Showing papers by "Roland E. Schmieder published in 2001"
TL;DR: Patients with moderate hypercholesterolemia show upregulation of the CD40 system, which may contribute to the known proinflammatory, proatherogenic, and prothrombotic milieu found in these patients.
Abstract: Background Hypercholesterolemia, a risk factor for cardiovascular disease, is associated with inflammation and hypercoagulability. Both can be mediated by the CD40 system. This study investigated whether the CD40 system is upregulated in patients with moderate hypercholesterolemia and whether it is influenced by therapy with a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor.
Methods and Results Fifteen patients with moderate hypercholesterolemia and 15 healthy control subjects were investigated. CD154 and P-selectin were analyzed on platelets and CD40 was analyzed on monocytes before and under therapy with the statin cerivastatin by double-label flow cytometry. Blood concentrations of soluble CD154 and monocyte chemoattractant protein-1 (MCP-1) were evaluated. Our main findings were as follows. Patients with moderate hypercholesterolemia showed a significant increase of CD154 and P-selectin on platelets and CD40 on monocytes compared with healthy subjects. Soluble CD154 showed a nonsignificant trend for higher plasma levels in patients. A positive correlation was found for total or LDL cholesterol and CD154, but not for CD40 on monocytes. The latter was upregulated in vitro by C-reactive protein, which was found to be significantly elevated in patients with moderate hypercholesterolemia. CD154 on platelets proved to be biologically active because it enhanced the release of MCP-1, which was markedly elevated in an in vitro platelet-endothelial cell coculture model and in the serum of patients. Short-term therapy with a HMG-CoA reductase inhibitor significantly downregulated CD40 on monocytes and serum levels of MCP-1.
Conclusion Patients with moderate hypercholesterolemia show upregulation of the CD40 system, which may contribute to the known proinflammatory, proatherogenic, and prothrombotic milieu found in these patients.
Received August 7, 2001; revision received September 7, 2001; accepted September 11, 2001.
196 citations
TL;DR: Despite different changes of systemic haemodynamics between CVVH and IHD,CVVH did not improve parameters of splanchnic regional perfusion like pHi, pCO(2)i or pCO (2) gap in septic shock patients.
Abstract: Background. Parameters of splanchnic regional perfusion, like intramucosal pH (pHi) and pCO 2 (pCO 2 i), may predict outcome in septic shock patients. Continuous venovenous haemofiltration (CVVH) has been considered beneficial in haemodynamically unstable septic shock patients. In a prospective, randomized, clinical study, we investigated whether CVVH, in comparison to intermittent haemodialysis (IHD), is able to improve splanchnic regional perfusion in critically ill patients. Methods. Thirty septic shock patients with acute renal failure were randomized to either CVVH (n = 20) or IHD (n = 10) groups for renal replacement therapy. Patient characteristics at baseline were not different in terms of severity of illness (APACHE II scores), haemodynamics, and pHi/pCO 2 i values. Systemic haemodynamics, oxygen transport variables, and splanchnic regional perfusion parameters were measured at 0.5, 2, 4 and 24 h after initiation of renal replacement therapy. There were no major changes in vasopressor support throughout the 24-h study period. Results. In contrast to IHD, CVVH caused a decrease in heart rate (-3 ± 11 vs + 9 ± 8/min, P < 0.01) and an increase in systolic blood pressure (+ 12 ± 1 vs -5 ± 17 mmHg, P < 0.05) after 2 h. After 24 h, increased systemic vascular resistance was found in the CVVH group in comparison with the IHD group (+ 312 ± 755 vs 29 ± 89 dyne/cm 5 , P < 0.05) and was accompanied by a decrease in cardiac output (-1.54 ± 1.4 vs -0.25 ± 0.9 l/min, P < 0.01). However pHi values remained constant throughout the 24-h study period in both groups and were not different between the groups (CVVH 7.19 ± 0.1 vs IHD 7.19 ± 0.1, n.s.) as did the pCO 2 i values (CVVH + 7 ± 17 vs IHD 0 ± 15 mmHg, n.s.) and pCO 2 gap values (CVVH +6 ± 15 vs IHD +5 ± 12 mmHg, n.s.). Conclusions. Despite different changes of systemic haemodynamics between CVVH and IHD, CVVH did not improve parameters of splanchnic regional perfusion like pHi, pCO 2 i or pCO 2 gap in septic shock patients.
172 citations
TL;DR: Short-term lipid-lowering therapy with cerivastatin can improve endothelium-dependent vasodilation and NO bioavailability after two weeks in patients with hypercholesterolemia.
112 citations
TL;DR: The data indicate that the X-chromosomal located +1675 G/A-polymorphism of the AT2-R gene is associated with LV structure in young male humans with early structural changes of the heart due to arterial hypertension.
98 citations
TL;DR: In the study population both statins were very effective in lowering elevated LDL cholesterol levels, and Cerivastatin did not influence CsA blood trough levels, whereas atorvastatin increased C sA levels in four of 10 patients.
Abstract: Background Hyperlipidaemia is an important risk factor for cardiovascular disease in renal transplant recipients. The aim of this study was to test the efficacy and possible drug-drug interactions of the new HMG-CoA reductase inhibitors (statins) atorvastatin and cerivastatin in cyclosporin A (CsA)-treated renal transplant patients. Subjects and methods. Thirty patients with stable graft function and LDL cholesterol of 130 mg/dl were randomly assigned to active treatment groups (10 mg atorvastatin or 0.2 mg cerivastatin), or a control group. CsA blood trough levels were controlled on a weekly basis and adapted if they changed more than 25% from baseline values (100-150 ng/ml). Lipid levels and routine laboratory parameters before and after a treatment period of 3 months were compared. Results In the group treated with cerivastatin no significant changes in CsA blood trough levels occurred (CsA 116+/-21 ng/ml vs 110+/-20 ng/ml). In contrast, in the group treated with atorvastatin, four of 10 patients had a rise in CsA blood trough levels of more than 25% within 7-14 days of starting therapy. In the remaining patients no significant changes in CsA drug levels occurred. After therapy with atorvastatin or cerivastatin, total cholesterol, LDL cholesterol, and triglycerides were significantly lower compared with baseline conditions. No changes of CsA or lipoprotein levels were present in the control group. Conclusion In our study population both statins were very effective in lowering elevated LDL cholesterol levels. Cerivastatin did not influence CsA blood trough levels, whereas atorvastatin increased CsA levels in four of 10 patients. Further research in a larger study is necessary in order to confirm these results and to investigate the possible reasons for this drug interaction.
56 citations
TL;DR: Hypertensive subjects with the -344 CC genotype of the aldosterone synthase promoter are characterized by a pattern of early eccentric left ventricular hypertrophy, and differences in renal sodium handling across the genotypes might contribute to this finding.
56 citations
TL;DR: The effects of endothelium destruction on Ang I formation support the notion that the endothelia mediates vascular angiotensin formation by taking up renin.
Abstract: We investigated the role of the vascular endothelium in the local production of angiotensin. Angiotensin release from isolated rat hindquarters perfused with an artificial medium was measured by high-performance liquid chromatography and radioimmunoassay. Perfused hindquarters with endothelium released angiotensin I spontaneously, indicating ongoing renin-angiotensinogen reaction. Endothelium denudation (by a detergent, validated by electron microscopy and by the absence of a vasodilator response to acetylcholine) reduced angiotensin I release by >90%, whereas bilateral nephrectomy 24 hours before perfusion abolished the release completely. Infusion of renin into perfused hindquarters induced sustained local angiotensin I release in the presence of an intact endothelium but not after endothelium denudation. The conversion of angiotensin I to angiotensin II was abrogated by endothelium denudation, whereas the disappearance of angiotensin II was unchanged. Endothelium denudation diminished the pressor response to angiotensin II but abolished the response to renin and angiotensin I. Expression of renin messenger RNA, investigated by reverse-transcription polymerase chain reaction using 4 different primer combinations, was not detected in up to 5 μg vascular RNA, whereas a renin signal was readily detected with 5 ng kidney RNA. The effects of endothelium destruction on Ang I formation support the notion that the endothelium mediates vascular angiotensin formation by taking up renin.
48 citations
TL;DR: The data suggest a relevance of increased G-protein activation in the pathogenesis of hypertension on early adaptive processes of the left ventricle and renal hemodynamic changes in young normotensive to mildly hypertensive subjects.
Abstract: The C825T polymorphism of the gene encoding the G-protein beta(3) subunit (GNB3) is associated with increased intracellular signal transduction and arterial hypertension. The aim of the study was to investigate the impact of this polymorphism on early adaptive processes of the left ventricle and renal hemodynamic changes in young normotensive to mildly hypertensive subjects. Ninety-five white male students with normal or mildly elevated blood pressure were genotyped for the GNB3 C825T polymorphism. In each participant, 24-hour ambulatory blood pressure, left ventricular structure and function (2D-guided M-mode echocardiography), renal plasma flow (para-aminohippurate clearance), glomerular filtration rate (inulin clearance), and 24-hour urinary sodium excretion were determined. The GNB3 825T allele was not associated with casual or ambulatory blood pressure, parameters of left ventricular structure or function, glomerular filtration, or 24-hour urinary sodium excretion. However, in T:-allele carriers (CT+TT), renal plasma flow was higher than in CC subjects (CT/TT: 659+/-96 versus CC: 614+/-91 mL/min, P:=0.019). ANOVA disclosed that renal plasma flow was independently influenced by both genotype and blood pressure, with hypertensives having a higher renal plasma flow than normotensive subjects. This was the fact irrespective of the criteria used for the definition of hypertension (World Health Organization or 24-hour ambulatory blood pressure criteria). The GNB3 825T variant is associated with increased renal perfusion in this study. Because early renal hemodynamic changes play a pivotal role in the pathogenesis of essential hypertension, our data suggest a relevance of increased G-protein activation in the pathogenesis of hypertension.
34 citations
TL;DR: Impaired sodium excretion occurs during mental stress in human essential hypertension but not in subjects with positive family history of hypertension, which appears to be mediated by angiotensin II.
Abstract: In hypertensive rats, environmental stress causes sodium retention by an exaggerated increase in renal sympathetic nerve activity, which is modulated by angiotensin II. We tested whether similar effects can be observed in humans. In 66 normotensive subjects (half of them with a family history of hypertension) and 36 subjects with mild essential hypertension, urinary sodium excretion and renal hemodynamics were examined at rest and during mental stress treated either with placebo or ACE inhibition in a double-blind, randomized, cross-over design. Despite a marked increase in glomerular filtration rate in response to mental stress (Deltaglomerular filtration rate, 4.3+/-7.7 mL/min in normotensives without versus 5.6+/-8.4 mL/min in normotensives with a family history versus 10.1+/-5.7 mL/min in patients with mild essential hypertension; P:<0.002), the increase in urinary sodium excretion was blunted in patients with mild essential hypertension (Deltaurinary sodium excretion, 0.12+/-0.17 mmol/min versus 0.10+/-0.14 mmol/min versus 0.05+/-0.14 mmol/min; P:<0.05). ACE inhibition corrected the natriuretic response to mental stress in subjects with mild essential hypertension (Deltaurinary sodium excretion, 0.05+/-0.14 mmol/min with placebo versus 0.13+/-0.19 mmol/min with ACE inhibition; P:<0.01); thus, after ACE inhibition, urinary sodium excretion increased similarly in all 3 groups. In conclusion, impaired sodium excretion occurs during mental stress in human essential hypertension but not in subjects with positive family history of hypertension. This abnormality in sodium handling during activation of the sympathetic nervous system appears to be mediated by angiotensin II.
27 citations
TL;DR: It is concluded that the −20 C variant or the − 20 C/−6 A haplotype of the angiotensinogen core promoter is associated with a blunted aldosterone response to Ang II and may thus contribute to the non-modulating phenotype.
Abstract: Non-modulation has been suggested as a possible intermediate phenotype defining a subgroup of genetic hypertension. The trait is characterized by an attenuated response of renal blood flow and/or aldosterone to angiotensin (Ang) II. We tested the hypothesis that functional polymorphisms of the core promoter of the angiotensinogen gene are associated with non-modulation. Fifty-six young, white, male, untreated hypertensive patients and 65 age-matched normotensive volunteers were genotyped for 3 known functional variants of the angiotensinogen core promoter. All subjects were infused with 2 doses (0.5 and 3 ng/kg per minute) of Ang II while they were on a high sodium diet (250 mmol/d). The blood pressure, renal plasma flow, and aldosterone responses to Ang II were not affected by the −6 G/A polymorphism. The −20 A/C variant had no significant effects on the blood pressure or renal hemodynamic response to Ang II. However, the aldosterone response to both doses of Ang II was significantly decreased in −20 C allele carriers compared with −20 AA homozygotes in a multivariate analysis. The −18 T allele was not detected in our population, and there was a linkage dysequilibrium between −20 C and −6 A: −20 C almost exclusively occurred on the −6 A allele. Haplotype analysis indicated that the −20 C/−6 A haplotype but not the −20 A/−6 A haplotype was associated with a decreased aldosterone response to Ang II. We conclude that the −20 C variant or the −20 C/−6 A haplotype of the angiotensinogen core promoter is associated with a blunted aldosterone response to Ang II and may thus contribute to the non-modulating phenotype.
21 citations
TL;DR: The pharmacokinetic characteristics of valsartan are altered in patients on haemodialysis under steady-state conditions, but not after single-dose administration, which is in the range of the bioavailability for the approved dose of up to 160mg in patients with or without renal impairment.
Abstract: Previous studies have indicated no relationship between renal function (creatinine clearance) and the pharmacokinetics of valsartan in patients with moderately impaired renal function. There are no pharmacokinetic data available for valsartan in patients on long-term haemodialysis. To examine the pharmacokinetics of valsartan 80mg in hypertensive patients on long-term haemodialysis. Secondary objectives were to evaluate the efficacy and tolerability of valsartan in this patient group. Multicentre, nonblind, parallel-group study. 20 hypertensive patients with no renal impairment and 20 hypertensive patients on long-term haemodialysis. All patients were treated with valsartan 80mg once daily for 15 days. After the first dose of valsartan and at the end of the treatment period, plasma concentrations of valsartan were determined over 24 hours. Significant differences in the area under the concentration-time curve from zero to 24 hours (AUC24h) at steady state were found between the patients on haemodialysis and those with normal renal function. In contrast, no differences were found for AUC24h during first-dose pharmacokinetics or for maximum plasma concentration and elimination half-life during first-dose and steady-state pharmacokinetics. Blood pressure decreased significantly in both groups, but the reduction in systolic blood pressure was greater in patients on haemodialysis (18mm Hg) than in the control group (6mm Hg). Valsartan 80mg was well tolerated in patients undergoing haemodialysis. The pharmacokinetic characteristics of valsartan are altered in patients on haemodialysis under steady-state conditions, but not after single-dose administration. The increased bioavailability at steady state was still in the range of the bioavailability for the approved dose of up to 160mg in patients with or without renal impairment. Valsartan 80 mg/day was well tolerated in this patient population.
TL;DR: Renal outcome was reported in almost all of the studies with angiotensin‐converting enzyme inhibitors, and despite concern about renal adverse events with drugs in this class, they seem to be safe in patients with congestive heart failure.
Abstract: In this paper we review the effect of medical treatment on renal function in patients with congestive heart failure. We have examined data from the large-scale heart failure studies with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, beta-receptor blockers, an aldosterone antagonist, and a vasopeptidase inhibitor. Renal outcome was reported in almost all of the studies with angiotensin-converting enzyme inhibitors. Despite concern about renal adverse events with drugs in this class, they seem to be safe in patients with congestive heart failure. In contrast, we did not find any report about renal function in patients treated with beta-receptor blockers for congestive heart failure.
TL;DR: In this outcome survey of unselected patients with type 2 diabetes mellitus and arterial hypertension, the ACE inhibitor cilazapril effectively lowered blood pressure and was associated with an improvement in glucose metabolism, cardiac function, and renal function.