Biomarker and Cardiovascular Risk Factor – What to do About It

By Ward Dean, M.D.

Inflammation is triggered within days of tissue injury or infection, stimulating a number of systemic and metabolic changes. One of the most dramatic changes is an increase in blood serum levels of an inflammatory marker known as C-Reactive Protein (CRP).1 CRP is one of a group of substances known as “acute phase reactants.” Among all acute-phase reactants, CRP rises the fastest and is the most reliable indicator of clinical disease and its severity (Fig. 1).2 CRP was first described in 1930 as a protein found in the blood of patients with pneumococcal pneumonia. It was named C-reactive protein because of its ability to react with and precipitate the C-polysaccharide of the pneumococcus.3 In the 1940s and 1950s, CRP was one of the most frequently requested clinical laboratory tests for initial evaluation of patients with acute inflammation of any origin,2 but because of the costs involved in its measurement, its lack of quantifiability (at that time), and the ease of measuring the Erythtroycyte sedimentation rate (ESR—an indirect measurement of acute phase reactants), CRP determinations fell out of favor. In recent years, however, with the development of highly sensitive quantitative tests for CRP, it is being used much more commonly.

CRP in Health and Disease
Any clinical disease characterized by tissue injury and/or inflammation is accompanied by significant elevation of serum CRP.2 The magnitude of the CRP elevation reflects the extent of tissue injury: more extensive lesions cause longer periods of rising levels and higher peak concentrations.1
Causes of CRP elevations include acute bacterial, viral and other infections, pulmonary tuberculosis, noninfectious illnesses such as rheumatic diseases (rheumatoid arthritis, Polymyalgia Rheumatica and Giant Cell Arteritis), heart attack, inflammatory bowel disease, and various malignant diseases. Other causes include Systemic Lupus Erythematosus (SLE), obesity, diabetes, uremia, hypertension, physical exertion, hormone replacement therapy, sleep disturbance, chronic fatigue, high levels of alcohol consumption, low levels of physical activity, and even depression.1,2  CRP concentrations less than 0.05 mg/dL are considered normal; between 0.06 and 10 mg/dL as moderate increases; and more than 10 mg/dL as marked increases. The majority of patients with very high levels have bacterial infection, whereas more moderate degrees of elevation are seen in most chronic inflammatory states.3 In general, CRP values rarely exceed 6 or 8 mg/dL in patients with chronic inflammatory states or malignancies. Concentrations greater than this should raise the possibility of superimposed bacterial infection. CRP levels average about 3 to 4 mg/dL in adult rheumatoid arthritis patients with moderate disease activity.3

CRP and Cardiovascular Disease
Half of all heart attacks occur in people with normal blood cholesterol levels. Atherosclerosis is now recognized to be an inflammatory process, and CRP has been identified as one of the most significant risk factors for cardiovascular disease and heart attacks. One large study (28,263 healthy postmenopausal women) assessed the significance of twelve serum markers of cardiovascular risk over a period of three years. The scientists found that of the 12 measures, CRP levels were the most powerful risk predictor of subsequent heart attacks. Of the lipid variables, the ratio of total cholesterol to HDL cholesterol and Apolipoprotein B-100 were the most powerful predictors. Homocysteine was also associated with increased risk. [Fibrinogen, a major risk factor, was inexplicably not investigated in this study]. Four markers of inflammation were found to be significant predictors of the risk of future heart attacks — CRP, Serum Amyloid A, interleukin 6, and sICAM-1 (Soluble Intracellular Adhesion Molecule type 1). However, CRP was the strongest and most significant predictor (Fig. 2).4

In another study, patients with unstable angina were followed for one year post-diagnosis. Sixty-nine percent of the patients with elevated CRP suffered a heart attack within one year. Conversely, there were significantly fewer heart attacks and increased survival in the group with CRP levels less than 0.3 mg/dL (Figures 3 and 4).5
In a year-long study of patients with stable angina who had undergone coronary artery stenting, those with the highest levels of CRP had the shortest survival time (Fig. 5).

CRP to Monitor Disease and as a Biomarker of Aging
Serial determinations of CRP have been recommended as the best single means of monitoring postoperative recovery and to follow the course of disease.2 It is probably of greatest value in following patients being treated for chronic inflammatory diseases.3 In recent years, aging has been recognized as the ultimate chronic inflammatory disease.

Lowering CRP
Not only does CRP rise as a result of inflammatory processes, but it now has been found to promote inflammation and contribute to the pathogenesis of coronary artery disease, as well.6,7 Thus, not only is it important to treat the underlying disease process to reduce CRP, but it is important to reduce CRP to prevent and speed recovery from the disease. A number of substances have been shown to effectively reduce C reactive protein, from whatever cause.

Statins/Red Yeast Rice Extract
Statin drugs and Red Yeast Rice Extract, the natural prototype of statins, have been found to significantly reduce CRP. In one long-term (5 year) study, treatment with the statin drug Pravastatin resulted in an overall 38% reduction in mean CRP levels, and a 54% reduction in coronary artery disease.8

Vitamin E
Researchers at Southwestern Medical Center in Dallas found that high intakes of vitamin E reduce the level of CRP. The scientists performed a study on 75 subjects—normal controls, and type 2 diabetics with and without cardiovascular disease. They found that supplementation with 1,200 IU of Vitamin E every day resulted in a decrease of CRP by 30 percent in all groups (Fig. 6).9

Vitamin B6
Scientists from the USDA Human Nutrition Research Center on Aging at Tufts University in Boston reported that low levels of vitamin B6 are associated with higher levels of C-Reactive Protein (and vice-versa).10

Aspirin
In the Physicians Health Study, men who regularly used aspirin had a 44% lower incidence of heart attacks. Significantly, the benefit was highest in those with the highest CRP.11 Thus, the anti-inflammatory properties of aspirin may contribute to its efficacy in preventing cardiovascular disease.5
Gugulipid

In a recent article in the Journal of the American Medical Association, it was found that gugulipid resulted in significant reduction of total cholesterol in only 20% of the people who took it.12 The article appeared to be a “take-out” piece designed to discredit any purported benefits of this nutrient. However, buried in the data was the fact that gugulipid consumption resulted in an overall lowering of CRP of nearly 30 percent! This article was recently reviewed in VR News.13
Proteolytic Enzymes

Anti-inflammatory proteolytic enzymes, like those contained in VRP’s UniZyme formula, have been shown effective in reducing CRP levels. In one double-blinded study, German researchers treated patients with proteolytic enzymes prior to dental surgery, and post-operatively for several days. By the third day after surgery, CRP levels were 300% higher in the placebo group compared to those treated with the proteolytic enzymes.15

Conclusion
Other anti-inflammatory substances, such as the herbs, Turmeric and Boswellia, and fish oil, have all been reported to have dramatic CRP-lowering properties. In any condition characterized by an elevation of CRP, measures to ameliorate the disease and lower CRP should be used simultaneously. The higher the level of CRP, the more aggressively the treatment program should be implemented. It is likely that the most effective results will be obtained from a combination approach.

References
1. Kushner, I. C-Reactive Protein and the Acute Phase Response. Hospital Practice, 1990, March 30, 13-28.
2. Deodhar, S.D. C-Reactive Protein: The best laboratory indicator available for monitoring disease activity. Cleveland Clinic J. Medicine, 1989, 56: 2, 126-129.
3. Kushner, I. The acute-phase response in humans. Whys is it important? Internal Medicine for the Specialist, 1988, 9: 5, 59-65.
4. Ridker, P., Hennekens, C., Buring, J., and Rifai, N. C-Reactive Protein and other markers of inflammation in the prediction of cardiovascular disease in women. New England J Med, 2000, 342: 836-43.
5. Patel, V., Robbins, M. and Topol, E. C-reactive protein: A “Golden Marker” for inflammation and coronary artery disease. Cleveland Clinic J Medicine, 2001, 68: 6, 521-534.
6. Kushner, I. C-reactive protein elevation can be caused by conditions other than inflammation and may reflect biologic aging. Cleveland Clinic Journal of Medicine, 2001, 68: 6, 535-540.
7. Pasceri, V., Willerson, J., Yeh, E. Direct proinflammatory effect of C reactive protein on human endothelial cells. Circulation, 2000, 102:2165-2168.
8. Ridker, P., Rifai, N., Pfefer, M., Sacks, F., Braunwald, E. Long term effects of pravastatin on plasma concentration of C-reactive protein. Circulation, 1999, 100: 230-235.
9. Devaraj, S., and Jialal, I. Alpha tocopherol supplementation decreases serum C-Reactive Protein and Monocyte interleukin 6 levels in normal volunteers and type 2 diabetic patients. Free Radical Biology and Medicine, 2000, 29: 8, 790-792.
10. Friso, S., Jacques, P., Wilson, P., Rosenberg, I., and Selhub, J. Low circulating Vitamin B6 is associated with elevation of the inflammation marker C-Reactive Protein independently of plasma homocysteine levels. Circulation, 2001, 103: 2788.
11. Ridker, P., Cushman, M., Stampfer, M., Tracy, R., Hennekens, C. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med, 1997, 336: 973-979.
12. Szapary PO, Wolfe ML, Bloedon LT, Cucchiara AJ, DerMarderosian AH, Cirigliano MD, Rader DJ. Guggulipid for the treatment of hypercholesterolemia: a randomized controlled trial. JAMA. 2003 Aug 13;290(6):765-72.
13. Dean, W. Guggulipid ineffective as lipid-lowering agent? Vitamin Research News, 2003, 17: 10, 1,12.
14. Tomassi, S., Carluccio, E., and Bentifoglio, M, et al. C reactive protein as a marker for cardiac ischemic events in the year after a first, uncomplicated myocardial infarction. Am J. Cardiol, 1999, 83: 1595-1599.
15. Cichoke A. Enzymes hasten pain relief. Nutrition Science News. Feb. 2001.