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C-reative protein: From acute phase reactant to cardiovascular disease risk factor. (Cover Story).

The statistics are startling. Half of all myocardial infarctions occur in patients with normal plasma lipid levels. (1) Despite changes in lifestyle and the use of new drugs such as statins to lower plasma cholesterol concentrations, cardiovascular disease continues to be the principal cause of death of both men and women in the United States, Europe, and much of Asia. According to 1997 estimates from the American Heart Association, almost 60 million Americans suffer from one or more forms of cardiovascular disease. In the same year, this disease claimed almost 1 million lives.

For many years, myocardial infarction was thought to be due to accumulation of lipid-laden plaques in coronary arteries that gradually enlarged and calcified, eventually blocking blood flow to the heart muscle or myocardium. Sometimes the plaques ruptured, causing acute blockages due to thrombosis. New studies have shown that the lesions of atherosclerosis are related to a specific series of molecular and cellular responses best described as an inflammatory disease. Low-density lipoproteins (LDL) and their oxidative modification through the inflammatory process play a key role in atherogenesis. (2)

C-reactive protein (CRP) is the classic acute phase reactant. With severe inflammation or infection, blood levels of CRP may increase up to 500 times to 1,000 times normal. Like other acute phase reactants, CRP plays a role in fighting infection. It binds to phosphocholine on the surface of invading microorganisms, allowing complement and phagocytes to kill them. CRP can also be proinflammatory and enhance coagulation. However, when the acute phase response is chronically activated, it can be harmful. New theories on atherogenesis and several large cohort studies have made CRP an intriguing potential risk factor for cardiovascular disease. (3)

Defining coronary heart disease risk

Cardiovascular disease is America's number-one killer. Many of these deaths are preventable because coronary heart disease (CHD) is associated with several risk factors that can be modified. There have been tremendous strides in medical treatment for heart disease over the last several decades. However, controlling risk factors remains the key to preventing development and progression of CHD.

CHD is associated with known risk factors. Some, such as male sex, age, and family history of early CHD, cannot be modified. However, others can be controlled and/or treated.

The Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol (Adult Treatment Panel III or ATP III) was released in May 2001, updating the National Cholesterol Education Program's (NCEP) clinical guidelines for cholesterol testing and management. (4) NCEP, which is coordinated by the National Heart, Lung, and Blood Institute (NHLBI), disseminates new guidelines as warranted by clinical research. The major change is a more aggressive focus on primary prevention in people with multiple CHD risk factors. The first update since 1993, ATP III builds on previous ATP reports and expands the indications for intensive cholesterol-lowering therapy in clinical practice. The new guidelines for healthy levels of cholesterol and its components are shown below.
ATP III Classification of LDL, Total and HDL Cholesterol (mg/dl)


LDL cholesterol <100 Optimal
 100-129 Near or above optimal
 130-159 Borderline high
 160-189 High
 [greater than or equal to]190 Very high
Total cholesterol <200 Desirable
 200-239 Borderline high
 [greater thanor equal to]240 High
HDL cholesterol <40 Low
 [greater than or equal to]60 High

Note: Table made from bar graph


Low density lipoprotein -- a major cause of injury

Lipids are essential components of cell walls and membranes found in all parts of the body. They are involved in the production of hormones and bile acids. Cholesterol and other lipids are also utilized to store energy and provide fuel for metabolism. It takes only a small amount to meet these needs. Excess cholesterol can be deposited in arteries, causing narrowing and obstruction.

LDL-cholesterol is the major component of atherosclerotic plaque in arteries. Oxidative modification of LDL plays a key role in the pathophysiology of this process. (5) LDL is a key factor in the formation of soft, unstable plaque prone to rupture.

Oxidation, glycation (in diabetes), aggregation, or incorporation into immune complexes may modify LDL. It is then a major cause of injury to vascular endothelium and smooth muscle. When trapped in an artery, LDL particles can undergo progressive oxidation and be internalized by macrophages. This facilitates the accumulation of cholesterol esters, resulting in the formation of foam cells. Modified LDL also attracts other macrophages, helping to further expand the inflammatory response. (3)

Generally, the higher the concentration of LDL-cholesterol in the blood, the greater the risk for developing heart disease and stroke. Reduction of LDL-cholesterol has become the main goal of cholesterol-lowering therapy based on dramatic lowering of CHD events in clinical trials.

Lowering of LDL cholesterol levels and primary prevention offers the greatest opportunity for reducing the public health burden of CHD in the United States. This approach focuses on lifestyle changes such as reduced intake of cholesterol and saturated fat, increased physical activity, and weight control. However, a number of people with very high LDL levels or multiple risk factors may benefit from cholesterol-lowering drugs. (4)

Some of the most useful cholesterol lowering agents are the HMG-CoA reductase inhibitors or statins. The principal metabolite in these drugs inhibits 3-hydroxy-3-methyglutaryl-coenzyme A (HMG-CoA). This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate limiting step in the biosynthesis of cholesterol. Statins such as lovastatin have been shown to reduce LDL levels. LDL is formed from very low-density lipoprotein (VLDL) and is catabolized primarily by the high affinity LDL receptor. Lovastatin may lower LDL by reducing VLDL concentrations and inducing the LDL receptor. This reduces production and increases catabolism of LDL.

In 1998, the Air Force/Texas Coronary Atherosclerosis Prevention Study showed that lowering cholesterol in generally healthy people with average cholesterol levels reduced their risk for a first time heart attack by 37 percent. (6) Study participants had no obvious evidence of CHD at study entry, with modestly elevated total cholesterol (average 221 mg/dl) and LDL-cholesterol levels (average 150 mg/dl) and lower than usual HDL-C levels (average 36 mg/dl for men and 40 mg/dl for women). A statin drug (lovastatin) at a dose of 40 mg/dl and a low-saturated fat, low-cholesterol diet were prescribed. Study participants who received a placebo drug also followed the low-fat diet. After one year, total cholesterol was lowered by 18 percent and LDL levels by 25 percent in the drug and diet treatment group as compared to the diet only group. Participants treated with lovastatin had a 37 percent lower incidence of an acute major coronary event defined as myocardial infarction, unstable angina, or sudden cardiac death t han did those treated with placebo.

Atherosclerosis -- an inflammatory disease

Blood vessels are lined by endothelium. The first step in development of atherosclerosis is endothelial dysfunction, according to new hypotheses. (2) Possible causes include elevated low density lipoprotein (LDL), genetic alteration, free radicals caused by hypertension, cigarette smoking, or diabetes mellitus, and even infectious organisms such as Chlamydia pneumoniae.

Whatever the cause, the endothelial dysfunction leads to alteration of the normal homeostatic properties of the endothelium. White blood cells and platelets can more easily adhere to the surface. The endothelium now begins to have procoagulant rather than anticoagulant properties. This inflammatory response stimulates smooth muscle cells to migrate in and proliferate, mixing with the inflammatory cells, forming a so-called intermediate lesion. These inflammatory cells consist primarily of macrophages and T lymphocytes. The arterial wall thickens and compensates by dilating. Thus, the lumen remains unaffected, and blood flow is unobstructed.

As inflammation continues, more macrophages and lymphocytes enter the plaque from the blood and multiply within the lesion. As these cells are activated, they release cytokines, growth factors, and chemokines that induce further damage and lead to focal necrosis. A fibrous cap forms over the lesion, enlarging and restructuring it. This fibrous cap overlying a core of lipid and necrotic tissue is called an advanced, complicated lesion. At some point, the artery can no longer compensate by dilating. This complicated lesion may protrude into the lumen and alter the flow of blood. (2)

There are parallels between atherosclerosis and other chronic inflammatory diseases such as rheumatoid arthritis, cirrhosis, and pulmonary fibrosis. These also involve activation of lymphocytes and macrophages, resulting in an inflammatory process with tissue fibrosis and destruction of normal tissue architecture.

Plaque rupture and instability

In most patients, myocardial infarctions occur as a result of thinning or erosion of the fibrous cap, often at the shoulders of the lesion where macrophages enter and accumulate. Stable, advanced lesions usually have dense uniform fibrous caps. Potentially dangerous unstable lesions may be nonocclusive and thus difficult to diagnose by angiography. At autopsy, active inflammation is noted by the accumulation of macrophages at the site of plaque rupture. Macrophage accumulation may be associated with increased plasma concentrations of fibrinogen and C-reactive protein. As many as 50 percent of acute coronary syndromes and myocardial infarction may be due to plaque rupture and thrombosis. (2)

"The old concept of atherosclerosis was that a blood vessel would slowly narrow over years until it finally closed off, resulting in a heart attack," says Dr. Kathleen W. Wilson, senior staff in Internal Medicine at the Ochsner Clinic in New Orleans, LA. "We now know that atherosclerotic plaque is dynamic rather than fixed. Plaque changes in configuration and danger, depending on the HDL and LDL-cholesterol, inflammation and antioxidant level in the blood vessel. If laden with LDL, a plaque can become unstable and rupture, setting off a cascade of biochemical events that result in occlusion of the artery by a thrombus and heart attack. C-reactive protein may also play an important role in atherogenesis and plaque formation."

C-reactive protein and the acute phase response

In 1930, a protein that could bind to the C-polysaccharide coat of the pneumoccus was found in the serum of patients with pneumonia. This was named C-reactive protein. As a ligand for specific receptors on phagocytes, it mediates activation responses on macrophages and monocytes and activates complement. It is one of the most sensitive acute phase reactants, part of the response to endothelial injury due to ongoing inflammation. (7)

Elevated serum levels of CRP are nonspecific but sensitive markers of the acute-phase response to infectious agents, immunologic stimuli, and tissue damage. Complexed CRP activates the complement system. It then initiates opsonization and phagocytosis of invading cells. Its main function is to bind and detoxify endogenous toxic substances produced as a result of tissue damage.

In the absence of any specific major inflammatory stimulus, CRP levels are relatively low. In a given individual, the level is moderately stable over time. Variation between people is thought to represent differences in low-level subclinical inflammation associated with chronic disease processes, including atherosclerosis.

The liver produces CRP in response to tissue injury or infection. Stimulated by a variety of proinflammatory cytokine mediators such as tumor necrosis factor and interleukin 1 and 2, CRP concentration rises rapidly and peaks in the serum within 24 hours to 48 hours. CRP values can increase 500 times to 1,000 times over the baseline values in a given person following a major inflammatory insult such as trauma, infection, or arthritis. (2)

Linkage of CRP to human atherogenesis

Although long studied, the exact physiologic role of CRP has remained largely unknown until recently. It has both proinflammatory and procoagulant activities. CRP binds to damaged cell membranes and activates complement. It enhances the activity of macrophages.

The acute inflammatory response is frequently accompanied by serious thrombotic events. Cermak et al. demonstrated that CRP induces the production of tissue factor by blood monocytes. Tissue factor is a powerful procoagulant that can lead to disseminated intravascular coagulation as well as to thrombosis. (8)

Of recent interest, CRP can also cause endothelial cells lining blood vessels to express cell adhesion molecules. Zwaka et al. noted this upregulation of adhesion molecule expression resulting in binding of apolipoprotein B-containing molecules (LDL and VLDL). Their data suggest a novel mechanism for foam cell formation by CRP-mediated uptake of LDL, linking LDL deposition to the onset of atherogenesis. (9)

Pasceri, et al. found that CRP has significant pro-inflammatory effects in endothelial cells, inducing high levels of expression of intercellular and vascular cell adhesion molecules. This increased expression of adhesion molecules in the vascular wall is an important factor in the development of atherosclerosis. It may enhance the local inflammatory response within atherosclerotic plaques by recruiting monocytes and lymphocytes. Thus, CRP may have complex modulatory functions that contribute to the development and evolution of inflammation/atherosclerosis. (10)

Serum measurements of CRP

There are two classes of C-reactive protein assays. One measures a wide range of CRP levels to include those found in patients with acute infections. These assays can be either nephelometric or immunoturbidimetric. This assay is used to detect systemic inflammatory processes such as wound infections, efficacy of treatment of bacterial infections and to monitor activity of rheumatic disease. The reportable range is typically 0.3 mg/dl to 20 mg/dl. (7)

The second is a high-sensitivity CRP assay. These assays differ from the usual CRP assays in that they have been adjusted to lower the detection level. They measure a much narrower range and lower detectable level of CRP to include those that may be of value in measuring the risk of a cardiac event. There are a number of high sensitivity CRP assays available. All are turbidimetric immunoassays that use an antibody directed to an epitope on the CRP molecule. These high sensitivity CRP immunoassays are sensitive to 0.01 mg/dl.

High sensitivity CRP is the assay used in all reported studies of CRP as a potential cardiovascular risk factor.

Effect of statin therapy in lowering CRP and reducing cardiac events

Some of the most powerful data linking CRP levels to the risk of cardiac events comes from a reanalysis of the data from the Air Force/Texas Coronary Atherosclerosis Prevention Study discussed above. This reanalysis showed that among all subjects randomly allocated to the statin drug lovastatin, coronary heart disease events dropped by almost 40 percent. (11) Ridker, et al. then retrospectively divided the study population based on whether LDL-C was above or below the median for the entire cohort (149 mg/dl) and then further subdivided these groups based on whether the CRP was above or below the median. In patients with above-median LDL-C, the event rate dropped by 50 percent, independently of the CRP level. Lovastatin did not decrease events significantly among subjects with low LDL-C and low CRP. However, in subjects with low lipids but above median CRP, treatment with lovastatin reduced the median CRP level a statistically significant 14.8 percent and cut the event rate by 50 percent, as much as those with high LDL-C.

The authors noted that overall, looking across all groups studied, the rates of coronary events increased with the baseline level of CRP. The risk of acute coronary events increased by 21 percent with each increasing quartile of baseline CRP levels. When age, sex, smoking status, hypertension, family history, and lipid levels were entered, the increase in risk associated with a one-quartile increase in the C-reactive protein level was almost identical in magnitude to that associated with an increase of 1.0 in the ratio of total to HDL-cholesterol.

Among the participants, baseline CRP levels were an independent predictor of first coronary events. Lovastatin appeared to be highly effective in reducing the risk of acute coronary events in participants with elevated CRP levels but no hyperlipidemia. These data suggest that lovastatin may be highly effective among persons with average and below-average LDL cholesterol levels who have C-reactive protein levels higher than the median."

C-reactive protein -- a measure of outcome in severe unstable angina?

When patients with unstable angina are admitted to the hospital, it is difficult to predict whether the angina will remit or progress to myocardial infarction. Although the causes of instability are unknown, there may be a role for inflammation, as suggested by histologic and other studies.

Liuzzo et al. prospectively studied patients with severe unstable angina, chronic stable angina, severe coronary artery disease, and those with a myocardial infarction of less than six hours duration. (12) Their results showed that the concentration of C-reactive protein is elevated in the majority of patients with unstable angina as well as those admitted with myocardial infarction and a history of unstable angina. A CRP value [greater than or equal to]0.3 mg/dl on admission had a sensitivity of 90 percent and a specificity of 82 percent for predicting subsequent cardiac events such as cardiac death, myocardial infarction, or an urgent need for cardiac revascularization. The sensitivity increased to 100 percent in patients with a CRP [greater than or equal to] 1.0 mg/dl on admission or in those with any rise in the CRP level during the study.

This study showed similar results with measurement of serum amyloid A protein, another very sensitive acute phase reactant. This predictive correlation between these acute phase reactants and clinical outcome provides another link between cardiovascular events and the acute phase inflammatory response.

C-reactive protein and cardiac risk in women on postmenopausal hormone therapy

For some years, hormone replacement therapy has been thought to reduce cardiovascular risk in women. This has been suggested by observational epidemiologic data. (13) The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial was a randomized placebo-controlled trial designed to determine the effect of different preparations of postmenopausal hormones on cardiac risk factors. (14) Cushman et al. analyzed PEPI data as it related to four inflammation-sensitive factors including CRP, soluble E-selectin, von Willebrand factor (vWF) antigen, and coagulation factor VIII c. (15) All were measured at baseline, 12 months, and 36 months in 365 participants.

The main findings were that compared to placebo, women on estrogen alone or combination estrogen/progestin developed an increased concentration of C-reactive protein and decreased concentration of soluble E-selectin. Factor VIIIc and vWF were not affected. The clinical significance of increased CRP with postmenopausal hormone use remains to be clarified. However, it may be a factor in a study finding of an earlier clinical trial that demonstrated an increased coronary risk with hormone treatment in women with established coronary disease. (16)

Endogenous hormones seem to have many protective effects on the cardiovascular system. Exogenous estrogen, which women younger than 50 years of age often take for menopausal symptoms, may increase the plasma level of CRP. (15) Elevated levels of CRP are seen in many inflammatory conditions and appear to be associated with a higher incidence of myocardial infarction in women. (17)

Other novel cardiovascular risk factors

In the last several years, several other novel markers of cardiovascular disease risk have emerged. In addition to C-reactive protein, total plasma homocysteine, fibrinogen, serum amyloid A protein, interleukin-6, and others have been studied. To be clinically useful, assays must be precise, reproducible, easy to standardize, and inexpensive. Although some of these novel potential risk factors are intriguing, more clinical studies must be performed before they are widely accepted. Studies must demonstrate that these novel markers can be detected in otherwise healthy individuals before the onset of clinical disease. (18, 19)

Conclusion

Half of all heart attacks occur in persons without overt hyperlipidemia. New approaches are needed to determine risk of cardiovascular diseases and initiate appropriate intervention in this population. C-reactive protein is showing promise as a predictor of risk for cardiovascular events. One of the acute phase reactants, it is a very sensitive marker of inflammation. It binds to damaged cell membranes and activates complement, and also activates macrophages. CRP causes vascular endothelium to express adhesion molecules and increase binding of LDL, resulting in foam cell formation. All of this may cause cardiac artery plaque instability and rupture.

Clinical studies have shown CRP to be an independent predictor of first coronary events. In patients without overt hyperlipidemia but with elevated CRP, statin therapy resulted in reduction of both CRP and the risk of acute coronary events. Elevated CRP has been associated with poorer outcomes in patients with unstable angina. It may be a risk factor for cardiac disease in women on postmenopausal hormone therapy. The data is interesting and compelling; however, most experts agree that further large scale, prospective studies will need to be done before CRP is introduced into general clinical practice as an established risk factor for cardiovascular disease.

References:

(1.) Braunwald E. Shattuck lecture -- Cardiovascular medicine at the tarn of the millenium: Triumphs, concerns, and opportunities. N Engl J Med 1997;337:1360-1369.

(2.) Ross R. Atherosclerosis -- an inflammatory disease. N Engl J Med 1999;340:115-126.

(3.) Lagrand WK, Visser CA, Hermens WT, et al. C-reactive protein as a cardiovascular risk factor. More than an epiphenomenon? Circulation 1999;100:96-102.

(4.) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486-2497.

(5.) Ogedegbe HO, Brown DW. Lipids, lipoproteins, and apolipoproteins and their disease associations. Lab Med 2001;32:384-388.

(6.) Downs JR. Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: Results of AFCAPS/TexCAPS. JAMA 1998;279:1615-1622.

(7.) Young B, Gleeson M, Cripps AW. C-reactive protein: A critical review. Pathology 1991;23:118-124.

(8.) Cermak J. Key NS, Bach RR, et al. C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor. Blood 1993;82:513-520.

(9.) Zweka TP, Hombach V. Torzewski J. C-reactive protein-mediated low-density lipoprotein uptake by macrophages. Circulation 2001;103:1194-1197.

(10.) Pasceri V. Willerson JT, Yeh ETH. Direct proin-flammatory effect of C-reactive protein on human endothelial cells. Circulation 2000;102:2165-2168.

(11.) Ridker PM, Rifai N, Clearfield M, 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;334:1959-1965.

(12.) 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;331:417-424.

(13.) Barrett-Conner E, Grady D, Hormone replacement therapy, heart disease, and other considerations. Annu Rev Public Health 1998;19:55-72.

(14.) The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women: The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 1995;273:199-208.

(15.) Cushman M, Legault C, Barrett-Conner E, et al. Effect of postmenopausal hormones on inflammation-sensitive proteins: The postmenopausal estrogen/progestin interventions (PEPI) study. Circulation 1999;100:717-722.

(16.) Hulley S, Grady D. Bush T, et al. For the Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605-613.

(17.) Ridker PM. Hennekens CH, Buring JE et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000;342:836-843.

(18.) Ridker PM, Evaluating novel cardiovascular risk factors: Can we hotter predict heart attacks? Ann Intern Med 1999;130:933-937.

(19.) Shah PK. Circulating markers of inflammation for vascular risk prediction. Are they ready for prime time? Circulation 2000;101:1758-1761.

RELATED ARTICLE: Coronary heart disease risk factors

* Smoking

* Hypertension

* Physical inactivity

* Obesity

* Diabetes

* High cholesterol and LDL

* Low HDL

* Male sex

* Family history of CHD

Other potential risk factors for CHD

* Homocysteine

* Lipoprotein A

* Apolipoprotein A-1

* Apolipoprotein B

* Apolipoprotein E

* Serum amyloid A protein

* Interleukin-6

Sherry Woodhouse, MD, is chair of the Division of Pathology and Laboratory Medicine, Cleveland Clinic Florida, Weston. FL.
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Publication:Medical Laboratory Observer
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Date:Mar 1, 2002
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