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The Role of Inflammatory Markers in CVD: Detection & Treatment  

OVERVIEW

According to the AHA, the death rate due to CHD declined approximately 25% from 1990 to 2000, due in part, to increased rates of treating elevated cholesterol levels (American Heart Association. Heart Disease and Stroke Statistics – 2003 Update. Dallas, TX: American Heart Association 2002). However, it is puzzling to note that approximately half of patients who experience some sort of cardiovascular event have below-average cholesterol levels (Mosca L. C-reactive protein – to screen or not to screen? N Engl J Med 2002;347:1615-1617).

Clearly, because these patients lack cardiovascular symptoms and have cholesterol levels classified as “normal,” they are not identified as being at risk for CVD (cardiovascular disease). Heart disease in these patients is often not detected until they experience an unexpected cardiovascular event, such as myocardial infarction (MI) or worse, sudden cardiac death. Therefore, although low-density lipoprotein cholesterol (LDL-C) is now accepted as an unassailable predictor of CHD, it may not be the only predictor. So while more intensive, aggressive lipid testing and treatment is reducing the death rate from CHD, the effort is missing approximately half of the patients who will go on to have a CHD event.

THE INFLAMMATORY CASCADE

Today’s understanding of atherosclerosis recognizes that it is fundamentally an inflammatory disorder. An inflammatory cascade of biochemical responses follows arterial endothelial injury. This injury can be caused by noxious stimuli from smoking, hypertension, atherogenic lipoproteins, hyperglycemia, or possibly even bacterial or viral agents such as Chlamydia pneumoniae or cytomegalovirus (Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002;105:1135-1143).

Researchers are trying to determine what role C-reactive protein (CRP) and other inflammatory markers may play in the development of atherosclerosis. For example, is CRP solely a marker of the atherosclerotic disease process, valuable for its predictive and prognostic potential, or does it actually play a causative role? In other words, is it a risk marker or a risk factor? It may be both. Studies have found that C-reactive protein may itself contribute to the inflammatory response necessary to the evolution of atherosclerosis.

C-REACTIVE PROTEIN

Elevated levels of CRP have long been noted as a prominent finding in various inflammatory diseases. Its levels also rise during localized infections and in patients who have autoimmune diseases. Higher levels of CRP associated with elevated blood pressure, insulin resistance, and high triglycerides are features of the metabolic syndrome. Other known elevators of CRP include injury, old age, smoking, obesity, estrogen therapy, and even coffee consumption (Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events. Circulation 2003;107:391). In contrast, moderate alcohol consumption, higher levels of high-density lipoprotein cholesterol (HDL-C), and statin therapy are associated with decreased levels of CRP (Conti CR. What is high-sensitivity C-reactive protein? Clin Cardiol 2001;24:639-640).

Until recently, assays to measure CRP were unrefined; able only to measure a serum presence of 3 mg/L or higher – good enough to suggest an inflammatory autoimmune disorder – but not sophisticated enough to measure the subtle elevations indicative of future cardiovascular events. Recent development of high-sensitivity (hs) assays can detect the low-grade elevations that are common in many patients who later exhibit symptoms of CVD.

In a body free of infection, immune disease, or injury, serum levels of CRP should be very small (< 0.8 mg/L). According to the AHA, hs-CRP values can be divided into three levels that indicate varying degrees of cardiovascular risk. An hs-CRP level of less than 1.0 mg/L indicates a lower degree of having a CVD event. Serum hs-CRP levels between 1 mg/L and 3 mg/L indicate an average risk, while a serum hs-CRP level of 3.0 mg/L or greater predicts a higher risk of a future CHD event. A very high level of hs-CRP, for example, 10 mg/L or higher, is most likely caused by a disease process other than atherosclerosis.

Of all the inflammatory markers, hs-CRP and fibrinogen (which are both acute-phase proteins) reliably predict future CVD events. C-reactive protein, but not fibrinogen, has an established, reliable, standard of measurement approved by the World Health Organization. Although studies involving IL-6 and SAA have also shown a relationship to incident CVD, these markers have so far not displayed the predictive value of CRP, nor do they yet have widely available or standardized assays (Libby P, Ridker PM. Novel inflammatory markers of coronary risk: theory versus practice. Circulation 1999;100:1148-1150).

WOMEN’S HEALTH STUDY

The recently published Women’s Health Study, involving large cohorts of apparently healthy, postmenopausal women showed that incorporating C-reactive protein into risk prediction models yielded more reliable information on future cardiovascular events than did LDL-C alone (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;342:836-843.)

The Women’s Health Study enrolled more than 28,000 women to evaluate the efficacy of aspirin and vitamin E for the primary prevention of cardiovascular events in women Ž 45. Participants were followed for a mean of eight years to determine the occurrence of a first cardiovascular event, defined as death from CHD, nonfatal MI, nonfatal ischemic stroke, or coronary revascularization procedure. This study compared 12 different plasma variables, including three inflammatory markers present in blood samples drawn at baseline. Among women with low levels of cholesterol but high levels of hs-CRP and SAA, the risk of CVD events significantly exceeded that experienced by those with low levels of these markers. Of the 12 markers measured, CRP was the strongest single predictor of cardiovascular events.

A Women’s Health Study subset compared CRP with LDL-C to assess the value of each in predicting the risk of cardiovascular events. This subset study found that combining LDL-C and CRP provided better prognostic information than did either marker, alone. However, the data suggested that CRP better predicted cardiovascular events than did LDL-C (Figure 1) (Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 2002;347:1557-1565).

OTHER EPIDEMIOLOGIC EVIDENCE

A previous study, conducted only in men, was one of the first large-scale, population-based studies to show a connection between CRP and first major CHD event. The MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) trial was a large, randomly selected cohort recruited by survey from 1984 to 1985 and followed for eight years. Subjects were 936 men between the ages 45 to 64 who had no history of CVD (Koenig W, Sund M, Frohlich M, et al. C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men. Results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation 1999;99:237-242).

The study found a positive and statistically significant relationship between CRP and the incidence of CHD events, even after adjusting for age and smoking status. First CHD event was defined as fatal or nonfatal MI, or sudden cardiac death. Those who had the highest baseline levels of CRP had a 2.6-fold increase in risk of having a future CHD event.

Several other large, prospective epidemiologic studies have shown that among primary-prevention patients, higher levels of
C-reactive protein reliably predict MI, stroke, peripheral arterial disease, and sudden cardiac death (Ridker PM. Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 2003;107:363-369).

THE NCEP PERSPECTIVE

The Expert Panel of the NCEP recognized the emerging data regarding CRP and other inflammatory markers such as fibrinogen, homocysteine, and impaired fasting plasma glucose in its Adult Treatment Panel III guidelines. The NCEP ATP III called these “emerging risk factors” to acknowledge that they might contribute to the development of CHD risk (National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). The National Cholesterol Education Program Adult Treatment Panel III Report, 2001. Bethesda, MD: National Heart, Lung, and Blood Institute, NIH publication no. 02-5215, 2002).

The ATP III recommended testing for CRP or other emerging risk factors to add predictive value or to better guide treatment decisions for patients who do not clearly fall into risk factor categories delineated elsewhere in the guidelines. The guidelines cite two examples of patients who could benefit from having an hs-CRP, Lp(a), fibrinogen, or homocysteine test performed. These tests could make a difference, in the clinical judgment of the physician, as to how aggressively a primary-prevention patient should be treated. One such example could be a patient who might have multiple risk factors but a 10-year Framingham risk score of <20%. A second example could be to use an emerging risk factor to guide a decision about using a pharmacologic approach in patients who have <1 risk factor but an LDL-C between 160 mg/dL and 189 mg/dL, after lifestyle changes are incorporated.

AHA/CDC SCIENTIFIC STATEMENT

The AHA and CDC have provided some clarification to when and how hs-CRP testing should be conducted by producing a scientific statement that was published in a January 2003 edition of the journal Circulation (Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice. A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003;107:499-511). This scientific statement was based on a thorough review of the scientific evidence supporting an association between CVD and various inflammatory markers (Table 1). It also considered the clinical chemistries and assays available to measure these markers. Most importantly, it attempted to identify which patients should be tested for these markers for the purpose of risk stratification and therapeutic monitoring, and it explored the public health ramifications of establishing an accepted connection between inflammatory markers and CVD.

The AHA/CDC Scientific Statement concluded that hs-CRP and other inflammatory markers can complement LDL-C and the other previously established and widely accepted risk factors in predicting CVD. However, like the NCEP ATP III, it deemed routine testing for all patients as unwarranted, based on current evidence.

HOW & WHEN TO TEST

C-reactive protein is now accepted, among clinicians in the lipid and cardiology communities, to add value to lipid panel testing. Indeed, CRP appears to predict cardiovascular events better than the ratio of total-to-high-density lipoprotein cholesterol or LDL-C testing alone (Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 2002;347:1557-1565).

Many inflammatory markers do not lend themselves well to routine clinical use because they are difficult to measure in a standardized manner or they vary during the day. A lack of standardization for the various assays used is one such drawback. For some markers, there is still no consensus regarding a reliable or precise assay (Table 2).

Cholesterol, particularly LDL-C, has long served as the cornerstone predictor of CHD and is the major determinant for which patients merit advice on lifestyle interventions and aggressive pharmacologic intervention. The growing understanding of the inflammatory nature of the atherosclerotic disease process does not diminish the importance of lipid risk predictors. Dyslipidemia, along with other risk factors, such as age, gender, smoking status, diabetes, overweight and obesity, and high blood pressure remain the foundations for determining the intensity of intervention.

The AHA/CDC statement asserted that using hs-CRP or other inflammatory marker tests for secondary-prevention patients or other high-risk patients yields little or no value since the NCEP and other guidelines clearly identify these patients as at extremely high risk for subsequent CVD events. These patients require aggressive treatment. Current evidence supports use of hs-CRP in aiding assessment of global risk for primary-prevention individuals who are at moderate or intermediate risk for CVD.

TREATMENT

Although there are many types of anti-inflammatory medications, none appear to have the beneficial effect on vascular biology proven for the HMG-CoA reductase inhibitors (“statins”). These drugs can reduce macrophage content within atherosclerotic plaques and inhibit the expression of enzymes that may weaken the fibrous cap of atherosclerotic plaques. Statin treatment can also inhibit adhesion molecules, which promote development of the atherosclerotic plaque as monocytes begin to embed themselves in the vascular wall. In addition, statins can promote endothelial vasodilation function through enhanced nitric oxide production (Albert MA, Danielson E, Rifai N, Ridker PM. Effect of statin therapy on C-reactive protein levels. The pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA 2001;286:64-70. Jones SP, Gibson MF, Rimmer DM 3rd, et al. Direct vascular and cardioprotective effects of rosuvastatin, a new HMG-CoA reductase inhibitor. J Am Coll Cardiol 2002;40:1172-1178).

Retrospective analyses of various lipid-lowering trials appeared to show that use of statins resulted in lower levels of CRP independent of any lipid-lowering effect. For example, a five-year follow-up analysis of the Cholesterol and Recurrent Events (CARE) trial showed that pravastatin (Pravachol®) significantly reduced plasma levels of CRP in a way that did not correlate with the individual’s LDL-C (Ridker PM, Rifai N, Pfeffer MA, et al. Long-term effects of pravastatin on plasma concentration of C-reactive protein.Circulation.1989;100:230-235). These data also suggest that statins have direct anti-inflammatory effects. For example, statins reduce risk of stroke, yet stroke correlates poorly with LDL-C (Byington RP, Davis BR, Plehn JF, et al. Reduction of stroke events with pravastatin: the Prospective Pravastatin Pooling (PPP) Project. Circulation 2001;103:387-392).

Approximately 25 million people in the United States have a low LDL-C with high CRP combination profile (Ridker PM. Should statin therapy be considered for patients with elevated C-reactive protein? The need for a definitive clinical trial. Eur Heart J 2001;22:2135-2137). These people are at risk for cardiovascular events yet would not be targeted for treatment according to the current NCEP ATP III guidelines. The high occurrence of CVD events in patients without hyperlipidemia led to the question of whether or not a statin could prevent cardiovascular events in patients who have lower levels of LDL-C but elevated levels of CRP. This hypothesis underlies the JUPITER (Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin) trial, the first trial designed to determine the effect of a statin on patients with low LDL-C but elevated CRP levels. The JUPITER trial began in March of 2003.

JUPITER is a randomized, placebo-controlled, multicenter study that will follow approximately 15,000 patients (men > 55 and women > 65) who have no history of CVD but do have low LDL-C concentrations (<130 mg/dL) with high CRP levels (> 2 mg/L). Because these patients have low LDL-C and a 10-year Framingham risk prediction score of <20%, they would not be candidates for pharmacologic therapy under NCEP ATP III guidelines. Subjects will be randomized to 20 mg/day of rosuvastatin (Crestor®), an HMG-CoA reductase inhibitor that was FDA approved in August of 2003, or placebo. It is the first study designed to ascertain the advent of first cardiovascular events in patients who have low LDL-C but elevated CRP.

 


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