@article {1421, title = {Laboratory methods and quality assurance in the Cardiovascular Health Study.}, journal = {Clin Chem}, volume = {41}, year = {1995}, month = {1995 Feb}, pages = {264-70}, abstract = {

The Cardiovascular Health Study is an observational cohort study of risk factors for cardiovascular disease in 5201 participants, ages > or = 65 years. We report the methods and quality-assurance results for blood procurement, processing, shipping, storage, and sample analysis used during the first examination period (May 1989-June 1990). The most frequent difficulty in phlebotomy and processing was the requirement of more than one venipuncture (in 2.6\% of the participants). The CVs for control materials ranged from 0.93\% for glucose to 10.7\% for insulin; most were < 4\%. In addition to standard quality-assurance methods, we applied two other methods: technical error calculation for replicates, and weighted linear regression to assess time trend in results of control materials. After outliers were excluded, technical error values ranged from 1.7 for uric acid to 18.8 for insulin. Factor VII and factor VIII had slight trends over the 12-month analysis period. Results of quality-assurance analyses used to resolve problems were successful, thereby improving the second laboratory examination.

}, keywords = {Aged, Blood Glucose, Blood Specimen Collection, Cardiovascular Diseases, Chemistry, Clinical, Factor VII, Factor VIII, Fibrinogen, Humans, Insulin, Quality Control, Regression Analysis, Triglycerides}, issn = {0009-9147}, author = {Cushman, M and Cornell, E S and Howard, P R and Bovill, E G and Tracy, R P} } @article {1457, title = {Association of fibrinogen and coagulation factors VII and VIII with cardiovascular risk factors in the elderly: the Cardiovascular Health Study. Cardiovascular Health Study Investigators.}, journal = {Am J Epidemiol}, volume = {143}, year = {1996}, month = {1996 Apr 01}, pages = {665-76}, abstract = {

The cross-sectional correlates of three hemostatic factors--fibrinogen, factor VII, and factor VIII--were examined in the Cardiovascular Health Study, a population-based cohort study of 5,201 subjects over age 65 years. Subjects were recruited in 1989-1990 in Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Pittsburgh, Pennsylvania. In multivariate linear regression models, cardiac risk factors significantly associated with fibrinogen were current smoking, race, lipids, and white blood count. In women, alcohol use, obesity, physical activity, and insulin level were also significant, while in men hypertension was correlated. The significant correlates of factor VII were lipids and white blood count in men and estrogen use, alcohol use, race, lipids, insulin level, white blood count, and obesity in women. The independent correlates of factor VIII were insulin, glucose, and race in both sexes; low density lipoprotein cholesterol, white blood count, and diuretic use in men; and alcohol use in women. In multivariate models, factors known to be modifiable risk factors for cardiovascular disease accounted for more of the population variance of these hemostatic factors in women than in men, especially for factor VII. The hemostatic factors may mediate some effects of risk factors on disease, and this should be considered in longitudinal studies.

}, keywords = {Age Distribution, Aged, Aged, 80 and over, Analysis of Variance, Cardiovascular Diseases, Cohort Studies, Factor VII, Factor VIII, Female, Fibrinogen, Humans, Linear Models, Logistic Models, Male, Prevalence, Risk Factors, Sex Distribution, United States}, issn = {0002-9262}, author = {Cushman, M and Yanez, D and Psaty, B M and Fried, L P and Heiss, G and Lee, M and Polak, J F and Savage, P J and Tracy, R P} } @article {1464, title = {Correlates of thrombin markers in an elderly cohort free of clinical cardiovascular disease.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {16}, year = {1996}, month = {1996 Sep}, pages = {1163-9}, abstract = {

Studies suggest that thrombosis is important in the progression of atherosclerotic lesions. The biochemical markers prothrombin fragment 1-2 and fibrinopeptide A reflect in vivo thrombin generation and activity, respectively. As such, they are markers that might be associated with cardiovascular risk. From the Cardiovascular Health Study, a cohort study of 5201 persons over 65 years of age, 399 persons free of clinical cardiovascular disease (CVD) at the baseline examination were selected for study of specialized markers of hemostasis. We report the cross-sectional relationships of the thrombin markers to CVD risk factors and measures of subclinical CVD. The range of fragment 1-2 2 was 0.12 to 0.85 nmol/L. The range of fibrinopeptide A was 0.9 to 44.1 micrograms/L. High levels of fragment 1-2 and fibrinopeptide A were associated with age, with levels higher in women than men. Fragment 1-2 was associated with smoking; high levels of triglyceride, creatinine, and C-reactive protein; and low levels of glucose. Fibrinopeptide A was associated with high C-reactive protein and apolipoprotein(a) and lower ankle-brachial index. There were no significant associations of the thrombin markers with race, fibrinogen, alcohol consumption, diabetes, or most measures of subclinical CVD. Study findings support a hypothesis that there are physiological interrelationships between cardiac risk factors, hemostasis, inflammation, and progression of atherosclerosis.

}, keywords = {Aged, Biomarkers, Cardiovascular Diseases, Cohort Studies, Female, Hemostasis, Humans, Male, Risk Factors, Thrombin}, issn = {1079-5642}, author = {Cushman, M and Psaty, B M and Macy, E and Bovill, E G and Cornell, E S and Kuller, L H and Tracy, R P} } @article {1490, title = {Lifetime smoking exposure affects the association of C-reactive protein with cardiovascular disease risk factors and subclinical disease in healthy elderly subjects.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {17}, year = {1997}, month = {1997 Oct}, pages = {2167-76}, abstract = {

Blood levels of C-reactive protein (CRP), a marker of inflammation, are related to cardiovascular disease risk. To determine cross-sectional correlates in the elderly, we measured CRP in 400 men and women older than 65 years and free of clinical cardiovascular disease at baseline as part of the Cardiovascular Health Study. Only 2\% of the values were greater than 10 mg/L, the cut-point usually used to identify inflammation. CRP levels appeared tightly regulated, since there were strong bivariate correlations between CRP and the following: inflammation-sensitive proteins such as fibrinogen (r = .52); measures of fibrinolysis such as plasmin-antiplasmin complex (r = .23); pack-years of smoking (r = .30); and body mass index (r = .24; all P values < or = .001). The association with pack-years was independent of the length of time since cessation of smoking. CRP levels were also associated with coagulation factors VIIc, IXc, and Xc; HDL cholesterol (negative) and triglyceride; diabetes status; diuretic use; ECG abnormalities; and level of exercise. Because of effect modification, two multiple linear regression prediction models were developed for CRP, one each for never smokers and ever smokers. An a priori physiologic model was used to guide these analyses, which disallowed the use of other inflammation-sensitive variables such as fibrinogen. In never smokers, the independent predictors were body mass index (+), diabetes status (+), plasmin-antiplasmin complex (+), and the presence of ECG abnormalities (+); this model predicted 15\% of the CRP population variance. In ever smokers, the predictors were body mass index (+), plasmin-antiplasmin complex (+), pack-years of smoking (+), HDL cholesterol (-), and ankle-arm blood pressure index (-); this model predicted 42\% of the population variance. We conclude that levels of CRP in the healthy elderly are tightly regulated and reflect lifetime exposure to smoking as well as level of obesity, ongoing level of fibrinolysis, diabetes status, and level of subclinical atherothrombotic disease. Moreover, exposure to smoking affects the relation of CRP to these other factors.

}, keywords = {Aged, Body Mass Index, C-Reactive Protein, Cardiovascular Diseases, Female, Humans, Male, Multivariate Analysis, Risk Factors, Smoking}, issn = {1079-5642}, author = {Tracy, R P and Psaty, B M and Macy, E and Bovill, E G and Cushman, M and Cornell, E S and Kuller, L H} } @article {1484, title = {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.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {17}, year = {1997}, month = {1997 Jun}, pages = {1121-7}, 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 < or = .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.

}, keywords = {Aged, Aging, C-Reactive Protein, Cardiovascular Diseases, Case-Control Studies, Female, Humans, Male, Prospective Studies, Sex Factors}, issn = {1079-5642}, author = {Tracy, R P and Lemaitre, R N and Psaty, B M and Ives, D G and Evans, R W and Cushman, M and Meilahn, E N and Kuller, L H} } @article {586, title = {Ankle-arm index as a predictor of cardiovascular disease and mortality in the Cardiovascular Health Study. The Cardiovascular Health Study Group.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {19}, year = {1999}, month = {1999 Mar}, pages = {538-45}, abstract = {

Peripheral arterial disease (PAD) in the legs, measured noninvasively by the ankle-arm index (AAI) is associated with clinically manifest cardiovascular disease (CVD) and its risk factors. To determine risk of total mortality, coronary heart disease, or stroke mortality and incident versus recurrent CVD associated with a low AAI, we examined the relationship of the AAI to subsequent CVD events in 5888 older adults with and without CVD. The AAI was measured in 5888 participants >/=65 years old at the baseline examination of the Cardiovascular Health Study. All participants had a detailed assessment of prevalent CVD and were contacted every 6 months for total mortality and CVD events (including CVD mortality, fatal and nonfatal myocardial infarction, congestive heart failure, angina, stroke, and hospitalized PAD). The crude mortality rate at 6 years was highest (32.3\%) in those participants with prevalent CVD and a low AAI (P<0.9), and it was lowest in those with neither of these findings (8.7\%, P<0.01). Similar patterns emerged from analysis of recurrent CVD and incident CVD. The risk for incident congestive heart failure (relative risk [RR]=1.61) and for total mortality (RR=1.62) in those without CVD at baseline but with a low AAI remained significantly elevated after adjustment for cardiovascular risk factors. Hospitalized PAD events occurred months to years after the AAI was measured, with an adjusted RR of 5.55 (95\% CI, 3.08 to 9.98) in those at risk for incident events. A statistically significant decline in survival was seen at each 0.1 decrement in the AAI. An AAI of <0.9 is an independent risk factor for incident CVD, recurrent CVD, and mortality in this group of older adults in the Cardiovascular Health Study.

}, keywords = {Age Distribution, Aged, Aged, 80 and over, Ankle, Arm, Blood Pressure Determination, Cardiovascular Diseases, Cohort Studies, Female, Humans, Hypertension, Male, Predictive Value of Tests, Risk Factors, Sex Distribution, Survival Analysis}, issn = {1079-5642}, doi = {10.1161/01.atv.19.3.538}, author = {Newman, A B and Shemanski, L and Manolio, T A and Cushman, M and Mittelmark, M and Polak, J F and Powe, N R and Siscovick, D} } @article {600, title = {Cardiovascular disease in older adults with glucose disorders: comparison of American Diabetes Association criteria for diabetes mellitus with WHO criteria.}, journal = {Lancet}, volume = {354}, year = {1999}, month = {1999 Aug 21}, pages = {622-5}, abstract = {

BACKGROUND: The new fasting American Diabetes Association (ADA) criteria for the diagnosis of diabetes mellitus rely mainly on fasting blood glucose concentrations and use a lower cut-off value for diagnosis than the WHO criteria. We aimed to assess the sensitivity of these criteria for the detection of cardiovascular disease, the main complication of diabetes mellitus in the elderly.

METHODS: We did a cross-sectional and prospective analysis of 4515 participants of the Cardiovascular Health Study, an 8 year longitudinal study designed to identify factors related to the onset and course of cardiovascular disease in adults aged at least 65 years. We calculated the prevalence and incidence of cardiovascular disease for the ADA and WHO criteria.

FINDINGS: There was a higher prevalence of cardiovascular disease among individuals with impaired glucose or newly diagnosed diabetes by both criteria than among those with normal glucose concentrations. However, because fewer individuals had abnormal glucose states by the fasting ADA criteria (22.3\%) than by the WHO criteria (46.8\%), the number of cases of cardiovascular disease attributable to abnormal glucose states was a third of that attributable by the WHO criteria (53 vs 159 cases per 10,000). For the two sets of criteria, the relative risk for incident cardiovascular disease (mean follow-up 5.9 years) was higher in individuals with impaired glucose and newly diagnosed diabetes than in those with normal glucose. Individuals classified as normal by the fasting ADA criteria had a higher absolute number of incident events (455 of 581 events) than those classified as normal by the WHO criteria (269 of 581 events). Fasting ADA criteria were therefore less sensitive than the WHO criteria for predicting cardiovascular disease among individuals with abnormal glucose (sensitivity, 28\% vs 54\%).

INTERPRETATION: The new fasting ADA criteria seem to be less predictive than the WHO criteria for the burden of cardiovascular disease associated with abnormal glucose in the elderly.

}, keywords = {Age Factors, Aged, Blood Glucose, Cardiovascular Diseases, Cross-Sectional Studies, Diabetes Complications, Diabetes Mellitus, Fasting, Female, Glucose Intolerance, Humans, Longitudinal Studies, Male, Prospective Studies, Risk Factors, Sensitivity and Specificity, Societies, Medical, United States, World Health Organization}, issn = {0140-6736}, doi = {10.1016/s0140-6736(98)12030-5}, author = {Barzilay, J I and Spiekerman, C F and Wahl, P W and Kuller, L H and Cushman, M and Furberg, C D and Dobs, A and Polak, J F and Savage, P J} } @article {626, title = {Clustering of procoagulation, inflammation, and fibrinolysis variables with metabolic factors in insulin resistance syndrome.}, journal = {Am J Epidemiol}, volume = {152}, year = {2000}, month = {2000 Nov 15}, pages = {897-907}, abstract = {

The known metabolic cardiovascular disease risk factors associated with insulin resistance syndrome (IRS) do not adequately explain the excess cardiovascular disease risk attributed to this syndrome, and abnormalities in hemostatic variables may contribute to this excess risk. Using data from 322 nondiabetic elderly men and women (aged 65-100 years) participating in the Cardiovascular Health Study during 1989-1990, the authors performed factor analysis on 10 metabolic risk factors associated with IRS and 11 procoagulation, inflammation, and fibrinolysis variables to examine the clustering of the metabolic and hemostatic risk markers. Factor analysis of the metabolic variables confirmed four uncorrelated factors: body mass, insulin/glucose, lipids, and blood pressure. Adding the hemostatic variables yielded three new factors interpreted as inflammation, vitamin K-dependent proteins, and procoagulant activity. Plasminogen activator inhibitor-1 clustered with the body mass factor, supporting the hypothesis that obesity is related to impaired fibrinolysis. Fibrinogen clustered with the inflammation summary factor rather than procoagulant activity, supporting the position that fibrinogen principally reflects underlying inflammation rather than procoagulant potential. The authors conclude that should hemostatic variables be shown to contribute to IRS-related cardiovascular disease, apart from plasminogen activator inhibitor-1, they may do so independently of the established metabolic abnormalities.

}, keywords = {Aged, Aged, 80 and over, Antigens, Blood Coagulation, Cardiovascular Diseases, Cluster Analysis, Factor Analysis, Statistical, Factor VII, Female, Fibrinogen, Fibrinolysis, Humans, Inflammation, Insulin Resistance, Male, Middle Aged, Plasminogen Activator Inhibitor 1, Risk Factors}, issn = {0002-9262}, doi = {10.1093/aje/152.10.897}, author = {Sakkinen, P A and Wahl, P and Cushman, M and Lewis, M R and Tracy, R P} } @article {628, title = {Association between physical activity and markers of inflammation in a healthy elderly population.}, journal = {Am J Epidemiol}, volume = {153}, year = {2001}, month = {2001 Feb 01}, pages = {242-50}, abstract = {

Higher levels of physical activity are associated with lower risk of cardiovascular disease. There is growing evidence that the development of the atherosclerotic plaque is associated with inflammation. In this study, the authors investigated the cross-sectional association between physical activity and markers of inflammation in a healthy elderly population. Data obtained in 1989-1990 and 1992-1993 from the Cardiovascular Health Study, a cohort of 5,888 men and women aged >/=65 years, were analyzed. Concentrations of the inflammation markers-C-reactive protein, fibrinogen, Factor VIII activity, white blood cells, and albumin-were compared cross-sectionally by quartile of self-reported physical activity. Compared with persons in the lowest quartile, those in the highest quartile of physical activity had 19\%, 6\%, 4\%, and 3\% lower concentrations of C-reactive protein, white blood cells, fibrinogen, and Factor VIII activity, respectively, after adjustment for gender, the presence of cardiovascular disease, age, race, smoking, body mass index, diabetes, and hypertension. Multivariate regression models suggested that the association of higher levels of physical activity with lower levels of inflammation markers may be mediated by body mass index and glucose. There was no association between physical activity and albumin. Higher levels of physical activity were associated with lower concentrations of four out of five inflammation markers in this elderly cohort. These data suggest that increased exercise is associated with reduced inflammation. Prospective studies will be required for verification of these findings.

}, keywords = {Aged, Analysis of Variance, Biomarkers, C-Reactive Protein, Cardiovascular Diseases, Factor VIII, Female, Fibrinogen, Humans, Inflammation, Leukocyte Count, Male, Physical Exertion, Sex Factors, Smoking}, issn = {0002-9262}, doi = {10.1093/aje/153.3.242}, author = {Geffken, D F and Cushman, M and Burke, G L and Polak, J F and Sakkinen, P A and Tracy, R P} } @article {646, title = {Factors associated with healthy aging: the cardiovascular health study.}, journal = {J Am Geriatr Soc}, volume = {49}, year = {2001}, month = {2001 Mar}, pages = {254-62}, abstract = {

OBJECTIVES: To identify factors associated with remaining healthy in older adults.

DESIGN: Longitudinal cohort study.

SETTING: Data were collected at the four Cardiovascular Health Study field centers.

PARTICIPANTS: 5,888 participants age 65 years and older in the Cardiovascular Health Study.

MEASUREMENTS: Presence of chronic disease was assessed at baseline and over a maximum 7-year follow-up period. Participants who were free of chronic disease (no cardiovascular disease (CVD), chronic obstructive pulmonary disease, or self-reported cancer, except nonmelanoma skin cancer) at the baseline examination were then monitored for the onset of incident cancer, cardiovascular disease, and fatal outcomes.

RESULTS: A high proportion of these older adults was healthy at the initial examination and remained healthy over the follow-up period. Numerous behavioral factors were associated with continued health, including physical activity, refraining from cigarette smoking, wine consumption (women), higher educational status, and lower waist circumference. A number of CVD risk factors and subclinical disease measures were associated with continued health, including higher high-density lipoprotein (HDL) cholesterol, lack of diabetes, thinner common carotid intimal nmedial thickness, lower blood pressure, lower C-reactive protein, and higher ankle-arm blood pressure ratio. Among the behavioral factors, exercise, not smoking, and not taking aspirin remained significant predictors of health even after controlling for CVD risk factors and subclinical disease in older adults.

CONCLUSIONS: These data suggest that a number of modifiable behavioral factors (physical activity, smoking, and obesity) and cardiovascular risk factors (diabetes, HDL cholesterol, and blood pressure) are associated with maintenance of good health in older adults.

}, keywords = {Aged, Aged, 80 and over, Aging, Cardiovascular Diseases, Cohort Studies, Diet, Exercise, Female, Health Status, Humans, Incidence, Life Style, Longitudinal Studies, Lung Diseases, Obstructive, Male, Neoplasms, Probability, Reference Values, Risk Factors, Sex Distribution, Socioeconomic Factors, Survival Rate, United States}, issn = {0002-8614}, doi = {10.1046/j.1532-5415.2001.4930254.x}, author = {Burke, G L and Arnold, A M and Bild, D E and Cushman, M and Fried, L P and Newman, A and Nunn, C and Robbins, J} } @article {661, title = {The relation of markers of inflammation to the development of glucose disorders in the elderly: the Cardiovascular Health Study.}, journal = {Diabetes}, volume = {50}, year = {2001}, month = {2001 Oct}, pages = {2384-9}, abstract = {

Several studies suggest that inflammation plays a role in the pathogenesis of some glucose disorders in adults. We tested this hypothesis in a longitudinal cohort study of older individuals who had normal fasting glucose (FG) values at baseline. We compared the baseline levels of six inflammatory markers in participants who had developed glucose disorders at follow-up with those of participants whose FG remained normal at follow-up. Participants were members of the Cardiovascular Health Study, a prospective study of risk factors for cardiovascular disease in adults > or =65 years. All 5,888 participants had baseline testing, including FG and markers of inflammation: white blood cell and platelet counts and albumin, fibrinogen, C-reactive protein (CRP), and factor VIIIc levels. At 3-4 years of follow-up, 4,481 (84.5\%) of those who were alive had FG levels retested. Participants who developed diabetes (n = 45) had higher median levels of CRP at baseline than those who remained normoglycemic. On multivariate analysis, those with elevated CRP levels (75th percentile [2.86 mg/l] vs. 25th percentile [0.82 mg/l]) were 2.03 times (95\% confidence intervals, 1.44-2.86) more likely to have diabetes on follow-up. Adjustment for confounders and other inflammatory markers did not appreciably change this finding. There was no relationship between the development of diabetes and other markers of inflammation. Inflammation, as measured by CRP levels, is associated with the development of diabetes in the elderly. Understanding the role of inflammation in the pathogenesis of glucose disorders in this age-group may lead to better classification and treatment of glucose disorders among them.

}, keywords = {Aged, Biomarkers, Blood Glucose, C-Reactive Protein, Cardiovascular Diseases, Cohort Studies, Diabetes Mellitus, Female, Humans, Hypoglycemia, Inflammation, Longitudinal Studies, Male, Reference Values, Risk Factors}, issn = {0012-1797}, doi = {10.2337/diabetes.50.10.2384}, author = {Barzilay, J I and Abraham, L and Heckbert, S R and Cushman, M and Kuller, L H and Resnick, H E and Tracy, R P} } @article {892, title = {The association of markers of inflammation with weight change in older adults: the Cardiovascular Health Study.}, journal = {Int J Obes (Lond)}, volume = {30}, year = {2006}, month = {2006 Sep}, pages = {1362-7}, abstract = {

OBJECTIVE: Elevated levels of inflammation factors often precede weight loss and may be causally related to it. Newer studies suggest that elevated levels of inflammation factors also precede weight gain. In this study, we examined whether inflammation factors are elevated in individuals, age >or=65 years, who lost or gained >5\% weight over a 3 year follow-up period compared to those with stable weight.

SUBJECTS: In total, 3254 participants in the Cardiovascular Health Study whose weight was stable; 661 who gained >5\% weight; and 842 who lost >5\% weight.

MEASUREMENTS: C-reactive protein (CRP), fibrinogen, factor VIIIc, white blood cell (WBC) and platelet counts, and interleukin-6 (IL-6) levels.

RESULTS: As compared to participants whose weight was stable, those who lost >5\% weight had higher baseline CRP concentration (1.05 (95\% CI, 1.02, 1.08) per interquartile increase) and WBC count (1.10 (1.01, 1.19) per interquartile increase) on adjusted analyses. Those who gained >5\% weight had higher baseline CRP (1.05 (1.01, 1.08)), fibrinogen (1.13 (1.01, 1.27)), and factor VIIIc (1.15 (1.03, 1.30)).

CONCLUSIONS: Inflammation factors are associated with weight gain and weight loss in older individuals. These findings suggest that subclinical inflammation, or unknown factors associated with subclinical inflammation, contribute to weight change.

}, keywords = {Aged, Biomarkers, C-Reactive Protein, Cardiovascular Diseases, Factor VIII, Female, Fibrinogen, Humans, Inflammation, Interleukin-6, Leukocyte Count, Male, Platelet Count, Weight Gain, Weight Loss}, issn = {0307-0565}, doi = {10.1038/sj.ijo.0803306}, author = {Barzilay, J I and Forsberg, C and Heckbert, S R and Cushman, M and Newman, A B} } @article {943, title = {Collaborative meta-analysis of individual participant data from observational studies of Lp-PLA2 and cardiovascular diseases.}, journal = {Eur J Cardiovasc Prev Rehabil}, volume = {14}, year = {2007}, month = {2007 Feb}, pages = {3-11}, abstract = {

BACKGROUND: A large number of observational epidemiological studies have reported generally positive associations between circulating mass and activity levels of lipoprotein-associated phospholipase A2 (Lp-PLA2) and the risk of cardiovascular diseases. Few studies have been large enough to provide reliable estimates in different circumstances, such as in different subgroups (e.g., by age group, sex, or smoking status) or at different Lp-PLA2 levels. Moreover, most published studies have related disease risk only to baseline values of Lp-PLA2 markers (which can lead to substantial underestimation of any risk relationships because of within-person variability over time) and have used different approaches to adjustment for possible confounding factors.

OBJECTIVES: By combination of data from individual participants from all relevant observational studies in a systematic {\textquoteright}meta-analysis{\textquoteright}, with correction for regression dilution (using available data on serial measurements of Lp-PLA2), the Lp-PLA2 Studies Collaboration will aim to characterize more precisely than has previously been possible the strength and shape of the age and sex-specific associations of plasma Lp-PLA2 with coronary heart disease (and, where data are sufficient, with other vascular diseases, such as ischaemic stroke). It will also help to determine to what extent such associations are independent of possible confounding factors and to explore potential sources of heterogeneity among studies, such as those related to assay methods and study design. It is anticipated that the present collaboration will serve as a framework to investigate related questions on Lp-PLA2 and cardiovascular outcomes.

METHODS: A central database is being established containing data on circulating Lp-PLA2 values, sex and other potential confounding factors, age at baseline Lp-PLA2 measurement, age at event or at last follow-up, major vascular morbidity and cause-specific mortality. Information about any repeat measurements of Lp-PLA2 and potential confounding factors has been sought to allow adjustment for possible confounding and correction for regression dilution. The analyses will involve age-specific regression models. Synthesis of the available observational studies of Lp-PLA2 will yield information on a total of about 15 000 cardiovascular disease endpoints.

}, keywords = {1-Alkyl-2-acetylglycerophosphocholine Esterase, Cardiovascular Diseases, Humans, Phospholipases A2}, issn = {1741-8267}, doi = {10.1097/01.hjr.0000239464.18509.f1}, author = {Ballantyne, C and Cushman, M and Psaty, B and Furberg, C and Khaw, K T and Sandhu, M and Oldgren, J and Rossi, G P and Maiolino, G and Cesari, M and Lenzini, L and James, S K and Rimm, E and Collins, R and Anderson, J and Koenig, W and Brenner, H and Rothenbacher, D and Berglund, G and Persson, M and Berger, P and Brilakis, E and McConnell, J P and Koenig, W and Sacco, R and Elkind, M and Talmud, P and Rimm, E and Cannon, C P and Packard, C and Barrett-Connor, E and Hofman, A and Kardys, I and Witteman, J C M and Criqui, M and Corsetti, J P and Rainwater, D L and Moss, A J and Robins, S and Bloomfield, H and Collins, D and Packard, C and Wassertheil-Smoller, S and Ridker, P and Ballantyne, C and Cannon, C P and Cushman, M and Danesh, J and Gu, D and Hofman, A and Nelson, J J and Thompson, S and Zalewski, A and Zariffa, N and Di Angelantonio, E and Kaptoge, S and Thompson, A and Thompson, S and Walker, M and Watson, S and Wood, A} } @article {984, title = {The Emerging Risk Factors Collaboration: analysis of individual data on lipid, inflammatory and other markers in over 1.1 million participants in 104 prospective studies of cardiovascular diseases.}, journal = {Eur J Epidemiol}, volume = {22}, year = {2007}, month = {2007}, pages = {839-69}, abstract = {

Many long-term prospective studies have reported on associations of cardiovascular diseases with circulating lipid markers and/or inflammatory markers. Studies have not, however, generally been designed to provide reliable estimates under different circumstances and to correct for within-person variability. The Emerging Risk Factors Collaboration has established a central database on over 1.1 million participants from 104 prospective population-based studies, in which subsets have information on lipid and inflammatory markers, other characteristics, as well as major cardiovascular morbidity and cause-specific mortality. Information on repeat measurements on relevant characteristics has been collected in approximately 340,000 participants to enable estimation of and correction for within-person variability. Re-analysis of individual data will yield up to approximately 69,000 incident fatal or nonfatal first ever major cardiovascular outcomes recorded during about 11.7 million person years at risk. The primary analyses will involve age-specific regression models in people without known baseline cardiovascular disease in relation to fatal or nonfatal first ever coronary heart disease outcomes. This initiative will characterize more precisely and in greater detail than has previously been possible the shape and strength of the age- and sex-specific associations of several lipid and inflammatory markers with incident coronary heart disease outcomes (and, secondarily, with other incident cardiovascular outcomes) under a wide range of circumstances. It will, therefore, help to determine to what extent such associations are independent from possible confounding factors and to what extent such markers (separately and in combination) provide incremental predictive value.

}, keywords = {Albumins, Biomarkers, Cardiovascular Diseases, Databases, Factual, Far East, Humans, Inflammation, Leukocyte Count, Lipids, Lipoproteins, HDL, Prospective Studies, Risk Factors, Triglycerides}, issn = {0393-2990}, doi = {10.1007/s10654-007-9165-7}, author = {Danesh, J and Erqou, S and Walker, M and Thompson, S G and Tipping, R and Ford, C and Pressel, S and Walldius, G and Jungner, I and Folsom, A R and Chambless, L E and Knuiman, M and Whincup, P H and Wannamethee, S G and Morris, R W and Willeit, J and Kiechl, S and Santer, P and Mayr, A and Wald, N and Ebrahim, S and Lawlor, D A and Yarnell, J W G and Gallacher, J and Casiglia, E and Tikhonoff, V and Nietert, P J and Sutherland, S E and Bachman, D L and Keil, J E and Cushman, M and Psaty, B M and Tracy, R P and Tybjaerg-Hansen, A and Nordestgaard, B G and Frikke-Schmidt, R and Giampaoli, S and Palmieri, L and Panico, S and Vanuzzo, D and Pilotto, L and Simons, L and McCallum, J and Friedlander, Y and Fowkes, F G R and Lee, A J and Smith, F B and Taylor, J and Guralnik, J and Phillips, C and Wallace, R and Blazer, D and Khaw, K T and Jansson, J H and Donfrancesco, C and Salomaa, V and Harald, K and Jousilahti, P and Vartiainen, E and Woodward, M and D{\textquoteright}Agostino, R B and Wolf, P A and Vasan, R S and Pencina, M J and Bladbjerg, E M and Jorgensen, T and Moller, L and Jespersen, J and Dankner, R and Chetrit, A and Lubin, F and Rosengren, A and Wilhelmsen, L and Lappas, G and Eriksson, H and Bjorkelund, C and Cremer, P and Nagel, D and Tilvis, R and Strandberg, T and Rodriguez, B and Bouter, L M and Heine, R J and Dekker, J M and Nijpels, G and Stehouwer, C D A and Rimm, E and Pai, J and Sato, S and Iso, H and Kitamura, A and Noda, H and Goldbourt, U and Salomaa, V and Salonen, J T and Nyyss{\"o}nen, K and Tuomainen, T-P and Deeg, D and Poppelaars, J L and Meade, T and Cooper, J and Hedblad, B and Berglund, G and Engstrom, G and D{\"o}ring, A and Koenig, W and Meisinger, C and Mraz, W and Kuller, L and Selmer, R and Tverdal, A and Nystad, W and Gillum, R and Mussolino, M and Hankinson, S and Manson, J and De Stavola, B and Knottenbelt, C and Cooper, J A and Bauer, K A and Rosenberg, R D and Sato, S and Naito, Y and Holme, I and Nakagawa, H and Miura, H and Ducimetiere, P and Jouven, X and Crespo, C and Garcia-Palmieri, M and Amouyel, P and Arveiler, D and Evans, A and Ferrieres, J and Schulte, H and Assmann, G and Shepherd, J and Packard, C and Sattar, N and Cantin, B and Lamarche, B and Despr{\'e}s, J-P and Dagenais, G R and Barrett-Connor, E and Wingard, D and Bettencourt, R and Gudnason, V and Aspelund, T and Sigurdsson, G and Thorsson, B and Trevisan, M and Witteman, J and Kardys, I and Breteler, M and Hofman, A and Tunstall-Pedoe, H and Tavendale, R and Lowe, G D O and Ben-Shlomo, Y and Howard, B V and Zhang, Y and Best, L and Umans, J and Onat, A and Meade, T W and Njolstad, I and Mathiesen, E and Lochen, M L and Wilsgaard, T and Gaziano, J M and Stampfer, M and Ridker, P and Ulmer, H and Diem, G and Concin, H and Rodeghiero, F and Tosetto, A and Brunner, E and Shipley, M and Buring, J and Cobbe, S M and Ford, I and Robertson, M and He, Y and Ibanez, A M and Feskens, E J M and Kromhout, D and Collins, R and Di Angelantonio, E and Kaptoge, S and Lewington, S and Orfei, L and Pennells, L and Perry, P and Ray, K and Sarwar, N and Scherman, M and Thompson, A and Watson, S and Wensley, F and White, I R and Wood, A M} } @article {950, title = {Inflammation and hemostasis biomarkers and cardiovascular risk in the elderly: the Cardiovascular Health Study.}, journal = {J Thromb Haemost}, volume = {5}, year = {2007}, month = {2007 Jun}, pages = {1128-35}, abstract = {

BACKGROUND: There are few studies of inflammation and hemostasis biomarkers and cardiovascular disease risk (CVD) in older adults.

OBJECTIVES: To assess multiple biomarkers simultaneously and in combinations for CVD risk assessment in older individuals.

PATIENTS/METHODS: Thirteen biomarkers, interleukin-6 (IL-6), C-reactive protein (CRP), D-dimer, fibrinogen, factor VII, factor VIII, leukocyte count (WBC), platelet count, lipoprotein(a), soluble intercellular adhesion molecule-1 (sICAM-1), albumin, homocysteine and uric acid, were correlated with incident CVD in 4510 individuals in the Cardiovascular Health Study. Baseline biomarkers were analyzed as gender-specific SD increments and quintiles in proportional hazards models adjusted for demographics, CVD risk factors and medications.

RESULTS: Over 9 years with 1700 CVD events, seven biomarkers were associated with CVD. Adjusted hazard ratios (HRs, 95\% CI) per SD increment were 1.16 (1.09, 1.23) for IL-6, 1.16 (1.09, 1.23) for CRP, 1.13 (1.05, 1.21) for D-dimer, 1.17 (1.09, 1.25) for homocysteine, 1.06 (1.00, 1.12) for WBC, 1.06 (1.00, 1.12) for factor VIII, and 1.07 (1.00, 1.13) for lipoprotein(a). Fibrinogen was associated with CVD in men only (HR 1.12, 95\% CI 1.04, 1.22) and sICAM-1 in women only (HR 1.16, 95\% CI 1.05, 1.27). IL-6 and CRP remained associated with CVD when modeled with WBC. Participants were classified by all combinations of two biomarkers being high or low (IL-6, CRP, WBC, factor VIII, cholesterol/HDL). All were associated with CVD when cholesterol/HDL was low and none when CRP was low.

CONCLUSIONS: Seven biomarkers were associated with CVD in older adults, with CRP having some advantages compared with others. Even larger studies are needed to better characterize these associations.

}, keywords = {Aged, Aging, Biomarkers, C-Reactive Protein, Cardiovascular Diseases, Cholesterol, Cohort Studies, Factor VIII, Female, Fibrinogen, Hemostasis, Homocysteine, Humans, Inflammation Mediators, Interleukin-6, Leukocyte Count, Lipoprotein(a), Male, Prospective Studies, Risk Factors}, issn = {1538-7933}, doi = {10.1111/j.1538-7836.2007.02528.x}, author = {Zakai, N A and Katz, R and Jenny, N S and Psaty, B M and Reiner, A P and Schwartz, S M and Cushman, M} } @article {1039, title = {Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis.}, journal = {JAMA}, volume = {300}, year = {2008}, month = {2008 Jul 09}, pages = {197-208}, abstract = {

CONTEXT: Prediction models to identify healthy individuals at high risk of cardiovascular disease have limited accuracy. A low ankle brachial index (ABI) is an indicator of atherosclerosis and has the potential to improve prediction.

OBJECTIVE: To determine if the ABI provides information on the risk of cardiovascular events and mortality independently of the Framingham risk score (FRS) and can improve risk prediction.

DATA SOURCES: Relevant studies were identified. A search of MEDLINE (1950 to February 2008) and EMBASE (1980 to February 2008) was conducted using common text words for the term ankle brachial index combined with text words and Medical Subject Headings to capture prospective cohort designs. Review of reference lists and conference proceedings, and correspondence with experts was conducted to identify additional published and unpublished studies.

STUDY SELECTION: Studies were included if participants were derived from a general population, ABI was measured at baseline, and individuals were followed up to detect total and cardiovascular mortality.

DATA EXTRACTION: Prespecified data on individuals in each selected study were extracted into a combined data set and an individual participant data meta-analysis was conducted on individuals who had no previous history of coronary heart disease.

RESULTS: Sixteen population cohort studies fulfilling the inclusion criteria were included. During 480,325 person-years of follow-up of 24,955 men and 23,339 women, the risk of death by ABI had a reverse J-shaped distribution with a normal (low risk) ABI of 1.11 to 1.40. The 10-year cardiovascular mortality in men with a low ABI (< or = 0.90) was 18.7\% (95\% confidence interval [CI], 13.3\%-24.1\%) and with normal ABI (1.11-1.40) was 4.4\% (95\% CI, 3.2\%-5.7\%) (hazard ratio [HR], 4.2; 95\% CI, 3.3-5.4). Corresponding mortalities in women were 12.6\% (95\% CI, 6.2\%-19.0\%) and 4.1\% (95\% CI, 2.2\%-6.1\%) (HR, 3.5; 95\% CI, 2.4-5.1). The HRs remained elevated after adjusting for FRS (2.9 [95\% CI, 2.3-3.7] for men vs 3.0 [95\% CI, 2.0-4.4] for women). A low ABI (< or = 0.90) was associated with approximately twice the 10-year total mortality, cardiovascular mortality, and major coronary event rate compared with the overall rate in each FRS category. Inclusion of the ABI in cardiovascular risk stratification using the FRS would result in reclassification of the risk category and modification of treatment recommendations in approximately 19\% of men and 36\% of women.

CONCLUSION: Measurement of the ABI may improve the accuracy of cardiovascular risk prediction beyond the FRS.

}, keywords = {Adult, Age Factors, Aged, Aged, 80 and over, Ankle, Atherosclerosis, Blood Pressure, Brachial Artery, Cardiovascular Diseases, Cohort Studies, Confidence Intervals, Female, Global Health, Humans, Male, Middle Aged, Odds Ratio, Predictive Value of Tests, Risk Assessment, Risk Factors, Severity of Illness Index}, issn = {1538-3598}, doi = {10.1001/jama.300.2.197}, author = {Fowkes, F G R and Murray, G D and Butcher, I and Heald, C L and Lee, R J and Chambless, L E and Folsom, A R and Hirsch, A T and Dramaix, M and deBacker, G and Wautrecht, J-C and Kornitzer, M and Newman, A B and Cushman, M and Sutton-Tyrrell, K and Fowkes, F G R and Lee, A J and Price, J F and D{\textquoteright}Agostino, R B and Murabito, J M and Norman, P E and Jamrozik, K and Curb, J D and Masaki, K H and Rodr{\'\i}guez, B L and Dekker, J M and Bouter, L M and Heine, R J and Nijpels, G and Stehouwer, C D A and Ferrucci, L and McDermott, M M and Stoffers, H E and Hooi, J D and Knottnerus, J A and Ogren, M and Hedblad, B and Witteman, J C and Breteler, M M B and Hunink, M G M and Hofman, A and Criqui, M H and Langer, R D and Fronek, A and Hiatt, W R and Hamman, R and Resnick, H E and Guralnik, J and McDermott, M M} } @article {1047, title = {PROC, PROCR and PROS1 polymorphisms, plasma anticoagulant phenotypes, and risk of cardiovascular disease and mortality in older adults: the Cardiovascular Health Study.}, journal = {J Thromb Haemost}, volume = {6}, year = {2008}, month = {2008 Oct}, pages = {1625-32}, abstract = {

BACKGROUND AND OBJECTIVES: Genes encoding protein C anticoagulant pathways are candidates for atherothrombotic and other aging-related disorders.

METHODS: Using a tagSNP approach, and data from the Cardiovascular Health Study (CHS), we assessed associations of common polymorphisms of PROC, PROS1 and PROCR with: (i) plasma protein C, soluble protein C endothelial receptor (sEPCR) and protein S levels measured in a subsample of 336 participants at study entry; and (ii) risk of incident clinical outcomes [coronary heart disease (CHD), stroke, and mortality] in 4547 participants during follow-up. Secondarily, we explored associations between plasma protein C, protein S and sEPCR levels and other candidate genes involved in thrombosis, inflammation, and aging.

RESULTS: The PROCR Ser219Gly polymorphism (rs867186) was strongly associated with higher sEPCR levels, explaining 75\% of the phenotypic variation. The PROCR Ser219Gly variant was also associated with higher levels of circulating protein C antigen. An IL10 polymorphism was associated with higher free protein S levels. The minor alleles of PROC rs2069901 and PROS1 rs4857343 were weakly associated with lower protein C and free protein S levels, respectively. There was no association between PROCR Ser219Gly and risk of CHD, stroke, or mortality. The minor allele of another common PROCR tagSNP, rs2069948, was associated with lymphoid PROCR mRNA expression and with increased risk of incident stroke and all-cause mortality, and decreased healthy survival during follow-up.

CONCLUSIONS: A common PROCR variant may be associated with decreased healthy survival in older adults. Additional studies are warranted to establish the role of PROCR variants in ischemic and aging-related disorders.

}, keywords = {Aged, Aged, 80 and over, Aging, Antigens, CD, Blood Coagulation Factor Inhibitors, Cardiovascular Diseases, Coronary Disease, Endothelial Protein C Receptor, Female, Humans, Inflammation, Male, Middle Aged, Mortality, Polymorphism, Genetic, Protein C, Protein S, Receptors, Cell Surface, Risk, Stroke, Thrombosis}, issn = {1538-7836}, doi = {10.1111/j.1538-7836.2008.03118.x}, author = {Reiner, A P and Carty, C L and Jenny, N S and Nievergelt, C and Cushman, M and Stearns-Kurosawa, D J and Kurosawa, S and Kuller, L H and Lange, L A} } @article {1251, title = {Association of coagulation-related and inflammation-related genes and factor VIIc levels with stroke: the Cardiovascular Health Study.}, journal = {J Thromb Haemost}, volume = {9}, year = {2011}, month = {2011 Feb}, pages = {267-74}, abstract = {

BACKGROUND: Thrombosis and inflammation are critical in stroke etiology, but associations of coagulation and inflammation gene variants with stroke, and particularly factor VII levels, are inconclusive.

OBJECTIVES: To test the associations between 736 single-nucleotide polymorphisms (SNPs) between tagging haplotype patterns of 130 coagulation and inflammation genes, and stroke events, in the 5888 participants aged >= 65 years of the observational Cardiovascular Health Study cohort.

PATIENTS/METHODS: With 16 years of follow-up, age-adjusted and sex-adjusted Cox models were used to estimate associations of SNPs and FVIIc levels with future stroke.

RESULTS: Eight hundred and fifteen strokes occurred in 5255 genotyped participants without baseline stroke (748 ischemic strokes; 586 among whites). Among whites, six SNPs were associated with stroke, with a nominal P-value of < 0.01: rs6046 and rs3093261 (F7); rs4918851 and rs3781387 (HABP2); and rs3138055 (NFKB1A) and rs4648004 (NFKB1). Two of these SNPs were associated with FVIIc levels (units of percentage activity): rs6046 (β = -18.5, P = 2.38 {\texttimes} 10(-83)) and rs3093261 (β = 2.99, P = 3.93 {\texttimes} 10(-6)). After adjustment for age, sex, race, and cardiovascular risk factors, the association of FVIIc quintiles (Q) with stroke were as follows (hazard ratio; 95\% confidence interval): Q1, reference; Q2, 1.4, 1.1-1.9); Q3, 1.1, 0.8-1.5); Q4, 1.5, 1.1-2.0); and Q5, 1.6, 1.2-2.2). Associations between SNPs and stroke were independent of FVIIc levels.

CONCLUSIONS: Variations in FVII-related genes and FVIIc levels were associated with risk of incident ischemic stroke in this elderly cohort, suggesting a potential causal role for FVII in stroke etiology.

}, keywords = {Blood Coagulation Factors, Cardiovascular Diseases, Cohort Studies, Factor VII, Female, Humans, Inflammation, Male, Polymorphism, Single Nucleotide, Prospective Studies, Risk Factors, Stroke}, issn = {1538-7836}, doi = {10.1111/j.1538-7836.2010.04149.x}, author = {Zakai, N A and Lange, L and Longstreth, W T and O{\textquoteright}Meara, E S and Kelley, J L and Fornage, M and Nikerson, D and Cushman, M and Reiner, A P} } @article {1250, title = {Lipoprotein-associated phospholipase A(2) and future risk of subclinical disease and cardiovascular events in individuals with type 2 diabetes: the Cardiovascular Health Study.}, journal = {Diabetologia}, volume = {54}, year = {2011}, month = {2011 Feb}, pages = {329-33}, abstract = {

AIMS/HYPOTHESIS: Type 2 diabetes is an established risk factor for cardiovascular disease (CVD). This increased risk may be due in part to the increased levels of inflammatory factors associated with diabetes. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is a risk marker for CVD and has pro-inflammatory effects in atherosclerotic plaques. We therefore sought to determine whether Lp-PLA(2) levels partially explain the greater prevalence of subclinical CVD and greater incidence of CVD outcomes associated with type 2 diabetes in the Cardiovascular Health Study.

METHODS: We conducted a cross-sectional and prospective study of 4,062 men and women without previous CVD from the Cardiovascular Health Study (1989 to 2007). Lp-PLA(2) mass and activity were measured in baseline plasma. Subclinical disease was determined at baseline and incident CVD was ascertained annually. We used logistic regression for cross-sectional analyses and Cox proportional hazards models for incident analyses.

RESULTS: At baseline, Lp-PLA(2) mass did not differ significantly by type 2 diabetes status; however, Lp-PLA(2) activity was significantly higher among type 2 diabetic individuals. Baseline subclinical disease was significantly associated with baseline diabetes and this association was similar in models unadjusted or adjusted for Lp-PLA(2) (OR 1.68 [95\% CI 1.31-2.15] vs OR 1.67 [95\% CI 1.30-2.13]). Baseline type 2 diabetes was also significantly associated with incident CVD events, including fatal CHD, fatal myocardial infarction (MI) and non-fatal MI in multivariable analyses. There were no differences in these estimates after further adjustment for Lp-PLA(2) activity.

CONCLUSIONS/INTERPRETATION: In this older cohort, differences in Lp-PLA(2) activity did not explain any of the excess risk for subclinical disease or CVD outcomes related to diabetes.

}, keywords = {1-Alkyl-2-acetylglycerophosphocholine Esterase, Aged, Cardiovascular Diseases, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Female, Humans, Male, Proportional Hazards Models, Prospective Studies, Risk Factors}, issn = {1432-0428}, doi = {10.1007/s00125-010-1969-4}, author = {Nelson, T L and Kamineni, A and Psaty, B and Cushman, M and Jenny, N S and Hokanson, J and Furberg, C and Mukamal, K J} } @article {1369, title = {Lipoprotein-associated phospholipase A2 (Lp-PLA2) and future risk of type 2 diabetes: results from the Cardiovascular Health Study.}, journal = {J Clin Endocrinol Metab}, volume = {97}, year = {2012}, month = {2012 May}, pages = {1695-701}, abstract = {

INTRODUCTION: Lipoprotein-associated phospholipase A2 (Lp-PLA(2)) has been consistently associated with cardiovascular disease (CVD) risk factors and predictive of CVD outcomes; furthermore, it is consistently higher among type 2 diabetics than nondiabetics. However, the relationships of circulating Lp-PLA(2) mass and activity with incident type 2 diabetes mellitus have not been examined. Therefore, the purpose of this study was to determine the association of Lp-PLA(2) mass and activity with type 2 diabetes among older adults.

METHODS: We conducted analyses of Lp-PLA(2) and prevalent and incident diabetes among 5474 men and women from the Cardiovascular Health Study (1989-2007). Lp-PLA(2) mass and activity were measured in baseline plasma. Diabetes status was ascertained annually with medication inventories and repeated blood glucose measurements. Generalized linear and Cox proportional hazards models were used to adjust for confounding factors including body mass index and inflammation.

RESULTS: At baseline, the top two quintiles of Lp-PLA(2) activity were significantly associated with prevalent type 2 diabetes with a multivariable relative risk = 1.35 [95\% confidence interval (CI) = 1.11-1.63] for quintile 4, and relative risk = 1.33 (95\% CI = 1.07-1.66) for quintile 5. Among participants free of diabetes at baseline, we found a significant positive association with both the homeostatic model assessment for insulin resistance and β-cell function per SD increase in Lp-PLA(2) activity (P values for both <0.01). In prospective analyses, the risk of incident type 2 diabetes was significantly higher among those in the highest quintile of Lp-PLA(2) activity [multivariable hazard ratio = 1.45 (95\% CI = 1.01-2.07)] compared with the lowest quintile. Lp-PLA(2) mass was not significantly associated with incident type 2 diabetes.

DISCUSSION: Lp-PLA(2) activity is positively associated with insulin resistance and predicts incident type 2 diabetes among older adults independent of multiple factors associated with diabetes pathogenesis.

}, keywords = {1-Alkyl-2-acetylglycerophosphocholine Esterase, Aged, Aged, 80 and over, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Female, Humans, Incidence, Insulin Resistance, Male, Middle Aged, Predictive Value of Tests, Prevalence, Prospective Studies, Risk, Risk Factors}, issn = {1945-7197}, doi = {10.1210/jc.2011-3026}, author = {Nelson, T L and Biggs, M L and Kizer, J R and Cushman, M and Hokanson, J E and Furberg, C D and Mukamal, K J} } @article {6803, title = {Development and validation of an ankle brachial index risk model for the prediction of cardiovascular events.}, journal = {Eur J Prev Cardiol}, volume = {21}, year = {2014}, month = {2014 Mar}, pages = {310-20}, abstract = {

BACKGROUND: The ankle brachial index (ABI) is related to risk of cardiovascular events independent of the Framingham risk score (FRS). The aim of this study was to develop and evaluate a risk model for cardiovascular events incorporating the ABI and FRS.

DESIGN: An analysis of participant data from 18 cohorts in which 24,375 men and 20,377 women free of coronary heart disease had ABI measured and were followed up for events.

METHODS: Subjects were divided into a development and internal validation dataset and an external validation dataset. Two models, comprising FRS and FRS + ABI, were fitted for the primary outcome of major coronary events.

RESULTS: In predicting events in the external validation dataset, C-index for the FRS was 0.672 (95\% CI 0.599 to 0.737) in men and 0.578 (95\% CI 0.492 to 0.661) in women. The FRS + ABI led to a small increase in C-index in men to 0.685 (95\% CI 0.612 to 0.749) and large increase in women to 0.690 (95\% CI 0.605 to 0.764) with net reclassification improvement (NRI) of 4.3\% (95\% CI 0.0 to 7.6\%, p = 0.050) and 9.6\% (95\% CI 6.1 to 16.4\%, p < 0.001), respectively. Restricting the FRS + ABI model to those with FRS intermediate 10-year risk of 10 to 19\% resulted in higher NRI of 15.9\% (95\% CI 6.1 to 20.6\%, p < 0.001) in men and 23.3\% (95\% CI 13.8 to 62.5\%, p = 0.002) in women. However, incorporating ABI in an improved newly fitted risk factor model had a nonsignificant effect: NRI 2.0\% (95\% CI 2.3 to 4.2\%, p = 0.567) in men and 1.1\% (95\% CI 1.9 to 4.0\%, p = 0.483) in women.

CONCLUSIONS: An ABI risk model may improve prediction especially in individuals at intermediate risk and when performance of the base risk factor model is modest.

}, keywords = {Adult, Aged, Aged, 80 and over, Ankle Brachial Index, Cardiovascular Diseases, Europe, European Continental Ancestry Group, Female, Humans, Male, Middle Aged, Models, Statistical, Predictive Value of Tests, Prognosis, Reproducibility of Results, Risk Assessment, Risk Factors, Sex Factors, Time Factors, United States, Young Adult}, issn = {2047-4881}, doi = {10.1177/2047487313516564}, author = {Fowkes, F G R and Murray, G D and Butcher, I and Folsom, A R and Hirsch, A T and Couper, D J and deBacker, G and Kornitzer, M and Newman, A B and Sutton-Tyrrell, K C and Cushman, M and Lee, A J and Price, J F and D{\textquoteright}Agostino, R B and Murabito, J M and Norman, Pe and Masaki, K H and Bouter, L M and Heine, R J and Stehouwer, C D A and McDermott, M M and Stoffers, H E J H and Knottnerus, J A and Ogren, M and Hedblad, B and Koenig, W and Meisinger, C and Cauley, J A and Franco, Oh and Hunink, M G M and Hofman, A and Witteman, J C and Criqui, M H and Langer, R D and Hiatt, W R and Hamman, R F} }