![[Postgraduate Medicine]](../../../graphics/logonew.gif)
[an error occurred while processing this directive] 
|
||||||||||||||||||||||||||||||||||||||||
|
C-reactive protein as a novel biomarkerReactant can flag atherosclerosis and help predict cardiac events Nader Elgharib, MD; David S. Chi, PhD; Walid Younis, MD; Salim Wehbe, MD; Guha Krishnaswamy, MD VOL 114 / NO 6 / DECEMBER 2003 / POSTGRADUATE MEDICINE
CME learning objectives
The authors disclose no financial interests in this article and no unlabeled uses of any product mentioned.
Preview: C-reactive protein (CRP) is a relatively nonspecific marker of inflammation. However, it can be used to monitor the severity and progression of some well-defined cardiovascular diseases. For example, it can predict serious events in patients with coronary artery disease (CAD) who are hospitalized with acute coronary syndrome, myocardial infarction (MI), or advanced peripheral vascular disease. In this article, the authors review the role of CRP in the diagnosis, monitoring, and treatment of various forms of ischemic and inflammatory cardiovascular disease.
Atherosclerosis is an inflammatory vascular disease characterized by endothelial activation, cellular influx, and production of mediators and cytokines. This process leads to the formation of foamy macrophages and atheromatous plaques and, finally, to atherothrombotic disease. Atherosclerosis is associated with high morbidity and mortality. Although measurement of lipid levels, stress testing, and coronary angiography are effective indicators of the extent and severity of the disease, circulating markers that could be easily and noninvasively measured would be powerful tools to diagnose, monitor, and intervene in this disease process. One promising marker is CRP, a major acute phase response protein synthesized in the liver in response to the elaboration of acute phase response cytokines, such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) (figure 1). Other associated acute phase proteins include serum amyloid A protein, fibrinogen, and mannan-binding lectin. What does CRP do?CRP is a member of the pentraxin protein family, which is so named because these proteins possess five identical subunits. CRP, which is elaborated dramatically during acute inflammation, augments the immune response to certain antigens, activates complement, and increases the monocytic production of tissue factors (1). CRP binds to phosphoryl choline on bacterial surfaces, acting as an opsonin and playing a pivotal role in host defense. Interestingly, CRP also appears to bind low-density lipoprotein cholesterol (LDL-C) in vitro, which suggests a direct interaction with the atherogenic lipids (2). Why use CRP as an indicator?Atherogenesis is initiated by endothelial injury, which is followed by activation of endothelial cells, up-regulation of cytokines and adhesion molecules (eg, soluble intercellular adhesion molecules, E-selectin), and migration of inflammatory cells into the subendothelium (see figure 1). In this scenario, IL-1, IL-6, and TNF-alpha stimulate CRP synthesis by inducing hepatic gene expression (3). Because atherosclerosis is now considered an inflammatory disease and an elevated level of CRP in the circulating blood suggests persistent inflammation, particularly in the coronary wall, it seems logical to use CRP to monitor the progression of vascular inflammation. Measurement of IL-1 and IL-6 levels is available only in specialized laboratories. However, serum levels of CRP have been used as an inflammatory marker for other diseases, and measurement is routinely performed in commercial laboratories. In some instances, erythrocyte sedimentation rate (ESR) has been used to measure the severity of inflammation, but it requires special processing and is a laborious process. In addition, ESR cannot be measured in stored serum samples. Hence, because of its availability, convenience, and relevance to inflammation, CRP has evolved rapidly as a promising way to monitor disease progression. How is CRP measured?To detect active inflammation and infection, CRP used to be measured using immunoturbidimetric or immunoelectrophoretic assays. The normal serum concentration of CRP ranges from 3 mg/dL (90th percentile of the general US population) to more than 200 mg/dL. Because these ranges are not sensitive for the values required to determine cardiovascular risk in otherwise healthy persons, investigators have developed new, modified techniques to measure high-sensitivity CRP. The high-sensitivity CRP assay has been shown to detect concentrations below 0.2 mg/mL and uses labeled monoclonal or polyclonal anti-CRP antibodies in an enzyme-linked immunosorbent assay (ELISA) or an immunofluorescent assay (4). Generally, insurance companies cover the test as a way to monitor for infection and inflammation. What conditions are linked to elevated CRP levels?CRP concentrations are elevated in almost all inflammatory, infectious, and neoplastic diseases (table 1). Specific conditions include rheumatologic diseases (eg, systemic lupus erythematosus, Sjögren's syndrome, rheumatoid arthritis), vasculitides (eg, Wegener's granulomatosis), and chronic infections (eg, tuberculosis, endocarditis).
Circulating levels of IL-6 and CRP can help discriminate between reactive and clonal thrombocytosis (5). Certain malignant neoplasms, such as solid tumors, also may be associated with an elevated CRP level and need to be excluded in patients with significant risk factors before elevated CRP levels can be attributed to overt or incipient CAD. Because CRP has a long half-life, CRP levels correlate well to its synthesis induced by persistent inflammation. Elevated levels of CRP are also associated with cardiovascular diseases such as endocarditis, angina pectoris, and myocardial infarction.
Infection and coronary risk Further studies have confirmed that the risk of angiographically documented CAD and the magnitude of increase in CRP levels are associated with an increased pathogen burden (including CMV and C pneumoniae). These associations emphasize the role of the inflammatory response and host defense mechanisms in atherosclerosis (7).
Angina pectoris CRP concentrations are significantly lower in patients with stable angina pectoris than in those with unstable angina pectoris or an acute coronary syndrome. Patients with chronic stable angina who have stable, low CRP levels over time have fewer subsequent cardiovascular events during follow-up (9). On the other hand, in patients with unstable angina pectoris, elevated CRP levels are strong predictors of plaque instability. Bazzino and associates (10) evaluated the prognostic value of the stress test and CRP concentration after medical stabilization of unstable angina (table 2). They showed that elevated levels of CRP (>1.5 mg/dL) were found more often in patients who had died or who had had an MI at 90 days after an acute coronary event. When compared with stress testing, CRP levels demonstrated a greater sensitivity (88% versus 47%) and specificity (81% versus 70%). Moreover, an elevated CRP level at the time of hospital discharge appears to be a more sensitive and specific test marker for increased risk than a positive stress test. Higher CRP levels are strong predictors of recurrent events, whereas low CRP levels suggest a good outcome.
Myocardial infarction In the Monitoring Trends and Determinants in Cardiovascular Disease trial (12), a long-term prospective study of cardiovascular risk, patients with the highest CRP levels had 2.6 times the risk of MI. In another study (13), postinfarction angina occurred in only 14% of patients with a normal CRP level. By comparison, 64% of patients admitted with high CRP levels had evidence of postinfarction angina; nearly 42% required revascularization, and 21% had recurrent MI. In patients with MI, increased CRP concentration is associated with the presence of complex angiographic lesions and the need for revascularization (14). Elevated CRP levels also may represent a biomarker for patients who are most susceptible to reocclusion. In patients with stable CAD who underwent stent implantation following angioplasty, CRP levels increased over 96 hours in those with restenosis; in patients without restenosis, CRP levels peaked at 48 hours and then declined. Looked at another way, in patients who have stable angina and disease in one vessel and have stent placement, normal CRP levels before the procedure or normalization of CRP levels within 72 hours after coronary artery stent placement identifies a large subset of patients who are unlikely to have cardiovascular events during the 12-month follow-up (15). In addition, among patients who undergo coronary artery bypass grafting, those with elevated CRP levels experience significant recurrent events in the 6 years following surgery compared with patients with normal or low CRP levels (16). In patients who receive a cardiac transplant, elevated CRP levels may be a significant biomarker for cardiac allograft vasculopathy or rejection, or both (17). Effects of statins and salicylates on CRP levelsThe 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors ("statins") have been shown to decrease blood levels of cholesterol and to induce regression of atherosclerotic lesions. Although a major mode of action of these drugs is to lower levels of atherogenic lipids, it is also likely that other mechanisms independent of their effects on lipid metabolism (eg, effects on the inflammatory response) may account for some of the benefits observed. For example, statins have been shown to suppress the expression of adhesion molecules on endothelium, decrease production of metalloproteinases by macrophages that allow plaque rupture, and alter macrophage contents within plaques. It is reasonable, therefore, to assume that the statins may have anti-inflammatory effects on the blood vessel wall (18). Accordingly, treatment with these agents has produced reductions in CRP levels. In the Cholesterol and Recurrent Events (CARE) trial (19), levels of both CRP and serum amyloid A were higher in post-MI patients who had recurrent coronary events. However, this association was significant only in patients receiving placebo and not in patients taking pravastatin, suggesting an antiinflammatory role for these drugs. In the Pravastatin Inflammation/CRP Evaluation trial (20), pravastatin reduced CRP levels at both 12 and 24 weeks independent of LDL-C, again pointing towards an anti-inflammatory action. Lovastatin therapy was recently shown to reduce CRP levels by 14.8% and decrease cardiac events in patients in a 5-year randomized trial of lovastatin for primary prevention of coronary events (21). Currently, the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol study (22) is evaluating the effects of atorvastatin and pravastatin on carotid artery intima-media thickness and on inflammatory markers, including CRP, in the primary and secondary prevention of CAD. The results of this study are eagerly awaited. Salicylates (eg, aspirin) have beneficial, cardioprotective effects in patients with CAD, as demonstrated in the Physicians' Health Study. Recent studies suggest that in addition to having antithrombotic effects, aspirin may have other immunologic effects that modulate vascular inflammation. Ridker and colleagues (23) first reported on the observation that aspirin reduced the risk of vascular disease (eg, MI, ischemic stroke) in apparently healthy men, but only in those with the highest levels of CRP. This conclusion suggests a role for aspirin in slowing the inflammatory cascade. These findings were further corroborated by Ikonomidis and associates (24), who demonstrated that aspirin reduced circulating levels of CRP and the atherogenic cytokines macrophage colony-stimulating factor and IL-6 in patients with documented CAD. Kennon and colleagues (25) demonstrated that aspirin lowered plasma levels of CRP in patients hospitalized with an acute coronary syndrome. These data suggest that novel approaches to modulating atherosclerosis may be provided by cyclooxygenase-2 inhibitors and statins as well as by other evolving and novel therapies that target the inflammatory cascade. ConclusionCRP represents a novel and evolving biomarker for the extent and severity of atherosclerotic lesions and provides a useful predictive indicator for subsequent events. Based on previous studies, increased CRP levels in patients at high risk of cardiovascular disease without documented CAD warrant treatment with statins even if LDL-C levels are within the target range. Patients with documented CAD and high CRP levels should be followed closely, and their risk factors should be managed aggressively. Currently, there is no consensus about the role of CRP levels in monitoring CAD. Formal guidelines about the use of CRP as an independent risk factor and in the day-to-day management of CAD are not yet available despite clear evidence of its usefulness in association with other tools, including the stress test. References
Drs Elgharib, Younis, and Wehbe are third-year residents, Dr Chi is professor and chief of the division of biomedical research, and Dr Krishnaswamy is professor and chief of the division of allergy and immunology, department of internal medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City. Correspondence: Guha Krishnaswamy, MD, Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, PO Box 70622, Johnson City, TN 37614-1709. E-mail: krishnas@mail.etsu.edu.
|
|
||||||||||||||||||||||||||||||||||||||
|
about us | cme | home | issue index | patient notes | pearls | ad services |
Please send technical questions related to the Web site to Ann Harste
|
||||||||||||||||||||||||||||||||||||||||
