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1.
Endothelial function in subjects with isolated low HDL cholesterol: role of nitric oxide and circulating progenitor cells.
Higashi, Y, Matsuoka, H, Umei, H, Sugano, R, Fujii, Y, Soga, J, Kihara, Y, Chayama, K, Imaizumi, T
American journal of physiology. Endocrinology and metabolism. 2010;(2):E202-9
Abstract
Epidemiologic studies have shown that a low level of high-density lipoprotein (HDL) cholesterol is a risk factor for cardiovascular diseases. The purpose of this study was to determine the contribution of isolated low HDL cholesterol to endothelial function. Thirty-nine subjects with low HDL cholesterol who had no other cardiovascular risk factors were selected from the 5,417 participants from our population. We evaluated flow-mediated vasodilation (FMD) before and after 4 wk of treatment with the HMG-CoA reductase inhibitor pravastatin in 29 of the 39 subjects with isolated low HDL cholesterol. FMD was lower in the low-HDL-cholesterol group (n = 29) than in the control group (n = 29), whereas NTG-induced vasodilation was similar in the two groups. Pravastatin increased HDL cholesterol, urinary excretion of nitrite/nitrate, circulating levels of progenitor cells, and cell migration response to vascular endothelial growth factor in 15 subjects with low HDL cholesterol but not in 14 placebo control subjects. FMD increased in the pravastatin treatment group but not in the control group. NTG-induced vasodilation was similar before and after 4 wk of treatment in the two groups. Multiple regression analysis revealed that changes in HDL cholesterol, the number of progenitor cells, and migration of progenitor cells were independent predictors of augmentation of FMD with pravastatin. These findings suggest that low HDL cholesterol is an independent risk factor for endothelial dysfunction and that pravastatin improves endothelial function in individuals with isolated low HDL cholesterol through, at least in part, an increase in circulating progenitor cells.
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2.
Statin potentiates human platelet eNOS activity without enhancing eNOS mRNA and protein levels.
Yemisci, M, Ay, H, Kocaefe, C, Qui, J, Topalkara, K, Ozgüç, M, Kirazli, S, Ozcebe, O, Moskowitz, MA, Dalkara, T
Cerebrovascular diseases (Basel, Switzerland). 2008;(2):190-8
Abstract
BACKGROUND/AIMS: Experimental studies suggest an enhanced endothelial and platelet nitric oxide (NO) generation after statin treatment, possibly due to increased endothelial NO synthase (eNOS) activity and protein levels. In parallel with experimental research, statins were shown to increase the forearm blood flow independently of serum cholesterol in humans. However, it was not possible to correlate blood flow changes with eNOS levels in these studies due to limitations in obtaining arterial samples. Hence, we investigated changes in eNOS activity, mRNA and protein levels after statin treatment in human platelets, which are readily accessible unlike arteries. METHODS In vitro bleeding times were measured in 22 patients by stimulating platelets with collagen-epinephrine or collagen-ADP. To assess platelet eNOS activity, the bleeding times were also determined after incubating platelets with L-arginine. The measurements were repeated following 14 days of pravastatin (40 mg/day) treatment. Platelet-rich plasma was collected before and after statin treatment to evaluate eNOS mRNA (semiquantitative RT-PCR) and protein levels (Western blotting). RESULTS The basal bleeding time was prolonged by 24 +/- 3% (mean +/- SE) when the samples were incubated with 500 microM of L-arginine. The NOS inhibitor L-N(5)-(I-iminoethyl)ornithine reversed this effect, suggesting that it was mediated by NO. After statin treatment, the NO-mediated prolongation of the bleeding time with 500 microM of L-arginine was significantly potentiated (to 44 +/- 10%). Despite enhanced eNOS activity, there was no significant change in platelet eNOS mRNA and protein levels after statin treatment. CONCLUSION These data demonstrate that platelet eNOS activity is potentiated after statin treatment in humans in parallel with experimental studies.
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3.
Effects of pravastatin treatment on blood pressure regulation after renal transplantation.
Lopau, K, Spindler, K, Wanner, C
Kidney & blood pressure research. 2006;(6):329-37
Abstract
BACKGROUND/AIM: Hypertension is one of the main cardiovascular risk factors and has an impact also on long-term kidney graft survival. In addition to their lipid-lowering properties, it was shown that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors also have a blood pressure lowering effect. We examined whether treatment with a statin interferes with blood pressure regulation and antihypertensive treatment after renal transplantation. METHODS 74 patients were treated with initially 20 mg of pravastatin daily immediately after kidney transplantation. This group was compared to a matched cohort of 76 patients without statin treatment. All patients received standard immunosuppressive triple therapy with ciclosporin A microemulsion together with an antiproliferative agent and prednisolone. Primary objective of this analysis was systolic and diastolic blood pressure regulation with and without pravastatin. Furthermore, graft function expressed as creatinine clearance and proteinuria, immunosuppressive regimen, and incidence of cardiovascular events and graft loss were recorded for 48 months. RESULTS The blood pressure regulation was comparable in both groups; however, to achieve this, significantly more antihypertensive drugs had to be used in the statin-treated patients as compared with the controls (2.9 vs. 2.2 agents at 48 months). A slightly higher ciclosporin A exposure of the statin-treated patients could have contributed to this observation. The graft function after 4 years was comparable between the groups (creatinine clearance 56.9 vs. 57.0 ml/min), and a trend of reduced proteinuria could be demonstrated after 4 years of statin treatment (0.4 vs. 0.9 g/day). The low-density lipoprotein cholesterol levels decreased as expected during treatment (3.1 vs. 3.7 mmol/l at 48 months), but the recommended target levels for patients with a high cardiovascular risk have not been reached. A trend towards lower incidences of acute rejection, chronic allograft nephropathy, and graft loss was noted in the statin-treated group. Adverse effects of statin treatment have not been observed. CONCLUSION Treatment with pravastatin at low to average dosages does not result in improved blood pressure regulation after kidney transplantation.
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4.
Plasma lipoproteins and apolipoproteins as predictors of cardiovascular risk and treatment benefit in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER).
Packard, CJ, Ford, I, Robertson, M, Shepherd, J, Blauw, GJ, Murphy, MB, Bollen, EL, Buckley, BM, Cobbe, SM, Gaw, A, et al
Circulation. 2005;(20):3058-65
Abstract
BACKGROUND Statins are important in vascular disease prevention in the elderly. However, the best method of selecting older patients for treatment is uncertain. We assessed the role of plasma lipoproteins as predictors of risk and of treatment benefit in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). METHOD AND RESULTS The association of LDLc and HDLc with risk was examined in the 5804 70- to 82-year-old subjects of PROSPER. Baseline LDLc showed no relation to risk of the primary end point in the placebo group (P=0.27), nor did on-treatment LDLc in the pravastatin group (P=0.12). HDLc was inversely associated with risk in subjects on placebo (P=0.0019) but not in those on pravastatin (P=0.24). Risk reduction on pravastatin treatment was unrelated to baseline LDLc (P=0.38) but exhibited a significant interaction with HDLc (P=0.012). Subjects in the lowest 2 quintiles of HDLc (<1.15 mmol/L) had a risk reduction of 33% (hazard ratio, 0.67; 95% confidence limits, 0.55, 0.81; P<0.0001), whereas those with higher HDLc showed no benefit (RR, 1.06; 95% confidence limits, 0.88, 1.27; P=0.53). During follow-up, there was no relation between achieved level of LDLc or HDLc and risk. However, the change in the LDLc/HDLc ratio on statin treatment appeared to account for the effects of therapy. CONCLUSIONS In people >70 years old, HDLc appears to be a key predictor of risk and of treatment benefit. Findings in PROSPER suggest that statin therapy could usefully be targeted to those with HDLc <1.15 mmol/L or an LDLc/HDLc ratio >3.3.
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5.
Pravastatin suppresses the increase in matrix metalloproteinase-2 levels after acute myocardial infarction.
Nakaya, R, Uzui, H, Shimizu, H, Nakano, A, Mitsuke, Y, Yamazaki, T, Ueda, T, Lee, JD
International journal of cardiology. 2005;(1):67-73
Abstract
BACKGROUND Matrix metalloproteinase (MMP) may contribute to myocardial remodeling after myocardial infarction. The goal of this study was to characterize the effects of pravastatin on circulating levels of MMP and on left ventricular dilatation after acute myocardial infarction (AMI). METHODS Thirty-four consecutive patients with successful reperfusion following AMI were assigned to either pravastatin group (group P, n=12) or non-pravastatin group (group NP, n=22). Serum MMP-2 and tissue inhibitor of MMP (TIMP)-2 were measured immediately after reperfusion, on days 2, 3, 7, 30, and at 6 months after MI. Left ventriculography was performed after reperfusion and at 4 weeks and 6 months. RESULTS MMP-2 levels were higher in patients with MI than control on days 1, 30, and at 6 months. Left ventricular end-diastolic volume index (LVEDVI) at 6 months correlated with MMP-2 levels on day 30 (r=0.47, p<0.01) and at 6 months (r=0.56, p<0.001). MMP-2 levels at 6 months were significantly lower in group P than group NP. Further, LVEDVI at 6 months tended to be smaller and DeltaLVEDVI was significantly smaller in group P when compared with group NP. CONCLUSION Serum MMP-2 varied in a time-dependent manner following AMI and correlated with late changes in LVEDVI. Serum MMP-2 levels were significantly lower in treatment group than in non-treatment group and DeltaLVEDVI was significantly smaller in treatment group after long-term pravastatin administration. Use of statins in AMI patients may provide beneficial effects in terms of preventing heart failure over and above its lipid-lowering effects.
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6.
Lipid and apolipoprotein ratios: association with coronary artery disease and effects of rosuvastatin compared with atorvastatin, pravastatin, and simvastatin.
Rader, DJ, Davidson, MH, Caplan, RJ, Pears, JS
The American journal of cardiology. 2003;(5A):20C-23C; discussion 23C-24C
Abstract
Plasma lipid and apolipoprotein ratios that include both an atherogenic and an antiatherogenic lipid component (eg, total cholesterol/high-density lipoprotein [HDL] cholesterol ratio, low-density lipoprotein [LDL] cholesterol/HDL cholesterol ratio, non-HDL cholesterol/HDL cholesterol ratio, and apolipoprotein [apo] B/apo A-I ratio) have been found to be strong predictors of coronary artery disease (CAD) risk. Three trials that compared the effects of rosuvastatin 10 mg versus atorvastatin 10 mg and 2 trials that compared the effects of rosuvastatin 10 mg versus simvastatin 20 mg and pravastatin 20 mg on lipid ratios in patients with hypercholesterolemia were prospectively designed for pooled analysis. At 12 weeks, in the 3-trial pooled analysis, rosuvastatin 10 mg (n = 389) showed significantly greater reductions in all 4 lipid ratios compared with atorvastatin 10 mg (n = 393) (p <0.001). The mean percent reduction from baseline in the LDL cholesterol/HDL cholesterol ratio was 51% in patients treated with rosuvastatin 10 mg versus 39% in patients treated with atorvastatin 10 mg. In the 2-trial pooled analysis, treatment with rosuvastatin 10 mg (n = 226) also resulted in significantly greater reductions in all 4 lipid ratios compared with both simvastatin 20 mg (n = 249) and pravastatin 20 mg (n = 252) (p <0.001). Mean percent reductions from baseline in the LDL cholesterol/HDL cholesterol ratio were 52%, 39%, and 30% for rosuvastatin 10 mg, simvastatin 20 mg, and pravastatin 20 mg, respectively, in these 2 trials.
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7.
Monocyte chemoattractant protein-1 and CC-chemokine receptor-2 in severe hypercholesterolaemia.
Blomqvist, HM, Olsson, AG
Scandinavian journal of clinical and laboratory investigation. 2003;(7-8):513-9
Abstract
OBJECTIVES To investigate whether plasma concentrations of monocyte chemoattractant protein-1 (MCP-1) and the gene expression of its receptor on the monocyte cell surface CCR-2 were elevated above normal in subjects with asymptomatic, isolated hypercholesterolaemia and if statin treatment could influence this cytokine. METHODS The investigation was designed as a cross sectional study followed by a single, blind, treatment study of patients receiving pravastatin 80 mg/day for 8 weeks. The study included 23 patients with severe hypercholesterolaemia (LDL>5.2 mmol/L) and 39 normocholesterolaemic controls. Blood samples were obtained from patients and controls at baseline and from patients at end of the study and analysed for lipoproteins and inflammatory mediators: MCP-1. high-sensitivity C-reactive protein (HS-CRP). Isolated peripheral mononuclear cells were analysed for CCR-2 gene expression. RESULTS Mean plasma LDL-C was significantly higher in patients than in controls. No difference in plasma MCP-1 levels or CCR-2 gene expression was seen between the groups at baseline, nor were there any differences in plasma concentrations of CRP. After treatment with pravastatin, LDL-C decreased by 31%. Treatment did not significantly affect the levels of MCP-1 or CCR-2 gene expression, nor was CRP affected by treatment with pravastatin. CONCLUSIONS Our study does not support the view that MCP-1 plasma levels and CCR-2 gene expression in circulating monocytes are directly responsible for the monocyte recruitment into the arterial intima in patients with severe asymptomatic hypercholesterolaemia. In addition, the inflammatory response of a high concentration of LDL-C in isolated asymptomatic hypercholesterolaemia is minute.
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8.
Effects of combined treatment with pravastatin and ursodeoxycholic acid on hepatic cholesterol metabolism.
Hillebrant, CG, Nyberg, B, Gustafsson, U, Sahlin, S, Björkhem, I, Rudling, M, Einarsson, C
European journal of clinical investigation. 2002;(7):528-34
Abstract
BACKGROUND Treatment with ursodeoxycholic acid and also, to some degree, statins reduces cholesterol saturation of bile. The present study aimed [1] to study the effects of combined treatment with ursodeoxycholic acid and pravastatin on hepatic cholesterol metabolism and [2] to evaluate if the addition of pravastatin to ursodeoxycholic acid treatment has beneficial effects on the lipid composition of gallbladder bile in gallstone patients. MATERIALS AND METHODS Nineteen patients with cholesterol gallstones were subjected to combined treatment with ursodeoxycholic acid (500 mg bid) and pravastatin (20 mg bid) for three weeks before cholecystectomy. Eleven patients received ursodeoxycholic acid only and 20 untreated gallstone patients served as controls. Gallbladder bile was collected, and for both the patients receiving combined treatment and the controls a liver biopsy was also obtained peroperatively. RESULTS The cholesterol saturation of bile averaged 59% in the patients on combined treatment, 60% in the ursodeoxycholic acid-treated patients, and 130% in the untreated controls. In the patients receiving ursodeoxycholic acid, this bile salt constituted approximately 60% of all bile salts. The patients receiving combined treatment had reduced cholesterol synthesis, as reflected by a 45% reduction in serum lathosterol. The activity and the mRNA levels of cholesterol 7 alpha-hydroxylase and the mRNA levels for the low density lipoprotein-receptor were not significantly affected. CONCLUSIONS Pravastatin does not further reduce the cholesterol saturation of bile in gallstone patients treated with ursodeoxycholic acid, although hepatic cholesterol synthesis is inhibited. The study supports the important concept that de novo synthesized cholesterol is not particularly important for biliary cholesterol secretion in humans.
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9.
Efficacy and safety of pravastatin vs simvastatin after cardiac transplantation.
Keogh, A, Macdonald, P, Kaan, A, Aboyoun, C, Spratt, P, Mundy, J
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2000;(6):529-37
Abstract
Prior studies of cardiac transplant recipients have shown that pravastatin reduces 12-month rejection and mortality after cardiac transplantation and simvastatin reduces 4-year mortality, low-density lipoprotein (LDL) cholesterol levels, and intimal thickening. In a 12-month observational study, cardiac transplant recipients received open-label pravastatin 40 mg (n = 42) or simvastatin 20 mg daily (n = 45) on an alternating basis from the time of transplantation. Lipid levels, safety, and post-transplant outcomes were compared. We found no significant differences in total LDL or high-density lipoprotein cholesterol, triglycerides, linearized infection or rejection rates, liver function tests, or immunosuppressant dosages between groups at 1, 3, 6, or 12 months. Rhabdomyolysis or myositis occurred only in patients on simvastatin (n = 6, 13.3%) with no episodes for patients on pravastatin (p = 0. 032). Survival at 12 months on an actual treatment basis was 97.6% for patients on pravastatin and 83.7% for those on simvastatin (p = 0.078). Immunosuppression-related deaths occurred in only 2.4% (1 patient) on pravastatin vs 15.6% (n = 7) on simvastatin (p = 0.06). Pravastatin and simvastatin resulted in comparable lipid profiles. Pravastatin use was however free from the high rates of rhabdomyolysis and myositis seen with simvastatin use. Pravastatin was additionally associated with a trend toward superior survival, attributable to fewer immunosuppression-related deaths. For safety and pharmacokinetic reasons, pravastatin should be considered the statin of choice after heart transplantation.
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10.
[Intensification in vivo of free radical oxidation of low density lipoproteins in plasma from patients with myocardial ischemia treated by HMG-CoA-reductase pravastatin and suppression of lipid peroxidation by ubiquinone Q10].
Lankin, VZ, Tikhaze, AK, Kaminnaia, VI, Kaminnyĭ, AI, Konovalova, GG, Kukharchuk, VV
Biulleten' eksperimental'noi biologii i meditsiny. 2000;(2):176-9