title: Comparative studies in experimental hypertension and cardiac failure
Creators: name: Lygate, Craig Alexander
Publisher: name: University of Glasgow
Year: 2000

description: The common theme of this thesis is the characterisation of cardiac and vascular hypertrophy in animal models of cardiovascular disease. The pathophysiology of hypertension, left ventricular hypertrophy and heart failure are discussed, with particular emphasis on cardiac and vascular alterations in animal models. Echocardiography was validated for use in rats, and applied to a genetic model of hypertension, the stroke-prone spontaneously hypertensive rat (SHRSP), and to the rat coronary artery ligation (CAL) model of heart failure. Likewise, laser scanning confocal microscopy (LSCM) was utilised to examine vascular remodelling in both these models. The utility of trans-thoracic echocardiography for estimating left ventricular (LV) mass was validated in lightly sedated SHRSP and WKY rats. Two-dimensional and M-mode parasternal short-axis views were readily obtainable and used to calculate LV mass using the cubed formula, which was then compared to blotted LV weight at autopsy. Left ventricular hypertrophy (LVH) was defined for this colony of rats as a LV mass-to-body weight ratio of greater than 2.86g/Kg. The accuracy of echocardiography in detecting LV hypertrophy was determined: sensitivity 92%, specificity 64%, false-positive rate 22%, and false negative rate 14%. LVH in the SHRSP was apparent as a 28% higher LV mass compared to WKY rats. The anterior wall was 23% thicker, and the posterior wall 17% thicker. Differences in systolic function were measured by ejection fraction and fractional shortening, and were found to be anaesthetic dependent, with the SHRSP being more prone to halothane-induced cardiac depression. Intra-observer variability was quantified using repeat examinations in a sub-group of 18 rats. Co-efficient of repeatability was calculated for a range of echocardiographic parameters. The most reliable measurements were myocardial cross-sectional area (15%), LV wall thickness (16%), and end diastolic dimension (18%). LV mass had a co-efficient of repeatability of 21%. The ability of antihypertensives to prevent the rise in blood pressure and associated complications of cardiac and vascular hypertrophy were examined in the SHRSP. At weeks 6-7 of age, 24 SHRSP (M:F=12:12) were assigned to three groups and given in their food either irbesartan (Irb, 16mg/kg/Day), hydrochlorothiazide + hydralazine (H+H, 4mg/kg/day of each), or control (C). Systolic blood pressure was measured twice weekly by tail cuff plythesmography, and cardiac hypertrophy quantified using echocardiography at 0, 4 and 8 weeks of treatment. LV gene expression of natriuretic peptides was assessed by Northern blot analysis. To examine the effects on vascular hypertrophy, 3rd order mesenteric resistance arteries were fixed in formalin at half systolic blood pressure, stained with propidium iodide, and imaged using LSCM. One-way ANOVA was used to compare between groups, correcting for multiple comparisons using the Newman-Keuls test. Conclusion - Heart failure was mild and well compensated in these animals. Despite this, a novel type of remodelling was observed in mesenteric resistance arteries, which could have implications for small artery function. A small study was undertaken to examine the feasibility of performing CAL in the SHRSP. Of eleven animals, six survived to 2-weeks, while only three of these, with the smallest infarcts, survived the full 8 weeks. Peri-surgical death was similar to WKY, but arrhythmic death more common. Future approaches to bring mortality within acceptable limits could include the use of anti-arrhythmic drugs or blood pressure lowering immediately after surgery. (Abstract shortened by ProQuest.).