Cardiovascular disease is a major global health problem as it is the leading cause of death in developed countries. Chronic hypertension results in a maladaptive pathological change to the structure and function of the cardiovascular system in a process known as cardiovascular remodelling, which leads to decreased cardiac function and ultimately heart failure. Cardiovascular remodelling is characterized by cardiac and vascular hypertrophy, excessive deposition of extracellular matrix proteins such as collagen as well as increased collagen cross-linking, and endothelial dysfunction. This thesis has characterized changes in cardiovascular structure and function in the spontaneously hypertensive rat (SHR) and deoxycorticosterone acetate (DOCA)-salt rat and the possible reversal of these changes by chronic drug treatment. Drugs used include the collagen cross-linking inhibitor aminoguanidine and the β-adrenoceptor antagonist metoprolol. Cardiovascular structure and function have been defined using in vivo echocardiography, ex vivo isolated Langendorff heart, isolated thoracic aortic rings, electrophysiological recordings of papillary muscles, histological analysis of the cardiac extracellular matrix and terminal organ weights.
DOCA-salt rats were hypertensive with increased left ventricular weight, left ventricular wall thickness and thoracic aortic wall thickness. Further, they exhibited higher left ventricular collagen deposition and prolonged action potential duration. Functionally, untreated DOCA-salt rats had increased stiffness, reduced rates of contraction and relaxation and impaired vascular reactivity. Treatment with aminoguanidine decreased blood pressure, left ventricular weight and cardiac stiffness while improving contractility, rate of relaxation and vascular reactivity. Treatment of DOCA-salt rats with metoprolol also reduced blood pressure, left ventricular weight and cardiac stiffness. In addition, metoprolol treatment of these rats decreased left ventricular collagen deposition, improved rates of contraction and relaxation and improved vascular reactivity.
Contrary to common belief, cardiovascular disease also occurs in women, even though premenopausal women appear to be more protected from cardiovascular disease than age-matched men indicating a potential gender difference. Both the ageing male SHR and female SHR developed hypertension, increased left ventricular weight, thoracic aortic wall thickness and ventricular wall thickness. However, male SHRs from 15 months of age exhibited left ventricular wall thinning and chamber dilatation, which was not present in the female SHRs. Furthermore male SHRs, but not female SHRs, developed systolic and diastolic dysfunction at around 15 to 18 months of age. Both the male and female SHR also exhibited increased collagen deposition, impaired rates of contractility and relaxation from 18 months and prolonged action potential. Further, the male SHR also developed increased stiffness and reduced vascular reactivity from about 15 months.
Although once a contraindication, β-adrenoceptor blockade is now an established treatment to prolong survival in heart failure, however few studies have examined changes in remodelling. Treatment with metoprolol in the ageing male SHR improved survival, decreased left ventricular weight, prevented chamber dilatation, improved systolic and diastolic function, reduced area of collagen and decreased cardiac stiffness. In addition, metoprolol attenuated action potential prolongation, impaired cardiac contractility and rate of relaxation, and improved endothelium-independent vasorelaxation.
Thus, these studies have characterized the ageing male and female SHR in hypertension and heart failure as well as the DOCA-salt rat and have shown them to be appropriate models of human cardiovascular remodelling associated with hypertension. Further, treatment with a collagen cross-linking inhibitor or a β-adrenoceptor antagonist have demonstrated favourable effects on cardiovascular remodelling which resulted in an improvement in cardiovascular function during chronic hypertension and heart failure.