Markus P. Schneider

Prevention of atrial fibrillation by Renin-Angiotensin system inhibition a meta-analysis.

OBJECTIVES The authors reviewed published clinical trial data on the effects of renin-angiotensin system (RAS) inhibition for the prevention of atrial fibrillation (AF), aiming to define when RAS inhibition is most effective. BACKGROUND Individual studies examining the effects of RAS inhibition on AF prevention have reported controversial results. METHODS All published randomized controlled trials reporting the effects of treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in the primary or secondary prevention of AF were included. RESULTS A total of 23 randomized controlled trials with 87,048 patients were analyzed. In primary prevention, 6 trials in hypertension, 2 trials in myocardial infarction, and 3 trials in heart failure were included (some being post-hoc analyses of randomized controlled trials). In secondary prevention, 8 trials after cardioversion and 4 trials assessing the medical prevention of recurrence were included. Overall, RAS inhibition reduced the odds ratio for AF by 33% (p < 0.00001), but there was substantial heterogeneity among trials. In primary prevention, RAS inhibition was effective in patients with heart failure and those with hypertension and left ventricular hypertrophy but not in post-myocardial infarction patients overall. In secondary prevention, RAS inhibition was often administered in addition to antiarrhythmic drugs, including amiodarone, further reducing the odds for AF recurrence after cardioversion by 45% (p = 0.01) and in patients on medical therapy by 63% (p < 0.00001). CONCLUSIONS This analysis supports the concept of RAS inhibition as an emerging treatment for the primary and secondary prevention of AF but acknowledges the fact that some of the primary prevention trials were post-hoc analyses. Further areas of uncertainty include potential differences among specific RAS inhibitors and possible interactions or synergistic effects with antiarrhythmic drugs.

Angiotensin converting enzyme inhibition and angiotensin II AT1-receptor blockade reduce the levels of asymmetrical NG, NG-dimethylarginine in human essential hypertension☆

Abstract Background Asymmetrical NG, NG-dimethylarginine (ADMA) is associated with impaired endothelium-dependent vasodilation in humans. Methods Twenty young, male, mildly hypertensive subjects were included in a randomized, double-blind, fourfold cross-over study with placebo, enalapril (20 mg/day), eprosartan (600 mg/day), or a combination of both drugs (10 and 300 mg/day, respectively) each over 1 week, followed by a 2-week wash-out phase. After each treatment phase, ADMA concentration was measured. Results ADMA concentration was 1.69 ± 0.59 μmol/L in the placebo phase, and was significantly lower in the enalapril, eprosartan, and combination phases (1.41 ± 0.29, 1.42 ± 0.43, and 1.38 ± 0.30 μmol/L, respectively; all P Conclusions Levels of ADMA were reduced with enalapril and eprosartan therapy. Our results suggest a specific action of these drugs on ADMA levels that is independent of BP.

Rapid Nongenomic Effects of Aldosterone on Human Forearm Vasculature

Abstract—The impact of aldosterone in cardiovascular disease and hypertension has recently gained new interest. Aldosterone is now suggested to be a more common cause of hypertension than previously believed and has been linked to myocardial fibrosis, independent of its hypertensive effects. Finally, rapid nongenomic aldosterone effects have been proposed to be important in hypertension, in addition to its genomic effects. Forty-eight healthy male volunteers were examined in a randomized, placebo-controlled, double-blind crossover trial to elucidate the rapid nongenomic, vascular effects of aldosterone in humans. Forearm blood flow was measured by venous occlusion plethysmography. First, aldosterone (500 ng/min) and placebo were infused into the brachial artery for 8 minutes. The volunteers then received ascending doses of acetylcholine, NG-monomethyl-l-arginine (L-NMMA), sodium nitroprusside, or phenylephrine. Aldosterone increased forearm blood flow (P <0.001, ANOVA). The maximum effect was an increase in forearm blood flow with aldosterone of 7.9±2.6% compared with 0.1±1.9% with placebo treatment after 8 minutes. With aldosterone, L-NMMA induced a greater vasoconstriction (P <0.05, ANOVA), sodium nitroprusside induced an attenuated vasoconstriction (P <0.01, ANOVA), and phenylephrine induced an exaggerated vasoconstriction (P <0.01, ANOVA) within minutes as compared with placebo. These data suggest that aldosterone acts through rapid nongenomic effects at the endothelium by increasing NO release and at the vascular smooth muscle cells by promoting vasoconstriction. This is consistent with in vitro data showing an increase in intracellular calcium in both cell types. Disturbances of these aldosterone effects on both levels might be important in promoting hypertension.

Rapid improvement of nitric oxide bioavailability after lipid-lowering therapy with cerivastatin within two weeks

OBJECTIVES We investigated whether improvement of endothelial dysfunction in hypercholesterolemia can be achieved with short-term lipid-lowering therapy. BACKGROUND Impaired endothelium-dependent vasodilation plays a pivotal role in the pathogenesis of atherosclerosis and acute coronary syndromes. METHODS In a randomized, double-blind, placebo-controlled trial, we studied 37 patients (52 +/- 11 yrs) with low density lipoprotein cholesterol > or = 160 mg/dl (196 +/- 44 mg/dl) randomly assigned to either cerivastatin (0.4 mg/d) or placebo. Endothelium-dependent vasodilation of the forearm vasculature was measured by plethysmography and intra-arterial infusion of acetylcholine (ACh 12, 48 microg/min) and endothelium-independent vasodilation by intra-arterial infusion of nitroprusside (3.2, 12.8 microg/min). RESULTS Low density lipoprotein cholesterol decreased after two weeks of treatment (cerivastatin -33 +/- 4% vs. placebo + 2 +/- 4%, x +/- SEM, p < 0.001). Endothelium-dependent vasodilation improved after two weeks of therapy with cerivastatin compared with baseline (ACh 12 microg/min: + 22.3 +/- 5.2 vs. + 11.2 +/- 1.9 ml/min/100 ml, p < 0.01; ACh 48 microg/min: +31.2 +/- 6.3 vs. +19.1 +/- 3.1 ml/min/100 ml, p < 0.05). In contrast, changes in forearm blood flow to ACh were similar before and after therapy in the placebo group (ACh 12 microg/min: + 12.9 +/- 3.6 vs. + 9.0 +/- 1.9 ml/min/100 ml, NS; ACh 48 microg/min: +20.7 +/- 3.7 vs. 19.4 +/- 2.9 ml/min/100 ml, NS). Endothelium-dependent vasodilation improved in comparison with placebo (ACh 48 microg/min: +203 +/- 85% [cerivastatin] vs. -26 +/- 71% [placebo], p < 0.05). This improvement in endothelium-dependent vasodilation was no longer observed when the nitric oxide-synthase inhibitor N(G)-monomethyl-L-arginine was coinfused (ACh 48 microg/min + N(G)-monomethyl-L-arginine 4 micromol/min -48 +/- 85% [cerivastatin]). CONCLUSIONS Short-term lipid-lowering therapy with cerivastatin can improve endothelial function and NO bioavailability after two weeks in patients with hypercholesterolemia.

Effect of AT1 receptor blockade on endothelial function in essential hypertension.

BACKGROUND Angiotensin II adversely affects endothelial function and NO availability. We analyzed the effect of AT(1) receptor blockade on endothelium-dependent vasodilation and basal nitric oxide (NO) production and release in hypertensive patients. METHODS AND RESULTS Sixty patients (53 +/- 10 years) with essential hypertension were randomized to 6 weeks of double-blind therapy with either valsartan (80 mg), hydrochlorothiazide (HCTZ) (25 mg), or placebo once daily. Basal NO production and release was assessed by measuring forearm blood flow (FBF) in response to intra-arterial infusion of N(G)-monomethyl-L-arginine (L-NMMA), and endothelium-dependent vasodilation by measuring FBF in response to intra-arterial administration of acetylcholine, respectively. Intra-arterial infusion of noradrenaline and sodium nitroprusside was used to assess endothelium-independent changes in FBF. Blood pressure (BP) similarly decreased with active treatments (P < .001). After valsartan treatment, the decrease of FBF in response to L-NMMA was augmented (4 micromol/min L-NMMA, -1.3 +/- 1.2 after v -0.5 +/- 1.1 mL/min/100 mL before therapy, P < .02; 8 micromol/min L-NMMA: -1.7 +/- 1.3 after v -1.1 +/- 1.2 mL/min 100 mL before therapy, P < .05). No improvement was found after placebo or HCTZ treatment. Changes in L-NMMA-induced decrease of FBF with valsartan treatment were not related to BP changes. Neither drug substantially modified the response of FBF induced by intra-arterial infusion of acetylcholine, noradrenaline, and sodium nitroprusside. CONCLUSIONS The AT(1) receptor blockade with valsartan improved basal NO production and release. The effect seems to be BP independent, as BP reduction with HCTZ failed to increase NO availability.

Functional gene testing of the Glu298Asp polymorphism of the endothelial NO synthase

Objectives To test whether the Glu298Asp polymorphism of the endothelial nitric oxide synthase (eNOS) gene is of functional relevance in humans by altering endothelium-dependent vasodilation. Background The Asp298 variant of the eNOS gene product has been associated with arterial hypertension, coronary artery disease and myocardial infarction. The pathogenetic mechanism has not yet been elucidated. Since endothelium-dependent vasodilation has been shown to be impaired in these disorders, we hypothesized that the Glu298Asp polymorphism of the eNOS gene influences endothelium-dependent vasodilation. Methods In 80 patients with normal or elevated cholesterol, endothelium-dependent and -independent vasodilation was assessed. Forearm blood flow was measured by plethysmography in response to intra-arterial (i.a.) infusion of 12 and 48 μg/min acetylcholine and 3.2 and 12.8 μg/min nitroprusside, respectively. NG-monomethyl-L-arginine (L-NMMA) in doses of 4, 8 and 16 μmol/min was infused to test basal nitric oxide (NO) production and release. Genomic DNA was extracted from blood samples to determine the Glu298Asp polymorphism of the eNOS gene at position 1917 G/T after BanII restriction. Results Baseline parameters (age, gender, blood pressure, body mass index, cholesterol level) were similar across the genotypes. Genotype frequencies did not deviate from the Hardy-Weinberg equilibrium. No differences in forearm blood flow to i.a. acetylcholine (average increase: + 554 ± 371±), nitroprusside or L-NMMA infusion were found across the eNOS genotypes, neither for endothelium-dependent or endothelium-independent vasodilation, nor for basal NO production and release. Our sample size of n = 80 had a power of > 80 > (α = 0.20) with a P value < 0.05 (β = 0.05) to detect a 200% difference in forearm blood flow response to 48 μg/min acetylcholine. Conclusions At a power of 80%, we can exclude a relevant effect on endothelium-dependent vasodilation due to the eNOS Glu298Asp polymorphism. Thus, our functional genetic study does not suggest any biological effect of the eNOS Glu298Asp genotype on the cardiovascular system via an influence on endothelium-dependent vasodilation.

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

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: β = 0.417, P = 0.012; diastolic blood pressure: β = 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.

Measurement of kidney perfusion by magnetic resonance imaging: comparison of MRI with arterial spin labeling to para-aminohippuric acid plasma clearance in male subjects with metabolic syndrome

BACKGROUND Magnetic resonance imaging with arterial spin labeling (MRI-ASL) is a non-invasive approach to measure organ perfusion. We aimed to examine whether MRI-ASL kidney perfusion measurements are related to measurements of renal plasma flow (RPF) by para-aminohippuric acid (PAH) plasma clearance and whether changes of kidney perfusion in response to treatment with telmisartan can be detected by MRI-ASL. METHODS Twenty-four patients with metabolic syndrome and an estimated creatinine clearance according to Cockroft and Gault of > or =60 ml/min were included in the study. Kidney perfusion was assessed by MRI-ASL measurements of a single coronal kidney slice (with flow-sensitive alternating inversion recovery and true fast imaging with steady-state processing sequence) and by measurements of RPF using PAH plasma clearance before and after 2 weeks of treatment with the angiotensin receptor blocker telmisartan. All MRI-ASL examinations were performed on a 1.5 T scanner. RESULTS Two weeks of therapy with telmisartan led to a significant increase of RPF (from 313 +/- 47 to 348 +/- 69 ml/min/m, P = 0.007) and MRI-ASL kidney perfusion measurements (from 253 +/- 20 to 268 +/- 25 ml/min/100 g, P = 0.020). RPF measurements were related with MRI-ASL kidney perfusion measurements (r = 0.575, P < 0.001). Changes of RPF measurements and changes of MRI-ASL kidney perfusion measurements in response to treatment with telmisartan revealed a close relationship when expressed in absolute terms (r = 0.548, P = 0.015) and in percentage changes (r = 0.514, P = 0.025). CONCLUSIONS Perfusion measurement of a single coronal kidney slice by MRI-ASL is able to approximate kidney perfusion and to approximate changes in kidney perfusion due to pharmacological intervention.

Effect of Irbesartan Versus Atenolol on Left Ventricular Mass and Voltage: Results of the CardioVascular Irbesartan Project

Regression of hypertensive left ventricular hypertrophy (LVH) is associated with improved prognosis. The aim of this trial was to compare the effects of irbesartan versus atenolol on LVH in subjects with essential hypertension. Because electrocardiographic and echocardiographic parameters of LVH carry disparate prognostic information, both methods were applied in this trial. In the randomized, double-blind, multicenter trial CardioVascular Irbesartan Project, 240 patients with essential hypertension were treated with irbesartan or atenolol for 18 months. Voltage criteria used for LVH were Sokolow index, Cornell index, Cornell voltage×QRS duration product and Lewis index. In parallel, left ventricular mass (LVM) was determined by 2-dimensional guided M-mode echocardiography. After 6 and 18 months, reductions of LVM and voltage criteria for LVH were only found in subjects treated with irbesartan. However, a reduction of LVM was only detectable in subjects within the highest quartile of baseline LVM but not overall. In contrast, reductions of voltage criteria for LVH were detectable after 6 and 18 months even within commonly used normal limits. In conclusion, treatment of hypertension with irbesartan resulted in a significant reduction in the voltage criteria for LVH, although an effect on LVM was only seen in subjects with high baseline LVM. In contrast, atenolol did not lead to reductions in electrocardiographic or echocardiographic parameters of LVH. Because voltage criteria for LVH have been shown to predict cardiovascular outcome independently from LVM, we suggest that both methods should be used to accurately assess the benefits of antihypertensive treatment.

Wall-to-lumen ratio of retinal arterioles is related with urinary albumin excretion and altered vascular reactivity to infusion of the nitric oxide synthase inhibitor N-monomethyl-L-arginine.

Objective We hypothesized that wall-to-lumen ratio (WLR) of retinal arterioles might serve as an in-vivo parameter of vascular damage. To test this hypothesis we examined whether WLR of retinal arterioles is related with increased urinary albumin excretion and altered vascular reactivity to infusion of the nitric oxide synthase inhibitor N-monomethyl-L-arginine (L-NMMA). Methods Thirty-nine never-treated male patients aged 18–65 years with a body mass index at least 25 kg/m2 and without diabetes mellitus or secondary or stage 3 arterial hypertension were examined. WLR of retinal arterioles was assessed using scanning laser Doppler flowmetry. Urinary albumin-to-creatinine ratio (UACR) was measured from first morning spot urine. Vascular reactivity was measured by the change of aortic augmentation index (aAIx) to infusion of L-NMMA. Results UACR was related with WLR of retinal arterioles (r = 0.352, P = 0.032). In response to L-NMMA infusion aAIx increased (from 10.7 ± 11 to 19.7 ± 11%, P < 0.001). The change of aAIx to L-NMMA infusion was inversely related with WLR of retinal arterioles (r = −0.462, P = 0.003) even after adjustment for changes of hemodynamic parameters to L-NMMA infusion (partial r = −0.475, P = 0.005). The relationships of UACR and the change of aAIx to L-NMMA infusion with WLR of retinal arterioles were found to be independently of other cardiovascular risk factors (ß = 0.386, P = 0.006; ß = −0.369, P = 0.004, respectively) in multiple regression analyses with separate models for both parameters. Conclusion Increased WLR of retinal arterioles may thus serve as an in-vivo marker of vascular damage.