Timing and Dose of Statin Therapy Define Its Impact on Inflammatory and Endothelial Responses During Myocardial Infarction

Objective-Clinical trials of statins during myocardial infarction (MI) have differed in their therapeutic regimes and generated conflicting results. This study evaluated the role of the timing and potency of statin therapy on its potential mechanisms of benefit during MI. Methods and Results-ST-elevation MI patients (n = 125) were allocated into 5 groups: no statin; 20, 40, or 80 mg/day simvastatin starting at admission; or 80 mg/day simvastatin 48 hours after admission. After 7 days, all patients switched their treatment to 20 mg/day simvastatin for an additional 3 weeks and then underwent flow-mediated dilation in the brachial artery. As of the second day, C-reactive protein (CRP) differed between non-statin users (12.0 +/- 4.1 mg/L) and patients treated with 20 (8.5 +/- 4.0 mg/L), 40 (3.8 +/- 2.5 mg/L), and 80 mg/day (1.4 +/- 1.5 mg/L), and the daily differences remained significant until the seventh day (P < 0.0001). The higher the statin dose, the lower the elevation of interleukin-2 and tumor necrosis factor-alpha, the greater the reduction of 8-isoprostane and low-density lipoprotein(-), and the greater the increase in nitrate/nitrite levels during the first 5 days (P < 0.001). Later initiation of statin was less effective than its early introduction in relation to attenuation of CRP, interleukin-2, tumor necrosis factor-alpha, 8-isoprostane, and low-density lipoprotein(-), as well as in increase in nitrate/nitrite levels (P < 0.0001). At the 30th day, there was no longer a difference in lipid profile or CRP between groups; the flow-mediated dilation, however, was proportional to the initial statin dose and was higher for those who started the treatment early (P = 0.001). Conclusion-This study demonstrates that the timing and potency of statin treatment during MI are key elements for their main mechanisms of benefit.

Effects of combined low-density lipoprotein apheresis and aggressive statin therapy on coronary calcified plaque as measured by computed tomography

Eight patients with heterozygous familial hypercholesterolemia who received combined long-term low-density lipoprotein apheresis and high-dose statin therapy showed a significant decrease in volume of coronary calcium over a period of 29 months as measured by, computed tomography. This suggests that the effects of aggressive lipid-lowering therapy can be assessed non-invasively and may be used as surrogate end points when testing new therapies.

Endothelial Effect of Statin Therapy at a High Dose Versus Low Dose Associated with Ezetimibe

Abstract Background: The effect of statins on the endothelial function in humans remains under discussion. Particularly, it is still unclear if the improvement in endothelial function is due to a reduction in LDL-cholesterol or to an arterial pleiotropic effect. Objective: To test the hypothesis that modulation of the endothelial function promoted by statins is primarily mediated by the degree of reduction in LDL-cholesterol, independent of the dose of statin administered. Methods: Randomized clinical trial with two groups of lipid-lowering treatment (16 patients/each) and one placebo group (14 patients). The two active groups were designed to promote a similar degree of reduction in LDL-cholesterol: the first used statin at a high dose (80 mg, simvastatin 80 group) and the second used statin at a low dose (10 mg) associated with ezetimibe (10 mg, simvastatin 10/ezetimibe group) to optimize the hypolipidemic effect. The endothelial function was assessed by flow-mediated vasodilation (FMV) before and 8 weeks after treatment. Results: The decrease in LDL-cholesterol was similar between the groups simvastatin 80 and simvastatin 10/ezetimibe (27% ± 31% and 30% ± 29%, respectively, p = 0.75). The simvastatin 80 group presented an increase in FMV from 8.4% ± 4.3% at baseline to 11% ± 4.2% after 8 weeks (p = 0.02). Similarly, the group simvastatin 10/ezetimibe showed improvement in FMV from 7.3% ± 3.9% to 12% ± 4.4% (p = 0.001). The placebo group showed no variation in LDL-cholesterol level or endothelial function. Conclusion: The improvement in endothelial function with statin seems to depend more on a reduction in LDL-cholesterol levels, independent of the dose of statin administered, than on pleiotropic mechanisms.

Cardiovascular risk estimation and eligibility for statin therapy using different scoring systems in Europe: a population-based study in Switzerland

BACKGROUND: Recommendations for statin use for primary prevention of coronary heart disease (CHD) are based on estimation of the 10- year CHD risk. We compared the 10-year CHD risk assessments and eligibility percentages for statin therapy using three scoring algorithms currently used in Europe. METHODS: We studied 5683 women and men, aged 35-75, without overt cardiovascular disease (CVD), in a population-based study in Switzerland. We compared the 10-year CHD risk using three scoring schemes, i.e., the Framingham risk score (FRS) from the U.S. National Cholesterol Education Program's Adult Treatment Panel III (ATP III), the PROCAM scoring scheme from the International Atherosclerosis Society (IAS), and the European risk SCORE for low-risk countries, without and with extrapolation to 60 years as recommended by the European Society of Cardiology guidelines (ESC). With FRS and PROCAM, high-risk was defined as a 10- year risk of fatal or non-fatal CHD>20% and a 10-year risk of fatal CVD≥5% with SCORE. We compared the proportions of high-risk participants and eligibility for statin use according to these three schemes. For each guideline, we estimated the impact of increased statin use from current partial compliance to full compliance on potential CHD deaths averted over 10 years, using a success proportion of 27% for statins. RESULTS: Participants classified at high-risk (both genders) were 5.8% according to FRS and 3.0% to the PROCAM, whereas the European risk SCORE classified 12.5% at high-risk (15.4% with extrapolation to 60 years). For the primary prevention of CHD, 18.5% of participants were eligible for statin therapy using ATP III, 16.6% using IAS, and 10.3% using ESC (13.0% with extrapolation) because ESC guidelines recommend statin therapy only in high-risk subjects. In comparison with IAS, agreement to identify eligible adults for statins was good with ATP III, but moderate with ESC. Using a population perspective, a full compliance with ATP III guidelines would reduce up to 17.9% of the 24′ 310 CHD deaths expected over 10 years in Switzerland, 17.3% with IAS and 10.8% with ESC (11.5% with extrapolation). CONCLUSIONS: Full compliance with guidelines for statin therapy would result in substantial health benefits, but proportions of high-risk adults and eligible adults for statin use varied substantially depending on the scoring systems and corresponding guidelines used for estimating CHD risk in Europe.

Eligibility for statin therapy in primary prevention: discrepancies using different guidelines in a population-based study in Switzerland

Introduction: Recommendations for statin use for primary prevention of coronary heart disease (CHD) are based on estimation of the 10-year CHD risk. We compared the 10-year CHD risk assessments and eligibility percentages for statin therapy using three scoring algorithms currently used in Switzerland. Methods: We studied 5683 women and men, aged 35-75, without overt cardiovascular disease (CVD), in a population-based study in Lausanne, Switzerland. We compared the 10-year CHD risk using three scoring schemes, i.e., the Framingham risk score (FRS) from the U.S. National Cholesterol Education Program's Adult Treatment Panel III (ATP III), the PROCAM scoring scheme from the International Atherosclerosis Society (IAS), and the European risk SCORE for low-risk countries, without and with extrapolation to 60 years as recommended by the European Society of Cardiology guidelines (ESC). With FRS and PROCAM, high-risk was defined as a 10-year risk of fatal or non-fatal CHD >20% and a 10-year risk of fatal CVD >= 5% with SCORE. We compared the proportions of high-risk participants and eligibility for statin use according to these three schemes. For each guideline, we estimated the impact of increased statin use from current partial compliance to full compliance on potential CHD deaths averted over 10 years, using a success proportion of 27% for statins. Results: Participants classified at high-risk (both genders) were 5.8% according to FRS and 3.0% to the PROCAM, whereas the European risk SCORE classified 12.5% at high-risk (15.4% with extrapolation to 60 years). For the primary prevention of CHD, 18.5% of participants were eligible for statin therapy using ATP III, 16.6% using IAS, and 10.3% using ESC (13.0% with extrapolation) because ESC guidelines recommend statin therapy only in high-risk subjects. In comparison with IAS, agreement to identify eligible adults for statins was good with ATP III, but moderate with ESC (Figure). Using a population perspective, a full compliance with ATP III guidelines would reduce up to 17.9% of the 24'310 CHD deaths expected over 10 years in Switzerland, 17.3% with IAS and 10.8% with ESC (11.5% with extrapolation). Conclusion: Full compliance with guidelines for statin therapy would result in substantial health benefits, but proportions of high-risk adults and eligible adults for statin use varied substantially depending on the scoring systems and corresponding guidelines used for estimating CHD risk in Switzerland.

Effect of statin therapy in the outcome of bloodstream infections due to Staphylococcus aureus: a prospective cohort study.

INTRODUCTION Statins have pleiotropic effects that could influence the prevention and outcome of some infectious diseases. There is no information about their specific effect on Staphylococcus aureus bacteremia (SAB). METHODS A prospective cohort study including all SAB diagnosed in patients aged ≥18 years admitted to a 950-bed tertiary hospital from March 2008 to January 2011 was performed. The main outcome variable was 14-day mortality, and the secondary outcome variables were 30-day mortality, persistent bacteremia (PB) and presence of severe sepsis or septic shock at diagnosis of SAB. The effect of statin therapy at the onset of SAB was studied by multivariate logistic regression and Cox regression analysis, including a propensity score for statin therapy. RESULTS We included 160 episodes. Thirty-three patients (21.3%) were receiving statins at the onset of SAB. 14-day mortality was 21.3%. After adjustment for age, Charlson index, Pitt score, adequate management, and high risk source, statin therapy had a protective effect on 14-day mortality (adjusted OR = 0.08; 95% CI: 0.01-0.66; p = 0.02), and PB (OR = 0.89; 95% CI: 0.27-1.00; p = 0.05) although the effect was not significant on 30-day mortality (OR = 0.35; 95% CI: 0.10-1.23; p = 0.10) or presentation with severe sepsis or septic shock (adjusted OR = 0.89; CI 95%: 0.27-2.94; p = 0.8). An effect on 30-day mortality could neither be demonstrated on Cox analysis (adjusted HR = 0.5; 95% CI: 0.19-1.29; p = 0.15). CONCLUSIONS Statin treatment in patients with SAB was associated with lower early mortality and PB. Randomized studies are necessary to identify the role of statins in the treatment of patients with SAB.

Lupus erythematosus and other autoimmune diseases related to statin therapy: a systematic review.

BACKGROUND: Statins have been increasingly associated with drug-induced autoimmune reactions, including lupus erythematosus. OBJECTIVE: To identify and determine the clinical and biological characteristics of statin-induced autoimmune reactions. MATERIAL AND METHODS: The MEDLINE database (1966 to September 2005) was used to identify all reported cases of statin-induced autoimmune diseases. The keywords used were statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, adverse effects, autoimmune disease, lupus erythematosus, dermatomyositis and polymyositis. RESULTS: Twenty-eight cases of statin-induced autoimmune diseases have been published so far. Systemic lupus erythematosus was reported in 10 cases, subacute cutaneous lupus erythematosus in three cases, dermatomyositis and polymyositis in 14 cases and lichen planus pemphigoides in one case. Autoimmune hepatitis was observed in two patients with systemic lupus erythematosus. The mean time of exposure before disease onset was 12.8+/-18 months; range 1 month-6 years. Systemic immunosuppressive therapy was required in the majority of cases. In many patients, antinuclear antibodies were still positive many months after clinical recovery. A lethal outcome has been recorded in two patients despite aggressive immunosuppressive therapy. CONCLUSION: Long-term exposure to statins may be associated with drug-induced lupus erythematosus and other autoimmune disorders. Fatal cases have been reported despite early drug discontinuation and aggressive systemic immunosuppressive therapy.

Lupus-like syndrome associated with statin therapy.

Statins are among the most widely prescribed drugs. An increasing number of lupus-like syndrome has recently been reported with these lipid-lowering agents. We describe a new case associated with simvastatin therapy. The presence of anti-dsDNA antibodies in the serum is for the first time reported confirming that statins may also induce a systemic autoimmune reaction. Statin-induced lupus-like syndrome is characterized by the long delay between the beginning of therapy and the skin eruption. Antinuclear antibodies may persist for many months after drug discontinuation. The causal relationship may be therefore difficult to establish, and probably many cases are unrecognized. Early diagnosis may avoid unnecessary immunosuppressive therapy.

Statin therapy and the expression of genes that regulate calcium homeostasis and membrane repair in skeletal muscle

In skeletal muscle of patients with clinically diagnosed statin-associated myopathy, discrete signs of structural damage predominantly localize to the T-tubular region and are suggestive of a calcium leak. The impact of statins on skeletal muscle of non-myopathic patients is not known. We analyzed the expression of selected genes implicated in the molecular regulation of calcium and membrane repair, in lipid homeostasis, myocyte remodeling and mitochondrial function. Microscopic and gene expression analyses were performed using validated TaqMan custom arrays on skeletal muscle biopsies of 72 age-matched subjects who were receiving statin therapy (n = 38), who had discontinued therapy due to statin-associated myopathy (n = 14), and who had never undergone statin treatment (n = 20). In skeletal muscle, obtained from statin-treated, non-myopathic patients, statins caused extensive changes in the expression of genes of the calcium regulatory and the membrane repair machinery, whereas the expression of genes responsible for mitochondrial function or myocyte remodeling was unaffected. Discontinuation of treatment due to myopathic symptoms led to a normalization of gene expression levels, the genes encoding the ryanodine receptor 3, calpain 3, and dystrophin being the most notable exceptions. Hence, even in clinically asymptomatic (non-myopathic) patients, statin therapy leads to an upregulation in the expression of genes that are concerned with skeletal muscle regulation and membrane repair.

Statin therapy induces ultrastructural damage in skeletal muscle in patients without myalgia

Muscle pain and weakness are frequent complaints in patients receiving 3-hydroxymethylglutaryl coenzymeA (HMG CoA) reductase inhibitors (statins). Many patients with myalgia have creatine kinase levels that are either normal or only marginally elevated, and no obvious structural defects have been reported in patients with myalgia only. To investigate further the mechanism that mediates statin-induced skeletal muscle damage, skeletal muscle biopsies from statin-treated and non-statin-treated patients were examined using both electron microscopy and biochemical approaches. The present paper reports clear evidence of skeletal muscle damage in statin-treated patients, despite their being asymptomatic. Though the degree of overall damage is slight, it has a characteristic pattern that includes breakdown of the T-tubular system and subsarcolemmal rupture. These characteristic structural abnormalities observed in the statin-treated patients were reproduced by extraction of cholesterol from skeletal muscle fibres in vitro. These findings support the hypothesis that statin-induced cholesterol lowering per se contributes to myocyte damage and suggest further that it is the specific lipid/protein organization of the skeletal muscle cell itself that renders it particularly vulnerable.

Annexin A1 is a biomarker of T-tubular repair in skeletal muscle of nonmyopathic patients undergoing statin therapy

Skeletal muscle complaints are a common consequence of cholesterol-lowering therapy. Transverse tubular (T-tubular) vacuolations occur in patients having statin-associated myopathy and, to a lesser extent, in statin-treated patients without myopathy. We have investigated quantitative changes in T-tubular morphology and looked for early indicators of T-tubular membrane repair in skeletal muscle biopsy samples from patients receiving cholesterol-lowering therapy who do not have myopathic side effects. Gene expression and protein levels of incipient membrane repair proteins were monitored in patients who tolerated statin treatment without myopathy and in statin-naive subjects. In addition, morphometry of the T-tubular system was performed. Only the gene expression for annexin A1 was up-regulated, whereas the expression of other repair genes remained unchanged. However, annexin A1 and dysferlin protein levels were significantly increased. In statin-treated patients, the volume fraction of the T-tubular system was significantly increased, but the volume fraction of the sarcoplasmic reticulum remained unchanged. A complex surface structure in combination with high mechanical loads makes skeletal muscle plasma membranes susceptible to injury. Ca(2+)-dependent membrane repair proteins such as dysferlin and annexin A1 are deployed at T-tubular sites. The up-regulation of annexin A1 gene expression and protein points to this protein as a biomarker for T-tubular repair.

Statin therapy and long-term adverse limb outcomes in patients with peripheral artery disease: insights from the REACH registry

AIMS Due to a high burden of systemic cardiovascular events, current guidelines recommend the use of statins in all patients with peripheral artery disease (PAD). We sought to study the impact of statin use on limb prognosis in patients with symptomatic PAD enrolled in the international REACH registry. METHODS Statin use was assessed at study enrolment, as well as a time-varying covariate. Rates of the primary adverse limb outcome (worsening claudication/new episode of critical limb ischaemia, new percutaneous/surgical revascularization, or amputation) at 4 years and the composite of cardiovascular death/myocardial infarction/stroke were compared among statin users vs. non-users. RESULTS A total of 5861 patients with symptomatic PAD were included. Statin use at baseline was 62.2%. Patients who were on statins had a significantly lower risk of the primary adverse limb outcome at 4 years when compared with those who were not taking statins [22.0 vs. 26.2%; hazard ratio (HR), 0.82; 95% confidence interval (CI), 0.72-0.92; P = 0.0013]. Results were similar when statin use was considered as a time-dependent variable (P = 0.018) and on propensity analysis (P < 0.0001). The composite of cardiovascular death/myocardial infarction/stroke was similarly reduced (HR, 0.83; 95% CI, 0.73-0.96; P = 0.01). CONCLUSION Among patients with PAD in the REACH registry, statin use was associated with an ∼18% lower rate of adverse limb outcomes, including worsening symptoms, peripheral revascularization, and ischaemic amputations. These findings suggest that statin therapy not only reduces the risk of adverse cardiovascular events, but also favourably affects limb prognosis in patients with PAD.