C-reactive protein and cardiovascular risk: an update on what is going on in cardiology

Wolfgang Koenig

Department of Internal Medicine II, Cardiology, University of Ulm Medical Center, Ulm, Germany

Keywords: C-reactive protein; cardiovascular risk; clinical relevance; mechanisms

C-reactive protein and cardiovascular risk prediction: what is already known

The role of elevated high-sensitivity (hs) C-reactive protein (CRP) as a risk marker for cardiovascular (CV) diseases, including coronary heart disease (CHD) [1], stroke [2] and peripheral arterial disease [3] is well established through consistent results from a number of prospective studies. But CRP also conveys important prognostic information in the setting of the acute coronary syndrome. Subjects presenting with unstable angina or non ST-elevation myocardial infarction (MI) and increased levels of hs-CRP are candidates for a variety of adverse events like recurrent angina, ST elevation MI or coronary death. This holds true short-term for in-hospital complications but also long-term over years as has recently convincingly been shown by data from the FRISC trial [4]. Even in the presence of the results of troponin measurements, hs-CRP adds relevant prognostic information [5]. Moreover, persistent elevation of hs-CRP levels after optimal treatment of unstable angina according to current strategies, measured at the time of hospital discharge, is predictive of recurrent events [6]. Thus, from the clinical point of view, hs-CRP testing represents a valuable additional diagnostic tool.

New findings in primary prevention

More recent data have strongly supported the additional value of hs-CRP for CV risk assessment in primary prevention. They also suggest that hs-CRP is superior to other markers of inflammation for risk evaluation [7]. Whereas current guidelines recommend a lipid profile as the only blood test, compelling evidence suggests considerable improvement of risk prediction by adding measurement of hs-CRP [8]. An initial report by Ridker et al. [9] has already demonstrated that the combination of elevated hs-CRP (>2.11 mg/l) and elevated total cholesterol (TC, >234 mg/dl) was associated with a 5-fold increased risk for coronary events compared with a 1.5- and 2.3-fold increase, respectively, if only one parameter was elevated. The combined assessment of the most powerful predictor among lipoproteins, the TC/high-density-lipoprotein (HDL) cholesterol ratio and hs-CRP further improved risk estimates. In quintile analyses, those in the top quintile of both hs-CRP and the TC/HDL cholesterol ratio exhibited an 8.7-fold increased risk compared with a 2.2- and 4.2-fold increase in risk if the subject belonged to the top quintile of TC/HDL cholesterol ratio or the top quintile of hs-CRP alone and the bottom quintile of the respective variable [10].

Data from the AFCAPS/TexCAPS trial in primary prevention have shown that lovastatin effectively reduced CV endpoints in those with LDL-cholesterol levels >150 mg/dl, with or without elevated hs-CRP concentrations (>1.65 mg/l). Interestingly, lovastatin was equally effective in those with high CRP concentrations but with low LDL levels <150 mg/dl [11]. This finding is clearly in support of a central role of inflammation in CV complications and underlines the importance of hs-CRP measurement in these patients. Yet, before targeting statin use by hs-CRP measurements, this concept has to be tested in an adequately sized, randomized controlled clinical trial. Indeed, this is the purpose of the JUPITER trial that has just started recruiting its 15 000 subjects. Most recently [12] in the Womens' Health Study, the CV risk associated with elevated CRP concentrations has been compared directly with that of elevated low-density-lipoprotein (LDL)-cholesterol in 27 939 middle-aged women followed for 8 years. Both variables showed a clear linear relation with incident CV events. After multivariable adjustments, however, the association was stronger for CRP showing a 2.3-fold increased risk in those in the top quintile of the CRP distribution compared with the bottom quintile. In contrast, elevated LDL-cholesterol was associated with a relative risk of 1.5 in those belonging to the top quintile compared with those in the bottom quintile. In likelihood-ratio {chi}2 statistics, the model based on CRP discriminated better than LDL-cholesterol between events and non-events. Most importantly, the information conveyed by these two variables seemed to be complementary and thus identified different high-risk groups. Thus, screening for both markers may provide better information than screening for either alone. In spring 2003, new guidelines will be issued by the American Heart Association (AHA) and the Centers for Disease Control (CDC) including the potential role of CRP in CV risk assessment. Such additional blood tests may be combined with new imaging techniques, like computed tomography scanning for coronary calcium to even further improve risk prediction [13].

New associations with CRP relevant to cardiology

New-onset type 2 diabetes
Patients with type 2 diabetes mellitus (DM) but without presence of CHD exhibit a similar risk for coronary events as patients who have already suffered an acute MI but who are non-diabetic. Furthermore, several risk factors are relevant in both diseases, supporting the concept of a ‘common soil’ hypothesis [14]. Thus, it seems conceivable to suggest that inflammation may also play a role in the pathogenesis of type 2 DM, and indeed earlier studies have found increased levels of markers of systemic inflammation in patients with manifest type 2 DM, and prognosis of diabetic patients has been linked to such markers of inflammation [15]. Over the last year, several prospective studies have shown clearly that markers of inflammation, in particular CRP, are able to predict new-onset of type 2 DM [1620].

The insulin resistance syndrome
Several studies have investigated the association between CRP and measures of insulin resistance. Although definitions differed slightly among them, CRP concentrations were consistently associated with the various components of this syndrome [15].

Renal insufficiency
Patients with end-stage renal disease are at high risk for CV complications. Recent studies have accumulated compelling evidence for a role of CRP in improving risk prediction in this setting [21]. In the large Cardiovascular Health Study [22], renal insufficiency (serum creatinine level >=1.3 mg/dl in women and >=1.5 mg/dl in men) was independently associated with elevations of CRP, which may indicate an important pathway mediating the increased CV risk in persons with kidney disease.

Obstructive sleep apnea
Obstructive sleep apnea (OSA) has been linked to CV disease in a number of studies. In a recent report [23], OSA was associated in a dose-dependent manner with an inflammatory state, as assessed by elevated CRP levels. This may represent a pathophysiologic mechanism relevant for the occurrence of adverse CV events seen in these patients.

Persistent atrial fibrillation
CRP was found to be elevated in patients with non-postoperative atrial fibrillation (AF), in particular in those with higher AF burden. Inflammation may contribute to structural remodelling in the atria and increase the propensity for the persistence of this disorder [24].

Air pollution
Hospital admissions for CV diseases including the acute coronary syndrome and severe rhythm disturbances increase in association with particulate air pollution. However, the underlying mechanisms are not well understood. During a natural experiment, exposure to current levels of particulate matter resulted in an acute phase response with elevated CRP concentrations, which may in part explain the increased CV risk seen after exposure to air pollution [25].

CRP: risk marker or risk factor?

For an overview see Rosenson and Koenig [26]. Increasing evidence suggests that CRP may be directly involved in atherothrombogenesis that extends beyond its previously accepted role as an inflammatory marker. CRP is present in the vessel wall, where it induces expression of the adhesion molecules E-selectin, VCAM-1 and ICAM-1 by endothelial cells, and serves as a chemoattractant for monocytes as mediated by induction of MCP-1. CRP opsonizes LDL and facilitates native LDL entry into macrophages. CRP binds to plasma membranes of damaged cells and activates complement via the classical pathway; and an intact complement system seems to be crucial for maturation of atherosclerotic lesions [27]. CRP is associated with endothelial cell dysfunction and progression of atherosclerosis [26], possibly by decreasing nitric oxide synthesis [28]; and predicts enhanced vasoreactivity of the culprit lesion in patients with unstable angina [16]. In line with these observations is the finding that CRP has the ability to sensitize endothelial cells to destruction by cytotoxic CD4+ T cells [29]. In addition, CRP facilitates thrombogenesis through stimulation of tissue factor biosynthesis by macrophages [26], which nicely relates to autoptic findings suggesting that high CRP plasma concentrations and the extent of its deposition in the atherosclerotic plaque are associated with plaque vulnerability and the occurrence of acute thrombotic events [30].

Taken together, these recent findings on the pathophysiological role of CRP in atherogenesis may have several implications for future research, including the implementation of therapeutic strategies in CV diseases: (i) CRP plasma levels may become a target for intervention, e.g. by inhibiting hepatic biosynthesis. (ii) It is intriguing to speculate that direct interference with CRP-mediated effects either on the receptor level or on the level of CRP-mediated complement activation may influence progression of atherosclerosis and its complications. However, the primary cause for the accumulation and activation of inflammatory cells in the arterial subintimal space and the subsequent expression of pro-inflammatory cytokines and other mediators which play an important role in plaque progression and finally contribute to plaque destabilization and rupture, still remains largely unclear.

Conclusions

In summary, recent research on CRP has further established its role as a powerful risk marker for various CV endpoints in different settings; new potential indications are emerging, and experimental studies have provided new insights in a possibly important direct role of CRP in atherogenesis. This might be of major importance for the advancement of our understanding of atherosclerosis and may open new horizons to combat this far spread disease.

Conflict of interest statement. None declared.

Notes

Correspondence and offprint requests to: Wolfgang Koenig, MD, FESC, FACC, Professor of Medicine/Cardiology, Department of Internal Medicine II, Cardiology, University of Ulm Medical Center, Robert-Koch Strasse 8, D-89081 Ulm/Germany. Email: http://wolfgang.koenig{at}medizin.uni-ulm.de Back

References

  1. Danesh J, Whincup P, Walker M et al. Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. Br Med J 2000; 321:199–204[Abstract/Free Full Text]
  2. Gussekloo J, Schaap MCL, Frölich M, Blauw GJ, Westendorp RGJ. C-reactive protein is a strong but nonspecific risk factor of fatal stroke in elderly persons. Arterioscler Thromb Vasc Biol 2000; 20:1047–1051[Abstract/Free Full Text]
  3. 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. J Am Med Assoc 2001; 285:2481–2585[Abstract/Free Full Text]
  4. Lindahl B, Toss H, Siegbahn A et al. 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; 343:1139–1147[Abstract/Free Full Text]
  5. 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. J Am Coll Cardiol 2000; 35:1535–1542[CrossRef][ISI][Medline]
  6. Ferreiros ER, Boissonet CP, Pizarro R et al. Independent prognostic value of elevated C-reactive protein in unstable angina. Circulation 1999; 100:1958–1963[Abstract/Free Full Text]
  7. Ridker PM, Hennekens CH, Burin J, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardivascular disease in women. N Engl J Med 2000; 342:836–843[Abstract/Free Full Text]
  8. 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[Abstract/Free Full Text]
  9. Ridker PM, Glynn RJ, Hennekens CH. C-reactive protein adds to the predictive values of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation 1998; 97:2007–2011[Abstract/Free Full Text]
  10. Rifai N, Ridker PM. High-sensitivity C-reactive protein: a novel and promising marker of coronary heart disease. Clin Chem 2001; 47:403–411[Abstract/Free Full Text]
  11. Ridker PM, Rifai N, Clearfield DO 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[Abstract/Free Full Text]
  12. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in prediction of first cardiovascular events. N Engl J Med 2002; 347:1557–1565[Abstract/Free Full Text]
  13. Park R, Detrano R, Xiang M et al. Combined use of computed tomography coronary calcium scores and C-rective protein levels in predicting cardiovascular events in nondiabetic individuals. Circulation 2002; 106:2073–2077[Abstract/Free Full Text]
  14. Stern MP. Diabetes and cardiovascular disease. The ‘common soil’ hypothesis. Diabetes 1995; 44:369–374[Abstract]
  15. Koenig W. Insulin resistance, heart disease and inflammation: identifying the ‘at risk’ patient: the earlier the better? The role of inflammatory markers. Int J Clin Pract Suppl 2002; 132:23–30[Medline]
  16. Pradhan AD, Manson JAF, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. J Am Med Assoc 2002; 286:327–334[ISI]
  17. Barzilay JI, Abraham L, Heckbert SR et al. The relation of markers of inflammation to the development of glucose disorders in the elderly. The Cardiovascular Health Study. Diabetes 2001; 50:2384–2389[Abstract/Free Full Text]
  18. Festa A, D'Agostino R, Tracy RP, Haffner SE. Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes. The Insulin Resistance Atherosclerosis Study. Diabetes 2002; 51:1131–1137[Abstract/Free Full Text]
  19. Freeman DJ, Norrie J, Caslake MJ et al. C-reactive protein is an independent predictor of risk for the development of diabetes in the West of Scotland Coronary Prevention Study. Diabetes 2002; 51:1596–1600[Abstract/Free Full Text]
  20. Thorand B, Löwel H, Schneider A et al. C-reactive protein as a predictor for incident diabetes mellitus among middle-aged men. Results from the MONICA Augsburg Cohort Study, 1984 to 1998. Arch Intern Med 2003; 163:93–99[Abstract/Free Full Text]
  21. Arici M, Walls J. End-stage renal disease, atherosclerosis, and cardiovascular mortality: is C-reactive protein the missing link? Kidney Int 2001; 59:407–414[CrossRef][ISI][Medline]
  22. Shlipak MG, Fried LF, Crump C et al. Elevations of inflammatory and procoagulant biomarkers in elderly persons with renal insufficiency. Circulation 2003; 107:32–37[Abstract/Free Full Text]
  23. Shamsuzzaman ASM, Winnicki M, Lanfranchi P et al. Elevated C-reactive protein in patients with obstructive sleep apnea. Circulation 2002; 105:2462–2464[Abstract/Free Full Text]
  24. Chung MK, Martin DO, Sprecher D et al. C-reactive protein elevation in patients with atrial arrythmias. Inflammatory mechanisms and persistence of artial fibrillation. Circulation 2001; 104:2886–2891[Abstract/Free Full Text]
  25. Peters A, Fröhlich M, Döring A et al. Particulate air pollution is associated with an acute phase response in men. Results from the MONICA-Augsburg Study. Eur Heart J 2001; 22:1198–1204[Abstract/Free Full Text]
  26. Rosenson RS, Koenig W. High-sensitivity CRP and cardiovascular risk in CHD patients. Curr Opin Cardiol 2002; 17:325–331[CrossRef][ISI][Medline]
  27. Buono C, Come CE, Witztum JL et al. Influence of C3 deficiency on atherosclerosis. Circulation 2002; 105:3025–3031[Abstract/Free Full Text]
  28. Verma S, Wang C-H, Li S-H et al. A self-fulfilling prophecy. C-reactive protein attenuates nitric oxide production and inhibits angiogenesis. Circulation 2002; 106:913–919[Abstract/Free Full Text]
  29. Nakajimi T, Schulte S, Warrington KJ et al. T-cell mediated lysis of endothelial cells in acute coronary syndromes. Circulation 2002; 105:570–575[Abstract/Free Full Text]
  30. Burke AP, Tracy RP, Kolodgie F et al. Elevated C-reactive protein values and atherosclerosis in sudden coronary death. Association with different pathologies. Circulation 2002; 105:2019–2023[Abstract/Free Full Text]