An elevated level of C-reactive protein (CRP), an acute phase protein, is one of many

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1 REVIEW ARTICLE Diagnostic Implications of C-Reactive Protein Michael A. Zimmerman, MD; Craig H. Selzman, MD; Clay Cothren, MD; Amy C. Sorensen, BS; Christopher D. Raeburn, MD; Alden H. Harken, MD An elevated level of C-reactive protein (CRP), an acute phase protein, is one of many downstream indicators of inflammation. Physiologically, CRP enhances cellmediated immunity by promoting phagocytosis, accelerating chemotaxis, and activating platelets. The purposes of this article are (1) to review the clinical data implicating serum CRP level as a systemic marker of focal inflammation and (2) to explore serum CRP level as a reflection of the inflammatory component of atherogenesis. Our findings indicate that CRP levels serve as an early marker of the magnitude of inflammation in events as dissimilar as appendicitis and myocardial infarction. The level of circulating CRP correlates with endovascular disease and may serve to identify otherwise asymptomatic patients at sufficient cardiovascular risk to warrant aggressive therapy. Determining whether CRP has a direct pathologic role in the vascular wall itself may have the most clinical relevance. Arch Surg. 2003;138: Systemic inflammation is associated with leukocyte-mediated endothelial dysfunction. 1 Proinflammatory cytokines, chemokines, and glucocorticoid hormones are elaborated and stimulate hepatocytes to synthesize a wide array of acute phase proteins (Figure). 2,3 A dominant acute phase protein in mammals, C-reactive protein (CRP) is a 206 amino acid pentameric polypeptide. 4 Originally isolated from the serum of patients with pneumonia, it has a high binding affinity for pneumococcal C polysaccharide. 5 Although CRP level correlated with infection, this qualitative relationship did not predict disease severity. By the 1980s a sensitive and specific quantitative assay for CRP was commercially available. Subsequently, mounting clinical evidence suggests an early quantitative correlation between plasma CRP levels and several inflammatory states. Rapidly synthesized acute phase proteins support host defenses by neutralizing offending antigens, controlling tissue damage, and promoting tissue repair. C- reactive protein acts as an opsonin for invading bacteria and circulating immune From the Department of Surgery, University of Colorado Health Sciences Center, Denver, Colo. complexes. 6 C-reactive protein may also activate the complement cascade and scavenge chromatin after cellular necrosis. 7 These functions promote phagocytosis, accelerate chemotaxis, and activate circulating platelets. Ultimately, CRP accelerates the clearance of microbial debris from the circulation and enhances cellmediated immunity. Plasma levels of CRP can be detected as early as 4 hours after injury and peak (1000-fold increase) between 24 and 72 hours after injury. 8,9 The purposes of this article are (1) to review the clinical data implicating CRP level as a systemic marker of focal inflammation, (2) to explore CRP level as an indicator of the endovascular inflammation that leads to atherogenesis, and (3) to examine anti-inflammatory strategies against atherosclerosis. C-REACTIVE PROTEIN AND SURGICAL DISEASE C-reactive protein is a reliable early indicator of inflammation or injury. Mustard and colleagues 10 documented that serial postoperative CRP levels could predict septic complications before their clinical manifestation. Indeed, serial CRP levels in 220

2 Injury/Inflammation Cytokines (TNF-α, IL-1β) Chemokines (MCP-1, IL-8) Liver CRP ( ) Aspirin Statins C-reactive protein (CRP) in vascular injury. The inflammatory response to vascular injury results in cytokine and chemokine expression. Hepatic production of CRP may be directly attenuated (minus sign) by aspirin or statin drugs. TNF- indicates tumor necrosis factor ; IL-1, interleukin 1 ; and MCP-1, monocyte chemoattractant protein 1. trauma patients aid in the discrimination of bacterial sepsis from noninfectious systemic inflammatory response syndrome. 11 A cutoff value of 17 mg/dl or more for CRP gives a sensitivity of 74% and a specificity of 75% in predicting the presence of infection. Level of CRP also predicts the severity of acute cholecystitis ( 10 mg/dl is strongly related to tissue necrosis) 12 and serves as an accurate marker in risk assessment for postoperative amputation in patients undergoing femoropopliteal bypass. 13 If CRP level indicates local infection, can CRP levels enhance the precision of the difficult diagnosis of common entities such as acute appendicitis? A large retrospective study has documented that the sensitivity of CRP in these patients is greater than 90%. 14 Furthermore, the negative appendectomy rate is reduced by approximately 8% if surgery is canceled in patients with CRP levels and white blood cell counts within the reference range. 15 Eriksson and colleagues 16 prospectively measured serial CRP and white blood cell levels in patients with suspected appendicitis. Levels were determined every 4 hours following admission and the operating surgeon was blinded to all but initial values. The sensitivity of CRP level in predicting appendicitis was 60% on admission and increased to 100% by the fourth draw. Conversely, white blood cell counts exhibited a sensitivity of 95% on admission, but dropped to 75% by the fourth draw. Multiple studies 17,18 confirm that an elevated CRP level serves as a systemic marker of focal inflammation and infection. INFLAMMATION AND CARDIOVASCULAR DISEASE Accumulating data pathologically link atherosclerosis and the inflammatory response to vascular injury. 19,20 Luminal injury associated with hyperlipidemia, hypertension, and/or angioplasty results in endothelial cell dysfunction, adhesion molecule expression, and inflammatory cell infiltration. 1 The autocrine and paracrine effects of cytokines and chemokines promote oxidized lipid deposition with vascular smooth muscle cell proliferation and migration. This chronic vascular wall inflammation leads not only to progressive luminal stenosis but also to plaque instability. 21 Thus, a systemic marker that identifies the patient with smoldering vascular inflammation is intuitively attractive. Several prospective studies have demonstrated a direct correlation between acute myocardial infarction (MI) rise in CRP, postinfarction adverse events, 22,23 and subsequent infarct size 24 (Table). The European Concerted Action on Thrombosis and Disabilities (ECAT) Angina Pectoris Study also reported elevated CRP levels in more than 2000 outpatients with stable and unstable angina. 25 This study identified a 2-fold increase in the risk Cardiovascular Disease and CRP Source No. of Patients Comment Symptomatic Berk et al CRP associated with acute coronary events in patients with unstable angina Pietila et al Post-MI CRP correlates with infarct size Liuzzo et al CRP predicts coronary events in patients with unstable angina Haverkate et al CRP predictive of MI or stroke Toss et al CRP associated with mortality Asymptomatic Kuller et al CRP associated with coronary heart disease mortality Mendall et al High CRP associated with CVD Tracy et al CRP associated with CVD Ridker et al Baseline CRP predicts MI or stroke Ridker et al Baseline CRP predicts symptomatic PAD Ridker et al CRP an independent risk factor for cardiovascular disease in women Koenig et al CRP predicts coronary heart disease Harris et al CRP associated with increased mortality Roivainen et al CRP associated with coronary events in dyslipidemic men Danesh et al CRP associated with future coronary disease Ridker et al CRP associated with coronary disease and stroke in women Lowe et al CRP associated with ischemic heart disease Ridker et al CRP an independent predictor of PAD Abbreviations: CRP, C-reactive protein level; CVD, cardiovascular disease; MI, myocardial infarction; PAD, peripheral arterial disease. 221

3 of MI and sudden cardiac death in any patient with a CRP level greater than 0.36 mg/dl. Toss and colleagues 26 observed more than 900 patients with unstable angina or non Q-wave infarction and reported a positive correlation between elevated CRP level and mortality. 26 Thus, an elevated CRP level does appear to correlate with incidence of acute coronary syndromes. Elevated CRP Level as an Indicator of Endovascular Instability Elevated CRP level is also associated with an increased risk of both 30-day mortality and MI following angioplasty. 40 Elevated preangioplasty CRP levels of greater than 0.3 mg/dl predicted an increased rate of procedural and in-hospital complications. 41 At 1-year follow-up, clinical restenosis developed in 63% of patients with high preangioplasty CRP levels vs only 27% of those with values in the reference range. Milazzo and colleagues 42 reported a similar trend in 86 patients who underwent elective coronary artery bypass grafting. Twenty-five percent of patients with initial CRP values of 0.3 mg/dl or higher experienced postoperative ischemic events, vs only 4% of those with values in the reference range. Direct CRP-Mediated Vascular Disease The evolving concept of CRP acting as a direct pathologic mediator in vascular remodeling may ultimately provide the most clinical relevance. C-reactive protein has been localized to the neointima of atherosclerotic plaque 43 and activates complement in early lesions. 44 Although hepatic production has classically been identified as the primary source, Yasojima and colleagues 45 recently demonstrated that CRP is also expressed by vascular smooth muscle cells and macrophages resident in atherosclerotic lesions. Furthermore, CRP induces endothelial cell expression of adhesion molecules and monocyte chemoattractant protein Recently, Fu and Borensztajn 47 demonstrated that CRP promotes the aggregation of lowdensity lipoprotein, thus contributing to foam-cell formation within atherosclerotic lesions. This local influence, coupled with the well-documented proinflammatory effects of CRP on monocytes and macrophages, supports a direct deleterious role of CRP in the vascular wall itself. 48 Although systemic markers of focal inflammatory processes are becoming increasingly useful for risk stratification in cardiovascular disease, targeting specific pathologic culprits within the inflammatory cascade may permit a direct therapeutic benefit. Elevated CRP Level in Asymptomatic Patients Several small cross-sectional and case-control studies have even suggested that CRP levels may be predictive of cardiovascular disease in asymptomatic patients The Multiple Risk Factor Intervention Trial (MRFIT) 27 was the first prospective study to report the relationship between CRP and coronary disease in asymptomatic, but high-risk, men. In this 17-year study, increased CRP levels directly correlated with mortality. Results from the Physicians Health Study, 28 a randomized, double-blind trial of treatment with aspirin and beta carotene in the prevention of cardiovascular disease, also documented the link between CRP levels and risk of MI and stroke in healthy men. Interestingly, when smoldering endovascular inflammation is suppressed with aspirin therapy, risk reduction is directly related to CRP levels. The Monitoring Trends and Determinants in Cardiovascular Disease (MONICA) 31 study measured CRP levels in healthy men with an 8-year followup. This study also identified an association between elevated CRP levels and the risk of both fatal and nonfatal MI in 936 patients. Recently, the Speedwell Prospective Study 34 also correlated systemic inflammation and ischemic heart disease and reported a decrease in CRP level with smoking cessation in more than 1000 men. High CRP levels have also proven to be predictive of adverse cardiovascular events in healthy women 30,33 and the elderly. 32 Not surprisingly, a positive association has been found between CRP level and the risk of developing peripheral arterial disease. 29,35 ANTI-INFLAMMATORY THERAPY Antiplatelet and/or lipid-lowering agents have traditionally been used for the prevention of acute cardiovascular events. 49 An evolving pharmacologic paradigm links these drugs and serum CRP levels. The Nurses Health Study 50 analyzed the incidence of coronary events in more than women who were taking aspirin regularly. Overall, 1 to 6 aspirin tablets per week resulted in a decrease in nonfatal MI and fatal coronary disease. These results have been corroborated in several large, randomized studies Ridker and colleagues 28 documented that the benefit of aspirin therapy was greatest in healthy men with the highest CRP levels. Although the risk reduction of MI in this group was 55.7%, the beneficial effect was reduced as CRP levels decreased. These data emphasize the inflammatory component of cardiovascular disease and suggest that aspirin therapy may directly affect endovascular dysfunction, as indicated by CRP production. Furthermore, CRP level may serve as an indicator of patients at risk and as a practical marker of the efficacy of the preventive strategy. Several large trials have linked the use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) to the attenuation of serum CRP levels. Recently, the Air Force/Texas Coronary Artery Prevention Study (AFCAPS/TexCAPS) investigators reported the effects of lovastatin on CRP levels in patients with and without hyperlipidemia. 59 Apart from its lipid-lowering effects, lovastatin reduced CRP levels by 14.8%. Lovastatin was effective in preventing coronary events in patients with elevated cholesterol levels and was also effective in patients with low cholesterol and high CRP levels. Thus, not only does CRP level reliably reflect inflammation, but its suppression is associated with a reduction in adverse cardiovascular events. Although the effects of these prophylactic agents on CRP level are promising, there are concerns regarding widespread use of aspirin for primary prevention. A recent review of the cumulative experience with aspirin summarizes the results of 5 randomized studies. 60 With the exception of one British study, 51 4 trials docu- 222

4 mented a reduction in the rate of MI in patients treated with aspirin However, a meta-analysis evaluating these trials reported a 69% increase in bleeding complications. 61 Thus, aspirin prophylaxis can be justified only in patients who are at increased risk for cardiovascular events. Sanmuganathan and colleagues 61 recommend preventative aspirin therapy only in patients with a coronary event risk of at least 1.5% per year. In addition to nausea, abdominal discomfort, and headaches, all statins pose the risk of myopathy and fatal rhabdomyolysis. 62 The mechanism of skeletal muscle toxic effects is likely due to inhibition of drug metabolism and subsequent increase in plasma statin concentrations. In addition, statins interact with a wide array of drugs, including immunosuppressants, azole antifungals, coumarin anticoagulants, and calcium channel antagonists. Despite their widespread use in cardiovascular patients, the precise mechanism by which aspirin and statins reduce CRP levels is unknown. Although the antiinflammatory effects of each agent are well documented, it is unknown whether these drugs mediate CRP expression directly or whether this effect is secondary to a decrease in well-described inflammatory promoters of CRP production. While the prognostic role of CRP levels in numerous surgical diseases is still being defined, its value in risk stratification of cardiovascular patients is increasingly convincing. Recently, Ridker and colleagues 63 reported that serum CRP levels might be more predictive than lowdensity lipoprotein cholesterol levels of adverse cardiovascular events. More than 75% of patients with elevated CRP levels experienced a major cardiac event despite low-density lipoprotein cholesterol levels that were lower than the threshold recommended for pharmacologic intervention. The implications of these observations are significant in that patients not receiving statins and other risk-factor modifications may, in fact, require aggressive therapy. This study was supported by grants GM49222 and GM08315 from the National Institutes of Health, Bethesda, Md (Dr Harken). Corresponding author and reprints: Michael A. Zimmerman, MD, Department of Surgery, Campus Box C-320, University of Colorado Health Sciences Center, 4200 East Ninth Ave, Denver, CO ( REFERENCES 1. Higashi Y, Sasaki S, Nakagawa K, Matsuura H, Oshima T, Chayama K. Endothelial function and oxidative stress in renovascular hypertension. N Engl J Med. 2002;346: Gambino R. C-reactive protein undervalued, underutilized. Clin Chem. 1997; 43: Baumann H, Jahreis GP, Morella KK, et al. Transcriptional regulation through cytokine and glucocorticoid response elements of rat acute phase plasma protein genes by C/EBP and JunB. J Biol Chem. 1991;266: Gotschlich EC. C-reactive protein: a historical overview. Ann N Y Acad Sci. 1989; 557: Tillet WS, Francis T Jr. Serologic reactions in pneumonia with a nonprotein fraction from Pneumococcus. J Exp Med. 1930;52: Babu ED. Would measurement of C-reactive protein reduce the rate of negative exploration for acute appendicitis? J R Coll Surg Edinb. 2000;45: Robey FA, Jones KD, Tanaka T, Liu TY. Binding of C-reactive protein to chromatin and nucleosome core particles: a possible physiological role of C-reactive protein. J Biol Chem. 1984;259: Foglar C, Lindsey RW. C-reactive protein in orthopedics. Orthopedics. 1998;21: Steel DM, Whitehead AS. The major acute phase reactants: C-reactive protein, serum amyloid P component and serum amyloid A protein. Immunol Today. 1994; 15: Mustard RA Jr, Bohnen JM, Haseeb S, Kasina R. C-reactive protein levels predict postoperative septic complications. Arch Surg. 1987;122: Miller PR, Munn DD, Meredith JW, Chang MC. Systemic inflammatory response syndrome in the trauma intensive care unit: who is infected? J Trauma. 1999; 47: Schafer M, Krahenbuhl L, Buchler MW. Predictive factors for the type of surgery in acute cholecystitis. Am J Surg. 2001;182: Matzke S, Biancari F, Ihlberg L, et al. Increased preoperative C-reactive protein level as a prognostic factor for postoperative amputation after femoropopliteal bypass surgery for CLI. Ann Chir Gynaecol. 2001;90: Paajanen H, Mansikka A, Laato M, Kettunen J, Kostiainen S. Are serum inflammatory markers age dependent in acute appendicitis? J Am Coll Surg. 1997; 184: Eriksson S, Granstrom L, Bark S. Laboratory tests in patients with suspected acute appendicitis. Acta Chir Scand. 1989;155: Eriksson S, Granstrom L, Carlstrom A. The diagnostic value of repetitive preoperative analyses of C-reactive protein and total leucocyte count in patients with suspected acute appendicitis. Scand J Gastroenterol. 1994;29: Andersson RE, Hugander AP, Ghazi SH, et al. Diagnostic value of disease history, clinical presentation, and inflammatory parameters of appendicitis. World J Surg. 1999;23: Gronroos JM, Gronroos P. Leucocyte count and C-reactive protein in the diagnosis of acute appendicitis. Br J Surg. 1999;86: Ross R. Atherosclerosis an inflammatory disease. N Engl J Med. 1999;340: Selzman CH, Miller SA, Harken AH. Therapeutic implications of inflammation in atherosclerotic cardiovascular disease. Ann Thorac Surg. 2001;71: Plutzky J. Inflammatory pathways in atherosclerosis and acute coronary syndromes. Am J Cardiol. 2001;88:10K-15K. 22. Berk BC, Weintraub WS, Alexander RW. Elevation of C-reactive protein in active coronary artery disease. Am J Cardiol. 1990;65: Liuzzo G, Biasucci LM, Gallimore JR, et al. The prognostic value of C-reactive protein and serum amyloid A protein in severe unstable angina. N Engl J Med. 1994;331: Pietila K, Harmoinen A, Hermens W, Simoons ML, Van de Werf F, Verstraete M. Serum C-reactive protein and infarct size in myocardial infarct patients with a closed versus an open infarct-related coronary artery after thrombolytic therapy. Eur Heart J. 1993;14: Haverkate F, Thompson SG, Pyke SD, Gallimore JR, Pepys MB, and the European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Production of C-reactive protein and risk of coronary events in stable and unstable angina. Lancet. 1997;349: Toss H, Lindahl B, Siegbahn A, Wallentin L, for the FRISC Study Group (Fragmin during Instability in Coronary Artery Disease). Prognostic influence of increased fibrinogen and C-reactive protein levels in unstable coronary artery disease. Circulation. 1997;96: Kuller LH, Tracy RP, Shaten J, Meilahn EN. Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study: Multiple Risk Factor Intervention Trial. Am J Epidemiol. 1996;144: 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: Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Plasma concentration of C-reactive protein and risk of developing peripheral vascular disease. Circulation. 1998;97: Ridker PM, Buring JE, Shih J, Matias M, Hennekens CH. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation. 1998;98: 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 Circulation. 1999;99: Harris TB, Ferrucci L, Tracy RP, et al. Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. Am J Med. 1999;106: 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: Lowe GD, Yarnell JW, Rumley A, Bainton D, Sweetnam PM. C-reactive protein, fibrin D-dimer, and incident ischemic heart disease in the Speedwell study: are inflammation and fibrin turnover linked in pathogenesis? Arterioscler Thromb Vasc Biol. 2001;21: Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease. JAMA. 2001;285:

5 36. Mendall MA, Patel P, Ballam L, Strachan D, Northfield TC. C-reactive protein and its relation to cardiovascular risk factors: a population based cross sectional study. BMJ. 1996;312: Tracy RP, Lemaitre RN, Psaty BM, et al. Relationship of C-reactive protein to risk of cardiovascular disease in the elderly: results from the Cardiovascular Health Study and the Rural Health Promotion Project. Arterioscler Thromb Vasc Biol. 1997;17: Danesh J, Whincup P, Walker M, et al. Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. BMJ. 2000;321: Roivainen M, Viik-Kajander M, Palosuo T, et al. Infections, inflammation, and the risk of coronary heart disease. Circulation. 2000;101: Chew DP, Bhatt DL, Robbins MA, et al. Incremental prognostic value of elevated baseline C-reactive protein among established markers of risk in percutaneous coronary intervention. Circulation. 2001;104: Buffon A, Liuzzo G, Biasucci LM, et al. Preprocedural serum levels of C-reactive protein predict early complications and late restenosis after coronary angioplasty. J Am Coll Cardiol. 1999;34: Milazzo D, Biasucci LM, Luciani N, et al. Elevated levels of C-reactive protein before coronary artery bypass grafting predict recurrence of ischemic events. Am J Cardiol. 1999;84: 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: Torzewski J, Torzewski M, Bowyer DE, et al. C-reactive protein frequently colocalizes with the terminal complement complex in the intima of early atherosclerotic lesions of human coronary arteries. Arterioscler Thromb Vasc Biol. 1998; 18: Yasojima K, Schwab C, McGeer EG, McGeer PL. Generation of C-reactive protein and complement components in atherosclerotic plaques. Am J Pathol. 2001; 158: Pasceri V, Cheng JS, Willerson JT, Yeh ET, Chang J. Modulation of C-reactive protein mediated monocyte chemoattractant protein-1 induction in human endothelial cells by anti-atherosclerosis drugs. Circulation. 2001;103: Fu T, Borensztajn J. Macrophage uptake of LDL bound to aggregated C-reactive protein: possible mechanism of foam cell formation in atherosclerotic lesions. Biochem J. 2002;366: Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002; 105: Selzman CH. Current approaches to therapy for vascular injury. Expert Opin Pharmacother. 2001;2: Manson JE, Stampfer MJ, Colditz GA, et al. A prospective study of aspirin use and primary prevention of cardiovascular disease in women. JAMA. 1991;266: Peto R, Gray R, Collins R, et al. Randomised trial of prophylactic daily aspirin in British male doctors. Br Med J. 1988;296: Hansson L, Zanchetti A, Carruthers SG, et al, for the HOT Study Group. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1998;351: de Gaetano G, and the Collaborative Group of the Primary Prevention Project. Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Lancet. 2001;357: The Medical Research Council s General Practice Research Framework. Thrombosis Prevention Trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. Lancet. 1998;351: Steering Committee of the Physicians Health Study Research Group. Final report on the aspirin component of the ongoing Physicians Health Study. N Engl J Med. 1989;321: Ridker PM, Rifai N, Lowenthal SP. Rapid reduction in C-reactive protein with cerivastatin among 785 patients with primary hypercholesterolemia. Circulation. 2001; 103: Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E, for the Cholesterol and Recurrent Events (CARE) Investigators. Long-term effects of pravastatin on plasma concentration of C-reactive protein. Circulation. 1999;100: Albert MA, Danielson E, Rifai N, Ridker PM. Effect of statin therapy on C-reactive protein levels: the Pravastatin Inflammation/CRP Evaluation (PRINCE): a randomized trial and cohort study. JAMA. 2001;286: 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: Lauer MS. Clinical practice: aspirin for primary prevention of coronary events. N Engl J Med. 2002;346: Sanmuganathan PS, Ghahramani P, Jackson PR, Wallis EJ, Ramsay LE. Aspirin for primary prevention of coronary heart disease: safety and absolute benefit related to coronary risk derived from meta-analysis of randomised trials. Heart. 2001;85: Igel M, Sudhop T, von Bergmann K. Metabolism and drug interactions of 3-hydroxy- 3-methylglutaryl coenzyme A reductase inhibitors (statins). Eur J Clin Pharmacol. 2001;57: 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: Surgical Anatomy T he triangular ligaments of the liver are the sharp, bloodless, peritoneal folds at the extreme right and left limits of the attachment of the liver to the diaphragm. They lie at the opposite ends of the posterior surface of the liver. The left triangular ligament is an extensive fold which can be clamped between the right index and middle fingers much as can the pedicle of the spleen. The right triangular ligament is less well marked. It is attached to the right inferior end of the posterior surface of the right lobe of the liver. Its two layers at once diverge and, as the upper and lower layers of the coronary ligament, limit the bare area on the back of the liver above and below. Source: Boileau Grant JC. A Method of Anatomy: Descriptive and Deductive. 5th ed. Baltimore, Md: Williams & Wilkins Co; 1952: