Hyperlipidemias: Schmieder RE

Ott C, Schmieder RE. · Department of Nephrology and Hypertension, University of Erlangen-Nürnberg, Krankenhausstrasse 12, 91054 Erlangen, Germany. · Curr Hypertens Rep. · Pubmed #19278604 No free full text.

Abstract: The metabolic syndrome is a cluster of cardiometabolic risk factors associated with higher risk for atherosclerotic cardiovascular (CV) disease and diabetes. Its prevalence is about 20% to 30% among adults worldwide and is increasing. The primary goal is reduction of CV risk through lifestyle changes and drug therapy if required. Post hoc analyses of prospective trials showed the benefit of lowering low-density lipoprotein (LDL) cholesterol in patients with the metabolic syndrome. Statin therapy exerts beneficial effects not only by lowering LDL cholesterol but also via its so-called pleiotropic effects. These effects seem particularly important for reducing risk of CV disease in patients with the metabolic syndrome. Thus, evidence is accumulating that statins are very effective therapeutic agents in the treatment of individuals with the metabolic syndrome.

Schmieder RE, Ruilope LM. · Department of Nephrology and Hypertension, University Hospital Erlangen, Erlangen, Germany. · J Clin Hypertens (Greenwich). · Pubmed #18772645 No free full text.

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.

John S, Schmieder RE. · Department of Medicine IV, University of Erlangen-Nürnberg,Klinikum Nürnberg-Süd, Breslauerstr 201, 90471 Nürnberg, Germany. · Curr Hypertens Rep. · Pubmed #12724051 No free full text.

Abstract: This review focuses on the role of impaired endothelial function for the development of atherosclerosis in human arterial hypertension and hypercholesterolemia in vivo. Potential mechanisms underlying impaired endothelial function and decreased bioavailability of nitric oxide under these clinical conditions are discussed. It further addresses therapeutic strategies aimed at improving the bioavailability of nitric oxide in these patients. The overall conclusion is that the bioavailability of nitric oxide is probably impaired, not by a single defect, but by various mechanisms affecting nitric oxide synthesis as well as nitric oxide breakdown. In both diseases increased superoxide anion production and oxidative stress represent a major mechanism. Decreased bioavailability of nitric oxide not only impairs endothelium-dependent vasodilation, but also activates other mechanisms that play an important role in the pathogenesis of atherosclerosis. Thus, therapeutic strategies should aim to restore bioavailability of nitric oxide, which has been demonstrated for lipid-lowering therapy in hypercholesterolemia and blood pressure control in hypertension. In addition, antioxidative strategies will represent a major therapeutic tool against atherosclerotic diseases in the future. Statins and blockers of the renin-angiotensin system seem to have such antioxidative effects independent from their effects on lipid profiles or blood pressure control.

John S, Schmieder RE. · Department of Medicine IV, University of Erlangen-Nürnberg, Klinikum Nürnberg-Süd, Nürnberg, Germany. · J Hypertens. · Pubmed #10779084 No free full text.

Abstract: This review focuses on the role of impaired endothelial function for the development of atherosclerosis in human arterial hypertension and hypercholesterolemia in vivo. Potential mechanisms underlying impaired endothelial function and decreased bioavailability of nitric oxide under these clinical conditions are discussed and potential differences in these mechanisms between arterial hypertension and hypercholesterolemia are outlined. It further addresses therapeutic strategies aiming to improve the bioavailability of nitric oxide in these patients. The overall conclusion is that the bioavailability of nitric oxide is probably impaired not by a single defect, but by various mechanisms affecting nitric oxide synthesis as well as nitric oxide breakdown. In both diseases, increased superoxide anion production and oxidative stress represents a major mechanism. However, potential differences in the underlying mechanisms of superoxide production or nitric oxide synthesis are evident between arterial hypertension and hypercholesterolemia. Decreased bioavailability of nitric oxide does not only impair endothelium-dependent vasodilation, but also activates other mechanisms that play an important role in the pathogenesis of atherosclerosis. Thus, therapeutic strategies should aim to restore bioavailability of nitric oxide, which has been demonstrated for lipid-lowering therapy in hypercholesterolemia. The mechanisms by which nitric oxide bioavailability can be improved by any drug therapy remain to be elucidated and may provide further insights into the mechanisms that are involved in impaired endothelial function and atherogenesis.

Schlaich MP, Oehmer S, Schneider MP, Delles C, Schmidt BM, Schmieder RE. · Department of Medicine 4/Nephrology and Hypertension, University of Erlangen-Nürnberg, Erlangen, Germany. · Atherosclerosis. · Pubmed #16765359 No free full text.

Abstract: BACKGROUND: Aging and a variety of cardiovascular risk factors are associated with oxidative stress and impaired endothelial function. Whether such an association is already evident in the renal vascular bed in young patients at high cardiovascular risk has not yet been determined. METHODS: We compared renal haemodynamics in 23 young (age 30+/-5 years) male patients at high cardiovascular risk with impaired lipid metabolism and elevated blood pressure with 23 matched, healthy control subjects (age 28+/-3 years) without cardiovascular risk factors at baseline and following infusions of the nitric oxide (NO) synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA: 4.25mg/kg), the substrate of NO synthase L-arginine (100mg/kg) and the antioxidant Vitamin C (3g, co-infused with L-arginine 100mg/kg). RESULTS: Baseline renal haemodynamics did not differ between the two groups. Infusion of L-NMMA decreased renal plasma flow (RPF) in both groups to a similar extent (-113+/-95 ml/min versus -128+/-133 ml/min, p=NS). The response of RPF to infusion of L-arginine was more pronounced in high risk patients than in control subjects (+123+/-64.4 ml/min versus +75.6+/-60.2 ml/min, p=0.012) and further exaggerated during co-infusion of L-arginine and Vitamin C (+299+/-164 ml/min versus +175+/-148 ml/min, p=0.003). CONCLUSIONS: Basal NO activity of the renal vasculature appears to be unaltered in young patients at high cardiovascular risk. However, the greater response of RPF to L-arginine and to Vitamin C co-infused with L-arginine in these young patients suggests that decreased substrate availability for NO synthase and oxidative stress are key factors for alterations in endothelium-dependent vasodilation of the renal vasculature in this young high risk group of patients.

John S, Schneider MP, Delles C, Jacobi J, Schmieder RE. · Department of Medicine IV, University of Erlangen-Nürnberg, Erlangen, Germany. · Am Heart J. · Pubmed #15864218 No free full text.

Abstract: BACKGROUND: Experimental evidence suggests a lipid-independent effect of statins on endothelial function and nitric oxide (NO) availability in humans. We investigated whether improvement in NO availability in hypercholesterolemia can be achieved rapidly with statins before lipid-lowering therapy is complete. METHODS: We studied 41 patients (52 +/- 11 years) with low-density lipoprotein (LDL) cholesterol > or = 130 mg/dL (179 +/- 45 mg/dL) randomly assigned to treatment either with atorvastatin (20 mg/day) or cerivastatin (0.4 mg/day). Endothelium-dependent vasodilation of the forearm vasculature was measured by plethysmography and intra-arterial infusion of acetylcholine (ACh) after 3 days (n = 18) and 14 days (n = 39) of treatment. NO availability and oxidative stress were assessed by coinfusion of l-NMMA and vitamin C. RESULTS: After 3 days of treatment, LDL-cholesterol decreased by 11.9% with a further decrease to 29.6% after 14 days ( P < .001). Endothelium-dependent vasodilation improved by +46.7% after 3 days of statin therapy compared with before therapy (ACh 48 microg/min: +15.7 +/- 10.6 vs +10.7 +/- 10.8 mL/min per 100 mL, P < .05). No further improvement in endothelium-dependent vasodilation (+42.7% compared with before therapy) could be demonstrated after 14 days of treatment (ACh 48 microg/min: +17.7 +/- 10.3 vs +12.4 +/- 9.3 mL/min per 100 mL before therapy, P < .001). Coinfusion of ACh plus vitamin C was able to improve endothelium-dependent vasodilation before but not after 3 or 14 days of statin therapy either. The improvement in endothelium-dependent vasodilation after therapy was no longer observed when the NO-synthase inhibitor l-NMMA was coinfused together with ACh. CONCLUSIONS: Short-term lipid-lowering therapy with statins is able to improve endothelial function and NO availability almost completely after 3 days in hypercholesterolemic patients probably by decreasing oxidative stress. This improvement seems to be more rapid than the accompanying decline in LDL-cholesterol and not related to these lipid changes. This finding can support the concept of lipid-independent effects of statins in humans.

Fleischmann EH, John S, Delles C, Schneider MP, Schmidt BM, Schmieder RE. · Department of Medicine 4/IV, University Erlangen-Nuremberg, 90475 Nuremberg, Germany. · Am J Hypertens. · Pubmed #15607618 No free full text.

Abstract: BACKGROUND: Angiotensin II type 1 (AT(1)) receptors are well known to mediate angiotensin II (Ang II)-induced pro-atherosclerotic effects. It has been found that hypercholesterolemia influences the expression of AT(1) receptors on vascular smooth muscle cells and that increased density of AT(1) receptors exaggerates the hemodynamic response to Ang II. We analyzed to what extent statins and AT(1) receptor antagonists diminish the vasoconstrictive response to Ang II infusion in hypercholesterolemic patients. METHODS: A total of 24 male patients with LDL cholesterol levels >130 mg/dL were enrolled in a randomized, cross-over study. After baseline evaluation, 12 patients received first cerivastatin (0.3 mg/day) and the other 12 patients initially received candesartan (8 mg/day) for 3 weeks, with subsequent cross-over of the medication for the second 3-week drug period. The vascular response was analyzed by the increase in mean arterial pressure (MAP) and total peripheral resistance (TPR) during infusion of increasing doses of Ang II at baseline and the end of each treatment period. Hemodynamic changes were also compared with those in 24 normocholesterolemic subjects without any therapy. RESULTS: At baseline, Ang II provoked a similar increase of MAP and TPR in patients and control subjects. Treatment with cerivastatin did not affect the response to Ang II compared with baseline. By contrast, treatment with candesartan attenuated significantly the response to Ang II compared with baseline and cerivastatin. CONCLUSIONS: Our hemodynamic data indicate the hypothesis that statins do not reduce the responsiveness to Ang II in resistance arteries of young, mildly hypercholesterolemic patients.

Fleischmann EH, Schlaich MP, Schmidt BM, Oehmer S, Schmieder RE. · Department of Medicine IV/4/Nephrology, University of Erlangen-Nürnberg, Germany. · Nephrol Dial Transplant. · Pubmed #12270981 links to  free full text

Abstract: BACKGROUND: Hypercholesterolaemia has been found to impair endothelial function in the systemic and coronary circulations and lipid-lowering therapy with statins has been shown to improve this abnormality. METHODS: We examined the impact of hypercholesterolaemia on L-arginine-induced renal vascular relaxation by a cross-sectional study, and the effects of lipid-lowering therapy by a double-blind, randomized, placebo-controlled study. Using constant infusion input clearance technique (PAH and inulin respectively), changes of renal plasma flow (RPF) and glomerular filtration rate (GFR) in response to intravenous infusions of L-arginine (100 mg/kg/30 min and 500 mg/kg/30 min) were studied in 21 hypercholesterolaemic humans (age 57+/-9 years, LDL-cholesterol 211+/-35 mg/dl) and in 20 young healthy (age 26+/-2 years, LDL-cholesterol 90+/-27 mg/dl) and 20 older healthy age-matched control individuals (age 50+/-8 years, LDL-cholesterol 106+/-20 mg/dl). In addition, changes of blood pressure, heart rate, urinary excretion of sodium, and cyclic guanosine monophosphate were measured. Patients were analysed before and after 3 months treatment with either fluvastatin (40 mg twice daily, n=11) or placebo (n=10). RESULTS: In hypercholesterolaemic patients, L-arginine increased RPF and GFR (P<0.01) and urinary excretion of sodium (P<0.05) in a dose-dependent manner. Interestingly, changes were similar between the hypercholesterolaemic patients and the young and the age-matched control individuals (DeltaRPF 100 mg/kg/30 min, 40+/-51 ml/min vs 40+/-52 ml/min, P=NS; DeltaRPF 500 mg/kg/30 min, 114+/-85 ml/min vs 130+/-78 ml/min, P=NS). L-arginine significantly lowered systemic arterial pressure and increased heart rate in all groups. Despite significant reductions in LDL-cholesterol levels (291+/-35 mg/dl vs 213+/-30 mg/dl, P<0.001), treatment with fluvastatin did not alter the renal haemodynamic response pattern to L-arginine infusion when compared to baseline values and to those with placebo. CONCLUSION: In contrast to studies performed in the vasculature of the human forearm or the coronary circulation, our results suggest that hypercholesterolaemia is not associated with an impaired L-arginine-induced renal vascular relaxation.

John S, Delles C, Jacobi J, Schlaich MP, Schneider M, Schmitz G, Schmieder RE. · Department of Medicine IV, University of Erlangen-Nürnberg, Klinikum Nürnberg-Süd, Nürnberg, Germany. · J Am Coll Cardiol. · Pubmed #11300446 No free full text.

Abstract: 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.

Renders L, Mayer-Kadner I, Koch C, Schärffe S, Burkhardt K, Veelken R, Schmieder RE, Hauser IA. · Medizinische Klinik IV, University of Erlangen-Nürnberg, Erlangen, Germany. · Nephrol Dial Transplant. · Pubmed #11209008 links to  free full text

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.

Ott C, Schlaich MP, Harazny J, Schmidt BM, Michelson G, Schmieder RE. · Department of Nephrology and Hypertension, University of Erlangen-Nürnberg, Germany. · J Hypertens. · Pubmed #18300863 No free full text.

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 (<or=6 mmHg) (16.2 +/- 16% versus 6.88 +/- 11%; P = 0.042). CONCLUSION: AT1-receptor blockade with irbesartan improves endothelial function of the retinal vasculature, taken as a model of cerebral circulation.

Ott C, Schlaich MP, Schmidt BM, Titze SI, Schäufele T, Schmieder RE. · Department of Nephrology and Hypertension, University of Erlangen-Nürnberg, Germany. · Atherosclerosis. · Pubmed #17298834 No free full text.

Abstract: OBJECTIVE: Impaired endothelium-dependent vasodilation represents an early manifestation of atherosclerosis. Prospective studies have demonstrated that impaired endothelial function in the peripheral circulation of hypercholesterolemic patients predicts CV events and can be restored by statin treatment. Whether this also holds true in the renal circulation has not yet been adequately addressed. METHODS: In a double-blind, randomized, placebo-controlled cross-over trial, 40 hypercholesterolemic patients were randomly assigned to receive rosuvastatin (10mg/day) and matching placebo. The primary objective of the study was to assess the effect of 6-week treatment with rosuvastatin on basal NOS activity of the renal vasculature, as assessed by measuring renal plasma flow (RPF) both before and after blockade of NOS with systemic infusion of N(G)-monomethyl-L-arginine (L-NMMA). In a subgroup of 20 patients we also studied the effects of a 3-day treatment regimen. RESULTS: Compared to placebo treatment, rosuvastatin decreased LDL-cholesterol levels both after 3 days and 6 weeks of treatment. The decrease in RPF in response to L-NMMA was significantly more pronounced after 6-week therapy with rosuvastatin compared to placebo (-13.7+/-1.0% versus -11.3+/-0.7%; p=0.046), indicating increased basal NOS activity with rosuvastatin treatment. A trend towards improved basal NOS activity was already evident after 3-day treatment. CONCLUSION: Treatment with rosuvastatin improved basal NOS activity in the renal circulation of hypercholesterolemic patients, suggestive of a nephroprotective effect. In view of the close relation between altered renal function and cardiovascular events, these nephroprotective effects may contribute to the improved CV prognosis associated with statin treatment.

Barlage S, Hauser IA, Elbracht R, Abletshauser C, Schmieder RE, Weidinger G, Lackner KJ, Rothe G, Schmitz G. · Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, Germany. · J Biol Regul Homeost Agents. · Pubmed #16602632 No free full text.

Abstract: Flow cytometric T-cell analysis is capable of adding valuable information for balancing immunosuppression in transplant recipients as it can take into account individual effects of immunosuppressive drugs on each patient as well as effects of other drugs which may modify the overall immunosuppression. Studies suggest that HMG-CoA-reductase-inhibitors (statins) reduce the frequency of organ rejection, although the precise mechanism of this effect is unknown. We therefore evaluated the effect of fluvastatin on size and activation of T-cell subpopulations and NK-cell activity in renal transplant recipients. At baseline, the population size of activated (HLA-DR+) T-cells was negatively correlated to serum HDL cholesterol suggesting an increased T-cell activation at low HDL levels. Fluvastatin treatment of a hypercholesterolemic group of patients for two months significantly decreased the LDL cholesterol. A longitudinal analysis revealed a relative increase in non-MHC restricted cytotoxic T-cells (CD3+/CD16+ or CD56+) over time which was significantly attenuated in fluvastatin treated patients but not in normocholesterolemic controls. Moreover, a relative decrease of activated MHC class I-restricted cytotoxic CD8+ T-cells was only observed upon fluvastatin treatment. NK-cell number and activity did not differ between groups. In summary, fluvastatin treatment of hypercholesterolemic renal transplant recipients is associated with a specific modulation of T-cells exerting cytotoxic effector functions.

Schneider MP, Hilgers KF, Huang Y, Delles C, John S, Oehmer S, Schmieder RE. · Universität Erlangen-Nürnberg, Medizinische Klinik IV/4, Klinikum Nürnberg Süd, Breslauer Strasse 201, D-90471 Nuremberg, Germany. · Clin Sci (Lond). · Pubmed #12639216 No free full text.

Abstract: Oxidative stress plays a major pathogenetic role in cardiovascular disease. The C242T variant of the CYBA gene encoding the p22phox subunit of the NAD(P)H oxidase, a major source of superoxide production, has been shown to be associated with coronary artery disease and with vascular superoxide production in human veins ex vivo. Since superoxide degrades nitric oxide (NO), we hypothesized that the C242T variant influences endothelium-dependent vasodilation of the human forearm vasculature in vivo. In the present study, 90 subjects with elevated cholesterol levels were stratified for the C242T polymorphism of the CYBA p22phox gene. Endothelium-dependent and -independent vasodilation were assessed by plethysmographic monitoring of forearm blood flow responses to intra-arterial infusion of acetylcholine and sodium nitroprusside respectively. N(G)-Monomethyl-L-arginine (L-NMMA) was infused to analyse NO-mediated basal vascular tone. Baseline parameters (age, gender, blood pressure, body mass index, cholesterol level) were similar across the genotypes. No differences in forearm blood flow responses to the intra-arterial infusion of acetylcholine, sodium nitroprusside or L-NMMA were found across the CYBA p22phox genotypes. Our sample size of n =90 had a power of >80% (beta=0.20) with a P value of <0.05 (alpha=0.05) to detect a difference greater than 156% in the forearm blood flow response to acetylcholine across genotypes (S.D. 336%; average increase in forearm blood flow=514%). In conclusion, at a power of 80%, our study excludes a major effect of the C242T CYBA p22phox polymorphism on acetylcholine-mediated endothelium-dependent vasodilation and basal NO-mediated vascular tone of the human forearm circulation in subjects with hypercholesterolaemia.

Schneider MP, Delles C, Fleischmann E, Schmidt BM, John S, Schmieder RE. · Department of Medicine/Nephrology, University of Erlangen-Nürnberg, Nürnberg, Germany. · Am J Cardiol. · Pubmed #12586274 No free full text.

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Schlaich MP, John S, Jacobi J, Lackner KJ, Schmieder RE. · Department of Medicine IV/Nephrology, University of Erlangen-Nürnberg, Nurnberg, Germany. · Atherosclerosis. · Pubmed #11164427 No free full text.

Abstract: BACKGROUND: Elevated low density lipoproteins (LDL)-cholesterol and homocysteine levels have both been found to be associated with an increased risk for atherosclerotic vascular disease. To assess the effects of elevated homocysteine levels in hypercholesterolemic subjects on endothelial function, we examined basal and stimulated nitric oxide (NO) mediated vasodilation in the forearm vascular bed in hypercholesterolemic subjects with normal or elevated homocysteine levels. METHODS: Twenty-seven white subjects (age: 48 +/- 12 years) with elevated LDL-cholesterol (> or = 160 mg/dl) were divided into two groups with normal (n = 11) or mildly elevated (n = 16) homocysteine plasma concentration. We used strain gauge plethysmography to measure changes in forearm blood flow in response to intraarterial administration of increasing doses of acetylcholine (3, 12, 24, 48 microg/min), sodium nitroprusside (200, 800, 3200 ng/min), and N-monomethyl L-arginine (L-NMMA) (1, 2, 4 micromol/min). Total homocysteine plasma concentrations were determined by high performance liquid chromatography fluorimetry. RESULTS: Endothelium independent vascular relaxation tested by i.a. sodium nitroprusside and changes in forearm blood flow after i.a. L-NMMA indicating basal production and release of nitric oxide were similar between the two groups with normal or elevated homocysteine levels. In contrast, endothelium dependent vasodilation as assessed by the administration of i.a. acetylcholine differed between the groups with normal or elevated homocysteine levels for all doses tested (MANOVA P < 0.01: ACH 48 microg/min: 480 +/- 237% with normal vs 234 +/- 130% with elevated homocysteine; P < 0.002). This was significant even after taking possible covariates such as age, blood pressure, body mass index, LDL-, high density lipoproteins (HDL)-cholesterol, and trigylcerides into account (MANOVA P < 0.02). CONCLUSIONS: From our study we conclude that homocysteine impairs endothelium dependent vasodilation in subjects with elevated LDL-cholesterol levels. The most intriguing finding is that even mildly elevated homocysteine levels seem to be of crucial importance for deterioration of endothelial function, especially if other cardiovascular risk factors such as hypercholesterolemia preexist.

Danzer E, Gallert K, Henke J, Gustmann H, Walter H, Schmieder RE. · Institut für Präventive Medizin der Nieren-, Hochdruck- und Herzerkrankungen, Klinikum Nürnberg Süd. · MMW Fortschr Med. · Pubmed #10998905 No free full text.

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John S, Jacobi J, Delles C, Schlaich MP, Alter O, Schmieder RE. · Department of Medicine IV, University of Erlangen-Nürnberg, Klinikum Nürnberg-Süd, Breslauerstr. 201, 90471 Nürnberg, Germany. · Clin Sci (Lond). · Pubmed #10781382 No free full text.

Abstract: Levels of soluble cellular adhesion molecules are increased in patients with atherosclerosis, and have been found to predict coronary heart disease. Therefore these molecules have been suggested to represent laboratory markers for inflammation and activation of endothelial cells. Impaired endothelium-dependent vasodilation has been demonstrated to be an early marker of atherosclerosis. We hypothesized that soluble adhesion molecules are related to impaired endothelium-dependent vasodilation and may serve as an early marker of atherosclerosis. Patients (n=52) with moderate and uncomplicated hypercholesterolaemia [low-density lipoprotein (LDL)-cholesterol 4.89+/-1.26 mmol/l] were compared with healthy controls (n=43; LDL-cholesterol 2.44+/-0.79 mmol/l). Endothelium-dependent vasodilation of the forearm vasculature was assessed by intra-arterial infusion of acetylcholine (12 and 48 microg/min). Forearm blood flow was measured by venous occlusion plethysmography. Plasma concentrations of the soluble forms of ICAM-1 (intercellular cell adhesion molecule-1), VCAM-1 (vascular cell adhesion molecule-1) and E-selectin were measured by ELISA. Hypercholesterolaemic patients had impaired endothelium-dependent vasodilation in comparison with healthy controls (forearm blood flow after 48 microg/min acetylcholine: 21.3+/-10.6 and 30.4+/-16.3 ml. min(-1).100 ml(-1) respectively; P=0.002). Plasma concentrations of soluble adhesion molecules were not different between hypercholesterolaemic patients and controls (ICAM-1, 196+/-56 and 180+/-38 ng/ml respectively; VCAM-1, 431+/-137 and 405+/-65 ng/ml respectively; E-selectin, 39+/-17 and 37+/-12 ng/ml respectively). Moreover, levels of soluble adhesion molecules were not correlated with endothelium-dependent vasodilation. Thus, in hypercholesterolaemic patients without clinical atherosclerosis, levels of soluble adhesion molecules were not elevated in comparison with healthy controls. In addition, these markers of endothelial inflammation were not related to impaired endothelium-dependent vasodilation. Our data indicate that measurement of levels of soluble adhesion molecules cannot replace assessment of endothelium-dependent vasodilation in detection of early hypercholesterolaemic atherosclerosis.

John S, Drobnik W, Lackner K, Schmieder RE. · No affiliation provided · Lancet. · Pubmed #10560703 No free full text.

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