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Studies investigating the relation between circulating vascular biomarkers reflecting endothelial dysfunction and physiological methods to evaluate vascular function remain limited. We simultaneously evaluated the relation between circulating endothelial biomarkers with physiological non-invasive vascular methods in 107 hypertensive patients with a wide range of mean estimated glomerular filtration rate (eGFR). Endothelial glycocalyx hyaluronan (HA) and syndecan-1 (SDC-1), and cellular adhesion molecules (ICAM-1, VCAM-1, and E-selectin) were measured by enzyme-linked immunosorbent assays. Aortic stiffness (cfPWV) was assessed by pulse wave analysis. Endothelial function in different vascular beds was evaluated physiological by methods: flow mediated vasodilation (large arteries), pulse wave analysis and the reflection index change, using beta 2-adrenoceptor agonist stimulation (smaller resistance arteries), and laser Doppler fluxmetry and iontophoresis (skin microvascular function). Diastolic function and left atrial size were assessed by echocardiography. Mean blood pressure (BP) was 149 ± 17/87 ± 10 mm Hg, mean eGFR 74 (21–130) ml/min x 1.73 m 2 . HA was independently related to cfPWV (β = 0.23, P  = 0.02), whereas SDC-1 was independently inversely related to skin microvascular function, (β= − 0.27, P  = 0.042) and was independently related to resistance artery endothelial function (β = 0.29, P  = 0.026). All circulating biomarkers were unrelated to physiologically measured large artery endothelial function, and with echocardiographic parameters. The glycocalyx markers were associated with physiological vascular measures independent of eGFR but should not be considered as a proxy for these measures, due to the weak relations. However, combining circulating markers with physiological measures might give additional information about vascular function.

We aimed to study whether inhibition of the renin–angiotensin–aldosterone system has effects on vascular structure and function beyond the effects on blood pressure reduction alone. Patients with mild-to-moderate hypertension ( n  = 61, age 54 ± 12 years, 34% women) received the angiotensin converting enzyme inhibitor ramipril 10 mg or the alpha 1-adrenoceptor blocker doxazosin 8 mg double-blind for 12 weeks. Aortic blood pressure, pulse wave velocity, and augmentation index were assessed by applanation tonometry. Endothelial function was studied by forearm post-ischemic flow mediated vasodilatation and by pulse wave analysis with beta 2-adrenoceptor agonist stimulation. Skin microvascular reactivity was assessed by laser Doppler fluxmetry and iontophoresis. Treatment with doxazosin or ramipril reduced aortic and brachial blood pressures (all P  < 0.001), with greater reductions in aortic than brachial systolic blood pressures ( P  = 0.021) and aortic/brachial pulse pressure ratio ( P  = 0.005). Compared to doxazosin, ramipril reduced carotid-femoral and carotid-radial pulse wave velocity (both P  < 0.05). Forearm endothelial dependent and independent vasodilatation, assessed by post-ischemic flow mediated vasodilatation and glyceryl trinitrate, and by pulse wave analysis remained unchanged by both doxazosin and ramipril. In addition, skin microvascular endothelial dependent (acetylcholine) and independent vasodilatation (sodium nitroprusside) remained unchanged. In conclusion, ramipril reduced indices of aortic stiffness, suggesting that angiotensin converting enzyme inhibitor therapy may have effects beyond blood pressure reduction. However, treatment did not appear to influence endothelial function. Evidence of endothelial dysfunction and its possible improvement by antihypertensive treatment might require more advanced hypertension. This study is registered at ClinicalTrials.gov (NCT02901977) and at EudraCT (# 2007-000631-25).

Objectives: To study whether inhibition of the renin-angiotensin-aldosterone system has effects on arterial stiffness beyond blood pressure (BP) reduction alone. Methods: Hypertensive patients (age 54±12 years, 34% women) were randomized double-blind to ramipril (10 mg od, n=32) or doxazosin (8 mg od, n=26) for 12 weeks. Central aortic BP and pulse pressure (PP), aortic pulse wave velocity (PWV), and augmentation index (AIx) were assessed by a single cuff oscillometric cuff method (Arteriograph, Tensiomed). With PWV and Aix adjustments were made for potential confounding by height, age, gender, and baseline mean arterial pressure. Results: Seated office brachial BP on inclusion was (mean values ± SD) 154±10/93±9 mmHg. Baseline central BP was 154±19/93±9 mmHg, central PP was 61±13 mmHg, PWV 9.0±2.1 m/s, AIx 45±13%, and transit time 61±12 ms. Treatment induced changes (mean values ± SEM) in central BP (−8±2/−8±1%; both P<0.01), aortic PP (−9±2 mmHg; P<0.01), PWV (−5.2±2.0%; P<0.05), AIx (−12±3%; P<0.01), and transit time (8±3 ms; P<0.01). Ramipril induced greater changes than doxazosin in central BP (−13±2/−11±2 vs −2±2 /−3±2%; all P<0.01), central PP (−16±3 vs −2±3 mmHg; P<0.01), and AIx (−18±4 vs −5±4%; P<0.05). The reductions in PWV were similar for ramipril and doxazosin (−6±3 vs −4±3%, respectively). Conclusions: Both ramipril and doxazosin reduce BP and indices of arterial stiffness, with greater effects by ramipril on central BP and AIx. The results suggest that the single cuff oscillometric cuff technique can be used to evaluate effects of antihypertensive treatment on central BP and arterial function.

Objectives To study whether inhibition of the renin-angiotensin-aldosterone system has effects on vascular function beyond blood pressure (BP) reduction alone. Methods Mild-to-moderate hypertensive patients (age 54±12 years, 34% women) were randomized double-blind to ramipril (10 mg od, n = 33) or doxazosin (8 mg od, n = 28) for 12 weeks. Central BP, pulse wave velocity (PWV), and augmentation index (AIx) were assessed by applanation tonometry (SphygmoCor, AtCor Medical). Endothelial function was studied by forearm post-ischemic flow mediated vasodilatation (FMD) and pulse wave analysis with beta 2-adrenoceptor-agonist stimulation, and by skin microcirculation iontophoresis (acetylcholine and sodium nitroprusside). Results Baseline central and brachial BP were 140/89 and 148/89 mmHg, carotid and brachial pulse pressures 51 and 60 mmHg, carotid-femoral and carotid-radial PWV 8.8 and 8.9 m/s, and AIx 30.1%. Treatment induced reductions (means±SEM) in central and brachial BP (−7.9±1.1/−6.6±1.1 and −6.0±1.0/−6.8±1.1%; all P<0.001) with greater reductions in central BP (all P<0.05), carotid/brachial pulse pressure ratio (−4.7±1.7%; P<0.01), carotid-radial PWV (−2.9±2.0%; P<0.05), and AIx (−15.9±4.5%; P<0.01), but did not affect carotid-femoral PWV or carotid-femoral/carotid-radial PWV ratios. Ramipril induced greater changes than doxazosin in central and brachial systolic BP (−9.8±1.4 vs −5.4±1.6 and −7.9±1.3 vs −3.8±1.4%; all P<0.05) but central/brachial BP ratio reductions were similar. All endothelial function indices suggested normal endothelial function (eg FMD 5.5±4.1%, reflection index 0.79±0.06) with no treatment effects. Conclusions Angiotensin converting enzyme-inhibition and alpha 1-adrenoceptor-blockade similarly reduce central BP more than brachial BP and improve indices of aortic stiffness. Evidence of endothelial dysfunction might require more advanced stages of hypertensive disease.

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.