Rosuvastatin, inflammation, C-reactive protein, JUPITER, and primary prevention of cardiovascular disease--a perspective

Richard Kones, Richard Kones

Abstract

The major public health concern worldwide is coronary heart disease, with dyslipidemia as a major risk factor. Statin drugs are recommended by several guidelines for both primary and secondary prevention. Rosuvastatin has been widely accepted because of its efficacy, potency, and superior safety profile. Inflammation is involved in all phases of atherosclerosis, with the process beginning in early youth and advancing relentlessly for decades throughout life. C-reactive protein (CRP) is a well-studied, nonspecific marker of inflammation which may reflect general health risk. Considerable evidence suggests CRP is an independent predictor of future cardiovascular events, but direct involvement in atherosclerosis remains controversial. Rosuvastatin is a synthetic, hydrophilic statin with unique stereochemistry. A large proportion of patients achieve evidence-based lipid targets while using the drug, and it slows progression and induces regression of atherosclerotic coronary lesions. Rosuvastatin lowers CRP levels significantly. The Justification for Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial was designed after the observation that when both low density lipoprotein and CRP were reduced, patients fared better than when only LDL was lowered. Advocates and critics alike acknowledge that the benefits of rosuvastatin in JUPITER were real. After a review, the US Food and Drug Administration extended the indications for rosuvastatin to include asymptomatic JUPITER-eligible individuals with one additional risk factor. The American Heart Association and Centers of Disease Control and Prevention had previously recognized the use of CRP in persons with "intermediate risk" as defined by global risk scores. The Canadian Cardiovascular Society guidelines went further and recommended use of statins in persons with low LDL and high CRP levels at intermediate risk. The JUPITER study focused attention on ostensibly healthy individuals with "normal" lipid profiles and high CRP values who benefited from statin therapy. The backdrop to JUPITER during this period was an increasing awareness of a rising cardiovascular risk burden and imperfect methods of risk evaluation, so that a significant number of individuals were being denied beneficial therapies. Other concerns have been a high level of residual risk in those who are treated, poor patient adherence, a need to follow guidelines more closely, a dual global epidemic of obesity and diabetes, and a progressively deteriorating level of physical activity in the population. Calls for new and more effective means of reducing risk for coronary heart disease are intensifying. In view of compelling evidence supporting earlier and aggressive therapy in people with high risk burdens, JUPITER simply offers another choice for stratification and earlier risk reduction in primary prevention patients. When indicated, and in individuals unwilling or unable to change their diet and lifestyles sufficiently, the benefits of statins greatly exceed the risks. Two side effects of interest are myotoxicity and an increase in the incidence of diabetes.

Keywords: C-reactive protein; Framingham risk score; HMG CoA reductase; JUPITER study; Reynolds risk score; cardiovascular risk; carotid intima-media thickness; cholesterol; coronary artery calcification; coronary heart disease; diabetes; dolichol; dyslipidemia; high-density lipoprotein; hypertension; inflammation; low-density lipoprotein; metabolic syndrome; mevalonate; obesity; pleiotropic; prenylation; primary prevention; rosuvastatin; statin drugs; statin myopathy.

Figures

Figure 1
Figure 1
A picture of C-reactive protein (CRP) from 1B09.pdb made using pymol. CRP is a pentameric molecule containing a recognition face that binds phosphocholine and calcium ions, and on the opposite side, an effector face that contains a C1q-binding site. Function depends upon Ca2+-dependent ligand binding. See text for details. Reproduced by permission of Skolstoe through Wikipedia commons.
Figure 2
Figure 2
Cholesterol is synthesized via the mevalonate pathway. Acetyl-CoA forms 3-hydroxyl-3-methylglutaryl CoA (HMG-CoA) in several steps. The conversion of 3-hydroxy-3-methylglutaryl (HMG)-CoA to mevalonate, the rate-limiting step in cholesterol synthesis, is catalyzed by HMG-CoA reductase (HMGR), an enzyme within the endoplasmic reticulum. Rosuvastatin is an efficient competitive inhibitor of HMGR, reducing not only mevalonate levels, but also prenylated downstream products. The post-translational process of prenylation is needed for the function of small G proteins, including geranylgeranylation of Rho, Ras, and Rab, necessary for cellular signaling, transduction, and intermembrane translocation. As beneficial as statins are, there are obligatory molecular consequences inherent in their use, some related to their beneficial pleiotropic actions, but also to their side effects. Many steps and enzymes are omitted for clarity.
Figure 3
Figure 3
The structure of rosuvastatin, uniquely containing sulfur, a fluorophenyl group, and a modified hydroxyglutaric acid moiety. The IUPAC name of rosuvastatin is (E,3R,5R)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-propan- 2-ylpyrimidin-5-yl]-3,5-dihydroxyhept-6-enoic acid.

References

    1. USDHHS, National Center for Health Statistics. Second National Health and Nutrition Examination Survey (NHANES II) Hyattsville MD: CDC; pp. 1976–1980.
    1. USDHHS, National Center for Health Statistics. Second National Health and Nutrition Examination Survey (Continuous NHANES) Hyattsville MD: CDC; pp. 1999–2002.
    1. Young F, Capewell S, Ford ES, Critchley JA. Coronary mortality declines in the US between 1980 and 2000. Quantifying the contributions from primary and secondary prevention. Am J Prev Med. 2010;39:228–234.
    1. Ford ES, Capewell S. Coronary heart disease mortality among young adults in the US from 1980 to 2002: concealed leveling or mortality rates. J Am Coll Cardiol. 2007;50:2128–2132.
    1. CDC National Center for Health Statistics. CDC mortality data, 2008: CDC latest release mortality data, 2005. [Accessed 2010 Oct 7]. .
    1. Sacker A, Head J, Bartley M. Impact of coronary heart disease on health functioning in an aging population: are there differences according to socioeconomic position. Psychosom Med. 2008;70:133–140.
    1. Allender S, Scarborough P, Peto V, et al. European cardiovascular disease statistics 2008. European Heart Network, 2008. [Accessed 2010 Oct 7]. .
    1. WHO Statistical Information System. Mortality data for ICD 10 codings. [Accessed 2010 Oct 7]. .
    1. Ridker PM, Danielson E, Fonseca FA, et al. for JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195–2207.
    1. Thompson D, Pepys MB, Wood SP. The physiological structure of human C-reactive protein and its complex with phosphocholine. Structure. 1999;7:169–177.
    1. Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest. 2003;111:1805–1812.
    1. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336:973–979.
    1. Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol. 2006;6:508–519.
    1. Hwang SJ, Ballantyne CM, Sharrett AR, et al. Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 1997;96:4219–4225.
    1. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation. 2000;101:1767–1772.
    1. Ross R. Atherosclerosis–an inflammatory disease. N Engl J Med. 1999;340:115–126.
    1. Libby P, Ridker PM. Inflammation and atherothrombosis: from population biology and bench research to clinical practice. J Am Coll Cardiol. 2006;48:A33–46.
    1. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352:1685–1695.
    1. Libby P, Nahrendorf M, Pittet MJ, Swirski FK. Diversity of denizens of the atherosclerotic plaque: not all monocytes are created equal. Circulation. 2008;117:3168–3170.
    1. Mach F, Schoenbeck U, Bonnefoy JY, Pober J, Libby P. Activation of monocyte/macrophage functions related to acute atheroma complication by ligation of CD40. Induction of collagenase, stromelysin, and tissue factor. Circulation. 1997;96:396–399.
    1. Spagnoli LG, Bonanno E, Mauriello A, et al. Multicentric inflammation in epicardial coronary arteries of patients dying of acute myocardial infarction. J Am Coll Cardiol. 2002;40:1579–1588.
    1. Abbate A, Bonanno E, Mauriello A, et al. Widespread myocardial inflammation and infarct-related artery patency. Circulation. 2004;110:46–50.
    1. Lombardo A, Biasucci LM, Lanza GA, et al. Inflammation as a possible link between coronary and carotid plaque instability. Circulation. 2004;109:3158–3163.
    1. Nakajima T, Schulte S, Warrington KJ, et al. T-cell-mediated lysis of endothelial cells in acute coronary syndromes. Circulation. 2002;105:570–575.
    1. Blake GJ, Ridker PM. Inflammatory bio-markers and cardiovascular risk prediction. J Intern Med. 2002;252:283–294.
    1. Esposito K, Giugliano D. Diet and inflammation: a link to metabolic and cardiovascular diseases. Eur Heart J. 2006;27:15–20.
    1. Freedman JE, Loscalzo J. Platelet–monocyte aggregates: bridging thrombosis and inflammation. Circulation. 2002;105:2130–2132.
    1. Steinhubl SR. Platelets as mediators of inflammation. Hematol Oncol Clin North Am. 2007;21:115–121.
    1. Nettleton JA, Matijevic N, Follis JL, Folsom AR, Boerwinkle E. Associations between dietary patterns and flow cytometry-measured biomarkers of inflammation and cellular activation in the Atherosclerosis Risk in Communities (ARIC) Carotid Artery MRI Study. Atherosclerosis. 2010;212:260–267.
    1. Libby P. Inflammation in atherosclerosis. Nature. 2002;420:868–874.
    1. Ridker PM. Testing the inflammatory hypothesis of atherothrombosis: scientific rationale for the cardiovascular inflammation reduction trial (CIRT) J Thromb Haemost. 2009;7(Suppl 1):332–339.
    1. Brugaletta S, Biasucci LM, Pinnelli M, et al. Novel anti-inflammatory effect of statins: reduction of CD4+CD28null T lymphocyte frequency in patients with unstable angina. Heart. 2006;92:249–250.
    1. Taubes G. Does Inflammation cut to the heart of the matter. Science. 2002;296:242–245.
    1. Williams KJ, Tabas I. Atherosclerosis and inflammation. Science. 2002;297:521–522.
    1. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342:836–843.
    1. Packard RRS, Libby P. Inflammation in atherosclerosis: from vascular biology to biomarker discovery and risk prediction. Clin Chem. 2008;43:24–38.
    1. Altman R. Risk factors in coronary atherosclerosis ather-inflammation: the meeting point. Thrombosis J. 2003;1:4.
    1. Vorchheimer DA, Fuster V. Inflammatory markers in coronary artery disease. Let prevention douse the flames. JAMA. 2001;286:2154–2156.
    1. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:801–809.
    1. Cybulsky MI, Gimbrone MA., Jr Endothelial expression of a mono-nuclear leukocyte adhesion molecule during atherogenesis. Science. 1991;251:788–791.
    1. Bonetti PO, Lerman LO, Lerman A. Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol. 2003;23:168–175.
    1. Liuzzo G, Biasucci LM, Gallimore JL, et al. The prognostic value of C-reactive protein and serum amyloid A protein in severe unstable angina. N Engl J Med. 1994;331:417–424.
    1. Biasucci LM, Vitelli A, Liuzzo G, et al. Elevated level of interleukin-6 in unstable angina. Circulation. 1996;94:874–877.
    1. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002;105:1135–1143.
    1. Wu KK, Aleksic N, Ballantyne ChM, Ahn Ch, Juneja H, Boerwinkle E. Interaction between soluble thrombomodulin and Intercellular Adhesion Molecule-1 in predicting risk of coronary heart disease. Circulation. 2003;107:1729–1732.
    1. Bhatt DL, Topol EJ. Need to test the arterial inflammation hypothesis. Circulation. 2002;106:136–140.
    1. Kereiakes DJ. The fire that burns within. C-reactive protein. Circulation. 2003;107:373–374.
    1. Ridker PM. High-sensitivity C-reactive protein, inflammation, and cardiovascular risk: from concept to clinical practice to clinical benefit. Am Heart J. 2004;148:S19–26.
    1. Dhingra R, Gona P, Nam B-H, et al. C-reactive protein, inflammatory conditions, and cardiovascular disease risk. Am J Med. 2007;120:1054–1062.
    1. Gustafson B, Hammarstedt A, Andersson CX, Smith U. Inflamed adipose tissue: a culprit underlying the metabolic syndrome and atherosclerosis. Atheroscler Thromb Vasc Biol. 2007;27:2276–2283.
    1. Liu Y, Yu H, Zhang Y, Zhao Y. TLRs are important inflammatory factors in atherosclerosis and may be a therapeutic target. Med Hypoth. 2008;70:314–316.
    1. Virani SS, Polsani VR, Nambi ZV. Novel markers of inflammatioin in atherosclerosis. Curr Atheroscler Rep. 2008;10:164–170.
    1. Peisajovich A, Marnell L, Mold C, Du Clos TW. C-reactive protein at the interface between innate immunity and inflammation. Expert Rev Clin Immunol. 2008;4:379–390.
    1. Ikonomidis I, Stamatelopoulos K, Lekakis J, Vamvakou GD, Kremastinos DT. Inflammatory and non-invasive vascular markers: the multimarker approach for risk stratification in coronary artery disease. Atherosclerosis. 2008;199:3–11.
    1. Otake H, Shite J, Shinke T, et al. Relation between plasma adiponectin, high sensitivity C-reactive protein, and coronary plaque components in patients with acute coronary syndrome. Am J Cardiol. 2008;101:1–7.
    1. Chamberlain J, Francis S, Brookes Z, et al. Interleukin-1 regulates multiples atherogenic mechanisms in response to fat feeding. PLoS ONE. 2009;4:e5073.
    1. Libby P, Okamoto Y, Rocha VZ, Folco E. Inflammation in atherosclerosis: transition from theory to practice. Circ J. 2010;74:213–220.
    1. Ikeda U. Inflammation and coronary artery disease. Curr Vasc Pharmacol. 2003;1:65–70.
    1. Heinisch RH, Zanetti CR, Comin F, Fernandes JL, Ramires JA, Serrano CV., Jr Serial changes in plasma levels of cytokines in patients with coronary artery disease. Vasc Health Risk Manag. 2005;1:245–250.
    1. Ridker PM. Inflammation, high-sensitivity C-reactive protein, and vascular protection. Tex Heart Inst J. 2010;37:40–41.
    1. Curtiss LK. Reversing atherosclerosis. N Eng J Med. 2009;360:1144–1146.
    1. Tillett WS, Francis T., Jr Serological reactions in pneumonia with a non-protein fraction of pneumococcus. J Exp Med. 1930;52:561–571.
    1. Norata GD, Marchesi P, Pulakazhi VK, et al. Deficiency of the long pentraxin PTX3 promotes vascular inflammation and atherosclerosis. Circulation. 2009;120:699–708.
    1. Hansson GK, Libby P, Schönbeck U, Yan ZQ. Innate and adaptive immunity in the pathogenesis of atherosclerosis. Circ Res. 2002;91:281–291.
    1. Abou-Raya A, Abou-Raya S. Inflammation: a pivotal link between autoimmune diseases and atherosclerosis. Autoimmun Rev. 2006;5:331–337.
    1. Sun J, Hartvigsen K, Chou M-Y, et al. Deficiency of antigen-presenting cell invariant chain reduces atherosclerosis in mice. Circulation. 2010;122:808–820.
    1. Okemefuna AI, Nan R, Miller A, Gor J, Perkins SJ. Complement factor H binds at two independent sites to C-reactive protein in acute phase concentrations. J Biol Chem. 2010;285:1053–1065.
    1. Bodman-Smith KB, Melendez AJ, Campbell I, Harrison PT, Allen JM, Raynes JG. C-reactive protein-mediated phagocytosis and phospholipase D signaling through the high-affinity receptor for immunoglobulin G (FcγRI) Immunology. 2002;207:252–260.
    1. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Eng J Med. 1999;340:448–454.
    1. Vigushin DM, Pepys MB, Hawkins PN. Metabolic and scintigraphic studies of radioiodinated human C-reactive protein in health and disease. J Clin Invest. 1993;91:1351–1357.
    1. Lau DC, Dhillon B, Yan H, Szmitko PE, Verma S. Adipokines: molecular links between obesity and atheroslcerosis. Am J Physiol Heart Circ Physiol. 2005;288:H2031–2041.
    1. Brull DJ, Serrano N, Zito F, et al. Human CRP gene polymorphism influences CRP levels: implications for the prediction and pathogenesis of coronary heart disease. Arterioscler Thromb Vasc Biol. 2003;23:2063–2069.
    1. Kathiresan S, Larson MG, Vasan RS, et al. Contribution of clinical correlates and 13 C-reactive protein gene polymorphisms to inter-individual variability in serum C-reactive protein level. Circulation. 2006;113:1415–1423.
    1. Shah T, Newcombe P, Smeeth L, et al. Ancestry as a determinant of mean population C-reactive protein values: implications for cardiovascular risk prediction. Circ Cardiovasc Genet. 2010;3:436–444.
    1. Rückerl R, Greven S, Ljungman P, et al. for the Airgene study. Air pollution and inflammation (interleukin-6, C-reactive protein, fibrinogen) in myocardial infarction survivors. Environ Health Perspect. 2007;115:1072–1080.
    1. King DE, Egan BM, Woolson RF, Mainous AG, III, Al-Solaiman Y, Jesri A. Effect of a high-fiber diet vs a fiber-supplemented diet on C-reactive protein level. Arch Intern Med. 2007;167:502–506.
    1. Bo S, Durazzo M, Guidi S, et al. Dietary magnesium and fiber intakes and inflammatory and metabolic indicators in middle-aged subjects from a population-based cohort. Am J Clinical Nutrition. 2006;84:1062–1069.
    1. King DE, Mainous AG, III, Egan BM, Woolson RF, Geesey ME. Effect of psyllium fiber supplementation on C-reactive protein: the trial to reduce inflammatory markers (TRIM) Ann Fam Med. 2008;6:100–106.
    1. Ajani UA, Ford ES, Mokdad AH. Dietary fiber and C-reactive protein: findings from national health and nutrition examination survey data. J Nutr. 2004;134:1181–1185.
    1. Zampelas A, Panagiotakos DB, Pitsavos C, et al. Associations between coffee consumption and inflammatory markers in healthy persons: the ATTICA study. Am J Clin Nutr. 2004;80:862–867.
    1. Cavicchia PP, Steck SE, Hurley TF, et al. A new dietary inflammatory index predicts interval changes in serum high-sensitivity C-reactive protein. J Nutr. 2009;139:2365–2372.
    1. Masters RC, Liese AD, Haffner SM, Wagenknecht LE, Hanley AJ. Whole and refined grain intakes are related to inflammatory protein concentrations in human plasma. J Nutr. 2010;140:587–594.
    1. Esmaillzadah A, Kimiagar M, Mehrabi Y, Azadbakht L, Hu FB, Willett WC. Fruit and vegetable intakes, C-reactive protein, and the metabolic syndrome. Am J Clin Nutr. 2006;84:1489–2497.
    1. Micallef MA, Munro IA, Garg ML. An inverse relationship between plasma n-3 fatty acids and C-reactive protein in healthy individuals. Eur J Clin Nutr. 2009;63:1154–1156.
    1. Yen ML, Yang CY, Yen BL, et al. Increased high sensitivity C-reactive protein and neutrophil count are related to increased standard cardiovascular risk factors in healthy Chinese men. Int J Cardiol. 2006;110:191–198.
    1. Danesh J, Wheeler JG, Hirschfield GM, et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med. 2004;350:1387–1397.
    1. Faber DR, van der Graaf Y, Westerink J, Visseren FLJ. Increased visceral adipose tissue mass is associated with increased C-reactive protein in patients with manifest vascular diseases. Atherosclerosis. 2010;212:274–280.
    1. Imhof A, Froehlich M, Brenner H, et al. Effect of alcohol consumption on systemic markers of inflammation. Lancet. 2001;357:763–767.
    1. Albert MA, Glynn RJ, Ridker PM. Alcohol consumption and plasma concentration of C-reactive protein. Circulation. 2003;107:443–447.
    1. Dreon DM, Slavin JL, Phinney SD. Oral contraceptive use and increased plasma concentration of C-reactive protein. Life Sci. 2003;73:1245–1252.
    1. Frohlich M, Muhlberger N, Hanke H, et al. Markers of inflammation in women on different hormone replacement therapies. Ann Med. 2003;35:353–361.
    1. Black S, Kushner I, Samols D. C-reactive protein. J Biol Chem. 2004;279:48487–48490.
    1. McDade TW, Rutherford JN, Adair L, Kuzawa C. Population differences in associations between C-reactive protein concentration and adiposity: comparison of young adults in the Philippines and the United States. Am J Clin Nutr. 2009;89:1237–1245.
    1. Russell AI, Cunninghame Graham DS, Shepherd C, et al. Polymorphism at the C-reactive protein locus influences gene expression and predisposes to systemic lupus erythematosus. Hum Mol Genet. 2004;13:137–147.
    1. Jönsen A, Gunnarsson I, Gullstrand B, et al. Association between SLE nephritis and polymorphic variants of the CRP and Fcgamma;RIIIa genes. Rheumatology (Oxford) 2007;46:1417–1421.
    1. Edberg JC, Wu J, Langefeld CD, et al. Genetic variation in the CRP promoter: association with systemic lupus erythematosus (SLE) Hum Mol Genet. 2008;17:1147–1455.
    1. Graf J, Scherzer R, Grunfeld C, Imboden J. Levels of C-reactive protein associated with high and very high cardiovascular risk are prevalent in patients with rheumatoid arthritis. PLoS ONE. 2009;4:e6242.
    1. Coventry BJ, Ashdown ML, Quinn MA, Markovic SN, Yatomi-Clarke SL, Robinson AP. CRP identifies homeostatic immune oscillations in cancer patients: a potential treatment targeting tool. J Transl Med. 2009;7:102.
    1. Morin-Papunen L, Rautio K, Ruokonen A, Hedberg P, Puukka M, Tapanainen JS. Metformin reduces serum C-reactive protein levels in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2003;88:4649–4654.
    1. Tosi F, Dorizzi R, Castello R, et al. Body fat and insulin resistance independently predict increased serum C-reactive protein in hyperandrogenic women with polycystic ovary syndrome. Eur J Endocrinol. 2009;161:737–745.
    1. Sathyapalan T, Kilpatrick ES, Coady AM, Atkin SL. The effect of atorvastatin in patients with polycystic ovary syndrome: a randomized double-blind placebo-controlled study. J Clin Endocrinol Metab. 2009;94:103–108.
    1. Hoeger KM. Polycystic ovary syndrome, inflammation and statins: do we have the right target. J Clin Endocrinol Metab. 2009;94:35–37.
    1. De Beer F, Soutar AK, Baltz ML, Trayner IM, Feinstein A, Pepys MB. Low density lipoprotein and very low density lipoprotein are selectively bound by aggregated C-reactive protein. J Exp Med. 1982;156:230–242.
    1. Zhang YX, Cliff WJ, Schoefl GI, Higgins G. Coronary C-reactive protein distribution: its relation to development of atherosclerosis. Atherosclerosis. 1999;145:375–379.
    1. Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation. 2000;102:2165–2168.
    1. Torzewski M, Rist C, Mortensen RF, et al. C-reactive protein in the arterial intima: role of C-reactive protein receptor-dependent monocyte recruitment in atherogenesis. Arterioscler Thromb Vasc Biol. 2000;20:2094–2099.
    1. Devaraj S, Davis B, Simon SI, Jialal I. CRP promotes monocyte-endothelial cell adhesion via Fcgamma;receptors in human aortic endothelial cells under static and shear flow conditions. Am J Physiol Heart Circ Physiol. 2006;291:H1170–1176.
    1. Rocker C, Manolov DE, Kuzmenkina EV, et al. Affinity of C-reactive protein toward FcgammaRI is strongly enhanced by the gamma-chain. Am J Pathol. 2007;170:755–763.
    1. Schwartz R, Osborne-Lawrence S, Hahner L, et al. C-reactive protein downregulates endothelial NO synthase and attenuates reendothelialization in vivo in mice. Circ Res. 2007;100:1452–1459.
    1. Szmitko PE, Verma S. C-reactive protein and reendothelialization: NO involvement. Circ Res. 2007;100:1405–1407.
    1. Xing D, Hage FG, Chen YF, et al. Exaggerated neointima formation in human C-reactive protein transgenic mice is IgG Fc receptor type 1 (Fc gamma RI)-dependent. Am J Pathol. 2008;172:22–30.
    1. Salio M, Chimenti S, de Angelis N, et al. Cardioprotective function of the long pentraxin PTX3 in acute myocardial infarction. Circulation. 2008;117:1055–1064.
    1. Van Vré EA, Bult H, Hoymans VY, van Tendeloo FI, Vrints CJ, Bosmans JM. Human C-reactive protein activates monocyte-derived dendritic cells and induces dendritic cell-mediated T-cell activation. Arterioscler Thromb Vasc Biol. 2008;28:511–518.
    1. Fujita Y, Kakino A, Nishimichi N, et al. Oxidized LDL receptor LOX-1 binds to C-reactive protein and mediates its vascular effects. Clin Chem. 2009;55:285–294.
    1. Filep JG. Platelets affect the structure and function of C-reactive protein. Circ Res. 2009;105:109–111.
    1. Jin C, Lu L, Zhang RY, et al. Association of serum glycated albumin, C-reactive protein and ICAM-1 levels with diffuse coronary artery disease in patients with type 2 diabetes mellitus. Clin Chim Acta. 2009;408:45–49.
    1. Ridker PM. C-reactive protein: eighty years from discovery to emergence as a major risk marker for cardiovascular disease. Clin Chem. 2009;55:209–215.
    1. Geluk CA, Post WJ, Hillege HL, et al. C-reactive protein and angiographic characteristics of stable and unstable coronary artery disease: data from the prospective PREVEND cohort. Atherosclerosis. 2008;196:372–382.
    1. Nabata A, Kuroki M, Ueba H, et al. C-reactive protein induces endothelial cell apoptosis and matrix metalloproteinase-9 production in human mononuclear cells: implications for the destabilization of atherosclerotic plaque. Atherosclerosis. 2008;196:129–135.
    1. Scirica BM, Cannon CP, Sabatine MS, et al. Concentrations of C-reactive protein and B-type natriuretic peptide 30 days after acute coronary syndromes independently predict hospitalization for heart failure and cardiovascular death. Clin Chem. 2009;55:265–273.
    1. Scirica BM, Morrow DA, Cannon CP, et al. Thrombolysis in Myocardial Infarction (TIMI) Study Group. Clinical application of C-reactive protein across the spectrum of acute coronary syndromes. Clin Chem. 2007;53:1800–1807.
    1. Scirica BM, Morrow DA. Is C-reactive protein an innocent bystander or proatherogenic culprit? The verdict is still out. Circulation. 2006;113:2128–2134.
    1. Verma S, Devaraj S, Jialal I. Is C-reactive protein an innocent bystander or proatherogenic culprit? C-reactive protein promotes atherothrombosis. Circulation. 2006;113:2135–2150.
    1. Jialal I, Verma S, Devaraj S. Inhibition of endothelial nitric oxide synthase by C-reactive protein: clinical relevance. Clin Chem. 2009;55:206–208.
    1. Guan H, Wang P, Hui R, Edin ML, Zeldin DC, Wang DW. Adeno-associated virus-mediated human C-reactive protein gene delivery causes endothelial dysfunction and hypertension in rats. Clin Chem. 2009;55:274–284.
    1. Radjesh J, Bisoendial S, Boekholdt M, Vergeer M, Stroes ESG, Kastelein JJP. C-reactive protein is a mediator of cardiovascular disease. Eur Heart J. 2010;31:2087–2091.
    1. Sinclair KA, Bogart A, Buchwald D, Henderson JA. The prevalence of metabolic syndrome and associated risk factors in Northern Plains and Southwest American Indians. Diabetes Care. 2010 Sep 23; [Epub ahead of print]
    1. Kearney MT. Targeting the endothelium to prevent diabetes-related atherosclerosis. Diab Vasc Dis Res. 2010;7:177.
    1. Ford ES, Giles WH, Myers GL, Mannino DM. Population distribution of high-sensitivity C-reactive protein among US men: findings from national health and nutrition examination survey 1999–2000. Clin Chem. 2003;49:686–690. .
    1. Centers for Disease Control and Prevention. NHANES 1999–2000 public data release file documentation. [Accessed 2010 Oct 18]. .
    1. Rifai N, Ridker PM. Population distributions of C-reactive protein in apparently healthy men and women in the United States: implication for clinical interpretation. Clin Chem. 2003;49:666–669.
    1. Woloshin S, Schwartz LM. Distribution of C-reactive protein values in the United States. N Eng J Med. 2005;352:1611–1613.
    1. Kushner I, Rzewnicki W, Samols D. What does minor elevation of C-reactive protein signify? Am J Med. 2006;119:166.e17–166.e28.
    1. Kao PC, Shiesh S-C, Wu TJ. Serum C-reactive protein as a marker for wellness assessment. Ann Clin Lab Sci. 2006;36:163–169.
    1. Koenig W, Sund M, Frohlich M, et al. C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation. 1999;99:237–242.
    1. Miller M, Zhan M, Havas S. High attributable risk of elevated C-reactive protein level to conventional coronary heart disease risk factors: the Third National Health and Nutrition Examination Survey. Arch Intern Med. 2005;165:2063–2068.
    1. Greenfield JR, Samaras K, Jenkins AB, et al. Obesity is an important determinant of baseline serum C-reactive protein concentration in monozygotic twins, independent of genetic influences. Circulation. 2004;109:3022–3028.
    1. Currie CJ, Poole CD, Conway P. Evaluation of the association between the first observation and the longitudinal change in C-reactive protein, and all-cause mortality. Heart. 2008;94:457–462.
    1. Marsik C, Kazemi-Shirazi L, Schickbauer T, et al. C-reactive protein and all-cause mortality in a large hospital-based cohort. Clin Chem. 2008;54:343–349.
    1. Kravitz BA, Corrada MM, Kawas CH. High levels of serum C-reactive protein are associated with greater risk of all-cause mortality, but not dementia, in the oldest-old: results from the 90+ study. J Am Ger Soc. 2009;57:641–646.
    1. Wassel CL, Barrett-Connor E, Laughlin GA. Association of circulating C-reactive protein and interleukin-6 with longevity into the 80s and 90s: The Rancho Bernardo Study. J Clin Endocrinol Metab. 2010;95:4748–4755.
    1. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002;347:1557–1565.
    1. Diaz JJ, Arguelles J, Malaga I, et al. C-reactive protein is elevated in the offspring of parents with essential hypertension. Arch Dis Child. 2007;92:304–308.
    1. Mancia G, de Backer G, Dominiczak A, et al. Guidelines for the management of arterial hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC) Eur Heart J. 2007;2007;28:1462–1536.
    1. Ridker PM, Danielson E, Rifai N, Glynn RJ. Valsartan, blood pressure reduction, and C-reactive protein: primary report of the Val-MARC trial. Hypertension. 2006;48:73–79.
    1. Sesso HD, Buring JE, Rifai N, Blake GJ, Gaziano JM, Ridker PM. C-reactive protein and the risk of developing hypertension. JAMA. 2003;290:2945–2951.
    1. Sathiyapriya V, Nandeesha H, Selvaraj N, Bobby Z, Agrawal A, Pavithran P. Association between protein-bound sialic acid and high-sensitivity C-reactive protein in essential hypertension: a possible indication of underlying cardiovascular risk. Angiology. 2009;59:721–726.
    1. Lande MB, Pearson TA, Vermilion RP, Auinger P, Fernandez ID. Elevated blood pressure, race/ethnicity, and C-reactive protein levels in children and adolescents. Pediatrics. 2008;122:1252–1257.
    1. Black GJ, Rifai N, Buring JE, Ridker PM. Blood pressure, C-reactive protein, and risk of future cardiovascular events. Circulation. 2003;108:2993–2999.
    1. Perticone F, Maio R, Sciacqua A, et al. Enodthelial dysfunction and C-reactive protein are risk factors for diabetes in essential hypertension. Diabetes. 2008;57:167–171.
    1. Vardas PE, Marketou ME. CRP in non-dippers: new perspectives and old queries. J Human Hypertension. 2008;22:447–449.
    1. Veerabhadrappa P, Diaz KM, Feairheller DL, et al. Enhanced blood pressure variability in a high cardiovascular risk group of African Americans: FIT4 Life Study. J Am Soc Hypertens. 2010;4:187–195.
    1. Iijima R, Byrne RA, Ndrepepa G, et al. Pre-procedural C-reactive protein levels and clinical outcomes after percutaneous coronary interventions with and without abciximab: pooled analysis of four ISAR trials. Heart. 2009;95:107–112.
    1. Ishii H, Toriyama T, Aoyama T, et al. Prognostic values of C-reactive protein levels on clinical outcome after implantation of sirolimuseluting stents in patients on hemodialysis. Circ Cardiovasc Interv. 2009;2:513–518.
    1. Iliodromitis EK, Kyrzopoulos S, Paraskevaidis IA, et al. Increased C reactive protein and cardiac enzyme levels after coronary stent implantation. Is there protection by remote ischaemic preconditioning. Heart. 2006;92:1821–1826.
    1. Kangasniemi OP, Biancari F, Luukkonen J, et al. Preoperative C-reactive protein is predictive of long-term outcome after coronary artery bypass surgery. Eur J Cardiothorac Surg. 2006;29:983–985.
    1. Wypasek E, Undas A, Sniezek-Maciejewska M, et al. The increased plasma C-reactive protein and interleukin-6 levels in patients under-going coronary artery bypass grafting surgery are associated with the interleukin-6-174G. C gene polymorphism. Ann Clin Biochem. 2010;47:343–349.
    1. Lo B, Fijnheer R, Nierich AP, Bruins P, Kalkman CJ. C-reactive protein is a risk indicator for atrial fibrillation after myocardial revascularization. Ann Thorac Surg. 2005;79:1530–1535.
    1. Kardys I, Knetsch AM, Bleumink GS, et al. C-reactive protein and risk of heart failure. The Rotterdam Study. Am Heart J. 2006;152:514–520.
    1. Williams ES, Shah SJ, Ali S, Na BY, Schiller NB, Whooley MA. C-reactive protein, diastolic dysfunction, and risk of heart failure in patients with coronary disease: Heart and Soul Study. Eur J Heart Fail. 2008;10:63–69.
    1. Braunwald E. Biomarkers in heart failure. N Engl J Med. 2008;358:2148–2159.
    1. Bozkurt B, Mann DL, Deswal A. Biomarkers of inflammation in heart failure. Heart Fail Rev. 2010;15:331–341.
    1. Araujo JP, Lourenco P, Azevedo A, et al. Prognostic value of high-sensitivity C-reactive protein in heart failure: a systematic review. J Cardiac Fail. 2009;15:256–266.
    1. Collinson PO. Concentrations of C-reactive protein and B-type natriuretic peptide 30 days after acute coronary syndromes independently predict hospitalization for heart failure and cardiovascular death: just another brick in the wall. Clin Chem. 2009;55:203–205.
    1. Lamblin N, Mouquet F, Hennache B, et al. High-sensitivity C-reactive protein: potential adjunct for risk stratification in patients with stable congestive heart failure. Eur Heart J. 2005;26:2245–2250.
    1. Anand IS, Latini R, Florea VG, et al. C-reactive protein in heart failure: prognostic value and the effect of valsartan. Circulation. 2005;112:1428–1434.
    1. Vasan RS, Sullivan LM, Roubenoff R, et al. Inflammatory markers and risk of heart failure in elderly subjects without prior myocardial infarction: the Framingham Heart Study. Circulation. 2003;107:1486–1491.
    1. Conen D, Rexrode KM, Creager MA, Ridker PM, Pradhan AD. Metabolic syndrome, inflammation, and risk of symptomatic peripheral artery disease in women: a prospective study. Circulation. 2009;120:1041–1047.
    1. Pande RL, Perlstein TS, Beckman JA, Creager MA. Association of insulin resistance and inflammation with peripheral arterial disease: the National Health and Nutrition Examination Survey, 1999 to 2004. Circulation. 2008;118(1):33–41.
    1. Schlager O, Exner M, Mlekusch W, et al. C-reactive protein predicts future cardiovascular events in patients with carotid stenosis. Stroke. 2007;38:1263–1268.
    1. Albert CM, Ma J, Rifai N, et al. Prospective study of C-reactive protein, homocysteine, and plasma lipid levels as predictors of sudden cardiac death. Circulation. 2002;4(105):2595–2599.
    1. Spooner PM, Zipes DP. Sudden death predictors: an inflammatory association. Circulation. 2002;105:2574–2576.
    1. Beri A, Contractor T, Khasnis A, Thakur R. Statins and the reduction of sudden cardiac death: antiarrhythmic or anti-ischemic effect. Am J Cardiovasc Drugs. 2010;10:155–164.
    1. Corbalán R, Braun S, Pereira J, Navarrete C, Gonzalez I. C-reactive protein and atrial fibrillation: evidence for the presence of inflammation in the perpetuation of the arrhythmia. Int J Cardiol. 2006;108:326–331.
    1. Conen D, Ridker PM, Everett BM, et al. A multimarker approach to assess the influence of inflammation on the incidence of atrial fibrillation in women. Eur Heart J. 2010;31:1730–1736.
    1. Marott SCW, Nordestgaard BG, Zacho J, et al. Does elevated C-reactive protein increase atrial fibrillation risk? A mendelian randomization of 47,000 individuals from the general population. J Am Coll Cardiol. 2010;56:789–795.
    1. Blangy H, Sadoul N, Dousset B, et al. Serum BNP, hs-C-reactive protein, procollagen to assess the risk of ventricular tachycardia in ICD recipients after myocardial infarction. Europace. 2007;9:724–729.
    1. Jeevanantham V, Singh N, Izuora K, D’souza JP, His DH. Correlation of high sensitivity C-reactive protein and calcific aortic valve disease. Mayo Clin Proc. 2007;82:171–174.
    1. Jones P, Davidson M, Stein E, et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial) Am J Cardiol. 2003;92:152–160.
    1. Ay C, Tengler T, Vormittag R, et al. Venous thromboembolism a manifestation of the metabolic syndrome. Haematologica. 2007;92:374–380.
    1. Quarck R, Nawrot T, Meyns B, Delcroix M. C-reactive protein a new predictor of adverse outcome in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;53:1211–1218.
    1. Soinio M, Marniemi J, Laakso M, et al. High-sensitivity C-reactive protein and coronary heart disease mortality in patients with type 2 diabetes: a 7-year follow-up study. Diabetes Care. 2006;29:329–333.
    1. Marcovecchio ML, Giannini C, Widmer B, et al. C-reactive protein in relation to the development of microalbuminuria in type 1 diabetes. Diabetes Care. 2008;31:974–976.
    1. Dehghan A, Kardys I, de Maat MPM, et al. Genetic variation, C-reactive protein levels, and incidence of diabetes. Diabetes. 2007;56:872–878.
    1. Kahn SE, Zinman B, Haffner SM, et al. Obesity is a major determinant of the association of C-reactive protein levels and the metabolic syndrome in type 2 diabetes. Diabetes. 2006;55:2357–2364.
    1. Goldberg RB. Cytokine and cytokine-like inflammation markers, endothelial dysfunction, and imbalanced coagulation in development of diabetes and its complications. J Clin Endocrinol Metab. 2009;94:3171–3182.
    1. Ridker PM, Pare G, Parker A, et al. Loci related to metabolic-syndrome pathways including LEPR, HNF1A, IL6R, and GCKR associate with plasma C-reactive protein: the Women’s Genome Health Study. Am J Hum Genet. 2008;82:1185–1192.
    1. Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14,719 initially healthy American women. Circulation. 2003;107:391–397.
    1. Moreno-Navarrete JM, Martinez-Barricarte R, Catalan V, et al. Complement factor H is expressed in adipose tissue in association with insulin resistance. Diabetes. 2010;59:200–209.
    1. Jialal I. The role of the laboratory in the diagnosis of the metabolic syndrome. Am J Clin Pathol. 2009;132(2):161–162.
    1. Steinberger J, Daniels SR, Eckel RH, et al. American Heart Association Atherosclerosis, Hypertension, and Obesity in the Young Committee of the Council on Cardiovascular Disease in the Young; Council on Cardiovascular Nursing; and Council on Nutrition, Physical Activity, and Metabolism. Progress and challenges in metabolic syndrome in children and adolescents: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in the Young Committee of the Council on Cardiovascular Disease in the Young; Council on Cardiovascular Nursing; and Council on Nutrition, Physical Activity, and Metabolism. Circulation. 2009;119:628–647.
    1. Cornier MA, Dabelea D, Hernandez TL, et al. The metabolic syndrome. Endocr Rev. 2008;29:777–822.
    1. Suzuki T, Katz R, Jenny NS, et al. Metabolic syndrome, inflammation, and incident heart failure in the elderly: the Cardiovascular Health Study. Circ Heart Fail. 2008;1:242–248.
    1. You T, Nicklas BJ, Ding J, et al. The metabolic syndrome is associated with circulating adipokines in older adults across a wide range of adiposity. J Gerontol A Biol Sci Med Sci. 2008;63:414–419.
    1. Dai DF, Lin JW, Kao JH, et al. The effects of metabolic syndrome versus infectious burden on inflammation, severity of coronary atherosclerosis, and major adverse cardiovascular events. J Clin Endocrinol Metab. 2007;92:2532–2537.
    1. Ye X, Yu Z, Li H, Franco OH, Liu Y, Lin X. Distributions of C-reactive protein and its association with metabolic syndrome in middle-aged and older Chinese people. J Am Coll Cardiol. 2007;49:1798–1805.
    1. Pitsavos C, Panagiotakos DB, Tzima N, et al. Diet, exercise, and C-reactive protein levels in people with abdominal obesity: the ATTICA epidemiological study. Angiology. 2007;58:225–233.
    1. Devaraj S, Valleggi D, Siegel D, Jialal I. Role of C-reactive protein in contributing to increased cardiovascular risk in metabolic syndrome. Curr Atheroscler Rep. 2010;12:110–118.
    1. Wang A, Nakayama T. Inflammation, a link between obesity and cardiovascular disease. Mediators Inflamm. 2010;2010:535918.
    1. Alyan O, Metin F, Kacmaz F, et al. High levels of high sensitivity C-reactive protein predict the progression of chronic rheumatic mitral stenosis. J Thromb Thrombolysis. 2009;28:63–69.
    1. Lee HM, Le TV, Lopez VA, Wong ND. Association of C-reactive protein with reduced forced vital capacity in a nonsmoking US population with metabolic syndrome and diabetes. Diabetes Care. 2008;31:2000–2002.
    1. Magnussen H, Watz H. Systemic inflammation in chronic obstructive pulmonary disease and asthma: relation with comorbidities. Proc Am Thorac Soc. 2009;6:648–651.
    1. Eickhoff P, Valipour A, Kiss D, et al. Determinants of systemic vascular function in patients with stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2008;178:1211–1218.
    1. Wahba IM, Mak RH. Obesity and obesity-initiated metabolic syndrome: mechanistic links to chronic kidney disease. J Am Soc Nephrol. 2007;2:550–562.
    1. Chen HY, Chiu YL, Hsu SP, et al. Elevated C-reactive protein level in hemodialysis patients with moderate/severe uremic pruritus: a potential mediator of high overall mortality. QJM. 2010;103:837–846.
    1. Lahrach H, Ghalim N, Taki H, et al. Serum paraoxonase activity, high-sensitivity C-reactive protein, and lipoprotein disturbances in end-stage renal disease patients on long-term hemodialysis. J Clin Lipidol. 2008;2:43–50.
    1. Lui MM, Lam JC, Mak HK-F, et al. C-reactive protein is associated with obstructive sleep apnea independent of visceral obesity. Chest. 2009;135:950–956.
    1. Schiza SE, Mermigkis C, Panagiotis, et al. C-reactive protein evolution in obstructive sleep apnoea patients under CPAP therapy. Eur J Clin Invest. 2010;40:968–975.
    1. Zeka A, Sullivan JR, Vokonas PS, Sparrow D, Schwartz J. Inflammatory markers and particulate air pollution: characterizing the pathway to disease. Int J Epidemiol. 2006;35:1347–1354.
    1. Dixon JB, Hayden MJ, Lambert GW, et al. Raised CRP Levels in obese patients: symptoms of depression have an independent positive association. Obesity. 2008;16:2010–2015.
    1. Hak AE, Stehouwer CD, Bots ML, et al. Associations of C-reactive protein with measures of obesity, insulin resistance, and subclinical atherosclerosis in healthy, middle-aged women. Arterioscler Thromb Vasc Biol. 1999;19:1986–1991.
    1. McLaughlin T, Abbasi F, Lamendola C, et al. Differentiation between obesity and insulin resistance in the association with C-reactive protein. Circulation. 2002;106:2908–2912.
    1. Wee CC, Mukamal KJ, Huang A, Davis RB, McCarthy EP, Mittleman MA. Obesity and C-reactive protein levels among white, black, and hispanic US adults. Obesity. 2008;16:875–880.
    1. Skinner AC, Steiner MJ, Henderson FW, Perrin EM. Multiple markers of inflammation and weight status: cross-sectional analyses throughout childhood. Pediatrics. 2010;125:e801–e809.
    1. Puglisi MJ, Fernandez ML. Modulation of C-reactive protein, tumor necrosis factor α, and adiponectin by diet, exercise, and weight loss. J Nutr. 2008;138:2293–2296.
    1. Sacheck J. Pediatric obesity: an inflammatory condition. JPEN J Parenter Enteral Nutr. 2008;32:633–637.
    1. Rankin JW, Turpyn AD. Low carbohydrate, high fat diet increases C-reactive protein during weight loss. J Am Coll Nutr. 2007;26:163–169.
    1. Selvin E, Paynter NP, Erlinger TP. The effect of weight loss on C-reactive protein: a systematic review. Arch Intern Med. 2007;167:31–39.
    1. Pope CA., III Particulate air pollution, C-reactive protein, and cardiac risk. Eur Heart J. 2001;22:1149–1150.
    1. Nicklas BJ, You T, Pahor M. Behavioural treatments for chronic systemic inflammation: effects of dietary weight loss and exercise training. CMAJ. 2005;172:1199–1209.
    1. Gentile M, Panico S, Rubba F, et al. Obesity, overweight, and weight gain over adult life are main determinants of elevated hs- CRP in a cohort of Mediterranean women. Eur J Clin Nutr. 2010;64:873–878.
    1. Hamer M, Steptoe A. Prospective study of physical fitness, adiposity, and inflammatory markers in healthy middle-aged men and women. Am J Clin Nutr. 2009;89:85–89.
    1. Welsh P, Polisecki E, Robertson M, et al. Unraveling the directional link between adiposity and inflammation: a bidirectional Mendelian randomization approach. J Clin Endocrinol Metab. 2010;95:93–99.
    1. Hubel CA, Powers RW, Snaedal S, et al. C-reactive protein is elevated 30 years after eclamptic pregnancy. Hypertension. 2008;51:1499–1505.
    1. Lau B, Sharrett SR, Kingsley LA, et al. C-reactive protein is a marker for human immunodeficiency virus disease progression. Arch Intern Med. 2006;166:64–70.
    1. Surtees PG, Wainwright NWJ, Boekholdt SM, Luben RN, Wareham NJ, Khaw KT. Major depression, C-reactive protein, and incident ischemic heart disease in healthy men and women. Psychosom Med. 2008;70:850–855.
    1. Ridker PM. High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation. 2001;103:1813–1818.
    1. Pankow JS, Folsom AR, Cushman M, et al. Familial and genetic determinants of systemic markers of inflammation: the NHLBI family heart study. Atherosclerosis. 2001;154:681–689.
    1. Lee CC, You NC, Song Y, et al. Relation of genetic variation in the gene coding for C-reactive protein with its plasma protein concentrations: findings from the Women’s Health Initiative Observational Cohort. Clin Chem. 2009;55(2):351–360.
    1. Kelley-Hedgepeth A, Lloyd-Jones DM, Colvin A, et al. Ethnic differences in C-reactive protein concentrations. Clin Chem. 2008;54:1027–1037.
    1. Smith GD, Ebrahim S. Mendelian randomization: can genetic epidemiology contribute to understanding environmental determinants of disease. Int J Epidemiol. 2003;32:1–22.
    1. Zacho J, Tybjaerg-Hansen A, Jensen JS, Grande P, Sillesen H, Nordestgaard BG. Genetically elevated C-reactive protein and ischemic vascular disease. N Engl J Med. 2008;359:1897–1908.
    1. Smith DG. Capitalizing on Mendelian randomization to assess the effects of treatments. J R Soc Med. 2007;100:432–435.
    1. Sheehan NA, Didelez V, Burton PR, Tobin MD. Mendelian randomisation and causal inference in observational epidemiology. PLoS Med. 2008;5:e177.
    1. Elliott P, Chambers JC, Zhang W, et al. Genetic loci associated with C-reactive protein levels and risk of coronary heart disease. JAMA. 2009;302:37–48.
    1. Smith GD, Ebrahim S. Mendelian randomization: prospects, potentials, and limitations. Int J Epidemiol. 2004;33:30–42.
    1. Emerging Risk, Factors Collaboration, Kaptoge S, Di Angelantonio E, Lowe G, et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet. 2010;375:132–140.
    1. Danesh J, Kaptoge S, Mann AG, et al. Long-term interleukin-6 levels and subsequent risk of coronary heart disease: two new prospective studies and a systematic review. PLoS Med. 2008;5:e78.
    1. Clarke R, Emberson JR, Breeze E, et al. Biomarkers of inflammation predict both vascular and non-vascular mortality in older men. Eur Heart. 2008;29:800–809.
    1. Heikkila K, Harris R, Lowe G, et al. Associations of circulating C-reactive protein and interleukin-6 with cancer risk: findings from two prospective cohorts and a meta-analysis. Cancer Causes Control. 2009;20:15–26.
    1. Habersberger J, Eisenhardt S, Peter K. C-reactive protein measurement and cardiovascular disease. Original Text. Lancet. 2010;9720:1078.
    1. Ji SR, Wu Y, Zhu L, et al. Cell membranes and liposomes dissociate C-reactive protein (CRP) to form a new, biologically active structural intermediate: mCRP(m) FASEB J. 2007;21:284–294.
    1. Molins B, Pena E, Vilahur G, Mendieta C, Slevin M, Badimon L. C-reactive protein isoforms differ in their effects on thrombus growth. Arterioscler Thromb Vasc Biol. 2008;28:2239–2246.
    1. Eisenhardt SU, Habersberger J, Murphy A, et al. Dissociation of pentameric to monomeric C-reactive protein on activated platelets localizes inflammation to atherosclerotic plaques. Circ Res. 2009;105:128–137.
    1. Ji SR, Ma L, Bai CJ, et al. Monomeric C-reactive protein activates endothelial cells via interaction with lipid raft microdomains. FASEB J. 2009;23:1806–1816.
    1. Ridker PM, Rifai N, Clearfield M, et al. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med. 2001;344:1959–1965.
    1. Tuzcu EM, Kapadia SR, Tutar E, et al. High prevalence of coronary atherosclerosis in asymptomatic teenagers and young adults: evidence from intravascular ultrasound. Circulation. 2001;103:2705–2710.
    1. Ridker PM, Cannon CP, Morrow D, et al. Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT – TIMI 22) Investigators. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352:20–28.
    1. De Beer FC, Hind CR, Fox KM, et al. Measurement of serum C-reactive protein concentration in myocardial ischaemia and infarction. Br Heart J. 1982;47:239–243.
    1. Haverkate F, Thompson SG, Pyke SD, et al. Production of C-reactive protein and risk of coronary events in stable and unstable angina. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Lancet. 1997;349:462–466.
    1. Niccoli G, Biasucci LM, Biscione C, et al. Independent prognostic value of C-reactive protein and coronary artery disease extent in patients affected by unstable angina. Atherosclerosis. 2008;196:779–785.
    1. Ridker PM, Cushman M, Stampfer MJ, et al. Plasma concentration of C-reactive protein and risk of developing peripheral vascular disease. Circulation. 1998;97:425–428.
    1. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med. 2005;352:29–38.
    1. Hemingway H, Philipson P, Chen R, Fitzpatrick NK, Damant J, et al. Evaluating the quality of research into a single prognostic biomarker: a systematic review and meta-analysis of 83 studies of C-reactive protein in stable coronary artery disease. PLoS Med. 2010;7:e1000286.
    1. Boekholdt SM, Hack CE, Sandhu MS, et al. C-reactive protein levels and coronary artery disease incidence and mortality in apparently healthy men and women: the EPIC-Norfolk prospective population study 1993–2003. Atherosclerosis. 2006;187:415–422.
    1. Cook NR, Buring JE, Ridker PM. The effect of including C-reactive protein in cardiovascular risk prediction models for women. Ann Intern Med. 2006;145:21–29.
    1. Genest J, McPherson R, Frohlich J, et al. Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult – 2009 recommendations. Can J Cardiol. 2009;2009;25:567–579.
    1. Albert MA, Glynn RJ, Ridker PM. Plasma concentration of C-reactive protein and the calculated Framingham Coronary Heart Disease Risk Score. Circulation. 2003;108:161–165.
    1. Ridker PM, Rifai N, Cook NR, Bradwin G, Buring JE. Non-HDL cholesterol, apolipoproteins A-I and B100, standard lipid measures, lipid ratios, and CRP as risk factors for cardiovascular disease in women. JAMA. 2005;294:326–333.
    1. Shah T, Casas JP, Cooper JA, et al. Critical appraisal of CRP measurement for the prediction of coronary heart disease events: new data and systematic review of 31 prospective cohorts. Int J Epidemiol. 2009;38:217–231.
    1. Wald DS, Kasturiratne A, Bestwick JP. The value of C-reactive protein in screening for future coronary heart disease events. J Med Screen. 2009;16:212–214.
    1. Lakoski SG, Greenland P, Wong ND, Schreiner PJ, et al. Coronary artery calcium scores and risk for cardiovascular events in women classified as “low risk” based on Framingham risk score: the Multi- Ethnic Study of Atherosclerosis (MESA) Arch Intern Med. 2007;167:2437–2442.
    1. Ridker PM, Buring JE, Rifai N, Cook NR. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score. JAMA. 2007;297:611–619.
    1. Wilson PW, Pencina M, Jacques P, Selhub J, D’Agostino R, Sr, O’Donnell CJ. C-reactive protein and reclassification of cardiovascular risk in the Framingham Heart Study. Circ Cardiovasc Qual Outcomes. 2008;1:92–97.
    1. Ridker PM, Paynter NP, Rifai N, Gaziano JM, Cook NR. C-reactive protein and parental history improve global cardiovascular risk prediction: the Reynolds Risk Score for Men. Circulation. 2008;118:2243–2251.
    1. Cook NR. The case for C-reactive protein as a risk marker for coronary heart disease. Ann Intern Med. 2010;152:406.
    1. Cook NR, Ridker PM. Advances in measuring the effect of individual predictors of cardiovascular risk: the role of reclassification measures. Ann Intern Med. 2009;50:795–802.
    1. Ridker PM, MacFadyen J, Libby P, Glynn RJ. Relation of baseline high-sensitivity C-reactive protein level to cardiovascular outcomes with rosuvastatin in the Justification for Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) Am J Cardiol. 2010;106:204–209.
    1. Slejko JF, Page RL, II, Sullivan PW. Implications of Jupiter prevention in adults with elevated C-reactive protein: statin therapy is cost-effective for vascular event. J Am Coll Cardiol. 2010;55:A131.E1229.
    1. Rao AD, Milbrandt EB. To JUPITER and beyond: statins, inflammation, and primary prevention. Critical Care. 2010;14:310.
    1. MacDonald GP. Cost-effectiveness of rosuvastatin for primary prevention of cardiovascular events according to Framingham Risk Score in patients with elevated C-reactive protein. J Am Osteopath Assoc. 2010;110:427–436.
    1. Danesh J, Collins R, Appleby P, Peto R. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. JAMA. 1998;279:1477–1482.
    1. Danesh J, Whincup P, Walker M, et al. Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. BMJ. 2000;321:199–204.
    1. Nambi V, Ballantyne CM. Utility of statin therapy using high- sensitivity C-reactive protein as an indicator of coronary heart disease risk. Curr Atheroscler Rep. 2005;7:22–28.
    1. Ridker PM. High-sensitivity C-reactive protein and cardiovascular risk: rationale for screening and primary prevention. Am J Cardiol. 2003;92:17K–22K.
    1. Roche VF. Antihyperlipidemic statins: a self-contained, clinically relevant medicinal chemistry lesson. Am J Pharm Educ. 2005;69:546–560.
    1. Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science. 2001;292:1160–1164.
    1. Hamelin BA, Turgeon J. Hydrophilicity/lipophilicity: relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors. Trends Pharmacol Sci. 1998;19:26–37.
    1. McTaggart F. Comparative pharmacology of rosuvastatin. Atheroscler Suppl. 2003;4:9–14.
    1. Kapur NK. Rosuvastatin: a highly potent statin for the prevention and management of coronary artery disease. Expert Rev Cardiovasc Ther. 2007;5:161–175.
    1. Holtzman CW, Wiggins BS, Spinler SA. Role of P-glycoprotein in statin drug interactions. Pharmacotherapy. 2006;26:1601–1607.
    1. Kostapanos MS, Haralampos J, Elisaf MS. Rosuvastatin-associated adverse effects and drug-drug interactions in the clinical setting of dyslipidemia. Am J Cardiovasc Drugs. 2010;10:11–28.
    1. Baigent C, Keech A, Kearney PM, et al. Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterollowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomized trials of statins. Lancet. 2005;366:1267–1278.
    1. McKenney JM. Pharmacologic options for aggressive low-density lipoprotein cholesterol lowering: benefits versus risks. Am J Cardiol. 2005;96:60E–66E.
    1. The Galaxy Program. [Accessed 2010 Oct 18]. .
    1. Crouse JR, III, Raichlen JS, Riley WA, et al. METEOR study group. Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis. JAMA. 2007;297:1344–1353.
    1. Crouse JR, III, Bots ML, Evans GW, et al. Does baseline carotid intima-media thickness modify the effect of rosuvastatin when compared with placebo on carotid intima-media thickness progression? The METEOR study. Eur J Cardiovasc Prev Rehabil. 2010;17:223–229.
    1. Kjekshus J, Apetrei E, Barrios V, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med. 2007;357:2248–2261.
    1. McMurray JJV, Kjekshus J, Gullestad L, et al. CORONA Study Group. Effects of statin therapy according to plasma high-sensitivity C-reactive protein concentration in the Controlled Rosuvastatin Multinational trial in Heart Failure (CORONA). A retrospective analysis. Circulation. 2009;120:2188–2196.
    1. Gissi-HF Investigators, Tavazzi L, Maggioni AP, Marchioli R, et al. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:1231–1239.
    1. Van der Harst P, de Boer RA. Statins in the treatment of heart failure. Circ Heart Fail. 2010;3:462–464.
    1. Fellström BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Eng J Med. 2009;373:1175–1182.
    1. Narla V, Blaha MJ, Blumenthal RS, Michos ED. The JUPITER and AURORA clinical trials for rosuvastatin in special primary prevention populations: perspectives, outcomes, and consequences. Vasc Health Risk Manag. 2009;5:1033–1042.
    1. Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006;295:1556–1565.
    1. Ballantyne CM, Raichlen JS, Nicholls S, et al. ASTEROID Investigators. Effect of rosuvastatin therapy on coronary artery stenoses assessed by quantitative coronary angiography: a study to evaluate the effect of rosuvastatin on intravascular ultrasound-derived coronary atheroma burden. Circulation. 2008;117:2458–2466.
    1. Mack WJ, Xiang M, Selzer RH, Hodis HN. Serial quantitative coronary angiography and coronary events. Am Heart J. 2000;139:993–999.
    1. Buchwald H, Matts JP, Fitch LL, et al. Program on the Surgical Control of the Hyperlipidemias (POSCH) Group. Changes in sequential coronary arteriograms and subsequent coronary events. JAMA. 1992;268:1429–1433.
    1. Fonseca FAH, Izar MCO. Primary prevention of vascular events in patients with high levels of C-reactive protein: the JUPITER Study. Expert Rev Cardiovasc Ther. 2009;7:1041–1056.
    1. Libby P, Ridker PM. Novel inflammatory markers of coronary risk: theory versus practice. Circulation. 1999;100:1148–1150.
    1. Lemieux I, Pascot A, Prud’homme D, Almeras N, et al. Elevated C-reactive protein: another component of the atherothrombotic profile of abdominal obesity. Arterioscler Thromb Vasc Biol. 2001;21:961–967.
    1. Ridker PM, Rifai N, Pfeffer MA, et al. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators. Circulation. 1998;98:839–844.
    1. Ridker PM JUPITER Study Group. Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial. Circulation. 2003;108:2292–2297.
    1. Ridker PM, Fonseca FAH, Genest J, et al. JUPITER Trial Study Group. Baseline characteristics of participants in the JUPITER Trial, a randomized placebo-controlled primary prevention trial of statin therapy among individuals with low low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein. Am J Cardiol. 2007;100:1659–1664.
    1. De Lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle N. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction – final report of the Lyon Diet Heart Study. Circulation. 1999;99:779–785.
    1. Rembold CM. To statin or to non-statin in coronary disease – considering absolute risk is the answer. Atherosclerosis. 2007;195:1–6.
    1. Everett BM, Ridker PM. Using inflammatory biomarkers to guide lipid therapy. Curr Cardiovasc Risk Reports. 2008;2:29–34.
    1. Kritek P, Campion EW. JUPITER Clinical Directions – polling results. N Eng J Med. 2009;360:e14.
    1. Spatz ES, Canavan ME, Desai MM. From here to JUPITER. Identifying new patients for statin therapy using data from the 1999–2004 National Health and Nutrition Examination Survey. Circ Qual Outcomes. 2009;2:41–48.
    1. Michos ED, Blumenthal RS. Prevalence of the JUPITER ( Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin) Study. J Am Coll Cardiol. 2009;53:931–935.
    1. Ridker PM. The JUPITER trial. Results, controversies, and implications for prevention. Circ Cardiovasc Qual Outcomes. 2009;2:279–285.
    1. Ridker PM, MacFadyen JG, Fonseca FAH, et al. JUPITER Study Group. Number needed to treat with rosuvastatin to prevent first cardiovascular events and death among men and women with low low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein. Justification for the Use of statins in Prevention: an Intervention Trial Evaluation Rosuvastatin (JUPITER) Circ Cardiovasc Qual Outcomes. 2009;2:616–623.
    1. Yang EY, Nambi V, Tang Z, et al. Clinical implications of JUPITER (Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) in a US population: insights from the ARIC (Atherosclerosis Risk in Communities) study. J Am Coll Cardiol. 2009;54:2388–2395.
    1. Vaccarino V, Bremmer JD, Kelley ME. JUPITER. A few words of caution. Circ Cardiovasc Qual Outcomes. 2009;2:286–288.
    1. Kones R. Recent advances in the management of chronic stable angina. II. Anti-ischemic therapy, options for refractory angina, risk factor reduction, and revascularization. Vasc Health Risk Manag. 2010;6:749–774.
    1. Eyre H, Kahn R, Robertson RM. Preventing cancer, cardiovascular disease, and diabetes: a common agenda for the American Cancer Society, the American Diabetes Association, and the American Heart Association. Diabetes Care. 2004;27:1812–1824.
    1. Levi J, Segal LM, Juliano C. Prevention for a healthier America: investments in disease prevention yield significant savings, stronger communities: Trust for America’s Health. [Accessed 2010 Sep 1]. Issue Report 2008 Jul.
    1. Heart Protection Study Collaborative Group. Statin cost-effectiveness in the United States for people at different vascular risk levels. Circ Cardiovasc Qual Outcomes. 2009;2:65–72.
    1. Accad M, Fred HL. Is JUPITER also a God of primary prevention. Tex Heart Inst J. 2010;37:6–7.
    1. Kappagoda CT, Amsterdam EA. Another look at the results of the JUPITER trial. Am J Cardiol. 2009;104:1603–1605.
    1. Ridker PM, Danielson E, Fonseca FA, et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet. 2009;373:1175–1182.
    1. Despres JP. Bringing JUPITER down to Earth. Lancet. 2009;373:1147–1148.
    1. Kostapanos MS, Milionis HJ, Elisaf MS. An overview of the extra-lipid effects of rosuvastatin. J Cardiovasc Pharmacol Ther. 2008;13:157–174.
    1. Kendrick M. Should women be offered cholesterol lowering drugs to prevent cardiovascular disease? No. BMJ. 2007;334:983.
    1. Eisenberg T, Wells M. Statins and adverse cardiovascular events in moderate-risk females: a statistical and legal analysis with implications for FDA preemption claims. J Empir Leg Stud. 2008;5:507–550.
    1. Rosenberg H, Allard D. Women and statin use: a women’s health advocacy perspective. Scand Cardiovasc J. 2008;42:268–273.
    1. Mora S, Glynn RJ, Hsia J, MacFadyen JG, Genest J, Ridker PM. Statins for the primary prevention of cardiovascular events in women with elevated high-sensitivity C-reactive protein or dyslipidemia: results from the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) and meta-analysis of women from primary prevention trials. Circulation. 2010;121:1069–1077.
    1. Duvernoy CS, Blumenthal R. The numbers are in: statins for the primary prevention of cardiovascular disease in women. Circulation. 2010;121:1063–1065.
    1. Highlights of prescribing information: Crestor (rosuvastatin calcium) tablets. [Accessed 2010 Apr 16]. .
    1. Kaul S, Morrissey RP, Diamond GA. By Jove! What is a clinician to make of JUPITER. Arch Int Med. 2010;170:1073–1077.
    1. Jupiter criticism addressed again in more detail. 2010. Oct 1, [Accessed 2010 Oct 15]. .
    1. Bassler D, Briel M, Montori VM, et al. STOPIT-2 Study Group. Stopping randomized trials early for benefit and estimation of treatment effects: systematic review and meta-regression analysis. JAMA. 2010;303:1180–1187.
    1. Montori VM, Devereaux PJ, Adhikari NKJ, et al. Randomized trials stopped early for benefit: a systematic review. JAMA. 2005;294:2203–2209.
    1. Pocock SJ. Current controversies in data monitoring for clinical trials. Clin Trials. 2006;3:513–521.
    1. McCatney M. Leaping to conclusions. BMJ. 2008;336:1213–1214.
    1. Department of Health and Human Services, United States Food and Drug Administration, Center for Drug Evaluation and Research. Transcript for the 2009 Dec 15, Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee. [Accessed 2010 Oct 7]. .
    1. De Lorgeril M, Salen P, Abramson J, et al. Cholesterol lowering, cardiovascular diseases, and the rosuvastatin-JUPITER controversy: a critical reappraisal. Arch Intern Med. 2010;170:1032–1036.
    1. De Lorgeril M. Answers to R. Ridker by M. de Lorgeril. 2010. Jun 30, [Accessed 2010 Aug 15]. .
    1. Glynn RJ, Danielson E, Fonseca FAH, et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med. 2009;360:1851–1861.
    1. Ridker PM, Macfadyen J, Cressman M, Glynn RJ. Efficacy of rosuvastatin among men and women with moderate chronic kidney disease and elevated high-sensitivity C-reactive protein: a secondary analysis from the JUPITER (Justification for the Use of Statins in Prevention – an Intervention Trial Evaluating Rosuvastatin) trial. J Am Coll Cardiol. 2010;55:1266–1273.
    1. Glynn RJ, Koenig W, Nordestgaard BG, Shepherd J, Ridker PM. Rosuvastatin for primary prevention in older persons with elevated C-reactive protein and low to average low-density lipoprotein cholesterol levels: exploratory analysis of a randomized trial. Ann Intern Med. 2010;152:488–496. W174.
    1. Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003;107:499–511.
    1. Ridker PM, MacFadyen JG, Børge G, Nordestgaard BG, et al. Rosuvastatin for primary prevention among individuals with elevated high-sensitivity C-reactive protein and 5% to 10% and 10% to 20% 10-year risk: implications of the Justification for Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) Trial for “Intermediate Risk”. Circ Cardiovasc Qual Outcomes. 2010;3:447–452.
    1. Kones R. Recent advances in the management of chronic stable angina I: approach to the patient, diagnosis, pathophysiology, risk stratification, and gender disparities. Vasc Health Risk Manag. 2010;6:635–656.
    1. Ridker PM, Glynn RJ. The JUPITER Trial: Responding to the critics. Am J Cardiol. 2010;106:1351–1356.
    1. Harrington R, Ridker PM. The Bob Harrington Show. Episode #26: Dissecting the controversy around JUPITER with Dr Paul Ridker. 2010. Aug 27, .
    1. [Accessed 2010 Oct 7]. . (FDA memorandum, 2009 Nov 12, Appendix, page 11)
    1. Friedlin B, Korn E. Stopping clinical trials early for benefit: impact on estimation. Clin Trials. 2009;6:119–125.
    1. Korn EL, Friedlin B, Mooney M. Stopping or reporting early for positive results in randomized clinical trials: the National Cancer Institute Cooperative Experience from 1990 to 2005. J Clin Oncol. 2009;27:1712–1721.
    1. Bruckert E, Hayem G, Dejager S, et al. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients: the PRIMO study. Cardiovasc Drugs Ther. 2005;19:403–414.
    1. Hsu I, Spinler SA, Johnson NE. Comparative evaluation of the safety and efficacy of HMG-CoA reductase inhibitor monotherapy in the treatment of primary hypercholesterolemia. Ann Pharmacother. 1995;29:743–759.
    1. Garcia-Rodriguez LA, Masso-Gonzalez EL, Wallander MA, Johansson S. The safety of rosuvastatin in comparison with other statins in over 100,000 statin users in UK primary care. Pharmacoepidemiol Drug Saf. 2008;17:943–952.
    1. Garcia-Rodriguez LA, Gonzalez-Perez A, Stang MR, et al. The safety of rosuvastatin in comparison with other statins in over 25,000 statin users in the Saskatchewan Health Databases. Pharmacoepidemiol Drug Saf. 2008;17:953–961.
    1. Sukhija R, Prayaga S, Marashdeh M, et al. Effect of statins on fasting plasma glucose in diabetic and nondiabetic patients. J Investig Med. 2009;57:495–499.
    1. Koh KK, Quon MJ, Han SH, Lee Y, Kim SJ, Shin EK. Atorvastatin causes insulin resistance and increases ambient glycemia in hypercholesterolemic patients. J Am Coll Cardiol. 2010;55:1209–1216.
    1. Kostapanos MS, Milionis HJ, Agouridis AD, Rizos CV, Elisaf MS. Rosuvastatin treatment is associated with an increase in insulin resistance in hyperlipidaemic patients with impaired fasting glucose. Int J Clin Pract. 2009;63:1308–1313.
    1. Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy of cholesterol-lowering therapy in 18,696 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008;371:117–125.
    1. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375:735–742.
    1. Baker WL, Talati R, White CM, Coleman CI. Differing effect of statins on insulin sensitivity in non-diabetics: a systematic review and meta-analysis. Diab Res Clin Pract. 2010;87:98–107.
    1. Zhang FL, Casey PJ. Protein prenylation: molecular mechanisms and functional consequences. Annu Rev Biochem. 1996;65:241–269.
    1. Takai Y, Sasaki T, Matozaki T. Small GTP-binding proteins. Physiol Rev. 2001;81:153–208.
    1. Greenwood J, Steinman L, Zamvil SS. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nature Rev Immunol. 2006;6:358–370.
    1. Chakrabarti R, Engleman EG. Interrelationships between mevalonate metabolism and the mitogenic signaling pathway in T lymphocyte proliferation. J Biol Chem. 1991;266:12216–12222.
    1. Graham I, Atar D, Borch-Johnsen K, et al. Fourth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (Constituted by representatives of nine societies and by invited experts). European guidelines on cardiovascular disease prevention in clinical practice: executive summary. Eur Heart J. 2007;28:2375–2414.
    1. Liu PY, Chen JH, Lin LJ, Liao JK. Increased Rho kinase activity in a Taiwanese population with metabolic syndrome. J Am Coll Cardiol. 2007;49:1619–1624.
    1. Liao JK. Does it matter whether or not a lipid-lowering agent inhibits Rho kinase. Curr Atheroscler Rep. 2007;9:384–388.
    1. Dong M, Yan BP, Liao JK, Lam YY, Yip GWK, Yu CM. Rho-kinase inhibition: a novel therapeutic target for the treatment of cardiovascular diseases. Drug Discov Today. 2010;15:622–629.
    1. Brozinick JT, Jr, Berkemeier BA, Elmendorf JS. “Acting” on GLUT 4: membrane and cytoskeletal components of insulin action. Curr Diabetes Rev. 2007;3:111–122.
    1. Horvath EM, Tackett L, Elmendorf JS. A novel membrane-based anti-diabetic action of atorvastatin. Biochem Biophys Res Commun. 2008;372:639–643.
    1. Nakata M, Nagasaka S, Kusaka I, Matsuoka H, Ishibashi S, Yada T. Effects of statins on the adipocyte maturation and expression of glucose transporter 4 (SLC2A4): implications in glycemic control. Diabetologia. 2006;49:1881–1892.
    1. White CM. A review of the pharmacologic and pharmacokinetic aspects of rosuvastatin. J Clin Pharmacol. 2002;42:963–970.
    1. Mita T, Watada H, Nakayama S, et al. Preferable effect of pravastatin compared to atorvastatin on beta cell function in Japanese early-state type 2 diabetes with hypercholesterolemia. Endocr J. 2007;54:441–447.
    1. Yada T, Nakata M, Shiraishi T, Kakei M. Inhibition by simvastatin, but not pravastatin, of glucose-induced cytosolic Ca2+ signaling and insulin secretion due to blockade of L-type Ca2+ channels in rat islet b-cells. Br J Pharmacol. 1999;126:1205–1213.
    1. Siddals KW, Marshman E, Westwood M, Gibson JM. Abrogation of insulin-like growth factor-I (IGF-I) and insulin action by mevalonic acid depletion: synergy between protein prenylation and receptor glycosylation pathways. J Biol Chem. 2004;279:38353–38359.
    1. Otokozawa S, Ai M, van Himbergen T, et al. Effects of intensive atorvastatin and rosuvastatin treatment on apolipoprotein B-48 and remnant lipoprotein cholesterol levels. Atherosclerosis. 2009;205:197–201.
    1. American Diabetes Association. Standards of Medical Care in Diabetes – 2009. Diabetes Care. 2009;32(Suppl 1):S13–61.
    1. Pasternak RC, Smith SC, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. Stroke. 2002;33:2337–2341.
    1. Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy. JAMA. 2003;289:1681–1690.
    1. Tomlinson SS, Mangione KK. Potential adverse effects of statins on muscle. Phys Ther. 2005;85:459–465.
    1. SEARCH Collaborative Group. Link E, Parish S, Armitage J, et al. SLCO1B1 variants and statin-induced myopathy – a genomewide study. N Eng J Med. 2008;359:789–799.
    1. Gomes MD, Lecker SH, Jagoe RT, Navon A, Goldberg AL. Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy. Proc Natl Acad Sci U S A. 2001;98:14440–14445.
    1. Hanai J, Cao P, Tanksale P, et al. The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity. J Clin Invest. 2007;117:3940–3951.
    1. Cao P, Hanai J-i, Tanksale P, Imamura S, Sukhatme VP, Lecker SH. Statin-induced muscle damage and atrogin-1 induction is the result of a geranylgeranylation defect. FASEB J. 2009;23:2844–2854.
    1. Knauer MJ, Urquhart BL, Meyerzu Schwabedissen HE, et al. Human skeletal muscle drug transporters determine local exposure and toxicity of statins. Circ Res. 2010;106:297–306.
    1. Dorajoo R, Pereira BP, Yu Z, et al. Role of multidrug resistance-associated protein-1 transporter in statin-induced myopathy. Life Sci. 2008;82:823–830.
    1. Masters BA, Palmoski MJ, Glint OP, Gregg RE, Wang-Iverson D, Durham SK. In vitro myotoxicity of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, pravastatin, lovastatin, and simvastatin, using neonatal rat skeletal myocytes. Toxicol Appl Pharmacol. 1995;131:163–174.
    1. Thalacker-Mercer A, Baker M, Calderon C, Bamman M. Simvastatin Reduces Human Primary Satellite Cell Proliferation in Culture. Presentation, American Physiological Society, The Integrative Biology of Exercise V; 2008 Sep 24–27; Hilton Head, SC. . [Accessed 2010 Nov 20]. and .
    1. Marcoff L, Thompson PD. The role of coenzyme Q10 in statinassociated myopathy: a systematic review. J Am Coll Cardiol. 2007;49:2231–2237.
    1. Dirks AJ, Jones KM. Statin-induced apoptosis and skeletal myopathy. Am J Physiol Cell Physiol. 2006;291:C1208–1212.
    1. Sirvent P, Mercier J, Lacampagne A. New insights into mechanisms of statin-associated myotoxicity. Curr Opin Pharmacol. 2008;8:333–338.
    1. Needham M, Fabian V, Knezevic W, et al. Progressive myopathy with upregulation of MHC-I associated with statin therapy. Neuromuscul Disord. 2007;17:194–200.
    1. Grable-Esposito P, Katzberg HD, Greenberg SA, et al. Immune-mediated necrotizing myopathy associated with statins. Muscle Nerve. 2010;41:185–190.
    1. Vaklavas C, Chatzizisis YS, Ziakas A, Zamboulis C, Giannoglou GD. Molecular basis of statin-associated myopathy. Atherosclerosis. 2009;202:18–28.
    1. Mas E, Mori TA. Coenzyme Q10 and statin myalgia: what is the evidence. Curr Atheroscler Rep. 2010;12:407–413.
    1. Vandenberg BF, Robinson J. Management of the patient with statin intolerance. Curr Atheroscler Rep. 2010;12:48–57.
    1. Mammen AL, Amato AA. Statin myopathy: a review of recent progress. Curr Opin Rheumatol. 2010;22:644–650.
    1. Thompson PD, Clarkson PM, Rosenson RS. An assessment of statin safety by muscle experts. Am J Cardiol. 2006;97:69C–76C.
    1. Armitage J. The safety of statins in clinical practice. Lancet. 2007;370:1781–1790.
    1. Ford ES, Li C, Zhao G, Tsai J. Trends in obesity and abdominal obesity among adults in the United States from 1999–2008. Int J Obes (Lond) 2010 Sep 7; [Epub ahead of print]
    1. Filion KB, Genest J, Joseph L, et al. The metabolic syndrome and cardiovascular risk: a systematic review and meta-analysis. J Am Coll Cardiol. 2010;56:1113–1132.
    1. DeMazumder D, Hasan RK, Blumenthal RS, Michos ED, Jones S. Should statin therapy be allocated on the basis of global risk or on the basis of randomized trial evidence. Am J Cardiol. 2010;106:905–909.
    1. Nambi V, Ballantyne CM. “Risky Business”: ten years is not a lifetime. Circulation. 2009;119:362–364.
    1. Lloyd-Jones DM, Hong Y, Labarthe D, et al. American Heart Association Strategic Planning Task Force and Statistics Committee. Defining and setting national goals for cardiovascular health promotion and disease reduction: the American Heart Association’s strategic Impact Goal through 2020 and beyond. Circulation. 2010;121:586–613.
    1. Webster R, Heeley E. Perceptions of risk: understanding cardiovascular disease. Risk Management and Healthcare Policy. 2010;3:49–60.

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