Vascular and endothelial function in human hypertension, and the importance of the renin-angiotensin-aldosterone system

Background: Hypertension induces structural vascular and cardiac changes with increased arterial stiffness and left ventricular (LV) hypertrophy and is major risk factor for cardiovascular morbidity and mortality. The renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system are important for blood pressure regulation and vascular function. Angiotensin II, the main effector of the RAAS, induces vasoconstriction, inflammation, structural vascular changes, and LV hypertrophy. Thus, treating hypertension with drugs blocking the RAAS might have advantages compared to other drug classes. The overall objective of this thesis was to increase our knowledge about the evaluation of arterial structure and function in human hypertension. Thus, the effects of treatment on indices of arterial stiffness and endothelial function were studied, and the effects beyond blood pressure reduction by blocking the RAAS were evaluated by comparison to drugs acting on the sympathetic nervous system.

Material and methods: This work is based on two clinical studies. In the “Swedish irbesartan left ventricular hypertrophy versus atenolol project” (SILVHIA), 115 patients with hypertension and LV hypertrophy were randomized to treatment based on the AT1-receptor blocker irbesartan or the beta-adrenoceptor blocker atenolol for 48 weeks. Two matched control groups consisting of hypertensive patients with no LV hypertrophy and normotensive control subjects were also investigated. We studied arterial stiffness (by pulse pressure, total vascular compliance, and ambulatory arterial stiffness index) and circulating markers of inflammation and of endothelial activation. In the “Doxazosin-ramipril study” (DoRa), 71 hypertensive patients were randomized to treatment with the angiotensin-converting enzyme inhibitor ramipril or the alpha 1-adrenoceptor blocker doxazosin for 12 weeks. The effects of treatment on arterial stiffness (by pulse wave analysis with applanation tonometry and by an oscillometric single-arm cuff method) and on endothelial function were evaluated simultaneously in different vascular beds (by forearm flow-mediated vasodilatation, pulse wave analysis and beta 2-adrenoceptor agonist stimulation, skin microcirculation by laser Doppler fluxmetry and iontophoresis, and myocardial microcirculation by the subendocardial viability ratio).

Results and conclusions: Antihypertensive treatment improved indices of arterial stiffness, and blocking the RAAS had additional effects on arterial stiffness beyond blood pressure reduction. There were no effects on endothelial function from the treatment. The oscillometric single cuff method was a simple and useful method to assess arterial function and to evaluate drug-induced treatment effects. Endothelial functions in different vascular beds were all related to future cardiovascular mortality risk (according to the “Systematic coronary risk evaluation”, SCORE), but not to hypertension-induced heart disease. However, the studied methods to evaluate endothelial function were poorly interrelated. Thus, drugs blocking the RAAS may offer an advantage in the treatment of hypertension beyond the effects on blood pressure reduction, as compared to other drug classes.

List of scientific papers

I. Jekell A, Malmqvist K, Wallén NH, Mörtsell D, Kahan T. Markers of inflammation, endothelial activation, and arterial stiffness in hypertensive heart disease and the effects of treatment: Results from the SILVHIA study. J Cardiovasc Pharmacol. 2013; 62:559-566.
https://doi.org/10.1097/FJC.0000000000000017

II. Jekell A, Kalani M, Kahan T. The effects of alpha 1-adrenoceptor blockade and angiotensin converting enzyme inhibition on central and brachial blood pressure and vascular reactivity: the doxazosin-ramipril study. Heart Vessels. 2017; 32:674-684.
https://doi.org/10.1007/s00380-016-0924-9

III. Jekell A, Kahan T. The usefulness of a single arm oscillometric method (Arteriograph) to assess changes in central aortic blood pressure and arterial stiffness by antihypertensive treatment: results from the Doxazosin-Ramipril Study. Blood Press. 2018; 27:88-98.
https://doi.org/10.1080/08037051.2017.1394791

IV. Jekell A, Kalani M, Kahan T. Endothelial function and microvascular reactivity in relation to cardiovascular risk in hypertension: Results from the Doxazosin-ramipril study. [Manuscript]