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Abstract

  1. Top of page
  2. Abstract
  3. CRP as a Clinical Marker for Global CV Risk
  4. CRP as a Clinical Marker for and Mediator of the Metabolic Syndrome
  5. Who Should Be Tested?
  6. CRP-Driven Therapy: The Future
  7. Conclusions
  8. References

The inflammatory marker C-reactive protein has emerged as a powerful independent predictor of cardiovascular disease risk. C-reactive protein may also be a mediator of inflammatory processes such as atherosclerosis development and progression, and it appears to be useful in identifying patients with, or at risk for developing, diabetes mellitus and the metabolic syndrome. In the clinical practice setting, measurement of C-reactive protein levels can add information to help guide management decisions in persons who are at intermediate risk based on Framingham risk scores, who have preexisting cardiovascular disease, or who exhibit components of the metabolic syndrome. A large ongoing trial is investigating whether statin therapy will decrease the risk of cardiovascular disease in patients with elevated levels of C-reactive protein and low-to-normal levels of low-density lipoprotein cholesterol.

One fifth of all cardiovascular disease (CVD) events occur in persons who do not have an identifiable traditional risk factor,1 and the majority of cardiovascular (CV) events tend to occur in patients with normal cholesterol levels.2 Novel CVD risk factors that provide information beyond existing risk-assessment tools would greatly improve primary prevention strategies. C-reactive protein (CRP), a nonspecific marker of inflammatory processes,3 has emerged as one potentially useful addition to the CV risk profile.

CRP as a Clinical Marker for Global CV Risk

  1. Top of page
  2. Abstract
  3. CRP as a Clinical Marker for Global CV Risk
  4. CRP as a Clinical Marker for and Mediator of the Metabolic Syndrome
  5. Who Should Be Tested?
  6. CRP-Driven Therapy: The Future
  7. Conclusions
  8. References

Several prospective epidemiologic studies have shown that elevated levels of high-sensitivity CRP (hsCRP) independently predict CVD risk in a wide variety of clinical settings.4–8 Furthermore, hsCRP predicts not only incident myocardial infarction (MI) and CVD death, but also the risk for ischemic stroke, sudden cardiac death, incident peripheral vascular disease, and restenosis after percutaneous coronary intervention.9–12 The greatest utility of hsCRP, however, may lie in the realm of primary prevention, where it confers additional prognostic value at all levels of Framingham risk and blood pressure.2,13

In the Women's Health Study (WHS),2 low-density lipoprotein cholesterol (LDL-C) and hsCRP were compared for their ability to predict first MI, ischemic stroke, coronary revascularization, or CVD in 27,939 American women with no history of CVD. At the study's outset, participants underwent a Framingham risk assessment, hsCRP evaluation, and a full lipid screening. Mean follow-up was 8 years. The relative risks for a future CV event for increasing quintiles of baseline hsCRP were 1.0, 1.8, 2.3, 3.2, and 4.5 (p <0.001). The risk of a first CV event increased with increasing quintiles of both LDL-C and hsCRP (both p <0.001). Participants with baseline LDL-C levels below currently recommended goals accounted for 46% of all the CV events that occurred. LDL-C and hsCRP levels correlated poorly (r =0.08), suggesting that each of these biomarkers predicted events in different risk groups. A combined approach using both LDL-C and hsCRP levels provided an improvement in the prediction of CV event-free survival. The predictive power of hsCRP remained significant after adjustment for the Framingham risk score.

Two recent trials add strong support for the use of CRP as a predictor of CVD in primary prevention. In the first, CRP was compared with various lipid measures, including total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C), lipid ratios, and apolipoproteins, in a prospective cohort analysis of 15,652 middle-aged American women.14 Participants were followed for 10 years for the occurrence of CV events. After adjustment for age, blood pressure, smoking, diabetes, and obesity, CRP added prognostic information beyond that conveyed by all the lipid measures.14 In the Cardiovascular Health Study,15 baseline CRP was measured in 3971 men and women 65 years of age and older without prior vascular disease who were followed for 10 years. Among men with elevated CRP levels (>3 mg/L), the 10-year cumulative coronary heart disease risk was 33%; among women, it was 17%. Among men with a 10-year Framingham-predicted risk of 10%–20%, the observed incidence of a coronary event was 32%. Among women who had a 10-year predicted risk >20%, 31% of those with elevated CRP experienced an event vs. 10% of those with normal CRP levels. Tus, a single CRP measurement was able to provide information beyond conventional risk assessment, especially in men with intermediate Framingham risk and women with high Framingham risk.

CRP as a Clinical Marker for and Mediator of the Metabolic Syndrome

  1. Top of page
  2. Abstract
  3. CRP as a Clinical Marker for Global CV Risk
  4. CRP as a Clinical Marker for and Mediator of the Metabolic Syndrome
  5. Who Should Be Tested?
  6. CRP-Driven Therapy: The Future
  7. Conclusions
  8. References

The Third Report of the Adult Treatment Panel of the National Cholesterol Education Program (ATP III) defined the metabolic syndrome as the presence of any three of the following: elevated triglycerides, low levels of HDL-C, abdominal obesity, elevated blood pressure, and high fasting glucose levels. The clustering of these CVD risk factors, which can lead to premature illness and death, has been estimated to affect one in four adults, making the metabolic syndrome a leading public health problem. Inflammation appears to be associated with the development of insulin resistance and diabetes; thus, hsCRP may likely play a significant role. , In fact, hsCRP levels correlate with the components of the metabolic syndrome and with direct measures of insulin resistance and endothelial dysfunction. Large-scale clinical studies have demonstrated that hsCRP evaluation may add prognostic information as an additional clinical criterion for the diagnosis of the metabolic syndrome.

An association among inflammation, hsCRP level, and diabetogenesis emerged with the observation that baseline levels of hsCRP served as a strong predictor for identifying patients at risk for developing type 2 diabetes mellitus even after adjusting for obesity, family history of diabetes, smoking, exercise, and alcohol use. In the WHS, women with hsCRP levels in the highest quartile had a relative risk for developing diabetes of 4.2 (95% confidence interval, 1.5–12.0) compared with women in the lowest quartile. Among women who met the ATP III criteria for the metabolic syndrome, the risk of first-ever CVD events was significantly greater when baseline levels of hsCRP were taken into consideration (Figure). Tus, hsCRP provides a practical means of obtaining additional information to characterize CVD risk among individuals before the onset of disease.

image

Figure Figure. Cardiovascular disease (CVD) event-free survival probability according to baseline high-sensitivity C-reactive protein (CRP) levels in 3597 women with the metabolic syndrome in the Women's Health Study. Women with the metabolic syndrome and the highest levels of CRP (>3 mg/L) had a relative risk of future CVD events twice that of women with CRP levels <1 mg/L (95% confidence interval, 1.1–4.2; p=0.001). Reprinted with permission from Circulation. 2003;107:391–397.20

The proinflammatory effects of CRP actively foster a physiologic environment conducive to development of the metabolic syndrome. Circulating plasma CRP levels are correlated with body mass index and elevated in obese subjects, and weight loss by either hypocaloric diets or surgical intervention appears to reduce CRP levels.24,25 The detrimental effects of CRP on endothelial dysfunction are potentiated by hyperglycemia, and these effects are attenuated by rosiglitazone, an insulin-sensitizing thiazolidinedione antidiabetic drug.26 Furthermore, CRP appears to amplify the proinflammatory activity of adipokines, cytokines released from adipose tissue that participate in the development of insulin resistance. Plasma levels of plasminogen activator inhibitor-1, which are elevated in obese humans and decreased with weight loss, are positively correlated with CVD risk and mortality, as well as the development of diabetes.27,28 Adipose tissue has been found to be a potential source of CRP,29,30 supporting the notion of a vicious metabolic circle fuelled by CRP that promotes atherogenesis, dyslipidemia, and insulin resistance.

Who Should Be Tested?

  1. Top of page
  2. Abstract
  3. CRP as a Clinical Marker for Global CV Risk
  4. CRP as a Clinical Marker for and Mediator of the Metabolic Syndrome
  5. Who Should Be Tested?
  6. CRP-Driven Therapy: The Future
  7. Conclusions
  8. References

CRP levels remain stable over time and do not exhibit circadian variability. Unlike cholesterol testing, hsCRP evaluation does not require a fasting blood sample and hence may be done at any time of day. The simplicity of hsCRP evaluation strengthens its clinical use in the assessment of global CVD risk and the metabolic syndrome. Also, CRP levels correlate well with direct measures of insulin resistance, oral glucose tolerance, and hypofibrinolysis, which are either too difficult or time-consuming to measure in usual outpatient settings. An approach in which hsCRP levels of <1, 1–3, and >3 mg/L differentiate low-, moderate-, and high-risk patients has been generally adopted clinically.31 Individuals with persistent elevations of hsCRP >10 mg/L appear to represent a group with the very highest levels of risk. Moreover, there is an almost linear relation between hsCRP levels and risk across a full range of values, such that persons with the very lowest levels (<0.5 mg/L) have exceptionally low CVD risk regardless of other risk factors.32

The Centers for Disease Control and Prevention (CDC) and the American Heart Association (AHA) have released joint recommendations on the application of hsCRP for the assessment of CVD risk.33,34 The CDC/AHA Scientific Statement recognizes that hsCRP adds to the predictive ability of established risk factors. Similarly, in the setting of secondary prevention, hsCRP is a reliable predictor of poorer outcomes following acute coronary syndromes, percutaneous transluminal interventions, or stroke. The use of hsCRP screening is recommended as a routine part of global CVD risk assessment in patients judged at intermediate risk (10%–20% risk of CVD within 10 years) and in patients with stable coronary disease33 or acute coronary syndromes.34 Results of subsequent clinical and biologic studies supporting elevated hsCRP levels as a component of the metabolic syndrome and a risk factor for developing diabetes, however, suggest that hsCRP testing should be expanded. We believe that if a patient is at increased risk for developing CVD, has preexisting CVD, or exhibits components of the metabolic syndrome, confirming an elevated level of hsCRP may assist with decisions to start more aggressive medical treatment and, simultaneously, to aggressively encourage appropriate lifestyle changes.

CRP-Driven Therapy: The Future

  1. Top of page
  2. Abstract
  3. CRP as a Clinical Marker for Global CV Risk
  4. CRP as a Clinical Marker for and Mediator of the Metabolic Syndrome
  5. Who Should Be Tested?
  6. CRP-Driven Therapy: The Future
  7. Conclusions
  8. References

An elevated hsCRP level of >3 mg/L is a strong predictor of CVD and the metabolic syndrome, with levels persistently above 10 mg/L representing very high risk. Metabolic syndrome patients should be informed that an elevated hsCRP suggests that they may be at increased risk for developing CVD or for having their current condition worsen. They should be counselled that the best ways to lower hsCRP levels are the already well-established methods for improving CV health and warding off the metabolic syndrome. Smoking cessation, exercise, blood pressure control, and cholesterol lowering with statins have been identified as interventions that may lower a person's hsCRP level.

Results from large-scale, randomized, controlled trials of statin therapy35–39 show that, in addition to their cholesterol-lowering effect, statins reduce hsCRP levels. It has recently been demonstrated that patients who have lower hsCRP levels after statin therapy have better clinical outcomes, including reduced rates of atherosclerosis progression, than those with higher hsCRP levels, regardless of the LDL-C level.40 Analysis of the Pravastatin or Atorvastatin Evaluation and Infection Therapy—Trombolysis in Myocardial Infarction 22 (PROVE IT—TIMI 22) study40 demonstrated that the best clinical outcomes were obtained among statin-treated patients who achieved the dual goal of LDL-C <70 mg/dL and hsCRP levels <2.0 mg/L.

The Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER)41 was initiated to determine whether long-term treatment with rosuvastatin will reduce the rate of first major CV events among persons with LDL-C levels <130 mg/dL but who are considered to be at increased risk due to hsCRP levels ≥2.0 mg/L. In this study, 15,000 middle-aged persons with no history of CVD and not receiving lipid-lowering therapy will be randomly assigned to either rosuvastatin 20 mg/d or placebo and followed for at least 3 years for major CV events. If successful, the JUPITER trial would provide the first indication for primary prevention with statin therapy in patients who are not candidates for statin treatment based on current guidelines.41

Conclusions

  1. Top of page
  2. Abstract
  3. CRP as a Clinical Marker for Global CV Risk
  4. CRP as a Clinical Marker for and Mediator of the Metabolic Syndrome
  5. Who Should Be Tested?
  6. CRP-Driven Therapy: The Future
  7. Conclusions
  8. References

The role of CRP in atherosclerosis, vascular inflammation, the metabolic syndrome, and the development of insulin resistance continues to emerge. Epidemiologic and biologic evidence shows that CRP is a powerful biomarker for, and may be a participant in, CVD. Furthermore, as a useful prognostic factor for the metabolic syndrome, as well as a biologically active substance that may participate in its development, an elevated CRP level should now be considered a clinical criterion for the metabolic syndrome. As our understanding of the molecular mechanisms involved in atherogenesis and insulin resistance expands, new therapeutic targets will emerge that will improve our ability not only to identify, but also to treat, the growing epidemic of CVD.

Disclosure: This work was supported by a grant from AstraZeneca.

References

  1. Top of page
  2. Abstract
  3. CRP as a Clinical Marker for Global CV Risk
  4. CRP as a Clinical Marker for and Mediator of the Metabolic Syndrome
  5. Who Should Be Tested?
  6. CRP-Driven Therapy: The Future
  7. Conclusions
  8. References
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