- Email: [email protected]
C-reactive protein and primary prevention of ischemic heart disease
Clinica Chimica Acta 311 Ž2001. 45–48 www.elsevier.comrlocaterclinchim
C-reactive protein and primary prevention of ischemic heart disease Giovanna Liuzzo ) , Vittoria Rizzello Institute of Cardiology, Catholic UniÕersity, Ospedale Gemelli, Largo Gemelli, 8, 00168 Rome, Italy
Abstract C-reactive protein ŽCRP. is the prototype acute phase reactant and therefore a marker of systemic inflammation. In the last decades, accumulating data have demonstrated the role of inflammation in the pathogenesis of ischemic heart disease. High CRP levels, measured by high-sensitivity methods, on admission have a short-term negative prognostic value and are associated with a worse outcome. In epidemiological studies, minor elevations of CRP are associated with future risk of myocardial infarction, stroke and peripheral vascular disease. This increased risk is independent of other biochemical and clinical risk factors, and the association between high CRP and an abnormal cholesterol ratio significantly increases the risk in the individual patient. Finally, the observation of an increased level of CRP may be of clinical utility in primary prevention, because these subjects favourably benefit from statin therapy. q 2001 Published by Elsevier Science B.V. Keywords: Inflammatory conditions; Vascular risk; LDL-cholesterol; Primary prevention; Status
1. Introduction C-reactive protein is the prototypic acute phase reactant; indeed its levels increase rapidly after an inflammatory stimulus and may raise hundreds of fold according to the intensity of stimulus w1x. In human beings the major inducer of CRP is interleukin-6 ŽIL-6., which in turn, is induced by tumor necrosis factor-a ŽTNF-a ., interleukin 1 ŽIL-1., platelet derived growth factor ŽPDGF., antigens and endotoxins. Although small amounts of m-RNA for CRP have been detected in alveolar macrophages and in monocytes, these cells do not secrete CRP and, in human beings, the major amount of CRP is produced by the liver w2,3x. A half-life of 19 h, its )
Corresponding author. Tel.: q390-6-3015-4187; fax: q390-63055-535.
stability in blood samples even after prolonged storage at ambient temperature and finally the commercial availability of easy, inexpensive, precise and reproducible methods for CRP measurement, make CRP an ideal marker of disease activity in many inflammatory and infective diseases. In the last 20 years, accumulating data have demonstrated the role of inflammation in the pathogenesis of ischemic heart disease ŽIHD., particularly in unstable angina ŽUA.. Indeed, patients with UA show atherosclerotic plaques with a significant infiltration of inflammatory cells and elevated systemic levels of acute phase proteins, such as CRP. Actually, because CRP levels in IHD are much lower than those detected in other inflammatory conditions, all of the up-to-date published studies have used a high-sensitivity method for CRP measurement Žhs-CRP..
0009-8981r01r$ - see front matter q 2001 Published by Elsevier Science B.V. PII: S 0 0 0 9 - 8 9 8 1 Ž 0 1 . 0 0 5 5 7 - 5
46
G. Liuzzo, V. Rizzellor Clinica Chimica Acta 311 (2001) 45–48
In 1994, for the first time, we have demonstrated that in patients with UA, high CRP levels on admission have a short-term negative prognostic value, predicting in-hospital recurrence of coronary events w4x. Following several studies w5–14x have seen that elevated CRP levels are associated with a worse early and late outcome. In clinical practice then, CRP levels may be used to stratify UA patients into low- and high-risk subjects, the latter of whom could benefit from a more aggressive approach.
2. CRP and risk of coronary artery disease Interestingly, CRP may be used as marker of ischemic risk also in apparently healthy subjects. Indeed, prospective studies have shown a strong and consistent association between baseline levels of CRP and cardiovascular end-points, in broad, apparently healthy populations. The most important data relating CRP and vascular disease derive from large-scale epidemiological studies, in which minor elevations in CRP among apparently healthy men were associated with future risk of myocardial infarction, stroke and peripheral vascular disease. In the Physician’s Health Study w15x, about 22 000 middle-aged healthy men, with no prior history of myocardial infarction, stroke or cancer had blood samples drawn at baseline. To exclude acute or chronic significant inflammatory conditions, any CRP value 3 standard deviation above the mean was excluded from the data-base, which resulted in a loss of less of 0.5% of the whole study population. In this study, CRP was measured in 543 apparently healthy men in whom myocardial infarction, stroke or venous thrombosis subsequently developed, and in 543 matched apparently healthy men who did not report vascular disease during a follow-up exceeding 8 years. Participants were randomly assigned to receive aspirin or placebo at the beginning of the study. The study resulted in a more than threefold increase in the risk of future myocardial infarction. Intriguingly, aspirin in a dosage between 250 and 300 mgrday, which is far below any dosage showing known anti-inflammatory effect, brought a risk reduction of roughly 50–55% in the fourth quartile of CRP concentrations, with decreasing effects in the lower CRP quartiles.
A remarkably consistent series of studies w16–19x have confirmed in different populations, such as high-risk smokers, elderly, post-menopausal women and a cohort of apparently healthy men from a large European population, that CRP in the upper quartile is associated with a 2- to 4-fold increase in future risk of cardiovascular events. Although CRP levels are associated with smoking habitus, in the Physician’s Health Study, where the nonsmokers were 85% of the total population, a very profound increased risk was observed also in this group. At variance in the MRFIT trial w16x, including younger patients but with a higher-risk profile, and a majority of smokers, the increase in risk was confined to the smoker population. This observation raise the question of whether or not CRP is independent from other risk factors, and whether or not it has additive effect on the power of risk detection. In the Physician’s Health Study and in the more recent Women’s Health Study w18x, CRP was a significant predictor of risk, independently from other risk factors as cholesterol Žtotal and HDL., triglycerides, lipoprotein Ža., t-PA antigen, homocystine, D-dimer, fibrinogen, and body mass index, diabetes, hypertension, family history of coronary heart disease. Of particular interest is the additive value of CRP on the top of the total cholesterolrHDL cholesterol ratio, a well-known risk factor for ischemic heart disease. Analysis of the data of the Physician’s Health Study, considering the risk associated with cholesterol ratio Žtotal cholesterolrHDL cholesterol. and CRP levels expressed in tertiles, has shown that the association of both CRP and cholesterol ratio in the top tertiles carries a risk much higher than that associated with the top tertile of cholesterol ratio alone w20x. On the other hand, also patients in the middle tertile of cholesterol ratio but in the higher tertile of CRP have a risk higher than that associated with being in the top tertile of cholesterol ratio alone. These data are highly reproducible and consistent, as similar results have been presented by other authors in different populations w9x, and may profoundly change the approach to risk profile in healthy subjects as well as in patients with ischemic heart disease. In fact, these data raise the question of whether CRP and cholesterol should be measured together, and whether it is appropriate to treat all patients with elevated cholesterol, but not those with moderately elevated cholesterol and high
G. Liuzzo, V. Rizzellor Clinica Chimica Acta 311 (2001) 45–48
CRP. In the CARE trial w21,22x, a group of patients with medium cholesterol levels was randomized to pravastatin or placebo: only the group with high CRP showed significant benefits, but many of these patients would not be qualified for statin therapy if the decision is only based on lipid parameters. A further confirmation to the initial data from the Physician’s Health Study has come from the Monica–Ausburg study w19x, which represent the first population based study investigating the prognostic role of CRP in relation to other risk factors. Also in this study, CRP was an independent marker of risk, with hazard risk ratio ŽHRR. increasing 1.67-fold for any SD increase in log-CRP.
3. CRP and therapeutic options for primary prevention The observation that the addition of CRP testing to standard lipid screening provides an improved method to determine vascular risk, as well as accumulating evidence that CRP may have direct inflammatory effects at the endothelial level w23x, have implications for the use of statins. For example, in the Cholesterol and Recurrent Events ŽCARE. trial, random allocation to pravastatin both attenuated the excess vascular risk associated with low-grade, systemic inflammation and significantly reduced CRP levels over a 5-year follow-up period w22x. Moreover, in that study, the change in CRP attributable to pravastatin was unrelated to changes in LDL cholesterol ŽLDL-C., an observation supporting the hypothesis that statin therapy may have important nonlipid anti-inflammatory effects. These data have been recently confirmed in a randomized trial of cerivastatin in a cohort of 785 patients with primary hypercholesterolemia w24x; in this study, CRP levels were significantly reduced within 8 weeks of initiating cerivastatin therapy in a lipid-independent manner. These results are supported by data from Ridker et al. w25x in the Air ForcerTexas Coronary Atherosclerosis Prevention Study ŽAFCAPSrTexCAPS. of lovastatin. Because primary prevention studies have consistently found that individuals with low LDL-C but high CRP levels are at high vascular risk, these data also support the hypothesis that statin therapy might
47
be effective even in the absence of overt hyperlipidemia, an issue in need of direct testing in future clinical trials.
4. Conclusions In conclusion, all prospective studies so far published, including only individuals without known cardiovascular disease, have highly consistent results reporting a relative risk between 3 and 3.5 for levels of CRP elevated, but still within the normal range. This increased risk is independent of other risk factors. These observations have clinical utility in primary prevention, as hs-CRP is an easy measurable marker that identify high-risk individuals who can benefit of more careful monitoring and more aggressive treatment of other known cardiovascular risk factors.
References w1x Kushner I. The phenomenon of the acute phase response. Ann N Y Acad Sci 1982;389:39–48. w2x Pepys MB, Baltz ML. Acute phase proteins withspecial reference to C-reactive Protein and related proteins Žpentaxins. and plasma amyloid A protein. Adv Immunol 1983;34: 141–212. w3x Hurlimann J, Thorbecke GJ, Hochwald GM. The liver as the site of C-reactive protein formation. J Exp Med 1966;123: 365–78. w4x 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;331:417–24. w5x Thompson SG, Kienast J, Pyke SD, Haverkate F, van de Loo JC. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris: European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. N Engl J Med 1995;332Ž10.:635–41. Mar 9. w6x Haverkate F, Thompson SG, Pyke SD, Gallimore JR, Pepys MB. 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;349Ž9050.:462–6. Feb. 15. w7x Toss H, Lindahl B, Siegbahn A, Wallentin L. Prognostic influence of increased fibrinogen and C-reactive protein levels in unstable coronary artery disease. FRISC Study Group: Fragmin during Instability in Coronary Artery Disease. Circulation 1997;96Ž12.:4204–10. Dec. 16. w8x Morrow DA, Rifai N, Antman EM, et al. C-reactive protein
48
w9x
w10x
w11x
w12x
w13x
w14x
w15x
w16x
G. Liuzzo, V. Rizzellor Clinica Chimica Acta 311 (2001) 45–48 is a potent predictor of mortality independently of and in combination with troponin T in acute coronary syndromes: a TIMI 11A substudy. Thrombolysis in Myocardial Infarction. J Am Coll Cardiol 1998;31Ž7.:1460–5. Jun. Biasucci LM, Liuzzo G, Grillo RL, et al. Elevated levels of C-reactive protein at discharge in patients with unstable angina predict recurrent instability. Circulation 1999;99Ž7.: 855–60. Feb. 23. Ferreiros ER, Boissonnet CP, Pizarro R, et al. Independent prognostic value of elevated C-reactive protein in unstable angina. Circulation 1999;100Ž19.:1958–63. Nov. 9. Rebuzzi AG, Quaranta G, Liuzzo G, et al. Incremental prognostic value of serum levels of troponin T and C-reactive protein on admission in patients with unstable angina pectoris. Am J Cardiol 1998;82Ž6.:715–9. Sep. 15. Heeschen C, Hamm CW, Bruemmer J, Simoons ML. Predictive value of C-reactive protein and troponin T in patients with unstable angina: a comparative analysis. CAPTURE Investigators: Chimeric c7E3 AntiPlatelet Therapy in Unstable angina REfractory to standard treatment trial. J Am Coll Cardiol 2000;35Ž6.:1535–42. May. Lindahl B, Toss H, Siegbahn A, Venge P, Wallentin L. Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC study group: Fragmin during Instability in Coronary Artery Disease. N Engl J Med 2000;343Ž16.:1139–47. Oct. 19. Biasucci LM, Meo A, Buffon A, et al. Independent prognostic value of CRP levels for in-hospital death and myocardial infarction in unstable angina. Circulation 2000;102Ž18 suppl..:499 Žabstract.. 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;336:973–9. Kuller LH, Russel PT, Shaten J. Meilahn for the MRFIT
w17x
w18x
w19x
w20x
w21x
w22x
w23x
w24x
w25x
research group: relation of C-reactive protein and coronary heart disease in the MIRFT nested case-control study. Am J Epidemiol 1996;144:537–47. 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;98:731–3. 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; 342Ž12.:836–43. Koenig W, Pepys MP. C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease initially healthy middle-aged men. Circulation 1999;99: 237–42. Ridker PM, Glynn RJ, Hennekens CH. C-reactive Protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation 1998;97:2007. 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 ŽCARE. Investigators. Circulation 1998;98Ž9.:839–44. Ridker PM, Rifai N, Pfeffer M, et al. Long-term effects of pravastatin on plasma concentration of C-reactive protein. Circulation 1999;100:230–5. 11. Pasceri V, Willerson JT, Yeh ETH. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation 2000;102:2165–8. Ridker PM, Rifai N, Lowenthal SP. Rapid reduction in C-reactive protein with cerivastatin among 785 patients with primary hypercholesterolemia. Circulation 2001;103:1191–3. Ridker PM, Rifai N, et al. Lovastatin 20–40 mgrday lowers high sensitivity C-reactive protein levels in AFCAPSr TexCAPS. Circulation 2000;102Žsuppl. 18.:4005 Žabstr...
C-reactive protein and primary prevention of ischemic heart disease Giovanna Liuzzo ) , Vittoria Rizzello Institute of Cardiology, Catholic UniÕersity, Ospedale Gemelli, Largo Gemelli, 8, 00168 Rome, Italy
Abstract C-reactive protein ŽCRP. is the prototype acute phase reactant and therefore a marker of systemic inflammation. In the last decades, accumulating data have demonstrated the role of inflammation in the pathogenesis of ischemic heart disease. High CRP levels, measured by high-sensitivity methods, on admission have a short-term negative prognostic value and are associated with a worse outcome. In epidemiological studies, minor elevations of CRP are associated with future risk of myocardial infarction, stroke and peripheral vascular disease. This increased risk is independent of other biochemical and clinical risk factors, and the association between high CRP and an abnormal cholesterol ratio significantly increases the risk in the individual patient. Finally, the observation of an increased level of CRP may be of clinical utility in primary prevention, because these subjects favourably benefit from statin therapy. q 2001 Published by Elsevier Science B.V. Keywords: Inflammatory conditions; Vascular risk; LDL-cholesterol; Primary prevention; Status
1. Introduction C-reactive protein is the prototypic acute phase reactant; indeed its levels increase rapidly after an inflammatory stimulus and may raise hundreds of fold according to the intensity of stimulus w1x. In human beings the major inducer of CRP is interleukin-6 ŽIL-6., which in turn, is induced by tumor necrosis factor-a ŽTNF-a ., interleukin 1 ŽIL-1., platelet derived growth factor ŽPDGF., antigens and endotoxins. Although small amounts of m-RNA for CRP have been detected in alveolar macrophages and in monocytes, these cells do not secrete CRP and, in human beings, the major amount of CRP is produced by the liver w2,3x. A half-life of 19 h, its )
Corresponding author. Tel.: q390-6-3015-4187; fax: q390-63055-535.
stability in blood samples even after prolonged storage at ambient temperature and finally the commercial availability of easy, inexpensive, precise and reproducible methods for CRP measurement, make CRP an ideal marker of disease activity in many inflammatory and infective diseases. In the last 20 years, accumulating data have demonstrated the role of inflammation in the pathogenesis of ischemic heart disease ŽIHD., particularly in unstable angina ŽUA.. Indeed, patients with UA show atherosclerotic plaques with a significant infiltration of inflammatory cells and elevated systemic levels of acute phase proteins, such as CRP. Actually, because CRP levels in IHD are much lower than those detected in other inflammatory conditions, all of the up-to-date published studies have used a high-sensitivity method for CRP measurement Žhs-CRP..
0009-8981r01r$ - see front matter q 2001 Published by Elsevier Science B.V. PII: S 0 0 0 9 - 8 9 8 1 Ž 0 1 . 0 0 5 5 7 - 5
46
G. Liuzzo, V. Rizzellor Clinica Chimica Acta 311 (2001) 45–48
In 1994, for the first time, we have demonstrated that in patients with UA, high CRP levels on admission have a short-term negative prognostic value, predicting in-hospital recurrence of coronary events w4x. Following several studies w5–14x have seen that elevated CRP levels are associated with a worse early and late outcome. In clinical practice then, CRP levels may be used to stratify UA patients into low- and high-risk subjects, the latter of whom could benefit from a more aggressive approach.
2. CRP and risk of coronary artery disease Interestingly, CRP may be used as marker of ischemic risk also in apparently healthy subjects. Indeed, prospective studies have shown a strong and consistent association between baseline levels of CRP and cardiovascular end-points, in broad, apparently healthy populations. The most important data relating CRP and vascular disease derive from large-scale epidemiological studies, in which minor elevations in CRP among apparently healthy men were associated with future risk of myocardial infarction, stroke and peripheral vascular disease. In the Physician’s Health Study w15x, about 22 000 middle-aged healthy men, with no prior history of myocardial infarction, stroke or cancer had blood samples drawn at baseline. To exclude acute or chronic significant inflammatory conditions, any CRP value 3 standard deviation above the mean was excluded from the data-base, which resulted in a loss of less of 0.5% of the whole study population. In this study, CRP was measured in 543 apparently healthy men in whom myocardial infarction, stroke or venous thrombosis subsequently developed, and in 543 matched apparently healthy men who did not report vascular disease during a follow-up exceeding 8 years. Participants were randomly assigned to receive aspirin or placebo at the beginning of the study. The study resulted in a more than threefold increase in the risk of future myocardial infarction. Intriguingly, aspirin in a dosage between 250 and 300 mgrday, which is far below any dosage showing known anti-inflammatory effect, brought a risk reduction of roughly 50–55% in the fourth quartile of CRP concentrations, with decreasing effects in the lower CRP quartiles.
A remarkably consistent series of studies w16–19x have confirmed in different populations, such as high-risk smokers, elderly, post-menopausal women and a cohort of apparently healthy men from a large European population, that CRP in the upper quartile is associated with a 2- to 4-fold increase in future risk of cardiovascular events. Although CRP levels are associated with smoking habitus, in the Physician’s Health Study, where the nonsmokers were 85% of the total population, a very profound increased risk was observed also in this group. At variance in the MRFIT trial w16x, including younger patients but with a higher-risk profile, and a majority of smokers, the increase in risk was confined to the smoker population. This observation raise the question of whether or not CRP is independent from other risk factors, and whether or not it has additive effect on the power of risk detection. In the Physician’s Health Study and in the more recent Women’s Health Study w18x, CRP was a significant predictor of risk, independently from other risk factors as cholesterol Žtotal and HDL., triglycerides, lipoprotein Ža., t-PA antigen, homocystine, D-dimer, fibrinogen, and body mass index, diabetes, hypertension, family history of coronary heart disease. Of particular interest is the additive value of CRP on the top of the total cholesterolrHDL cholesterol ratio, a well-known risk factor for ischemic heart disease. Analysis of the data of the Physician’s Health Study, considering the risk associated with cholesterol ratio Žtotal cholesterolrHDL cholesterol. and CRP levels expressed in tertiles, has shown that the association of both CRP and cholesterol ratio in the top tertiles carries a risk much higher than that associated with the top tertile of cholesterol ratio alone w20x. On the other hand, also patients in the middle tertile of cholesterol ratio but in the higher tertile of CRP have a risk higher than that associated with being in the top tertile of cholesterol ratio alone. These data are highly reproducible and consistent, as similar results have been presented by other authors in different populations w9x, and may profoundly change the approach to risk profile in healthy subjects as well as in patients with ischemic heart disease. In fact, these data raise the question of whether CRP and cholesterol should be measured together, and whether it is appropriate to treat all patients with elevated cholesterol, but not those with moderately elevated cholesterol and high
G. Liuzzo, V. Rizzellor Clinica Chimica Acta 311 (2001) 45–48
CRP. In the CARE trial w21,22x, a group of patients with medium cholesterol levels was randomized to pravastatin or placebo: only the group with high CRP showed significant benefits, but many of these patients would not be qualified for statin therapy if the decision is only based on lipid parameters. A further confirmation to the initial data from the Physician’s Health Study has come from the Monica–Ausburg study w19x, which represent the first population based study investigating the prognostic role of CRP in relation to other risk factors. Also in this study, CRP was an independent marker of risk, with hazard risk ratio ŽHRR. increasing 1.67-fold for any SD increase in log-CRP.
3. CRP and therapeutic options for primary prevention The observation that the addition of CRP testing to standard lipid screening provides an improved method to determine vascular risk, as well as accumulating evidence that CRP may have direct inflammatory effects at the endothelial level w23x, have implications for the use of statins. For example, in the Cholesterol and Recurrent Events ŽCARE. trial, random allocation to pravastatin both attenuated the excess vascular risk associated with low-grade, systemic inflammation and significantly reduced CRP levels over a 5-year follow-up period w22x. Moreover, in that study, the change in CRP attributable to pravastatin was unrelated to changes in LDL cholesterol ŽLDL-C., an observation supporting the hypothesis that statin therapy may have important nonlipid anti-inflammatory effects. These data have been recently confirmed in a randomized trial of cerivastatin in a cohort of 785 patients with primary hypercholesterolemia w24x; in this study, CRP levels were significantly reduced within 8 weeks of initiating cerivastatin therapy in a lipid-independent manner. These results are supported by data from Ridker et al. w25x in the Air ForcerTexas Coronary Atherosclerosis Prevention Study ŽAFCAPSrTexCAPS. of lovastatin. Because primary prevention studies have consistently found that individuals with low LDL-C but high CRP levels are at high vascular risk, these data also support the hypothesis that statin therapy might
47
be effective even in the absence of overt hyperlipidemia, an issue in need of direct testing in future clinical trials.
4. Conclusions In conclusion, all prospective studies so far published, including only individuals without known cardiovascular disease, have highly consistent results reporting a relative risk between 3 and 3.5 for levels of CRP elevated, but still within the normal range. This increased risk is independent of other risk factors. These observations have clinical utility in primary prevention, as hs-CRP is an easy measurable marker that identify high-risk individuals who can benefit of more careful monitoring and more aggressive treatment of other known cardiovascular risk factors.
References w1x Kushner I. The phenomenon of the acute phase response. Ann N Y Acad Sci 1982;389:39–48. w2x Pepys MB, Baltz ML. Acute phase proteins withspecial reference to C-reactive Protein and related proteins Žpentaxins. and plasma amyloid A protein. Adv Immunol 1983;34: 141–212. w3x Hurlimann J, Thorbecke GJ, Hochwald GM. The liver as the site of C-reactive protein formation. J Exp Med 1966;123: 365–78. w4x 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;331:417–24. w5x Thompson SG, Kienast J, Pyke SD, Haverkate F, van de Loo JC. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris: European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. N Engl J Med 1995;332Ž10.:635–41. Mar 9. w6x Haverkate F, Thompson SG, Pyke SD, Gallimore JR, Pepys MB. 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;349Ž9050.:462–6. Feb. 15. w7x Toss H, Lindahl B, Siegbahn A, Wallentin L. Prognostic influence of increased fibrinogen and C-reactive protein levels in unstable coronary artery disease. FRISC Study Group: Fragmin during Instability in Coronary Artery Disease. Circulation 1997;96Ž12.:4204–10. Dec. 16. w8x Morrow DA, Rifai N, Antman EM, et al. C-reactive protein
48
w9x
w10x
w11x
w12x
w13x
w14x
w15x
w16x
G. Liuzzo, V. Rizzellor Clinica Chimica Acta 311 (2001) 45–48 is a potent predictor of mortality independently of and in combination with troponin T in acute coronary syndromes: a TIMI 11A substudy. Thrombolysis in Myocardial Infarction. J Am Coll Cardiol 1998;31Ž7.:1460–5. Jun. Biasucci LM, Liuzzo G, Grillo RL, et al. Elevated levels of C-reactive protein at discharge in patients with unstable angina predict recurrent instability. Circulation 1999;99Ž7.: 855–60. Feb. 23. Ferreiros ER, Boissonnet CP, Pizarro R, et al. Independent prognostic value of elevated C-reactive protein in unstable angina. Circulation 1999;100Ž19.:1958–63. Nov. 9. Rebuzzi AG, Quaranta G, Liuzzo G, et al. Incremental prognostic value of serum levels of troponin T and C-reactive protein on admission in patients with unstable angina pectoris. Am J Cardiol 1998;82Ž6.:715–9. Sep. 15. Heeschen C, Hamm CW, Bruemmer J, Simoons ML. Predictive value of C-reactive protein and troponin T in patients with unstable angina: a comparative analysis. CAPTURE Investigators: Chimeric c7E3 AntiPlatelet Therapy in Unstable angina REfractory to standard treatment trial. J Am Coll Cardiol 2000;35Ž6.:1535–42. May. Lindahl B, Toss H, Siegbahn A, Venge P, Wallentin L. Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC study group: Fragmin during Instability in Coronary Artery Disease. N Engl J Med 2000;343Ž16.:1139–47. Oct. 19. Biasucci LM, Meo A, Buffon A, et al. Independent prognostic value of CRP levels for in-hospital death and myocardial infarction in unstable angina. Circulation 2000;102Ž18 suppl..:499 Žabstract.. 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;336:973–9. Kuller LH, Russel PT, Shaten J. Meilahn for the MRFIT
w17x
w18x
w19x
w20x
w21x
w22x
w23x
w24x
w25x
research group: relation of C-reactive protein and coronary heart disease in the MIRFT nested case-control study. Am J Epidemiol 1996;144:537–47. 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;98:731–3. 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; 342Ž12.:836–43. Koenig W, Pepys MP. C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease initially healthy middle-aged men. Circulation 1999;99: 237–42. Ridker PM, Glynn RJ, Hennekens CH. C-reactive Protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation 1998;97:2007. 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 ŽCARE. Investigators. Circulation 1998;98Ž9.:839–44. Ridker PM, Rifai N, Pfeffer M, et al. Long-term effects of pravastatin on plasma concentration of C-reactive protein. Circulation 1999;100:230–5. 11. Pasceri V, Willerson JT, Yeh ETH. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation 2000;102:2165–8. Ridker PM, Rifai N, Lowenthal SP. Rapid reduction in C-reactive protein with cerivastatin among 785 patients with primary hypercholesterolemia. Circulation 2001;103:1191–3. Ridker PM, Rifai N, et al. Lovastatin 20–40 mgrday lowers high sensitivity C-reactive protein levels in AFCAPSr TexCAPS. Circulation 2000;102Žsuppl. 18.:4005 Žabstr...