Use of proteomics to identify biomarkers associated with chronic kidney disease and long-term outcomes in patients with myocardial infarction.

BACKGROUND: Patients with chronic kidney disease (CKD) have poor outcomes following myocardial infarction (MI). We performed an untargeted examination of 175 biomarkers to identify those with the strongest association with CKD and to examine the association of those biomarkers with long-term outcomes. METHODS: A total of 175 different biomarkers from MI patients enrolled in the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) registry were analysed either by a multiple reaction monitoring mass spectrometry assay or by a multiplex assay (proximity extension assay). Random forests statistical models were used to assess the predictor importance of biomarkers, CKD and outcomes. RESULTS: A total of 1098 MI patients with a median estimated glomerular filtration rate of 85 mL min-1 /1.73 m2 were followed for a median of 3.2 years. The random forests analyses, without and with adjustment for differences in demography, comorbidities and severity of disease, identified six biomarkers (adrenomedullin, TNF receptor-1, adipocyte fatty acid-binding protein-4, TNF-related apoptosis-inducing ligand receptor 2, growth differentiation factor-15 and TNF receptor-2) to be strongly associated with CKD. All six biomarkers were also amongst the 15 strongest predictors for death, and four of them were amongst the strongest predictors of subsequent MI and heart failure hospitalization. CONCLUSION: In patients with MI, a proteomic approach could identify six biomarkers that best predicted CKD. These biomarkers were also amongst the most important predictors of long-term outcomes. Thus, these biomarkers indicate underlying mechanisms that may contribute to the poor prognosis seen in patients with MI and CKD.

Pregnancy-associated plasma protein-A is positively correlated with first-trimester skin microvascular reactivity.

OBJECTIVE: To investigate the relationship between levels of circulating maternal pregnancy-associated plasma protein-A (PAPP-A) and first-trimester maternal vascular function. METHODS: This was a cross-sectional study of 53 healthy, non-smoking, nulliparous pregnant women in Stockholm, Sweden. PAPP-A levels and vascular function were assessed during gestational weeks 11-14. Forearm skin microcirculation was investigated by laser Doppler perfusion imaging during iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP) to assess endothelium-dependent and -independent microvascular vasodilatation, respectively. Microvascular endothelial function index was calculated as peak ACh/peak SNP. Endothelium-dependent and -independent vasodilatation in the brachial artery was evaluated, respectively, by postischemic hyperemia-induced flow-mediated vasodilatation (FMD) and by response to sublingual intake of glyceryl trinitrate (GTN). RESULTS: PAPP-A was correlated with skin microvascular endothelial function index (ß = 1.008 (95% CI, 0.34-1.68), r2  = 0.17, P = 0.004). PAPP-A also correlated inversely with FMD (ß = -0.052 (95% CI, -0.094 to -0.011), r2  = 0.13, P = 0.014) but did not relate to forearm endothelial function index (i.e. FMD/GTN). The results were retained in multivariate analyses including known confounding factors. CONCLUSIONS: First-trimester endothelium-dependent skin microvascular reactivity was positively related to PAPP-A levels. If confirmed, these novel findings suggest that first-trimester skin microvascular reactivity could be a useful early pregnancy marker of placental function. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Longitudinal study of vascular structure and function during normal pregnancy.

OBJECTIVE: To examine alterations in maternal vascular structure and function during normal pregnancy. METHODS: We assessed brachial and central blood pressure, pulse-wave velocity and augmentation index (by pulse-wave analysis and applanation tonometry), common carotid artery structure (by ultrasonography) and endothelial function in the brachial artery (by postischemic hyperemia-induced flow-mediated vasodilatation by glyceryl trinitrate) and in the forearm skin microcirculation (by laser Doppler perfusion imaging during iontophoretic administration of acetylcholine and sodium nitroprusside) in 52 healthy nulliparous women at 14, 24 and 34 weeks' gestation, and at 9 months postpartum. RESULTS: During pregnancy, brachial and central systolic and diastolic blood pressures initially decreased but subsequently increased (all P < 0.05). Flow-mediated vasodilatation in the brachial artery increased during early pregnancy (P < 0.05), whereas non-specific vasodilatation by glyceryl trinitrate decreased (P < 0.01), indicating improved endothelial function. Thus, endothelial function index (forearm blood flow/glyceryl trinitrate) increased during pregnancy (0.30 ± 0.18 in the non-pregnant state at 9 months postpartum and 0.51 ± 0.19, 0.61 ± 0.39 and 0.49 ± 0.30 in the first, second and third trimesters, respectively) (P < 0.001). Endothelium-dependent skin microvascular reactivity to acetylcholine also increased (P < 0.01). Carotid-femoral pulse-wave velocity decreased during pregnancy (5.88 ± 0.91 m/s in the non-pregnant state and 5.55 ± 0.67, 5.12 ± 0.66 and 5.62 ± 0.74 m/s in the first, second and third trimesters, respectively) (P < 0.001). CONCLUSION: During normal pregnancy, the blood volume expansion necessary for sufficient fetal growth is accommodated by early and marked changes in the matvascular system. This seems to be dependent on normal adaptive endothelial and vascular function. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Fetal growth is associated with first-trimester maternal vascular function.

OBJECTIVE: To investigate the relationship between maternal endothelial function in the first trimester, assessed in both the brachial artery and the forearm skin microcirculation, and fetal growth. METHODS: Vascular function was assessed in 56 pregnant women during gestational weeks 11-14. Vascular reactivity in the brachial artery was evaluated by postischemic hyperemia-induced flow-mediated vasodilatation (FMD) and by vasodilatation following administration of sublingual glyceryl trinitrate (GTN). Forearm skin microcirculation was investigated by laser Doppler perfusion imaging during iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP) to assess endothelium-dependent and -independent microvascular vasodilatation, respectively. Fetal growth was measured at study inclusion and birth-weight centile was calculated after delivery. RESULTS: FMD and GTN-induced vasodilatation were both associated with birth-weight centile. On multivariate analysis (adjusted for brachial artery diameter at rest, blood pressure, maternal age and heart rate), for FMD ß = 1.7 (95% CI, 0.06-3.34), r2 = 0.26 and P = 0.042, and for GTN-induced vasodilatation ß = 2.6 (95% CI, 0.44-4.68), r2 = 0.15 and P = 0.02. Endothelium-dependent and -independent microvascular reactivity were also associated with birth-weight centile: for ACh ß = 7.82 (95% CI, 1.81-13.83), r2 = 0.12 and P = 0.029, and for SNP ß = 6.27 (95% CI, 1.20-11.34), r2 = 0.11 and P = 0.016. CONCLUSION: First-trimester maternal vascular dilatation capacity (rather than endothelial function alone) is associated with fetal growth. These findings were consistent in both the brachial artery and the forearm skin microcirculation. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

The Impact of the Renin-Angiotensin-Aldosterone System on Inflammation, Coagulation, and Atherothrombotic Complications, and to Aggravated COVID-19.

Atherosclerosis is considered a disease caused by a chronic inflammation, associated with endothelial dysfunction, and several mediators of inflammation are up-regulated in subjects with atherosclerotic disease. Healthy, intact endothelium exhibits an antithrombotic, protective surface between the vascular lumen and vascular smooth muscle cells in the vessel wall. Oxidative stress is an imbalance between anti- and prooxidants, with a subsequent increase of reactive oxygen species, leading to tissue damage. The renin-angiotensin-aldosterone system is of vital importance in the pathobiology of vascular disease. Convincing data indicate that angiotensin II accelerates hypertension and augments the production of reactive oxygen species. This leads to the generation of a proinflammatory phenotype in human endothelial and vascular smooth muscle cells by the up-regulation of adhesion molecules, chemokines and cytokines. In addition, angiotensin II also seems to increase thrombin generation, possibly via a direct impact on tissue factor. However, the mechanism of cross-talk between inflammation and haemostasis can also contribute to prothrombotic states in inflammatory environments. Thus, blocking of the renin-angiotensin-aldosterone system might be an approach to reduce both inflammatory and thrombotic complications in high-risk patients. During COVID-19, the renin-angiotensin-aldosterone system may be activated. The levels of angiotensin II could contribute to the ongoing inflammation, which might result in a cytokine storm, a complication that significantly impairs prognosis. At the outbreak of COVID-19 concerns were raised about the use of angiotensin converting enzyme inhibitors and angiotensin receptor blocker drugs in patients with COVID-19 and hypertension or other cardiovascular comorbidities. However, the present evidence is in favor of continuing to use of these drugs. Based on experimental evidence, blocking the renin-angiotensin-aldosterone system might even exert a potentially protective influence in the setting of COVID-19.

The economic consequences of non-adherence to lipid-lowering therapy: results from the Anglo-Scandinavian-Cardiac Outcomes Trial.

BACKGROUND: Adherence to lipid-lowering therapy in clinical practice is less than ideal. Analysis of registry data has indicated that this is associated with poor outcomes. The objective of the present analysis was to assess the impact of high adherence to drug (defined as > 80% of days covered), compared with low adherence to drug (< 50% of days covered) in terms of risk of events and long-term economic consequences. DESIGN: Open-label follow up of a randomised placebo-controlled trial in hypertensive patients. METHODS: Cox proportional hazards and Poisson regression models were used to assess the hazard ratio of patients with high adherence compared with low adherence while controlling for cardiovascular risk. A Markov model was used to predict the long-term costs and health outcomes associated with poor adherence during the follow-up period. RESULTS: Both statistical models indicated that high adherence is associated with improved prognosis [Cox model: 0.75; 95% confidence interval (CI): 0.56-0.98, Poisson model hazard ratio: 0.73; 95% CI: 0.58-0.98]. Discounted at 3.5% per year, the Markov model predicts that as a consequence of higher adherence during the follow-up period, costs would be higher (1689 pounds per patient compared with 1323 pounds per patient) because of higher drug costs, but the projected survival and quality-adjusted survival (QALY) would also be longer (10.83 compared with 10.81 life years and 8.13 compared with 8.11 QALYs). CONCLUSION: Given the higher risk of cardiovascular events associated with low adherence shown here, measures to improve adherence are an important part of the prevention of cardiovascular disease.

Self-association of naphthalene at the air-ice interface.

We present a molecular dynamics study of the interactions between two molecules of naphthalene present at air-water versus air-ice interfaces. In agreement with the inference from our previous experimental work [Kahan, T. F.; Donaldson, D. J. J. Phys. Chem. A 2007, 111, 1277], the results suggest that self-association of the molecules is more likely to take place on the ice surface than on the water surface. A shorter average distance between the two naphthalene molecules, in conjunction with a stronger interaction energy and free energy of association, point to a stronger tendency to self-associate on ice than on water. The distinct behavior at the two interfaces appears be due to more favorable interactions between naphthalene molecules on liquid water surfaces than on ice surfaces.

Overview of HOMEChem: House Observations of Microbial and Environmental Chemistry.

The House Observations of Microbial and Environmental Chemistry (HOMEChem) study is a collaborative field investigation designed to probe how everyday activities influence the emissions, chemical transformations and removal of trace gases and particles in indoor air. Sequential and layered experiments in a research house included cooking, cleaning, variable occupancy, and window-opening. This paper describes the overall design of HOMEChem and presents preliminary case studies investigating the concentrations of reactive trace gases, aerosol particles, and surface films. Cooking was a large source of VOCs, CO2, NOx, and particles. By number, cooking particles were predominantly in the ultrafine mode. Organic aerosol dominated the submicron mass, and, while variable between meals and throughout the cooking process, was dominated by components of hydrocarbon character and low oxygen content, similar to cooking oil. Air exchange in the house ensured that cooking particles were present for only short periods. During unoccupied background intervals, particle concentrations were lower indoors than outdoors. The cooling coils of the house ventilation system induced cyclic changes in water soluble gases. Even during unoccupied periods, concentrations of many organic trace gases were higher indoors than outdoors, consistent with housing materials being potential sources of these compounds to the outdoor environment. Organic material accumulated on indoor surfaces, and exhibited chemical signatures similar to indoor organic aerosol.

Design and methods of a randomized controlled trial on early speech and language therapy in patients with acute stroke and aphasia.

PURPOSE: Most clinicians would recommend speech and language therapy (SLT) for aphasic patients. The question of when and for how long SLT should be administered still remains controversial. The aim of this trial is to evaluate the efficacy of early SLT in patients with acute stroke and aphasia in a randomized controlled trial. This report will present design and methods and discuss feasibility. METHOD: Consecutive patients with first ever ischemic stroke and aphasia are assessed by the Amsterdam-Nijmegen Everyday Language Test (ANELT) and a short version of the Norsk Grunntest for Afasi. The treatment is language enrichment therapy, and the therapy is given 45 min/day for 15 weekdays. The primary outcome is the difference in the degree of aphasia between the SLT treated group and the control group measured by ANELT at 3 weeks. RESULTS: Around 10% of acute consecutive patients with aphasia are included. Of the first 79 included patients, 86% have completed the study according to protocol. We intend to include 125 patients, which provide sufficient statistical power to detect a clinically significant difference in the degree of aphasia. CONCLUSION: It is feasible to conduct a randomized controlled study on very early SLT for acute aphasic patients.

Cardiac repolarization and its relation to ventricular geometry and rate in reverse remodelling during antihypertensive therapy with irbesartan or atenolol: results from the SILVHIA study.

Hypertensive left ventricular (LV) hypertrophy is associated with a substantial risk for malignant arrhythmias and sudden death. According to recent results, antihypertensive therapy with the angiotensin II type 1 receptor blocker irbesartan reverses both structural and electrical remodelling. However, the relation between the LV geometric pattern (concentric vs eccentric) and electrical reverse remodelling has not been characterized, neither has the relation between repolarization and rate (QT/RR and JT/RR relation), which presumably reflects the propensity for bradycardia-dependent ventricular arrhythmia. In this study, repeat echocardiographic and electrocardiographic measurements were performed in hypertensive patients with LV hypertrophy, randomized to double-blind therapy with irbesartan (n = 44) or the beta(1)-adrenoceptor blocker atenolol (n = 48) for 48 weeks; 53 patients had concentric and 39 eccentric LV hypertrophy. In addition, 37 matched hypertensive subjects without LV hypertrophy and no current therapy served as controls. Irbesartan induced structural and electrophysiological reverse remodelling, independent of LV geometry. In contrast, atenolol had similar beneficial effect only in patients with concentric LV hypertrophy, while the response in those with eccentric hypertrophy was unfavourable with both prolonged repolarization time and an increased QT/RR slope (suggesting reverse-use dependence). In conclusion, there is a significant geometry-related difference in the reverse remodelling processes induced by irbesartan and atenolol. Echocardiographic characterization of the geometry in hypertension-induced LV hypertrophy might become an important step in the selection of optimal antihypertensive therapy.

Individual differences in cortisol levels and performance on a test of executive function in men and women.

Despite evidence for a high concentration of corticosteroid receptors in prefrontal cortex, little research has examined the relationship between cortisol and prefrontal cortical function other than working memory. We investigated the association between salivary cortisol levels and performance on the Wisconsin Card Sorting Test (WCST) of executive function and on a test of mental rotation (to test specificity of the relationship between cortisol and cognitive performance) in men and women (n=116, ages 17-22). Higher cortisol levels at the beginning of the test session were associated with more errors in women on the WCST and fewer errors in men. However, men's cortisol levels were lower than women's at this point in time. Cortisol levels were not associated with mental rotation scores. Our results suggest that individual differences in cortisol levels among participants upon arrival to a test situation influence performance on a task involving the prefrontal cortex.

Predicting readmissions and cardiovascular events in heart failure patients.

AIMS: To analyse measures of clinical data, functional capacity, left ventricular function and neurohormonal activation for the ability to predict mortality and morbidity in patients after a hospitalisation for heart failure. METHODS: In a prospective study, patients 60 years or above with systolic heart failure NYHA II-IV were followed for at least 18 months. At study start, a physical examination, echocardiography, blood samples and measurements of quality of life (QoL) by Nottingham Health Profile were obtained. Data on mortality and readmission rates were collected. RESULTS: 208 patients, 58% men, with a mean age of 76 years, and an ejection fraction of 0.34 were included and followed for a mean of 1,122 days. In all, 74 (36%) patients died and 171 (82%) were readmitted. By univariate analysis, readmissions were predicted by poor QoL (169 +/- 118 vs. 83 +/- 100, p < 0.001), age, creatinine, haemoglobin (p < 0.01 all) and diabetes (p < 0.1). By multivariate analyses, QoL at study start was the only independent predictor of readmissions (chi(2) = 25.2, p < 0. 001). Mortality was univariately associated with QoL (183 +/- 117 vs. 142 +/- 115, p < 0.05) and in multivariate analyses to traditional variables: age, male gender, systolic function, BNP and serum creatinine (chi(2) = 48.9, p < 0.001). CONCLUSIONS: Measurements representing different aspects of the heart failure syndrome can easily be obtained to stratify long-term risks of mortality and morbidity in hospitalised heart failure patients. Poor QoL was a univariate predictor for mortality and a strong multivariate predictor for the important outcome of readmission, pointing to the need for a simple assessment of QoL.

Antihypertensive treatment and control according to gender, education, country of birth and psychiatric disorder: the Swedish Primary Care Cardiovascular Database (SPCCD).

The reasons why women and men are treated with different antihypertensive drugs are not clear. Whether socioeconomic factors influence prescription patterns and blood pressure control differently in women and men has not been investigated. This cross-sectional study performed in a cohort of hypertensive patients from the Swedish Primary Care Cardiovascular Database (SPCCD) examined the influence of educational level, country of birth, gender and concomitant psychiatric disorder on prescription pattern and blood pressure control in 40,825 hypertensive patients. Men were more often than women treated with calcium channel blocker and angiotensin-converting enzyme inhibitor (ACEI), irrespective of education, country of birth and psychiatric disorder. Educational level influenced the prescription pattern to some extent, where the gender differences were reduced in patients with a higher educational level. In women, but not in men, high educational level and concomitant psychiatric disorder were associated with a higher proportion reaching target blood pressure. The predominant use of ACEI and calcium channel blockers in men is not influenced by educational level, country of birth or psychiatric disorder. Thus other explanations must be considered such as gender differences in side effects. Educational level seems to have a greater impact on reaching target blood pressure in women compared with men.

Acute and chronic calcium antagonist treatment elevates sympathetic activity in primary hypertension.

Eleven men with mild to moderate primary hypertension were studied at rest and during mental stress before and during intravenous infusion of the calcium antagonist felodipine. Eight of them were restudied during long-term treatment (extended-release felodipine, 10 mg daily). For comparison, 10 normotensive control subjects were studied with the short-term protocol. Heart rate, cardiac output, central cardiovascular pressures, and forearm blood flow were registered. Arterial and venous sampling was performed. Norepinephrine spillovers to arterial plasma and from the forearm were assessed with the use of radiotracer methodology. In the hypertensive patients, felodipine lowered mean arterial blood pressure acutely by 8% (P < .01). Systemic vascular resistance decreased by 22% (P < .001), cardiac output increased by 20% (P < .01), and norepinephrine spillover to arterial plasma increased by 61% (P < .001). Forearm vascular resistance fell by 30% (P < .001), but norepinephrine overflow from the forearm increased by 115% (P < .001). These forearm responses were not seen in normotensive subjects despite similar systemic responses to felodipine infusion. After 8 weeks of treatment, mean arterial pressure decreased to 15% below baseline (P < .001), cardiac output returned toward pretreatment levels, and systemic vascular resistance remained low. Forearm blood flow returned toward basal levels, but forearm vascular resistance remained lowered. Total body and forearm norepinephrine spillover values were as elevated as in the acute situation. The hemodynamic "defense reaction" and the sympathoadrenal response to mental stress were essentially unaffected by felodipine. Stress-induced small elevations of neuropeptide Y-like immunoreactivity persisted during felodipine. Thus, the vasodilatation induced by felodipine elicits sympathetic counterregulation, which persists in the long term with respect to peripheral and total sympathetic activities, despite resetting of the baroreflex control of heart rate.

Soluble intercellular adhesion molecule-1 is related to endothelial vasodilatory function in healthy individuals.

OBJECTIVE: To investigate the associations between markers of systemic and vascular inflammation, and indicators of vascular morphology and function. METHODS: In 59 apparently healthy individuals, we measured serum levels of highly sensitive C-reactive protein (hsCRP), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin. Endothelium-dependent (EDV) and -independent (EIDV) vasodilatation was evaluated in the forearm by venous occlusion plethysmography and local infusions of methacholine and sodium nitroprussid. Endothelial function index (EFI) was expressed as the EDV/EIDV ratio. The intima-media thickness (IMT) of the common carotid artery was investigated with ultrasound (far wall). RESULTS: EFI was inversely related only to ICAM-1 (r=-0.31, P<0.02) by univariate analysis. This association remained significant after adjustment for age, sex, blood pressure, smoking and serum cholesterol. EFI did not relate to hsCRP, VCAM-1 or E-selectin. Neither hsCRP, nor the adhesion molecules were significantly related to carotid artery IMT. CONCLUSION: ICAM-1 was related to endothelial vasodilatory function, but not to IMT, suggesting that endothelial inflammatory activation is related to an impaired vascular relaxation in apparently healthy individuals.

Circulatory and sympatho-adrenal responses to stress in borderline and established hypertension.

Responses to mental stress [a colour word test (CWT), orthostatic testing (ORT) and a cold pressor test (CPT) were studied in 33 subjects with essential hypertension (EHT), 16 subjects with borderline hypertension (BHT) and 17 age and sex-matched normotensive controls (NT). Venous plasma noradrenaline (NA) was similar in all groups. CWT induced marked circulatory responses and metabolic activation with minor increases in NA. Circulatory and NA responses to ORT and CPT were similar in all groups. CWT elevated diastolic blood pressure more in BHT and tended to elevate HR more in EHT and BHT than in NT. Plasma adrenaline (ADR) tended to be higher in BHT and increased during all provocations in EHT and BHT but not in NT. Early hypertension appears to be associated with enhanced cardiovascular and sympatho-adrenal reactivity (resembling a hypothalamic defence reaction) which is revealed by mental stress, rather than stimuli such as ORT or CPT. Venous plasma NA has limitations in defining neurogenic alterations in hypertension since it reflects poorly sympathetic activity in the organs responsible for pressor responses to emotional stimuli. Plasma ADR is more valuable in this respect.

Left ventricular mass is not related to insulin sensitivity in never-treated primary hypertension.

OBJECTIVE: Insulin has been suggested to promote myocardial cell growth and the development of left ventricular (LV) hypertrophy. This study examines the possible relationship between LV mass and insulin sensitivity. DESIGN: Previously untreated non-diabetic hypertensive patients. PATIENTS: Fifty-one patients with mean age 51 +/- 8 years, body mass index (BMI) 25.9 +/- 3.2 kg/m2 and blood pressure 158/102 mmHg were included. LV mass was determined by echocardiography. Glucose metabolism was assessed by an euglycemic insulin clamp (40 mU/m2 body surface area/min). RESULTS: Insulin sensitivity index (MI) and insulin clearance were inversely related to LV mass (r = -0.37, P < 0.01 and -0.33, P < 0.05, respectively) and LV mass indexed to height (r = -0.33, P < 0.05 and -0.29, P < 0.05, respectively). C-peptide and fasting insulin were related to LV mass (r = 0.33, P < 0.05 and r = 0.36, P < 0.01, respectively) and LV mass indexed to height (r = 0.30, P < 0.05 and r = 0.34, P < 0.05, respectively). In contrast, when LV mass was indexed by body surface area there was no longer a relation to MI, insulin clearance, C-peptide or fasting insulin. When adjusting for BMI in a multiple regression analysis, MI and LV mass no longer showed a relation. Indeed, MI, insulin clearance, C-peptide and insulin were all strongly related to weight and BMI. CONCLUSION: Insulin sensitivity is related to body size in untreated hypertension. However, insulin sensitivity is not related to LV mass, if adjusting for body size. This does not support a direct growth-promoting effect of insulin on the myocardium. Insulin does not appear to be strongly involved in development of hypertensive LV hypertrophy.

Nerve stimulation augments angiotensin II overflow from canine gracilis muscle in vivo.

The overflow of endogenous angiotensin-(1-8)octapeptide (angiotensin II) from blood-perfused canine gracilis muscle vasculature in situ was studied. A positive veno-arterial concentration difference for angiotensin II over the gracilis muscle was found, indicating a net generation of angiotensin II under basal conditions. Angiotensin II levels in the venous effluent were elevated during 2 Hz (4-min) nerve stimulation, suggesting enhanced local angiotensin II generation both in the presence and absence of alpha-adrenoceptor blockade. Thus, our results in this in vivo model demonstrate a local overflow of angiotensin II from the skeletal muscle vasculature which can be enhanced by nerve stimulation. Whether this overflow of angiotensin II is due to conversion of circulating angiotensin I to angiotensin II or local de novo synthesis of angiotensin II remains to be established.

Treatment with irbesartan or atenolol improves endothelial function in essential hypertension.

OBJECTIVES: To investigate if antihypertensive treatment could improve endothelium-dependent vasodilatation in hypertensive patients, and whether the angiotensin II subtype-1 (AT1)-receptor antagonist irbesartan and the beta1-receptor antagonist atenolol would differ in this respect. SUBJECTS AND METHODS: Thirty-four patients (28 men and six women) with mild-to-moderate essential hypertension (diastolic blood pressure 90-120 mmHg) were randomized to once daily 150-300 mg irbesartan or 50-100 mg atenolol in a double-blind fashion, preceded by a placebo run-in period. Forearm blood flow (FBF) was assessed by venous occlusion plethysmography during local intra-arterial infusions of methacholine and sodium nitroprusside, to evaluate endothelium-dependent and endothelium-independent vasodilatation, respectively. Measurements of FBF were undertaken at the end of the run-in placebo period and repeated after 3 months of active antihypertensive treatment. RESULTS: Irbesartan and atenolol induced a similar decline in blood pressure (from 171/107 to 158/98 mmHg, P < 0.05), and improved endothelium-dependent vasodilatation (e.g. an increase in FBF response to 4 microg/min methacholine from 325 +/- 29% to 411 +/- 41%, P < 0.05), with no difference between the two study drugs. No significant changes in endothelium-independent vasodilatation were induced by irbesartan or by atenolol. CONCLUSIONS: The present study shows that 3 months of antihypertensive therapy with irbesartan or atenolol improves endothelium-dependent vasodilatation.

Angiotensin converting enzyme gene polymorphism predicts blood pressure response to angiotensin II receptor type 1 antagonist treatment in hypertensive patients.

OBJECTIVES: To determine whether polymorphisms in the renin-angiotensin system can predict blood pressure-lowering response to antihypertensive treatment; more specifically, in response to treatment with irbesartan or atenolol. DESIGN AND METHODS: Eighty-six patients with hypertension were randomized to double-blind treatment with either the angiotensin II type 1 receptor antagonist irbesartan or the beta1 adrenergic receptor blocker atenolol and followed for 3 months. We analysed angiotensinogen T174M and M235T, angiotensin converting enzyme (ACE) I/D and angiotensin II type 1 receptor A1166C polymorphisms and related them to blood pressure reduction. RESULTS: The mean reductions in blood pressure were similar for both treatments. In the irbesartan group, individuals homozygous for the ACE gene I allele showed a greater reduction in diastolic blood pressure, exceeding those with the D allele (-18 +/- 11 SD versus -7 +/- 10 mmHg, P = 0.0096). This was not the case during treatment with atenolol, and the interaction term between type of treatment and ACE II genotype was significant (P = 0.0176). The angiotensinogen and angiotensin II type 1 receptor polymorhisms were not related to the response to treatment. CONCLUSIONS: ACE genotyping predicted the blood pressure-lowering response to antihypertensive treatment with irbesartan but not atenolol. Thus, specific genotypes might predict the response to specific antihypertensive treatment.