Endothelial Dysfunction in Cardiovascular Disease
Endotheel dysfunctie in cardiovasculaire ziektes
The measurement of endothelial function might predict the presence of CAD in patients. Therefore, we tested in part I of this thesis the applicability of peripheral endothelial dysfunction as a measurement for the presence of coronary artery disease (CAD) in symptomatic patients. We showed that endothelial function measurement with peripheral arterial tonometry is a heterogeneous measurement with poor correlation with traditional measurements. Moreover, the measurement failed to predict revascularization within one year. Therefore, in spite of the pathophysiological basis of endothelial dysfunction in CAD, no evidence was found for peripheral endothelial function measurement as a diagnostic tool to detect clinically relevant CAD.
Since patient studies to unravel underlying disease processes are usually hampered by limited measurements because of ethical concerns; experimental disease models in animals can enhance our understanding of the pathogenesis of CAD. Therefore, we studied and developed an animal model of CAD, in which we studied the coronary microcirculation. We demonstrated that small coronary arteries showed functional alterations in vitro in the process of early systemic atherosclerosis development in diabetic pigs on a high fat diet, reflecting an altered coronary microvascular balance. This balance changed over time during CAD progression and was shown to be a systemic process.
In part II of this thesis, we studied endothelial dysfunction in relation to percutaneous coronary interventions. We demonstrated that specific first generation drug-eluting stents impair the microcirculation in the distal perfusion area of the stent. Also, the latest percutaneous coronary intervention, the bioresorbable vascular scaffold, was studied with regard to endothelial dysfunction. We demonstrated that specifically in diabetic pigs coronary conduit segments proximal and distal to the scaffold edges showed reduced endothelium-dependent vasodilation.
In part III of this thesis, we studied endothelial dysfunction related to diabetes mellitus and the renin-angiotensin-aldosterone system (RAAS). To examine which RAAS components are activated in diabetes, we examined these components in both plasma and urine samples of both diabetic and non-diabetic patients with hypertension.
We proved that urinary renin more closely reflects renal RAAS activity than urinary angiotensinogen or aldosterone. The relation between an overactive RAAS, DM and endothelial dysfunction was further studied with use of diabetic, hypertensive, transgenic rats with high prorenin, renin and (pro)renin receptor levels. We evaluated whether the renin inhibitor aliskiren, with or without the (pro)renin receptor antagonist HRP, improved the disturbed vascular function and end organ disease of diabetic transgenic rats. Endothelial dysfunction with an altered vasomotor balance was demonstrated to be present within this animal model and we demonstrated that treatment with the renin inhibitor aliskiren reversed the vascular effects, as well as end organ disease. This indicates that renin inhibition can at least partially reverse the altered endothelial balance of diabetes and an overactive RAAS. Remarkably, when blocking the (pro)renin receptor on top of renin inhibition, the beneficial effects disappeared.
|, , ,|
|D.J.G.M. Duncker (Dirk) , A.H.J. Danser (Jan)|
|Erasmus University Rotterdam|
|Een deel van de onderzoeken werd mede mogelijk gemaakt door financiële ondersteuning van het Netherlands Heart Institute te Utrecht, waarvoor dankbare erkenning.|
|Organisation||Department of Pharmacology|
van den Heuvel, M.M. (2018, May 15). Endothelial Dysfunction in Cardiovascular Disease. Erasmus University Rotterdam. Retrieved from http://hdl.handle.net/1765/105789