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author:("bushman, Mary")
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.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  Circulating Soluble Cytokine Receptors and Colorectal Cancer Risk 
Background
Soluble cytokine receptors and receptor antagonist of proinflammatory cytokines can modify cytokine signaling and may affect cancer risk.
Methods
In a case-cohort study nested within the Women’s Health Initiative cohort of postmenopausal women, we assessed the associations of plasma levels of IL-1 receptor antagonist (IL-1Ra) and the soluble receptors of IL-1 (sIL-1R2), IL-6 (sIL-6R and sgp130), and TNF (sTNFR1 and sTNFR2) with risk of colorectal cancer in 433 cases and 821 subcohort subjects. Baseline levels of estradiol, insulin, leptin, IL-6, and TNF-α measured previously were also available for data analysis.
Results
After adjusting for significant covariates – including age, race, smoking, colonoscopy history, waist circumference, and levels of estrogen, insulin, and leptin – relatively high levels of sIL-6R and sIL-1R2 were associated with reduced colorectal cancer risk [hazard ratios comparing extreme quartiles (HRQ4-Q1) for sIL-6R = 0.56, 95% CI = 0.38–0.83; HRQ4-Q1 for sIL-1R2 = 0.44, 95% CI = 0.29–0.67]. The associations with IL-1Ra, sgp130, sTNFR1, and sTNFR2 were null. The inverse association of sIL-1R2 with colorectal cancer risk persisted in cases diagnosed ≤5 and >5 years from baseline blood draw; the association with sIL-6R, however, was not evident in the latter group, possibly indicating that relatively low levels of sIL-6R in cases might be due to undiagnosed cancer at the time of blood draw.
Conclusions
High circulating levels of sIL-1R2 may be protective against colorectal carcinogenesis and/or be a marker of reduced risk for the disease.
Impact
sIL-1R2 has potential to be a chemopreventive and/or immunotherapeutic agent in inflammation-related diseases.
doi:10.1158/1055-9965.EPI-13-0545
PMCID: PMC3947182  PMID: 24192010
soluble cytokine receptor; receptor antagonist; colorectal cancer; IL-1; IL-6; TNF
13.  A genome-wide association study for venous thromboembolism: the extended Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium 
Genetic epidemiology  2013;37(5):512-521.
Venous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a 2-stage genome-wide association study (GWAS) among individuals of European ancestry in the extended CHARGE VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community-based studies. Genotypes for genome-wide single-nucleotide polymorphisms (SNPs) were imputed to ~2.5 million SNPs in HapMap and association with VTE assessed using study-design appropriate regression methods. Meta-analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (p≤0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case-control studies. In the combined data from these two stages, additional genome-wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG) (p<5.0×10−13 for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (p<5.0×10-6) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations.
doi:10.1002/gepi.21731
PMCID: PMC3990406  PMID: 23650146
venous thrombosis; genetics; genome-wide association; genetic epidemiology
14.  Genetic ancestry and lower extremity peripheral artery disease in the Multi-Ethnic Study of Atherosclerosis 
Using self-report of race/ethnicity, African Americans consistently have a higher prevalence of peripheral artery disease (PAD) compared to other ethnic groups. We aimed to determine the associations between estimated genetic admixture and PAD among African and Hispanic Americans. We studied the association between genetic ancestry and PAD among 1417 African and Hispanic American participants in the Multi-Ethnic Study of Atherosclerosis who were genotyped for ancestry informative markers (AIMs). PAD was defined as an ankle–brachial index (ABI) < 0.90. The overall prevalence of PAD among the 712 self-identified African American subjects was 15.2% and 4.6% among the 705 self-identified Hispanic Americans. A one standard deviation increment in European ancestry was associated with non-significant reductions in the odds for PAD among African (OR: 0.96 [95% CI: 0.78–1.18]) and Hispanic Americans (0.84 [0.58–1.23]), while the same increment in Native American ancestry was significantly associated with a lower odds of PAD in Hispanic Americans (0.56 [0.36–0.96]). Adjustment for demographic variables, field center, cardiovascular disease (CVD) risk factors and inflammatory markers strengthened the odds for European ancestry among African (0.85 [0.66–1.10]) and Hispanic Americans (0.68 [0.41–1.11]). The magnitude of the association for Native American ancestry among Hispanic Americans did not materially change (0.56 [0.29–1.09]). In conclusion, a higher percent Native American ancestry in Hispanics is associated with a lower odds of PAD while in both Hispanics and African Americans, greater European ancestry does not appear to be associated with lower odds for PAD.
doi:10.1177/1358863X10375586
PMCID: PMC4077267  PMID: 20926494
epidemiology; genetics; peripheral artery disease
15.  Sunlight exposure and cardiovascular risk factors in the REGARDS study: a cross-sectional split-sample analysis 
BMC Neurology  2014;14:133.
Background
Previous research has suggested that vitamin D and sunlight are related to cardiovascular outcomes, but associations between sunlight and risk factors have not been investigated. We examined whether increased sunlight exposure was related to improved cardiovascular risk factor status.
Methods
Residential histories merged with satellite, ground monitor, and model reanalysis data were used to determine previous-year sunlight radiation exposure for 17,773 black and white participants aged 45+ from the US. Exploratory and confirmatory analyses were performed by randomly dividing the sample into halves. Logistic regression models were used to examine relationships with cardiovascular risk factors.
Results
The lowest, compared to the highest quartile of insolation exposure was associated with lower high-density lipoprotein levels in adjusted exploratory (−2.7 mg/dL [95% confidence interval: −4.2, −1.2]) and confirmatory (−1.5 mg/dL [95% confidence interval: −3.0, −0.1]) models. The lowest, compared to the highest quartile of insolation exposure was associated with higher systolic blood pressure levels in unadjusted exploratory and confirmatory, as well as the adjusted exploratory model (2.3 mmHg [95% confidence interval: 0.8, 3.8]), but not the adjusted confirmatory model (1.6 mg/dL [95% confidence interval: −0.5, 3.7]).
Conclusions
The results of this study suggest that lower long-term sunlight exposure has an association with lower high-density lipoprotein levels. However, all associations were weak, thus it is not known if insolation may affect cardiovascular outcomes through these risk factors.
doi:10.1186/1471-2377-14-133
PMCID: PMC4075775  PMID: 24946776
Sunlight; Temperature; Weather; Climate; Environment; Blood pressure; Lipids and lipoproteins
16.  Resistin, but not Adiponectin and Leptin, is Associated with the Risk of Ischemic Stroke Among Postmenopausal Women: Results from the Women’s Health Initiative 
Background
Adipose tissue is considered an endocrine organ that secretes adipokines which possibly mediate the effects of obesity on risk of cardiovascular disease. However, there are yet limited prospective data on the association between circulating adipokine levels and risk of ischemic stroke. We aimed to examine the associations of three adipokines (adiponectin, leptin and resistin) with risk of ischemic stroke.
Methods and Results
We conducted a prospective nested case-control study (972 stroke cases and 972 matched controls) within the Women’s Health Initiative Observational Study cohort. The controls were matched to cases on age, race/ethnicity, date of study enrollment and follow-up time. Adipokine levels were associated with established stroke risk factors, such as obesity and systolic blood pressure. Adjusted for body mass index, the odds ratios (OR) for incident ischemic stroke comparing the highest (Q4) to the lowest quartile (Q1) were 0.81 (95% confidence intervals [CI]: 0.61–1.08; p-trend: 0.068) for adiponectin, 1.15 (95% CI: 0.83–1.59; p-trend: 0.523) for leptin, and 1.57 (95% CI: 1.18–2.08; p-trend: 0.002) for resistin. The association for resistin remained significant even after accounting for established stroke risk factors (OR: 1.39; 95% CI: 1.01–1.90; p-trend: 0.036). Further adjustment for markers for inflammation, angiogenesis, and endothelial function also did not affect our results.
Conclusions
Circulating levels of resistin, but not those of adiponectin or leptin, are associated with an increased risk of incident ischemic stroke in postmenopausal women, independent of obesity and other CVD risk factors.
doi:10.1161/STROKEAHA.110.607853
PMCID: PMC4059356  PMID: 21546486
stroke; adipokines; women
17.  Statin Therapy and Levels of Hemostatic Factors in a Healthy Population: the Multi-Ethnic Study of Atherosclerosis 
Background
HMG CoA reductase inhibitors (statins) reduce risk of venous thromboembolism (VTE) in healthy people. Statins reduce levels of inflammation biomarkers, however the mechanism for reduction in VTE risk is unknown. In a large cohort of healthy people, we studied associations of statin use with plasma hemostatic factors related to VTE risk.
Methods
Cross-sectional analyses were performed in the Multi-Ethnic Study of Atherosclerosis (MESA), a cohort study of 6814 healthy men and women age 45–84, free of clinical cardiovascular disease at baseline; 1001 were using statins at baseline. Twenty-three warfarin users were excluded. Age, race, and sex-adjusted mean hemostatic factor levels were compared between statin users and nonusers, and multivariable linear regression models were used to assess associations of statin use with hemostasis factors, adjusted for age, race/ethnicity, education, income, hormone replacement therapy (in women), and major cardiovascular risk factors.
Results
Participants using statins had lower adjusted levels of D-dimer (−9%), C-reactive protein (−21%) and factor VIII (−3%) than non-users (p<0.05). Homocysteine and von Willebrand factor were non-significantly lower with statin use. Higher fibrinogen (2%) and PAI-1 (22%) levels were observed among statin users than nonusers (p<0.05). Further adjustment for LDL and triglyceride levels did not attenuate the observed differences in these factors by statin use.
Conclusions
Findings of lower D-dimer, factor VIII and C-reactive protein levels with statin use suggest hypotheses for mechanisms whereby statins might lower VTE risk. A prospective study or clinical trial linking these biochemical differences to VTE outcomes in statin users and nonusers is warranted.
doi:10.1111/jth.12223
PMCID: PMC3702638  PMID: 23565981
statins; thrombosis; risk factor; blood coagulation; inflammation; fibrinolysis
18.  The American Heart Association Life's Simple 7 and Incident Cognitive Impairment: The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study 
Background
Life's Simple 7 is a new metric based on modifiable health behaviors and factors that the American Heart Association uses to promote improvements to cardiovascular health (CVH). We hypothesized that better Life's Simple 7 scores are associated with lower incidence of cognitive impairment.
Methods and Results
For this prospective cohort study, we included REasons for Geographic And Racial Differences in Stroke (REGARDS) participants aged 45+ who had normal global cognitive status at baseline and no history of stroke (N=17 761). We calculated baseline Life's Simple 7 score (range, 0 to 14) based on smoking, diet, physical activity, body mass index, blood pressure, total cholesterol, and fasting glucose. We identified incident cognitive impairment using a 3‐test measure of verbal learning, memory, and fluency obtained a mean of 4 years after baseline. Relative to the lowest tertile of Life's Simple 7 score (0 to 6 points), odds ratios of incident cognitive impairment were 0.65 (0.52, 0.81) in the middle tertile (7 to 8 points) and 0.63 (0.51, 0.79) in the highest tertile (9 to 14 points). The association was similar in blacks and whites, as well as outside and within the Southeastern stroke belt region of the United States.
Conclusions
Compared with low CVH, intermediate and high CVH were both associated with substantially lower incidence of cognitive impairment. We did not observe a dose‐response pattern; people with intermediate and high levels of CVH had similar incidence of cognitive impairment. This suggests that even when high CVH is not achieved, intermediate levels of CVH are preferable to low CVH.
doi:10.1161/JAHA.113.000635
PMCID: PMC4309046  PMID: 24919926
cardiovascular disease prevention; cardiovascular disease risk factors; cognitive impairment; cognitive tests; lifestyle
19.  Risk Factors for Intracerebral Hemorrhage: The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study 
Background and Purpose
Risk factors for intracerebral hemorrhage (ICH) have been largely identified in case-control studies, with few longitudinal studies available.
Methods
Predictors of incident ICH among 27,760 African American (AA) and white participants from the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort study were assessed.
Results
There were 62 incident ICH events during an average follow-up of 5.7 years. The increase in risk with age differed substantially between AAs and whites (p = 0.006), with a 2.25-fold (95% CI: 1.63 – 3.12) increase per decade in whites, but no age association with ICH risk in AAs (HR = 1.09; 95% CI: 0.70 – 1.68). We observed increased risk among men, those with higher systolic blood pressure (SBP), and warfarin users.
Conclusions
The racial differences in the impact of age contributed to a risk of ICH that was over 5 times higher for AA than whites at age 45, but only about one-third as great by age 85. Confirming findings from other studies, men, participants with elevated SBP and warfarin users were also at greater risk. The contributors to the racial differences in ICH risk require additional investigation.
doi:10.1161/STROKEAHA.111.000529
PMCID: PMC3753577  PMID: 23532012
21.  Nondisease-Specific Problems and All-Cause Mortality in the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study 
Background/Objectives
Problems that cross multiple domains of health are frequently assessed in older adults. We evaluated the association between six of these nondisease-specific problems and mortality among middle-aged and older adults.
Design
Prospective, observational cohort
Setting
U.S. population sample
Participants
Participants included 23,669 black and white US adults ≥ 45 years of age enrolled in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study.
Measurements
Nondisease-specific problems included cognitive impairment, depressive symptoms, falls, polypharmacy, impaired mobility and exhaustion. Age-stratified (<65, 65-74, and ≥ 75 years) hazard ratios for all-cause mortality were calculated for each problem individually and by number of problems.
Results
Among participants < 65, 65-74, ≥ 75 years old, one or more nondisease-specific problems occurred in 40%, 45% and 55% of participants, respectively. Compared to those with none of these problems the multivariable adjusted hazard ratios and 95% confidence intervals for all-cause mortality associated with each additional nondisease-specific problem was 1.34 (1.23–1.46), 1.24 (1.15–1.35) and 1.30 (1.21–1.39), among participants < 65, 65 – 74 years, ≥ 75 years of age, respectively.
Conclusion
Nondisease-specific problems were associated with mortality across a wide age spectrum. Future studies should determine if treating these problems will improve survival and identify innovative healthcare models to address multiple nondisease-specific problems simultaneously.
doi:10.1111/jgs.12214
PMCID: PMC3656135  PMID: 23617688
nondisease-specific problems; geriatrics; mortality
22.  C-reactive protein level and the incidence of eligibility for statin therapy: the Multi-Ethnic Study of Atherosclerosis (MESA) 
Clinical cardiology  2012;36(1):15-20.
Introduction
Given the results of the JUPITER trial, statin initiation may be considered for individuals with elevated high sensitivity C-reactive protein (CRP). However, if followed prospectively, many individuals with elevated CRP may become statin-eligible, limiting the impact of elevated CRP as a treatment indication. This analysis estimates the proportion of people with elevated CRP that become statin eligible over time.
Methods
We followed 2,153 Multi-Ethnic Study of Atherosclerosis (MESA) participants free of cardiovascular disease (CVD) and diabetes with LDL-cholesterol (LDL-C) <130 mg/dL at baseline to determine the proportion who become eligible for statins over 4.5 years. The proportion eligible for statin therapy, defined by the National Cholesterol Education Program (NCEP) 2004 updated guidelines, was calculated at baseline and during follow-up stratified by baseline CRP level (≥2 mg/L).
Results
At baseline, 47% of the 2,153 participants had elevated CRP. Among participants with elevated CRP, 29% met NCEP criteria for statins, compared to 28% without elevated CRP at baseline. By 1.5 years later, 26% and 22% (p=0.09) of those with and without elevated CRP at baseline reached NCEP LDL-C criteria and/or had started statins, respectively. These increased to 42% and 39% (p=0.24) at 3 years and 59% and 52% (p=0.01) at 4.5 years following baseline.
Conclusions
A substantial proportion of those with elevated CRP did not achieve NCEP based statin eligibility over 4.5 years of follow-up. These findings suggest that many patients with elevated CRP may not receive the benefits of statins if CRP is not incorporated into the NCEP screening strategy.
doi:10.1002/clc.22046
PMCID: PMC3953418  PMID: 22886783
23.  Geographic Variation in CKD Prevalence and ESRD Incidence in the United States: Results From the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study 
Background
It is not known whether geographic differences in the prevalence of chronic kidney disease (CKD) exist and are associated with end-stage renal disease (ESRD) incidence rates across the US.
Study Design
Cross-sectional and ecologic.
Setting & Participants
White (n=16,410) and black (n=11,109) participants from across the continental US in the population-based Reasons for Geographic and Racial Differences in Stroke (REGARDS) study.
Predictor
Geographic region, defined by the 18 Networks of the US ESRD Network Program.
Outcomes & Measurements
Albuminuria, defined as an albumin-creatinine ratio ≥30 mg/g and reduced estimated glomerular filtration rate (eGFR), defined as levels <60 ml/min/1.73m2, were measured in the REGARDS study. ESRD incidence rates were obtained from the US Renal Data System.
Results
For whites, the Network-specific prevalence of albuminuria ranged from 8.4% (95% CI, 3.3%–13.5%) in Network 15 to 14.8% (95% CI, 8.0%–21.6%) in Network 3, and reduced eGFR ranged from 4.3% (95% CI, 2.0%–6.6%) in Network 4 to 16.7% (95% CI, 12.7%–20.7%) in Network 7. For blacks, the prevalence of albuminuria ranged from 12.1% (95% CI, 8.7%–15.5%) in Network 5 to 26.5% (95% CI, 16.7%–36.3%) in Network 4, and reduced eGFR ranged from 6.7% (95% CI, 5.0%–8.4%) in Network 17/18 to 13.4% (95% CI, 7.8%–19.1%) in Network 12. The Spearman correlation coefficients for the prevalence of albuminuria and reduced eGFR with Network-specific ESRD incidence rates were 0.49 and 0.24, respectively, for whites and 0.29 and 0.25, respectively, for blacks.
Limitations
There were few cases of albuminuria and reduced eGFR in some geographic regions.
Conclusions
In the US, substantial geographic variations in the prevalence of albuminuria and reduced eGFR exist but were only modestly correlated with ESRD incidence, suggesting the CKD burden may not explain the geographic variation in ESRD incidence.
doi:10.1053/j.ajkd.2012.10.018
PMCID: PMC3659181  PMID: 23228944
24.  Hepatocyte Growth Factor and the Risk of Developing Ischemic Stroke Among Postmenopausal Women: Results from the Women’s Health Initiative 
Background
Hepatocyte growth factor (HGF) is a potent angiogenic factor and may play a role in the development and progression of atherosclerotic lesions, the underlying mechanism of cardiovascular disease. However, there have been no prospective studies examining the relationship between HGF levels and risk of stroke.
Methods and Results
We conducted a nested case-control study (972 incident stroke cases and 1:1 age- and race-matched controls) to prospectively evaluate the association between plasma HGF and risk of ischemic stroke within the Women’s Health Initiative Observational Study, a cohort of postmenopausal women aged 50–79 years. Baseline HGF levels were correlated positively with body mass index (BMI), systolic blood pressure, low-density lipoprotein cholesterol, insulin resistance, and inflammatory markers such as C-reactive protein, and inversely with high-density lipoprotein cholesterol (all P-values <0.05). Baseline HGF levels were higher among cases than controls (geometric means 601.8 vs. 523.2 pg/mL, p = 0.003). Furthermore, the risk of incident ischemic stroke was significantly greater amongst women in the highest versus lowest quartile of plasma HGF levels (odds ratio [OR] = 1.46; 95% confidence interval [CI]: 1.12–1.91; Ptrend = 0.003), in a conditional logistic regression model that adjusted for BMI. These results were only slightly attenuated after further adjustment for additional stroke risk factors (OR=1.39; 95% CI=1.04–1.85, Ptrend=0.023).
Conclusions
Circulating levels of HGF are associated with an increased risk of incident ischemic stroke, independent of obesity and other risk factors for cardiovascular disease among postmenopausal women aged 50–79 years.
doi:10.1161/STROKEAHA.109.567719
PMCID: PMC3903044  PMID: 20203323
Hepatocyte growth factor; ischemic stroke; women
25.  Self-report of stroke, transient ischemic attack, or stroke symptoms and risk of future stroke in the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study 
Background and Purpose
History of stroke and Transient Ischemic Attack (TIA) are documented risk factors for subsequent stroke and all-cause mortality. Recent reports suggest increased risk among those reporting stroke symptoms absent stroke or TIA. However, the relative magnitude of increased stroke risk has not been described across the symptomatic spectrum: 1) asymptomatic (Asx), 2) stroke symptoms only (SS), 3) TIA, 4) stroke in the distant past (DS), and 5) recent stroke (RS).
Methods
Between 2003–2007 the REasons for Geographic And Racial Differences in Stroke (REGARDS) study enrolled 30,239 black and white Americans aged 45+. DS and RS were defined as self-report of physician diagnosis of stroke >5 or <5 years before baseline, respectively. SS was defined as a history of any of six sudden onset stroke symptoms absent TIA/stroke diagnosis. Kaplan-Meier and proportional hazards analysis were used to contrast stroke risk differences.
Results
Over 5.0 ± 1.72 years of follow up, 737 strokes were validated. Compared to Asx persons, those with SS, TIA, DS and RS all had increased risk of future stroke. After adjustment for age, race, sex, income, education, alcohol intake, current smoking, and a history of diabetes, hypertension, myocardial infarction, atrial fibrillation, and dyslipidemia, there was 1.20-fold (not statistically significant) increased stroke risk for SS (95% CI 0.96, 1.51), 1.73-fold for TIA (95% CI 1.27, 2.36), 2.23-fold for DS (95% CI 1.61, 3.09) and 2.85-fold for RS (95% CI 2.16, 3.76).
Discussion
Results suggest a spectrum of risk from stroke symptoms to TIA, distant stroke, and recent stroke, and imply a need for establishing these categories in health screenings to manage risk for future stroke, reinforcing the clinical importance of stroke history including the presence of stroke symptoms.
doi:10.1161/STROKEAHA.112.675033
PMCID: PMC3558975  PMID: 23233382
stroke; TIA; stroke symptoms; mortality

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