Skin microvascular reactivity and subendocardial viability ratio in relation to dyslipidemia and signs of insulin resistance in non-diabetic hypertensive patients.

OBJECTIVE: The aim of this study was to evaluate the influence of dyslipidemia and insulin resistance for the development of microvascular dysfunction in non-diabetic primary hypertension. METHODS: Seventy-one patients with untreated primary hypertension were included. Skin microvascular reactivity was evaluated by laser Doppler fluxmetry with iontophoresis (acetylcholine, ACh and sodium nitroprusside, SNP) and heat-induced hyperemia. Myocardial microvascular function was estimated by the subendocardial viability ratio (SEVR) calculated from pulse wave analysis and applanation tonometry. Triglyceride x glucose (TyG index) and triglyceride/HDL cholesterol ratio were used as measurements of insulin resistance. RESULTS: Skin microvascular dysfunction was associated with low HDL cholesterol, where Ach-mediated peak flux (r = .27, p = .025) and heat-induced peak flux (r = .29, p = .017) related to HDL cholesterol levels. ACh peak flux was inversely related to TG/HDL ratio (r = -.29, p = .016), while responses to local heating and SNP did not. SEVR did not relate to HDL and was unrelated to markers of insulin resistance. These findings were confirmed by multivariable analyses, including potential confounders. CONCLUSIONS: Early microvascular dysfunction can be detected in non-diabetic hypertensive patients and is related to dyslipidemia and to signs of insulin resistance, thus predicting future cardiovascular risk.

Aortic stiffness and aortic-brachial stiffness mismatch as markers of renal dysfunction in hypertension.

PURPOSE: The dismal combination of hypertension and chronic kidney disease potentiates both cardiovascular disease and loss of renal function. Research points to the importance of arterial and left ventricular stiffening in this process but few studies have compared aspects of central and peripheral hemodynamics in relation to renal function in hypertension. MATERIALS AND METHODS: We investigated 107 hypertensive individuals with renal function ranging from normal to severe dysfunction with pulse wave analysis to obtain central blood pressures (BP), augmentation index, carotid-femoral and carotid-radial pulse wave velocity (cfPWV, crPWV), aortic-to-brachial stiffness mismatch (cfPWV/crPWV), endothelial function by forearm flow-mediated vasodilation and myocardial microvascular function by subendocardial viability ratio, and indices of left ventricular structure (left ventricular mass index and relative wall thickness, RWT) and diastolic function (left atrial volume index, E/A, and E/é). RESULTS: Mean age was 58 years, BP 149/87 mm Hg, 9% had cardiovascular disease, and 31% were on antihypertensive treatment. Mean estimated glomerular filtration rate (eGFR) was 74 (range 130-21) ml/min × 1.73 m2. Whereas cfPWV and cfPWV/crPWV were independently related to eGFR (r = -0.20, p = 0.002, r = -0.16, p = 0.01), central diastolic BP (r = 0.21, p = 0.04), RWT (r = -0.34, p = 0.001), E/é (r = -0.39, p < 0.001) and E/A (r = 0.27, p = 0.01) were related to eGFR in bivariate correlations, but these findings were not retained in multivariate analyses. Remaining markers of hypertensive heart disease and measures of microvascular function were not related to eGFR. CONCLUSION: Increased aortic stiffness and aortic-to-brachial stiffness mismatch are independently related to reduced eGFR in hypertensive patients, suggesting an important role for aortic stiffness in the evolution of hypertension-mediated renal dysfunction. Aortic stiffness and aortic-brachial stiffness mismatch may be useful early markers to find hypertensive patients at risk for decline in renal function.

The interrelation of endothelial function and microvascular reactivity in different vascular beds, and risk assessment in hypertension: results from the Doxazosin-ramipril study.

There are several non-invasive methods to study endothelial function, but their interrelation and association to cardiovascular risk have not been well evaluated. We studied macrovascular and microvascular endothelial function simultaneously in different vascular beds in relation to cardiovascular mortality risk (Systematic Coronary Risk Evaluation, SCORE) and hypertension induced cardiac organ damage, and their interrelationship. The study investigated 71 hypertensive patients by forearm post-ischemic flow-mediated vasodilation, pulse wave analysis (applanation tonometry) and beta 2-adrenoceptor agonist stimulation for changes in reflection index, skin microvascular reactivity by laser Doppler fluxmetry with iontophoresis and heat-induced hyperaemia, and coronary microvascular function by subendocardial viability ratio (derived from pulse wave analysis). Flow mediated vasodilation related inversely to SCORE (r = 0.34, P = 0.011). Adding microalbuminuria and pulse wave velocity strengthened the associations. Pulse wave reflection changes did not relate to SCORE. Skin microvascular reactivity related inversely to SCORE (peak flux change to sodium nitroprusside r = 0.29, P = 0.033, and to heating r = 0.31, P = 0.018). Subendocardial viability ratio did not relate to SCORE. Endothelial function indices showed no consistent relation to cardiac target organ damage. The agreement between the different methods for evaluating indices of macrovascular and microvascular endothelial function was weak. In conclusion, indices of macrovascular and microvascular endothelial function relate to cardiovascular mortality risk. Their use may improve cardiovascular risk prediction in hypertension. However, methods representing different vascular beds show little interrelationship and are not interchangeable, which may depend on different pathogenetic mechanisms representing different aspects of future cardiovascular risk.Trial registry: NCT02901977.

Effects of Angiotensin-Converting Enzyme Inhibition and Alpha 1-Adrenergic Receptor Blockade on Inflammation and Hemostasis in Human Hypertension.

Drugs blocking the renin-angiotensin-aldosterone system may offer benefit on endothelial function, inflammation, and hemostasis in addition to the effects of reducing blood pressure. We examined the contribution of the angiotensin-converting enzyme inhibitor ramipril and the alpha 1-adrenergic receptor blocker doxazosin on blood pressure and on markers of inflammation and hemostasis in 59 individuals with mild-to-moderate hypertension randomized to receive double-blind ramipril 10 mg od or doxazosin 8 mg od for 12 weeks. Inflammatory markers (interleukin-6, soluble interleukin-6 receptor, interleukin-8, tumor necrosis factor-α, monocyte chemoattractant protein-1, and C-reactive protein) and hemostasis (plasminogen activator inhibitor-1 activity, tissue plasminogen activator antigen, thrombin-antithrombin complex, and thrombin generation by calibrated automated thrombogram) were assessed. The treatment reduced blood pressure in both groups. Thrombin-antithrombin complex decreased by treatment, and this was dependent on a reduction in thrombin-antithrombin complex in the ramipril group alone. There were no changes in plasminogen activator inhibitor-1 activity, whereas tissue plasminogen activator antigen increased by ramipril and decreased by doxazosin. Only minor changes were observed in systemic inflammation by treatment. Treatment with ramipril seems to reduce thrombin generation beyond effects on reducing blood pressure. Drugs blocking the renin-angiotensin-aldosterone system may reduce atherothrombotic complications beyond their effects to reduce blood pressure.

The usefulness of a single arm cuff oscillometric method (Arteriograph) to assess changes in central aortic blood pressure and arterial stiffness by antihypertensive treatment: results from the Doxazosin-Ramipril Study.

PURPOSE: Inhibition of the renin-angiotensin system may have effects on vascular structure and function beyond the effects on blood pressure (BP) reduction. We studied the ability of a single arm cuff oscillometric method (Arteriograph, TensioMed, Hungary) to assess effects of antihypertensive treatment on BP and arterial stiffness. Furthermore, this technique was compared to pulse wave analysis and applanation tonometry (SphygmoCor, AtCor Medical, Australia). MATERIALS AND METHODS: Brachial and aortic BP, augmentation index (AIx), and carotid-femoral pulse wave velocity (PWV) was simultaneously assessed by both techniques in 71 untreated hypertensive patients. Thereafter, 58 completed double-blind randomized treatment for 12 weeks with ramipril or doxazosin. RESULTS: Treatment (assessed by the Arteriograph) reduced aortic more than brachial systolic BP (-13.2 vs. -11.2 mm Hg; p = .002) and improved all indices of arterial stiffness. This greater reduction in aortic to brachial systolic BP was more marked by ramipril than by doxazosin (-20.9 and -17.1 vs. -4.3 and -4.2 mm Hg; p = .006), with a similar trend for AIx (-6.2 vs. -2.2%; p = .058). Both devices showed correlations for aortic and brachial systolic and diastolic BP and AIx (r = 0.75-0.86, all p < .001), while agreement for PWV was weaker (r = 0.28; p = .043). The Arteriograph generally recorded higher values for aortic BP and AIx than the SphygmoCor. CONCLUSIONS: Antihypertensive treatment reduced aortic systolic BP more than brachial BP and improved arterial stiffness. Blocking the renin-angiotensin system may have additional effects beyond BP reduction. We demonstrate the feasibility of the Arteriograph to monitor changes in BP and arterial stiffness by treatment.

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.

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).

Markers of inflammation, endothelial activation, and arterial stiffness in hypertensive heart disease and the effects of treatment: results from the SILVHIA study.

We assessed the contribution of blood pressure (BP), inflammation, and endothelial activation to the development of structural vascular and cardiac changes in hypertension. Furthermore, the effects of antihypertensive therapy were studied. We studied 114 patients with hypertension and left ventricular hypertrophy and 38 matched hypertensive subjects without cardiac hypertrophy and 38 normotensive subjects. The group with hypertension and cardiac hypertrophy were randomized to treatment with an angiotensin receptor blocker (irbesartan) or a beta-adrenergic receptor blocker (atenolol) for 48 weeks. Markers of inflammation (high-sensitive C-reactive protein, interleukin-6, leukocyte counts), vascular function (ambulatory aortic stiffness index, arterial compliance, and pulse pressure), and endothelial activation (E-selectin, intracellular adhesion molecule-1, vascular adhesion molecule-1) were assessed. Markers of inflammation and arterial stiffness were lowest in the normotensive group and highest in patients with hypertensive heart disease; endothelial markers were similar between groups. Inflammation was independently related to BP. Markers of arterial stiffness were independently related to BP and to a lesser extent to left ventricular mass. Antihypertensive treatment improved arterial compliance; inflammatory and endothelial markers remained unchanged. In conclusion, markers of inflammation and arterial stiffness are independently related to BP. Antihypertensive therapy seems to improve arterial stiffness, but effects on markers of inflammation and endothelial activation are small.

Treatment of Hypertensive Left Ventricular Hypertrophy.

BACKGROUND: The development and risk potential of hypertension-induced left ventricular (LV) hypertrophy has been well described in epidemiological studies. Regression of LV hypertrophy reduces cardiovascular morbidity and mortality. However, the best treatment strategy is still debated, as well as the appropriate blood pressure target in these patients. OBJECTIVE: We here review the treatment of LV hypertrophy and the potential benefit on clinical outcomes, against a background of the epidemiology and pathophysiology. RESULTS: Both hemodynamic and non-hemodynamic mechanisms contribute to hypertensive LV hypertrophy, which is characterized by an inappropriate myocardial fibrosis. Stringent blood pressure control reduces LV hypertrophy. Blockers of the renin-angiotensin-aldosterone system may have valuable effects on cardiac and electrophysiological remodelling beyond the effects of blood pressure reduction. Thus, they represent a cornerstone in the treatment of hypertensive LV hypertrophy, but most often other antihypertensive drug classes need to be added. Current guidelines indicate a blood pressure target in most patients with hypertensive LV hypertrophy of 120-130/80 mmHg. CONCLUSIONS: LV hypertrophy and myocardial fibrosis are important characteristics of hypertensive heart disease and associated with untoward prognosis. Regression of LV hypertrophy reduces cardiovascular morbidity and mortality. New drugs under development may add additional benefit.

Elevated circulating levels of thioredoxin and stress in chronic heart failure.

BACKGROUND: Chronic heart failure (CHF) is a complex syndrome, in which reactive oxygen species and inflammatory cytokines are important stressors that contribute to the pathogenesis. AIM: We have studied physiological stress response parameters in CHF, in particular the redox-active regulator thioredoxin. SUBJECTS: A case-control study was conducted including a consecutive sample of CHF patients (n=27) of NYHA class II and III; comparison control subjects (n=29) were recruited from an association for retired people. METHOD: Baseline levels of Trx, lipid peroxides (oxidative stress), TNF and IL-6 cytokines, platelet-activation marker P-selectin, cortisol (as peripheral effector of HPA axis), and the potent antioxidant selenoprotein Trx-reductase were assessed. RESULTS: Mean (+/-S.E.M.) plasma levels of Trx were significantly higher in patients with CHF (32+/-3 ng/ml), than in the healthy subjects (12+/-3 ng/ml, P<0.0001). Trx levels increased in proportion to severity of disease (NYHA class III>NYHA class II) and degree of stress. Trx elevation correlated well with increased oxidative stress (lipid peroxides, P<0.0001), circulatory P-selectin (P<0.0001), morning level of free salivary cortisol (P=0.0002), and serum creatinine (P=0.0417), but not with pro-inflammatory cytokines TNF and IL-6. CONCLUSION: Trx was strikingly elevated in heart failure cases compared with controls, signifying an adaptive stress response that is higher the more severe the disease.