As early as 1997 it was reported that baseline high-sensitivity C-reactive protein (hs-CRP) levels predicted the risk of heart attack and stroke in apparently healthy men (1). These findings were confirmed in a large study of healthy women, which additionally found that hs-CRP was a stronger predictor of cardiovascular events than LDL cholesterol (2).

Based on these findings physicians could start using both lipid and hs-CRP measurements to improve the prediction of global CVD risk. hs-CRP also adds prognostic information at all levels of the Framingham Risk Score (2) and predicts CVD risk in patients with the metabolic syndrome (3).

Recent data suggest that hypertension is in part an inflammatory disorder. In a study of over 15, 000 healthy American women it was found that hs-CRP and blood pressure were independent predictors of CVD events, and that hs-CRP added prognostic information at all levels of blood pressure in the prediction of first incident cardiovascular events (4). hs-CRP levels were also found to predict incident hypertension in a large study of initially normotensive women, even in subjects having low baseline blood pressure levels (5).

Experimental studies have shown that angiotensin II induces interleukin-6 production by human vascular smooth muscle cells (6). IL-6 in turn is known to induce CRP production.

The Val-MARC (Valsartan-Managing BP Agressively and Evaluating Reductions in hsCRP) trial which is currently underway, was designed to ask whether blood pressure reduction will lower hs-CRP levels in patients with stage II hypertension, and also whether moderate or aggressive blood pressure reduction would have different effects on hs-CRP levels.

CRP is now understood to play a role in several processes related to atherothrombosis and the genesis of high blood pressure. Of interest is a study done in human CRP transgenic mice that showed increased thrombosis after arterial injury (7). Another study showed that human CRP transgene expression in apoE deficient mice caused accelerated aortic atherosclerosis (8).

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After viewing this presentation the participant will be able to discuss:

- Studies demonstrating the increased risk of cardiovascular events and incident hypertension with elevated hs-CRP levels
- The aims and design of the Val-MARC trial
- Experimental evidence supporting a role for CRP in atherothrombosis.

1. Paul M. Ridker, M.D., Mary Cushman, M.D., Meir J. Stampfer, M.D., Russell P. Tracy, Ph.D., and Charles H. Hennekens, M.D.Inflammation, Aspirin, and the Risk of Cardiovascular Disease in Apparently Healthy MenNEJM.1997;336:973-979.

2. Paul M. Ridker, M.D., Nader Rifai, Ph.D., Lynda Rose, M.S., Julie E. Buring, Sc.D., and Nancy R. Cook, Sc.D.Comparison of C-Reactive Protein and Low-Density Lipoprotein Cholesterol Levels in the Prediction of First Cardiovascular EventsNEJM.2002;347:1557-1565.

3. Paul M Ridker, MD; Julie E. Buring, ScD; Nancy R. Cook, ScD; Nader Rifai, PhD.C-Reactive Protein, the Metabolic Syndrome, and Risk of Incident Cardiovascular Events: An 8-Year Follow-Up of 14 719 Initially Healthy American Women Circulation. 2003;107:391.

4. Gavin J. Blake, MD, MPH, MRCPI; Nader Rifai, PhD; Julie E. Buring, ScD; Paul M Ridker, MD, MPH.Blood Pressure, C-Reactive Protein, and Risk of Future Cardiovascular Events Circulation. 2003;108:2993.

5. Howard D. Sesso, ScD, MPH; Julie E. Buring, ScD; Nader Rifai, PhD; Gavin J. Blake, MD, MPH; J. Michael Gaziano, MD, MPH; Paul M. Ridker, MD, MPH. C-Reactive Protein and the Risk of Developing Hypertension JAMA. 2003;290:2945-2951.

6. Roger Kranzhofer; Joachim Schmidt; Carolein A. H. Pfeiffer; Siegfried Hagl; Peter Libby; Wolfgang Kubler.Angiotensin Induces Inflammatory Activation of Human Vascular Smooth Muscle Cells Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:1623-1629.

7. Haim D. Danenberg, MD; Alexander J. Szalai, PhD; Rajesh V. Swaminathan, BSc; Lin Peng, MD; Zhiping Chen, MS; Philip Seifert, MS; William P. Fay, MD; Daniel I. Simon, MD; Elazer R. Edelman, MD, PhD.Increased Thrombosis After Arterial Injury in Human C-Reactive Protein-Transgenic Mice Circulation. 2003;108:512.

8. Antoni Paul, PhD; Kerry W.S. Ko, PhD; Lan Li, MD; Vijay Yechoor, MD; Mark A. McCrory, BS; Alexander J. Szalai, PhD; Lawrence Chan, MBBS, DSc.C-Reactive Protein Accelerates the Progression of Atherosclerosis in Apolipoprotein E-Deficient Mice Circulation. 2004;109:647-655.

Others

Claudia U. Chae; Richard T. Lee; Nader Rifai; Paul M. Ridker.Blood Pressure and Inflammation in Apparently Healthy Men Hypertension. 2001;38:399.

Peter Libby, MD.Current Concepts of the Pathogenesis of the Acute Coronary Syndromes Circulation. 2001;104:365.

Pradyumna E. Tummala, MD; Xi-Lin Chen, MD, PhD; Cynthia L. Sundell, PhD; Jorn Bech Laursen, MD; C. Patricia Hammes, BS; R. Wayne Alexander, MD, PhD; David G. Harrison, MD; Russell M. Medford, MD, PhD.Angiotensin II Induces Vascular Cell Adhesion Molecule-1 Expression In Rat Vasculature: A Potential Link Between the Renin-Angiotensin System and Atherosclerosis Circulation. 1999;100:1223-1229.