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December 2002

C-reactive protein

Lack of association between cholesterol and coronary heart disease mortality and morbidity and all-cause mortality in persons older than 70 years.

OBJECTIVES: To determine whether elevated serum cholesterol level is associated with all-cause mortality, mortality from coronary heart disease, or hospitalization for acute myocardial infarction and unstable angina in persons older than 70 years. Also, to evaluate the association between low levels of high-density lipoprotein cholesterol (HDL-C) and elevated ratio of serum cholesterol to HDL-C with these outcomes. DESIGN: Prospective, community-based cohort study with yearly interviews. PARTICIPANTS--A total of 997 subjects who were interviewed in 1988 as part of the New Haven, Conn. cohort of the Established Population for the Epidemiologic Study of the Elderly (EPESE) and consented to have blood drawn. MAIN OUTCOME MEASURES: The risk factor-adjusted odds ratios of the four-year incidence of all-cause mortality, mortality from coronary heart disease, and hospitalization for myocardial infarction or unstable angina were calculated for the following: subjects with total serum cholesterol levels greater than or equal to 6.20 mmol/L (> or = 240 mg/dL) compared with subjects with cholesterol levels less than 5.20 mmol/L (< 200 mg/dL); subjects in the lowest tertile of HDL-C level compared with those in the highest tertile; and subjects in the highest tertile of the ratio of total serum cholesterol to HDL-C level compared with those in the lowest tertile. RESULTS: Elevated total serum cholesterol level, low HDL-C, and high total serum cholesterol to HDL-C ratio were not associated with a significantly higher rate of all-cause mortality, coronary heart disease mortality or hospitalization for myocardial infarction or unstable angina after adjustment for cardiovascular risk factors. The risk factor-adjusted odds ratio for all-cause mortality was 0.99 (95% confidence interval [CI], 0.56 to 2.69) for the group who had cholesterol levels greater than or equal to 6.20 mmol/L (> or = 240 mg/dL) compared with the group that had levels less than 5.20 mmol/L (< 200 mg/dL); 1.00 (95% CI, 0.59 to 1.70) for the group in the lowest tertile of HDL-C compared with those in the highest tertile; and 1.03 (95% CK, 0.62 to 1.71) for subjects in the highest tertile of the ratio of total serum cholesterol to HDL-C compared with those in the lowest tertile. CONCLUSIONS: Our findings do not support the hypothesis that hypercholesterolemia or low HDL-C are important risk factors for all-cause mortality, coronary heart disease mortality or hospitalization for myocardial infarction or unstable angina in this cohort of persons older than 70 years.

JAMA 1994 Nov 2;272(17):1335-40

Report of the conference on low blood cholesterol: mortality associations.

BACKGROUND: A National Heart, Lung and Blood Institute (NHLBI) Conference was held October 9-10, 1990, to review and discuss existing data on U-shaped relations found between mortality rates and blood total cholesterol levels (TC) in some but not other studies. Presentations were given from 19 cohort studies from the United States, Europe, Israel and Japan. A representative of each study presented its findings and also submitted tables of proportional hazards regression coefficients for entry TC levels in regard to death, and these were incorporated into a formal statistical overview adjusted for age, diastolic blood pressure, cigarette smoking, body mass index and alcohol intake, as available. METHODS AND RESULTS: The U-shape for total mortality in men and the flat relation in women resulted largely from a positive relation of TC with coronary heart disease death and an inverse relation with deaths caused by some cancers (e.g., lung but not colon), respiratory disease, digestive disease, trauma and residual deaths. Risk for combined noncardiovascular, noncancer causes of death decreased steadily across the range of TC. The conference considered possible explanations for the statistical associations found between low TC levels or active TC lowering and certain causes of death. One is that TC is lowered by some disease conditions themselves, such as wasting in chronic pulmonary disease or reduced production and secretion of cholesterol-bearing lipoproteins with liver disease. In this sort of situation, the TC:mortality association found in observational studies may be due to preexisting disease. This was addressed by excluding early deaths from the analysis, which did not change the results. The conference considered as well the biological function of cholesterol, which, if seriously deranged, might hypothetically cause a wide variety of diseases and dysfunction. The conference also considered the biological functions that might provide plausible mechanisms for the associations found. CONCLUSIONS: Definitive interpretation of the associations observed was not possible, although most participants considered it likely that many of the statistical associations of low or lowered TC level are explainable by confounding in one form or another. The conference focused on the apparent existence and nature of these associations and on the need to understand their source rather than on any pertinence of the findings for public health policy. Further research is recommended to explain the observed associations of low TC levels (and TC lowering) with certain noncardiovascular diseases. This includes studies of the time course of TC change in disease, the relation of TC to morbidity, further studies of possible epidemiological confounding, monitoring of population trends in TC and mortality, further studies of the relations in women, auditing of noncardiovascular events in trials, studies of cell membrane, genetic and molecular links to cholesterol metabolism, TC level and disease, studies of disease manifestations in specific lipid disorders, and further study of the proposed causal mechanisms linking low TC and hemorrhagic stroke.

Circulation 1992 Sep;86(3):1046-60

Inflammatory markers and coronary heart disease.

PURPOSE OF REVIEW: Despite changes in lifestyle and the use of effective pharmacologic interventions to lower cholesterol levels, coronary heart disease remains the major cause of morbidity and mortality in the developed world. Cholesterol screening fails to identify almost 50% of those individuals who will present with acute coronary syndromes. Recent evidence from laboratory and prospective clinical studies demonstrates that atherosclerosis is not simply a disease of lipid deposition, but rather is an inflammatory process with highly specific cellular and molecular responses. The clinical utility of inflammatory markers has been examined in a variety of atherothrombotic diseases. Because C-reactive protein is highly stable in stored frozen samples, and automated and robust analytical systems for its measurement are available, it has become the most widely examined inflammatory marker. RECENT FINDINGS: C-reactive protein has consistently been shown to be a useful prognostic indicator in acute coronary syndromes and is a strong predictor of future coronary events in apparently healthy individuals. In addition, C-reactive protein can identify individuals with normal lipid levels who are at increased risk for future coronary events. Because drugs such as aspirin and statins reduce inflammatory risk, C-reactive protein has the potential to guide the use of these therapies in high-risk individuals for primary prevention. SUMMARY: C-reactive protein may have a role in global risk assessment for primary prevention and in targeting those patients who will benefit from anti-inflammatory therapies. In addition, it may also be a good prognostic indicator in patients with acute coronary syndromes.

Curr Opin Lipidol 2002 Aug;13(4):383-9

Prospective study of C-reactive protein, homocysteine and plasma lipid levels as predictors of sudden cardiac death.

BACKGROUND: Sudden cardiac death (SCD) is an important cause of mortality even among apparently healthy populations. However, our ability to identify those at risk for SCD in the general population is poor, and more specific markers are needed. METHODS AND RESULTS: To compare and contrast the relative importance of C-reactive protein (CRP), homocysteine and lipids as long-term predictors of SCD, we performed a prospective, nested, case-control analysis involving 97 cases of SCD among apparently healthy men enrolled in the Physician’s Health Study. Of these plasma markers measured, only baseline CRP levels were significantly associated with the risk of SCD over the ensuing 17 years of follow-up (P for trend=0.001). The increase in risk associated with CRP levels was primarily seen among men in the highest quartile, who were at a 2.78-fold increased risk of SCD (95% CI 1.35 to 5.72) compared with men in the lowest quartile. These results were not significantly altered in analyses that (in addition to the matching variables of age and smoking status) controlled for lipid parameters, homocysteine, and multiple cardiac risk factors (relative risk for highest versus lowest quartile 2.65, 95% CI 0.79 to 8.83; P for trend=0.03). In contrast to the positive relationship observed for CRP, neither homocysteine nor lipid levels were significantly associated with risk of SCD. CONCLUSIONS: These prospective data suggest that CRP levels may be useful in identifying apparently healthy men who are at an increased long-term risk of SCD.

Circulation 2002 Jun 4;105(22):2595-9

C-reactive protein, statins and the primary prevention of atherosclerotic cardiovascular disease.

Emerging data implicate inflammation as integral to atherosclerosis and its complications. From a clinical perspective, the inflammatory biomarker C-reactive protein has demonstrated consistent predictive value in the detection of individuals at high risk for cardiovascular disease. Therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) reduces C-reactive protein as well as low-density lipoprotein cholesterol, thus providing a potential additional mechanism for the reduction in cardiovascular events associated with the use of these agents. Evidence from the Air Force/Texas Coronary Atherosclerosis Prevention Study suggests that statin therapy may be effective in reducing incident coronary events among those with elevated levels of C-reactive protein but normal levels of low-density lipoprotein cholesterol. These data, along with accumulating laboratory data, support a potential anti-inflammatory benefit of statins. Large-scale, randomized trials in the primary prevention of acute coronary events among individuals without overt hyperlipidemia but with evidence of elevated C-reactive protein are now needed to directly test this hypothesis.

Prev Cardiol 2002 Winter;5(1):42-6

Inflammatory mechanisms in atherosclerosis: from laboratory evidence to clinical application.

From the initial stages of leukocyte recruitment to diseased endothelium, to eventual rupture of unstable atheromatous plaque, pro-inflammatory mechanisms mediate key steps in atherogenesis and its complications. Lipid lowering, both with diet and statin therapy, has been shown to have favorable effects on inflammatory processes in atheromatous plaque. Several plasma markers of inflammation have been found to predict future cardiovascular risk, both among patients with acute coronary syndromes and myocardial infarction, and among healthy men and women. C-reactive protein (CRP), a pattern recognition molecule linked to the innate immune system, is a sensitive marker of low-grade vascular inflammation, which may also have direct pro-inflammatory actions. Recent studies have shown that statin therapy may lower CRP levels independent of lipid-lowering effects. Statin therapy may also be highly effective for the prevention of cardiovascular events among individuals with elevated CRP levels. The role of statin therapy for plaque stabilization in acute coronary syndromes, and for prevention of future plaque rupture among healthy individuals with evidence of vascular inflammation, is an area of active research.

Ital Heart J 2001 Nov;2(11):796-800

Inflammatory biomarkers, hormone replacement therapy and incident coronary heart disease: prospective analysis from the Women’s Health Initiative observational study.

CONTEXT: Postmenopausal hormone replacement therapy (HRT) has been shown to elevate C-reactive protein (CRP) levels. Several inflammatory biomarkers, including CRP, are associated with increased cardiovascular risk. However, whether the effect of HRT on CRP represents a clinical hazard is unknown. OBJECTIVES: To assess the association between baseline levels of CRP and interleukin 6 (IL-6) and incident coronary heart disease (CHD) and to examine the relationship between baseline use of HRT, CRP, and IL-6 levels as they relate to subsequent vascular risk. DESIGN, SETTING, AND PARTICIPANTS: Prospective, nested case-control study of postmenopausal women, forming part of the Women’s Health Initiative, a large, nationwide, observational study. Among 75,343 women with no history of cardiovascular disease or cancer, 304 women who developed incident CHD were defined as cases and matched by age, smoking status, ethnicity, and follow-up time with 304 study participants who remained event free during a median observation period of 2.9 years. MAIN OUTCOME MEASURE: Incidence of first myocardial infarction or death from CHD. RESULTS: Median baseline levels of CRP (0.33 vs 0.25 mg/dL; interquartile range [IQR], 0.14-0.71 vs 0.10-0.47; P<.001) and IL-6 (1.81 vs 1.47 pg/mL; IQR, 1.30-2.75 vs 1.05-2.15; P<.001) were significantly higher among cases compared with controls. In matched analyses, the odds ratio (OR) for incident CHD in the highest vs lowest quartile was 2.3 for CRP (95% confidence interval [CI], 1.4-3.7; P for trend =.002) and 3.3 for IL-6 (95% CI, 2.0-5.5; P for trend <.001). After additional adjustment for lipid and nonlipid risk factors, both inflammatory markers were significantly associated with a two-fold increase in odds for CHD events. As anticipated, current use of HRT was associated with significantly elevated median CRP levels. However, there was no association between HRT and IL-6. In analyses comparing individuals with comparable baseline levels of either CRP or IL-6, those taking or not taking HRT had similar CHD ORs. In analyses stratified by HRT, we observed a positively graded relationship between plasma CRP levels and the OR for CHD among both users and nonusers of HRT across the full spectrum of baseline CRP. CONCLUSIONS: These prospective findings indicate that CRP and IL-6 independently predict vascular events among apparently healthy postmenopausal women and that HRT increases CRP. However, use or nonuse of HRT had less importance as a predictor of cardiovascular risk than did baseline levels of either CRP or IL-6.

JAMA 2002 Aug 28;288(8):980-7


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