Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease.
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BACKGROUND: Therapeutic neovascularization may constitute an important strategy to salvage tissue from critical ischemia. Circulating bone marrow-derived endothelial progenitor cells (EPCs) were shown to augment the neovascularization of ischemic tissue. In addition to lipid-lowering activity, hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins) reportedly promote the neovascularization of ischemic tissue in normocholesterolemic animals. Methods and Results-Fifteen patients with angiographically documented stable coronary artery disease (CAD) were prospectively treated with 40 mg of atorvastatin per day for 4 weeks. Before and weekly after the initiation of statin therapy, EPCs were isolated from peripheral blood and counted. In addition, the number of hematopoietic precursor cells positive for CD34, CD133, and CD34/kinase insert domain receptor was analyzed. Statin treatment of patients with stable CAD was associated with an approximately 1.5-fold increase in the number of circulating EPCs by 1 week after initiation of treatment; this was followed by sustained increased levels to approximately 3-fold throughout the 4-week study period. Moreover, the number of CD34/kinase insert domain receptor-positive hematopoietic progenitor cells was significantly augmented after 4 weeks of therapy. Atorvastatin treatment increased the further functional activity of EPCs, as assessed by their migratory capacity. CONCLUSION: The results of the present study define a novel mechanism of action of statin treatment in patients with stable CAD: the augmentation of circulating EPCs with enhanced functional activity. Given the well-established role of EPCs of participating in repair after ischemic injury, stimulation of EPCs by statins may contribute to the clinical benefit of statin therapy in patients with CAD. (+info)
Cerivastatin triggers tumor-specific apoptosis with higher efficacy than lovastatin.
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The statin family of drugs inhibits 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme of the mevalonate pathway, and is used clinically as a safe and effective approach in the control of hypercholesterolemia. We have shown previously (Dimitroulakos, J., Nohynek, D., Backway, K. L., Hedley, D. W., Yeger, H., Freedman, M. H., Minden, M D., and Penn, L. Z. Increased sensitivity of acute myelogenous leukemias to lovastatin-induced apoptosis: a potential therapeutic approach. Blood, 93: 1308-1318, 1999) that lovastatin, a prototypic member of the statin family, can induce apoptosis of human acute myeloid leukemia (AML) cells in a sensitive and specific manner. In the present study, we evaluated the relative potency and mechanism of action of the newer synthetic statins, fluvastatin, atorvastatin, and cerivastatin, to trigger tumor-specific apoptosis. Cerivastatin is at least 10 times more potent than the other statins at inducing apoptosis in AML cell lines. Cerivastatin-induced apoptosis is reversible with the addition of the immediate product of the HMG-CoA reductase reaction, mevalonate, or with a distal product of the pathway, geranylgeranyl pyrophosphate. This suggests protein geranylgeranylation is an essential downstream component of the mevalonate pathway for cerivastatin similar to lovastatin-induced apoptosis. The enhanced potency of cerivastatin expands the number of AML patient samples as well as the types of malignancies, which respond to statin-induced apoptosis with acute sensitivity. Cells derived from acute lymphocytic leukemia are only weakly sensitive to lovastatin cytotoxicity but show robust response to cerivastatin. Importantly, cerivastatin is not cytotoxic to nontransformed human bone marrow progenitors. These results strongly support the further testing of cerivastatin as a novel anticancer therapeutic alone and in combination with other agents in vivo. (+info)
Human breath isoprene and its relation to blood cholesterol levels: new measurements and modeling.
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Numerous publications have described measurements of breath isoprene in humans, and there has been a hope that breath isoprene analyses could be a noninvasive diagnostic tool to assess blood cholesterol levels or cholesterol synthesis rate. However, significant analytic problems in breath isoprene analysis and variability in isoprene levels with age, exercise, diet, etc., have limited the usefulness of these measurements. Here, we have applied proton transfer reaction-mass spectrometry to this problem, allowing on-line detection of breath isoprene. We show that breath isoprene concentration increases within a few seconds after exercise is started as a result of a rapid increase in heart rate and then reaches a lower steady state when breath rate stabilizes. Additional experiments demonstrated that increases in heart rate associated with standing after reclining or sleeping are associated with increased breath isoprene concentrations. An isoprene gas-exchange model was developed and shows excellent fit to breath isoprene levels measured during exercise. In a preliminary experiment, we demonstrated that atorvastatin therapy leads to a decrease in serum cholesterol and low-density-lipoprotein levels and a parallel decrease in breath isoprene levels. This work suggests that there is constant endogenous production of isoprene during the day and night and reaffirms the possibility that breath isoprene can be a noninvasive marker of cholesterologenesis if care is taken to measure breath isoprene under standard conditions at constant heart rate. (+info)
Use of intravascular ultrasound to compare effects of different strategies of lipid-lowering therapy on plaque volume and composition in patients with coronary artery disease.
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BACKGROUND: We studied whether lipid-lowering therapy with atorvastatin (target LDL cholesterol [LDL-C] <100 mg/dL) compared with a moderate treatment regimen that used other lipid-lowering drugs led to a lesser progression of atherosclerosis and to different changes in plaque echogenicity in patients with coronary artery disease. METHODS AND RESULTS: This study was a 12-month, open-label, randomized, multicenter trial, which used serial 3D intracoronary ultrasound to calculate plaque volume and plaque echogenicity. After transcatheter therapy, 131 patients were randomized (atorvastatin n=65, usual care n=66). The target plaque had to be a minor lesion (ie, a diameter stenosis of <50% on angiography). After 12 months, mean LDL-C was reduced from 155 to 86 mg/dL in the atorvastatin group and from 166 to 140 mg/dL in the usual care group. Mean absolute plaque volume showed a larger increase in the usual care group compared with the atorvastatin group (usual care 9.6+/-28.1 mm(3), atorvastatin 1.2+/-30.4 mm(3); P=0.191). The hyperechogenicity index of the plaque increased to a larger extent for the atorvastatin group than for the usual care group, with a significant treatment effect for the percent change (atorvastatin 42.2%, usual care 10.1%; P=0.021). CONCLUSIONS: One year of lipid-lowering therapy to <100 mg/dL LDL-C most likely led to a slowdown of plaque growth of minor lesions. The significantly larger increase in plaque hyperechogenicity is most likely due to a change in plaque composition. (+info)
Atorvastatin improves endothelial function in renal-transplant recipients.
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BACKGROUND: Hyperlipidaemia and endothelial dysfunction are common features in cyclosporin A (CsA)-treated renal transplant recipients. Endothelial dysfunction may contribute to the risk of premature atherosclerosis and cardiovascular death in these patients. A beneficial effect of statin therapy beyond cholesterol lowering may be an improvement of endothelial function. The present study was designed to assess the effect of atorvastatin on serum lipids and endothelial function in CsA treated renal transplant recipients. METHODS: This pilot study was an open trial of 4 weeks atorvastatin (10 mg per day) treatment in renal transplant recipients (n=22). All patients received a CsA- and prednisolone-based immunosuppressive regimen. Endothelial function was assessed in the forearm skin microvasculature by acetylcholine stimulation and laser Doppler flowmetry, before and after atorvastatin treatment. Serum lipids, plasma endothelin-1 (ET-1), nitric oxide (NO), and von Willebrand factor (vWF) were also measured. RESULTS: Both total and LDL cholesterol were significantly reduced by 26.8 +/- 8.4 and 41.5 +/- 11.0% respectively, after 4 weeks of treatment. Endothelial function was significantly improved during atorvastatin treatment, area under the flux versus time curve (AUC)(ACh) was 538 +/- 362 AU x min before and 682 +/- 276 AU x min after treatment (P=0.042). Plasma NO levels also showed a borderline significant increase from 49 +/- 30 to 57 +/- 37 micromol/l during the treatment period (P=0.051), though plasma ET-1 (0.37+/-0.08 vs 0.37+/-0.12 fmol/ml) and vW (196+/-57 vs 197+/-37%) were unchanged. CONCLUSION: Atorvastatin lowered serum cholesterol significantly and improved endothelial function in renal transplant recipients after 4 weeks of treatment. Plasma NO levels were increased during atorvastatin treatment, indicating a possible endothelial protective effect through an "endothelial-NO pathway". (+info)
Raman spectroscopic evaluation of the effects of diet and lipid-lowering therapy on atherosclerotic plaque development in mice.
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Quantitative characterization of atherosclerotic plaque composition with standard histopathological methods remains limited to sectioned plaques. Raman spectroscopy enables nondestructive quantification of atherosclerotic plaque composition. We used Raman spectroscopy to study the effects of diet and lipid-lowering therapy on plaque development in apolipoprotein (APO) E*3-Leiden transgenic mice. Raman spectra were obtained over the full width and entire length of the ascending aorta and aortic arch. Spectra were modeled to calculate the relative dry weights of cholesterol and calcium salts, and quantitative maps of their distribution were created. In male mice (n=20) that received a high-fat/high-cholesterol (HFC) diet for 0, 2, 4, or 6 months, Raman spectroscopy showed good correlation between cholesterol accumulation and total serum cholesterol exposure (r approximately 0.87, P<0.001). In female mice (n=10) that were assigned to an HFC diet, with or without 0.01% atorvastatin, a strong reduction in cholesterol accumulation (57%) and calcium salts (97%) (P<0.01) was demonstrated in the atorvastatin-treated group. In conclusion, Raman spectroscopy can be used to quantitatively study the size and distribution of depositions of cholesterol and calcification in APOE*3-Leiden transgenic mice. This study encourages Raman spectroscopy for the quantitative investigation of atherosclerosis and lipid-lowering therapy in larger animals or humans in vivo. (+info)
Effect of statins on bone mineral density and bone histomorphometry in rodents.
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Statins have been postulated to affect bone metabolism. We investigated the effects of different doses of simvastatin (1, 5, 10, and 20 mg. kg(-1). d(-1)), atorvastatin (2.5 mg. kg(-1). d(-1)), and pravastatin (10 mg. kg(-1). d(-1)) administered orally for 12 weeks to intact female Sprague-Dawley rats and the effect of 20 mg. kg(-1). d(-1) simvastatin in sham-operated and ovariectomized rats on femoral bone mineral density (BMD) and quantitative bone histomorphometry (QBH) and compared them with controls. BMD was decreased by 1 mg. kg(-1). d(-1) simvastatin (P=0.042), atorvastatin (P=0.0002), and pravastatin (P=0.002). The effect on QBH parameters differed with different doses of simvastatin (ANOVA, P=0.00012). QBH parameters of both bone formation and resorption were equivalently and markedly increased by 20 mg. kg(-1). d(-1) simvastatin in 2 separate groups of intact rats and were reflected by a relatively unchanged BMD. At lower doses, 1 mg. kg(-1). d(-1) simvastatin decreased bone formation while increasing bone resorption, as reflected by a marked decrease in BMD. Ovariectomized animals receiving 20 mg. kg(-1). d(-1) simvastatin showed no change in BMD relative to the untreated, ovariectomized controls; their increase in bone formation was smaller than in sham-operated rats receiving simvastatin, and there was no change in bone resorption. Dose-response curves of simvastatin for bone formation and resorption differed. These studies indicate that (1) statins decrease BMD in rodents, (2) high-dose simvastatin increases bone formation and resorption, (3) low-dose simvastatin decreases bone formation and increases bone resorption, (4) the effects of simvastatin on QBH differ at different dosages, (5) the effects of simvastatin seen in intact rats are not observed in ovariectomized rats, and (6) simvastatin is unable to prevent bone loss caused by ovariectomy. (+info)
Simvastatin and atorvastatin enhance hypotensive effect of diltiazem in rats.
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Effects of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, simvastatin and atorvastatin, on diltiazem-induced hypotension were examined in anaesthetized rats and compared to that of pravastatin. Vehicle, 2 mg/kg/day simvastatin, 2 mg/kg/day atorvastatin, or 4 mg/kg/day pravastatin was administered orally for 4 days. Diltiazem at 3 mg/kg was given orally 2 hours after the final administration of the inhibitors. Arterial blood pressure was measured via a cannula introduced into the left carotid artery, and heart rate was counted from the pulse pressure. In all groups, diltiazem significantly decreased the mean arterial blood pressure without any changes in heart rate. Pretreatment with simvastatin and atorvastatin significantly enhanced the hypotensive effect of diltiazem, while that with pravastatin did not. Heart rate was not modified by pretreatment with the inhibitors. The results indicate that concomitant use of diltiazem with simvastatin or atorvastatin enhances diltiazem-induced hypotension, probably by competitive inhibition of diltiazem metabolism with simvastatin and atorvastatin metabolisms. (+info)