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Nossuli, T. O., V. Lakshminarayanan, G. Baumgarten, G. E. Taffet, C. M. Ballantyne, L. H. Michael, and M. L. Entman. A chronic mouse model of myocardial ischemia-reperfusion: essential in cytokine studies. Am J Physiol Heart Circ Physiol 278: H1049-H1055, 2000.--Reperfusion of the ischemic myocardium is associated with a cytokine cascade that reflects a cellular response to injury. We studied this cascade in the mouse and found that acute surgical trauma in sham-operated animals obscured early changes in cytokine induction that occur during myocardial ischemia-reperfusion (MI/R). Therefore, we utilized a new implantable device that allows occlusion and reperfusion of the left anterior descending coronary artery in a closed-chest mouse at any time after instrumentation. Induction of interleukin (IL)-6 and tumor necrosis factor (TNF)-[Alpha] mRNA in the whole heart was examined by RNase protection assay and quantitated by Phosphor-Imager. At 3 h after instrumentation, levels of IL-6 mRNA in sham-operated animals increased above those of control naive hearts, whereas this increase did not occur until after 1 day for TNF-[Alpha] mRNA. The surgical trauma led to exaggeration of I/R cytokine induction with greater variance in response. At 3 days and 1 wk after instrumentation, levels of both IL-6 and TNF-[Alpha] mRNA in sham-operated animals were comparable to those of naive hearts and induction responses in I/R were much less variant. We also found that 1 h of ischemia and 2 h of reperfusion at all time points of recovery (i.e., 3 h and 1, 3, and 7 days after instrumentation) led to a significant increase in IL-6 and TNF-[Alpha] mRNA levels. In addition, 3 h of permanent occlusion, which did not induce any mRNA increase after 1 wk postinstrumentation, caused marked upregulation of IL-6 mRNA in an acutely prepared animal. This study of early cytokine responses evoked by MI/R highlights the need for dissipation of acute surgical trauma by using a chronic, closed-chest mouse preparation. murine; cytokine; interleukin; inflammation; surgery

Objective: To review and analyse the evidence for the cholesterol-lowering effect of ezetimibe in adult patients with hypercholesterolaemia who are not at low-density lipoprotein cholesterol (LDL-C) goal on statin monotherapy.Research Design: Systematic review and meta-analysis.Methods: MEDLINE and EMBASE were searched to identify ezetimibe randomised controlled trials (RCTs) published between January 1993 and December 2005. The meta-analysis combined data from RCTs, with a minimum treatment duration of 6 weeks, that compared treatment with ezetimibe 10 mg/day or placebo added to current statin therapy. The difference between treatments was analysed for four co-primary outcomes: mean percentage change from baseline in total cholesterol (TC), LDL-C, and high-density lipoprotein cholesterol (HDL-C), and number of patients achieving LDL-C treatment goal. Meta-analysis results are presented for a modified version of the inverse variance random effects model.Results: Five RCTs involving a total of 5039 patients were included in the meta-analysis. The weighted mean difference (WMD) between treatments significantly favoured the ezetimibe/statin combination over placebo/statin for TC (-16.1% (-17.3, -14.8); p < 0.0001), LDL-C (-23.6% (-25.6, -21.7); p < 0.0001) and HDL-C (1.7% (0.9, 2.5); p < 0.0001). The relative risk of reaching the LDL-C treatment goal was significantly higher for patients on ezetimibe/statin relative to those on placebo/statin (3.4 (2.0, 5.6); p < 0.0001). In pre-defined sub-group analyses of studies in patients with coronary heart disease, the WMD between treatments remained significantly in favour of ezetimibe/statin (p < 0.0001) for TC and LDL-C but was no longer significant for HDL-C. Elevations in creatine kinase, alanine aminotransferase or aspartate aminotransferase that were considered as an adverse effect did not differ significantly between treatments.Conclusions: The meta-analysis we performed included only five studies and was restricted to analysis of the changes in cholesterol levels relative to baseline. However, the results suggest that ezetimibe co-administered with ongoing statin therapy provides significant additional lipid-lowering in patients not at LDL-C goal on statin therapy alone, allowing more patients to reach their LDL-C goal. [ABSTRACT FROM AUTHOR]

Accelerated atherosclerosis is a leading cause of death in long-term survivors of heart and renal transplantation and may be exacerbated by the frequent occurrence of posttransplant hyperlipidemia. Attempts to define the mechanism for hyperlipidemia in transplant recipients are confounded by dramatic changes in metabolism and nutritional status after transplantation, as well as by treatment with multiple immunosuppressive and antihypertensive drugs. To avoid these pitfalls and to determine if cyclosporine alone adversely affects lipid levels, we measured lipoprotein levels in a prospective, double-blind, randomized, placebo-controlled trial of cyclosporine in 36 men with amyotrophic lateral sclerosis. Plasma total cholesterol, triglyceride, high-density lipoprotein cholesterol, and apolipoprotein B levels were measured at baseline, 2 weeks, 1 month, and 2 months. Significant increases of 21% in total cholesterol, 31% in low-density lipoprotein cholesterol, and 12% in apolipoprotein B levels occurred only in the cyclosporine group. Cyclosporine therapy alone adversely affects plasma lipoprotein levels by increasing total cholesterol levels, primarily due to an increase in low-density lipoprotein cholesterol level. [ABSTRACT FROM AUTHOR]

In addition to elevated low-density lipoprotein (LDL) cholesterol, which has been conclusively proven to play a critical role in atherogenesis and coronary artery disease (CAD), other lipoprotein abnormalities are associated with CAD, such as reduced high-density lipoprotein (HDL) cholesterol; increased triglyceride-rich lipoproteins (very low density and intermediate-density lipoproteins); increased lipoprotein(a); small, dense LDL; and LDL with increased susceptibility to oxidation. Other, nonlipid factors such as homocysteine, fibrinogen, C-reactive protein, and soluble cell adhesion molecules may also have a role in risk stratification. The present US treatment guidelines, which focus on LDL cholesterol, stratify risk assessment and intensity of treatment by the presence of CAD; therefore, noninvasive imaging techniques such as ultrafast computed tomography and positron-emission tomography (PET) of the heart, which enable early detection of CAD, are useful in risk assessment. Because the influence of risk factors depends on their severity and combination, global risk assessment provides a necessary guide to the appropriate intensity of treatment. Agents are available that reduce LDL cholesterol and triglyceride and increase HDL cholesterol; although lipoprotein(a), LDL particle size, LDL oxidation, and homocysteine can also be altered, the clinical effects of such alterations are not known. Combination therapy that simultaneously improves multiple components of the lipid profile may provide additional benefit compared with monotherapy. To provide cost-effective treatment to the most patients, high-risk patients must be identified through systematic screening. Then each patient should be treated with the most cost-effective agent(s) that will enable achievement of the lipid levels recommended in the guidelines. [ABSTRACT FROM AUTHOR]

Based on the established relation between low-density lipoprotein (LDL) cholesterol and coronary artery disease (CAD), the treatment guidelines of the US National Cholesterol Education Program (NCEP) focus on LDL cholesterol reduction for primary and secondary prevention of CAD events. Abundant clinical trial evidence supports the importance of LDL cholesterol-lowering in decreasing CAD risk, both in angiographic trials, which measure CAD progression, and in trials with morbidity and mortality endpoints. The LDL cholesterol targets in the guidelines remain important treatment goals, and ongoing trials should answer questions of whether further reduction in LDL cholesterol will provide much additional benefit. Even in trials of statin therapy, in which substantial reductions of LDL cholesterol have been obtained, statins decrease (by 23-37%) but do not entirely eliminate events, suggesting that lipid parameters besides LDL cholesterol, such as high-density lipoprotein (HDL) cholesterol, triglyceride, lipoprotein(a), and LDL particle size and susceptibility to oxidation, as well as other risk factors, influence CAD risk. Unfortunately, at present, the majority of high-risk patients are not receiving either diet or drug therapy. Systematic screening to identify high-risk patients and methodical follow-up to implement diet, lifestyle modification, and drug therapy to lower LDL cholesterol, as provided for in the NCEP guidelines, should lead to significant benefits in the prevention of CAD events. [ABSTRACT FROM AUTHOR]

Clinical trials provide evidence on methods for risk assessment of coronary artery disease and on interventions used to decrease risk. Plaque rupture, which leads to either progression of coronary artery disease or myocardial infarction, is the critical biologic event in the pathophysiology of atherothrombosis that leads to morbidity and mortality. Trials with endpoints of myocardial infarction and death provide direct information on the effect of intervention on morbidity and mortality, but these trials require extremely large sample sizes and long duration. To obtain clinical information more quickly and with fewer patients, investigators have conducted trials using surrogate endpoints that examine the effect of treatment on the underlying disease process through measures of atherosclerotic lesion progression and/or regression and new lesion development. Coronary angiography studies have consistently shown that lipid-modifying therapy decreases coronary artery disease progression. The correlation between rate of progression of coronary artery disease and clinical coronary events such as myocardial infarction and coronary death may be explained by the relation of both to the biologic process of plaque rupture and thrombosis. [ABSTRACT FROM AUTHOR]

Background Inflammation is linked to cognitive impairment (CI) in cancer survivors. But its role in survivors who develop dementia is unclear. Methods We evaluated dementia risk per log2 increase in 580 inflammatory proteins in 391 dementia-free long-term (>5 yrs) older adult survivors of prostate, breast, colorectal, endometrial and bladder cancers in ARIC. Plasma inflammatory proteins were measured at visit 5 (2011-13) using SomaScan, an aptamer-based assay. Participants were followed through visit 6 (2016-17). We adjusted for age, sex, race, years since cancer diagnosis, ApoE4, renal function, anti-inflammatory drug use and cancer/CVD shared risk factors. We also investigated proteins associated with dementia in 196 prostate and 135 breast cancer survivors, accounting for multiple testing by Bonferroni correction and false discovery rate Q-values. Results Survivors were 20% Black, 54% male, mean age of 76yrs, median time since diagnosis of 12yrs. 67 dementia cases occurred in 1780 person-yrs. After FDR correction, 73 proteins were statistically significantly associated with dementia risk. TMEM87B, CD9, RAF1, IL21sR and FGF7 showed the strongest positive association, with HR:3.4-3.8 per Δlog2. LAIR1, IL36B, FGFR3, FLRT3 and LSAMP showed the strongest inverse association, HR:0.1-0.2. Only syntaxin12 (STX12) was significant after Bonferroni correction, HR:2.2. Associations of some inflammatory proteins with dementia were cancer site-specific. In breast cancer survivors, IL6, HMGA2, IFN-GR1, SAP, TNFRSF1a, TNFRSF14, and TNFAIP3, were associated with dementia. STX12 and RAF1 were significantly associated (q <0.05) with dementia in all, prostate, and breast cancer survivors. Conclusion Inflammatory proteins were associated with dementia in older adult cancer survivors, including STX12 (enriched in brain, linked to WNT signaling loss, exerts CNS effects) and RAF1 (regulates MAPK/ERK pathway, previously identified in dementia etiology). Inflammatory proteins previously associated with CI, including TNF proteins/receptors, were associated with dementia in breast cancer survivors. If confirmed, these proteins may warrant evaluation as potential biomarkers for dementia risk screening, and possibly preventive/therapeutic targets in cancer survivors. Funding: NHLBI, NCI, NPCR. [ABSTRACT FROM AUTHOR]

The article presents a study on the combination therapy with ezetimibe and simvastatin for reduction of low-density lipoprotein cholesterol to the patients with heart disease. The researchers assessed the patients after a 4-week placebo and diet run-in period and 6 weeks of active drug therapy. The study demonstrates that the combination of ezetimibe and simvastatin provides greater reduction in total cholesterol compared with rosuvastatin monotherapy at the corresponding dose.

The article focuses on research studies conducted by scientists on statins. Trials with statins have demonstrated repeatedly that they can reduce cardiovascular risk in numerous patient populations, including those with established coronary heart disease. In the lipid-lowering arm of the Anti-hypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial study, the benefits of statin treatment were not observed when the degree of low-density lipoprotein cholesterol reduction was small.

Patients at risk for coronary heart disease often have multiple underlying risk factors, including hypertension, type 2 diabetes mellitus, and dyslipidemia. The focus of this month's CME case study is recognition of these often silent and coexisting diseases, and the selection of appropriate therapy that will not adversely affect management of comorbid conditions. [ABSTRACT FROM AUTHOR]

Apolipoprotein B has been shown to be a better predictor of coronary heart disease than low-density lipoprotein (LDL) cholesterol, and non-high-density lipoprotein (non-HDL) cholesterol may also be a better parameter for coronary heart disease risk assessment and as a target for therapy. Data from the Atorvastatin Comparative Cholesterol Efficacy and Safety Study (ACCESS) were used to assess the correlation between lipid and apolipoprotein B levels before and after lipid-lowering therapy and to examine the effects of 5 hydroxymethylglutaryl coenzyme A reductase inhibitors on lipids and apolipoprotein B. The 54-week study randomized 3,916 hypercholesterolemic patients to atorvastatin, fluvastatin, lovastatin, pravastatin, or simvastatin, initiated at recommended starting doses with titrations as needed at weeks 6, 12, and 18 to achieve National Cholesterol Education Program LDL targets. Compared with LDL cholesterol, non-HDL cholesterol correlated better with apolipoprotein B levels at baseline (r = 0.914, p <0.0001) and at week 54 (r = 0.938, p <0.0001), and the correlation was strong across all baseline triglyceride strata. At starting doses, atorvastatin (10 mg) lowered non-HDL cholesterol by 33.3% compared with 26.6% with simvastatin (10 mg), 24.1% with lovastatin (20 mg), 17.2% with fluvastatin (20 mg), and 17.0% with pravastatin (10 mg). Atorvastatin also provided greater reductions in non-HDL cholesterol after dose titration, and a greater percentage of patients taking atorvastatin achieved non-HDL cholesterol targets. Baseline triglyceride did not affect non-HDL cholesterol reductions with any of the 5 hydroxymethylglutaryl coenzyme A reductase inhibitors. Fewer patients achieved non-HDL cholesterol targets than LDL cholesterol targets, particularly among high-risk patients, implying that if non-HDL cholesterol was used as a target for treatment, more patients would need to be treated more aggressively than National Cholesterol Education Program guidelines require. [ABSTRACT FROM AUTHOR]

An extended-release (ER) formulation of fluvastatin 80 mg has been developed for once-daily treatment of primary hypercholesterolemia in patients who require fluvastatin dosages of > 40 mg/day. The study aimed to determine the efficacy and safety of the new formulation and to assess the dose response over the range of 40 to 160 mg/day. After a 4-week placebo/dietary run-in period, 123 patients with primary hypercholesterolemia (Fredrickson type IIa/IIb) were randomized to receive fluvastatin 40, 80, or 160 mg/day for 6 weeks. The 40 mg/day dosage was administered as the marketed immediate-release (IR) capsule and the 80 mg/day dosage as 1 80-mg ER tablet. Patients receiving 160 mg/day were administered 80 mg/day (1 ER tablet) for the first 2 weeks, followed by 160 mg/day (2 ER tablets) for the remainder of the study. All doses were administered once daily at bedtime. The results showed a linear dose-response relation. Doubling the fluvastatin dosage resulted in a 6% greater mean percent reduction in low-density lipoprotein cholesterol (40 mg IR -29%; 80 mg ER -35%; 160 mg ER -41%). In the 160-mg ER group, 62% of patients achieved > or = 40% reductions in low-density lipoprotein cholesterol compared with 32% and 10% of patients in the 80-mg ER and 40-mg IR groups, respectively. Dose ordering of the response was also observed for the other lipid parameters. Fluvastatin ER was well tolerated. Thus, the new ER formulation of fluvastatin was effective and well tolerated in the once-daily treatment of primary hypercholesterolemia. [ABSTRACT FROM AUTHOR]

A multidisciplinary program was designed to improve patient outcomes after an acute coronary event. The primary objective of the program was that lipid-lowering therapy be prescribed at the time of discharge for acute myocardial infarction (AMI) and percutaneous transluminal coronary angioplasty (PTCA) patients. Secondary objectives for this program were (1) a baseline lipid panel within the first 24 hours of admission and (2) documentation of discharge counseling for lipid-lowering therapy in the patient medical record. Improvements were reported for all 3 objectives. For the primary indicator, lipid-lowering therapy prescribed at discharge, the baseline value increased from 40% to 72-81%. The percentage of patients with a lipid panel within 24 hours of admission improved from a baseline of 13% to 38-71%. Overall, 28-77% of patient records contained documentation of lipid-lowering medication counseling after initiation of the program. This information should provide the necessary benchmarking data to maintain competitiveness in the dynamic healthcare environment. Overall, this program provides high-quality, cost-effective health care for the patient with established coronary artery disease. [ABSTRACT FROM AUTHOR]

Hyperlipidemia occurs frequently after heart transplantation, and accelerated coronary artery disease remains the major cause of morbidity and mortality in patients who survive more than 1 year after heart transplantation. However, the risks and benefits of lipid-lowering therapy after heart transplantation remain poorly defined, and national guidelines for lipid-lowering drug therapy do not specifically address treatment of dyslipidemia in transplant recipients. Since the initial reports in the 1980s of rhabdomyolysis in heart transplant patients receiving high-dosage lovastatin, results of 11 post-transplantation series that used lovastatin, simvastatin, or pravastatin at lower dosages as drug monotherapy have been published. These studies have shown an overall 1% incidence of rhabdomyolysis, defined as creatine kinase > 10 times the upper limit of normal plus muscle symptoms. One randomized, controlled prospective trial has investigated the effects of lipid-lowering pharmacotherapy on patient outcome in cardiac transplant recipients. At 1-year follow-up in this nonblinded, single-center trial, patients treated with pravastatin (20 or 40 mg/day) initiated within 2 weeks of transplantation had a significant reduction in mortality rate and a significantly lower incidence of transplant arteriopathy. A number of important issues remain unanswered regarding treatment guidelines in patients with hyperlipidemia after heart transplantation. In January 1995 we began the Heart Transplant Lipid Registry, with 12 participant centers, to gather data prospectively on the efficacy and safety of lipid-lowering drugs in the treatment of dyslipidemia after heart transplantation. [ABSTRACT FROM AUTHOR]

Improving the quality of lipid management requires an objective assessment of current practice and the ability to monitor whether quality is improved by implementing changes in practice. In a competitive healthcare environment, documentation of quality of care and patient outcomes may be important in securing contracts. It would be almost impossible to perform a meaningful clinical-outcome analysis in a timely fashion without the support of a computerized database. However, evaluating, selecting, and implementing computerized databases can be a daunting task. Before the purchase of a database, the following steps should be performed: (1) consider and prioritize the goals for the computerized database; (2) audit charts to determine whether the existing chart format meets the current guidelines for reimbursement and medical-legal standards; (3) revise the paper chart to improve fulfillment of the goals from step 1; (4) consider the specific clinical environment, including the skill level of personnel using the system, how user-friendly the system is, whether the system is multifunctional, and the costs associated with the software and implementation. We have evaluated 3 types of computerized databases and report their strengths and weaknesses; we also briefly discuss the electronic medical record. [ABSTRACT FROM AUTHOR]