV compliance. Growth hormone deficiency induced vascular dysfunction and prolongation of the cardiac action potential which increased with age. Ten-month old Zucker rats, as a model of obesity, were moderately hypertensive and hyperglycaemic which induced significant concentric LVH. Diastolic dysfunction was apparent with a decreased E/A mitral flow rate ratio accompanied by increased left ventricular fibrosis which decreased cardiac compliance.
Cardiovascular responses in the ageing spontaneously hypertensive rat (SHR) were assessed from 3 to 24 months of age and compared to both age-matched WKY and Wistar control animals. The SHR developed hypertension and significant concentric LVH from 3 to 9 months of age indicated by increased LV wet weights, decreased internal dimensions and increased posterior wall thicknesses. This was accompanied by increasing diastolic dysfunction from 12 to 15 months of age with HP becoming apparent by 15 to 18 months of age. LV geometry transitioned to the eccentric dilated presentation with both diastolic and systolic dysfunction. Diastolic stiffness and LV collagen deposition were significantly higher in the SHR hearts and increased with worsening of the pathology.
Angiotensin II plays a major role in the progression of these disease states. The second part of this study was chronically treating STZ-induced diabetic rats and ageing SHR with the ACE inhibitor perindopril (1 mg/kg/day). Perindopril treatment prevented the maladaptive LVH and collagen deposition and normalised cardiac function in the STZ-diabetic rat. Additionally perindopril therapy normalised the endothelial dysfunction following diabetes. Perindopril treatment improved survival and reduced the signs of HP in the aged SHR. Both diastolic (E/A mitral flow rate ratio) and systolic (fractional shortening and ejection fraction) functional indices were improved. Perindopril normalised the increased stiffness and collagen deposition and prevented the increase in action potential duration in the failing SHR. Endothelial function was also improved. These results demonstrate the underlying differences in the type of LV remodelling and changes in cardiovascular structure and function in rat models of endurance exercise, growth hormone deficiency, type I and II diabetes, obesity, hypertension and HP. Additionally the treatment studies have shown that maladaptive cardiovascular remodelling can be prevented and reversed by ACE inhibition with perindopril without normalising blood pressure. Further, cardiac function was significantly improved.