Showing papers by "Roland E. Schmieder published in 2008"

Reduced incidence of new-onset atrial fibrillation with angiotensin II receptor blockade: The VALUE trial

Abstract: BackgroundAtrial fibrillation (AF) is the most common arrhythmia and increases cardiovascular risk in hypertensive patients. Therefore, in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) a prespecified objective was to compare the effects of valsartan and amlodipine on new-onset AF.M

The PHARAO study: prevention of hypertension with the angiotensin-converting enzyme inhibitor ramipril in patients with high-normal blood pressure: a prospective, randomized, controlled prevention trial of the German Hypertension League.

Abstract: BackgroundThe prevention of hypertension with the angiotensin-converting enzyme inhibitor ramipril in patients with high-normal blood pressure study addresses the issue of whether progression to manifest hypertension in patients with high-normal blood pressure can be prevented with treatment.Methods

RAS blockade with ARB and ACE inhibitors: current perspective on rationale and patient selection

Abstract: Cardiovascular disease represents a continuum that starts with risk factors such as hypertension and progresses to atherosclerosis, target organ damage, and ultimately to myocardial infarction, heart failure, stroke or death. Renin-angiotensin system (RAS) blockade with angiotensin converting enzyme (ACE) inhibitors or angiotensin AT1-receptor blockers (ARBs) has turned out to be beneficial at all stages of this continuum. Both classes of agent can prevent or reverse endothelial dysfunction and atherosclerosis, thereby reducing the risk of cardiovascular events. Such a reduction has been shown mainly for ACE inhibitors in patients with coronary artery disease, but recent studies revealed that ARBs are not inferior in this respect. However, no such data are currently available on the combination of these drugs. Both ACE inhibitors and ARBs have been shown to reduce target organ damage in organs such as the kidney, brain and heart, and to decrease cardiovascular mortality and morbidity in patients with congestive heart failure. Experimental data point to an influence of ACE inhibitors and ARBs on the number and function of endothelial progenitor cells revealing additional mechanisms of action of these drugs. The VALIANT trial has shown equivalent effects of ARB valsartan and the ACE-inhibitor captopril in patients post myocardial infarction, but the dual RAS-blockade, compared to monotherapy, did not further reduce events. In secondary prevention, the most-recently published ONTARGET study provides evidence that on top of a better tolerability AT1-receptors antagonists are equal to ACE inhibitors in the prevention of clinical endpoints like cardiovascular mortality and morbidity, myocardial infarction and stroke. The combined RAS blockade, however, achieved no further benefits in vascular high-risk patients and was associated with more adverse events. In chronic heart failure, ValHeFT and CHARM-ADDED have shown that combined RAS inhibition with ACE inhibitor and valsartan or candesartan reduced morbidity and mortality in certain patient subgroups. Accumulating evidence also points to benefits of the combination therapy in individuals with proteinuric nephropathies. In conclusion, while combined RAS-inhibition is not generally indicated in patients along the cardio-reno-vascular continuum, it has already proven to be effective in heart failure patients with incomplete neuroendocrine blockade. In secondary prevention, monotherapy with either RAS inhibitor is equally efficacious. Furthermore, novel pharmacologic agents such as renin inhibitors may prove useful in preventing common side effects of RAS blockade such as angiotensin escape and AT1-receptor upregulation, giving clinicians additional therapeutic tools to optimally treat the individual patient.

Impact of New-Onset Diabetes Mellitus on Development of Atrial Fibrillation and Heart Failure in High-Risk Hypertension (from the VALUE Trial)

Abstract: Hypertension and diabetes mellitus (DM) are known risk factors for atrial fibrillation (AF). We investigated the influence of new-onset DM on developing AF in the VALUE trial population of high-risk hypertensive patients. Five thousand two hundred fifty patients of the 15,245 participants in the VALUE trial had DM at baseline and 1,298 of the initially nondiabetic patients developed DM during the average 4.2-year follow-up. The presence of AF was determined by central analyzed electrocardiograms at baseline and changes were assessed yearly. Patients without AF at baseline and with any AF by later electrocardiograms were defined as patients with new-onset AF. Patients with new-onset and baseline DM were compared with patients without DM by a Cox regression model with adjustment for prespecified covariates. Five hundred fifty-one patients developed new-onset AF during the trial. Patients with new-onset DM had a significantly higher event rate of new-onset AF with a hazard ratio of 1.49 (1.14 to 1.94, p = 0.0031) compared with patients without DM, and there was a trend toward more AF in patients with DM at baseline. Patients with new-onset DM had also more persistent AF (hazard ratio 1.87, 1.28 to 2.74, p = 0.0014). Patients with new-onset DM and AF had a hazard ratio of 3.56 for heart failure (2.86 to 4.44, p <0.0001) compared with patients with new-onset DM without AF. In conclusion, hypertensive patients who developed DM during the VALUE trial had more AF than did patients without DM, and this may explain some of their concomitant high risk of hospitalization for heart failure.

(Pro)renin receptor peptide inhibitor "handle-region" peptide does not affect hypertensive nephrosclerosis in Goldblatt rats.

Abstract: The (pro)renin receptor [(P)RR], a new component the renin-angiotensin system, was cloned recently. The (P)RR promotes direct mitogen-activated protein kinase signaling and nonproteolytic prorenin activation. We investigated the role of a (P)RR blocker, a peptide consisting of 10 amino acids from the prorenin prosegment called the "handle-region" peptide (HRP), on target organ damage in renovascular hypertensive 2-kidney, 1-clip (2K1C) rats. Vehicle-treated 2K1C rats were compared with HRP-treated 2K1C rats (3.5 mug/kg per day) and sham-operated controls. Vehicle-treated 2K1C rats developed hypertension (186+/-17 mm Hg), cardiac hypertrophy (3.16+/-0.16 mg/g), renal inflammation, fibrosis, vascular, and tubular damage. Chronic HRP treatment did not affect blood pressure (194+/-15 mm Hg), cardiac hypertrophy (2.97+/-0.11 mg/g), or renal damage. Furthermore, we investigated the renal renin and (P)RR expression. The clipped kidney of 2K1C and HRP-treated 2K1C rats showed a higher renin expression and juxtaglomerular index compared with sham-operated kidneys. The unclipped kidney showed suppressed renin expression. In contrast, (P)RR mRNA expression was not altered in any group. Plasma renin activity and aldosterone were increased in 2K1C rats compared with sham controls. HRP-treated 2K1C rats tended to lower plasma renin activity but showed similar aldosterone levels as vehicle-treated 2K1C rats. Our results indicate that blockade of the (P)RR with HRP does not improve target organ damage in renovascular hypertensive rats.

Analysis of retinal arteriolar structure in never-treated patients with essential hypertension.

Abstract: OBJECTIVE Increased wall-to-lumen ratio of small arteries is a predictor of adverse cardiovascular prognosis. We aimed to analyze retinal arteriolar structure in never-treated patients with essential hypertension and to test whether elevated blood pressure is associated with an increased wall-to-lumen ratio of retinal arterioles. METHODS The study cohort comprised 21 untreated male patients with essential hypertension (mean age 39.1 +/- 5.4 years) and 29 untreated normotensive men (mean age 36.7 +/- 5.9 years). Wall-to-lumen ratio of retinal arterioles was assessed in vivo using scanning laser Doppler flowmetry. RESULTS Patients with essential hypertension had a higher wall-to-lumen ratio of retinal arterioles than normotensive individuals (0.36 +/- 0.1 vs. 0.28 +/- 0.1, P = 0.028). Wall cross-sectional area of retinal arterioles did not differ between the study groups. The growth index, indicating the percentage of difference in average wall cross-sectional area of retinal arterioles between both groups, was 18%. Both systolic (r = 0.360, P = 0.010) and diastolic (r = 0.536, P < 0.001) blood pressures were related to wall-to-lumen ratio of retinal arterioles. Multiple regression analysis including a variety of known cardiovascular risk factors revealed that blood pressure is independently associated with an increased wall-to-lumen ratio of retinal arterioles (systolic blood pressure: beta = 0.417, P = 0.012; diastolic blood pressure: beta = 0.548, P = 0.001). CONCLUSION The changes in arteriolar structure of retinal vessels in our study cohort revealed a similar pattern to that observed previously by other investigators in subcutaneous small arteries in essential hypertension. Blood pressure emerged as an important and independent determinant of wall-to-lumen ratio of retinal arterioles.

Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice

Abstract: The aim of the present study was to investigate the role of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) and its degrading enzyme dimethylarginine dimethylamino...

Blood pressure versus direct mineralocorticoid effects on kidney inflammation and fibrosis in DOCA-salt hypertension

Abstract: Objective We examined the contribution of high blood pressure versus direct mineralocorticoid effects to the progression of kidney inflammation and fibrosis in established experimental deoxycorticosterone-acetate (DOCA)-salt hypertension. Methods Male Sprague-Dawley rats underwent unilateral nephrectomy and received subcutaneous DOCA pellets as well as 1% NaCl for drinking. After 4 weeks of DOCA-salt hypertension, rats were either killed (n = 6), or treated with a non-hypotensive dose of spironolactone (n = 7) or triple therapy (hydrochlorothiazide, reserpine and hydralazine, n = 8) to normalize blood pressure or with vehicle (n = 19) for two further weeks. Mean arterial pressure (MAP) was measured intra-arterially. Glomerulosclerosis, interstitial fibrosis, macrophage infiltration and complement deposition were evaluated on kidney sections. Expression of collagens, chemokines and cytokines was measured by real-time PCR. Results MAP was elevated in DOCA rats, not affected by spironolactone and normalized by triple therapy. Glomerulosclerosis and interstitial fibrosis of DOCA rats were alleviated by spironolactone and triple therapy. Macrophage infiltration, complement C3 deposition and nitrotyrosine staining in the kidney were significantly reduced by spironolactone as well as triple therapy. The expression of collagens, chemokines, adhesion molecules and profibrotic cytokines in the kidney was elevated in hypertension and decreased by triple therapy but not significantly affected by spironolactone. Conclusion Direct mineralocorticoid effects as well as high blood pressure per se contribute to inflammation and fibrosis of the kidney. Oxidative stress may mediate the direct mineralocorticoid effects on kidney inflammation.

Glutathione S-transferase variants and hypertension.

Abstract: ObjectivesGlutathione S-transferases are involved in defences against oxidative stress. We have recently demonstrated reduced expression of glutathione S-transferase mu type 1 (Gstm1) in a rat model of hypertension. Here, we examine the association between GSTM variants and hypertension in human.Met

Blood Pressure Control in Patients With Comorbidities

Abstract: Hypertension frequently coexists with obesity, diabetes, hyperlipidemia, or the metabolic syndrome; their association with cardiovascular disease is well established. The identification and management of these risk factors is an important part of the overall management of hypertensive patients. Because patients in these special populations are more predisposed to target organ damage (TOD), stringent targets for blood pressure (BP) control have been set in clinical guidelines. However, clinical trial and real-life evidence suggest that these targets are difficult to achieve. Patients with these comorbidities are more likely to require combination therapy, yet physicians are often reluctant to adjust the number and doses of medications to achieve target BP. There is a particular need for effective 24-hour BP control in these patients, due to the increased likelihood of nondipping status, which is a risk factor for TOD and mortality. Not all available antihypertensives are equally effective in controlling BP over 24 hours, and some may exacerbate underlying metabolic abnormalities.

Hypertensive Retinopathy A Window to Vascular Remodeling in Arterial Hypertension

Abstract: At the end of the 19th century, hypertensive retinopathy was first described by Markus Gunn in hypertensive patients with renal disease. Nearly 50 years later, Keith and colleagues documented the prognostic value of funduscopic abnormalities in hypertensive patients and categorized hypertensive nephropathy into 4 groups of increasing severity that since then have been taught in medical university schools. In 1966, the ophthalmoscopic changes were confirmed to be predictive of death in patients with essential hypertension.1,2 The usefulness of the classification system and its relevance to current clinical practice, however, have been questioned repeatedly.3 The direct ophthalmoscopic examination has been shown to be unreliable, with high rates of interobserver (20% to 40%) and intraobserver (10% to 33%) variability.4 The criticism refers to stages 1 and 2 of the Keith-Wagner-Barker classification. Only hemorrhages and exudates can be reliably assessed in retinal photographs. A systematic review identified 6 studies that provided data on interobserver agreement for hypertensive retinopathy using retinal photographs.3 In these studies interobserver agreement was modest and fair for focal arterial narrowing and arteriovenous nicking, good for the arteriovenous ratio, and excellent only for hemorrhages and exudates. Most current guidelines for the management of arterial hypertension, therefore, do not recommend funduscopy as a routine diagnostic test, but advanced retinopathy (hemorrhages, exudates, or papilledema) is accepted as a factor influencing prognosis in hypertensive patients.5 Hypertensive retinopathy is generally considered to be a marker and/or …

Effect of angiotensin receptor blockade on central haemodynamics in essential hypertension: results of a randomised trial.

Abstract: Objective. Angiotensin-converting enzyme (ACE) inhibitors have been shown to lower central augmentation index (cAI), an index of arterial wave reflection, more than β-blockers. We tested whether this is also true for long-term treatment with an angiotensin receptor blocker (ARB).Methods. One-hundred and fifty-six subjects with essential hypertension were randomised to treatment with either irbesartan or atenolol. cAI and central blood pressure (BP) were determined by pulse wave analysis from the radial and the carotid artery after six and after 18 months treatment.Results. Peripheral and central systolic and diastolic BP were reduced to a similar extent A in the two groups. cAI was reduced with irbesartan, but increased with atenolol (derived from the carotid artery: -6±10 vs. -4±12% after six months, p<0.001; —4±12 vs. +1±11% after 18 months; p=0.011). Furthermore, central to peripheral pulse pressure (PP) amplification was unaffected by treatment with irbesartan, but decreased with atenolol.Conclusions....

A novel-1364A/C aquaporin 5 gene promoter polymorphism influences the responses to salt loading of the renin-angiotensin-aldosterone system and of blood pressure in young healthy men

Abstract: The family of aquaporin water channels contributes to water and salt homeostasis. AQP5 is a ubiquitously expressed exocrine-type water channel. Functional single nucleotide polymorphisms in AQP5 which alter gene transcription have not yet been described. We, therefore, sequenced the human AQP5 promoter to detect novel sequence variants which could impact upon AQP5 expression and contribute to the phenotypic variability of the renin-angiotensin-aldosterone system (RAAS). Sequencing of the whole AQP5 promoter revealed a novel-1364A/C polymorphism. Substitution of C for A was associated with increased transcription factor binding as tested by electrophoretic mobility shift assay, but significantly reduced transcriptional activation of the AQP5 gene by cAMP and serum. The C allele was associated with significantly decreased mRNA in human heart and with decreased protein expression in erythrocyte membranes. Finally, we associated AQP5 genotypes with the variability of the RAAS in two independent study cohorts. First, we studied the phenotypic variability of the RAAS in 103 young (26 ± 3 years) healthy males under an increased dietary salt intake. Increasing salt intake decreased plasma angiotensin II by 25% in AC/CC genotypes but only by 2% in AA genotypes (P = 0.012), and it decreased serum aldosterone by 34% in subjects with AC/CC genotypes but only by 19% in the AA genotypes (P = 0.005). Both genotypes had increased blood pressure under salt diet (P < 0.01), which was significantly more pronounced in AA genotypes (P = 0.029). Second, we investigated associations with variables of the RAAS in 96 old patients (68 ± 10 years) with coronary artery disease scheduled for coronary artery bypass grafting. Aldosterone serum concentrations were 2-fold (P < 0.001) and angiotensin II plasma concentrations were 4-fold higher in AA genotypes than in AC/CC genotypes while ADH plasma concentrations did not differ. A novel single nucleotide polymorphism in the AQP5 gene promoter alters AQP5 expression in different in vitro systems and cells, and is associated with alterations of variables of the RAAS both in young healthy males and in patients with coronary artery disease.

Basal nitric oxide synthase activity is a major determinant of glomerular haemodynamics in humans.

Abstract: BACKGROUND Experimental data suggest that increased nitric oxide synthase (NOS) activity contributes to preglomerular vasodilation and subsequent glomerular hyperfiltration. Whether such a relationship also exists in the human renal vasculature has not yet been adequately determined. METHODS AND RESULTS We assessed systemic, renal, and intragomerular haemodynamics in 310 subjects with normal renal function [glomerular filtration rate (GFR) > 60 ml/min per 1.73 m], before and after NOS inhibition with L-Nmonomethyl arginine (L-NMMA). Subjects were arbitrarily divided into tertiles according to their basal NOS activity, as assessed by the decrease in renal plasma flow in response to L-NMMA (high -23.4 +/- 8.1 versus medium -10.8 +/- 2.2 versus low -1.0 +/- 4.8%). Resting GFR differed significantly between tertiles: high 114 +/- 21 versus medium 109 +/- 19 versus low 104 +/- 21 ml/min per 1.73 m; analysis of variance P = 0.003. In a multiple stepwise regression analysis, basal NOS activity was the major factor to explain resting GFR (beta = -0.344; P < 0.001). Body weight (beta = -0.295; P < 0.001) and age (beta = -0.164; P < 0.001) emerged as additional factors, whereas body mass index and blood pressure did not enter the final model. The close relationship between resting GFR and basal NOS activity was also mirrored in the renal microcirculation, as demonstrated by an exaggerated effect of L-NMMA on the increase in arteriolar resistance, particularly that of the afferent (RA) arteriole, with higher basal nitric oxide (NO) activity (RA: high +1542 +/- 1065 versus medium +1024 +/- 718 versus low +675 +/- 861 dyne/s per cm; P < 0.001). CONCLUSION Our data clearly support experimental evidence linking NOS activity with increased glomerular filtration, and suggest that basal NO activity is also a major determinant of glomerular haemodynamics in the human renal vasculature.

Efficacy of manidipine/delapril versus losartan/hydrochlorothiazide fixed combinations in patients with hypertension and diabetes.

Abstract: BACKGROUND Hypertension markedly increases the already high risk for cardiovascular complications in patients with diabetes mellitus. Less than one in eight patients with hypertension and type 2 diabetes have adequately controlled blood pressure. As a result, antihypertensive combinations are now widely used in management of hypertension associated with diabetes. METHODS This double-blind study investigated efficacy of a new fixed dose combination of a calcium antagonist, manidipine 10 mg, and an angiotensin-converting enzyme inhibitor, delapril 30 mg, compared with a combination of an angiotensin receptor blocker, losartan 50 mg, and a diuretic, hydrochlorothiazide 12.5 mg. Patients with hypertension (blood pressure > or = 130/80 mmHg) with controlled type 2 diabetes (HbA1c < or = 7.5%) were randomized to manidipine/delapril (n = 153) or losartan/hydrochlorothiazide (n = 161), administered once daily for 12 weeks. Patients underwent ambulatory blood pressure monitor evaluation at baseline and end of treatment. RESULTS Mean decreases in 24-h systolic blood pressure were seen with both manidipine/delapril (-9.3 mmHg) and losartan/hydrochlorothiazide (-10.7 mmHg) combinations. The mean (95% confidence interval) treatment difference was -1.4 (-4.5/1.8) mmHg, demonstrating noninferiority of the manidipine/delapril combination. Reduction in 24-h diastolic blood pressure (-4.6 versus -4.5 mmHg) and daytime (systolic blood pressure -10.5 versus -11.1 mmHg) and night-time (systolic blood pressure -7.1 versus -9.3 mmHg) blood pressure were also not significantly different between treatments. Compliance and adverse events were comparable for both groups. CONCLUSION The study demonstrated that the combination of manidipine and delapril is as effective as losartan and hydrochlorothiazide in treatment of hypertension in type 2 diabetes.

A promoter polymorphism of the alpha 8 integrin gene and the progression of autosomal-dominant polycystic kidney disease.

Abstract: Background/Aims: Dysregulation of integrins is a feature of tissue remodeling in autosomal-dominant polycystic kidney disease (ADPKD). The alpha 8 beta 1 integrin (α8β1) affects kid

Impact of the endothelial nitric oxide synthase gene G894T polymorphism on renal endothelial function in patients with type 2 diabetes.

Abstract: OBJECTIVE: Endothelial dysfunction and increased oxidative stress contribute to the progression of diabetic nephropathy To analyze the functional significance of the G894T polymorphism of NOS3, the gene encoding endothelial nitric oxide synthase (NOS), we assessed basal nitric oxide activity and the amount of oxidative stress in the renal circulation of patients with type 2 diabetes METHODS: Renal plasma flow (RPF) was assessed by steady-state input clearance technique with sodium para-aminohippurate in 84 patients with type 2 diabetes and 84 patients without diabetes RPF was measured at baseline and after the infusion of the NOS inhibitor N-monomethyl-L-arginine (425 mg/kg); the substrate of NOS L-arginine (100 mg/kg); and coinfusion of vitamin C (3 g) with L-arginine (100 mg/kg) RESULTS: The decrease of RPF to N-monomethyl-L-arginine was similar between carriers of the T allele and homozygous carriers of the G allele in patients with diabetes (-56+/-40 vs -681+/-74 ml/min/173 m, P=0342) and patients without diabetes (-667+/-81 vs -583+/-63 ml/min/173 m, P=0606) In patients with diabetes, however, carriers of the T allele revealed a more pronounced increase of RPF to coinfusion of vitamin C with L-arginine than homozygous carriers of the G allele (618+/-75 vs 223+/-73 ml/min/173 m, P=0021), whereas in patients without diabetes the response of RPF to coinfusion of vitamin C with L-arginine was similar between both groups (462+/-80 vs 707+/-86 ml/min/173 m, P=0217) Gene-environment interaction between disease (diabetes) and genotype (genotype GG vs genotype GT/TT) was observed for increase of RPF to coinfusion of vitamin C with L-arginine (P=0020) CONCLUSION: G894T polymorphism of NOS3 has no impact on the basal nitric oxide activity of renal circulation In contrast, the T allele is associated with increased oxidative stress in the renal circulation in patients with diabetes suggesting a specific role of the G894T polymorphism in the pathogenesis of diabetic nephropathy

Progressive effects of valsartan compared with amlodipine in prevention of diabetes according to categories of diabetogenic risk in hypertensive patients: The VALUE trial

Abstract: We have previously shown that the angiotensin receptor blocker valsartan is associated with a lower incidence of new-onset type 2 diabetes than that with the calcium-channel antagonist amlodipine in the treatment of hypertensive patients at high cardiovascular risk. We have now investigated the benefits of valsartan vs amlodipine in patients of different categories of diabetogenic risk. Some 9995 patients without diabetes at onset participated in VALUE, with average follow-up of 4.2 years. Predictors of new diabetes were analyzed by stepwise logistic regression. A diabetes risk score for each patient was calculated based on a multivariate model. The risk of developing new diabetes in quartiles of risk for the disease was calculated as an odds ratio (OR) with 95% confidence intervals (CI). New diabetes was reported in 580 (11.5%) patients on valsartan and in 718 (14.5%) patients on amlodipine (p<0.0001). There was a more than sevenfold rise in the development of new diabetes from the lowest to the highest quartile of risk. When study treatment was included in the risk model, the odds in favor of valsartan in preventing new diabetes progressively increased with higher risk. Fifty-two (4.03%) patients developed diabetes on valsartan and 50 (4.14%) patients on amlodipine in the lowest quartile of risk, 73 (5.70%) patients on valsartan and 83 (6.81%) patients on amlodipine in the second quartile, and 126 (10.27%) patients on valsartan and 160 (12.58%) patients on amlodipine in the third quartile. The difference between treatments was highly significant in quartile 4 with 329 (26.68%) patients developing new diabetes on valsartan vs 425 (33.57%) patients on amlodipine (OR = 0.72, 95% CI 0.61-0.86, p = 0.0002). The number of patients needed for treatment for the duration of the trial in order to gain the benefit of valsartan over amlodipine in preventing one new case of diabetes was 43 in the third quartile and 15 in the fourth quartile of risk categories. We conclude that valsartan compared with amlodipine reduces the risk of developing diabetes mellitus, particularly in hypertensive patients with the highest susceptibility for development of diabetes.

Effects of angiotensin II type 1-receptor blockade on retinal endothelial function.

Abstract: OBJECTIVE Hypercholesterolemia is an important risk factor for atherosclerotic vascular disease including stroke. Low-density lipoprotein-cholesterol may induce upregulation of angiotensin II type 1 (AT1)-receptors and their activation plays a pathogenetic role in atherosclerosis, possibly via enhanced breakdown of nitric oxide. We tested whether AT1-receptor blockade improved endothelial function of the retinal vasculature in normocholesterolemic and hypercholesterolemic subjects. METHODS Thirty-one hypercholesterolemic and 17 normocholesterolemic subjects were randomly assigned to treatment with irbesartan and placebo in a double-blind crossover study. Retinal capillary flow was measured using scanning laser Doppler flowmetry. Diffuse luminance flicker was applied to provoke vasodilation that is in part nitric oxide dependent. RESULTS Flicker-induced increases in retinal capillary flow were similar between hypercholesterolemic and normocholesterolemic subjects. In contrast to placebo, treatment with irbesartan led to a significant reduction of blood pressure, in our patients with normal blood pressure values. Therefore we divided our study cohort according to the median blood pressure reduction in response to irbesartan. Flicker-induced increases in retinal capillary flow were substantially higher in subjects with a systolic blood pressure reduction above median (> 6 mmHg) than in those with a reduction below median (

Efficacy, safety and tolerability of valsartan 80 mg compared to irbesartan 150 mg in hypertensive patients on long-term hemodialysis (VALID study).

Abstract: BACKGROUND End stage renal disease (ESRD) patients mainly die of cardiovascular disease, and hypertension is regarded as the major risk factor. Valsartan is an angiotensin receptor blocker (ARB) with a well-established efficacy and safety profile in hypertensive patients, but with relatively few data in patients on hemodialysis (HD). The aim of this 2 A 5-week, open-label, multicenter, randomized cross-over study was to investigate whether valsartan (Val) 80 mg is as effective, safe and well-tolerated as irbesartan (Irb) 150 mg in patients with arterial hypertension on long-term hemodialysis. METHODS After a wash-out of previous ARBs for 1 week, 67 patients (ITT) on long-term hemodialysis, between 18 and 80 years, with mean supine systolic blood pressure (MSupSBP) >or= 140 mmHg and < 180 mmHg were randomized to either Val 40 or Irb 75 for 1 week with forced titration to Val 80 or Irb 150 for another 4 weeks. After a second wash-out period of 1 week, patients were switched from Val to Irb or vice versa for another 5 weeks (1 week low-dose, 4 weeks target dose). The primary objective was non-inferiority of Val versus Irb on predialytic MSupSBP. Secondary objectives were predialytic MSupDBP, adverse events (AEs), laboratory abnormalities, hypotension during and after dialysis and quality of life. BP values are given as mean A+/- SD. RESULTS Baseline BP values were 158 A+/- 11 / 78 A+/- 13 mmHg (Val) and 161 A+/- 13 / 83 A+/- 10 mmHg (Irb). The predialytic MSupSBP and MSupDBP after 4 weeks of treatment were similar in both treatment groups (Val 150 A+/- 19 / 79 A+/- 13 mmHg; Irb 151 A+/- 16 / 78 A+/- 14 mmHg). Most of the reported AEs were mild to moderate. The percentage of AEs considered by the investigator to be possibly drug-related was similar between both groups: 15.4% in the valsartan group and 20.4% in the irbesartan group. The most common AEs were nausea, muscle spasms and nasopharyngitis. Eight SAEs occurred, four in each treatment group (all not drug-related), including one death (cardiovascular insufficiency) in the Irb group. Laboratory changes were similar in both groups and not clinically relevant. The number of patients with symptomatic hypotension was similar during (9% each) as well as after dialysis (1.3% each). The quality of life data (SF-36) were comparable for each category. CONCLUSIONS Valsartan 80 mg is as effective, safe and well tolerated as irbesartan 150 mg in hypertensive patients on chronic hemodialysis.

Effekte der antihypertensiven Langzeittherapie mit Losartan auf den Blutdruck und die kognitive Funktion bei Patienten mit essentieller Hypertonie und weiteren zerebrovaskulären Risikofaktoren (AWARE-Beobachtungsstudie)

Abstract: Die arterielle Hypertonie ist der wichtigste Risikofaktor fur den ischamischen Schlaganfall, weshalb die einschlagigen Leitlinien eine stringente Therapie zur Blutdrucknormalisierung empfehlen. Daruber hinaus kann die Hypertonie auch mit einer kognitiven Leistungsminderung sowie Demenz assoziiert zu sein. Deshalb wurde in der vorliegenden Studie bei Patienten mit essentieller Hypertonie und weiteren zerebrovaskularen Risikofaktoren der Effekt einer Langzeittherapie, basierend auf dem AT1-Blocker Losartan (± Hydrochlorothiazid [HCTZ]), auf die kognitive Funktion untersucht. Prospektive, offene Beobachtungsstudie mit 6 206 erwachsenen Patienten mit bekannter essentieller Hypertonie und zerebrovaskularen Risikofaktoren (uberwiegend mit 10-Jahres-Schlaganfallrisiko nach dem Framingham-Score von ≥ 20%). Demographische Daten, Blutdruck, ausgewahlte Laborparameter und die kognitive Funktion (c.I.-Test) wurden zu Studienbeginn sowie nach 3, 6 und 12 Monaten bestimmt. Die Patienten waren im Mittel 65,8 ± 10,7 Jahre alt; 46,1% waren Manner. Zusatzlich zur Behandlung mit Losartan ± HCTZ erhielten 54,1% der Patienten noch ein oder mehrere weitere Antihypertensiva. Der systolische/diastolische Blutdruck nahm von einem Ausgangswert von 158,1/90,3 mmHg nach 1-jahriger Behandlung auf 137,3/80,6 mmHg ab (–20,8/–9,7 mmHg). Die Proportion der Patienten mit keiner/leichter/starker kognitiver Beeintrachtigung betrug zu Beginn 30,0%/30,3%/39,7%, und zum Studienende 34,8%/28,1%/37,1%. Bei Patienten mit verminderter kognitiver Funktion waren die Fibrinogen- bzw. hsCRP-Spiegel (hochsensitives C-reaktives Protein) signifikant erhoht. Bei 231 Patienten (3,7%) wurden unerwunschte Ereignisse (UE) beobachtet; nur bei sechs (0,1%) bzw. 38 Patienten (0,6%) wurden schwerwiegende/nicht schwerwiegende UE mit moglichem Zusammenhang mit der Medikation berichtet. Ein hoher Anteil von Patienten mit Hypertonie hat eine eingeschrankte kognitive Funktion; deshalb sollten entsprechende Tests erwogen werden. Die Behandlung mit Losartan in der taglichen Praxis erhohte den Anteil der Patienten mit normaler kognitiver Funktion und war hinsichtlich der blutdrucksenkenden Wirkung wirksam und gut vertraglich.

Compliance großer elastischer Arterien nach blutdrucksenkender Therapie mit einem Calciumantagonisten

Abstract: A decrease in the vascular compliance of the large elastic vessels (reduction of their "Windkessel" function) is of decisive importance for the pathogenesis and prognosis of cardiovascular complications such as arteriosclerosis, left ventricular hypertrophy and heart failure. The effect of the antihypertensive calcium antagonist isradipine on the "Windkessel" function of the aorta was measured in terms of the central haemodynamics in ten patients (eight men, two women; mean age 58 +/- 3 years) with essential hypertension (WHO stage I-II) before and 3 months after treatment. The mean arterial blood pressure was obtained invasively from the aortic arch, cardiac output or stroke volume being obtained by the indicator dilution method. The ratio stroke volume/blood pressure amplitude was calculated as a measure of vascular compliance. After 3 months of treatment with isradipine the mean arterial blood pressure fell from 114 +/- 4 to 97 +/- 3 mm Hg (P < 0.01), and total peripheral resistance from 22 +/- 1 to 18 +/- 1 U, P < 0.05), while vascular compliance rose from 1.07 +/- 0.10 to 1.58 +/- 0.10 ml/mm Hg, P < 0.05. The increase in compliance resulted from both the fall in blood pressure per se and the pressure-independent increase in the distensibility of the vessel wall (87 +/- 8% as against 107 +/- 13%, P < 0.05). As the fall in afterload favoured regression in left ventricular hypertrophy and heart failure, this pressure-independent structural and (or) functional change in the great elastic arteries could be decisive for the cardiovascular prognosis of hypertensives.

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Abstract: We bewail if the impression should have occurred that only local vessel properties have been considered responsible for the effect observed. We want to use the opportunity to point out that we agree with the presented influence of the reflected waves from the lower body on the local vasculature of the eye. However, in blood flow regulation to the eye, an important regulatory role of the different endothelium-derived vasoactive substances in the extraocular ophthalmic circulation has been suggested.3 That is, it was reported that the human ophthalmic artery exhibits a basal release of NO, indicating that the human ophthalmic circulation normally is in a state of constant vasodilation.4 In arterial hypertension this and other protecting mechanisms of the ocular circulation may be deranged as a result of endothelial dysfunction, whereas the reactivity of vascular smooth muscle may be normal, increased, or reduced.5 Thus, a certain contribution of the locally affected vascular tone to the envelope waveform of the blood flow velocity occurs in arterial hypertension, which, however, may be much smaller than the reflected waves from the lower body. Future studies should examine whether pharmacological interventions in the local metabolism (NO, bradykinin, or endothelin-1) may unmask the hidden secrets in the flow waveforms.