© 1997 American Heart Association, Inc.
Articles |
Relationship of C-Reactive Protein to Risk of Cardiovascular Disease in the Elderly
Results From the Cardiovascular Health Study and the Rural Health Promotion Project
From the University of Vermont (R.P.T., M.C.), Colchester; Cardiovascular Health Research Unit (R.N.L., B.M.P.), University of Washington, Seattle; and the University of Pittsburgh (Pa) (D.G.I., R.W.E., E.N.M., L.H.K.).
Correspondence to Dr Russell Tracy, University of Vermont, Aquatec Bldg, 55A S Park Dr, Colchester, VT 05446. E-mail rtracy{at}moose.uvm.edu
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Abstract |
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Abstract Markers of inflammation, such as C-reactive protein (CRP), are related to risk of cardiovascular disease (CVD) events in those with angina, but little is known about individuals without prevalent clinical CVD. We performed a prospective, nested case-control study in the Cardiovascular Health Study (CHS; 5201 healthy elderly men and women). Case subjects (n=146 men and women with incident CVD events including angina, myocardial infarction, and death) and control subjects (n=146) were matched on the basis of sex and the presence or absence of significant subclinical CVD at baseline (average follow-up, 2.4 years). In women but not men, the mean CRP level was higher for case subjects than for control subjects (P
.05). In general, CRP was higher in those with subclinical disease. Most of the association of CRP with female case subjects versus control subjects was in the subgroup with subclinical disease: 3.33 versus 1.90 mg/L, P<.05, adjusted for age and time of follow-up. Case-control differences were greatest when the time between baseline and the CVD event was shortest. The strongest associations were with myocardial infarction, and there was an overall odds ratio for incident myocardial infarction for men and women with subclinical disease (upper quartile versus lower three quartiles) of 2.67 (confidence interval [CI]=1.04 to 6.81), with the relationship being stronger in women (4.50 [CI=0.97 to 20.8]) than in men (1.75 [CI=0.51 to 5.98]). We performed a similar study in the Rural Health Promotion Project, in which mean values of CRP were higher for female case subjects than for female control subjects, but no differences were apparent for men. Comparing the upper quintile with the lower four, the odds ratio for CVD case subjects was 2.7 (CI=1.10 to 6.60). In conclusion, CRP was associated with incident events in the elderly, especially in those with subclinical disease at baseline.
Key Words: clotting • inflammation • coronary heart disease • C-reactive protein
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Introduction |
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The C-reactive protein is an acute-phase protein originally named by Tillet and Francis in 1930.1 Elevated levels of CRP have been related to increased risk of CHD, MI, and CHD deaths among individuals with angina pectoris.2 3 The level of CRP also predicted subsequent risk of CHD death among MRFIT participants, men aged 35 to 57 years who smoked at baseline and were followed up for an average of 10 to 17 years.4 The levels of CRP can increase several hundredfold within 24 to 48 hours after an acute inflammatory stimulus; however, the regulation of CRP in chronic low-level disease is less well understood.1 5 Inflammation of arteries may be an important component of changes in plaque morphology, rupture, and thrombosis.6 7 In this setting, inflammation may or may not include immune activation but would certainly include the elaboration of proinflammatory cytokines. CRP taken up by monocytes may also increase production of tissue factor and the propensity for subsequent thrombosis.8
The correlates of CRP have not been studied extensively. It is known that levels of CRP are increased among cigarette smokers.9 In a cross-sectional CHS analysis, the levels of CRP were positively correlated with smoking, body mass index, and triglyceride levels and inversely correlated with HDL cholesterol.10
The present study is a prospective, nested case-control design using stored plasma collected at baseline from CHS participants. We also report confirming results from a similar analysis in the RHPP. The goal of this study was to determine the relationship of CRP to CHD, angina pectoris, and CHD deaths among men and women with and without subclinical CVD at baseline.11 12 Subjects with clinical CVD were excluded. The hypothesis was that among individuals with subclinical CVD by CHS criteria,11 12 elevated CRP levels would be associated with an increased incidence of clinical CVD, especially MI.
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Methods |
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Populations
The CHS cohort was recruited from four communities in the United States from a defined sample of Medicare beneficiaries aged 65 years or older in 1989 to 1990 (mean age, 72 years).13 14 15 16 There were 5201 participants in the original sample, including 2955 women (153 black) and 2246 men (91 black). A baseline evaluation included a home interview and a physical examination in the clinic.13 Clinical and subclinical vascular disease definitions were based on the resting electrocardiogram, echocardiogram, carotid artery duplex scanning, ankle-brachial blood pressure, history of CVD, Rose questionnaire, cardiovascular surgery, and use of selected medications consistent with the diagnosis of angina or congestive heart failure.11 The definition of subclinical CVD in the present study is the same as previously described12 : ankle-arm index <0.9; internal carotid wall thickness >80th percentile; common carotid wall thickness >80th percentile; carotid stenosis >25%; major electrocardiogram abnormalities; abnormal ejection fraction on echocardiogram; abnormal wall motion on echocardiogram; Rose questionnaire claudication positive; or Rose questionnaire angina positive.
The CHS protocol involved intensive data collection for incident CVD events and all deaths.15 16 The potential incident cardiovascular events were initially identified from telephone calls at 6-month periods and annual clinic visits, with further verification from Medicare part A hospital discharge lists.15 For MI and angina, ICD codes 410 through 414, 427.4, 427.5, and 428 were reviewed in detail. The hospital records, outpatient records, and physician reports were obtained for the selected diagnostic codes and then reviewed by an events subcommittee of the CHS.16 At baseline, 31.6% of the participants had neither subclinical nor clinical CVD, 37.2% had subclinical CVD alone, and 31.2% had clinical CVD.11
The participants included in this analysis had no clinical CVD at baseline and had an average of 2.4 years (maximum of 3 years) of follow-up.12 The incidence of clinical CVD, including MI, angina pectoris, and CHD deaths, and the relation of events to both subclinical disease and cardiovascular risk factors have been published previously.12 There were 69 (8.2%) total CHD events (fatal and nonfatal) among men, 42 (3.8%) among women with subclinical disease at baseline, 23 (4.3%) for men, and 16 (1.5%) for women without subclinical disease. Plasma samples, stored at -70°C, were available for the present study for 89 of these 92 men and 57 of these 58 women. The control subjects were individually matched with the case subjects on the basis of sex, presence or absence of subclinical disease, and duration of follow-up, at a matching ratio of 1:1.
The RHPP was a Medicare-funded preventive healthcare demonstration project17 in five rural counties in northwestern Pennsylvania targeting Medicare beneficiaries aged 65 to 79 years who participated in both part A and part B of Medicare.18 Participants, identified through Medicare entitlement records,18 were community dwelling, ambulatory, and without life-threatening diagnosis of cancer within the 5 years preceding the study. They completed a 1.5-hour health-risk appraisal including information about demographics, medical care, health habits, self-reported history of disease, and symptomatology and were randomized to a control group or one of two treatment groups: (1) those eligible to receive selected interventions to reduce blood cholesterol, weight, cigarette smoking, alcohol abuse, and evaluation of depression and dementia at community health centers or (2) those who could receive similar interventions in physicians' offices. There were 3884 participants in the study (1312 in the hospital-based group, 1347 in the physician-intervention group, and 1225 in the control group), with a mean age of 71 years. Overall, 56.8% were women, and all were white, characteristic of the rural community in which they were recruited. There were no substantial differences in outcome or changes in risk factors during the study across the three groups, and therefore their data have been pooled.
Follow-up of the participants was primarily through annual telephone interviews and review of both part A and part B Medicare utilization records. Deaths were ascertained through the Medicare entitlement records. Death certificates were obtained to determine the causes of death. Hospital discharge diagnoses were determined from Medicare part A data. No independent review of the hospital records was included in the study. Case subjects came from the 77% of the participants who were without a prior history of CHD at baseline. Two end points have been included in the study to define a case: (1) incident MI (ICD code 410) as the primary discharge diagnosis on the hospital discharge form and no hospitalization for CVD during the baseline year of the study (n=73; a report from the CHS has shown previously that ICD code 410 as the primary hospital discharge diagnosis is usually verified as MI16 ) and (2) death attributed to CHD (n=92). During the 3 years of follow-up, 21 (28.4%; 9 women, 12 men) of the MI case subjects died and have been included with the death end point, leaving 53 (28 women, 25 men) surviving MI case subjects. Control subjects were matched by sex and age, had no history of MI or angina pectoris at their baseline interview, and did not die and had no hospitalization for MI or angina pectoris during the 3-year follow-up.
Laboratory Methods
CRP was measured by use of an enzyme-linked immunosorbent assay developed at the CHS central blood laboratory.19 It is a colorimetric competitive immunoassay that uses purified protein and polyclonal anti-CRP antibodies. The interassay coefficient of variation is 5.5%. The samples from the case subjects and matched control subjects were assayed together by a technician who was blinded to the case-control status of the samples. Measurement of fibrinogen by a modified clot-rate assay and all other assay methods have been described previously.20
Statistical Methods
Mean CRP levels in case and control subjects, adjusted for age, were obtained from ANOVA procedures. Because the distribution of CRP levels was skewed to the right, the distribution was log-normalized, and the transformed values were used for analyses. For ease of interpretation, means and standard deviations of untransformed values are reported. The analyses were stratified or adjusted on the matching factors. Quartiles (CHS) or quintiles (RHPP) of CRP were defined on the basis of the distribution of CRP levels among the control subjects. In the CHS analysis, we estimated the OR for CVD events for subjects in the upper quartile of CRP levels compared with subjects in the combined lower quartiles using conditional logistic regression to account for the matching factors. In the RHPP analysis, CRP values were divided into quintiles, and distribution of case and control subjects by quintile was evaluated by calculating the OR and CIs using Cornfield's method, comparing the fifth quintile of CRP with the remaining four quintiles.21
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The baseline characteristics of CHS case and control subjects are shown in Table 1
. Case subjects (n=146) had a higher prevalence of hypertension, higher systolic blood pressure, and lower HDL cholesterol than control subjects (n=146). Triglyceride levels were also significantly higher for case subjects than for control subjects. There were 89 men and 57 women in each of the case and control groups.
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Because we matched subjects on the basis of subclinical disease, the prevalences of selected markers of subclinical disease by CHS criteria were similar among the case and control subjects (all comparisons were nonsignificant at P>.05; Table 2).
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In women, the mean CRP levels were significantly higher for case subjects than for control subjects, with the major difference being confined to those with subclinical disease (Table 3). For men with or without subclinical disease, there were no differences in mean CRP levels. The CRP levels were higher for participants with subclinical disease at baseline than for those without, except in the female control group.
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In women, case subjects with subclinical disease had higher CRP levels than control subjects at every time point from baseline blood sample (Fig 1). In general, the levels of CRP declined for case subjects with duration of follow-up (except for the last time point, at 24 months), with little change for control subjects, so that the difference in CRP between case and control subjects for women with subclinical disease was greater for more proximate case-control comparisons. These differences were not present for men or for the few female case subjects who did not have subclinical disease. In fact, it appeared that CRP levels in subclinical disease–free women with clinical events early in the study were actually lower than in the corresponding case subjects with clinical events later in the study.
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The distribution of case and control subjects by quartiles was further evaluated by sex and for presence or absence of subclinical disease (Table 4). There were no significant associations in men. However, there was approximately a 2.3-fold (CI=0.9 to 6.1) increased risk of incident CHD among women with subclinical disease in the highest quartile versus the combined lower quartiles. There was no linear relationship with risk for quartiles 1 through 3, indicating that the increased risk was primarily in women in the upper quartile.
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The higher OR for CHD among women with subclinical disease was primarily limited to those with MI (Table 5). The OR comparing the upper versus the lower quartiles was 4.50 (CI=0.97 to 20.8). For men, the OR for MI was 1.75 (CI=0.51 to 5.98). The overall OR for men and women combined with incident MI was 2.67 (CI=1.04 to 6.81; P=.04). A formal test for interaction with gender gave a value of P=.33. If the association of CRP with MI is truly weaker in men than in women, we did not have enough power to detect it.
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There were six control subjects and seven case subjects among the women who reported current cigarette smoking at baseline. After excluding these individuals, the unmatched OR for total incident CHD for women (highest quartile of CRP compared with the lower three quartiles) was 3.3, similar to the analysis of smokers and nonsmokers combined.
In previous reports, lower levels of albumin and higher levels of fibrinogen (both inflammation-sensitive proteins, like CRP) have also been associated with increased risk of CHD.22 23 The mean levels of albumin adjusted for age, sex, subclinical disease, and length of follow-up were 4.03 g/dL among 148 control subjects and 3.99 g/dL among 148 case subjects. The distribution of albumin for female case and control subjects with subclinical disease was not different: 15 of 41 female control subjects and 16 of 41 female case subjects had albumin levels in the lowest quartile.
Fibrinogen was correlated with CRP (r=.52) in the CHS (Tracy et al, manuscript submitted). However, mean fibrinogen levels (adjusted for age, sex, subclinical disease, and length of follow-up) were only slightly higher for case subjects (319.9 mg/dL) than control subjects (315.0 mg/dL). There was no difference in distribution of fibrinogen levels among the 41 female case subjects and their matched control subjects with subclinical disease: 8 control subjects and 10 case subjects had fibrinogen levels in the upper quartile of the distribution (345 to 570 mg/dL). There was, however, a tendency for higher fibrinogen values to be associated with risk of MI: 13 control subjects and 22 MI case subjects distributed in the upper quartile of fibrinogen, yielding an OR for upper quartile compared with lower three quartiles of 2.00 (CI=0.90 to 4.45; P=.09). This tendency was found for both men and women with subclinical disease, with a combined OR of 2.33 (CI=0.90 to 6.07; P=.08) for MI.
CHS participants with both CRP and fibrinogen in the upper quartile had a 2.20-fold (CI=0.76 to 6.33; P=.13) risk of MI compared with those in the lower three quartiles. Participants with prevalent subclinical disease at baseline and both fibrinogen and CRP in the upper quartile had a 3.33-fold (CI=0.92 to 12.11; P=.05) increased risk of MI. Participants who had either fibrinogen or CRP in the upper quartile had a 2.37-fold (CI=1.04 to 5.42; P=.03) risk of MI, and if they had prevalent subclinical disease at baseline, the risk was 3.0 (CI=1.09 to 8.25; P=.02). There was no consistent association between CRP, fibrinogen, and MI for participants without subclinical disease at baseline.
We confirmed these results by performing a similar analysis in the RHPP, although without matching on the basis of subclinical CVD. In our sample, there were 145 case subjects (80 men, 65 women) and 146 control subjects (one case subject's serum was lost) including 55 CHD deaths in men and 37 in women.
Comparing mean log-adjusted CRP values between case and control subjects, the only significant differences (P=.03) were in women: case subjects, 7.3 mg/L; control subjects, 2.9 mg/L. In women, the distribution of CRP was skewed toward higher levels, especially for case subjects (Fig 2). The OR for women, quintile 5 versus 1 through 4 of CRP, for total case subjects compared with control subjects was 2.7 (95% CI=1.10 to 6.69), and for CHD deaths, the OR was 3.74 (95% CI=1.36 to 10.4). For men, the ORs were 2.0 (CI=0.82 to 4.87) for total CHD and 1.4 (CI=0.50 to 3.95) for CHD deaths.
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Discussion |
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Subclinical CVD, as defined in the CHS, was a strong, independent predictor of subsequent clinical CVD over a 2.4-year follow-up.11 12 The current study extended these findings by examining whether CRP was associated with incident CVD even when case and control subjects were matched for the presence or absence of subclinical disease. The strengths of the present study are the quality of sample collection and the use of a central laboratory,20 the clear definitions and adjudication of events,12 the rich CHS data set that includes variables allowing us to define subclinical disease, and the matching design, which takes subclinical disease into account. The major weakness of the present study is the relatively small number of case and control subjects, which necessitates caution in the interpretation of the results. However, we were able to confirm our results in a separate but similar study, the RHPP.
Among the elderly with subclinical disease, CRP was a risk factor for CVD, primarily MI. The association of CRP with MI was apparently stronger among women than men. However, we could not detect a statistically significant interaction with sex, leaving open the question of whether there is a difference in the elderly in the association of CRP with events. In support of an answer in the affirmative, we have observed the same apparently sex-specific association in the RHPP analysis.
Although we found a significant association of CRP with CVD events, there was no trend for increased risk in the lower three quartiles of CRP, with the increased risk limited to those in the highest quartile. In both the case and control subjects, however, only seven subjects had values >10 mg/L, the generally accepted cutoff for clinical significance for CRP. Of these, only two were women. For individuals without clinical CVD, a CRP value that represents clinical "inflammation" is less important with respect to CVD risk than is a CRP value that, although <10 mg/L, is in the upper portion of the distribution, suggesting an important role for chronic, low-level "inflammation."24
In our study, the association of CRP and risk of disease was time dependent. The CRP levels were higher and the differences between case and control subjects greater the closer the proximity of the case event to the time of blood collection, especially for subjects with subclinical disease. This finding suggests the hypothesis that elevated CRP is associated with the short-term process leading to the clinical event, including changes in the arterial wall and/or in clotting status. In support of this hypothesis, CRP has been shown to elaborate the protein responsible for initiating arterial thrombosis, tissue factor.8
This study is limited by the relatively small numbers of case and control subjects, and it included only baseline CRP measurements. However, CRP was significantly associated with risk even after subclinical disease status was taken into consideration, and higher CRP levels in close proximity to the clinical event among individuals with subclinical disease were the most predictive of events. These results suggest that recent elevations of CRP might be the strongest predictor of short-term clinical events and that the changes in the levels of CRP over time before an MI may be an even stronger predictor of the risk of incident CVD.
In the follow-up of the MRFIT, high CRP levels were a strong predictor of subsequent CHD deaths among middle-aged (35 to 57 years old) cigarette-smoking men after a relatively long follow-up of no less than 12 years and up to 17 years.4 Unfortunately, there was no opportunity to examine the relationship of CRP to more proximal events in the MRFIT. The fact that baseline CRP levels were related to chronologically distant events in MRFIT and chronologically close events in CHS suggests potentially important differences in the relationship of inflammation to CHD at different times in the natural history of this disease.
In the CHS, the association of CRP and clinical disease was not changed by excluding current cigarette smokers. The same findings were noted in the RHPP (data not shown). However, there were too few events in either study among individuals who were never cigarette smokers to determine whether CRP was an independent risk factor in older, lifelong never-smokers.
The fact that the strongest relationship between CRP and risk of CVD in the present study was in those with subclinical disease is consistent with previous studies2 23 in which a strong relationship was observed in individuals with existing clinical CVD. The role of inflammation in CVD is currently being investigated in a variety of studies. It is possible that injury or inflammation of arteries and pulmonary disease may increase the risk of infection with Chlamydia TWAR or other similar agents, which may themselves increase the risk of CVD.25 26 27 28 29 30 31 The prevalence of Chlamydia TWAR infection is higher among smokers and has been linked to both increased prevalence of atherosclerosis and clinical CVD.
We have suggested the possibility that CRP and other inflammation-sensitive proteins are primarily related to changes in plaque morphology and possibly to rupture and acute thrombosis.32 33 If true, this would be consistent with the relationship of CRP to clinical disease being primarily limited to individuals who already have moderate to extensive subclinical atherosclerosis or clinical CVD. In the present study, we observed a similar association with incident disease for fibrinogen and albumin as we observed for CRP, although the association for fibrinogen did not reach statistical significance. This result, in addition to the strong association of acute-phase proteins, such as fibrinogen, with subclinical disease,34 is consistent with a model in which the pathophysiological progression is from atherosclerosis to subclinical disease to ruptured plaque to thrombosis and MI.7 35 36 37 It would also suggest that with the use of epidemiological data, it may be difficult to determine any causal relationship of an acute inflammatory marker with risk of CHD because such a marker would be a measure of underlying vascular disease.
If the results of our study are confirmed in other analyses, the measurement of CRP as a risk factor for MI in individuals with subclinical disease has important implications. For example, in the CHS we found that the risk of CHD was 2.5-fold higher in women with subclinical disease than in women without subclinical disease.12 The addition of CRP in the highest quartile to the women with subclinical disease may raise this risk for CHD by another 2.5-fold (see Fig 1
, Table 4) and for MI 
4.5-fold (Table 5). The incidence of total CHD was 3.8% for those with subclinical disease and 1.5% for those with no subclinical diseases.12 A further increase by 2.5-fold would increase the overall incidence for women with subclinical disease to 9.5%. This is similar to that for men, 8.2%,13 or 4% per year of follow-up. Approximately 50% of women without clinical disease have subclinical disease at baseline, and 25% would be in the upper quartile of CRP. The use of CRP may aid in the identification of the 12.5% of elderly women who are at high risk of future events.
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Acknowledgments |
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This work was supported by a grant from the National Heart, Lung, and Blood Institute, RO1 HL-46696 (Dr Tracy), and by NHLBI contracts NO1-HC-85079 through NO1-HC-85086. Dr Cushman was supported by USPHS training grant T3207594. We also thank the investigators and staff of the Cardiovascular Health Study: Bowman Gray School of Medicine of Wake Forest University, Forsyth County, NC—Gregory L. Burke, Alan Elster, Walter H. Ettinger, Curt D. Furberg, Edward Haponik, Gerardo Heiss, Dalane Kitzman, H. Sidney Klopfenstein, Margie Lamb, David S. Lefkowitz, Mary F. Lyles, Maurice B. Mittelmark, Cathy Nunn, Ward Riley, Grethe S. Tell, James F. Toole, and Beverly Tucker; Bowman Gray School of Medicine, Forsyth County, NC (electrocardiogram reading center)—Kris Calhoun, Harry Calhoun, Farida Rautaharju, Pentti Rautaharju, and Loralee Robertson; University of California, Davis—William Bommer, Charles Bernick, Andrew Duxbury, Mary Haan, Calvin Hirsch, Paul Kellerman, Lawrence Laslett, Marshall Lee, Virginia Poirier, John Robbins, Marc Schenker, and Nemat Borhani; The Johns Hopkins University, Baltimore, Md—M. Jan Busby-Whitehead, Joyce Chabot, George W. Comstock, Linda P. Fried, Joel G. Hill, Steven J. Kittner, Shiriki Kumanyika, David Levine, Joao A. Lima, Neil R. Powe, Thomas R. Price, Jeff Williamson, Moyses Szklo, and Melvyn Tockman; The Johns Hopkins University, Baltimore, Md (MRI reading center)—R. Nick Bryan, Carolyn C. Meltzer, Douglas Fellows, Melanie Hawkins, Patrice Holtz, Michael Kraut, Grace Lee, Larry Schertz, Earl P. Steinberg, Scott Wells, Linda Wilkins, and Nancy C. Yue; University of Pittsburgh, Pa—Diane G. Ives, Charles A. Jungreis, Laurie Knepper, Lewis H. Kuller, Elaine Meilahn, Peg Meyer, Roberta Moyer, Anne Newman, Richard Schulz, Vivienne E. Smith, and Sidney K. Wolfson; University of California, Irvine, (baseline echocardiography reading center)—Hoda Anton-Culver, Julius M. Gardin, Margaret Knoll, Tom Kurosaki, and Nathan Wong; Georgetown Medical Center, Washington, DC (follow-up echocardiography reading center)—John Gottdiener, Eva Hausner, Stephen Kraus, Judy Gay, Sue Livengood, Mary Ann Yohe, and Retha Webb; Geisinger Medical Center, Danville, Pa (ultrasound reading center)—Daniel H. O'Leary, Joseph F. Polak, and Laurie Funk; Respiratory Sciences, University of Arizona at Tucson—Paul Enright; University of Washington, Seattle (coordinating center)—Alice Arnold, Annette L. Fitzpatrick, Bonnie K. Lind, Richard A. Kronmal, Bruce M. Psaty, David S. Siscovick, Lynn Shemanski, Lloyd Fisher, Will Longstreth, Patricia W. Wahl, David Yanez, Paula Diehr, and Maryann McBurnie; and NHLBI Project Office, Bethesda, Md—Diane E. Bild, Teri A. Manolio, Peter J. Savage, Patricia Smith, and Rachel Solomon.
Received May 28, 1996; accepted October 9, 1996.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
- Young B, Gleeson M, Cripps A. C-reactive protein: a critical review. Pathology. 1991;23:118-124.[Medline] [Order article via Infotrieve]
-
Thompson S, Kienast J, Pyke S, Haverkate F, van de Loo J. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med. 1995;332:635-641.
[Abstract/Free Full Text] - Liuzzo G, Biasucci L, Gallimore J, Grillo R, Rebuzzi A, Pepys M, Maseri A. The prognostic value of C-reactive protein and serum amyloid A protein in severe unstable angina. N Engl J Med. 1994; 331:417-424.
- Kuller L, Tracy R, Shaten J, Meilahn E, for the MRFIT Research Group. Relationship of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Am J Epidemiol. In press.
- Pepys M, Baltz M. Acute phase proteins with special reference to C-reactive protein and related proteins and serum amyloid A protein. Adv Immunol. 1983;34:141-212.[Medline] [Order article via Infotrieve]
- Fuster V, Stein B, Ambrose JA, Badimon L, Badimon JJ, Chesebro JH. Atherosclerotic plaque rupture and thrombosis: evolving concepts. Circulation. 1990;82(part 3):II-47-II-59.
- Fuster V, Badimon L, Badimon J, Chesebro J. The pathogenesis of coronary artery disease and the acute coronary syndromes, I. N Engl J Med. 1992;326:242-250.[Medline] [Order article via Infotrieve]
-
Cermak J, Key N, Bach R, Balla J, Jacob H, Vercellotti G. C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor. Blood. 1993;82:513-520.
[Abstract/Free Full Text] - Das I. Raised C-reactive protein levels from smokers. Clin Chim Acta. 1985;153:9-13.[Medline] [Order article via Infotrieve]
- Tracy R, Bovill EG, Macy EM, Cornell ES, Kuller LH, Psaty BM, Wahl PW. Presented at the American Heart Association Scientific Conference on Atherosclerosis, Thrombosis, and Cell Proliferation; February 23-26, 1994; Orlando, Fla.
-
Kuller L, Borhani N, Furberg C, Gardin J, Manolio T, O'Leary D, Psaty B, Robbins J. Prevalence of subclinical atherosclerosis and cardiovascular disease and association with risk factors in the Cardiovascular Health Study. Am J Epidemiol. 1994;139:1164-1179.
[Abstract/Free Full Text] -
Kuller L, Shemanski L, Psaty B, Borhani N, Gardin J, Haan M, O'Leary D, Savage P, Tell G, Tracy R. Subclinical disease as an independent risk factor for cardiovascular disease. Circulation. 1995;92:720-726.
[Abstract/Free Full Text] - Fried L, Borhani N, Enright P, Furberg C, Gardin J, Kronmal R, Kuller L, Manolio T, Mittelmark M, Newman A, O'Leary D, Psaty B, Rautaharju P, Tracy R, Weiler P, for the CHS Research Group. The Cardiovascular Health Study: design and rationale. Ann Epidemiol. 1991;1:263-276.[Medline] [Order article via Infotrieve]
-
Mittelmark MB, Psaty BM, Rautaharju PM, Fried LP, Borhani NO, Tracy RP, Gardin JM, O'Leary DH, Group for the CHS Investigators. Prevalence of cardiovascular disease among older adults: the Cardiovascular Health Study. Am J Epidemiol. 1993;137:311-317.
[Abstract/Free Full Text] - Ives D, Fitzpatrick A, Bild D, Psaty B, Kuller L, Crowley P, Cruise R, Theroux S. Surveillance and ascertainment of cardiovascular events. Ann Epidemiol. 1995;5:278-285.[Medline] [Order article via Infotrieve]
- Psaty B, Kuller L, Bild D, Burke G, Kittner S, Mittelmark M, Price T, Rautahaju P, Robbins J. Methods of assessing prevalent cardiovascular disease in the Cardiovascular Health Study. Ann Epidemiol. 1995;5:270-277.[Medline] [Order article via Infotrieve]
- Lave J, Ives D, Traven N, Kuller L. Participation in health promotion programs by the rural elderly. Am J Prev Med. 1995;11:46-53.[Medline] [Order article via Infotrieve]
- Ives D, Kuller L, Schultz R, Traven N, Lave J. Comparison of recruitment strategies and associated disease prevalence for health promotion in rural elderly. Prev Med. 1992;21:582-591.[Medline] [Order article via Infotrieve]
-
Macy E, Hayes T, Tracy R. Variability in the measurement of C-reactive protein in healthy subjects: implications for reference interval and epidemiological applications. Clin Chem. 1997;43:52-58.
[Abstract/Free Full Text] -
Cushman M, Cornell E, Howard P, Bovill E, Tracy R. Laboratory methods and quality assurance in the Cardiovascular Health Study. Clin Chem. 1995;41:264-270.
[Abstract/Free Full Text] - Kahn H, Sempos C. Statistical Methods in Epidemiology. New York, NY: Oxford University Press; 1989.
-
Kuller L, Eichner J, Orchard T, Grandits G, McCallum L, Tracy R, for the MRFIT Research Group. The relation between serum albumin levels and risk of coronary heart disease in the Multiple Risk Factor Intervention Trial. Am J Epidemiol. 1991;134:1266-1277.
[Abstract/Free Full Text] - Meade T, Brozovic M, Chakrabarti R, Haines A, Imeson J, Mellows S, Miller G, North W, Stirling Y, Thompson S. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet. 1986;2:533-537.[Medline] [Order article via Infotrieve]
- Haverkate F. Low-grade acute-phase reactions in arteriosclerosis and the consequences for haemostasis. Fibrinolysis. 1992;6(suppl 3): 17-18.
- Patel P, Carrington D, Strachan D, Leatham E, Goggin P, Northfield T, Mendall M. Fibrinogen: a link between chronic infection and coronary heart disease. Lancet. 1994;343:1634-1635. Letter.[Medline] [Order article via Infotrieve]
-
Karvonen M, Tuomilehto J, Pitkaniemi J, Naukkarinen A, Saikku P. Importance of smoking for Chlamydia pneumoniae. Int J Epidemiol. 1994;23:1315-1320.
[Abstract/Free Full Text] - Grayston J. Chlamydia pneumoniae, strain TWAR pneumonia. Ann Rev Med. 1992;43:317-323.[Medline] [Order article via Infotrieve]
-
Linnanmani E, Leinonen M, Mattila K, Nieminen M, Valtonen V, Saikku P. Chlamydia pneumoniae–specific circulating immune complexes in patients with chronic coronary heart disease. Circulation. 1993;87:1130-1134.
[Abstract/Free Full Text] - Saikku P, Leinonen M, Tenkanen L, Manninen V, Huttunen J. Chronic Chlamydia pneumoniae infection as a risk factor for coronary heart disease (CHD) in the Helsinki Heart Study (HHS). Ann Intern Med. 1992;116:273-278.
- Saikku P, Leinonen M, Mattila K, Ekman M, Nieminen M, Makela P, Huttunen J, Valtonen V. Serological evidence of an association of a novel Chlamydia, TWAR, with chronic coronary heart disease and acute myocardial infarction. Lancet. 1988;2:983-985.[Medline] [Order article via Infotrieve]
- Kuo C, Grayston J, Campbell L, Goo Y, Wissler R, Benditt E. Chlamydia pneumoniae (TWAR) in coronary arteries of young adults (15-34 years old). Proc Natl Acad Sci U S A. 1995;92: 6911-6914.
- Tracy R, Bovill E. Hemostasis and risk of ischemic disease: epidemiologic evidence with emphasis on the elderly. In: Califf R, Mark D, Wagner G, eds. Acute Coronary Care in the Thrombolytic Era. St Louis, Mo: Mosby-Year Book Inc; 1995:27-43.
- Tracy R, Bovill E. Thrombosis and cardiovascular risk in the elderly. Arch Pathol Lab Med. 1992;116:1307-1312.[Medline] [Order article via Infotrieve]
-
Tracy R, Bovill E, Yanez D, Psaty B, Fried L, Heiss G, Lee M, Polak J, Savage P, for the CHS Investigators. Fibrinogen and factor VIII, but not factor VII, are associated with measures of subclinical cardiovascular disease in the elderly: results from the Cardiovascular Health Study. Arterioscler Thromb Vasc Biol. 1995;15:1269-1279.
[Abstract/Free Full Text] -
Alexander R. Inflammation and coronary artery disease. N Engl J Med. 1994;331:468-469. Editorial.
[Free Full Text] - Fuster V, Badimon L, Badimon J, Chesebro J. The pathogenesis of coronary artery disease and the acute coronary syndromes, II. N Engl J Med. 1992;326:310-318.[Medline] [Order article via Infotrieve]
- Muller J, Abela G, Nesto R, Tofler G. Triggers, acute risk factors and vulnerable plaques: the lexicon of a new frontier. J Am Coll Cardiol. 1994;23:809-813.[Abstract]
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