Nader Rifai

C-Reactive Protein and Other Markers of Inflammation in the Prediction of Cardiovascular Disease in Women

BACKGROUND Since inflammation is believed to have a role in the pathogenesis of cardiovascular events, measurement of markers of inflammation has been proposed as a method to improve the prediction of the risk of these events. METHODS We conducted a prospective, nested case-control study among 28,263 apparently healthy postmenopausal women over a mean follow-up period of three years to assess the risk of cardiovascular events associated with base-line levels of markers of inflammation. The markers included high-sensitivity C-reactive protein (hs-CRP), serum amyloid A, interleukin-6, and soluble intercellular adhesion molecule type 1 (sICAM-1). We also studied homocysteine and a variety of lipid and lipoprotein measurements. Cardiovascular events were defined as death from coronary heart disease, nonfatal myocardial infarction or stroke, or the need for coronary-revascularization procedures. RESULTS Of the 12 markers measured, hs-CRP was the strongest univariate predictor of the risk of cardiovascular events; the relative risk of events for women in the highest as compared with the lowest quartile for this marker was 4.4 (95 percent confidence interval, 2.2 to 8.9). Other markers significantly associated with the risk of cardiovascular events were serum amyloid A (relative risk for the highest as compared with the lowest quartile, 3.0), sICAM-1 (2.6), interleukin-6 (2.2), homocysteine (2.0), total cholesterol (2.4), LDL cholesterol (2.4), apolipoprotein B-100 (3.4), HDL cholesterol (0.3), and the ratio of total cholesterol to HDL cholesterol (3.4). Prediction models that incorporated markers of inflammation in addition to lipids were significantly better at predicting risk than models based on lipid levels alone (P<0.001). The levels of hs-CRP and serum amyloid A were significant predictors of risk even in the subgroup of women with LDL cholesterol levels below 130 mg per deciliter (3.4 mmol per liter), the target for primary prevention established by the National Cholesterol Education Program. In multivariate analyses, the only plasma markers that independently predicted risk were hs-CRP (relative risk for the highest as compared with the lowest quartile, 1.5; 95 percent confidence interval, 1.1 to 2.1) and the ratio of total cholesterol to HDL cholesterol (relative risk, 1.4; 95 percent confidence interval, 1.1 to 1.9). CONCLUSIONS The addition of the measurement of C-reactive protein to screening based on lipid levels may provide an improved method of identifying persons at risk for cardiovascular events.

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

In 1998, the American Heart Association convened Prevention Conference V to examine strategies for the identification of high-risk patients who need primary prevention. Among the strategies discussed was the measurement of markers of inflammation.1 The Conference concluded that “many of these markers (including inflammatory markers) are not yet considered applicable for routine risk assessment because of: (1) lack of measurement standardization, (2) lack of consistency in epidemiological findings from prospective studies with endpoints, and (3) lack of evidence that the novel marker adds to risk prediction over and above that already achievable through the use of established risk factors.” The National Cholesterol Education Program Adult Treatment Panel III Guidelines identified these markers as emerging risk factors,1a which could be used as an optional risk factor measurement to adjust estimates of absolute risk obtained using standard risk factors. Since these publications, a large number of peer-reviewed scientific reports have been published relating inflammatory markers to cardiovascular disease (CVD). Several commercial assays for inflammatory markers have become available. As a consequence of the expanding research base and availability of assays, the number of inflammatory marker tests ordered by clinicians for CVD risk prediction has grown rapidly. Despite this, there has been no consensus from professional societies or governmental agencies as to how these assays of markers of inflammation should be used in clinical practice. On March 14 and 15, 2002, a workshop titled “CDC/AHA Workshop on Inflammatory Markers and Cardiovascular Disease: Applications to Clinical and Public Health Practice” was convened in Atlanta, Ga, to address these issues. The goals of this workshop were to determine which of the currently available tests should be used; what results should be used to define high risk; which patients should be tested; and the indications for which the tests would be most useful. These …

Plasma Concentration of Interleukin-6 and the Risk of Future Myocardial Infarction Among Apparently Healthy Men

BACKGROUND Interleukin-6 (IL-6) plays a central role in inflammation and tissue injury. However, epidemiological data evaluating the role of IL-6 in atherogenesis are sparse. METHODS AND RESULTS In a prospective study involving 14 916 apparently healthy men, we measured baseline plasma concentration of IL-6 in 202 participants who subsequently developed myocardial infarction (MI) and in 202 study participants matched for age and smoking status who did not report vascular disease during a 6-year follow-up. Median concentrations of IL-6 at baseline were higher among men who subsequently had an MI than among those who did not (1.81 versus 1. 46 pg/mL; P=0.002). The risk of future MI increased with increasing quartiles of baseline IL-6 concentration (P for trend <0.001) such that men in the highest quartile at entry had a relative risk 2.3 times higher than those in the lowest quartile (95% CI 1.3 to 4.3, P=0.005); for each quartile increase in IL-6, there was a 38% increase in risk (P=0.001).This relationship remained significant after adjustment for other cardiovascular risk factors, was stable over long periods of follow-up, and was present in all low-risk subgroups, including nonsmokers. Although the strongest correlate of IL-6 in these data was C-reactive protein (r=0.43, P<0.001), the relationship of IL-6 with subsequent risk remained after control for this factor (P<0.001). CONCLUSIONS In apparently healthy men, elevated levels of IL-6 are associated with increased risk of future MI. These data thus support a role for cytokine-mediated inflammation in the early stages of atherogenesis.

C-Reactive Protein Levels and Outcomes after Statin Therapy

BACKGROUND Statins lower the levels of low-density lipoprotein (LDL) cholesterol and C-reactive protein (CRP). Whether this latter property affects clinical outcomes is unknown. METHODS We evaluated relationships between the LDL cholesterol and CRP levels achieved after treatment with 80 mg of atorvastatin or 40 mg of pravastatin per day and the risk of recurrent myocardial infarction or death from coronary causes among 3745 patients with acute coronary syndromes. RESULTS Patients in whom statin therapy resulted in LDL cholesterol levels of less than 70 mg per deciliter (1.8 mmol per liter) had lower event rates than those with higher levels (2.7 vs. 4.0 events per 100 person-years, P=0.008). However, a virtually identical difference was observed between those who had CRP levels of less than 2 mg per liter after statin therapy and those who had higher levels (2.8 vs. 3.9 events per 100 person-years, P=0.006), an effect present at all levels of LDL cholesterol achieved. For patients with post-treatment LDL cholesterol levels of more than 70 mg per deciliter, the rates of recurrent events were 4.6 per 100 person-years among those with CRP levels of more than 2 mg per liter and 3.2 events per 100 person-years among those with CRP levels of less than 2 mg per liter; the respective rates among those with LDL cholesterol levels of less than 70 mg per deciliter were 3.1 and 2.4 events per 100 person-years (P<0.001). Although atorvastatin was more likely than pravastatin to result in low levels of LDL cholesterol and CRP, meeting these targets was more important in determining the outcomes than was the specific choice of therapy. Patients who had LDL cholesterol levels of less than 70 mg per deciliter and CRP levels of less than 1 mg per liter after statin therapy had the lowest rate of recurrent events (1.9 per 100 person-years). CONCLUSIONS Patients who have low CRP levels after statin therapy have better clinical outcomes than those with higher CRP levels, regardless of the resultant level of LDL cholesterol. Strategies to lower cardiovascular risk with statins should include monitoring CRP as well as cholesterol.

C-Reactive Protein, the Metabolic Syndrome, and Risk of Incident Cardiovascular Events

Background—The metabolic syndrome describes a high-risk population having 3 or more of the following clinical characteristics: upper-body obesity, hypertriglyceridemia, low HDL, hypertension, and abnormal glucose. All of these attributes, however, are associated with increased levels of C-reactive protein (CRP). Methods and Results—We evaluated interrelationships between CRP, the metabolic syndrome, and incident cardiovascular events among 14 719 apparently healthy women who were followed up for an 8-year period for myocardial infarction, stroke, coronary revascularization, or cardiovascular death; 24% of the cohort had the metabolic syndrome at study entry. At baseline, median CRP levels for those with 0, 1, 2, 3, 4, or 5 characteristics of the metabolic syndrome were 0.68, 1.09, 1.93, 3.01, 3.88, and 5.75 mg/L, respectively (Ptrend <0.0001). Over the 8-year follow-up, cardiovascular event-free survival rates based on CRP levels above or below 3.0 mg/L were similar to survival rates based on having 3 or more characteristics of the metabolic syndrome. At all levels of severity of the metabolic syndrome, however, CRP added prognostic information on subsequent risk. For example, among those with the metabolic syndrome at study entry, age-adjusted incidence rates of future cardiovascular events were 3.4 and 5.9 per 1000 person-years of exposure for those with baseline CRP levels less than or greater than 3.0 mg/L, respectively. Additive effects for CRP were also observed for those with 4 or 5 characteristics of the metabolic syndrome. The use of different definitions of the metabolic syndrome had minimal impact on these findings. Conclusions—These prospective data suggest that measurement of CRP adds clinically important prognostic information to the metabolic syndrome.

Measurement of C-Reactive Protein for the Targeting of Statin Therapy in the Primary Prevention of Acute Coronary Events

Background Elevated levels of C-reactive protein, even in the absence of hyperlipidemia, are associated with an increased risk of coronary events. Statin therapy reduces the level of C-reactive protein independently of its effect on lipid levels. We hypothesized that statins might prevent coronary events in persons with elevated C-reactive protein levels who did not have overt hyperlipidemia. Methods The level of C-reactive protein was measured at base line and after one year in 5742 participants in a five-year randomized trial of lovastatin for the primary prevention of acute coronary events. Results The rates of coronary events increased significantly with increases in the base-line levels of C-reactive protein. Lovastatin therapy reduced the C-reactive protein level by 14.8 percent (P<0.001), an effect not explained by lovastatin-induced changes in the lipid profile. As expected, lovastatin was effective in preventing coronary events in participants whose base-line ratio of total cholesterol to high-de...

Long-Term Effects of Pravastatin on Plasma Concentration of C-reactive Protein

Background—Elevated plasma concentrations of C-reactive protein (CRP) are associated with increased cardiovascular risk. We evaluated whether long-term therapy with pravastatin, an agent that reduces cardiovascular risk, might alter levels of this inflammatory parameter. Methods and Results—CRP levels were measured at baseline and at 5 years in 472 randomly selected participants in the Cholesterol and Recurrent Events (CARE) trial who remained free of recurrent coronary events during follow-up. Overall, CRP levels at baseline and at 5 years were highly correlated (r50.60, P,0.001). However, among those allocated to placebo, median CRP levels and the mean change in CRP tended to increase over time (median change, 14.2%; P50.2 and mean change, 10.07 mg/dL; P50.04). By contrast, median CRP levels and the mean change in CRP decreased over time among those allocated to pravastatin (median change, 217.4%; P50.004 and mean change, 20.07 mg/dL; P50.002). Thus, statistically significant differences were observed at 5 years between the pravastatin and placebo groups in terms of median CRP levels (difference, 221.6%; P50.007), mean CRP levels (difference, 237.8%; P50.002), and absolute mean change in CRP (difference, 20.137 mg/dL; P50.003). These effects persisted in analyses stratified by age, body mass index, smoking status, blood pressure, and baseline lipid levels. Attempts to relate the magnitude of change in CRP to the magnitude of change in lipids in both the pravastatin and placebo groups did not reveal any obvious relationships. Conclusions—Among survivors of myocardial infarction on standard therapy plus placebo, CRP levels tended to increase over 5 years of follow-up. In contrast, randomization to pravastatin resulted in significant reductions in this inflammatory marker that were not related to the magnitude of lipid alterations observed. Thus, these data further support the potential for nonlipid effects of this agent. (Circulation. 1999;100:230-235.)

Inflammation, Pravastatin, and the Risk of Coronary Events After Myocardial Infarction in Patients With Average Cholesterol Levels

BACKGROUND We studied whether inflammation after myocardial infarction (MI) is a risk factor for recurrent coronary events and whether randomized treatment with pravastatin reduces that risk. METHODS AND RESULTS A nested case-control design was used to compare C-reactive protein (CRP) and serum amyloid A (SAA) levels in prerandomization blood samples from 391 participants in the Cholesterol and Recurrent Events (CARE) trial who subsequently developed recurrent nonfatal MI or a fatal coronary event (cases) and from an equal number of age- and sex-matched participants who remained free of these events during follow-up (control subjects). Overall, CRP and SAA were higher among cases than control subjects (for CRP P=0.05; for SAA P=0.006) such that those with levels in the highest quintile had a relative risk (RR) of recurrent events 75% higher than those with levels in the lowest quintile (for CRP RR= 1.77, P=0.02; for SAA RR= 1.74, P=0.02). The study group with the highest risk was that with consistent evidence of inflammation (elevation of both CRP and SAA) who were randomly assigned to placebo (RR=2.81, P=0.007); this risk estimate was greater than the product of the individual risks associated with inflammation or placebo assignment alone. In stratified analyses, the association between inflammation and risk was significant among those randomized to placebo (RR=2.11, P=0.048) but was attenuated and nonsignificant among those randomized to pravastatin (RR=1.29, P=0.5). CONCLUSIONS Evidence of inflammation after MI is associated with increased risk of recurrent coronary events. Therapy with pravastatin may decrease this risk, an observation consistent with a nonlipid effect of this agent.

Protein biomarker discovery and validation: the long and uncertain path to clinical utility

Better biomarkers are urgently needed to improve diagnosis, guide molecularly targeted therapy and monitor activity and therapeutic response across a wide spectrum of disease. Proteomics methods based on mass spectrometry hold special promise for the discovery of novel biomarkers that might form the foundation for new clinical blood tests, but to date their contribution to the diagnostic armamentarium has been disappointing. This is due in part to the lack of a coherent pipeline connecting marker discovery with well-established methods for validation. Advances in methods and technology now enable construction of a comprehensive biomarker pipeline from six essential process components: candidate discovery, qualification, verification, research assay optimization, biomarker validation and commercialization. Better understanding of the overall process of biomarker discovery and validation and of the challenges and strategies inherent in each phase should improve experimental study design, in turn increasing the efficiency of biomarker development and facilitating the delivery and deployment of novel clinical tests.

Prevalence of the Metabolic Syndrome in American Adolescents Findings From the Third National Health and Nutrition Examination Survey

Background—Metabolic syndrome (MetS) is defined by the Third Report of the Adult Treatment Panel (ATP III) using criteria easily applied by clinicians and researchers. There is no standard pediatric definition. Methods and Results—We defined pediatric MetS using criteria analogous to ATP III as ≥3 of the following: (1) fasting triglycerides ≥1.1 mmol/L (100 mg/dL); (2) HDL <1.3 mmol/L (50 mg/dL), except in boys aged 15 to 19 years, in whom the cutpoint was <1.2 mmol/L (45 mg/dL); (3) fasting glucose ≥6.1 mmol/L (110 mg/dL); (4) waist circumference >75th percentile for age and gender; and (5) systolic blood pressure >90th percentile for gender, age, and height. MetS prevalence in US adolescents was estimated with the Third National Health and Nutritional Survey 1988 to 1994. Among 1960 children aged ≥12 years who fasted ≥8 hours, two thirds had at least 1 metabolic abnormality, and nearly 1 in 10 had MetS. The racial/ethnic distribution was similar to adults: Mexican-Americans, followed by non-Hispanic whites, had a greater prevalence of MetS compared with non-Hispanic blacks (12.9%, [95% CI 10.4% to 15.4%]; 10.9%, [95% CI 8.4% to 13.4%]; and 2.5%, [95% CI 1.3% to 3.7%], respectively). Nearly one third (31.2% [95% CI 28.3% to 34.1%]) of overweight/obese adolescents had MetS. Conclusions—Our definition of pediatric MetS, designed to be closely analogous to ATP III, found MetS is common in adolescents and has a similar racial/ethnic distribution to adults in this representative national sample. Because childhood MetS likely tracks into adulthood, early identification may help target interventions to improve future cardiovascular health.