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Cascade plasma filtration during the first year after CABG in patients with hyperlipidemia refractory to statins.
Ezhov, MV, Il'ina, LN, Safarova, MS, Afanasieva, OI, Adamova, IY, Atanesyan, RV, Konovalov, GA, Akchurin, RS, Pokrovsky, SN
Atherosclerosis. Supplements. 2013;(1):101-5
Abstract
OBJECTIVE To evaluate the effect of a 12-month course of weekly lipid apheresis on vein graft patency after coronary artery bypass grafting (CABG) in patients with hyperlipidemia refractory to statins. METHODS In a 12-month prospective controlled clinical trial we enrolled 34 male patients (mean age 57 ± 8 years) who passed through successful CABG and low-density lipoprotein cholesterol (LDL-C) level >2.6 mmol/L prior to the operation despite statin treatment. Patients were allocated into 2 groups: active (n = 17, weekly apheresis by cascade plasma filtration (CPF) plus atorvastatin), and control (n = 17, atorvastatin alone). Graft patency was evaluated by multislice computed tomography at 3 months and by angiography at 12 months after an operation. RESULTS Both groups were comparable in clinical and biochemical characteristics. During each CPF procedure, LDL-C level decreased by 64 ± 9%, apoB - by 65 ± 8%, Lp(a) - by 52 ± 15%,; these changes were significant compared to baseline and the control group. Mean net difference in LDL-C level between apheresis and control groups was 1.1 ± 0.3 mmol/L. Vein graft patency at study end was 88.2% (45 of 51) in the apheresis group versus 72.7% (40 of 55) in the control group (p = 0.05). Use of apheresis was associated with decreased vein graft occlusions by 46%: relative risk 0.54; 95% confidence interval 0.27 to 1.02; p = 0.05. CONCLUSION Our data suggest that the use of lipoprotein apheresis with CPF results in a better vein graft patency during the first year after CABG in patients with hyperlipidemia refractory to statins.
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Atorvastatin treatment improves myocardial and peripheral blood flow in familial hypercholesterolemia subjects without evidence of coronary atherosclerosis.
Lario, FC, Miname, MH, Tsutsui, JM, Santos, RD, Kowatsch, I, Sbano, JC, Ramires, JA, Kalil Filho, R, Mathias, W
Echocardiography (Mount Kisco, N.Y.). 2013;(1):64-71
Abstract
BACKGROUND Hypercholesterolemia induces early microcirculatory functional and structural alterations that are reversible by cholesterol reduction. Real time myocardial contrast echocardiography (RTMCE) and vascular ultrasound evaluate the effects of hyperlipidemia on peripheral and central blood flow reserve. This study investigated the effects of lipid-lowering therapy on coronary and peripheral artery circulation in patients with familial hypercholesterolemia (FH). METHODS RTMCE and vascular ultrasound were performed in 10 healthy volunteers (validation group) at baseline and after 12-week clinical observation, and in 16 age- and sex-matched FH patients without obstructive coronary artery disease (CAD) by computed tomography angiography at baseline and after 12-week atorvastatin treatment. Indexes of relative myocardial blood flow (MBF) were obtained at rest and during adenosine infusion. RESULTS In validation group, there was no significant difference between flow-mediated dilation (FMD) at baseline and after 12 weeks (0.15 ± 0.02 vs. 0.14 ± 0.03; P = 0.39). Similarly, no differences were observed in MBF reserve at baseline and after 12 weeks (3.31 ± 0.63 vs. 3.48 ± 0.89; P = 0.89). FMD was blunted in FH patients, at baseline, as compared with validation group (0.08 ± 0.04 vs. 0.15 ± 0.02; P < 0.001) and became similar to that group (0.13 ± 0.05 vs. 0.14 ± 0.03; P = 0.07) after treatment. MBF reserve was blunted at baseline in FH patients in comparison with the validation group (2.78 ± 0.71 vs. 3.31 ± 0.63; P = 0.003). After treatment, MBF reserve values were no longer different (3.43 ± 0.66 and 3.48 ± 0.89; P = 0.84, respectively, for FH and validation groups). CONCLUSION Patients with FH and no obstructive CAD have blunted MBF reserve and lower FMD values as compared with healthy volunteers. Both FMD and MBF reserve were normalized after atorvastatin treatment.
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High-dose atorvastatin enhances impaired cerebral vasomotor reactivity.
Forteza, A, Romano, JG, Campo-Bustillo, I, Campo, N, Haussen, DC, Gutierrez, J, Koch, S
Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. 2012;(6):487-92
Abstract
The influence of statin therapy on cerebral vasomotor function has not been fully characterized. We report the effects of high-dose atorvastatin therapy on cerebral vasomotor reactivity (VMR) in patients with controlled hypertension and dyslipidemia. We prospectively enrolled 36 patients with controlled hypertension and a low-density lipoprotein (LDL) cholesterol concentration >100 mg/dL. Atorvastatin 80 mg was given daily for 6 months and then discontinued. VMR was assessed by hypercapnic and hypocapnic transcranial Doppler challenge in both the right and left middle cerebral artery (MCA) at baseline, and after 3 and 6 months of therapy. Forty-five days after statin cessation, a repeat VMR was performed. VMR impairment was defined as ≤70%. Blood pressure, lipid levels, liver function, and creatine kinase level were monitored. Mean patient age was 60 years, 16 were men, and 13 had a previous history of subcortical infarction. Mean LDL cholesterol level before treatment was 154 ± 30 mg/dL. Atorvastatin lowered LDL by 53% at 3 months and by 46% at 6 months. Baseline VMR was 71% ± 21% in the right MCA and 70% ± 19% in the left MCA. No significant effect of atorvastatin on VMR was seen at 3 months and 6 months in the study population as a whole. In the subgroup of patients with baseline VMR impairment, atorvastatin therapy was associated with significantly improved VMR at both 3 and 6 months. This effect persisted for at least 45 days after discontinuation of therapy. Our findings indicate that high-dose atorvastatin therapy can significantly improve impaired cerebral VMR, and that the effects of atorvastatin on VMR persist for 1.5 months after discontinuation of therapy. We found no benefit of atorvastatin therapy in patients with preserved baseline vasoreactivity.
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Oral atorvastatin therapy restores cutaneous microvascular function by decreasing arginase activity in hypercholesterolaemic humans.
Holowatz, LA, Santhanam, L, Webb, A, Berkowitz, DE, Kenney, WL
The Journal of physiology. 2011;(Pt 8):2093-103
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Abstract
Elevated low-density lipoproteins (LDLs) are associated with vascular dysfunction evident in the cutaneous microvasculature. We hypothesized that uncoupled endothelial nitric oxide synthase (NOS3) through upregulated arginase contributes to cutaneous microvascular dysfunction in hyperocholesterolaemic (HC) humans and that a statin intervention would decrease arginase activity. Five microdialysis fibres were placed in the skin of nine normocholesterolaemic (NC: LDL level 95±4 mg dl⁻¹) and nine hypercholesterolaemic (HC: LDL: 177±6 mg dl⁻¹) men and women before and after 3 months of systemic atrovastatin. Sites served as control, NOS inhibited, arginase inhibited, L-arginine supplemented and arginase inhibited plus L-arginine supplemented. Skin blood flow was measured while local skin heating (42°C) induced NO-dependent vasodilatation. L-NAME was infused after the established plateau in all sites to quantify NO-dependent vasodilatation. Data were normalized to maximum cutaneous vascular conductance (CVC(max)). Skin samples were obtained to measure total arginase activity and arginase I and arginase II protein. Vasodilatation was reduced in hyperocholesterolaemic subjects (HC: 76±2 vs. NC: 94±3%CVC(max), P < 0.001) as was NO-dependent vasodilatation (HC: 43±5 vs. NC: 62±4%CVC(max), P < 0.001). The plateau and NO-dependent vasodilatation were augmented in HC with arginase inhibition (92±2, 67±2%CVC(max), P < 0.001), L-arginine (93±2, 71±5%CVC(max), P < 0.001) and combined treatments (94±4, 65±5%CVC(max), P < 0.001) but not in NC. After statin intervention (LDL: 98±5 mg dl⁻¹) there was no longer a difference between control sites (88±4, 61±5%CVC(max)) and localized microdialysis treatment sites (all P > 0.05). Arginase activity and protein were increased in HC skin (P < 0.05 vs. NC) and activity decreased with atrovastatin treatment (P < 0.05). Reduced NOS3 substrate availability through upregulated arginase contributes to cutaneous microvascular dysfunction in hyperocholesterolaemic humans, which is corrected with atorvastatin therapy.
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CYP3AP1*3 allele is associated with lipid-lowering efficacy of simvastatin and atorvastatin in Chinese women.
Li, YP, Zhang, LR, Jia, M, Hu, XJ
Journal of clinical pharmacology. 2011;(2):181-8
Abstract
Response to statin therapy for cardiovascular disease is variable among different individuals. The authors aimed to investigate the effect of the CYP3AP1*3 polymorphism on the lipid-lowering efficacy of statins. They recruited 379 unrelated hyperlipidemic patients: 202 (103 men) treated with simvastatin and 177 (87 men) with atorvastatin as single-agent therapy (20 mg day(-1) orally) for 4 weeks. CYP3AP1*3(-44G>A) was genotyped using the PCR restriction fragment-length polymorphism method. Serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TGs) were determined before and after treatment. The frequency of the CYP3AP1*3 variant allele in Chinese hyperlipidemic patients was 70.6%. In the simvastatin treatment group, the percentage reduction of LDL-C level was greater in the CYP3AP1*3/*3 carriers than in the CYP3AP1*1 carriers. This difference was statistically significant for women but not for men. In contrast, the authors found no significant association between the lipid-lowering efficacy of atorvastatin and the CYP3AP1*3 polymorphism in all participants. However, in women, the percentage change of the TC level was significantly lower in the CYP3AP1*3/*3 carriers than in the CYP3AP1*1 carriers. These findings suggest that the CYP3AP1*3 allele may be a biomarker for the lipid-lowering efficacy of simvastatin and atorvastatin in Chinese women with hyperlipidemia.
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Modulating effect of atorvastatin on paraoxonase 1 activity in type 2 diabetic Egyptian patients with or without nephropathy.
Abdin, AA, Hassanien, MA, Ibrahim, EA, El-Noeman, Sel-D
Journal of diabetes and its complications. 2010;(5):325-33
Abstract
The aim of this study was to investigate the modulating effect of atorvastatin on serum paraoxonase 1 enzyme (PON1) activity in type 2 diabetic Egyptian patients with or without nephropathy. The present study was carried out on the following groups: control group, which consisted of 30 healthy persons; Group I, which consisted of 20 type 2 diabetic patients without nephropathy; and Group II, which consisted of 20 type 2 diabetic patients with nephropathy. All the patients selected were under an antidiabetic regimen of insulin, and patients receiving antihypertensive agents were excluded from the follow-up study to avoid drug interaction fallacies. Twenty-two patients (15 without nephropathy and seven with nephropathy) received atorvastatin in individually adjusted oral dosage (range 10-20 mg) once per day for 12 weeks. All cases were subjected to thorough clinical examination and history taking and measurement of serum levels of PON1 activity, malondialdehyde (MDA), glutathione reductase activity, fasting glucose, total cholesterol, triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL), urea, and creatinine. Urine samples were collected for determination of proteinuria. The obtained results showed that PON1 activity and HDL significantly decreased and fasting glucose significantly increased in Group I and Group II when compared to the control group, with significant difference in their levels between Group II and Group I. MDA, total cholesterol, and LDL levels significantly increased and glutathione reductase activity significantly decreased in Group I and Group II when compared to the control group. Urea, creatinine, and proteinuria levels showed significant increase in Group II when compared to the control group and Group I, with nonsignificant difference between control group and Group I. Atorvastatin therapy caused a significant increase in PON1 activity, and serum levels of MDA and glutathione reductase activity were significantly decreased and increased, respectively. Also, total cholesterol, triglyceride and LDL-cholesterol levels were significantly reduced with a significant increase in HDL-cholesterol levels. There was a significant modest reduction in serum urea and creatinine levels as well as in proteinuria level. Fasting glucose level was significantly reduced under the antidiabetic regimen of insulin through the follow-up period. PON1 activity showed a significant negative correlation with glucose and LDL, and a significant positive correlation with HDL in all the studied groups. It could be concluded that atorvastatin with its pleiotropic effects could provide optimal therapeutic intervention to control not only dyslipidemia, but also oxidative stress status with consequent improvement in the course of type 2 diabetes and diabetic nephropathy. More specifically, restoration of PON1 activity by atorvastatin opens a window to investigate other drugs that could provide a new adjuvant therapeutic line for better control of diabetes and diabetic nephropathy. Further research is also recommended to study the distribution of PON1 genetic polymorphism among the Egyptian population to explain the variability in its activity and its relationship with other factors that associate diabetes and its complications.
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Metastatic renal carcinoma: evaluation of antiangiogenic therapy with dynamic contrast-enhanced CT.
Fournier, LS, Oudard, S, Thiam, R, Trinquart, L, Banu, E, Medioni, J, Balvay, D, Chatellier, G, Frija, G, Cuenod, CA
Radiology. 2010;(2):511-8
Abstract
PURPOSE To determine whether tumor perfusion parameters assessed by using dynamic contrast material-enhanced computed tomography (CT) could help predict and detect response in patients receiving antiangiogenic therapy for metastatic renal cell carcinoma. MATERIALS AND METHODS Institutional ethics committee approval and informed consent were obtained. In two phase-III trials involving 51 patients with metastatic renal cell carcinoma (38 men, 13 women; age range, 30-80 years) receiving antiangiogenic drugs (sorafenib [n = 10], sunitinib [n = 22]), a placebo (n = 12), or interferon alfa (n = 7), serial dynamic contrast-enhanced CT was performed, during 90 seconds before and after injection of 80 mL of iobitridol. Perfusion parameters of a target metastatic tumor (tumor blood flow [TBF], tumor blood volume [TBV], mean transit time, and vascular permeability-surface area product) were calculated. Values before and after treatment were compared by using a Wilcoxon signed rank test, and relative changes in groups were compared by using the Wilcoxon rank sum test. Results were compared with Response Evaluation Criteria in Solid Tumors response and with progression-free and overall survival by using Kaplan-Meier curves. RESULTS Among patients receiving antiangiogenic drugs, baseline perfusion parameters were higher in responders than in stable patients (TBF = 245.3 vs 119.5 mL/min/100 mL, P = .04; TBV = 15.5 vs 8.2 mL/100 mL, P = .02) but were not significantly predictive of survival. After the first cycle of treatment, there was a significant decrease in TBF (162.5 vs 76.7 mL/min/100 mL, P = .0002) and TBV (9.1 vs 3.9 mL/100 mL, P < .0001) in patients receiving antiangiogenic treatment. CONCLUSION Renal carcinoma perfusion parameters determined with dynamic contrast-enhanced CT can help predict biologic response to antiangiogenic drugs before beginning therapy and help detect an effect after a single cycle of treatment.
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Effects of atorvastatin 80 mg daily on indices of matrix remodelling in 'high-risk' patients with ischemic heart disease.
López-Cuenca, A, Marín, F, Roldán, V, Climent, VE, Valdés, M, Lip, GY
International journal of cardiology. 2010;(1):95-7
Abstract
Recent evidence suggests that higher doses of statins could improve clinical outcomes compared to conventional doses, but whether this benefit is due to "additional" pleiotropic effects is uncertain. We tested the hypothesis that atorvastatin 80 mg/day would have beneficial effects on indices of matrix remodelling (matrix metalloproteinase-1, MMP-1, and its tissue inhibitor, TIMP-1) in high-risk cardiovascular disease. We studied 27 "high-risk" patients (inclusion criteria: severe triple vessel but rejected for by-pass for extensive coronary disease, severe effort angina after coronary artery by-pass and premature coronary disease with > or =3 risk factors) with an abnormal lipid profile despite atorvastatin 40 mg/day, at baseline and at 3 months after increasing the statin dose to 80 mg/day. Baseline results in patients were compared to 22 healthy controls. At baseline, patients had lower levels of MMP-1 compared to controls. When atorvastatin was increased to 80 mg/day, significant reduction in LDL-cholesterol was observed, whereas MMP-1 and TIMP-1 levels were increased. These, despite of atorvastatin 40 mg daily, 'high-risk' patients still demonstrated abnormal extracellular remodelling indices. Doubling the dose of atorvastatin resulted in significant improvement in extracellular remodelling indices.
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[Atorvastatin use and coronary flow reserve in patients with coronary slow flow].
Fan, Y, Yang, SS, Yu, JB, Hao, JH, Han, W, Gan, RT, Wang, Z, Li, WM, Huang, YL
Zhonghua xin xue guan bing za zhi. 2010;(2):143-6
Abstract
OBJECTIVE To investigate the impact of statin use on coronary flow reserve (CFR) in patients with slow coronary flow. METHODS A total of 91 patients with chest pain and coronary slow flow but normal coronary angiography were included in this study, patients were divided into statin group (atorvastatin 20 mg/d for 8 weeks, n = 51) and non-statin group (n = 40), 26 healthy subjects with normal angiography and negative exercise ECG test served as normal controls. Blood cholesterol was measured. Doppler coronary flow velocity and Doppler reserve measurement of distal left anterior descending were recorded at rest and adenosine infusion (140 microgxkg(-1)xmin(-1)) induced hyperemia state, CFR was calculated by the ratio of maximal hyperemia and baseline peak diastolic coronary flow velocity (hCFV and bCFV) before and after atorvastatin treatment. RESULTS (1) Eight weeks later, total cholesterol and LDL-C levels were significantly lower in statin group than in non-statin group and control group [TC (3.83 +/- 0.80) mmol/L vs. (5.30 +/- 1.18) mmol/L vs. (5.32 +/- 1.17) mmol/L, P < 0.05; LDL-C (2.26 +/- 0.64) mmol/L vs. (3.28 +/- 0.85) mmol/L vs. (3.30 +/- 0.82) mmol/L, P < 0.05]. (2)Baseline CFR levels were significantly lower in statin group and non-statin group than that in control group (2.32 +/- 0.30 vs. 2.25 +/- 0.33 vs. 3.15 +/- 0.34, P < 0.05). Compared with non-statin group and statin group before treatment, 8 weeks statin treatment was associated with reduced bCFV [(26.06 +/- 3.22) cm/s vs. (29.02 +/- 3.36) cm/s and (26.06 +/- 3.22) cm/s vs. (28.43 +/- 3.40) cm/s, P < 0.05], increased hCFV [(77.63 +/- 8.96) cm/s vs. (65.17 +/- 7.22) cm/s and (77.63 +/- 8.96) cm/s vs. (64.58 +/- 6.26) cm/s, P < 0.05] and increased CFR (3.07 +/- 0.29 vs. 2.28 +/- 0.35 and 3.07 +/- 0.29 vs. 2.32 +/- 0.30, P < 0.05). bCFV, hCFV and CFR of statin group post treatment were similar to those of controls (P > 0.05). CONCLUSION Patients with coronary slow flow were associated with lower CFR which could be significantly improved by statin therapy.
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(TTA)n polymorphism in 3-hydroxy-3-methylglutaryl-coenzyme A and response to atorvastatin in coronary artery disease patients.
Noriega, V, Pennanen, C, Sánchez, MP, Chiong, M, Llancaqueo, M, Lavandero, S, Prieto, JC
Basic & clinical pharmacology & toxicology. 2009;(3):211-5
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Abstract
3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors have been used clinically for lowering total and low-density lipoprotein cholesterol. Interindividual pharmacological differences observed with this treatment have been attributed to genetic differences. The aim of this study was to assess the association in the low-density lipoprotein cholesterol reduction by atorvastatin and (TTA)n polymorphism in the 3-hydroxy-3-methylglutaryl-coenzyme A reductase gene in patients with coronary artery disease. Changes in total cholesterol levels, triglycerides, high-sensitivity C-reactive protein and free F(2)-isoprostanes were also evaluated. In an open study, patients received 40 mg atorvastatin daily for 8 weeks. Genotyping was done through polymerase chain reaction. The genotype distribution of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (TTA)n polymorphism was: >10/>10 in 22 out of 64 patients (34%), >10/10 in 14 out of 64 patients (22%) and 10/10 in 28 out of 64 patients (44%). The reduction of low-density lipoprotein cholesterol levels by atorvastatin was not different between allelic variants (TTA)n repeat polymorphism. Reductions in high-sensitivity C-reactive protein were observed in atorvastatin-treated patients with alleles >10/>10 and 10/10. Free F(2)-isoprostanes and total cholesterol were also significantly lower after treatment for all alleles, irrespective of type of polymorphism. In conclusion, the changes induced by atorvastatin treatment on low-density lipoprotein cholesterol, total cholesterol, triglycerides, high-sensitivity C-reactive protein and free F(2)-isoprostane concentrations were not related to the presence of 3-hydroxy-3-methylglutaryl-coenzyme A reductase polymorphism (TTA)n.