Hyperlipidemias: Shishehbor MH

Patel TN, Shishehbor MH, Bhatt DL. · Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA. · Eur Heart J. · Pubmed #17242008 links to  free full text

Abstract: Lipid lowering with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or 'statins' has dramatically reduced morbidity and mortality in patients with established cardiovascular disease. Recently, there have been multiple studies investigating the role of high-dose statin therapy with more aggressive lipid lowering in this setting. Concomitantly, there is increasing evidence implicating a role of inflammation in the pathogenesis of atherosclerosis. These high-dose statin trials and other studies have also provided a wealth of data suggesting that statins have anti-inflammatory and anti-oxidant properties that go beyond their lipid-lowering effects. In this review, we will provide a brief overview of recent, large-scale, randomized, placebo and active controlled trials of high-dose statin therapy in the setting of stable and unstable coronary artery disease and percutaneous coronary intervention. Further, we will discuss the evidence for effects of high-dose statin therapy on inflammation and C-reactive protein.

Zhao SP, Liu L, Cheng YC, Shishehbor MH, Liu MH, Peng DQ, Li YL. · Department of Cardiology, Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, PR China. · Circulation. · Pubmed #15313947 links to  free full text

Abstract: BACKGROUND: Endothelial dysfunction is associated with inflammation and postprandial hypertriglyceridemia. Xuezhikang, an extract of Cholestin, a dietary supplement, has lipid-modulating and antiinflammatory effects. We explored the effects of xuezhikang on endothelial function and high-sensitivity C-reactive protein (hs-CRP) in patients with coronary heart disease (CHD). METHODS AND RESULTS: We prospectively randomized 50 CHD patients to xuezhikang 1200 mg/d or placebo for 6 weeks. Fasting hs-CRP concentrations, flow-mediated vasodilation (FMD) at 0 and 4 hours, and lipid parameters at 0, 2, 4, and 6 hours were monitored after a high-fat meal (800 calories; 50 g fat) in all patients. All patients underwent a high-fat meal test at the beginning of the study and after 6 weeks of treatment. Postprandial FMD was significantly worse at 4 hours after a high-fat meal (P<0.05), and this was associated with the area under the triglyceride curve (TG-AUC) (r=0.345, P<0.01). After 6 weeks of xuezhikang, fasting hs-CRP levels and TG-AUC (P<0.001 for each) decreased. Furthermore, preprandial and postprandial FMD significantly improved (P<0.001). There were no significant changes in serum lipids and FMD in the placebo arm. In multivariable regression analysis, changes in TG-AUC and fasting hs-CRP levels were predictive of improvement in preprandial FMD (P<0.05). CONCLUSIONS: Xuezhikang effectively improved preprandial and postprandial endothelial function through its potent antiinflammatory and lipid-lowering effects.

Shishehbor MH, Brennan ML, Aviles RJ, Fu X, Penn MS, Sprecher DL, Hazen SL. · Department of Cell Biology, and Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic Foundation, 9500 Euclid Ave, NC10, Cleveland, Ohio 44195, USA. · Circulation. · Pubmed #12860913 links to  free full text

Abstract: BACKGROUND: The pleiotropic actions of hydroxymethylglutaryl CoA reductase inhibitors (statins) include antiinflammatory and antioxidant actions. We recently reported that statins induce reductions in plasma protein levels of nitrotyrosine (NO2Tyr), a modification generated by nitric oxide-derived oxidants. Whether alternative oxidative pathways are suppressed in vivo after statin administration has not yet been reported. METHODS AND RESULTS: As an extension of our prior study, hypercholesterolemic subjects with no known coronary artery disease were evaluated at baseline and after 12 weeks of atorvastatin therapy (10 mg/d). Plasma levels of protein-bound chlorotyrosine, NO2Tyr, dityrosine, and orthotyrosine, specific molecular fingerprints for distinct oxidative pathways upregulated in atheroma, were determined by mass spectrometry. In parallel, alterations in lipoproteins and C-reactive protein were determined. Statin therapy caused significant reductions in chlorotyrosine, NO2Tyr, and dityrosine (30%, 25%, and 32%, respectively; P<0.02 each) that were similar in magnitude to reductions in total cholesterol and apolipoprotein B-100 (25% and 29%, P<0.001 each). Nonsignificant decreases in orthotyrosine and C-reactive protein levels were observed (9% and 11%, respectively; P>0.10 each). Statin-induced reductions in oxidation markers were independent of decreases in lipids and lipoproteins. CONCLUSIONS: Statins promote potent systemic antioxidant effects through suppression of distinct oxidation pathways. The major pathways inhibited include formation of myeloperoxidase-derived and nitric oxide-derived oxidants, species implicated in atherogenesis. The present results suggest potential mechanisms that may contribute to the beneficial actions of statins. They also have important implications for monitoring the antiinflammatory and antioxidant actions of these agents.

Shishehbor MH, Aviles RJ, Brennan ML, Fu X, Goormastic M, Pearce GL, Gokce N, Keaney JF, Penn MS, Sprecher DL, Vita JA, Hazen SL. · Department of Cell Biology, and the Center for Cardiovascular Diagnostics and Prevention, the Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. · JAMA. · Pubmed #12672736 links to  free full text

Abstract: CONTEXT: Formation of nitric oxide-derived oxidants may serve as a mechanism linking inflammation to development of atherosclerosis. Nitrotyrosine, a specific marker for protein modification by nitric oxide-derived oxidants, is enriched in human atherosclerotic lesions and low-density lipoprotein (LDL) recovered from human atheroma. OBJECTIVES: To determine whether systemic levels of nitrotyrosine are associated with the prevalence of coronary artery disease (CAD) and are modulated by hydroxymethylglutaryl coenzyme-A reductase inhibitor (statin) therapy.Design, Setting, and PATIENTS: A case-control and interventional study at 2 urban tertiary-care referral centers; recruitment for each was from June 1, 2001, until January 1, 2002. For the case-control study, 100 case-patients with established CAD and 108 patients with no clinically evident CAD were recruited consecutively. In the interventional study, participants aged 21 years or older with hypercholesterolemia (LDL cholesterol > or =130 mg/dL [> or =3.5 mmol/L]) underwent nutrition and exercise counseling. Those whose levels did not decrease with 6 to 8 weeks were enrolled in the study (n = 35). For 12 weeks, they received 10 mg/d of oral atorvastatin therapy. MAIN OUTCOME MEASURES: In the case-control study, the association between systemic levels of protein-bound nitrotyrosine, CAD risk, and presence of CAD. In the interventional study, the change in nitrotyrosine, lipoprotein, and C-reactive protein (CRP) levels. RESULTS: Nitrotyrosine levels were significantly higher among patients with CAD (median 9.1 micromol/mol [interquartile range, 4.8-13.8 micromol/mol] tyrosine vs 5.2 micromol/mol [interquartile range, 2.2-8.4 micromol/mol]; P<.001). Patients in the upper quartile of nitrotyrosine (29%; P<.001) had a higher odds of CAD compared with those in the lowest quartile (unadjusted odds ratio, 6.1; 95% confidence interval, 2.6-14.0; P<.001). In multivariate models adjusting for Framingham Global Risk Score and CRP, upper quartiles of nitrotyrosine remained associated with CAD (odds ratio, 4.4; 95% confidence interval, 1.8-10.6; P<.001). Statin therapy reduced nitrotyrosine levels significantly (25%; P<.02) with a magnitude similar to reductions in total cholesterol levels (25%; P<.001) and LDL particle number (29%; P<.001) yet were independent of alterations in lipoproteins and inflammatory markers like CRP. CONCLUSIONS: The findings from this preliminary study indicate that nitrotyrosine levels are associated with the presence of CAD and appear to be modulated by statin therapy. These results suggest a potential role for nitric oxide-derived oxidants as inflammatory mediators in CAD and may have implications for atherosclerosis risk assessment and monitoring of anti-inflammatory actions of statins.