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PubMed2005

Impact of statin treatment on 1-year functional and histologic renal allograft outcome.

BACKGROUND: Statins are antilipidemic agents that exhibit a variety of cellular effects independent of their lipid-lowering action. A retrospective study was undertaken to establish the impact of statins on graft outcome in the first year posttransplantation. METHODS: Data from patients with uniform immunosuppression (cyclosporine, mycophenolate mofetil, and prednisolone) who underwent transplantation at the authors' unit from 1997 to 2002 were reviewed. Patients prescribed statins were compared with those not on a statin. Mean change in creatinine clearance (CrCl) from 3 to 12 months posttransplantation was calculated. Histomorphometric analysis was used to quantify fractional interstitial area and collagen III deposition in matched preperfusion and 12-month protocol biopsy specimens. RESULTS: Seventy-seven patients met study criteria: statin, n=44 patients; nonstatin, n=33 patients. Median time to commencing a statin was 5 weeks. At 3 months, CrCl (+/-SEM) was similar: 51.6+/-2.9 mL/min (statin) versus 51.3+/-1 mL/min (nonstatin). At 12 months, the mean change in CrCl was 4.1+/-1 mL/min (statin) compared with -2.0+/-1.8 mL/min (nonstatin), resulting in a difference of 6.13 mL/min at 12 months (P<0.005). Mean preperfusion fractional interstitial areas were similar (23.9+/-1.6%; P=not significant [NS]). On 12-month biopsy specimens, the fractional interstitial area had increased to 34+/-3.2% in the nonstatin group (P<0.005), with no change in the statin group. Interstitial collagen III deposition was similar in preperfusion biopsy specimens (10.4+/-1%; P=NS), but at 12 months it was significantly greater in the nonstatin group (17.6+/-1%; P<0.05) CONCLUSIONS: Early introduction of statins may be associated with improved 1-year graft outcome.

Adult↗
PubMed2003

Statins as potential therapeutic agents in neuroinflammatory disorders.

PURPOSE OF REVIEW: Multiple sclerosis is a central nervous system inflammatory demyelinating disease that is thought to have an autoimmune pathogenesis. Recent results indicate that 'statins', 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, which are the most commonly used oral cholesterol-lowering drugs, have immunomodulatory properties. In this article we will review those findings that indicate that statins may be beneficial in the treatment of multiple sclerosis, neurodegenerative disease, and ischemic stroke. RECENT FINDINGS: It was reported that statin treatment could either inhibit or reverse chronic and relapsing experimental autoimmune encephalomyelitis, a model of multiple sclerosis. Several immunomodulatory properties of statins may account for their beneficial clinical effect: Statins decreased the migration of leukocytes into the central nervous system, inhibited MHC class II and costimulatory signals required for activation of proinflammatory T cells, induced a T(H)2 phenotype in T cells, and decreased the expression of inflammatory mediators in the central nervous system, including nitric oxide and tumor necrosis factor alpha. It was also demonstrated that statin use significantly reduced beta-amyloid secretion in the cerebrospinal fluid of experimental animals. Clinically, there is emerging evidence that statins have beneficial effects in patients with multiple sclerosis, Alzheimer's disease, and ischemic stroke. SUMMARY: In-vitro studies have indicated that statins may have anti-inflammatory properties. Results from in-vivo animal models suggest that statins may be beneficial in treatment of different central nervous system conditions. Larger scale, randomized, double-blind trials are needed to validate the role of statins as a treatment of inflammatory central nervous system diseases.

Alzheimer Disease↗
PubMed2005

Not all statins interfere with clopidogrel during antiplatelet therapy.

BACKGROUND: Clopidogrel and statins are frequently coadministered in patients with ischemic heart diseases. Recent reports suggested that clopidogrel's effectiveness in inhibiting adenosine diphosphate (ADP)-induced platelets aggregation is attenuated by co-administration of certain statins. The objective of the present study was to define which statin might interfere with the antiaggregation property of clopidogrel. METHODS: We designed a pharmacokinetic study and tested ex vivo platelet function on 21 healthy volunteers who received clopidogrel and all currently commercially available statins: rosuvastatin [10 mg o.d.], simvastatin [20 mg o.d.], fluvastatin [80 mg o.d.], pravastatin [40 mg o.d.], and atorvastatin [20 mg o.d.]. Each statin was administered for 7 days followed by 1 week of wash-out period with clopidogrel treatment alone. Detection of the statins in the plasma was performed on all blood samples, using HPLC analytical method. RESULTS: All individuals, except one, were responders to clopidogrel with inhibition of ex vivo ADP induced platelet aggregation. All statins, except pravastatin, were detectable in the plasma at the end of each treatment period in all patients, and no statin was detectable after any of the wash-out periods. Clopidogrel was significantly less efficient to prevent platelet aggregation when coadministrated with simvastatin or fluvastatin. No difference was observed in clopidogrel efficacy when coadministered with rosuvastatin, pravastatin or atorvastatin. CONCLUSIONS: This is the first study investigating clopidogrel-statin interactions on ex vivo platelet function with all commercially available statins and which were administered to the same individuals. It demonstrates in healthy volunteers that at the doses used in this study, simvastatin and fluvastatin, but not atorvastatin, pravastatin or rosuvastatin interfere with the anti-aggregation effect of clopidogrel.

Adult↗
PubMed2004

Undertreatment and overtreatment with statins: the Oslo Health Study 2000-2001.

OBJECTIVE: We examined the prevalence and factors associated with use of cholesterol-lowering statins in the population. METHODS: Demographic, medical, anthropometric and lifestyle data was obtained from 6233 men and 7521 women born in 1924/25, 1940/41, 1955 and 1960 that participated in the Oslo Health Study 2000-2001. A nonfasting blood sample was collected. RESULTS: Of subjects with a heart attack, angina, stroke or diabetes 45% of men and 35% of women were taking a statin (P < 0.001). Of subjects with cardiovascular disease (CVD) or diabetes taking statins 61% of men and 40% of women achieved total serum cholesterol levels < or =5 mmol L(-1). The odds ratio for taking a statin was increased amongst subjects who also took antihypertensive drug(s) or acetylsalicylic acid, subjects with a family history of coronary heart disease (CHD) and women who had visited the general practitioner within the last year. Amongst presumed healthy subjects use of statins increased from about 1% in women aged 40-45 years, to 7% at age 60 and to 12% at age 75 whilst the corresponding figures for men were 3%, 8% and 9%, respectively. About 22% of men but <2% of women aged 60 who were not taking statins had a 10-year Framingham CHD risk score >20%. Determinants of statin use were similar to those amongst subjects with CVD or diabetes. CONCLUSION: People with CVD or diabetes remain undertreated with statins, women more so than men. Use of other preventive drugs, the family history and recent contact with the general practitioner were the most important determinants of statin use in primary and secondary prevention. Amongst healthy subjects aged 60 or 75 years women received statins disproportionately to their low CHD risk compared with men.

Adult↗
PubMed2002

Adherence to statin treatment and readmission of patients after myocardial infarction: a six year follow up study.

OBJECTIVE: To investigate patients' adherence to statin treatment prescribed following their first myocardial infarction (MI) and to estimate the effect of adherence to statins on recurrence of MI and all cause mortality. DESIGN: Cohort study using a record linkage database. SETTING: Tayside, Scotland, UK. PATIENTS: Patients who experienced their first MI between January 1990 and November 1995. MAIN OUTCOME MEASURES: Percentage of statin use and adherence to statins by patients after an MI and the relative risk of hospitalisation for recurrent MI. The effect of adherence on all cause mortality was also examined. The covariates used were age, sex, socioeconomic deprivation, serum cholesterol concentration, diabetes mellitus, cardiovascular drug use, and other hospitalisations. RESULTS: Of 5590 patients who experienced an incident MI, 717 (12.8%) experienced at least one further MI. Only 7.7% of patients used statins after an MI during the study period. Compared with those not taking statins, those who had 80% or better adherence to statin treatment had an adjusted relative risk of recurrent MI of 0.19 (95% confidence interval (CI) 0.08 to 0.47) and all cause mortality of 0.47 (95% CI 0.22 to 0.99). There was no significant reduction in either end point for those who were less than 80% adherent to statins. CONCLUSIONS: Despite the infrequent use of statin during the study period, good adherence to statin treatment was associated with lower risk of recurrent MI.

Adult↗
PubMed2005

Lack of clopidogrel-CYP3A4 statin interaction in patients with acute coronary syndrome.

OBJECTIVE: To assess a clinically significant interaction between cytochrome P450 3A4 (CYP3A4) metabolised statin and clopidogrel. DESIGN: Prospective single centre cohort study. SETTING: Academic teaching hospital in the USA. PATIENTS: 1651 patients presenting with acute coronary syndromes between January 1999 and February 2003 were studied. Data on baseline demographics, co-morbidities, and in-hospital management were collected. MAIN OUTCOME MEASURE: Association of CYP3A4 metabolised statin and clopidogrel use with in-hospital and six month mortality. The impact of the combined use of a CYP3A4 statin and clopidogrel on six month mortality and major adverse cardiac events was analysed by a risk adjusted logistic regression model. RESULTS: The odds ratios for six month mortality were: for CYP3A4 statin, 0.43 (95% confidence interval (CI) 0.27 to 0.71, p = 0.0009); for CYP3A4 statin plus clopidogrel, 0.36 (95% CI 0.23 to 0.60, p < 0.001); for non-CYP3A4 statin, 0.22 (95% CI 0.08 to 0.59, p = 0.002); and for non-CYP3A4 statin plus clopidogrel, 0.22 (95% CI 0.06 to 0.75, p = 0.016). CONCLUSIONS: Use of a combination of a CYP3A4 statin plus clopidogrel was associated with lower six month mortality and morbidity in patients with acute coronary syndromes. There was no significant difference in clinical benefit between a CYP3A4 statin and a non-CYP3A4 statin when used in conjunction with clopidogrel. This suggests that the proposed interaction is probably an ex vivo phenomenon and may not be clinically relevant.

Aged↗
PubMed2006

Breast cancer growth prevention by statins.

Statins are cholesterol-lowering drugs with pleiotropic activities including inhibition of isoprenylation reactions and reduction of signals driving cell proliferation and survival responses. The objectives of this study were to examine the effects of statins on breast cancer cells, both in vitro and in vivo, and to begin to determine their mechanism of action. We evaluated the effects of statins on breast cancer cell growth, phosphoprotein signaling intermediates, survival/apoptosis regulators, cell cycle regulators, and activated transcription factors. We also examined the in vivo effect of statin administration in a mouse ErbB2(+) breast cancer model. Only lipophilic statins had direct anticancer activity in vitro. Breast cancer cells with activated Ras or ErbB2 pathways seemed to be more sensitive than those overexpressing estrogen receptor, and this correlated with endogenous levels of activated nuclear factor kappaB (NF-kappaB). Key intermediates regulating cell survival by NF-kappaB activation, as well as cell proliferation by the mitogen activated protein kinase cascade, were among the earliest phosphoproteins influenced by statin treatment. These early effects were followed by declines in activator protein-1 and NF-kappaB activation and concordant changes in other mediators of proliferation and apoptosis. In vivo results showed that oral dosing of statins significantly inhibited the growth of a mouse mammary carcinoma. Lipophilic statins can exert direct anticancer activity in vitro by reducing proliferation and survival signals in susceptible breast cancer phenotypes. Tumor growth inhibition in vivo using a clinically relevant statin dose also seems to be associated with reduced tumor cell proliferation and survival. These findings provide supporting rationale for future statin trials in breast cancer patients.

Antineoplastic Agents↗
PubMed2004

Patients with Alzheimer's disease may be particularly susceptible to adverse effects of statins.

In epidemiological, cross-sectional studies, treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) prevented to a large extent the development of Alzheimer's disease (AD), but the results of randomized, placebo-controlled studies, focused on statin therapy in patients with ischemic heart disease (IHD), are at variance. Nonetheless, data from epidemiological, longitudinal studies in humans as well as studies on transgenic mouse models and cultured neuronal cell lines indicate that cholesterol may contribute to the pathogenesis of AD. Statins have proven therapeutic and preventive effects in IHD and other vascular diseases in man. They generally are well tolerated, but some adverse effects, probably due to antiproliferative and proapoptotic properties of the statins, are matters of concern. AD patients may be extrasusceptible to adverse effects of statins due to preexisting aberrations in signal transduction and energy metabolism in the neurons and a perturbed cholesterol metabolism in the brain. This problem might be addressed in randomized, double-blind studies with statins in AD. The statins differ from each other in several aspects, and they are not considered to be therapeutically interchangeable. It could be fruitful to use both a placebo and two different types of statins, i.e. an essentially hydrophilic statin and a lipophilic statin, in a double-blinded fashion, and to compare the effects on the cognitive decline in AD.

Aged↗
PubMed2002

Statin therapy, cardiovascular events, and total mortality in the Heart and Estrogen/Progestin Replacement Study (HERS).

BACKGROUND: Although effects of statins on cardiovascular outcomes are well established in men, fewer data exist for women. Furthermore, the effects of statins plus hormone replacement therapy (HRT) on cardiovascular outcomes are uncertain. METHODS AND RESULTS: We examined statin use, cardiovascular events, and total mortality in the Heart and Estrogen/progestin Replacement Study (HERS), a randomized clinical trial of estrogen plus progestin versus placebo in postmenopausal women with heart disease (n=2763). A nonrandomized comparison of statin users and nonusers revealed lower rates of the primary outcome, nonfatal myocardial infarction or coronary heart disease death (relative hazard [RH]=0.79, 95% confidence intervals [CI] 0.63 to 0.99, P=0.04), and total mortality (RH=0.67, 95% CI 0.51 to 0.87, P=0.003). Rates of venous thromboembolic events were also lower among statin users (RH=0.45, 95% CI 0.23 to 0.88, P=0.02). HRT resulted in a significant increase in early risk for primary events in women who did not use statins (RH=1.75, 95% CI 1.02 to 3.03, P=0.04) but not in statin users (RH=1.34, 95% CI 0.63 to 2.86, P=0.45). Adjustment for postrandomization statin use showed no effect of HRT on risk for the primary outcome (RH=0.96, 95% CI 0.77 to 1.29; P=0.72). CONCLUSIONS: In HERS, statin use was associated with lower rates of cardiovascular events, venous thromboembolic events, and total mortality. These data provide strong support for statin use in eligible women with coronary disease.

Aged↗
PubMed2004

Statins are associated with a reduced incidence of perioperative mortality after coronary artery bypass graft surgery.

BACKGROUND: Statin therapy in nonsurgical patient populations is associated with a significant reduction in adverse cardiovascular events, including death, myocardial infarction (MI), and stroke. Recently, statin therapy was shown to be associated with a reduced incidence of postoperative mortality in patients undergoing major noncardiac vascular surgery. We investigated the influence of preoperative statin therapy on adverse outcomes after primary coronary artery bypass graft (CABG) surgery. METHODS AND RESULTS: A retrospective cohort study of patients undergoing primary CABG surgery with cardiopulmonary bypass (CPB) (n=1663) between January 1, 2000 and December 31, 2001 at the Texas Heart Institute was performed. Patients were classified into 2 groups: patients receiving preoperative statin therapy (n=943) and patients not receiving preoperative antihyperlipidemic therapy (n=720). To determine if preoperative statin therapy was independently associated with a reduction in the risk of adverse postoperative outcomes, multivariate stepwise logistic regression was performed controlling for patient demographics, medical history, and preoperative medications. Multivariate logistic regression analysis demonstrated that preoperative statin therapy was independently associated with a significant reduction ( approximately 50%) in the risk of 30-day all-cause mortality (3.75% versus 1.80%; P<0.05). The adjusted odds ratio for early mortality in patients receiving preoperative statin therapy compared with patients not receiving antihyperlipidemic agents was 0.53 (95% CI, 0.28 to 0.99). Statin therapy was not independently associated with a reduced risk of postoperative MI, cardiac arrhythmias, stroke, or renal dysfunction. In an attempt to further control for selection bias related to the choice of therapy, multivariate analysis of a propensity-matched cohort of 1362 patients revealed that preoperative statin therapy was independently associated with a significant reduction in the composite endpoint of 30-day all-cause mortality and stroke (7.1% versus 4.6%; P<0.05). CONCLUSIONS: Preoperative statin therapy may reduce the risk of early mortality after primary CABG surgery with CPB.

Aged↗
PubMed2005

Statins are associated with better outcomes after carotid endarterectomy in symptomatic patients.

BACKGROUND AND PURPOSE: Statins have been associated with a reduction in mortality from noncardiac surgery. This study aimed to determine whether statin use on admission to hospital for carotid endarterectomy was associated with a reduction of in-hospital adverse outcomes. METHODS: Data describing patient characteristics, surgical indication, statin treatment, and in-hospital outcomes of death, ischemic stroke or death and cardiac outcomes were collected from a chart review of all patients (3360) undergoing carotid endarterectomy in Western Canada from January 2000 to December 2001. Outcomes of patients on statins versus those not on statins were compared using logistic regression to account for differences in patient characteristics, and propensity score methods to account for factors influencing patient allocation to statins. RESULTS: Eight hundred and fifteen of 2031 symptomatic patients and 665 of 1252 asymptomatic patients were on a statin at the time of hospital admission. Statin use by symptomatic patients was associated with reduced in-hospital mortality and in-hospital ischemic stroke or death, but not in-hospital cardiac outcomes (adjusted odds ratio 0.25 [CI, 0.07 to 0.90], 0.55 [CI, 0.32 to 0.95], 0.87 [CI, 0.49 to 1.54], respectively). The improvement in outcomes was robust when tested using propensity score matching. This association was not seen in asymptomatic patients on statins (adjusted odds ratio, in-hospital mortality 0.54 [CI, 0.13 to 2.24]; in-hospital ischemic stroke or death 1.34 [CI, 0.61 to 2.93]; in-hospital cardiac outcomes 1.37 [CI, 0.73 to 2.58]). CONCLUSIONS: These findings are suggestive of a protective effect of statin therapy in symptomatic patients pre-treated at the time of carotid endarterectomy, though this needs confirmation in a randomized controlled trial.

Aged↗
PubMed2006

Statin treatment is not associated with consistent alterations in inflammatory status of carotid atherosclerotic plaques: a retrospective study in 378 patients undergoing carotid endarterectomy.

BACKGROUND AND PURPOSE: Anti-inflammatory qualities are held partially responsible for the reduction of cardiovascular events after statin treatment. We examined the phenotype of carotid atherosclerotic plaques harvested during carotid endarterectomy in relation to the previous use of different statins prescribed in clinical practice. METHODS: Three hundred and seventy-eight patients were included. Atherosclerotic plaques were harvested, immunohistochemically stained and semiquantitively examined for the presence of macrophages (CD68), smooth muscle cells, collagen and fat. Adjacent atherosclerotic plaques were used to study protease activity and interleukin levels. Patients' demographics were recorded and blood samples were stored. RESULTS: Serum cholesterol, low-density lipoprotein, apolipoprotein B, and C-reactive protein levels were lower in patients treated with statins compared with patients without statin treatment. Atheromatous plaques were less prevalent in patients receiving statins compared with patients without statin therapy (29% versus 42%, P=0.04). An increase of CD68 positive cells was observed in patients receiving statins compared with nonstatin treatment (P=0.05). This effect was specifically related to atorvastatin treatment. In patients treated with atorvastatin, the increased amount of CD68 positive cells were not associated with increased protease activity. In contrast, a dose-dependent decrease in protease activity was shown in the atorvastatin group. Interleukin 6 expression was lower in plaques obtained from patients treated with statins (P=0.04). CONCLUSIONS: Statin use may exert pleiotropic effects on plaque phenotype. However, not the presence of macrophages but activation with subsequent protease and cytokine release may be attenuated by statin use.

Antigens, CD↗
PubMed1999

Neuroprotective properties of statins in cerebral ischemia and stroke.

BACKGROUND: The atheroma-retarding properties of beta-hydroxy-beta-methylglutaryl coenzyme A reductase (HMG-CoA) inhibitors, or "statins," in both the coronary and carotid arterial beds are well established. However, a growing body of recent data suggests that statins possess important adjunctive properties that may confer additional benefit beyond the retardation of atherosclerosis. In this article, we review the emerging evidence that statins have beneficial effects within the cerebral circulation and brain parenchyma during ischemic stroke and reperfusion. SUMMARY OF REVIEW: Clinical studies show that statins reduce the incidence of ischemic stroke through probable effects on precerebral atherosclerotic plaque and through antithrombotic mechanisms. Additionally, statins have been shown to reduce infarct size in experimental animal models of stroke. Statins both upregulate endothelial nitric oxide synthase (eNOS) and inhibit inducible nitric oxide synthase (iNOS), effects that are potentially neuroprotective. The preservation of eNOS activity in cerebral vasculature, particularly in the ischemic penumbra, may be especially important in preserving blood flow and limiting neurological loss. Statins may also attenuate the inflammatory cytokine responses that accompany cerebral ischemia, and they possess antioxidant properties that likely ameliorate ischemic oxidative stress in the brain. CONCLUSIONS: In addition to reducing stroke, the statin class of drugs exhibits a number of important neuroprotective properties that likely attenuate the effects of ischemia on the brain vasculature and parenchyma. Further investigation of the role of statins in human neuroprotection by use of neuroimaging and cognitive studies is warranted to explore these preliminary observations. In addition to reducing ischemic stroke, early evidence indicates that statins may also be neuroprotective.

Animals↗
PubMed2006

Statins and mortality among elderly patients hospitalized with heart failure.

BACKGROUND: Small studies suggest that statins may improve mortality in patients with heart failure (HF). Whether these results are generalizable to a broader group of patients with HF remains unclear. Our objective was to evaluate the association between statin use and survival among a national sample of elderly patients hospitalized with HF. METHODS AND RESULTS: A nationwide sample of 61 939 eligible Medicare beneficiaries > or =65 years of age who were hospitalized with a primary discharge diagnosis of HF between April 1998 and March 1999 or July 2000 and June 2001 was evaluated. The analysis was restricted to patients with no contraindications to statins (n=54,960). Of these patients, only 16.7% received statins on discharge. Older patients were less likely to receive a statin at discharge. Patients with hyperlipidemia and those cared for by a cardiologist or cared for in a teaching hospital were more likely to receive a statin at discharge. In a Cox proportional hazards model that took into account demographic, clinical characteristics, treatments, physician specialty, and hospital characteristics, discharge statin therapy was associated with significant improvements in 1- and 3-year mortality (hazard ratio, 0.80; 95% CI, 0.76 to 0.84; and hazard ratio, 0.82; 95% CI, 0.79 to 0.85, respectively). Regardless of total cholesterol level or coronary artery disease status, statin therapy was associated with significant differences in mortality. CONCLUSIONS: Our data demonstrate that statin therapy is associated with better long-term mortality in older patients with HF. This study suggests a potential role for statins as an adjunct to current HF therapy. Randomized clinical trials are required to determine the role of these agents in improving outcomes in the large and growing group of patients with HF.

Aged↗
PubMed2002

Early and sustained survival benefit associated with statin therapy at the time of percutaneous coronary intervention.

BACKGROUND: Long-term administration of statin therapy has been shown to reduce major coronary events and cardiac mortality within randomized clinical trials. In addition to lowering lipids, statins favorably affect platelet adhesion, thrombosis, endothelial function, inflammation, and plaque stability, which may potentially improve outcome after percutaneous coronary intervention (PCI). Therefore, we hypothesized that statin therapy has an early beneficial effect among patients undergoing PCI. METHODS AND RESULTS: Each year from 1993 to 1999, we prospectively collected data among the first 1000 patients undergoing PCI. Patients who presented with acute or recent myocardial infarction or cardiogenic shock were excluded from the analysis. Baseline, procedural, and 6-month data of statin-treated and non-statin-treated patients were compared. Propensity score and multivariate survival analysis were used to adjust for heterogeneity between the two groups. Of 5052 patients who completed follow-up, 26.5% were treated with statin at the time of the procedure. Statin therapy was associated with a mortality reduction at 30 days (0.8% versus 1.5%; hazard ratio, 0.53; P=0.048) and at 6 months (2.4% versus 3.6%; hazard ratio, 0.67; P=0.046). After adjusting for the propensity to receive statin therapy before the procedure and other confounders, statin therapy remained an independent predictor for survival at 6 months after coronary intervention (hazard ratio, 0.65; 95% CI, 0.42 to 0.99; P=0.045). CONCLUSIONS: In this large study cohort, statin therapy among PCI patients seems to be associated with a significant mortality advantage at early and intermediate-term follow-up.

Aged↗
PubMed2001

Statin-induced inhibition of the Rho-signaling pathway activates PPARalpha and induces HDL apoA-I.

Statins are inhibitors of the rate-limiting enzyme in cholesterol synthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. In addition to reducing LDL cholesterol, statin treatment increases the levels of the antiatherogenic HDL and its major apolipoprotein apoA-I. Here, we investigated the molecular mechanisms of apoA-I regulation by statins. Treatment with statins increased apoA-I mRNA levels in human HepG2 hepatoma cells, and this effect was reversed by the addition of mevalonate, implicating HMG-CoA reductase as the relevant target of these drugs. Pretreatment with Actinomycin D abolished the increase of apoA-I mRNA, indicating that statins act at the transcriptional level. Indeed, statins increased the human apoA-I promoter activity in transfected cells, and we have identified a statin response element that coincides with a PPARalpha response element known to confer fibrate responsiveness to this gene. The statin effect could be abolished not only by mevalonate, but also by geranylgeranyl pyrophosphate, whereas inhibition of geranylgeranyl transferase activity or treatment with an inhibitor of the Rho GTP-binding protein family increased PPARalpha activity. Using dominant negative forms of these proteins, we found that Rho A itself mediates this response. Because cotreatment with statins and fibrates activated PPARalpha in a synergistic manner, these observations provide a molecular basis for combination treatment with statins and fibrates in coronary heart disease.

Animals↗
PubMedDate not supplied

Prevention of positive coronary artery remodeling with statin therapy in patients with coronary artery diseases.

Since positive coronary artery remodeling with large plaque burden is associated with subsequent coronary events, the authors tested their hypothesis that secondary prevention of coronary events by a statin may be associated with inhibition of the process of positive coronary artery remodeling in underlying coronary atherosclerotic lesions in patients with coronary artery diseases. They evaluated the intravascular ultrasound imaging in angiographically normal coronary lesions at baseline and after 6 months of therapy in 64 patients with coronary artery diseases. External elastic membrane area was defined as the vessel area, and the difference between the vessel and lumen area was calculated as plaque area. The relative echogenicity of coronary plaque to adventitia was evaluated as acoustic characteristics of coronary plaque. Twenty-five patients were treated with a statin and 39 patients did not receive a statin. In patients treated with a statin, plaque area decreased by 12% (p = 0.013) compared to an increase in plaque area of 13% (p = 0.023) in those who did not receive a statin. The vessel area was not enlarged in patients treated with a statin but did show positive remodeling in patients who had plaque progression without a statin. The relative echogenicity of plaque was unchanged in patients treated with a statin but significantly decreased in patients not receiving a statin. A statin may prevent positive coronary artery remodeling via inhibition of plaque progression in underlying coronary atherosclerotic lesions in patients with coronary artery diseases.

Angioplasty, Balloon, Coronary↗
PubMed2004

Rising statin use and effect on ischemic stroke outcome.

BACKGROUND: Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) have neuroprotective effects in experimental stroke models and are commonly prescribed in clinical practice. The aim of this study was to determine if patients taking statins before hospital admission for stroke had an improved clinical outcome. METHODS: This was an observational study of 436 patients admitted to the National Institutes of Health Suburban Hospital Stroke Program between July 2000 and December 2002. Self-reported risk factors for stroke were obtained on admission. Stroke severity was determined by the admission National Institutes of Health Stroke Scale score. Good outcome was defined as a Rankin score < 2 at discharge. Statistical analyses used univariate and multivariate logistic regression models. RESULTS: There were 436 patients with a final diagnosis of ischemic stroke; statin data were available for 433 of them. A total of 95/433 (22%) of patients were taking a statin when they were admitted, rising from 16% in 2000 to 26% in 2002. Fifty-one percent of patients taking statins had a good outcome compared to 38% of patients not taking statins (p = 0.03). After adjustment for confounding factors, statin pretreatment was associated with a 2.9 odds (95% CI: 1.2-6.7) of a good outcome at the time of hospital discharge. CONCLUSIONS: The proportion of patients taking statins when they are admitted with stroke is rising rapidly. Statin pretreatment was significantly associated with an improved functional outcome at discharge. This finding could support the early initiation of statin therapy after stroke.

Aged↗