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

As a population ages, an increase in the number of patients with cardiac complications who undergo non-cardiac surgeries is observed. The perioperative mortality for noncardiac surgery is approximately 1-5%; approximately 20-35% of these cases are due to cardiovascular complications. Among them, perioperative myocardiac infarction/ischemia is a factor that leads to poor prognosis, and the ACC/AHA guidelines emphasize this aspect. An important task of the anesthesiologist is to accurately assess risks in patients undergoing noncardiac surgeries and avoid adverse cardiovascular events.

Topics: Adrenergic beta-Antagonists; Anesthesia; Atenolol; Bisoprolol; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Indoles; Intraoperative Complications; Metoprolol; Monitoring, Intraoperative; Morpholines; Myocardial Infarction; Myocardial Ischemia; Perioperative Care; Postoperative Complications; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Risk Assessment; Urea

In patients undergoing vascular surgery there is a high incidence of adverse cardiac events, due to sudden coronary plaque rupture. The non-lipid lowering or pleiotropic effects of statins can help reduce adverse cardiovascular events associated with vascular surgery.. The evidence for perioperative use of fluvastatin, as well as other statins, in high-risk surgery patients is summarized in this review. Data on pharmacokinetics and metabolism is presented, together with considerations on possible drug interactions in the perioperative period.. The reader will gain a comprehensive understanding of the existing safety and efficacy data for fluvastatin and other statins in the perioperative period. The practical considerations of perioperative fluvastatin therapy will be presented, including potential side-effects and management of the early non-oral phase immediately post surgery. Finally, advice on when to initiate therapy and safety recommendations are offered.. In patients scheduled for high-risk vascular surgery, fluvastatin improves postoperative outcome, reducing the incidence of myocardial damage by approximately 50% in the first 30 days following vascular surgery. In comparison with placebo, fluvastatin was not associated with a rise in liver enzymes or creatine kinase levels. To bridge the non-oral phase, an extended-release formula is recommended.

Topics: Administration, Oral; Anesthetics; Biotransformation; Cardiac Surgical Procedures; Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme System; Delayed-Action Preparations; Drug Interactions; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Male; Muscular Diseases; Myocardial Ischemia; Plaque, Atherosclerotic; Postoperative Complications; Premedication; Randomized Controlled Trials as Topic; Risk; Rupture, Spontaneous; Substance Withdrawal Syndrome

Patients with acute coronary syndrome (ACS) are at high risk for recurrent coronary events, sudden death, and all-cause mortality. Conventional revascularization therapies reduce the risk of further ischemia but do not affect the underlying atherosclerotic disease. Statins have a proven record in the secondary prevention of coronary heart disease. Furthermore, statins have been shown to exert varying degrees of pleiotropic effects, which may stabilize vulnerable atherosclerotic plaques. A compelling body of evidence from randomized controlled trials demonstrates that high-dose, potent statin therapy initiated immediately after an acute coronary event can significantly reduce early as well as longer-term morbidity and mortality. Furthermore, high-dose, potent statin therapy displays a reasonable safety profile. National guidelines now recommend that in patients with ACS, statin therapy should be initiated in hospital prior to discharge, irrespective of baseline low-density lipoprotein cholesterol levels, to improve clinical outcomes. Every effort should be made to ensure all eligible patients with ACS are initiated and maintained on statin therapy.

Topics: Angina, Unstable; Atorvastatin; Cholesterol, HDL; Cholesterol, LDL; Fatty Acids, Monounsaturated; Fluvastatin; Heptanoic Acids; Hospitalization; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Myocardial Ischemia; Pravastatin; Pyrroles; Syndrome; Treatment Outcome

Adverse cardiac events are common after vascular surgery. We hypothesized that perioperative statin therapy would improve postoperative outcomes.. In this double-blind, placebo-controlled trial, we randomly assigned patients who had not previously been treated with a statin to receive, in addition to a beta-blocker, either 80 mg of extended-release fluvastatin or placebo once daily before undergoing vascular surgery. Lipid, interleukin-6, and C-reactive protein levels were measured at the time of randomization and before surgery. The primary end point was the occurrence of myocardial ischemia, defined as transient electrocardiographic abnormalities, release of troponin T, or both, within 30 days after surgery. The secondary end point was the composite of death from cardiovascular causes and myocardial infarction.. A total of 250 patients were assigned to fluvastatin, and 247 to placebo, a median of 37 days before vascular surgery. Levels of total cholesterol, low-density lipoprotein cholesterol, interleukin-6, and C-reactive protein were significantly decreased in the fluvastatin group but were unchanged in the placebo group. Postoperative myocardial ischemia occurred in 27 patients (10.8%) in the fluvastatin group and in 47 (19.0%) in the placebo group (hazard ratio, 0.55; 95% confidence interval [CI], 0.34 to 0.88; P=0.01). Death from cardiovascular causes or myocardial infarction occurred in 12 patients (4.8%) in the fluvastatin group and 25 patients (10.1%) in the placebo group (hazard ratio, 0.47; 95% CI, 0.24 to 0.94; P=0.03). Fluvastatin therapy was not associated with a significant increase in the rate of adverse events.. In patients undergoing vascular surgery, perioperative fluvastatin therapy was associated with an improvement in postoperative cardiac outcome. (Current Controlled Trials number, ISRCTN83738615.)

Topics: Adrenergic beta-Antagonists; C-Reactive Protein; Cardiovascular Diseases; Cholesterol; Double-Blind Method; Electrocardiography; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Interleukin-6; Kaplan-Meier Estimate; Myocardial Ischemia; Perioperative Care; Postoperative Period; Troponin T; Vascular Surgical Procedures

The "Mediterranean" diet and statin treatment have both independently been shown to improve survival and reduce the risk of cardiovascular events in patients with ischemic heart disease (IHD), but no studies have evaluated the effect of this combination on endothelial function. We therefore sought to evaluate the effect of the combination dietary intervention and lipid-lowering treatment on brachial vasoreactivity.. A total of 131 consecutive patients with documented IHD and a serum cholesterol level > or =5 mmol/L (193 mg/dL) were randomized to receive Mediterranean dietary advice (n = 68) or no specific dietary advice (n = 63). Endothelial function was assessed at baseline and after 12 months with noninvasive ultrasound scanning vessel-wall tracking of brachial artery flow-mediated vasodilatation (FMD). All patients started statin treatment with Fluvastatin (40 mg once daily) at baseline.. A total of 115 patients completed the study. At baseline, FMD was 4.30% +/- 4.89% in the control group versus 4.32% +/- 6.15% in the intervention group (P = not significant). After 12 months of follow-up, FMD was significantly higher in the intervention group (control group 5.72% +/- 4.87% vs intervention group 8.62% +/- 6.60%, P <.01). This was accompanied by a larger intake of fatty fish and a significant decrease in triglyceride levels. In multivariate analysis, randomization status was a significant predictor of FMD after adjustment for classic cardiovascular risk factors and vessel size (P =.02; beta = -2.66 [-4.91; -0.41]).. Dietary intervention with the Mediterranean diet and statin treatment improve FMD in the brachial artery in patients with IHD and hypercholesterolemia to a greater degree than statin treatment alone.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Brachial Artery; Cholesterol; Cholesterol, LDL; Combined Modality Therapy; Diet, Mediterranean; Endothelium, Vascular; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Myocardial Ischemia; Prospective Studies; Regional Blood Flow; Ultrasonography

To assess efficacy of combination therapy with fluvastatin and fenofibrate in ischemic heart disease (IHD) patients with combined hyperlipidemia and type 2 diabetes.. Patients with IHD and combined hyperlipidemia with (n=56)) or without type 2 diabetes (n=30).. After 8-week diet period the patients were randomized to 4 weeks monotherapy with either fluvastatin (40 mg/day) or micronized fenofibrate (200 mg/day). In patients whose low-density lipoprotein cholesterol (LDL CH) remained > 2,6 mmol/1 and triglycerides (TG) > 2.3 mmol/1 combination of fluvastatin 40 mg/day and fenofibrate 200 mg/day was used for the next 12 weeks.. Target levels of LDL CH and TG were achieved in 75 and 88%, respectively, of diabetics, and in 73 and 88%, respectively, of non-diabetics.. The use of combination of fluvastatin and fenofibrate was more effective then monotherapy for correction of lipid abnormalities in combined hyperlipidemia both in diabetics and non-diabetics with IHD.

Topics: Adult; Aged; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Fatty Acids, Monounsaturated; Female; Fenofibrate; Fluvastatin; Humans; Hyperlipidemias; Hypolipidemic Agents; Indoles; Male; Middle Aged; Myocardial Ischemia; Treatment Outcome

Residual ischaemia following acute myocardial infarction (AMI) is related to an adverse outcome, although the effect of early initiation of statin therapy is unknown.. A randomized, placebo-controlled, double-blind, parallel study was performed, which compared fluvastatin 80 mg daily with placebo in patients with an AMI and total cholesterol of <6.5 mmol.l(-1). Ischaemia was measured by ambulatory electrocardiographic (AECG) monitoring over 48-h at baseline, after 6 weeks and at 12 months.. Five hundred and forty patients were included (83% male, age 61+/-11 years); 43% had an anterior AMI and 50% were treated with fibrinolytics in the acute phase. After 12 months, the total cholesterol (TC) level was reduced by 13% and LDL-C (low-density-lipoprotein cholesterol) by 21% (from 3.5 mmol.l(-1) to 2.7 mmol.l(-1)) in the fluvastatin treatment group. Both TC and LDL increased by 9% in the placebo group (P<0.001 between groups). At baseline, ischaemia on AECG was present in only 11% of patients, and absent in 77%; in the remaining 11%, recordings were technically inadequate. After 6 weeks, 32/48 (67%), and 12 months 35/46 (76%) of the patients with ischaemia on the baseline AECG, no longer showed signs of ischaemia. Nevertheless, ischaemia at baseline was predictive for the occurrence of any major clinical event (RR=2.35; 95% CI 1.39-3.2;P <0.001). Fluvastatin treatment did not affect ischaemia on AECG, nor the occurrence of any major clinical events as compared to placebo. Post-hoc analysis in patients with the most pronounced ischaemia at baseline showed a trend for a beneficial effect of fluvastatin on major clinical events (P=0.084).. Residual ischaemia after AMI is observed less frequently in the present study, than in earlier studies, although it is predictive for future cardiovascular events. As a result, the present study was underpowered, and no effect of fluvastatin on AECG ischaemia, or major clinical events in the first year after AMI, could be detected. The present data do not confirm other reports which support widespread use of statin treatment early after AMI.

Topics: Adult; Aged; Aged, 80 and over; Cholesterol, LDL; Double-Blind Method; Electrocardiography, Ambulatory; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia

Percutaneous coronary intervention (PCI) is associated with excellent short-term improvements in ischemic symptoms, yet only three fifths of PCI patients at 5 years and one third of patients at 10 years remain free of major adverse cardiac events (MACE).. To determine whether treatment with fluvastatin reduces MACE in patients who have undergone PCI.. Randomized, double-blind, placebo-controlled trial conducted at 77 referral centers in Europe, Canada, and Brazil.. A total of 1677 patients (aged 18-80 years) recruited between April 1996 and October 1998 with stable or unstable angina or silent ischemia following successful completion of their first PCI who had baseline total cholesterol levels between 135 and 270 mg/dL (3.5-7.0 mmol/L), with fasting triglyceride levels of less than 400 mg/dL (4.5 mmol/L).. Patients were randomly assigned to receive treatment with fluvastatin, 80 mg/d (n = 844), or matching placebo (n = 833) at hospital discharge for 3 to 4 years.. Survival time free of MACE, defined as cardiac death, nonfatal myocardial infarction, or reintervention procedure, compared between the treatment and placebo groups.. Median time between PCI and first dose of study medication was 2.0 days, and median follow-up was 3.9 years. MACE-free survival time was significantly longer in the fluvastatin group (P =.01). One hundred eighty-one (21.4%) of 844 patients in the fluvastatin group and 222 (26.7%) of 833 patients in the placebo group had at least 1 MACE (relative risk [RR], 0.78; 95% confidence interval [CI], 0.64-0.95; P =.01). This result was independent of baseline total cholesterol levels (above [RR, 0.76; 95% CI, 0.56-1.04] vs below [RR, 0.77; 95% CI, 0.57-1.02] the median). In subgroup analysis, the risk of MACE was reduced in patients with diabetes (n = 202; RR, 0.53; 95% CI, 0.29-0.97; P =.04) and in those with multivessel disease (n = 614; RR, 0.66; 95% CI, 0.48-0.91; P =.01) who received fluvastatin compared with those who received placebo. There were no instances of creatine phosphokinase elevations 10 or more times the upper limit of normal or rhabdomyolysis in the fluvastatin group.. Fluvastatin treatment in patients with average cholesterol levels undergoing their first successful PCI significantly reduces the risk of major adverse cardiac events.

Topics: Adult; Aged; Angioplasty, Balloon, Coronary; Double-Blind Method; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Lipoproteins; Male; Middle Aged; Myocardial Ischemia; Proportional Hazards Models; Survival Analysis

Inhibitors of HMG-CoA reductase are widely used for the treatment of hypercholesterolaemia and have recently been shown in the Scandinavian Simvastatin Survival Study (4S), to reduce coronary mortality as well as total mortality in CH D patients. Although a couple of studies have already established the efficacy ratio between simvastatin and fluvastatin, one of the newest members of this class, we considered it to be important to verify the comparative efficacy in patients with coronary artery disease in the same type of patients that were included in 4S particularly since the previous studies include rather few patients with CHD, 17-28% only.. Three Scandinavian lipid clinics participated in this randomized double-blind study and enrolled a total of 113 hypercholesterolaemic patients with a profile similar to the 4S patients, i.e. either a history of typical angina pectoris lasting at least three months or a myocardial infarction at least six months before the study and with moderate hypercholesterolaemia, total serum cholesterol between 5.5 and 8.0 mmol/l. After a diet run-in period lasting at least 8 weeks, followed by a two week placebo period, patients received treatment with active drug for a 16 week period, with measurement of lipids using the same technique and laboratory as was used in 4S. Patients were randomly assigned to simvastatin 20 mg or fluvastatin 20 mg. If after 6 weeks of double-blind treatment, the 4S total cholesterol target of < or = 5.2 mmol/l total serum cholesterol had not been reached, the dose was doubled at the next visit, i.e. at week 10 based upon blinded titration information from the central lipid laboratory like in the 4S study. A final assessment of serum lipids and lipoproteins was made at week 16. The mean percent reductions in LDL-cholesterol from baseline were 37% and 40% in the simvastatin group compared to 19% and 26% in the fluvastatin group, at weeks 10 and 16, respectively (p < 0.001). In the simvastatin group 18 percent of the patients needed an increase in the dose to 40 mg compared to 63 percent in the fluvastatin group (p < 0.001). At the 20 mg dosage, simvastatin produced a lowering of LDL-cholesterol approximately twice that of fluvastatin 20 mg and resulted in 82% of patients achieving the cholesterol target levels as defined in the 4S study, compared to 19% for fluvastatin. All other recorded lipid variables showed differences which favoured simvastatin over fluvastatin at comparable doses including serum triglyceride reductions where serum triglycerides at week 6 were borderline significantly different between the two groups. Patient tolerability of the two drugs was similar.. At the recommended doses in patient with angina or a prior MI and mild to moderate hypercholesterolaemia simvastatin is considerably more effective than fluvastatin in lowering serum total cholesterol, LDL-cholesterol as well as other serum lipid risk factors. At an average titrated dose of 32 mg less than 50% of the fluvastatin patients reached the 4S cholesterol target of < 5.2 mmol/l compared to 89% of the simvastatin patients at an average dose of 23 mg daily and only 13% of the fluvastatin patients achieved an LDL-cholesterol reduction of at least 40% compared to 63% of the simvastatin patients.

Topics: Analysis of Variance; Apolipoproteins; Double-Blind Method; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hypercholesterolemia; Hypolipidemic Agents; Indoles; Likelihood Functions; Lipids; Male; Middle Aged; Myocardial Ischemia; Simvastatin; Statistics, Nonparametric

Fluvastatin, a traditional fat-decreasing drug, is widely used for curing cardiovascular disease. Previous reports demonstrated that fluvastatin pretreatment protected against myocardial ischemia/reperfusion (I/R) by inhibiting TLR4 signaling pathway and/or reducing proinflammatory cytokines. However, whether fluvastatin has a cardioprotective effect against apoptosis and autophagy remains unknown. This study aims to evaluate whether the cardioprotective role of fluvastatin in I/R is mediated by high-mobility group box 1 (HMGB1)/toll-like receptor 4 (TLR4) pathway via anti-apoptotic and anti-autophagic functions. Sprague-Dawley rats were anesthetized, artificially ventilated and subjected to 30 min of coronary occlusion, followed by 4 h of reperfusion. The animals were randomized into four groups: (i) Sham operation; (ii) I/R; (iii) I/R + low-dosage fluvastatin (10 mg/kg); and (iv) I/R + high-dosage fluvastatin (20 mg/kg). After reperfusion, the hemodynamic parameters, myocardial infarct size, structural alteration of myocardium, apoptosis index, pro-inflammatory cytokine production, Beclin-1, Light chain 3 (LC3), HMGB1, TLR4 and Nuclear factor kappa B (NF-κB) protein levels were measured and recorded. It was found that fluvastatin preconditioning improved left ventricular dysfunction, reduced HMGB1/TLR4/NF-κB expressions, and inhibited cardiomyocyte apoptosis, autophagy, and inflammation reaction. Moreover, treatment with fluvastatin ameliorated myocardial injury by reducing infarct size, causing less damage to cardiac structure, downregulating autophagy-related protein expression and releasing pro-inflammation mediators. Our findings indicate that fluvastatin exerts beneficial effects on cardiac ischemic damage, which may be associated with its anti-autophagic and anti-apoptotic functions via inhibition of HMGB1/TLR4-related pathway during I/R injury.

Topics: Animals; Apoptosis; Autophagy; Cardiotonic Agents; China; Fluvastatin; HMGB1 Protein; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Myocytes, Cardiac; NF-kappa B; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Signal Transduction; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Stellate ganglion (SG) plays an important role in cardiovascular diseases. The electrical activity of SG neurons is involved in the regulation of the autonomic nervous system. The aim of this research was to evaluate the effects of fluvastatin on the electrophysiological characteristics of SG neurons in a rabbit model of myocardial ischemia (MI).. The MI model was induced by abdominal subcutaneous injections of isoproterenol in rabbits. Using whole-cell patch clamp technique, we studied the characteristic changes of ion channels and action potentials (APs) in isolated SG neurons in control group (n = 20), MI group (n = 20) and fluvastatin pretreated group (fluvastatin group, n = 20), respectively. The protein expression of sodium channel in SG was determined by immunohistochemical analysis.. MI and the intervention of fluvastatin did not have significantly influence on the characteristics of delayed rectifier potassium channel currents. The maximal peak current density of sodium channel currents in SG neurons along with the characteristics of activation curves, inactivation curves, and recovery curves after inactivation were changed in the MI group. The peak current densities of control group, MI group, and fluvastatin group (n = 10 in each group) were -71.77 ± 23.22 pA/pF, -126.75 ± 18.90 pA/pF, and -86.42 ± 28.30 pA/pF, respectively (F = 4.862, P = 0.008). Fluvastatin can decrease the current amplitude which has been increased by MI. Moreover, fluvastatin induced the inactivation curves and post-inactive recovery curves moving to the position of the control group. But the expression of sodium channel-associated protein (Nav1.7) had no significantly statistical difference among the three groups. The percentages of Nav1.7 protein in control group, MI group, and fluvastatin group (n = 5 in each group) were 21.49 ± 7.33%, 28.53 ± 8.26%, and 21.64 ± 2.78%, respectively (F = 1.495, P = 0.275). Moreover, MI reduced the electrical activity of AP and increased amplitude of AP, fluvastatin pretreatment could recover amplitude and electrical activity of AP. The probability of neurons induced continuous APs were 44.44%, 14.29%, and 28.57% in control group, MI group, and fluvastatin group, respectively.. Fluvastatin pretreatment can recover electrophysiology characteristics of ion channel and AP in SG neurons in a rabbit model of MI. It could be considered as potential method for treating coronary heart diseases.

Topics: Action Potentials; Animals; Fatty Acids, Monounsaturated; Fluvastatin; Indoles; Myocardial Ischemia; Rabbits; Sodium Channels; Stellate Ganglion

Some new facts about the influence of different groups of drugs on myocardial perfusion were educed during the research. Educed facts conduce representation extension by matching the optimal therapy of ischemic heart disease. With the help of SPECT-scanning were educed myocardial blood flow, areas of maximal hypoperfusion and its influence on time pattern and redistribution of myocardial blood flow in patients receiving disease-modifying agents and statins. Some regularities of change of myocardial blood flow depending on applied group of drugs and peculiarities of influence of myocardial perfusion in certain time interval were revealed. Criteria with prognostic significance in prospective individual effectiveness of anti-ischemic drugs were pointed out. New approach, based on choice of anti-ischemic therapy depending on extent of influence on myocardial perfusion and also individual clinical and functional traits of patients, was applied.

Topics: Amlodipine; Antihypertensive Agents; Blood Flow Velocity; Cardiac-Gated Single-Photon Emission Computer-Assisted Tomography; Coronary Angiography; Coronary Circulation; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Male; Metoprolol; Myocardial Ischemia; Myocardial Reperfusion

Topics: Cardiovascular Diseases; Electrocardiography; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Myocardial Ischemia; Postoperative Period; Vascular Surgical Procedures

To investigate the potential determinants of the pleiotropic effects of statins, we measured NK cell cytotoxicity in samples from normal subjects and patients, including patients receiving statin therapy. In a multivariate analysis, NK cell cytotoxicity was related to total plasma cholesterol concentration rather than statin use. In vitro, we investigated the role of lipid modification, specifically the effects on membrane rafts and raft-dependent signal transduction. We demonstrate that statins reduce NK cell cytotoxicity and that membrane cholesterol depletion by cyclodextrins has a similar effect. In contrast, isoprenyl transferase inhibitors had little or no effect on NK cell function. We hypothesise that the pleiotropic effects of statins reflect changes in membrane cholesterol and, specifically, the density of membrane rafts. Moreover, there is likely to be a relationship between membrane cholesterol, membrane rafts and cell function that may be involved in the pathogenesis of cardiovascular and metabolic diseases.

Topics: Adult; Aged; Cholesterol; Cytotoxicity, Immunologic; Dose-Response Relationship, Drug; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; K562 Cells; Kidney Failure, Chronic; Kidney Transplantation; Killer Cells, Natural; Male; Membrane Microdomains; Middle Aged; Myocardial Ischemia; Pilot Projects; Protein Prenylation; Signal Transduction; Simvastatin

Long-term administration of nitrates results in the development of tolerance. Nitrate tolerance is considered to occur in association with oxidative stress, although its underlying mechanisms are multi-factorial. Fluvastatin, a newly developed statin, is considered to have not only a cholesterol-lowering effect but also anti-oxidative properties.. In this study, the effect of fluvastatin on nitrate tolerance was investigated in 12 dyslipidemic patients (nine men and three women, aged 63.5+/-6.7 years), who were complicated with ischemic heart disease and had received organic nitrates for a long period.. Four months after fluvastatin therapy, symptoms of angina were significantly reduced. Consumption of sublingual nitrates over 2 weeks significantly decreased (14.4+/-11.2 to 2.3+/-2.5 tablets, P<0.01). In exercise stress testing, exercise duration was significantly prolonged (275+/-73 to 360+/-86 s, P<0.01) and the blood pressure-heart rate products significantly increased (16368+/-2246 to 18381+/-1772, P<0.01). Both the percent change in forearm blood flow with reactive hyperemia (232+/-83 to 282+/-104%, P<0.05) and that after sublingual nitroglycerine (2.5+/-4.7 to 5.8+/-4.7%, P<0.05) were increased. Although the levels of total cholesterol, triglyceride, HDL-cholesterol, and LDL-cholesterol were unchanged, the serum anti-Ox-LDL titer (16.7+/-6.3 to 13.4+/-5.4 AcU/ml, P<0.05) and 8-OHdG level (1.11+/-0.34 to 0.73+/-0.34 ng/ml, P<0.05) decreased.. Fluvastatin attenuated nitrate tolerance in dyslipidemic patients complicated with ischemic heart disease who had been receiving organic nitrates over long period. The anti-oxidative effect of fluvastatin may attenuate nitrate tolerance.

Topics: Anticholesteremic Agents; Blood Flow Velocity; Drug Tolerance; Exercise Test; Fatty Acids, Monounsaturated; Female; Fluvastatin; Forearm; Humans; Hypercholesterolemia; Indoles; Lipoproteins, LDL; Male; Middle Aged; Myocardial Ischemia; Nitrates; Plethysmography

Topics: Angioplasty, Balloon, Coronary; Coronary Restenosis; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Lipoproteins; Myocardial Ischemia

We examined the effect of fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on the production of hydroxyl radical (*OH) generation via nitric oxide synthase (NOS) activation by an in vivo microdialysis technique. The microdialysis probe was implanted in the left ventricular myocardium of anesthetized rats and tissue was perfused with Ringer's solution through the microdialysis probe at a rate of 1 microl/min. Sodium salicylate in Ringer's solution (0.5 nmol/microl/min) was infused directly through a microdialysis probe to detect the generation of *OH. Induction of [K(+)](o) (70 mM) or tyramine (1 mM), significantly increased the formation of *OH trapped as 2,3-dihydroxybenzoic acid (DHBA). The application of N(G)-nitro-L-arginine methyl ester (L-NAME), a NOS inhibitor, significantly decreased the K(+) depolarization-induced *OH formation, but the effect of tyramine significantly increased the level of 2,3-DHBA. When fluvastatin (100 microM), an inhibitor of low-density lipoprotein (LDL) oxidation, was administered to L-NAME-pretreated animals, both KCl and tyramine failed to increase the level of 2,3-DHBA formation. The effect of fluvastatin may be unrelated to K(+) depolarization-induced *OH generation. To examine the effect of fluvastatin on ischemic/reperfused rat myocardium, the heart was subjected to myocardial ischemia for 15 min by occlusion of the left anterior descending coronary artery (LAD). When the heart was reperfused, a marked elevation of the level of 2,3-DHBA was observed. However, in the presence of fluvastatin (100 microM), the elevation of 2,3-DHBA was not observed in ischemia/reperfused rat heart. Fluvastatin, orally at a dose of 3 mg/kg/day for 4 weeks, significantly blunted the rise of serum creatine phosphokinase and improved the electrocardiogram 2 h after coronary occlusion. These results suggest that fluvastatin is associated with a cardioprotective effect due to the suppression of noradrenaline-induced *OH generation by inhibiting LDL oxidation in the heart.

Topics: Animals; Enzyme Inhibitors; Fatty Acids, Monounsaturated; Fluvastatin; Heart; Hydroxyl Radical; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Male; Microdialysis; Models, Chemical; Myocardial Ischemia; Myocardium; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Potassium Chloride; Rats; Rats, Wistar

Effects of pravastatin, simvastatin, atorvastatin, fluvastatin and cerivastatin on myocardial contractile dysfunction during reperfusion after brief ischemia were examined in dogs. Pretreatment of the dog with lipophilic HMG-CoA reductase inhibitors for 3 weeks, simvastatin (2 mg/kg/day), atorvastatin (2 mg/kg/day), fluvastatin (4 mg/kg/day), and cerivastatin (40 micrograms/kg/day) worsened recovery of myocardial contraction during reperfusion after brief ischemia in association with reduced myocardial ATP level. A hydrophilic HMG-CoA reductase inhibitor, pravastatin (2 and 4 mg/kg/day), did not affect the recovery of myocardial contractile function and ATP level during reperfusion following ischemia. The lipophilic inhibitors may enter the myocardial cell, inhibit ubiquinone biosynthesis, and depress ATP generation in mitochondria, leading to worsening of the myocardial stunning after reperfusion subsequent to ischemia.

Topics: Adenosine Triphosphate; Animals; Atorvastatin; Dogs; Fatty Acids, Monounsaturated; Fluvastatin; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Myocardial Contraction; Myocardial Ischemia; Myocardial Stunning; Myocardium; Pravastatin; Pyridines; Pyrroles; Simvastatin

The study included 30 IHD patients with primary hypercholesterolemia (22 males and 8 females). 18 and 12 patients have received a single daily dose of fluvastatin 20 and 40 mg, respectively, in the evening for 12 weeks. The drug effect was assessed by changes in the clinical status, lipid spectrum, transport-metabolic and absorption-secretory functions of the liver. IHD patients with hypercholesterolemia were found to have dysfunction of the hepatobiliary system. Fluvastatin treatment reduced the level of total cholesterol (Ch), LDLP Ch, triglycerides. HDLP Ch levels remained unchanged. Atherogenic lipoproteins aggregation diminished. Positive changes occurred in hepatic metabolism: bilirubin concentrations lowered, serum albumin went up, absorption-secretory function of hepatocytes normalized, hepatic mono-oxidase system activated. Fluvastatin-related hepatic damage was not reported in the course of 12-month follow-up.

Topics: Adult; Aged; Anticholesteremic Agents; Chronic Disease; Drug Evaluation; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Indoles; Lipids; Liver; Male; Middle Aged; Myocardial Ischemia; Radionuclide Imaging; Time Factors; Ultrasonography

In view of inducing action of hyperlipidemia on progression of nephropathy and relationships between thrombogenesis, atherogenesis and sclerosis, the authors examined fluvastatin effects on platelet-rheological hemostasis. The 12-week course in a dose 20-40 mg/ day produced minimal side effects while its hypolipidemic action was noticeable: a 18, 21 and 20% fall in concentrations of total cholesterol, LDL cholesterol, triglycerides, respectively. The platelet rheology underwent the following changes: spontaneous platelet aggregation went down from 2.58 +/- 0.3 to 1.64 +/- 0.27 r.units, ADP-induced platelet aggregation rose from 6.5 +/- 0.66 to 8.08 +/- 0.77 r.units. No marked changes were registered in hematocrit, plasma and blood density, red cell aggregation and deformability. Thus, active lowering of blood lipids was not associated with evident inhibition of platelet activity. The absence of this feedback in lipid-platelet relations probably indicates an independent significance of hemostatic disturbances in ischemic heart disease and needs further study.

Topics: Drug Evaluation; Erythrocyte Deformability; Fatty Acids, Monounsaturated; Fluvastatin; Hemorheology; Hemostasis; Humans; Hypolipidemic Agents; Indoles; Lipids; Myocardial Ischemia; Platelet Aggregation; Time Factors

Patients with hypercholesterolemia have impaired coronary and peripheral endothelial function. In patients with coronary artery disease, intracoronary acetylcholine infusion or mental stress causes paradoxical vasoconstriction, whereas lowering cholesterol restores endothelial function. The impact of lipid lowering by fluvastatin on myocardial perfusion in hypercholesterolemic patients with perfusion abnormalities was assessed by thallium-201 single photon-emission computed tomography (SPECT). A total of 22 patients were treated with fluvastatin (40 mg once daily) for 6 weeks, followed by 40 mg twice daily if low density lipoprotein cholesterol (LDL-C) levels were decreased by < or = 30%. During the 12-week treatment period, myocardial perfusion was measured by quantitative SPECT after standardized stress testing at baseline and after 12 weeks. Preliminary results for 17 male patients (mean age, 59.3 +/- 6.7 years) are presented here. LDL-C decreased from 191 +/- 26 to 146 +/- 28 mg/dL (p < 0.001). In ischemic segments myocardial perfusion increased by 30% (280 +/- 100 to 365 +/- 110 counts per matrix; p < 0.001). In normal segments perfusion increased by only 5% (451 +/- 74 to 473 +/- 69 counts per matrix; p < 0.005). The change in perfusion rate between ischemic and normal segments was significant (p < 0.005). In conclusion, LDL-C lowering with short-term fluvastatin therapy improved myocardial perfusion, especially in areas of ischemia. This suggests that improvement is due to functional restoration of coronary endothelium by fluvastatin, before anatomic regression of stenosis can occur following long-term treatment.

Topics: Adult; Aged; Anticholesteremic Agents; Cholesterol, LDL; Coronary Circulation; Coronary Disease; Endothelium, Vascular; Exercise Test; Fatty Acids, Monounsaturated; Female; Fluvastatin; Heart Rate; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Indoles; Male; Middle Aged; Myocardial Ischemia; Thallium Radioisotopes; Tomography, Emission-Computed, Single-Photon; Vasodilation