| Popis: |
Ischaemic heart disease (lHD) and diabetes are a cause of considerable morbidity and mortality worldwide. They cause several functional and structural changes in the myocardium leading to heart failure. Although functional changes in the diabetic heart are well established, the structural basis for these changes is not well defined, especially in man. This study quantified pathology of cardiomyocytes and myocardial microvasculature in relation to the expression of angiogenic factors namely HIF-1a, VEGF and VEGFR2 in the left atrial appendage (LAA) of 100 patients with IHD and/or diabetes compared to subjects without IHD or diabetes. There was a significant reduction in cardiomyocyte diameter in diabetic patients compared to controls. Furthermore, vascular density was reduced in diabetic patients and this was significant in those with IHD. Detailed quantification of distal myocardial capillaries in diabetic patients confirmed the presence of microangiopathy characterised by luminal narrowing, endothelial hypertrophy and hyperplasia and pericyte atrophy with basement membrane thickening. This pathology was associated with a significant increase in HIF-I a expression but with a significant reduction in VEGF expression on the endothelium of diabetic patients compared to controls. In IHD patients there was no change in cardiomyocyte diameter but there was a significant increase in arteriolar walllIumen ratio and a trend for an increase in capillary density. Myocardial capillaries showed a significant reduction in the luminal area without endothelial cell hypertrophy/hyperplasia or basement membrane thickening compared to controls. This was associated with a significant increase in the intensity and percentage of HIF-1a expression but no change in VEGF or VEGFR2 expression compared to controls. Pathology of cardiomyocytes and myocardial microvasculature has also been quantified in the atrium and ventricle of two different animal models of diabetic complications: the Zucker diabetic fatty (ZDF) rat and galactosaemic dog. There was a significant reduction in vascular density in the LAA but not the ventricle of the ZDF rats compared to lean Iittermates. The cardiomyocyte diameter was increased in the LAA, reaching significance in the left ventricle (LV) of the ZDF rats. There was no alteration in arteriolar or venular wall/lumen ratio, however, myocardial capillaries showed a reduction in lumen size in the LAA and basement membrane thickening in both LAA and LV. Galactosaemic dogs showed a significant increase in arteriole wall to lumen ratio in both the atrium and ventricle compared to controls. Myocardial capillaries of the galactosaemic dogs demonstrated a reduction in luminal area with hypertrophy of endothelial cells and a reduction in pericyte area but no basement membrane thickening or change in cardiomyocyte diameter. In conclusion, this thesis provides detailed pathological quantification of both cardiomyocytes and myocardial microvasculature in patients with IHD and diabetes as well as 2 animal models of diabetes. It demonstrates significant distal capillary abnormalities in patients with IHD and an abnormality of the cardiomyocyte and distal myocardial capillaries in the LAA of diabetic patients which have been related to both clinical and molecular alterations. In the 2 experimental models structural pathology though present differs in its characteristics and severity. |
