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1.  Assessing Risk Prediction Models Using Individual Participant Data From Multiple Studies 
Pennells, Lisa | Kaptoge, Stephen | White, Ian R. | Thompson, Simon G. | Wood, Angela M. | Tipping, Robert W. | Folsom, Aaron R. | Couper, David J. | Ballantyne, Christie M. | Coresh, Josef | Goya Wannamethee, S. | Morris, Richard W. | Kiechl, Stefan | Willeit, Johann | Willeit, Peter | Schett, Georg | Ebrahim, Shah | Lawlor, Debbie A. | Yarnell, John W. | Gallacher, John | Cushman, Mary | Psaty, Bruce M. | Tracy, Russ | Tybjærg-Hansen, Anne | Price, Jackie F. | Lee, Amanda J. | McLachlan, Stela | Khaw, Kay-Tee | Wareham, Nicholas J. | Brenner, Hermann | Schöttker, Ben | Müller, Heiko | Jansson, Jan-Håkan | Wennberg, Patrik | Salomaa, Veikko | Harald, Kennet | Jousilahti, Pekka | Vartiainen, Erkki | Woodward, Mark | D'Agostino, Ralph B. | Bladbjerg, Else-Marie | Jørgensen, Torben | Kiyohara, Yutaka | Arima, Hisatomi | Doi, Yasufumi | Ninomiya, Toshiharu | Dekker, Jacqueline M. | Nijpels, Giel | Stehouwer, Coen D. A. | Kauhanen, Jussi | Salonen, Jukka T. | Meade, Tom W. | Cooper, Jackie A. | Cushman, Mary | Folsom, Aaron R. | Psaty, Bruce M. | Shea, Steven | Döring, Angela | Kuller, Lewis H. | Grandits, Greg | Gillum, Richard F. | Mussolino, Michael | Rimm, Eric B. | Hankinson, Sue E. | Manson, JoAnn E. | Pai, Jennifer K. | Kirkland, Susan | Shaffer, Jonathan A. | Shimbo, Daichi | Bakker, Stephan J. L. | Gansevoort, Ron T. | Hillege, Hans L. | Amouyel, Philippe | Arveiler, Dominique | Evans, Alun | Ferrières, Jean | Sattar, Naveed | Westendorp, Rudi G. | Buckley, Brendan M. | Cantin, Bernard | Lamarche, Benoît | Barrett-Connor, Elizabeth | Wingard, Deborah L. | Bettencourt, Richele | Gudnason, Vilmundur | Aspelund, Thor | Sigurdsson, Gunnar | Thorsson, Bolli | Kavousi, Maryam | Witteman, Jacqueline C. | Hofman, Albert | Franco, Oscar H. | Howard, Barbara V. | Zhang, Ying | Best, Lyle | Umans, Jason G. | Onat, Altan | Sundström, Johan | Michael Gaziano, J. | Stampfer, Meir | Ridker, Paul M. | Michael Gaziano, J. | Ridker, Paul M. | Marmot, Michael | Clarke, Robert | Collins, Rory | Fletcher, Astrid | Brunner, Eric | Shipley, Martin | Kivimäki, Mika | Ridker, Paul M. | Buring, Julie | Cook, Nancy | Ford, Ian | Shepherd, James | Cobbe, Stuart M. | Robertson, Michele | Walker, Matthew | Watson, Sarah | Alexander, Myriam | Butterworth, Adam S. | Angelantonio, Emanuele Di | Gao, Pei | Haycock, Philip | Kaptoge, Stephen | Pennells, Lisa | Thompson, Simon G. | Walker, Matthew | Watson, Sarah | White, Ian R. | Wood, Angela M. | Wormser, David | Danesh, John
American Journal of Epidemiology  2013;179(5):621-632.
Individual participant time-to-event data from multiple prospective epidemiologic studies enable detailed investigation into the predictive ability of risk models. Here we address the challenges in appropriately combining such information across studies. Methods are exemplified by analyses of log C-reactive protein and conventional risk factors for coronary heart disease in the Emerging Risk Factors Collaboration, a collation of individual data from multiple prospective studies with an average follow-up duration of 9.8 years (dates varied). We derive risk prediction models using Cox proportional hazards regression analysis stratified by study and obtain estimates of risk discrimination, Harrell's concordance index, and Royston's discrimination measure within each study; we then combine the estimates across studies using a weighted meta-analysis. Various weighting approaches are compared and lead us to recommend using the number of events in each study. We also discuss the calculation of measures of reclassification for multiple studies. We further show that comparison of differences in predictive ability across subgroups should be based only on within-study information and that combining measures of risk discrimination from case-control studies and prospective studies is problematic. The concordance index and discrimination measure gave qualitatively similar results throughout. While the concordance index was very heterogeneous between studies, principally because of differing age ranges, the increments in the concordance index from adding log C-reactive protein to conventional risk factors were more homogeneous.
doi:10.1093/aje/kwt298
PMCID: PMC3927974  PMID: 24366051
C index; coronary heart disease; D measure; individual participant data; inverse variance; meta-analysis; risk prediction; weighting
2.  Lipoprotein-associated phospholipase A2 and Risk of Dementia in the Cardiovascular Health Study 
Atherosclerosis  2014;235(2):384-391.
Objective
To evaluate associations between Lipoprotein-associated phospholipase A2 (Lp-PLA2) mass and activity with risk of dementia and its subtypes.
Methods
Analysis were completed on 3,320 participants of the Cardiovascular Health Study (CHS), a population-based longitudinal study of community-dwelling adults age ≥ 65 years followed for an average of 5.4 years. Baseline serum Lp-PLA2 mass was measured using a sandwich enzyme immunoassay and Lp-PLA2 activity utilized a tritiated-platelet activating factor activity assay. Cox proportional hazards regression assessed the relative risk of incident dementia with higher baseline Lp-PLA2 adjusting for demographics, cardiovascular disease (CVD) and risk factors, inflammation markers and apolipoprotein E (APOE) genotype.
Results
Each standard deviation higher Lp-PLA2 mass and activity were related to increased risk of dementia (fully adjusted HR:1.11 per SD, 95% CI:1.00-1.24 for mass; HR:1.12 per SD, 95% CI:1.00-1.26 for activity). Persons in the highest quartile of Lp-PLA2 mass were 50% more likely to develop dementia than those in the lowest quartile in adjusted models (HR: 1.49; 95% CI: 1.08-2.06). Among dementia subtypes, the risk of AD was increased two-fold in the highest compared to lowest quartile of Lp-PLA2 mass (adjusted HR:1.98, 95% CI:1.22-3.21). Results were attenuated in models of mixed dementia and VaD. Lp-PLA2 activity also doubled the risk of mixed dementia in the highest compared to lowest quartile (HR:2.21, 95% CI:1.12-4.373).
Interpretation
These data support Lp-PLA2 as a risk factor for dementia independent of CVD and its risk factors. Further study is required to clarify the role of Lp-PLA2-related mechanisms in dementia subtypes.
doi:10.1016/j.atherosclerosis.2014.04.032
PMCID: PMC4096578  PMID: 24929287
Lp-PLA2; dementia; Alzheimer’s disease; cardiovascular risk factors
3.  Racial Differences in the Association of Insulin Resistance with Stroke Risk: The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study 
Background and Purpose
Insulin resistance is associated with increased stroke risk, but the effect has not been adequately examined separately in white and black populations.
Methods
The association of baseline insulin resistance with risk of cerebral infarction (CI) and intracerebral hemorrhage (ICH) was assessed in 12,366 white and 6,782 black participants from the REGARDS cohort, recruited between 2003 and 2007 and followed an average of 5.7 years. Insulin resistance was measured with the homeostasis model assessment (HOMA-IR).
Results
There were 364 incident CI and 41 incident ICH events. The risk for CI increased with the log of insulin resistance in whites (HRln(IR) = 1.17; 95% CI: 1.00 – 1.38), but was largely attenuated by adjustment for stroke risk factors (HRln(IR) = 1.05; 95% CI: 0.88 – 1.26). There was no association in blacks (HRln(IR) = 1.01; 95% CI: 0.81 – 1.25). After adjustment for demographic factors and risk factors, there was a significant difference by race in the association of insulin resistance with risk of ICH (p = 0.07), with a decrease in the risk of ICH in whites (HRln(IR) = 0.61; 95% CI: 0.35 – 1.04) but a non-significant increase for blacks (HRln(IR) = 1.20; 95% CI: 0.60 – 2.39).
Conclusion
These data support the growing evidence that insulin resistance may play a more important role in stroke risk among white than black individuals, and suggest a potentially discordant relationship of insulin resistance on CI and ICH among whites.
doi:10.1161/STROKEAHA.114.005306
PMCID: PMC4430474  PMID: 24968932
4.  THE ASSOCIATIONS OF ADIPOKINES WITH SELECTED MARKERS OF THE RENIN-ANGIOTENSINOGEN-ALDOSTERONE SYSTEM: THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS 
Journal of human hypertension  2014;29(2):127-133.
Among obese individuals, increased sympathetic nervous system activity results in increased renin and aldosterone production, as well as renal tubular sodium reabsorption. This study determined the associations between adipokines and selected measures of the reninangiotensinogen-aldosterone system (RAAS). The sample was 1,970 men and women from the Multi-Ethnic Study of Atherosclerosis who were free of clinical cardiovascular disease at baseline and had blood assayed for adiponectin, leptin, plasma renin activity (PRA) and aldosterone. The mean age was 64.7 years and 50% were female. The mean (SD) PRA and aldosterone were 1.45 (0.56) ng/ml and 150.1 (130.5) pg/ml, respectively. After multivariable adjustment, a 1-SD increment of leptin was associated with a 0.55 ng/ml higher PRA and 8.4 pg/ml higher aldosterone (p < 0.01 for both). Although adiponectin was not significantly associated with PRA levels, the same increment in this adipokine was associated with lower aldosterone levels (−5.5 pg/ml, p = 0.01). Notably, the associations between aldosterone and both leptin and adiponectin were not materially changed with additional adjustment for PRA. Exclusion of those taking anti-hypertensive medications modestly attenuated the associations. The associations between leptin and both PRA and aldosterone were not different by gender but were significantly stronger among non-Hispanic Whites and Chinese Americans than African and Hispanic Americans (p < 0.01). The findings suggest that both adiponectin and leptin may relevant to blood pressure regulation via the RAAS, that the associations appear to be robust to anti-hypertension medication use and that the associations are likely different by ethnicity.
doi:10.1038/jhh.2014.40
PMCID: PMC4265023  PMID: 24919752
Adipokines; Renin; Aldosterone; Ethnicity
5.  Association of Subsyndromal and Depressive Symptoms with Inflammatory Markers among different Ethnic groups: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Journal of affective disorders  2014;164:165-170.
Objective
Depressive symptoms are associated with inflammation yet the association between inflammation and different levels of depression remains unclear. Therefore, we studied the association of subsyndromal and depressive symptoms with inflammatory markers in a large multi-ethnic cohort.
Methods
C-reactive protein (CRP) (n=6,269), interleukin-6 (IL-6) (n=6,135) and tumor necrosis factor-alpha (TNF-α) (n=1,830) were measured in selected participants from the Multi-Ethnic Study of Atherosclerosis (MESA). Subsyndromal depressive symptoms were defined as a CES-D value from 8 to 15, depressive symptoms as a CES-D≥16 and normal as a CES-D≤7. Depressive states (subsyndromal and depressed) were entered into multivariable linear regression models incrementally adjusting for demographic, behavioral, biologic and comorbidities.
Results
Among 6,289 participants not taking antidepressants and free from CVD, the mean age was 62.2, while 52% were women, 36.4% were Caucasian, 28.9% African-American, 22.3% Hispanics and 12.4% Chinese-American. Of the total, 24.2% had subsyndromal depression and 11.8% had depressive symptoms. Compared to the non-depressed group and after controlling for demographics, there was no association between both subsyndromal and depressive symptoms with logCRP(β=−0.01, p=0.80 and β=−0.05, p=0.25; respectively), logIL-6(β=0.01, p=0.71 and β=−0.04, p=0.07; respectively) and logTNF-α(β=−0.03, p=0.29 and β=0.06, p=0.18; respectively). Moreover, fully adjusted models showed no significant associations for logIL-6 and logTNF-α and the different depressive categories. However, with full adjustment, we found a significant inverse association between depressive symptoms and lnCRP(β=−0.10; p=0.01) that was not present for subsyndromal depression (β=−0.05; p=0.11).
Conclusion
Among participants not taking anti-depressants, subsyndromal depression is not associated with inflammation. However, depressive symptoms measured by CES-D≥16 are associated with a lower inflammation (CRP).
doi:10.1016/j.jad.2014.04.018
PMCID: PMC4079665  PMID: 24856570
subsyndromal depression; inflammation; cardiovascular disease; depressive states
6.  A genetic association study of D-dimer levels with 50K SNPs from a candidate gene chip in four ethnic groups 
Thrombosis research  2014;134(2):462-467.
Introduction
D-dimer, a fibrin degradation product, is related to risk of cardiovascular disease and venous thromboembolism. Genetic determinants of D-dimer are not well characterized; notably, few data have been reported for African American (AA), Asian, and Hispanic populations.
Materials and Methods
We conducted a large-scale candidate gene association study to identify variants in genes associated with D-dimer levels in multi-ethnic populations. Four cohorts, comprising 6,848 European Americans (EAs), 2,192 AAs, 670 Asians, and 1,286 Hispanics in the NHLBI Candidate Gene Association Resource (CARe) consortium, were assembled. Approximately 50,000 genotyped SNPs in 2,000 cardiovascular disease gene loci were analyzed by linear regression, adjusting for age, sex, study site, and principal components in each cohort and ethnic group. Results across studies were combined within each ethnic group by meta-analysis.
Results
Twelve SNPs in coagulation factor V (F5) and 3 SNPs in the fibrinogen alpha chain (FGA) were significantly associated with D-dimer level in EAs with p < 2.0×10−6. The signal for the most associated SNP in F5 (rs6025, F5 Leiden) was replicated in Hispanics (p = 0.023), while that for the top functional SNP in FGA (rs6050) was replicated in AAs (p = 0.006). No additional SNPs were significantly associated with D-dimer.
Conclusions
Our study replicated previously reported associations of D-dimer with SNPs in F5 (F5-Leiden) and FGA in EAs; we demonstrated replication of the association of D-dimer with FGA rs6050 in AAs and the F5-Leiden variant in Hispanics.
doi:10.1016/j.thromres.2014.05.018
PMCID: PMC4111961  PMID: 24908450
D-dimer; genetic association study; CARe consortium; single nucleotide polymorphisms
7.  Metabolic Syndrome, C-Reactive Protein, and Mortality in U.S. Blacks and Whites: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study 
Diabetes Care  2014;37(8):2284-2290.
OBJECTIVE
We evaluate associations of metabolic syndrome (MetS), C-reactive protein (CRP), and a CRP-incorporated definition of MetS (CRPMetS) with risk of all-cause mortality in a biracial population.
RESEARCH DESIGN AND METHODS
We studied 23,998 participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort, an observational study of black and white adults ≥45 years old across the U.S. Elevated CRP was defined as ≥3 mg/L and MetS by the revised Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III; ATP III) criteria (three of five components). CRPMetS was defined as presence of three out of six components, with elevated CRP added to ATP III criteria as a sixth component. Cox models were used to calculate hazard ratios (HRs) for all-cause mortality, and population attributable risk (PAR) was calculated. Stratified analyses based on race and diabetes status were performed.
RESULTS
There were 9,741 participants (41%) with MetS and 12,179 (51%) with CRPMetS at baseline. Over 4.8 years of follow-up, 2,050 participants died. After adjustment for multiple confounders, MetS, elevated CRP, and CRPMetS were each significantly associated with increased mortality risk (HRs 1.26 [95% CI 1.15–1.38], 1.55 [1.41–1.70], and 1.34 [1.22–1.48], respectively). The PAR was 9.5% for MetS, 18.1% for CRP, and 14.7% for CRPMetS. Associations of elevated CRP and of CRPMetS with mortality were significantly greater in whites than blacks, while no differences in associations were observed based on diabetes status.
CONCLUSIONS
By definition, CRPMetS identifies more people at risk than MetS but still maintains a similar mortality risk. Incorporating CRP into the definition for MetS may be useful in identifying additional high-risk populations to target for prevention.
doi:10.2337/dc13-2059
PMCID: PMC4113170  PMID: 24879838
8.  Assessing the Performance of the Framingham Stroke Risk Score in the REGARDS Cohort 
Background and Purpose
The most well-known stroke risk score is the Framingham Stroke Risk Score (FSRS), which was developed during the higher stroke risk period of the 1990’s, and has not been validated for blacks. We assessed the performance of the FSRS among participants in the Reasons for Geographic And Racial Differences in Stroke (REGARDS) study to determine whether it is useful in both blacks and whites.
Methods
Expected annualized stroke rates from the FSRS were compared to observed stroke rates overall and within strata defined by FSRS risk factors (age, sex, systolic blood pressure, use of antihypertensive medications, diabetes, smoking, atrial fibrillation, left ventricular hypertrophy and prevalent coronary heart disease).
Results
Among 27,748 participants stroke-free at baseline, 715 stroke events occurred over 5.6 years of follow-up. FSRS-estimated incidence rates of stroke were 1.6 times higher than observed for black men, 1.9 times higher for white men, 1.7 times higher for black women and 1.7 times higher for white women. This overestimation was consistent among most subgroups of FSRS factors, although the magnitude of overestimation varied by the risk factor assessed.
Conclusions
While higher FSRS was associated with higher stroke risk, the FSRS overestimated observed stroke rates in this study, particularly in certain subgroups. This may be due to temporal declines in stroke rates, secular trends in prevention treatments, or differences in populations studied. More accurate estimates of event rates are critical for planning research, including clinical trials, and targeting health-care efforts.
doi:10.1161/STROKEAHA.114.004915
PMCID: PMC4102650  PMID: 24736237
Framingham Stroke Risk Score; REGARDS
9.  N-terminal pro-B-type natriuretic peptide and stroke risk: the REasons for Geographic And Racial Differences in Stroke cohort 
Background and Purpose
Improved identification of those at risk of stroke might improve prevention. We evaluated the association of the cardiac function biomarker N-terminal pro-B-type natriuretic peptide (NT-proBNP) with stroke risk in the 30,239 black and white participants of the REasons for Geographic And Racial Differences in Stroke cohort.
Methods
With 5.4 years follow-up after enrollment in 2003–7, NT-proBNP was measured in baseline blood samples of 546 subjects with incident ischemic stroke and 956 without stroke.
Results
NT-proBNP was higher with older age and in those with heart disease, kidney disease, atrial fibrillation and lower low-density lipoprotein cholesterol. Adjusting for age, race, sex, income, education and traditional stroke risk factors there was an increased risk of stroke across quartiles of NT-proBNP; participants with NT-proBNP in the top versus the bottom quartile had a hazard ratio of 2.9 (95% CI 1.9–4.5). There was no impact of added adjustment for kidney function and heart failure. Among etiologic stroke subtypes, the association was largest for cardioembolic stroke, with a hazard ratio of 9.1 (95% CI 2.9–29.2). Associations did not differ by age, sex or race, or after excluding those with baseline heart failure or atrial fibrillation. Predicted stroke risk was more accurate in 27% of participants if NT-proBNP was considered after traditional stroke risk factors (p<0.001).
Conclusion
NT-proBNP was a major independent risk marker for stroke. Considering this and other data for stroke, coronary disease, and atrial fibrillation, clinical use of NT-proBNP measurement in primary prevention settings should be considered.
doi:10.1161/STROKEAHA.114.004712
PMCID: PMC4142424  PMID: 24757103
stroke; risk factor; natriuretic peptides
10.  Markers of Inflammation and Coagulation after Long-Term Exposure to Coarse Particulate Matter: A Cross-Sectional Analysis from the Multi-Ethnic Study of Atherosclerosis 
Environmental Health Perspectives  2015;123(6):541-548.
Background
Toxicological research suggests that coarse particles (PM10–2.5) are inflammatory, but responses are complex and may be best summarized by multiple inflammatory markers. Few human studies have investigated associations with PM10–2.5 and, of those, none have explored long-term exposures. Here we examine long-term associations with inflammation and coagulation in the Multi-Ethnic Study of Atherosclerosis.
Methods
Participants included 3,295 adults (45–84 years of age) from three metropolitan areas. Site-specific spatial models were used to estimate 5-year concentrations of PM10–2.5 mass and copper, zinc, phosphorus, silicon, and endotoxin found in PM10–2.5. Outcomes included interleukin-6, C-reactive protein, fibrinogen, total homocysteine, D-dimer, factor VIII, plasmin–antiplasmin complex, and inflammation and coagulation scores. We used multivariable regression with multiply imputed data to estimate associations while controlling for potential confounders, including co-pollutants such as fine particulate matter.
Results
Some limited evidence was found of relationships between inflammation and coagulation and PM10–2.5. Endotoxin was the PM10–2.5 component most strongly associated with inflammation, with an interquartile range (IQR) increase (0.08 EU/m3) associated with 0.15 (95% CI: 0.01, 0.28; p = 0.03) and 0.08 (95% CI: –0.07, 0.23; p = 0.28) higher inflammation scores before and after control for city, respectively. Copper was the component with the strongest association with coagulation, with a 4-ng/m3 increase associated with 0.19 (95% CI: 0.08, 0.30; p = 0.0008) and 0.12 (95% CI: –0.05, 0.30; p = 0.16) unit higher coagulation scores before and after city adjustment, respectively.
Conclusions
Our cross-sectional analysis provided some evidence that long-term PM10–2.5 exposure was associated with inflammation and coagulation, but associations were modest and depended on particle composition.
Citation
Adar SD, D’Souza J, Mendelsohn-Victor K, Jacobs DR Jr, Cushman M, Sheppard L, Thorne PS, Burke GL, Daviglus ML, Szpiro AA, Diez Roux AV, Kaufman JD, Larson TV. 2015. Markers of inflammation and coagulation after long-term exposure to coarse particulate matter: a cross-sectional analysis from the Multi-Ethnic Study of Atherosclerosis. Environ Health Perspect 123:541–548; http://dx.doi.org/10.1289/ehp.1308069
doi:10.1289/ehp.1308069
PMCID: PMC4455582  PMID: 25616153
11.  Genome-Wide Association Study for Circulating Tissue Plasminogen Activator (tPA) Levels and Functional Follow-up Implicates Endothelial STXBP5 and STX2 
Huang, Jie | Huffman, Jennifer E. | Yamkauchi, Munekazu | Trompet, Stella | Asselbergs, Folkert W. | Sabater-Lleal, Maria | Trégouët, David-Alexandre | Chen, Wei-Min | Smith, Nicholas L. | Kleber, Marcus E. | Shin, So-Youn | Becker, Diane M. | Tang, Weihong | Dehghan, Abbas | Johnson, Andrew D. | Truong, Vinh | Folkersen, Lasse | Yang, Qiong | Oudot-Mellakh, Tiphaine | Buckley, Brendan M. | Moore, Jason H. | Williams, Frances M.K. | Campbell, Harry | Silbernagel, Günther | Vitart, Veronique | Rudan, Igor | Tofler, Geoffrey H. | Navis, Gerjan J. | DeStefano, Anita | Wright, Alan F. | Chen, Ming-Huei | de Craen, Anton J.M. | Worrall, Bradford B. | Rudnicka, Alicja R. | Rumley, Ann | Bookman, Ebony B. | Psaty, Bruce M. | Chen, Fang | Keene, Keith L. | Franco, Oscar H. | Böhm, Bernhard O. | Uitterlinden, Andre G. | Carter, Angela M. | Jukema, J. Wouter | Sattar, Naveed | Bis, Joshua C. | Ikram, Mohammad A. | Sale, Michèle M. | McKnight, Barbara | Fornage, Myriam | Ford, Ian | Taylor, Kent | Slagboom, P. Eline | McArdle, Wendy L. | Hsu, Fang-Chi | Franco-Cereceda, Anders | Goodall, Alison H. | Yanek, Lisa R. | Furie, Karen L. | Cushman, Mary | Hofman, Albert | Witteman, Jacqueline CM. | Folsom, Aaron R. | Basu, Saonli | Matijevic, Nena | van Gilst, Wiek H. | Wilson, James F. | Westendorp, Rudi G.J. | Kathiresan, Sekar | Reilly, Muredach P. | Tracy, Russell P. | Polasek, Ozren | Winkelmann, Bernhard R. | Grant, Peter J. | Hillege, Hans L. | Cambien, Francois | Stott, David J. | Lowe, Gordon D. | Spector, Timothy D. | Meigs, James B. | Marz, Winfried | Eriksson, Per | Becker, Lewis C. | Morange, Pierre-Emmanuel | Soranzo, Nicole | Williams, Scott M. | Hayward, Caroline | van der Harst, Pim | Hamsten, Anders | Lowenstein, Charles J. | Strachan, David P. | O'Donnell, Christopher J.
Objective
Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for endogenous fibrinolysis. In some populations, elevated plasma levels of tPA have been associated with myocardial infarction and other cardiovascular diseases (CVD). We conducted a meta-analysis of genome-wide association studies (GWAS) to identify novel correlates of circulating levels of tPA.
Approach and Results
Fourteen cohort studies with tPA measures (N=26,929) contributed to the meta-analysis. Three loci were significantly associated with circulating tPA levels (P <5.0×10−8). The first locus is on 6q24.3, with the lead SNP (rs9399599, P=2.9×10−14) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739, P=1.3×10−9) is intronic to POLB and less than 200kb away from the tPA encoding gene PLAT. We identified a non-synonymous SNP (rs2020921) in modest LD with rs3136739 (r2 = 0.50) within exon 5 of PLAT (P=2.0×10−8). The third locus is on 12q24.33, with the lead SNP (rs7301826, P=1.0×10−9) within intron 7 of STX2. We further found evidence for association of lead SNPs in STXBP5 and STX2 with expression levels of the respective transcripts. In in vitro cell studies, silencing STXBP5 decreased release of tPA from vascular endothelial cells, while silencing of STX2 increased tPA release. Through an in-silico lookup, we found no associations of the three lead SNPs with coronary artery disease or stroke.
Conclusions
We identified three loci associated with circulating tPA levels, the PLAT region, STXBP5 and STX2. Our functional studies implicate a novel role for STXBP5 and STX2 in regulating tPA release.
doi:10.1161/ATVBAHA.113.302088
PMCID: PMC4009733  PMID: 24578379
tissue plasminogen activator; genome-wide association study; meta-analysis; cardiovascular disease risk; fibrinolysis; hemostasis
12.  Achievement of Optimal Medical Therapy Goals for US Adults with Coronary Artery Disease: Results from the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study 
Objective
In a non-clinical trial setting, to determine the proportion of individuals with coronary artery disease (CAD) with optimal risk factor levels based on the Clinical Outcomes Utilizing Revascularization and Aggressive DruG Evaluation (COURAGE) trial.
Background
In COURAGE, the addition of percutaneous coronary intervention (PCI) to optimal medical therapy did not reduce the risk of death or myocardial infarction in stable CAD patients but resulted in more revascularization procedures.
Methods
REGARDS is a national prospective cohort study of 30,239 African American and White community-dwelling individuals aged >45 years enrolled in 2003-7. We calculated the proportion of 3,167 participants with self-reported CAD meeting 7 risk factor goals based on COURAGE: 1) aspirin use, 2) systolic blood pressure <130 mmHg and diastolic blood pressure <85 mmHg (<80 mmHg if diabetic), 3) low density lipoprotein cholesterol <85 mg/dL, high density lipoprotein cholesterol >40 mg/dL, and triglycerides <150 mg/dL, 4) fasting glucose <126 mg/dL, 5) nonsmoking status, 6) body mass index <25 kg/m,2 and 7) exercise ≥4 days per week.
Results
The mean age of participants was 69±9 years, 33% were African American, and 35% were female. Overall, the median number of goals met was 4. Less than a quarter met ≥5 of the 7 goals, and 16% met all 3 goals for aspirin, blood pressure, and LDL-C. Older age, white race, higher income, more education, and higher physical functioning were independently associated with meeting more goals.
Conclusions
There is substantial room for improvement in risk factor reduction among US individuals with CAD.
doi:10.1016/j.jacc.2013.12.042
PMCID: PMC4201851  PMID: 24534599
coronary artery disease; prevention; risk factors
13.  Validation of the Atherosclerotic Cardiovascular Disease Pooled Cohort Risk Equations 
JAMA  2014;311(14):1406-1415.
Importance
The American College of Cardiology/American Heart Association Pooled Cohort risk equations were developed to estimate atherosclerotic cardiovascular disease (ASCVD) risk and guide statin initiation.
Objective
Assess calibration and discrimination of the Pooled Cohort risk equations in a contemporary US population.
Design, Setting, and Participants
Adults 45-79 years enrolled in the REasons for Geographic And Racial Differences in Stroke study between January 2003 and October 2007 and followed through December 2010. We studied participants for whom ASCVD risk may trigger a discussion of statin initiation (those without clinical ASCVD or diabetes, LDL-C between 70-189 mg/dL, not taking statins; n=10,997).
Main Outcomes and Measures
Predicted risk and observed adjudicated ASCVD incidence (non-fatal myocardial infarction, coronary heart disease [CHD] death, non-fatal or fatal stroke) at 5 years as REGARDS participants have not been followed 10 years. Additional analyses, limited to Medicare beneficiaries (n=3,333), added ASCVD events identified in claims data.
Results
There were 338 adjudicated events (192 CHD events, 146 strokes). The observed and predicted 5-year ASCVD incidence per 1,000 person-years for participants with 10-year predicted ASCVD risk <5% was 1.9 (95%CI: 1.3 – 2.7) and 1.9, risk 5% to <7.5% was 4.8 (95%CI: 3.4 – 6.7) and 4.8, risk 7.5% to <10% was 6.1 (95%CI: 4.4 – 8.6) and 6.9, and risk ≥10% was 12.0 (95%CI: 10.6 – 13.6) and 15.1 (Hosmer-Lemeshow χ2 19.9 p-value=0.01). The c-index was 0.72 (95%CI: 0.70–0.75). There were 234 ASCVD events (120 CHD events, 114 strokes) among Medicare-linked participants and the observed and predicted 5-year ASCVD incidence per 1,000 person-years for participants with predicted risk <7.5% was 5.3 (95% CI: 2.8 – 10.1) and 4.0, risk 7.5% to <10% was 7.9 (95% CI: 4.6 – 13.5) and 6.4, and risk ≥10% was 17.4 (95% CI: 15.3–19.8) and 16.4 (Hosmer-Lemeshow χ2 5.4 p-value=0.71). The c-index was 0.67 (95%CI: 0.64 – 0.71)
Conclusions and Relevance
In this cohort of US adults for whom statin initiation is considered based on the ACC/AHA Pooled Cohort risk equations, observed and predicted 5-year ASCVD risks were similar, indicating that these risk equations were well calibrated in the population for which they were designed to be used.
doi:10.1001/jama.2014.2630
PMCID: PMC4189930  PMID: 24682252
14.  Glycated Hemoglobin Measurement and Prediction of Cardiovascular Disease 
Angelantonio, Emanuele Di | Gao, Pei | Khan, Hassan | Butterworth, Adam S. | Wormser, David | Kaptoge, Stephen | Kondapally Seshasai, Sreenivasa Rao | Thompson, Alex | Sarwar, Nadeem | Willeit, Peter | Ridker, Paul M | Barr, Elizabeth L.M. | Khaw, Kay-Tee | Psaty, Bruce M. | Brenner, Hermann | Balkau, Beverley | Dekker, Jacqueline M. | Lawlor, Debbie A. | Daimon, Makoto | Willeit, Johann | Njølstad, Inger | Nissinen, Aulikki | Brunner, Eric J. | Kuller, Lewis H. | Price, Jackie F. | Sundström, Johan | Knuiman, Matthew W. | Feskens, Edith J. M. | Verschuren, W. M. M. | Wald, Nicholas | Bakker, Stephan J. L. | Whincup, Peter H. | Ford, Ian | Goldbourt, Uri | Gómez-de-la-Cámara, Agustín | Gallacher, John | Simons, Leon A. | Rosengren, Annika | Sutherland, Susan E. | Björkelund, Cecilia | Blazer, Dan G. | Wassertheil-Smoller, Sylvia | Onat, Altan | Marín Ibañez, Alejandro | Casiglia, Edoardo | Jukema, J. Wouter | Simpson, Lara M. | Giampaoli, Simona | Nordestgaard, Børge G. | Selmer, Randi | Wennberg, Patrik | Kauhanen, Jussi | Salonen, Jukka T. | Dankner, Rachel | Barrett-Connor, Elizabeth | Kavousi, Maryam | Gudnason, Vilmundur | Evans, Denis | Wallace, Robert B. | Cushman, Mary | D’Agostino, Ralph B. | Umans, Jason G. | Kiyohara, Yutaka | Nakagawa, Hidaeki | Sato, Shinichi | Gillum, Richard F. | Folsom, Aaron R. | van der Schouw, Yvonne T. | Moons, Karel G. | Griffin, Simon J. | Sattar, Naveed | Wareham, Nicholas J. | Selvin, Elizabeth | Thompson, Simon G. | Danesh, John
JAMA  2014;311(12):1225-1233.
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.
doi:10.1001/jama.2014.1873
PMCID: PMC4386007  PMID: 24668104
15.  American Heart Association's Life's Simple 7 and Risk of Venous Thromboembolism: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study 
Background
The American Heart Association's Life's Simple 7 metric is being used to track the population's cardiovascular health (CVH) toward a 2020 goal for improvement. The metric includes body mass index (BMI), blood pressure, cholesterol, glucose, physical activity (PA), cigarette smoking, and diet. We hypothesized a lower risk of venous thromboembolism (VTE) with favorable Life's Simple 7 scores.
Methods and Results
REGARDS recruited 30 239 black and white participants ≥45 years of age across the United States in 2003–2007. A 14‐point summary score for Life's Simple 7 classified participants into inadequate (0 to 4 points), average (5 to 9 points), and optimal (10 to 14 points) categories. Hazard ratios (HRs) of incident VTE were calculated for these categories, adjusting for age, sex, race, income, education, and region of residence. For comparison, HRs of VTE were calculated using the Framingham 10‐year coronary risk score. There were 263 incident VTE cases over 5.0 years of follow‐up; incidence rates per 1000 person‐years declined from 2.9 (95% confidence interval [CI], 2.3 to 3.7) among those in the inadequate category to 1.8 (95% CI, 1.4 to 2.4) in the optimal category. Compared to the inadequate category, participants in the average category had a 38% lower VTE risk (95% CI, 11 to 57) and participants in the optimal category had a 44% lower risk (95% CI, 18 to 62). The individual score components related to lower VTE risk were ideal PA and BMI. There was no association of Framingham Score with VTE.
Conclusions
Life's Simple 7, a CVH metric, was associated with reduced VTE risk. Findings suggest that efforts to improve the population's CVH may reduce VTE incidence.
doi:10.1161/JAHA.114.001494
PMCID: PMC4392432  PMID: 25725088
epidemiology; risk; thrombosis
16.  HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials 
Swerdlow, Daniel I | Preiss, David | Kuchenbaecker, Karoline B | Holmes, Michael V | Engmann, Jorgen E L | Shah, Tina | Sofat, Reecha | Stender, Stefan | Johnson, Paul C D | Scott, Robert A | Leusink, Maarten | Verweij, Niek | Sharp, Stephen J | Guo, Yiran | Giambartolomei, Claudia | Chung, Christina | Peasey, Anne | Amuzu, Antoinette | Li, KaWah | Palmen, Jutta | Howard, Philip | Cooper, Jackie A | Drenos, Fotios | Li, Yun R | Lowe, Gordon | Gallacher, John | Stewart, Marlene C W | Tzoulaki, Ioanna | Buxbaum, Sarah G | van der A, Daphne L | Forouhi, Nita G | Onland-Moret, N Charlotte | van der Schouw, Yvonne T | Schnabel, Renate B | Hubacek, Jaroslav A | Kubinova, Ruzena | Baceviciene, Migle | Tamosiunas, Abdonas | Pajak, Andrzej | Topor-Madry, Romanvan | Stepaniak, Urszula | Malyutina, Sofia | Baldassarre, Damiano | Sennblad, Bengt | Tremoli, Elena | de Faire, Ulf | Veglia, Fabrizio | Ford, Ian | Jukema, J Wouter | Westendorp, Rudi G J | de Borst, Gert Jan | de Jong, Pim A | Algra, Ale | Spiering, Wilko | der Zee, Anke H Maitland-van | Klungel, Olaf H | de Boer, Anthonius | Doevendans, Pieter A | Eaton, Charles B | Robinson, Jennifer G | Duggan, David | Kjekshus, John | Downs, John R | Gotto, Antonio M | Keech, Anthony C | Marchioli, Roberto | Tognoni, Gianni | Sever, Peter S | Poulter, Neil R | Waters, David D | Pedersen, Terje R | Amarenco, Pierre | Nakamura, Haruo | McMurray, John J V | Lewsey, James D | Chasman, Daniel I | Ridker, Paul M | Maggioni, Aldo P | Tavazzi, Luigi | Ray, Kausik K | Seshasai, Sreenivasa Rao Kondapally | Manson, JoAnn E | Price, Jackie F | Whincup, Peter H | Morris, Richard W | Lawlor, Debbie A | Smith, George Davey | Ben-Shlomo, Yoav | Schreiner, Pamela J | Fornage, Myriam | Siscovick, David S | Cushman, Mary | Kumari, Meena | Wareham, Nick J | Verschuren, W M Monique | Redline, Susan | Patel, Sanjay R | Whittaker, John C | Hamsten, Anders | Delaney, Joseph A | Dale, Caroline | Gaunt, Tom R | Wong, Andrew | Kuh, Diana | Hardy, Rebecca | Kathiresan, Sekar | Castillo, Berta A | van der Harst, Pim | Brunner, Eric J | Tybjaerg-Hansen, Anne | Marmot, Michael G | Krauss, Ronald M | Tsai, Michael | Coresh, Josef | Hoogeveen, Ronald C | Psaty, Bruce M | Lange, Leslie A | Hakonarson, Hakon | Dudbridge, Frank | Humphries, Steve E | Talmud, Philippa J | Kivimäki, Mika | Timpson, Nicholas J | Langenberg, Claudia | Asselbergs, Folkert W | Voevoda, Mikhail | Bobak, Martin | Pikhart, Hynek | Wilson, James G | Reiner, Alex P | Keating, Brendan J | Hingorani, Aroon D | Sattar, Naveed
Lancet  2015;385(9965):351-361.
Summary
Background
Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target.
Methods
We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis.
Findings
Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05–0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18–0·43), waist circumference (0·32 cm, 0·16–0·47), plasma insulin concentration (1·62%, 0·53–2·72), and plasma glucose concentration (0·23%, 0·02–0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00–1·05); the rs12916-T allele association was consistent (1·06, 1·03–1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18–1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10–0·38 in all trials; 0·33 kg, 95% CI 0·24–0·42 in placebo or standard care controlled trials and −0·15 kg, 95% CI −0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9–6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06–1·18 in all trials; 1·11, 95% CI 1·03–1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04–1·22 in intensive-dose vs moderate dose trials).
Interpretation
The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition.
Funding
The funding sources are cited at the end of the paper.
doi:10.1016/S0140-6736(14)61183-1
PMCID: PMC4322187  PMID: 25262344
17.  Relation of Leptin to Left Ventricular Hypertrophy (From the Multi-Ethnic Study of Atherosclerosis) 
The American journal of cardiology  2013;112(5):726-730.
Increasing adiposity increases the risk for left ventricular hypertrophy. Adipokines are hormone-like substances from adipose tissue that influence several metabolic pathways relevant to LV hypertrophy. Data was from participants enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA) who underwent magnetic resonance imaging of the heart and who also had fasting venous blood assayed for 4 distinct adipokines (adiponectin, leptin, tumor necrosis factor – alpha and resistin). 1,464 MESA participants had complete data. The mean age was 61.5 years, the mean body mass index was 27.6 kg/m2 and 49% were female. With adjustment for age, sex, race, height and weight, multivariable linear regression modeling revealed that a 1-SD increment in leptin was significantly associated with smaller LV mass (ß: −4.66 % predicted, p-value: < 0.01), LV volume (−5.87 % predicted, < 0.01), stroke volume (−3.23 ml, p < 0.01) and cardiac output (−120 mL/min, p = 0.01) as well as a lower odds ratio for the presence of LV hypertrophy (OR: 0.65, p < 0.01), but a higher ejection fraction (0.44%, p = 0.05). Additional adjustment for the traditional cardiovascular disease (CVD) risk factors, insulin resistance, physical activity, education, income, inflammatory biomarkers, other selected adipokines and pericardial fat did not materially change the magnitude or significance of the associations. The associations between the other adipokines and LV structure and function were inconsistent and largely non-significant. In conclusion, the results indicate that higher levels of leptin are associated with more favorable values of several measures of LV structure and function.
doi:10.1016/j.amjcard.2013.04.053
PMCID: PMC3745795  PMID: 23711806
leptin; left ventricle; hypertrophy; mass
18.  Association between urinary albumin excretion and coronary heart disease in black versus white adults 
JAMA : the journal of the American Medical Association  2013;310(7):10.1001/jama.2013.8777.
Importance
Excess urinary albumin excretion is more common in black individuals than in white individuals and is more strongly associated with incident stroke risk in blacks than whites. Whether similar associations extend to coronary heart disease (CHD) is unclear.
Objective
To determine whether the association of urinary albumin excretion with CHD events differs by race.
Design, Setting and Participants
Within the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a prospective cohort of black and white US adults ≥45 years of age enrolled between 2003 and 2007 with follow-up through December 31 2009, we examined race-stratified associations of urinary albumin to creatinine ratio (ACR) with (1) incident CHD among 23,273 participants free of CHD at baseline, and (2) first recurrent CHD event among 4,934 participants with CHD at baseline.
Main Outcome Measure
Expert-adjudicated incident and recurrent myocardial infarction (MI) and acute CHD death.
Results
A total of 616 incident CHD events (421 non-fatal MIs and 195 CHD deaths) and 468 recurrent CHD events (279 non-fatal MIs and 189 CHD deaths) were observed over a mean 4.4 years of follow-up. Among those free of CHD at baseline, age- and sex-adjusted incidence rates of CHD per 1000 person-years of follow-up increased with increasing categories of ACR in blacks and whites, with rates being nearly 1.5-fold higher in the highest category of ACR (>300 mg/g) in blacks vs. whites (20.59, 95% confidence interval [14.36,29.51] in blacks vs. 13.60 [7.60,24.25] in whites). In proportional hazards models adjusted for traditional cardiovascular risk factors and medications, higher baseline urinary ACR was associated with higher risk of incident CHD among blacks (hazard ratio [HR] comparing ACR >300 vs. <10 mg/g, 3.21 [2.02,5.09]) but not whites (HR comparing ACR >300 vs. <10 mg/g, 1.49 [0.80,2.76]) (P-interaction=0.03). Among those with CHD at baseline, fully-adjusted associations of baseline urinary ACR with first recurrent CHD event were similar in blacks and whites (HR comparing ACR >300 vs. <10 mg/g, 2.21 [1.22,4.00] in blacks vs. 2.48 [1.61,3.78] in whites) (P-interaction=0.53).
Conclusions
Higher urinary ACR was associated with higher risk of incident but not recurrent CHD in blacks compared to whites.
doi:10.1001/jama.2013.8777
PMCID: PMC3837520  PMID: 23989654
19.  N-terminal Pro-B-Type Natriuretic Peptide, Left Ventricular Mass, and Incident Heart Failure: Multi-Ethnic Study of Atherosclerosis 
Circulation. Heart failure  2012;5(6):727-734.
Background
Elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) is associated with clinically overt heart failure (HF). However, whether it provides additive prognostic information for incident HF beyond traditional risk factors and left ventricular (LV) mass index among multi-ethnic asymptomatic individuals has not yet been determined. We studied the associations of plasma NT-proBNP and magnetic resonance imaging defined LV mass index with incident HF in an asymptomatic multi-ethnic population.
Methods and Results
A total of 5597 multi-ethnic participants without clinically apparent cardiovascular disease underwent baseline measurement of NT-proBNP and were followed for 5.5±1.1 years. Among them, 4163 also underwent baseline cardiac magnetic resonance imaging. During follow-up, 111 participants experienced incident HF. Higher NT-proBNP was significantly associated with incident HF, independent of baseline age, sex, ethnicity, systolic blood pressure, diabetes mellitus, smoking, estimated glomerular filtration rate, medications (anti-hypertensive and statin), LV mass index, and interim myocardial infarction (hazard ratio: 1.95 per 1U log NT-proBNP increment, 95% CI 1.54–2.46, P<0.001). This relationship held among different ethnic groups, non-Hispanic whites, African-Americans, and Hispanics. Most importantly, NT-proBNP provided additive prognostic value beyond both traditional risk factors and LV mass index for predicting incident HF (integrated discrimination index=0.046, P<0.001; net reclassification index; 6-year risk probability categorized by <3%, 3–10%, >10% =0.175, P=0.019; category-less net reclassification index=0.561, P<0.001).
Conclusions
Plasma NT-proBNP provides incremental prognostic information beyond traditional risk factors and the magnetic resonance imaging-determined LV mass index for incident symptomatic HF in an asymptomatic multi-ethnic population.
Clinical Trial Registration
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00005487.
doi:10.1161/CIRCHEARTFAILURE.112.968701
PMCID: PMC4124746  PMID: 23032197
N-terminal pro-B-type natriuretic peptide; heart failure; left ventricular mass
20.  Atrial Fibrillation and the Risk of Myocardial Infarction 
JAMA internal medicine  2014;174(1):107-114.
IMPORTANCE
Myocardial infarction (MI) is an established risk factor for atrial fibrillation (AF). However, the extent to which AF is a risk factor for MI has not been investigated.
OBJECTIVE
To examine the risk of incident MI associated with AF.
DESIGN, SETTING, AND PARTICIPANTS
A prospective cohort of 23 928 participants residing in the continental United States and without coronary heart disease at baseline were enrolled from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort between 2003 and 2007, with follow-up through December 2009.
MAIN OUTCOMES AND MEASURES
Expert-adjudicated total MI events (fatal and nonfatal).
RESULTS
Over 6.9 years of follow-up (median 4.5 years), 648 incident MI events occurred. In a sociodemographic-adjusted model, AF was associated with about 2-fold increased risk of MI (hazard ratio [HR], 1.96 [95% CI, 1.52–2.52]). This association remained significant (HR, 1.70 [95% CI, 1.26–2.30]) after further adjustment for total cholesterol, high-density lipoprotein cholesterol, smoking status, systolic blood pressure, blood pressure–lowering drugs, body mass index, diabetes, warfarin use, aspirin use, statin use, history of stroke and vascular disease, estimated glomerular filtration rate, albumin to creatinine ratio, and C-reactive protein level. In subgroup analysis, the risk of MI associated with AF was significantly higher in women (HR, 2.16 [95% CI, 1.41–3.31]) than in men (HR, 1.39 [95% CI, 0.91–2.10]) and in blacks (HR, 2.53 [95% CI, 1.67–3.86]) than in whites (HR, 1.26 [95% CI, 0.83–1.93]); for interactions, P = .03 and P = .02, respectively. On the other hand, there were no significant differences in the risk of MI associated with AF in older (≥75 years) vs younger (<75 years) participants (HR, 2.00 [95% CI, 1.16–3.35] and HR, 1.60 [95% CI, 1.11–2.30], respectively); for interaction, P = .44.
CONCLUSIONS AND RELEVANCE
AF is independently associated with an increased risk of incident MI, especially in women and blacks. These findings add to the growing concerns of the seriousness of AF as a public health burden: in addition to being a well-known risk factor for stroke, AF is also associated with increased risk of MI.
doi:10.1001/jamainternmed.2013.11912
PMCID: PMC4115282  PMID: 24190540
21.  Racial and Regional Differences in Venous Thromboembolism in the United States in Three Cohorts 
Circulation  2014;129(14):1502-1509.
Introduction
Blacks are thought to have a higher risk of venous thromboembolism (VTE) than whites however prior studies are limited to administrative databases that lack specific information on VTE risk factors or have limited geographic scope.
Methods and Results
We ascertained VTE from three prospective studies; the Atherosclerosis Risk in Communities study (ARIC), the Cardiovascular Health Study (CHS), and the REasons for Geographic and Racial Differences in Stroke study (REGARDS). We tested the association of race with VTE using Cox proportional hazard models adjusted for VTE risk factors. Over 438,090 person-years, 916 incident VTE events (302 in blacks) occurred in 51,149 individuals (17,318 blacks) followed. In risk factor-adjusted models, blacks had a higher rate of VTE than whites in CHS (HR 1.81; 95% CI 1.20, 2.73) but not ARIC (HR 1.21; 95% CI 0.96, 1.54). In REGARDS, there was a significant region by race interaction (p = 0.01); blacks in the southeast had a significantly higher rate of VTE than blacks in the rest of the US (HR 1.63; 95% CI 1.08, 2.48) which was not seen in whites (HR 0.83; 95% CI 0.61, 1.14).
Conclusions
The association of race with VTE differed in each cohort, which may reflect the different time periods of the studies and/or different regional rates of VTE. Further study of environmental and genetic risk factors for VTE are needed to determine which underlie racial and perhaps regional differences in VTE.
doi:10.1161/CIRCULATIONAHA.113.006472
PMCID: PMC4098668  PMID: 24508826
Venous Thrombosis; Epidemiology; Race
22.  ADIPOKINES ARE ASSOCIATED WITH LOWER EXTREMITY VENOUS DISEASE: THE SAN DIEGO POPULATION STUDY 
Background
Obesity is a risk factor for venous disease. We tested the associations between adipokines and the presence and severity of venous disease.
Methods
Participants for this analysis were drawn from a cohort of 2,408 employees and retirees of a university in San Diego who were examined for venous disease using duplex ultrasonography. From this cohort, a case-control study sample of all 352 subjects with venous disease and 352 age-, sex- and race-matched subjects without venous disease were included in this analysis. All subjects completed health history questionnaires, had a physical examination with anthropometric measurements and venous blood analyzed for adipokines.
Results
After adjustment for age, sex and race, those with venous disease had significantly higher levels of body mass index (BMI), leptin and interleukin-6. Levels of resistin and tumor necrosis factor-alpha were also higher but of borderline significance (0.05 < p < 0.10). Compared to the lowest tertile and with adjustment for age, sex, race and BMI, the 2nd and 3rd tertiles of resistin (Odds Ratios: 1.9 & 1.7 respectively), leptin (1.7 & 1.7) and tumor necrosis factor-alpha (1.4 & 1.7) were associated with increasing severity of venous disease. Conversely, a 5 kg/m2 increment in BMI was associated with an increased odds (1.5) for venous disease, which was independent of the adipokines included in this study.
Conclusions
Both obesity and adipokines are significantly associated with venous disease. These associations appear to be independent of each other suggesting potentially different pathways to venous disease.
doi:10.1111/j.1538-7836.2010.03941.x
PMCID: PMC4078899  PMID: 20546124
23.  The Association of Framingham and Reynolds Risk Scores with Incidence and Progression of Coronary Artery Calcification in the Multi-Ethnic Study of Atherosclerosis 
Objectives
To compare the association of the Framingham Risk Score (FRS) and Reynolds Risk Score (RRS) with subclinical atherosclerosis, assessed by incidence and progression of coronary artery calcium (CAC).
Background
The comparative effectiveness of competing risk algorithms for indentifying subclinical atherosclerosis is unknown.
Methods
The Multi-Ethnic Study of Atherosclerosis (MESA) is a prospective cohort study of 6,814 participants free of baseline CVD. All participants underwent risk factor assessment, as well as baseline and follow-up CAC testing. We assessed the performance of the FRS and RRS to predict CAC incidence and progression using relative risk and robust linear regression.
Results
The study population included 5,140 individuals (61±10 years, 47% males, mean follow-up: 3.1±1.3 years). Among 53% of subjects (n=2,729) with no baseline CAC, 18% (n=510) developed incident CAC. Both the FRS and RRS were significantly predictive of incident CAC [RR 1.40 (95% CI 1.29 – 1.52), and RR 1.41 (95% CI 1.30 – 1.54) per 5% increase in risk, respectively] and CAC progression [mean CAC score change 6.92 (95% CI 5.31 – 8.54) and 6.82 (95% CI 5.51 – 8.14) per 5% increase]. Discordance in risk category classification (< or > 10% 10-year CHD risk) occurred in 13.7%, with only the RRS consistently adding predictive value for incidence and progression of CAC. These subclinical atherosclerosis findings are supported by a CHD events analysis over 5.6±0.7 year follow-up.
Conclusion
Both the RRS and FRS predict onset and progression of subclinical atherosclerosis. However, the RRS may provide additional predictive information when discordance between the scoring systems exists.
doi:10.1016/j.jacc.2011.08.022
PMCID: PMC4079464  PMID: 22051329
coronary artery calcium progression; subclinical atherosclerosis; risk prediction; Reynolds Risk Score; Framingham Risk Score
24.  Lipoprotein-associated phospholipase A2 and venous thromboembolism: a prospective study 
Thrombosis research  2013;132(1):44-46.
Introduction
Plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) is an inflammatory marker associated positively with atherothrombotic risk. Whether Lp-PLA2 is related to risk of venous thromboembolism (VTE) is incompletely studied.
Methods
We assessed Lp-PLA2 activity in 10,687 Atherosclerosis Risk in Communities (ARIC) Study participants and followed them a median of 8.3 years (from 1996–98 through 2005) for VTE occurrence (n = 226).
Results
There was no significant association between baseline Lp-PLA2 quartiles and risk of VTE, neither overall nor stratified as provoked or unprovoked. Adjusted for other risk factors, the hazard ratios (95% confidence interval) of total VTE across quartiles of Lp-PLA2 were 1.0 (reference), 0.95 (0.64, 1.42), 1.03 (0.69, 1.56), and 1.26 (0.83, 1.91). In the subset of participants with LDL-cholesterol ≥ 130 mg/dL, hazard ratios of total VTE were 1.00, 1.39 (0.44, 4.44), 2.45 (0.84, 7.11), and 2.84 (0.99, 8.14).
Conclusion
Our study does not support the overall hypothesis that elevated Lp-PLA2 contributes to VTE occurrence in the general population. However, in the presence of high LDL-cholesterol there was some evidence that Lp-PLA2 may increase VTE risk.
doi:10.1016/j.thromres.2013.05.014
PMCID: PMC3742644  PMID: 23746626
lipoprotein-associated phospholipase A2; prospective study; pulmonary embolism; venous thromboembolism
25.  Life’s Simple 7 and Risk of Incident Stroke: REasons for Geographic And Racial Differences in Stroke (REGARDS) Study 
Stroke; a journal of cerebral circulation  2013;44(7):10.1161/STROKEAHA.111.000352.
Background and Purpose
The American Heart Association developed Life’s Simple 7 (LS7) as a metric defining cardiovascular health. We investigated the association between LS7 and incident stroke in black and white Americans.
Methods
REGARDS is a national population-based cohort of 30,239 blacks and whites, aged ≥45 years, sampled from the US population in 2003 – 2007. Data were collected by telephone, self-administered questionnaires and an in-home exam. Incident strokes were identified through bi-annual participant contact followed by adjudication of medical records. Levels of the LS7 components (blood pressure, cholesterol, glucose, body mass index, smoking, physical activity, and diet) were each coded as poor (0 point), intermediate (1 point) or ideal (2 points) health. An overall LS7 score was categorized as inadequate (0–4), average (5–9) or optimum (10–14) cardiovascular health.
Results
Among 22,914 subjects with LS7 data and no previous cardiovascular disease, there were 432 incident strokes over 4.9 years of follow-up. After adjusting for demographics, socioeconomic status, and region of residence, each better health category of the LS7 score was associated with a 25% lower risk of stroke (HR=0.75, 95% CI = 0.63, 0.90). The association was similar for blacks and whites (interaction p-value = 0.55). A one point higher LS7 score was associated with an 8% lower risk of stroke (HR=0.92, 95% CI=0.88, 0.95).
Conclusion
In both blacks and whites better cardiovascular health, based on the LS7 score, is associated with lower risk of stroke, and a small difference in scores was an important stroke determinant.
doi:10.1161/STROKEAHA.111.000352
PMCID: PMC3816734  PMID: 23743971
Stroke; Racial differences; Risk factors; Life’s Simple 7

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