(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Calcinosis

The aim of this study was to evaluate the effect of treatment with statins on the progression of coronary atherosclerotic plaques of a nonculprit vessel by serial volumetric virtual histology (VH) intravascular ultrasound (IVUS).. Recent clinical trials have demonstrated a reduction of atherosclerotic plaque, yet whether statin therapy affects the change in components of plaque remains unknown.. This study was a nonrandomized and nonblinded design. Eighty patients with stable angina pectoris were divided into either the fluvastatin group (n = 40) or the control group (n = 40) according to their total or low-density lipoprotein (LDL) cholesterol level. The volume of each plaque component (dense calcium, fibrous tissue, fibro-fatty, or necrotic core) was evaluated at baseline and at 12-month follow-up.. The LDL cholesterol and high-sensitivity C-reactive protein (hsCRP) levels in the fluvastatin group were significantly decreased at time of follow-up. In VH IVUS findings, fibro-fatty volume was significantly decreased (baseline 80.1 +/- 57.9 mm(3) vs. follow-up 32.5 +/- 27.7 mm(3), p < 0.0001) and fibrous tissue volume was increased (baseline 146.5 +/- 85.6 mm(3) vs. follow-up 163.3 +/- 94.5 mm(3), p < 0.0001) in the fluvastatin group. In the control group, the volumes of all plaque components without fibrous tissue were significantly increased. Change in fibro-fatty volume has a significant correlation with a change in LDL cholesterol level (R = 0.703, p < 0.0001) and change in hsCRP level (R = 0.357, p = 0.006).. One-year lipid-lowering therapy by fluvastatin showed significant regression of plaque volume and alterations in atherosclerotic plaque composition with a significant reduction of fibro-fatty volume.

Topics: Aged; Biomarkers; C-Reactive Protein; Calcinosis; Cholesterol, LDL; Coronary Artery Disease; Disease Progression; Fatty Acids, Monounsaturated; Female; Fibrosis; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Japan; Male; Middle Aged; Necrosis; Predictive Value of Tests; Prospective Studies; Severity of Illness Index; Time Factors; Treatment Outcome; Ultrasonography, Interventional; User-Computer Interface

Topics: Calcinosis; Coronary Artery Disease; Fatty Acids, Monounsaturated; Fibrosis; Fluorobenzenes; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Necrosis; Observer Variation; Predictive Value of Tests; Pyrimidines; Radiography; Rosuvastatin Calcium; Severity of Illness Index; Simvastatin; Sulfonamides; Time Factors; Treatment Outcome; Ultrasonography, Interventional; User-Computer Interface

Apoptosis is essential for the initiation and progression of vascular calcification. Recently, we showed that 3-hydroxy-3-methylglutaryl (HMG) CoA reductase inhibitors (statins) have a protective effect against vascular smooth muscle cell calcification by inhibiting apoptosis, where growth arrest-specific gene 6 (Gas6) plays a pivotal role. In the present study, we clarified the downstream targets of Gas6-mediated survival signaling in inorganic phosphate (Pi)-induced apoptosis and examined the effect of statins. We found that fluvastatin and pravastatin significantly inhibited Pi-induced apoptosis and calcification in a concentration-dependent manner in human aortic smooth muscle cells (HASMC), as was found with atorvastatin previously. Gas6 and its receptor, Axl, expression were downregulated in the presence of Pi, and recombinant human Gas6 (rhGas6) significantly inhibited apoptosis and calcification in a concentration-dependent manner. During apoptosis, Pi suppressed Akt phosphorylation, which was reversed by rhGas6. Wortmannin, a specific phosphatidylinositol 3-OH kinase (PI3K) inhibitor, abolished the increase in Akt phosphorylation by rhGas6 and eliminated the inhibitory effect of rhGas6 on both Pi-induced apoptosis and calcification, suggesting that PI3K-Akt is a downstream signal of the Gas6-mediated survival pathway. Pi reduced phosphorylation of Bcl2 and Bad, and activated caspase 3, all of which were reversed by rhGas6. The inhibitory effect of statins on Pi-induced apoptosis was accompanied by restoration of the Gas6-mediated survival signal pathway: upregulation of Gas6 and Axl expression, increased phosphorylation of Akt and Bcl2, and inhibition of Bad and caspase 3 activation. These findings indicate that the Gas6-mediated survival pathway is the target of statins' effect to prevent vascular calcification.

Topics: Androstadienes; Apoptosis; Axl Receptor Tyrosine Kinase; bcl-Associated Death Protein; Calcinosis; Caspase 3; Cells, Cultured; Enzyme Activation; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Intercellular Signaling Peptides and Proteins; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Oncogene Proteins; Phosphates; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Pravastatin; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Receptor Protein-Tyrosine Kinases; Signal Transduction; Wortmannin

Proteoheparan sulfate can be adsorbed to a methylated silica surface in a monomolecular layer via its transmembrane hydrophobic protein core domain. Due to electrostatic repulsion, its anionic glycosaminoglycan side chains are stretched out into the blood substitute solution, thereby representing a receptor site for specific lipoprotein binding through basic amino acid-rich residues within their apolipoproteins. The binding process was studied by ellipsometric techniques. Low-density lipoprotein (LDL) was found to deposit strongly at the proteoheparan sulfate-coated surface, particularly in the presence of Ca(2+), apparently through complex formation 'proteoglycan-LDL-calcium'. This ternary complex build-up may be interpreted as arteriosclerotic nanoplaque formation on the molecular level responsible for the arteriosclerotic primary lesion. HDL bound to heparan sulfate proteoglycan protected against LDL deposition and completely suppressed calcification of the proteoglycan-lipoprotein complex. In addition, HDL was able to decelerate the ternary complex deposition and to disrupt newly formed nanoplaques. Therefore, HDL attached to its proteoglycan receptor sites is thought to raise a multidomain barrier, selection and control motif for transmembrane and paracellular lipoprotein uptake into the arterial wall. The molecular arteriosclerosis model was tested on its reliability in a biosensor application in order to unveil possible acute pleiotropic effects of the lipid lowering drug fluvastatin. The very low-density lipoprotein (VLDL)/intermediate-density lipoprotein (IDL)/LDL and VLDL/IDL/LDL/HDL plasma fractions from a high-risk patient with dyslipoproteinemia and type 2 diabetes mellitus showed beginning arteriosclerotic nanoplaque formation already at a normal blood Ca(2+) concentration, with a strong increase at higher Ca(2+) concentrations. Nanoplaque formation and size of the HDL-containing lipid fraction remained well below that of the LDL-containing lipid fraction. Fluvastatin, whether applied acutely to the patient (one single 80 mg slow release matrix tablet) or in a 2-months medication regimen, markedly slowed down this process of ternary aggregational nanoplaque build-up and substantially inhibited nanoplaque size development at all Ca(2+) concentrations used. The acute action resulted without any significant change in lipid concentrations of the patient. Furthermore, after nanoplaque generation, fluvastatin, similar to HDL, was able to reduce na

Topics: Adsorption; Arteriosclerosis; Biosensing Techniques; Calcinosis; Calcium; Coated Materials, Biocompatible; Diabetes Mellitus, Type 2; Fatty Acids, Monounsaturated; Fluvastatin; Heparan Sulfate Proteoglycans; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Indoles; Lipoproteins; Materials Testing; Models, Biological; Particle Size; Silicon Dioxide; Surface Properties; Treatment Outcome

Recent studies have supported the hypothesis that calcific aortic stenosis is the product of an active inflammatory process, with similarities to atherosclerosis. We sought to determine whether therapy with hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) might slow the progression of aortic stenosis.. A retrospective study of 174 patients (mean age 68+/-12 years) with mild to moderate calcific aortic stenosis was conducted. Patients required normal left ventricular function, /=2 echocardiograms performed at least 12 months apart. Fifty-seven patients (33%) received treatment with a statin; the remaining 117 (67%) did not. The statin group was older and had a higher prevalence of hypertension, diabetes mellitus, and coronary disease. During a mean follow-up of 21 months, patients treated with statin had a smaller increase in peak and mean gradient and a smaller decrease in aortic valve area. When annualized, the decrease in aortic valve area for the nonstatin group was 0.11+/-0.18 cm(2) compared with 0.06+/-0.16 cm(2) for those treated with a statin (P=0.03). In multivariate analysis, statin usage was a significant independent predictor of a smaller decrease in valve area (P=0.01) and a lesser increase in peak gradient (P=0.02).. Statin-treated patients, despite a higher risk profile for progression, had reduced aortic stenosis progression compared with those not treated with a statin. These data provide justification for a prospective randomized trial to substantiate whether statin therapy slows the progression of aortic stenosis.

Topics: Aged; Aortic Valve Stenosis; Atorvastatin; Calcinosis; Cholesterol, HDL; Cholesterol, LDL; Disease Progression; Echocardiography; Electrocardiography; Fatty Acids, Monounsaturated; Female; Fluvastatin; Follow-Up Studies; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Lovastatin; Male; Multivariate Analysis; Pravastatin; Pyrroles; Retrospective Studies; Risk Factors; Simvastatin; Treatment Outcome; Triglycerides; Vascular Patency

Regression of atheroma with reduction of cholesterol levels is recognized to occur, but less is known about reversal of sclerosis. Non-invasive indices of sclerosis have largely been based on carotid ultrasound measurements.. To measure aortic compliance, coronary calcification and carotid intimal-medial thickness during reduction of cholesterol level in patients with and without coronary artery disease.. We studied 64 hypercholesterolaemic patients, 24 with and 40 without coronary artery disease. All were administered fluvastatin for 1 year. Aortic compliance was assessed using magnetic resonance and coronary calcification score was determined by electron beam computed tomography. Carotid intimal-medial thickness in 34 patients was measured by carotid ultrasound means.. There was a rise in high-density lipoprotein cholesterol level and falls in total cholesterol level, low-density lipoprotein cholesterol level, low: high-density lipoprotein ratio, triglyceride level and very-low-density lipoprotein cholesterol level. Coronary artery disease patients had a higher coronary calcification score (442 +/- 551) than did other patients (269 +/- 724, P = 0.0002). For both groups there was a small rise in coronary calcification score during the study. Mean aortic compliance rose and blood pressure and carotid intimal-medial thickness fell. Analysis revealed significant correlations between change in mean aortic compliance and changes in high-density lipoprotein level (r = 0.3, P = 0.036), very-low-density lipoprotein level (r = -0.31, P = 0.038) and low: high-density lipoprotein ratio (r = -0.35, P = 0.014). There was no significant difference in these changes between the two patient groups.. An improvement in aortic compliance over 1 year indicates that increase in high-density lipoprotein level, decrease in very-low-density lipoprotein level and improvement in low: high-density lipoprotein ratio caused by administration of fluvastatin beneficially influenced vascular pathophysiology in hypercholesterolaemic patients with and without coronary artery disease. In those patients studied with carotid ultrasound means, carotid intimal-medial thickness decreased from 1.09 to 0.87 mm (P = 0.004), corroborating these results.

Topics: Anticholesteremic Agents; Aorta, Thoracic; Calcinosis; Carotid Artery, Common; Compliance; Coronary Disease; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hypercholesterolemia; Indoles; Magnetic Resonance Imaging; Male; Middle Aged; Pilot Projects; Time Factors; Tomography, X-Ray Computed; Tunica Intima; Tunica Media; Vascular Resistance