@article {716, title = {Coagulation factors, inflammation markers, and venous thromboembolism: the longitudinal investigation of thromboembolism etiology (LITE).}, journal = {Am J Med}, volume = {113}, year = {2002}, month = {2002 Dec 01}, pages = {636-42}, abstract = {

PURPOSE: We sought to assess prospectively whether higher levels of blood coagulation factors and inflammation markers are risk factors for venous thromboembolism.

SUBJECTS AND METHODS: In two pooled population-based cohort studies, we measured levels of factor VII, factor VIII, von Willebrand factor, fibrinogen, and C-reactive protein, and white blood cell count, in samples obtained from 19,237 adults with no baseline history of venous thromboembolism, cancer, or warfarin use. The endpoint was validated venous thromboembolism during follow-up (median, 7.8 years).

RESULTS: A total of 159 venous thromboembolism events occurred. Factor VIII and von Willebrand factor were linearly associated with increased risk of venous thromboembolism (P for trend <0.0001). As compared with those in the lowest quartile, the multivariate-adjusted hazard ratio (HR) of venous thromboembolism was 2.6 (95\% confidence interval [CI]: 1.6 to 4.3) for factor VIII levels in the highest quartile and 3.8 (95\% CI: 2.0 to 7.2) for the highest fifth percentile. For von Willebrand factor, the hazard ratios in middle-aged subjects were 4.6 (95\% CI: 2.2 to 9.2) for the highest quartile and 7.6 (95\% CI: 3.1 to 18) for the highest fifth percentile. Factor VII levels above the 95th percentile, as compared with the lowest quartile, also conveyed a higher risk of venous thromboembolism (HR = 2.4; 95\% CI: 1.2 to 4.8). In contrast, there was no association of venous thromboembolism with fibrinogen or C-reactive protein levels, or white cell count.

CONCLUSIONS: In this prospective study, elevated factor VIII and von Willebrand factor levels were common, independent, and dose-dependent risk factors for venous thromboembolism, and an elevated factor VII level was a possible risk factor. Venous thromboembolism, unlike arterial disease, was not related to inflammatory markers.

}, keywords = {Aged, Biomarkers, Blood Coagulation Factors, C-Reactive Protein, Cohort Studies, Confidence Intervals, Factor VII, Female, Fibrinogen, Humans, Inflammation Mediators, Longitudinal Studies, Male, Middle Aged, Multivariate Analysis, Prospective Studies, Risk Assessment, Risk Factors, Sensitivity and Specificity, Thromboembolism, Venous Thrombosis, von Willebrand Factor}, issn = {0002-9343}, doi = {10.1016/s0002-9343(02)01345-1}, author = {Tsai, Albert W and Cushman, Mary and Rosamond, Wayne D and Heckbert, Susan R and Tracy, Russell P and Aleksic, Nena and Folsom, Aaron R} } @article {741, title = {C-reactive protein, carotid intima-media thickness, and incidence of ischemic stroke in the elderly: the Cardiovascular Health Study.}, journal = {Circulation}, volume = {108}, year = {2003}, month = {2003 Jul 15}, pages = {166-70}, abstract = {

BACKGROUND: Increased carotid artery intima-media thickness (IMT) and elevated C-reactive protein (CRP) are both associated with the occurrence of stroke. We investigated whether elevated CRP is a risk factor for ischemic stroke independent of carotid IMT and studied the interaction between CRP and IMT.

METHODS AND RESULTS: We studied 5417 participants aged 65 years or older without preexisting stroke or chronic atrial fibrillation who were participants in the Cardiovascular Health Study. The hazard ratio of incident ischemic stroke was estimated by Cox proportional hazards regression. During 10.2 years of follow-up, 469 incident ischemic strokes occurred. The adjusted hazard ratios for ischemic stroke in the 2nd to 4th quartiles of baseline CRP, relative to the 1st quartile, were 1.19 (95\% CI 0.92 to 1.53), 1.05 (95\% CI 0.81 to 1.37), and 1.60 (95\% CI 1.23 to 2.08), respectively. With additional adjustment for carotid IMT, there was little confounding. The association of CRP with stroke was significantly different depending on IMT (P<0.02), with no association of CRP with stroke among those in the lowest IMT tertile and a significant association among those with higher levels of IMT.

CONCLUSIONS: We conclude that elevated CRP is a risk factor for ischemic stroke, independent of atherosclerosis severity as measured by carotid IMT. The association of CRP with stroke is more apparent in the presence of a higher carotid IMT. CRP and carotid IMT may each be independent integrals in determining the risk of ischemic stroke.

}, keywords = {Aged, Brain Ischemia, C-Reactive Protein, California, Carotid Arteries, Cohort Studies, Comorbidity, Female, Follow-Up Studies, Humans, Incidence, Longitudinal Studies, Male, Maryland, North Carolina, Odds Ratio, Pennsylvania, Proportional Hazards Models, Risk Assessment, Risk Factors, Stroke, Tunica Intima, Tunica Media, Ultrasonography}, issn = {1524-4539}, doi = {10.1161/01.CIR.0000079160.07364.6A}, author = {Cao, Jie J and Thach, Chau and Manolio, Teri A and Psaty, Bruce M and Kuller, Lewis H and Chaves, Paulo H M and Polak, Joseph F and Sutton-Tyrrell, Kim and Herrington, David M and Price, Thomas R and Cushman, Mary} } @article {786, title = {Alcohol consumption and inflammatory markers in older adults: the Cardiovascular Health Study.}, journal = {Atherosclerosis}, volume = {173}, year = {2004}, month = {2004 Mar}, pages = {79-87}, abstract = {

OBJECTIVE: We sought to determine the relation of alcohol intake and systemic inflammation in a population-based sample of older adults.

METHODS AND RESULTS: As part of the Cardiovascular Health Study (CHS), 5865 adults aged 65 years and older reported their intake of beer, wine, and liquor. We determined white blood cell count (WBC), factor VIII coagulant activity (factor VIIIc), and levels of C-reactive protein (CRP), fibrinogen, and albumin as markers of systemic inflammation. Among participants without confirmed cardiovascular disease, alcohol consumption was inversely associated with WBC, factor VIIIc, and fibrinogen level, and positively associated with albumin concentration in multivariate analyses. We found no consistent modification of these results by sex, obesity, or beverage type. The relation of alcohol use and CRP levels was significantly modified by apoE genotype (P interaction 0.03), with a positive association among participants with an apoE4 allele (P = 0.05), but a trend toward an inverse association among those without an apoE4 allele (P = 0.15).

CONCLUSIONS: Alcohol intake is associated with lower levels of inflammatory markers in older adults free of cardiovascular disease.

}, keywords = {Aged, Aged, 80 and over, Alcohol Drinking, Apolipoproteins E, C-Reactive Protein, Coronary Artery Disease, Female, Fibrinogen, Geriatric Assessment, Humans, Inflammation Mediators, Leukocyte Count, Logistic Models, Longitudinal Studies, Male, Probability, Prospective Studies, Risk Assessment, Sensitivity and Specificity, Severity of Illness Index}, issn = {0021-9150}, doi = {10.1016/j.atherosclerosis.2003.10.011}, author = {Mukamal, Kenneth J and Cushman, Mary and Mittleman, Murray A and Tracy, Russell P and Siscovick, David S} } @article {855, title = {Risk factors for declining ankle-brachial index in men and women 65 years or older: the Cardiovascular Health Study.}, journal = {Arch Intern Med}, volume = {165}, year = {2005}, month = {2005 Sep 12}, pages = {1896-902}, abstract = {

BACKGROUND: An ankle-brachial index (ABI) of less than 0.9 is a noninvasive measure of lower extremity arterial disease and a predictor of cardiovascular events. Little information is available on longitudinal change in ABI or on risk factors for declining ABI in a community-based population.

METHODS: To assess risk factors for ABI decline, we studied 5888 participants in the Cardiovascular Health Study cohort (men and women 65 years or older). We measured ABI in 1992-1993 and again in 1998-1999. At baseline, we excluded individuals with an ABI less than 0.9, ABI greater than 1.4, or confirmed symptomatic lower extremity arterial disease (n = 823). The group with ABI decline included 218 participants with decline greater than 0.15 and to 0.9 or less. The comparison group comprised the remaining 2071 participants with follow-up ABI.

RESULTS: The percentage of participants with ABI decline was 9.5\% over 6 years of follow-up. The mean +/- SD decline was 0.33 +/- 0.12 in cases of ABI decline and 0.02 +/- 0.13 in non-cases. Independent predictors of ABI decline, reported as odds ratios, were age, 1.96 (95\% confidence interval [CI], 1.42-2.71) for 75 to 84 years and 3.79 (95\% CI, 1.36-10.5) for those older than 85 years compared with those younger than 75 years; current cigarette use, 1.74 (95\% CI, 1.02-2.96); hypertension, 1.64 (95\% CI, 1.18-2.28); diabetes, 1.77 (95\% CI, 1.14-2.76); higher low-density lipoprotein cholesterol level, 1.60 (95\% CI, 1.03-2.51), and lipid-lowering drug use 1.74 (95\% CI, 1.05-2.89).

CONCLUSION: Worsening lower extremity arterial disease, assessed as ABI decline, occurred in 9.5\% of this elderly cohort over 6 years and was associated with modifiable vascular disease risk factors.

}, keywords = {Aged, Aged, 80 and over, Ankle, Brachial Artery, Cardiovascular Diseases, Female, Humans, Male, Peripheral Vascular Diseases, Risk Assessment, Risk Factors}, issn = {0003-9926}, doi = {10.1001/archinte.165.16.1896}, author = {Kennedy, Margaret and Solomon, Cam and Manolio, Teri A and Criqui, Michael H and Newman, Anne B and Polak, Joseph F and Burke, Gregory L and Enright, Paul and Cushman, Mary} } @article {881, title = {Alcohol consumption and risk of coronary heart disease in older adults: the Cardiovascular Health Study.}, journal = {J Am Geriatr Soc}, volume = {54}, year = {2006}, month = {2006 Jan}, pages = {30-7}, abstract = {

OBJECTIVES: To evaluate several aspects of the relationship between alcohol use and coronary heart disease in older adults, including beverage type, mediating factors, and type of outcome.

DESIGN: Prospective cohort study.

SETTING: Four U.S. communities.

PARTICIPANTS: Four thousand four hundred ten adults aged 65 and older free of cardiovascular disease at baseline.

MEASUREMENTS: Risk of incident myocardial infarction or coronary death according to self-reported consumption of beer, wine, and spirits ascertained yearly.

RESULTS: During an average follow-up period of 9.2 years, 675 cases of incident myocardial infarction or coronary death occurred. Compared with long-term abstainers, multivariate relative risks of 0.90 (95\% confidence interval (CI)=0.71-1.14), 0.93 (95\% CI=0.73-1.20), 0.76 (95\% CI=0.53-1.10), and 0.58 (95\% CI=0.39-0.86) were found in consumers of less than one, one to six, seven to 13, and 14 or more drinks per week, respectively (P for trend=.007). Associations were similar for secondary coronary outcomes, including nonfatal and fatal events. No strong mediators of the association were identified, although fibrinogen appeared to account for 9\% to 10\% of the relationship. The associations were statistically similar for intake of wine, beer, and liquor and generally similar in subgroups, including those with and without an apolipoprotein E4 allele.

CONCLUSION: In this population, consumption of 14 or more drinks per week was associated with the lowest risk of coronary heart disease, although clinicians should not recommend moderate drinking to prevent coronary heart disease based on this evidence alone, because current National Institute on Alcohol Abuse and Alcoholism guidelines suggest that older adults limit alcohol intake to one drink per day.

}, keywords = {Aged, Alcohol Drinking, Apolipoproteins E, Beer, Cohort Studies, Coronary Disease, Female, Genotype, Health Behavior, Humans, Incidence, Male, Residence Characteristics, Risk Assessment, Socioeconomic Factors, United States, Wine}, issn = {0002-8614}, doi = {10.1111/j.1532-5415.2005.00561.x}, author = {Mukamal, Kenneth J and Chung, Hyoju and Jenny, Nancy S and Kuller, Lewis H and Longstreth, W T and Mittleman, Murray A and Burke, Gregory L and Cushman, Mary and Psaty, Bruce M and Siscovick, David S} } @article {900, title = {Factors associated with geographic variations in stroke incidence among older populations in four US communities.}, journal = {Stroke}, volume = {37}, year = {2006}, month = {2006 Aug}, pages = {1980-5}, abstract = {

BACKGROUND AND PURPOSE: In the Cardiovascular Health Study (CHS), we previously observed lower stroke incidence in Allegheny County, PA compared with the other 3 study sites. The purpose of this study was to study possible reasons for the lower stroke incidence in Allegheny County.

METHODS: CHS participants 65 years or older who were stroke-free at baseline (n=5639) were followed between 1989 to 1990 and 2000 for the development of stroke. Risk factors at baseline and their subsequent control were compared among both groups. Site-specific hazard ratios for stroke incidence were calculated using Cox regression models.

RESULTS: The unadjusted hazard ratio for total stroke incidence in Forsyth County, NC; Sacramento County, CA; and Washington County, MD combined compared with Allegheny County, PA was 1.74 (95\% CI: 1.42, 2.14). After adjustment for age and other traditional risk factors, there was modest reduction of the excess hazard in non-Allegheny sites compared with Allegheny County (hazard ratio=1.52, 95\% CI: 1.17, 1.98). Between baseline and the seventh-year visits, control of hypertension, diabetes, lipids, smoking, atrial fibrillation and transient ischemic attack were similar across sites. White matter grade > or = 3 on the baseline brain MRI was less common in Allegheny County (25.8\% versus 36.3\%, respectively; P<0.001) and accounted for 25\% of the excess hazard in non-Allegheny sites compared with Allegheny County.

CONCLUSIONS: Site differences in stroke risk factors at baseline and subsequent control only partially explain site differences in stroke incidence. White matter grade as a possible integrated measure of exposure and control of risk factors may help in explaining geographic variations in stroke incidence.

}, keywords = {Aged, Brain, California, Female, Humans, Incidence, Magnetic Resonance Imaging, Male, Maryland, North Carolina, Pennsylvania, Proportional Hazards Models, Risk Assessment, Risk Factors, Stroke}, issn = {1524-4628}, doi = {10.1161/01.STR.0000231454.77745.d9}, author = {El-Saed, Aiman and Kuller, Lewis H and Newman, Anne B and Lopez, Oscar and Costantino, Joseph and McTigue, Kathleen and Cushman, Mary and Kronmal, Richard} } @article {967, title = {Association of carotid artery intima-media thickness, plaques, and C-reactive protein with future cardiovascular disease and all-cause mortality: the Cardiovascular Health Study.}, journal = {Circulation}, volume = {116}, year = {2007}, month = {2007 Jul 03}, pages = {32-8}, abstract = {

BACKGROUND: Carotid atherosclerosis, measured as carotid intima-media thickness or as characteristics of plaques, has been linked to cardiovascular disease (CVD) and to C-reactive protein (CRP) levels. We investigated the relationship between carotid atherosclerosis and CRP and their joint roles in CVD prediction.

METHODS AND RESULTS: Of 5888 participants in the Cardiovascular Health Study, an observational study of adults aged > or = 65 years, 5020 without baseline CVD were included in the analysis. They were followed up for as long as 12 years for CVD incidence and all-cause mortality after baseline ultrasound and CRP measurement. When CRP was elevated (> 3 mg/L) among those with detectable atherosclerosis on ultrasound, there was a 72\% (95\% CI, 1.46 to 2.01) increased risk for CVD death and a 52\% (95\% CI, 1.37 to 1.68) increased risk for all-cause mortality. Elevated CRP in the absence of atherosclerosis did not increase CVD or all-cause mortality risk. The proportion of excess risk attributable to the interaction of high CRP and atherosclerosis was 54\% for CVD death and 79\% for all-cause mortality. Addition of CRP or carotid atherosclerosis to conventional risk factors modestly increased in the ability to predict CVD, as measured by the c statistic.

CONCLUSIONS: In older adults, elevated CRP was associated with increased risk for CVD and all-cause mortality only in those with detectable atherosclerosis based on carotid ultrasound. Despite the significant associations of CRP and carotid atherosclerosis with CVD, these measures modestly improve the prediction of CVD outcomes after one accounts for the conventional risk factors.

}, keywords = {African Americans, Aged, Biomarkers, C-Reactive Protein, Cardiovascular Diseases, Carotid Artery Diseases, Cohort Studies, Comorbidity, Diabetes Mellitus, European Continental Ancestry Group, Female, Follow-Up Studies, Humans, Hyperlipidemias, Hypertension, Incidence, Inflammation, Kaplan-Meier Estimate, Male, Mass Screening, Mortality, Myocardial Infarction, Obesity, Predictive Value of Tests, Proportional Hazards Models, Prospective Studies, Risk Assessment, Risk Factors, ROC Curve, Smoking, Stroke, Survival Analysis, Tunica Intima, Tunica Media, Ultrasonography, United States}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.106.645606}, author = {Cao, Jie J and Arnold, Alice M and Manolio, Teri A and Polak, Joseph F and Psaty, Bruce M and Hirsch, Calvin H and Kuller, Lewis H and Cushman, Mary} } @article {1019, title = {Associations between common fibrinogen gene polymorphisms and cardiovascular disease in older adults. The Cardiovascular Health Study.}, journal = {Thromb Haemost}, volume = {99}, year = {2008}, month = {2008 Feb}, pages = {388-95}, abstract = {

Elevated plasma fibrinogen is a risk factor for cardiovascular disease (CVD), but associations between fibrinogen single nucleotide polymorphisms (SNPs) and disease risk are inconsistent. We investigated whether common (> or = 5\% minor allele frequency) variation in the fibrinogen genes (FGA, FGB, FGG) is associated with fibrinogen concentration, carotid artery intima-medial thickness (IMT) and risk of incident myocardial infarction (MI), ischemic stroke and CVD mortality in European- (EA) and African-descent (AA) adults (> or = 65 years) from the Cardiovascular Health Study. TagSNPs were genotyped in 3,969 EA and 719 AA free of MI or stroke at baseline. Race-specific models included multiple testing correction and adjustment for sex, age and site. Among EA, minor alleles of FGA3807, FGB1437 and FGG902 were associated with higher fibrinogen levels; whereas FGA251, FGA2224, FGA6534 and FGG10034 were associated with lower levels, p<0.004 for each. Strongest associations were seen for FGB1437; each additional copy of the minor allele was associated with 13 mg/dl (95\%CI: 9-16) higher fibrinogen level. Similar trends in AA were not significant. Fibrinogen haplotypes were not significantly associated with internal or common carotid IMT. No associations with MI or CVD mortality were seen in EA, though FGB1038 and FGG902 were significantly associated with increased and decreased risk of stroke in men, respectively, as were related haplotypes. FGB1038 was also associated with CVD mortality in AA, HR = 1.9 (95\%CI: 1.3-2.7). In conclusion, while fibrinogen genetic variation was strongly associated with fibrinogen levels, there was less evidence of association with the more complex outcomes of IMT and CVD events.

}, keywords = {African Americans, Age Factors, Aged, Brain Ischemia, Cardiovascular Diseases, Carotid Artery Diseases, European Continental Ancestry Group, Female, Fibrinogen, Gene Frequency, Genetic Predisposition to Disease, Haplotypes, Humans, Male, Myocardial Infarction, Polymorphism, Single Nucleotide, Population Surveillance, Proportional Hazards Models, Prospective Studies, Reproducibility of Results, Risk Assessment, Risk Factors, Sex Factors, Stroke, United States}, issn = {0340-6245}, doi = {10.1160/TH07-08-0523}, author = {Carty, Cara L and Cushman, Mary and Jones, Daniel and Lange, Leslie A and Hindorff, Lucia A and Rice, Kenneth and Jenny, Nancy S and Durda, J Peter and Walston, Jeremy and Carlson, Christopher S and Nickerson, Debbie and Tracy, Russell P and Reiner, Alex P} } @article {1135, title = {Lipoprotein-associated phospholipase A(2) and risk of congestive heart failure in older adults: the Cardiovascular Health Study.}, journal = {Circ Heart Fail}, volume = {2}, year = {2009}, month = {2009 Sep}, pages = {429-36}, abstract = {

BACKGROUND: Inflammation may be a causative factor in congestive heart failure (CHF). Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an inflammation marker associated with vascular risk. One previous study showed an association of Lp-PLA(2) activity with CHF risk, but there were only 94 CHF cases and Lp-PLA(2) antigen, which is available clinically in the United States, was not measured.

METHODS AND RESULTS: We measured baseline Lp-PLA(2) antigen and activity in 3991 men and women without baseline CHF or cardiovascular disease who were participating in the Cardiovascular Health Study, a prospective observational study of adults 65 years or older. Cox proportional hazards models adjusted for age, sex, clinic site, race, low-density and high-density lipoprotein cholesterol, body mass index, systolic and diastolic blood pressure, hypertension, smoking status, pack-years, and diabetes were used to calculate hazard ratios and 95\% CIs for incident CHF. Further models adjusted for coronary disease events during follow-up and C-reactive protein. Eight hundred twenty-nine participants developed CHF during 12.1 years. Adjusted hazard ratios for CHF with Lp-PLA(2) in the fourth compared with the first quartile were 1.44 (95\% CI, 1.16 to 1.79) for Lp-PLA(2) antigen and 1.06 (95\% CI, 0.84 to 1.32) for activity. Adjustment for incident coronary disease attenuated the hazard ratio for Lp-PLA(2) antigen to 1.26 (95\% CI, 1.02 to 1.57), adjustment for C-reactive protein had minimal impact.

CONCLUSIONS: Lp-PLA(2) antigen was associated with risk of future CHF in older people, independent of CHF and coronary risk factors, and partly mediated by coronary disease events. Further clinical and basic research is needed to better understand the role of Lp-PLA(2) in CHF.

}, keywords = {1-Alkyl-2-acetylglycerophosphocholine Esterase, Aged, Biomarkers, C-Reactive Protein, Female, Fibrinogen, Heart Failure, Humans, Incidence, Inflammation Mediators, Interleukin-6, Kaplan-Meier Estimate, Male, Population Surveillance, Proportional Hazards Models, Prospective Studies, Risk Assessment, Risk Factors, Time Factors, United States}, issn = {1941-3297}, doi = {10.1161/CIRCHEARTFAILURE.108.839613}, author = {Suzuki, Takeki and Solomon, Cam and Jenny, Nancy Swords and Tracy, Russell and Nelson, Jeanenne J and Psaty, Bruce M and Furberg, Curt and Cushman, Mary} } @article {1124, title = {Total and cause-specific mortality in the cardiovascular health study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {64}, year = {2009}, month = {2009 Dec}, pages = {1251-61}, abstract = {

BACKGROUND: Few cohort studies have adequate numbers of carefully reviewed deaths to allow an analysis of unique and shared risk factors for cause-specific mortality. Shared risk factors could be targeted for prevention of premature death and the study of longevity.

METHODS: A total of 5,888 community-dwelling persons aged 65 years or older living in four communities in the United States participated in the Cardiovascular Health Study cohort. Participants were initially recruited from 1989 to 1990; an additional 687 black participants were recruited in 1992-1993. The average length of follow-up was 16 years. Total and cause-specific mortality, including cardiovascular disease, stroke, cancer, dementia, pulmonary disease, infection, and other cause, were examined as outcomes. Variables previously associated with total mortality were examined for each cause of death using Cox proportional hazard models.

RESULTS: Multiple risk factors were related to total mortality. When examining specific causes, many factors were related to cardiovascular death, whereas fewer were related to other causes. For most causes, risk factors were specific for that cause. For example, apolipoprotein E epsilon4 was strongly associated for dementia death and forced vital capacity with pulmonary death. Age, male sex, markers of inflammation, and cognitive function were related to multiple causes of death.

CONCLUSIONS: In these older adults, associations of risk factors with a given cause of death were related to specific deficits in that same organ system. Inflammation may represent a common pathway to all causes of death.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Aging, Cardiovascular Diseases, Cause of Death, Chronic Disease, Cohort Studies, Female, Geriatric Assessment, Health Surveys, Humans, Kaplan-Meier Estimate, Male, Probability, Proportional Hazards Models, Retrospective Studies, Risk Assessment, Severity of Illness Index, Sex Factors, Survival Analysis, United States}, issn = {1758-535X}, doi = {10.1093/gerona/glp127}, author = {Newman, Anne B and Sachs, Michael C and Arnold, Alice M and Fried, Linda P and Kronmal, Richard and Cushman, Mary and Psaty, Bruce M and Harris, Tamara B and Robbins, John A and Burke, Gregory L and Kuller, Lewis H and Lumley, Thomas} } @article {583, title = {Lipoprotein-associated phospholipase A(2) and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies.}, journal = {Lancet}, volume = {375}, year = {2010}, month = {2010 May 01}, pages = {1536-44}, abstract = {

BACKGROUND: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), an inflammatory enzyme expressed in atherosclerotic plaques, is a therapeutic target being assessed in trials of vascular disease prevention. We investigated associations of circulating Lp-PLA(2) mass and activity with risk of coronary heart disease, stroke, and mortality under different circumstances.

METHODS: With use of individual records from 79 036 participants in 32 prospective studies (yielding 17 722 incident fatal or non-fatal outcomes during 474 976 person-years at risk), we did a meta-analysis of within-study regressions to calculate risk ratios (RRs) per 1 SD higher value of Lp-PLA(2) or other risk factor. The primary outcome was coronary heart disease.

FINDINGS: Lp-PLA(2) activity and mass were associated with each other (r=0.51, 95\% CI 0.47-0.56) and proatherogenic lipids. We noted roughly log-linear associations of Lp-PLA(2) activity and mass with risk of coronary heart disease and vascular death. RRs, adjusted for conventional risk factors, were: 1.10 (95\% CI 1.05-1.16) with Lp-PLA(2) activity and 1.11 (1.07-1.16) with Lp-PLA(2) mass for coronary heart disease; 1.08 (0.97-1.20) and 1.14 (1.02-1.27) for ischaemic stroke; 1.16 (1.09-1.24) and 1.13 (1.05-1.22) for vascular mortality; and 1.10 (1.04-1.17) and 1.10 (1.03-1.18) for non-vascular mortality, respectively. RRs with Lp-PLA(2) did not differ significantly in people with and without initial stable vascular disease, apart from for vascular death with Lp-PLA(2) mass. Adjusted RRs for coronary heart disease were 1.10 (1.02-1.18) with non-HDL cholesterol and 1.10 (1.00-1.21) with systolic blood pressure.

INTERPRETATION: Lp-PLA(2) activity and mass each show continuous associations with risk of coronary heart disease, similar in magnitude to that with non-HDL cholesterol or systolic blood pressure in this population. Associations of Lp-PLA(2) mass and activity are not exclusive to vascular outcomes, and the vascular associations depend at least partly on lipids.

FUNDING: UK Medical Research Council, GlaxoSmithKline, and British Heart Foundation.

}, keywords = {1-Alkyl-2-acetylglycerophosphocholine Esterase, Blood Pressure, Coronary Disease, Female, Humans, Linear Models, Lipids, Male, Middle Aged, Prospective Studies, Risk Assessment, Risk Factors, Stroke, Systole}, issn = {1474-547X}, doi = {10.1016/S0140-6736(10)60319-4}, author = {Thompson, Alexander and Gao, Pei and Orfei, Lia and Watson, Sarah and Di Angelantonio, Emanuele and Kaptoge, Stephen and Ballantyne, Christie and Cannon, Christopher P and Criqui, Michael and Cushman, Mary and Hofman, Albert and Packard, Chris and Thompson, Simon G and Collins, Rory and Danesh, John} } @article {1564, title = {Soluble CD14: genomewide association analysis and relationship to cardiovascular risk and mortality in older adults.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {33}, year = {2013}, month = {2013 Jan}, pages = {158-64}, abstract = {

OBJECTIVE: CD14 is a glycosylphosphotidylinositol-anchored membrane glycoprotein expressed on neutrophils and monocytes/macrophages that also circulates as a soluble form (sCD14). Despite the well-recognized role of CD14 in inflammation, relatively little is known about the genetic determinants of sCD14 or the relationship of sCD14 to vascular- and aging-related phenotypes.

METHODS AND RESULTS: We measured baseline levels of sCD14 in >5000 European-American and black adults aged 65 years and older from the Cardiovascular Health Study, who were well characterized at baseline for atherosclerotic risk factors and subclinical cardiovascular disease, and who have been followed for clinical cardiovascular disease and mortality outcomes up to 20 years. At baseline, sCD14 generally showed strong positive correlations with traditional cardio-metabolic risk factors and with subclinical measures of vascular disease such as carotid wall thickness and ankle-brachial index (independently of traditional cardiovascular disease risk factors), and was also inversely correlated with body mass index. In genomewide association analyses of sCD14, we (1) confirmed the importance of the CD14 locus on chromosome 5q21 in European-American; (2) identified a novel African ancestry-specific allele of CD14 associated with lower sCD14 in blacks; and (3) identified a putative novel association in European-American of a nonsynonymous variant of PIGC, which encodes an enzyme required for the first step in glycosylphosphotidylinositol anchor biosynthesis. Finally, we show that, like other acute phase inflammatory biomarkers, sCD14 predicts incident cardiovascular disease, and strongly and independently predicts all-cause mortality in older adults.

CONCLUSIONS: CD14 independently predicts risk mortality in older adults.

}, keywords = {African Americans, Age Factors, Aged, Biomarkers, Cardiovascular Diseases, Chromosomes, Human, Pair 5, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Haplotypes, Hexosyltransferases, Humans, Incidence, Inflammation Mediators, Linear Models, Lipopolysaccharide Receptors, Logistic Models, Male, Membrane Proteins, Multivariate Analysis, Phenotype, Polymorphism, Single Nucleotide, Principal Component Analysis, Prognosis, Proportional Hazards Models, Prospective Studies, Risk Assessment, Risk Factors, Time Factors, United States}, issn = {1524-4636}, doi = {10.1161/ATVBAHA.112.300421}, author = {Reiner, Alex P and Lange, Ethan M and Jenny, Nancy S and Chaves, Paulo H M and Ellis, Jaclyn and Li, Jin and Walston, Jeremy and Lange, Leslie A and Cushman, Mary and Tracy, Russell P} } @article {6559, title = {Glycated hemoglobin measurement and prediction of cardiovascular disease.}, journal = {JAMA}, volume = {311}, year = {2014}, month = {2014 Mar 26}, pages = {1225-33}, abstract = {

IMPORTANCE: The value of measuring levels of glycated hemoglobin (HbA1c) for the prediction of first cardiovascular events is uncertain.

OBJECTIVE: To determine whether adding information on HbA1c values to conventional cardiovascular risk factors is associated with improvement in prediction of cardiovascular disease (CVD) risk.

DESIGN, SETTING, AND PARTICIPANTS: Analysis of individual-participant data available from 73 prospective studies involving 294,998 participants without a known history of diabetes mellitus or CVD at the baseline assessment.

MAIN OUTCOMES AND MEASURES: Measures of risk discrimination for CVD outcomes (eg, C-index) and reclassification (eg, net reclassification improvement) of participants across predicted 10-year risk categories of low (<5\%), intermediate (5\% to <7.5\%), and high (>= 7.5\%) risk.

RESULTS: During a median follow-up of 9.9 (interquartile range, 7.6-13.2) years, 20,840 incident fatal and nonfatal CVD outcomes (13,237 coronary heart disease and 7603 stroke outcomes) were recorded. In analyses adjusted for several conventional cardiovascular risk factors, there was an approximately J-shaped association between HbA1c values and CVD risk. The association between HbA1c values and CVD risk changed only slightly after adjustment for total cholesterol and triglyceride concentrations or estimated glomerular filtration rate, but this association attenuated somewhat after adjustment for concentrations of high-density lipoprotein cholesterol and C-reactive protein. The C-index for a CVD risk prediction model containing conventional cardiovascular risk factors alone was 0.7434 (95\% CI, 0.7350 to 0.7517). The addition of information on HbA1c was associated with a C-index change of 0.0018 (0.0003 to 0.0033) and a net reclassification improvement of 0.42 (-0.63 to 1.48) for the categories of predicted 10-year CVD risk. The improvement provided by HbA1c assessment in prediction of CVD risk was equal to or better than estimated improvements for measurement of fasting, random, or postload plasma glucose levels.

CONCLUSIONS AND RELEVANCE: In a study of individuals without known CVD or diabetes, additional assessment of HbA1c values in the context of CVD risk assessment provided little incremental benefit for prediction of CVD risk.

}, keywords = {Aged, C-Reactive Protein, Cholesterol, HDL, Coronary Disease, Diabetes Mellitus, Female, Glycated Hemoglobin A, Humans, Male, Middle Aged, Predictive Value of Tests, Prospective Studies, Risk Assessment, Stroke}, issn = {1538-3598}, doi = {10.1001/jama.2014.1873}, author = {Di Angelantonio, Emanuele and Gao, Pei and Khan, Hassan and Butterworth, Adam S and Wormser, David and Kaptoge, Stephen and Kondapally Seshasai, Sreenivasa Rao and Thompson, Alex and Sarwar, Nadeem and Willeit, Peter and Ridker, Paul M and Barr, Elizabeth L M and Khaw, Kay-Tee and Psaty, Bruce M and Brenner, Hermann and Balkau, Beverley and Dekker, Jacqueline M and Lawlor, Debbie A and Daimon, Makoto and Willeit, Johann and Nj{\o}lstad, Inger and Nissinen, Aulikki and Brunner, Eric J and Kuller, Lewis H and Price, Jackie F and Sundstr{\"o}m, Johan and Knuiman, Matthew W and Feskens, Edith J M and Verschuren, W M M and Wald, Nicholas and Bakker, Stephan J L and Whincup, Peter H and Ford, Ian and Goldbourt, Uri and G{\'o}mez-de-la-C{\'a}mara, Agust{\'\i}n and Gallacher, John and Simons, Leon A and Rosengren, Annika and Sutherland, Susan E and Bj{\"o}rkelund, Cecilia and Blazer, Dan G and Wassertheil-Smoller, Sylvia and Onat, Altan and Mar{\'\i}n Iba{\~n}ez, Alejandro and Casiglia, Edoardo and Jukema, J Wouter and Simpson, Lara M and Giampaoli, Simona and Nordestgaard, B{\o}rge G and Selmer, Randi and Wennberg, Patrik and Kauhanen, Jussi and Salonen, Jukka T and Dankner, Rachel and Barrett-Connor, Elizabeth and Kavousi, Maryam and Gudnason, Vilmundur and Evans, Denis and Wallace, Robert B and Cushman, Mary and D{\textquoteright}Agostino, Ralph B and Umans, Jason G and Kiyohara, Yutaka and Nakagawa, Hidaeki and Sato, Shinichi and Gillum, Richard F and Folsom, Aaron R and van der Schouw, Yvonne T and Moons, Karel G and Griffin, Simon J and Sattar, Naveed and Wareham, Nicholas J and Selvin, Elizabeth and Thompson, Simon G and Danesh, John} } @article {6568, title = {Mendelian randomization of blood lipids for coronary heart disease.}, journal = {Eur Heart J}, volume = {36}, year = {2015}, month = {2015 Mar 01}, pages = {539-50}, abstract = {

AIMS: To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization.

METHODS AND RESULTS: We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 {\texttimes} 10(-6)); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P <= 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95\% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95\% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95\% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95\% CI: 1.24, 2.11 and 1.61; 95\% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95\% CI: 0.59, 1.75).

CONCLUSION: The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.

}, keywords = {Case-Control Studies, Cholesterol, HDL, Coronary Artery Disease, Female, Gene Frequency, Genotype, Genotyping Techniques, Humans, Male, Mendelian Randomization Analysis, Middle Aged, Polymorphism, Single Nucleotide, Risk Assessment, Triglycerides}, issn = {1522-9645}, doi = {10.1093/eurheartj/eht571}, author = {Holmes, Michael V and Asselbergs, Folkert W and Palmer, Tom M and Drenos, Fotios and Lanktree, Matthew B and Nelson, Christopher P and Dale, Caroline E and Padmanabhan, Sandosh and Finan, Chris and Swerdlow, Daniel I and Tragante, Vinicius and van Iperen, Erik P A and Sivapalaratnam, Suthesh and Shah, Sonia and Elbers, Clara C and Shah, Tina and Engmann, Jorgen and Giambartolomei, Claudia and White, Jon and Zabaneh, Delilah and Sofat, Reecha and McLachlan, Stela and Doevendans, Pieter A and Balmforth, Anthony J and Hall, Alistair S and North, Kari E and Almoguera, Berta and Hoogeveen, Ron C and Cushman, Mary and Fornage, Myriam and Patel, Sanjay R and Redline, Susan and Siscovick, David S and Tsai, Michael Y and Karczewski, Konrad J and Hofker, Marten H and Verschuren, W Monique and Bots, Michiel L and van der Schouw, Yvonne T and Melander, Olle and Dominiczak, Anna F and Morris, Richard and Ben-Shlomo, Yoav and Price, Jackie and Kumari, Meena and Baumert, Jens and Peters, Annette and Thorand, Barbara and Koenig, Wolfgang and Gaunt, Tom R and Humphries, Steve E and Clarke, Robert and Watkins, Hugh and Farrall, Martin and Wilson, James G and Rich, Stephen S and de Bakker, Paul I W and Lange, Leslie A and Davey Smith, George and Reiner, Alex P and Talmud, Philippa J and Kivimaki, Mika and Lawlor, Debbie A and Dudbridge, Frank and Samani, Nilesh J and Keating, Brendan J and Hingorani, Aroon D and Casas, Juan P} } @article {6809, title = {Plasma Levels of Soluble Interleukin-2 Receptor α: Associations With Clinical Cardiovascular Events and Genome-Wide Association Scan.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {35}, year = {2015}, month = {2015 Oct}, pages = {2246-53}, abstract = {

OBJECTIVE: Interleukin (IL) -2 receptor subunit α regulates lymphocyte activation, which plays an important role in atherosclerosis. Associations between soluble IL-2Rα (sIL-2Rα) and cardiovascular disease (CVD) have not been widely studied and little is known about the genetic determinants of sIL-2Rα levels.

APPROACH AND RESULTS: We measured baseline levels of sIL-2Rα in 4408 European American (EA) and 766 African American (AA) adults from the Cardiovascular Health Study (CHS) and examined associations with baseline CVD risk factors, subclinical CVD, and incident CVD events. We also performed a genome-wide association study for sIL-2Rα in CHS (2964 EAs and 683 AAs) and further combined CHS EA results with those from two other EA cohorts in a meta-analysis (n=4464 EAs). In age, sex- and race- adjusted models, sIL-2Rα was positively associated with current smoking, type 2 diabetes mellitus, hypertension, insulin, waist circumference, C-reactive protein, IL-6, fibrinogen, internal carotid wall thickness, all-cause mortality, CVD mortality, and incident CVD, stroke, and heart failure. When adjusted for baseline CVD risk factors and subclinical CVD, associations with all-cause mortality, CVD mortality, and heart failure remained significant in both EAs and AAs. In the EA genome-wide association study analysis, we observed 52 single-nucleotide polymorphisms in the chromosome 10p15-14 region, which contains IL2RA, IL15RA, and RMB17, that reached genome-wide significance (P<5{\texttimes}10(-8)). The most significant single-nucleotide polymorphism was rs7911500 (P=1.31{\texttimes}10(-75)). The EA meta-analysis results were highly consistent with CHS-only results. No single-nucleotide polymorphisms reached statistical significance in the AAs.

CONCLUSIONS: These results support a role for sIL-2Rα in atherosclerosis and provide evidence for multiple-associated single-nucleotide polymorphisms at chromosome 10p15-14.

}, keywords = {Adult, African Americans, Age Distribution, Aged, Cardiovascular Diseases, Cohort Studies, Coronary Artery Disease, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Incidence, Interleukin-2 Receptor alpha Subunit, Kaplan-Meier Estimate, Male, Middle Aged, Polymorphism, Single Nucleotide, Proportional Hazards Models, Prospective Studies, Risk Assessment, Sex Distribution, Survival Analysis}, issn = {1524-4636}, doi = {10.1161/ATVBAHA.115.305289}, author = {Durda, Peter and Sabourin, Jeremy and Lange, Ethan M and Nalls, Mike A and Mychaleckyj, Josyf C and Jenny, Nancy Swords and Li, Jin and Walston, Jeremy and Harris, Tamara B and Psaty, Bruce M and Valdar, William and Liu, Yongmei and Cushman, Mary and Reiner, Alex P and Tracy, Russell P and Lange, Leslie A} } @article {6996, title = {Lipoprotein-Associated Phospholipase A2 and Incident Peripheral Arterial Disease in Older Adults: The Cardiovascular Health Study.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {36}, year = {2016}, month = {2016 Apr}, pages = {750-6}, abstract = {

OBJECTIVE: Although prior studies report a relationship between elevated lipoprotein-associated phospholipase A2 (Lp-PLA2) and incident cardiovascular disease, the prospective association of Lp-PLA2 with incident peripheral arterial disease (PAD) has not been studied. We investigated the association between Lp-PLA2 mass and activity and the risk of developing clinical PAD and low ankle-brachial index (ABI).

APPROACH AND RESULTS: Among Cardiovascular Health Study participants, a population-based cohort of 5888 adults aged >=65 years enrolled in 1989 to 1990, Lp-PLA2 mass and activity were measured in 4537 individuals without baseline PAD. Clinical PAD, defined as leg artery revascularization or diagnosed claudication, was ascertained through 2011. Incident low ABI, defined as ABI <0.9 and decline of >=0.15, was assessed among 3537 individuals who had an ABI >0.9 at baseline and a second ABI measurement 3 or 6 years later. Analyses were adjusted for demographics, cholesterol, smoking, comorbidities, and C-reactive protein. Each standard deviation increment in Lp-PLA2 mass (117 ng/mL) was associated with a higher risk of developing clinical PAD (hazard ratio 1.28; 95\% confidence interval 1.13, 1.45) and incident low ABI (odds ratio 1.16; 95\% confidence interval 1.00, 1.33). Results per standard deviation increment in Lp-PLA2 activity (13 nmol/min per mL) were similar for clinical PAD (hazard ratio 1.24; 95\% confidence interval 1.07, 1.44) and low ABI (odds ratio 1.28; 95\% confidence interval 1.09, 1.50).

CONCLUSIONS: Higher Lp-PLA2 mass and activity were associated with development of both incident clinical PAD and low ABI. Future studies are needed to determine whether pharmacological inhibition of Lp-PLA2 reduces the incidence of PAD.

}, keywords = {1-Alkyl-2-acetylglycerophosphocholine Esterase, Age Factors, Aged, Aging, Ankle Brachial Index, Biomarkers, Chi-Square Distribution, Female, Humans, Incidence, Inflammation Mediators, Logistic Models, Male, Odds Ratio, Peripheral Arterial Disease, Prognosis, Proportional Hazards Models, Risk Assessment, Risk Factors, Time Factors, United States, Up-Regulation}, issn = {1524-4636}, doi = {10.1161/ATVBAHA.115.306647}, author = {Garg, Parveen K and Arnold, Alice M and Hinckley Stukovsky, Karen D and Koro, Carol and Jenny, Nancy S and Mukamal, Kenneth J and Criqui, Michael H and Furberg, Curt D and Newman, Anne B and Cushman, Mary} } @article {8567, title = {Natriuretic peptides and integrated risk assessment for cardiovascular disease: an individual-participant-data meta-analysis.}, journal = {Lancet Diabetes Endocrinol}, volume = {4}, year = {2016}, month = {2016 10}, pages = {840-9}, abstract = {

BACKGROUND: Guidelines for primary prevention of cardiovascular diseases focus on prediction of coronary heart disease and stroke. We assessed whether or not measurement of N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentration could enable a more integrated approach than at present by predicting heart failure and enhancing coronary heart disease and stroke risk assessment.

METHODS: In this individual-participant-data meta-analysis, we generated and harmonised individual-participant data from relevant prospective studies via both de-novo NT-proBNP concentration measurement of stored samples and collection of data from studies identified through a systematic search of the literature (PubMed, Scientific Citation Index Expanded, and Embase) for articles published up to Sept 4, 2014, using search terms related to natriuretic peptide family members and the primary outcomes, with no language restrictions. We calculated risk ratios and measures of risk discrimination and reclassification across predicted 10 year risk categories (ie, <5\%, 5\% to <7{\textperiodcentered}5\%, and >=7{\textperiodcentered}5\%), adding assessment of NT-proBNP concentration to that of conventional risk factors (ie, age, sex, smoking status, systolic blood pressure, history of diabetes, and total and HDL cholesterol concentrations). Primary outcomes were the combination of coronary heart disease and stroke, and the combination of coronary heart disease, stroke, and heart failure.

FINDINGS: We recorded 5500 coronary heart disease, 4002 stroke, and 2212 heart failure outcomes among 95 617 participants without a history of cardiovascular disease in 40 prospective studies. Risk ratios (for a comparison of the top third vs bottom third of NT-proBNP concentrations, adjusted for conventional risk factors) were 1{\textperiodcentered}76 (95\% CI 1{\textperiodcentered}56-1{\textperiodcentered}98) for the combination of coronary heart disease and stroke and 2{\textperiodcentered}00 (1{\textperiodcentered}77-2{\textperiodcentered}26) for the combination of coronary heart disease, stroke, and heart failure. Addition of information about NT-proBNP concentration to a model containing conventional risk factors was associated with a C-index increase of 0{\textperiodcentered}012 (0{\textperiodcentered}010-0{\textperiodcentered}014) and a net reclassification improvement of 0{\textperiodcentered}027 (0{\textperiodcentered}019-0{\textperiodcentered}036) for the combination of coronary heart disease and stroke and a C-index increase of 0{\textperiodcentered}019 (0{\textperiodcentered}016-0{\textperiodcentered}022) and a net reclassification improvement of 0{\textperiodcentered}028 (0{\textperiodcentered}019-0{\textperiodcentered}038) for the combination of coronary heart disease, stroke, and heart failure.

INTERPRETATION: In people without baseline cardiovascular disease, NT-proBNP concentration assessment strongly predicted first-onset heart failure and augmented coronary heart disease and stroke prediction, suggesting that NT-proBNP concentration assessment could be used to integrate heart failure into cardiovascular disease primary prevention.

FUNDING: British Heart Foundation, Austrian Science Fund, UK Medical Research Council, National Institute for Health Research, European Research Council, and European Commission Framework Programme 7.

}, keywords = {Aged, Biomarkers, Cardiovascular Diseases, Female, Humans, Male, Middle Aged, Natriuretic Peptide, Brain, Peptide Fragments, Prospective Studies, Risk Assessment}, issn = {2213-8595}, doi = {10.1016/S2213-8587(16)30196-6}, author = {Willeit, Peter and Kaptoge, Stephen and Welsh, Paul and Butterworth, Adam and Chowdhury, Rajiv and Spackman, Sarah and Pennells, Lisa and Gao, Pei and Burgess, Stephen and Freitag, Daniel and Sweeting, Michael and Wood, Angela and Cook, Nancy and Judd, Suzanne and Trompet, Stella and Nambi, Vijay and Olsen, Michael and Everett, Brendan and Kee, Frank and Arnl{\"o}v, Johan and Salomaa, Veikko and Levy, Daniel and Kauhanen, Jussi and Laukkanen, Jari and Kavousi, Maryam and Ninomiya, Toshiharu and Casas, Juan-Pablo and Daniels, Lori and Lind, Lars and Kistorp, Caroline and Rosenberg, Jens and Mueller, Thomas and Rubattu, Speranza and Panagiotakos, Demosthenes and Franco, Oscar and de Lemos, James and Luchner, Andreas and Kizer, Jorge and Kiechl, Stefan and Salonen, Jukka and Goya Wannamethee, S and de Boer, Rudolf and Nordestgaard, B{\o}rge and Andersson, Jonas and J{\o}rgensen, Torben and Melander, Olle and Ballantyne, Christie and DeFilippi, Christopher and Ridker, Paul and Cushman, Mary and Rosamond, Wayne and Thompson, Simon and Gudnason, Vilmundur and Sattar, Naveed and Danesh, John and Di Angelantonio, Emanuele} } @article {8626, title = {Performance of the Pooled Cohort Equations to Estimate Atherosclerotic Cardiovascular Disease Risk by Body Mass Index.}, journal = {JAMA Netw Open}, volume = {3}, year = {2020}, month = {2020 10 01}, pages = {e2023242}, abstract = {

Importance: Obesity is a global health challenge and a risk factor for atherosclerotic cardiovascular disease (ASVCD). Performance of the pooled cohort equations (PCE) for ASCVD risk by body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) is unknown.

Objective: To assess performance of the PCE across clinical BMI categories.

Design, Setting, and Participants: This cohort study used pooled individual-level data from 8 community-based, prospective, longitudinal cohort studies with 10-year ASCVD event follow-up from 1996 to 2016. We included all adults ages 40 to 79 years without baseline ASCVD or statin use, resulting in a sample size of 37 311 participants. Data were analyzed from August 2017 to July 2020.

Exposures: Participant BMI category: underweight (<18.5), normal weight (18.5 to <25), overweight (25 to <30), mild obesity (30 to <35), and moderate to severe obesity (>=35).

Main Outcomes and Measures: Discrimination (Harrell C statistic) and calibration (Nam-D{\textquoteright}Agostino χ2 goodness-of-fit test) of the PCE across BMI categories. Improvement in discrimination and net reclassification with addition of BMI, waist circumference, and high-sensitivity C-reactive protein (hsCRP) to the PCE.

Results: Among 37 311 participants (mean [SD] age, 58.6 [11.8] years; 21 897 [58.7\%] women), 380 604 person-years of follow-up were conducted. Mean (SD) baseline BMI was 29.0 (6.2), and 360 individuals (1.0\%) were in the underweight category, 9937 individuals (26.6\%) were in the normal weight category, 13 601 individuals (36.4\%) were in the overweight category, 7783 individuals (20.9\%) were in the mild obesity category, and 5630 individuals (15.1\%) were in the moderate to severe obesity category. Median (interquartile range [IQR]) 10-year estimated ASCVD risk was 7.1\% (2.5\%-15.4\%), and 3709 individuals (9.9\%) developed ASCVD over a median (IQR) 10.8 [8.5-12.6] years. The PCE overestimated ASCVD risk in the overall cohort (estimated/observed [E/O] risk ratio, 1.22; 95\% CI, 1.18-1.26) and across all BMI categories except the underweight category. Calibration was better near the clinical decision threshold in all BMI groups but worse among individuals with moderate or severe obesity (E/O risk ratio, 1.36; 95\% CI, 1.25-1.47) and among those with the highest estimated ASCVD risk >=20\%. The PCE C statistic overall was 0.760 (95\% CI, 0.753-0.767), with lower discrimination in the moderate or severe obesity group (C statistic, 0.742; 95\% CI, 0.721-0.763) compared with the normal-range BMI group (C statistic, 0.785; 95\% CI, 0.772-0.798). Waist circumference (hazard ratio, 1.07 per 1-SD increase; 95\% CI, 1.03-1.11) and hsCRP (hazard ratio, 1.07 per 1-SD increase; 95\% CI, 1.05-1.09), but not BMI, were associated with increased ASCVD risk when added to the PCE. However, these factors did not improve model performance (C statistic, 0.760; 95\% CI, 0.753-0.767) with or without added metrics.

Conclusions and Relevance: These findings suggest that the PCE had acceptable model discrimination and were well calibrated at clinical decision thresholds but overestimated risk of ASCVD for individuals in overweight and obese categories, particularly individuals with high estimated risk. Incorporation of the usual clinical measures of obesity did not improve risk estimation of the PCE. Future research is needed to determine whether incorporation of alternative high-risk obesity markers (eg, weight trajectory or measures of visceral or ectopic fat) into the PCE may improve risk prediction.

}, keywords = {Adult, Aged, Body Mass Index, Cardiovascular Diseases, Cohort Studies, Correlation of Data, Female, Humans, Longitudinal Studies, Male, Middle Aged, Proportional Hazards Models, Prospective Studies, Risk Assessment, Risk Factors}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2020.23242}, author = {Khera, Rohan and Pandey, Ambarish and Ayers, Colby R and Carnethon, Mercedes R and Greenland, Philip and Ndumele, Chiadi E and Nambi, Vijay and Seliger, Stephen L and Chaves, Paulo H M and Safford, Monika M and Cushman, Mary and Xanthakis, Vanessa and Vasan, Ramachandran S and Mentz, Robert J and Correa, Adolfo and Lloyd-Jones, Donald M and Berry, Jarett D and de Lemos, James A and Neeland, Ian J} }