Pathology and Laboratory Medicine - part 7 pps

276 Wu et al 47 Barry WH Mechanisms of myocardial cell injury during ischemia and reperfusion J Card Surg 1987;2:375–383 48 Deves R, Krupka RM The comparative specificity of the inner and outer substrate transfer sites in the choline carrier of human erythrocytes J Membr Biol 1984;80:71–80 49 Danne O, Möckel M, Lueders C, Muegge C, Zschunke GA, Lufft H, Mueller CH, Frei U Prognostic implications of whole blood choline levels in acute coronary syndromes Am J Cardiol 2003; in press 50 Mizuno K, Satomura K, Miyamoto A, et al Angioscopic evaluation of coronary-artery thrombi in acute coronary syndromes N Engl J Med 1992;326:287–291 51 Mizuno K, Arakawa K, Isojima K, et al Angioscopy, coronary thrombi and acute coronary syndromes Biomed Pharmacother 1993;47:187–191 52 Haft JI, Goldstein JE, Niemiera ML Coronary arteriographic lesion of unstable angina Chest 1987;92:609–612 53 Ambrose JA Plaque disruption and the acute coronary syndromes of unstable angina and myocardial infarction: if the substrate is similar, why is the clinical presentation different? J Am Coll Cardiol 1992;19:1653–1658 54 Jones AW, Shukla SD, Geisbuhler BB Stimulation of phospholipase D activity and phosphatidic acid production by norepinephrine in rat aorta Am J Physiol 1993;264(3 Pt 1): C609–C616 55 Davies MJ, Thomas AC, Knapman PA, Hangartner JR Intramyocardial platelet aggregation in patients with unstable angina suffering sudden ischemic cardiac death Circulation 1986;73:418–427 56 Falk E Unstable angina with fatal outcome: dynamic coronary thrombosis leading to infarction and/or sudden death Autopsy evidence of recurrent mural thrombosis with peripheral embolization culminating in total vascular occlusion Circulation 1985;71:699–708 57 Tateishi J, Masutani M, Ohyanagi M, Iwasaki T Transient increase in plasma brain (B-type) natriuretic peptide after percutanoues transluminal coronary angioplasty Clin Cardiol 2000; 23:776–780 58 Sabatine MS, Morrow DA, De Lemos JA, et al Elevation of B-type natriuretic peptide in the setting of myocardial ischemia Circulation 2001;104:II–485 59 Mair J Glycogen phosphorylase isoenzyme BB to diagnose ischaemic myocardial damage Clin Chim Acta 1998;272:79–86 60 Rabitzsch G, Mair J, Lechleitner P, et al Isoenzyme BB of glycogen phosphorylase b and myocardial infarction Lancet 1993 Apr 17;341:1032–1033 61 Rabitzsch G, Mair J, Lechleitner P, et al Immunoenzymometric assay of human glycogen phosphorylase isoenzyme BB in diagnosis of ischemic myocardial injury Clin Chem 1995; 41:966–978 62 Mair P, Mair J, Krause EG, Balogh D, Puschendorf B, Rabitzsch G Glycogen phosphorylase isoenzyme BB mass release after coronary artery bypass grafting Eur J Clin Chem Clin Biochem 1994;32:543–547 63 Krause EG, Rabitzsch G, Noll F, Mair J, Puschendorf B Glycogen phosphorylase isoenzyme BB in diagnosis of myocardial ischaemic injury and infarction Mol Cell Biochem 1996;160–161:289–295 64 Lang K, Borner A, Figulla HR Comparison of biochemical markers for the detection of minimal myocardial injury: superior sensitivity of cardiac troponin—T ELISA J Intern Med 2000;247:119–123 65 Jaffe AS, Ravkilde J, Roberts R, et al It’s time for a change to a troponin standard Circulation 2000;102:1216–1220 66 Ishikawa Y, Saffitz JE, Mealman TL, Grace AM, Roberts R Reversible myocardial ischemic injury is not associated with increased creatine kinase activity in plasma Clin Chem 1997;43:467–475 Markers of Ischemia 277 67 Katus HG, Remppis A, Scheffold T Intracellular compartmentation of cardiac troponin T and its release kinetics in patients with reperfused and nonreperfused myocardial infarction Am J Cardiol 1991;67:1360–1367 68 Dean KJ Biochemistry and molecular biology of troponins I and T In: Cardiac Markers Wu AHB, ed Totowa, NJ: Humana Press, 1998, pp 193–204 69 Sobel BE, LeWinter MM Ingenuous interpretation of elevated blood levels of macromolecular markers of myocardial injury: a recipe for confusion J Am Coll Cardiol 2000;35: 1355–1358 70 Feng YJ, Chen C, Fallon JT, Ma L, Waters DD, Wu AHB Comparison of cardiac troponin I, creatine kinase-MB, and myoglobin for detection of acute myocardial necrosis in a swine myocardial ischemic model Am J Clin Pathol 1998;110:70–77 71 Hamm CW, Ravkilde J, Gerhardt W, Jorgensen P, Peheim E, Ljungdahl L The prognostic value of serum troponin T in unstable angina N Engl J Med 1992;327:146–150 72 Wu AHB Increased troponin in patients with sepsis and septic shock: myocardial necrosis or reversible myocardial depression (editorial) Crit Care Med 2001;27:959–960 73 Parker MM, Shelhamer JH, Bachrach SL, et al Profound but reversible myocardial depression in aptients with septic shock Ann Intern Med 1984;100:483–490 74 Ellrod AG, Riedinger MS, Kimchi A, et al Left ventricular performance in septic shock: reversible segmental and global abnormalities Am Heart J 1985;110:402–409 75 ver Elst KM, Spapen HD, Nguyen DN, et al Cardiac troponins I and T are biological markers of left ventricular dysfunction in septic shock Clin Chem 2000;46:650–657 76 Ammann P, Fehr T, Minder EI, et al Elevation of troponin I in sepsis and septic shock Crit Care Med 2001;29:965–969 77 Brett J, Gewrlach H, Nawroth P, et al Tumor necrosis factor/cachectin increases permeability of endothelial cell monolayers by a mechanism involving regulatory G proteins J Exp Med 1989;169:1977–1991 78 Suleiman MS, Lucchetti V, Caputo M, Angelini GD Short periods of regional ischaemia and reperfusion provoke release of troponin I from the human hearts Clin Chim Acta 1999; 284:25–30 79 Colantonio DA, Pickett W, Brison RJ, Collier CE, Van Eyk JE Detection of cardiac troponin I early after onset of chest pain in six patients Clin Chem 2002;48:668–671 278 Wu et al C-Reactive Protein for Risk Assessment 279 17 C-Reactive Protein for Primary Risk Assessment Gavin J Blake and Paul M Ridker INTRODUCTION Accumulating evidence suggests that inflammatory processes play a key role in the pathogenesis of atherosclerosis (1) Given that over half of all myocardial infarctions (MIs) occur in individuals without overt hyperlipidemia, attention has focused on whether plasma concentrations of inflammatory biomarkers can help predict cardiovascular risk (2) Of these inflammatory biomarkers, C-reactive protein (CRP) has been the most extensively studied Produced mainly by the liver in response to interleukin-6 (IL-6), CRP was initially considered to be a sensitive but innocent bystander marker of low-grade vascular inflammation Accumulating data, however, suggest that CRP may play a more direct role in atherogenesis CRP opsonization of low-density lipoprotein (LDL) mediates LDL uptake by macrophages (3), and CRP stimulates monocyte release of other proinflammatory cytokines such as IL-1b, IL-6, and tumor necrosis factor-a (TNF-a) (4) Furthermore, CRP mediates monocyte chemoattractant protein-1 (MCP-1) expression by endothelial cells (5) and causes endothelial cells to express intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) (6) Recent data suggest that arterial tissue can produce CRP, with CRP and complement mRNA being substantially up-regulated in atherosclerotic plaque (7) Thus CRP may serve as an endogenous activator of complement in atheroma As shown in Fig 1, there is robust evidence from several large-scale prospective studies in the United States and Europe that increased concentrations of CRP are a strong predictor of future MI, stroke, and peripheral vascular disease among healthy men and women (8–17) For example, in a cohort of 22,000 healthy middle-aged men, those with CRP concentrations in the highest quartile had a twofold increased risk of stroke or peripheral vascular disease and a threefold increased risk of MI (9,10) These findings were independent of lipid levels and other traditional cardiovascular risk factors Other promising inflammatory markers include soluble intercellular adhesion molecule-1 (sICAM-1), p-selectin, soluble CD 40 ligand, and lipoprotein-associated phospholipase A2 sICAM-1 and p-selectin are cell adhesion molecules involved in the tethering and adhesion of inflammatory cells to the diseased endothelium Interestingly, CRP induces expression of cellular adhesion molecules in human endothelial cells (6) Plasma concentrations of sICAM-1 and p-selectin have been found to be increased among apparently healthy individuals at risk for future cardiovascular events in prospective studies From: Cardiac Markers, Second Edition Edited by: Alan H B Wu @ Humana Press Inc., Totowa, NJ 279 280 Blake and Ridker Fig Prospective studies of CRP and future cardiovascular events among healthy individuals Risk estimates and 95% confidence intervals are calculated as comparison of top vs bottom quartile within each study group (Adapted from Blake GJ, Ridker PM Circ Res 2001;89:766– 768 and Ridker PM Circulation 2001;103:1814–1815.) from both the United States and Europe, although the predictive effect of these inflammatory biomarkers may be attenuated after adjustment for traditional cardiovascular risk factors (18–21) Lipoprotein-associated phospholipase A2 circulates in association with LDL cholesterol and may contribute directly to the progression of atherosclerosis by hydrolyzing oxidized phospholipids into proatherogenic fragments and by generating lysolecithin, which has proinflammatory properties In a study among hyperlipidemic men, baseline levels of lipoprotein-associated phospholipase A2 were an independent predictor of future cardiovascular events (22) However, in a recent study among lower risk women, the predictive effect of lipoprotein-associated phospholipase A2 was markedly attenuated in adjusted analyses, while CRP remained a strong independent predictor of risk (Fig 2) (23) Lipoprotein-associated phospholipase A2 is highly correlated with LDL cholesterol, which may in part account for these different results CD 40 ligand is a transmembrane protein structurally related to TNF-a, which binds to CD40 leading to the activation of macrophages and T lymphocytes Both CD40 and CD40 ligand are abundantly expressed in the shoulder regions of atherosclerotic plaque (24) Recent data show that apparently healthy women with increased plasma levels of soluble CD40 ligand at baseline are at increased risk for future cardiovascular events (25), and that CD40 ligand concentrations are increased among patients with unstable angina (26) Intriguingly, the administration of antiCD40 ligand antibody to hyperlipidemic mice leads to a dramatic reduction in lesion size and lipid content (27) These data suggest that novel targeted antiinflammatory interventions may soon have a role to play in the treatment of atherosclerosis and its complications C-Reactive Protein for Risk Assessment 281 Fig Adjusted relative risks of cardiovascular events according to increasing quartiles of lipoprotein-associated phospholipase A2 (Lp-PLA2) and CRP compared to the lowest quartile (Adapted from Blake GJ, et al JACC 2001:38;1305.) As shown in Fig 3, a recent analysis seeking to compare the predictive value of several traditional and inflammatory biomarkers found that CRP and the ratio of total cholesterol to high-density lipoprotein cholesterol were the strongest predictors of future cardiovascular risk among apparently healthy middle-aged women (8) Moreover, the predictive effect of CRP was additive to that of total cholesterol (TC) to high-density (HDL) lipoprotein cholesterol ratio Consistent data from large well-conducted prospective studies are a prerequisite for potential clinical application of any novel risk factor However, in addition, the candidate risk marker should improve on traditional risk assessment, should direct potential therapeutic intervention, and screening for the risk factor should be relatively cost effective Of the inflammatory markers currently investigated, CRP meets most, if not all, of these criteria Moreover, the potential prognostic utility of CRP is increased by its relatively long half-life, lack of circadian variation (28), and low coefficients of variation when measured with high-sensitivity assays (29), such as those now commercially available CAN CRP TESTING IMPROVE ON STANDARD LIPID TESTING? In current clinical practice, lipid screening is the only blood test routinely advocated for cardiovascular risk assessment However, data suggest that CRP testing may have 282 Blake and Ridker Fig Adjusted relative risks of future cardiovascular events for the highest quartile compared to the lowest quartile of plasma concentration of each risk marker among apparently healthy women (Adapted from Ridker PM, et al N Engl J Med 2000:342;839.) the potential to improve cardiovascular risk prediction when used as an adjunct to lipid testing (8,30,31) In this regard, in the Women’s Health Study, the area under the receiver– operator curve was significantly greater (p < 0.001) when CRP testing was added to lipid screening, compared with lipid screening alone (8) Furthermore, when the relative risks associated with combined lipid and CRP testing were estimated, it was evident that increasing concentrations of CRP had additive predictive value at all lipid levels Figure shows the interactive effects of CRP and lipid testing among healthy men and women (32) Men and women with both CRP and lipid levels in the highest quintile are at markedly increased risk, but even among those with average or low lipid levels, CRP testing can identify individuals with high relative risks of future cardiovascular events For instance, among postmenopausal women with LDL concentrations below 130 mg/dL (the current National Cholesterol Education Program target for lipid reduction in primary prevention [33]), women with high CRP concentrations were at markedly increased risk of future MI, coronary revascularization, and stroke, even after adjustment for other traditional cardiovascular risk factors (8) Recent data also suggest that CRP may be a strong predictor of prognosis at 30 d among patients undergoing percutaneous coronary intervention, and that the risk associated with increased CRP concentrations is independent of, but additive to, the American College of Cardiology/American Heart Association (ACC/AHA) lesion score (Fig 5) (34) CLINICAL ROLE OF CRP TESTING The finding that combining CRP testing with routine lipid assessment may significantly improve risk prediction has important clinical implications More than half of all MIs occur in individuals without increased lipid levels, and these individuals are at C-Reactive Protein for Risk Assessment 283 Fig Interactive effects of CRP and lipid tests in men (left) and women (right) (Adapted from Ridker PM Circulation 2001;103:1814–1815.) Fig Progressive increase in risk of death or MI stratified by increasing ACC/AHA lesion complexity score and CRP concentrations Numeric values indicate number of patients (Adapted from Chew DP, et al Circulation 2001:104;995.) higher risk if CRP concentrations are increased Thus, CRP testing might indicate a group to whom aggressive risk factor modification should be targeted, including weight loss, exercise, smoking cessation, and diet This concept also has pathophysiological appeal, given that CRP concentrations are higher in diabetics and individuals with obesity (35, 36) Indeed, adipose tissue is a potent source of IL-6, which is the main stimulus for CRP production in the liver Interestingly, recent data show that baseline concentrations of CRP and IL-6 are also strong independent predictors of the risk of incident type II diabetes among apparently healthy women (37) Although no studies have directly assessed the impact of CRP reduction on cardiovascular risk, intriguing data suggest that antiplatelet and statin therapy may be most 284 Blake and Ridker effective among individuals with chronic low-grade vascular inflammation, as evidenced by increased CRP concentrations For example, in the Physicians’ Health Study, randomization to aspirin was associated with a 56% risk reduction among those with baseline CRP concentrations in the highest quartile (9) The risk reduction declined with decreasing quartile concentrations of CRP Moreover, recent data suggest that the benefits of clopidogrel pretreatment in addition to aspirin for patients undergoing percutaneous coronary intervention may be greatest among those patients with increased CRP concentrations (38) Accumulating evidence suggests that statins may have powerful antiinflammatory effects (39,40) Indeed the risk reduction observed with these agents in large-scale clinical trials have been greater than that explained on the basis of changes in lipid parameters alone In this regard, several studies have recently demonstrated that statins reduce CRP concentrations, and that this effect is independent of lipid lowering (41–44) Data from the Cholesterol and Recurrent Events (CARE) trial, a secondary prevention study, indicates that statins may be most effective among patients with evidence of persistent inflammation (45) The CARE trial randomized patients with a prior history of MI to receive either pravastatin or placebo (46) Patients with evidence of persistent inflammation (as evidenced by an increase of both CRP and serum amyloid A) were at increased risk of recurrent cardiovascular events (45) The study group with the highest risk of recurrent events was that of patients with persistent evidence of inflammation who were assigned to placebo (relative risk 2.81; p = 0.007) The proportion of recurrent cardiovascular events prevented by pravastatin was 54% among those patients with high CRP and serum amyloid protein A (SAA) concentrations compared to 25% among those without persistent inflammation This difference was observed despite identical baseline LDL levels in these two groups A recent analysis from the Air Force/Texas Atherosclerosis Prevention Study (AFCAPS/ TexCAPS) population provides new data regarding the interaction between CRP concentrations and the benefits of statin therapy for primary prevention (31) In this analysis, individuals were divided into four groups according to median LDL (149 mg/dL) and CRP (0.16 mg/dL) concentrations The group with LDL < 149 mg/dL and low CRP concentrations were at low risk and showed no benefit from therapy with lovastatin compared to placebo Individuals with LDL >149 mg/dL were at more than twofold increased risk, regardless of CRP concentrations, and randomization to lovastatin for these individuals resulted in a large reduction in cardiovascular events compared to placebo However, the most intriguing results pertained to the group with low LDL (