@article {1562, title = {Association of genomic loci from a cardiovascular gene SNP array with fibrinogen levels in European Americans and African-Americans from six cohort studies: the Candidate Gene Association Resource (CARe).}, journal = {Blood}, volume = {117}, year = {2011}, month = {2011 Jan 06}, pages = {268-75}, abstract = {

Several common genomic loci, involving various immunity- and metabolism-related genes, have been associated with plasma fibrinogen in European Americans (EAs). The genetic determinants of fibrinogen in African Americans (AAs) are poorly characterized. Using a vascular gene-centric array in 23,634 EA and 6657 AA participants from 6 studies comprising the Candidate Gene Association Resource project, we examined the association of 47,539 common and lower frequency variants with fibrinogen concentration. We identified a rare Pro265Leu variant in FGB (rs6054) associated with lower fibrinogen. Common fibrinogen gene single nucleotide polymorphisms (FGB rs1800787 and FGG rs2066861) significantly associated with fibrinogen in EAs were prevalent in AAs and showed consistent associations. Several fibrinogen locus single nucleotide polymorphism associated with lower fibrinogen were exclusive to AAs; these include a newly reported association with FGA rs10050257. For IL6R, IL1RN, and NLRP3 inflammatory gene loci, associations with fibrinogen were concordant between EAs and AAs, but not at other loci (CPS1, PCCB, and SCL22A5-IRF1). The association of FGG rs2066861 with fibrinogen differed according to assay type used to measure fibrinogen. Further characterization of common and lower-frequency genetic variants that contribute to interpopulation differences in fibrinogen phenotype may help refine our understanding of the contribution of hemostasis and inflammation to atherothrombotic risk.

}, keywords = {Adult, African Americans, Aged, Cardiovascular Diseases, Cohort Studies, European Continental Ancestry Group, Female, Fibrinogen, Genetic Predisposition to Disease, Haplotypes, Humans, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Risk Factors}, issn = {1528-0020}, doi = {10.1182/blood-2010-06-289546}, author = {Wassel, Christina L and Lange, Leslie A and Keating, Brendan J and Taylor, Kira C and Johnson, Andrew D and Palmer, Cameron and Ho, Lindsey A and Smith, Nicholas L and Lange, Ethan M and Li, Yun and Yang, Qiong and Delaney, Joseph A and Tang, Weihong and Tofler, Geoffrey and Redline, Susan and Taylor, Herman A and Wilson, James G and Tracy, Russell P and Jacobs, David R and Folsom, Aaron R and Green, David and O{\textquoteright}Donnell, Christopher J and Reiner, Alexander P} } @article {1568, title = {A gene-centric association scan for Coagulation Factor VII levels in European and African Americans: the Candidate Gene Association Resource (CARe) Consortium.}, journal = {Hum Mol Genet}, volume = {20}, year = {2011}, month = {2011 Sep 01}, pages = {3525-34}, abstract = {

Polymorphisms in several distinct genomic regions, including the F7 gene, were recently associated with factor VII (FVII) levels in European Americans (EAs). The genetic determinants of FVII in African Americans (AAs) are unknown. We used a 50,000 single nucleotide polymorphism (SNP) gene-centric array having dense coverage of over 2,000 candidate genes for cardiovascular disease (CVD) pathways in a community-based sample of 16,324 EA and 3898 AA participants from the Candidate Gene Association Resource (CARe) consortium. Our aim was the discovery of new genomic loci and more detailed characterization of existing loci associated with FVII levels. In EAs, we identified three new loci associated with FVII, of which APOA5 on chromosome 11q23 and HNF4A on chromosome 20q12-13 were replicated in a sample of 4289 participants from the Whitehall II study. We confirmed four previously reported FVII-associated loci (GCKR, MS4A6A, F7 and PROCR) in CARe EA samples. In AAs, the F7 and PROCR regions were significantly associated with FVII. Several of the FVII-associated regions are known to be associated with lipids and other cardiovascular-related traits. At the F7 locus, there was evidence of at least five independently associated SNPs in EAs and three independent signals in AAs. Though the variance in FVII explained by the existing loci is substantial (20\% in EA and 10\% in AA), larger sample sizes and investigation of lower frequency variants may be required to identify additional FVII-associated loci in EAs and AAs and further clarify the relationship between FVII and other CVD risk factors.

}, keywords = {Adult, African Americans, Aged, Cardiovascular Diseases, European Continental Ancestry Group, Factor VII, Female, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide}, issn = {1460-2083}, doi = {10.1093/hmg/ddr264}, author = {Taylor, Kira C and Lange, Leslie A and Zabaneh, Delilah and Lange, Ethan and Keating, Brendan J and Tang, Weihong and Smith, Nicholas L and Delaney, Joseph A and Kumari, Meena and Hingorani, Aroon and North, Kari E and Kivimaki, Mika and Tracy, Russell P and O{\textquoteright}Donnell, Christopher J and Folsom, Aaron R and Green, David and Humphries, Steve E and Reiner, Alexander P} } @article {1344, title = {Adiposity and incident heart failure in older adults: the cardiovascular health study.}, journal = {Obesity (Silver Spring)}, volume = {20}, year = {2012}, month = {2012 Sep}, pages = {1936-41}, abstract = {

While several studies have reported a positive association between overall adiposity and heart failure (HF) risk, limited and inconsistent data are available on the relation between central adiposity and incident HF in older adults. We sought to examine the association between waist circumference (WC) and incident HF and assess whether sex modifies the relation between WC and HF. Prospective study using data on 4,861 participants of the Cardiovascular Health Study (1989-2007). HF was adjudicated by a committee using information from medical records and medications. We used Cox proportional hazard models to compute hazard ratio (HR). The mean age was 73.0 years for men and 72.3 years for women; 42.5\% were men and 15.3\% were African Americans. WC was positively associated with an increased risk of HF: each standard deviation of WC was associated with a 14\% increased risk of HF (95\% CI: 3\%-26\%) in a multivariable model. There was not a statistically significant sex-by-WC interaction (P = 0.081). BMI was positively associated with incident HF (HR: 1.22 (95\% CI: 1.15-1.29) per standard deviation increase of BMI); however, this association was attenuated and became nonstatistically significant upon additional adjustment for WC (HR: 1.09 (95\% CI: 0.99-1.21)). In conclusion, a higher WC is associated with an increased risk of HF independent of BMI in community-living older men and women.

}, keywords = {Adiposity, Aged, Aging, Body Fat Distribution, Body Mass Index, Female, Heart Failure, Humans, Incidence, Independent Living, Male, Obesity, Predictive Value of Tests, Proportional Hazards Models, Prospective Studies, Risk Factors, Sex Factors, United States, Waist Circumference}, issn = {1930-739X}, doi = {10.1038/oby.2011.320}, author = {Djouss{\'e}, Luc and Bartz, Traci M and Ix, Joachim H and Zieman, Susan J and Delaney, Joseph A and Mukamal, Kenneth J and Gottdiener, John S and Siscovick, David S and Kizer, Jorge R} } @article {6188, title = {Enhancing case ascertainment of Parkinson{\textquoteright}s disease using Medicare claims data in a population-based cohort: the Cardiovascular Health Study.}, journal = {Pharmacoepidemiol Drug Saf}, volume = {23}, year = {2014}, month = {2014 Feb}, pages = {119-27}, abstract = {

PURPOSE: We sought to improve a previous algorithm to ascertain Parkinson{\textquoteright}s disease (PD) in the Cardiovascular Health Study by incorporating additional data from Medicare outpatient claims. We compared our results to the previous algorithm in terms of baseline prevalence and incidence of PD, as well as associations with baseline smoking characteristics.

METHODS: Our original case ascertainment used self-reported diagnosis, antiparkinsonian medication, and hospitalization discharge International Classification of Diseases-Ninth version code. In this study, we incorporated additional data from fee-for-service Medicare claims, extended follow-up time, review of hospitalization records, and adjudicated cause of death. Two movement disorders specialists adjudicated final PD status. We used logistic regression models and controlled for age, sex, African American race, and education.

RESULTS: We identified 75 additional cases but reclassified 80 previously identified cases as not having PD. We observed significant inverse association with smoking status (odds ratio = 0.42; 95\% confidence interval (CI) = 0.22, 0.79), and inverse linear trends with pack-years (p = 0.005), and cigarettes per day (p = 0.019) with incident PD. All estimates were stronger than those from the previous algorithm.

CONCLUSIONS: Our enhanced method did not alter prevalence and incidence estimates compared with our previous algorithm. However, our enhanced method provided stronger estimates of association, potentially due to reduced level of disease misclassification.

}, keywords = {Aged, Aged, 80 and over, Algorithms, Antiparkinson Agents, Cohort Studies, Databases, Factual, Female, Hospitalization, Humans, Incidence, Logistic Models, Male, Medicare, Parkinson Disease, Prevalence, Prospective Studies, Smoking, Time Factors, United States}, issn = {1099-1557}, doi = {10.1002/pds.3552}, author = {Ton, Thanh G N and Biggs, Mary Lou and Comer, Diane and Curtis, Lesley and Hu, Shu-Ching and Thacker, Evan L and Searles Nielsen, Susan and Delaney, Joseph A and Landsittel, Douglas and Longstreth, William T and Checkoway, Harvey and Jain, Samay} } @article {6611, title = {A genetic association study of D-dimer levels with 50K SNPs from a candidate gene chip in four ethnic groups.}, journal = {Thromb Res}, volume = {134}, year = {2014}, month = {2014 Aug}, pages = {462-7}, abstract = {

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 National Heart, Lung, and Blood Institute Candidate Gene Association Resource consortium, were assembled. Approximately 50,000 genotyped single nucleotide polymorphisms (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{\texttimes}10(-6). The signal for the most associated SNP in F5 (rs6025, factor V 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 and FGA in EAs; we demonstrated replication of the association of D-dimer with FGA rs6050 in AAs and the factor V Leiden variant in Hispanics.

}, keywords = {Adult, Aged, Cardiovascular Diseases, Ethnic Groups, Factor V, Female, Fibrin Fibrinogen Degradation Products, Fibrinogen, Genetic Association Studies, Genotype, Humans, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Young Adult}, issn = {1879-2472}, doi = {10.1016/j.thromres.2014.05.018}, author = {Weng, Lu-Chen and Tang, Weihong and Rich, Stephen S and Smith, Nicholas L and Redline, Susan and O{\textquoteright}Donnell, Christopher J and Basu, Saonli and Reiner, Alexander P and Delaney, Joseph A and Tracy, Russell P and Palmer, Cameron D and Young, Taylor and Yang, Qiong and Folsom, Aaron R and Cushman, Mary} } @article {6664, title = {Circulating and dietary trans fatty acids and incident type 2 diabetes in older adults: the Cardiovascular Health Study.}, journal = {Diabetes Care}, volume = {38}, year = {2015}, month = {2015 Jun}, pages = {1099-107}, abstract = {

OBJECTIVE: To investigate the effects of trans fatty acids (TFAs) on type 2 diabetes mellitus (DM) by specific TFA subtype or method of assessment.

RESEARCH DESIGN AND METHODS: In the Cardiovascular Health Study, plasma phospholipid trans (t)-16:1n9, t-18:1, and cis (c)/t-, t/c-, and t/t-18:2 were measured in blood drawn from 2,919 adults aged 74 {\textpm} 5 years and free of prevalent DM in 1992. Dietary TFA was estimated among 4,207 adults free of prevalent DM when dietary questionnaires were initially administered in 1989 or 1996. Incident DM was defined through 2010 by medication use or blood glucose levels. Risks were assessed by Cox proportional hazards.

RESULTS: In biomarker analyses, 287 DM cases occurred during 30,825 person-years. Both t-16:1n9 (extreme quartile hazard ratio 1.59 [95\% CI 1.04-2.42], P-trend = 0.04) and t-18:1 (1.91 [1.20-3.03], P-trend = 0.01) levels were associated with higher incident DM after adjustment for de novo lipogenesis fatty acids. In dietary analyses, 407 DM cases occurred during 50,105 person-years. Incident DM was positively associated with consumption of total TFAs (1.38 [1.03-1.86], P-trend = 0.02), t-18:1 (1.32 [1.00-1.76], P-trend = 0.04), and t-18:2 (1.41 [1.05-1.89], P-trend = 0.02). After further adjustment for other dietary habits, however, the associations of estimated dietary TFA with DM were attenuated, and only nonsignificant positive trends remained.

CONCLUSIONS: Among older adults, plasma phospholipid t-16:1n9 and t-18:1 levels were positively related to DM after adjustment for de novo lipogenesis fatty acids. Estimated dietary TFA was not significantly associated with DM. These findings highlight the need for further observational, interventional, and experimental studies of the effects TFA on DM.

}, keywords = {Aged, Biomarkers, Diabetes Mellitus, Type 2, Diabetic Angiopathies, Dietary Fats, Unsaturated, Epidemiologic Methods, Female, Food Habits, Humans, Male, Phospholipids, Trans Fatty Acids}, issn = {1935-5548}, doi = {10.2337/dc14-2101}, author = {Wang, Qianyi and Imamura, Fumiaki and Ma, Wenjie and Wang, Molin and Lemaitre, Rozenn N and King, Irena B and Song, Xiaoling and Biggs, Mary L and Delaney, Joseph A and Mukamal, Kenneth J and Djouss{\'e}, Luc and Siscovick, David S and Mozaffarian, Dariush} } @article {7376, title = {Gene-centric approach identifies new and known loci for FVIII activity and VWF antigen levels in European Americans and African Americans.}, journal = {Am J Hematol}, volume = {90}, year = {2015}, month = {2015 Jun}, pages = {534-40}, abstract = {

Coagulation factor VIII and von Willebrand factor (VWF) are key proteins in procoagulant activation. Higher FVIII coagulant activity (FVIII :C) and VWF antigen (VWF :Ag) are risk factors for cardiovascular disease and venous thromboembolism. Beyond associations with ABO blood group, genetic determinants of FVIII and VWF are not well understood, especially in non European-American populations. We performed a genetic association study of FVIII :C and VWF:Ag that assessed 50,000 gene-centric single nucleotide polymorphisms (SNPs) in 18,556 European Americans (EAs) and 5,047 African Americans (AAs) from five population-based cohorts. Previously unreported associations for FVIII :C were identified in both AAs and EAs with KNG1 (most significantly associated SNP rs710446, Ile581Thr, Ile581Thr, P = 5.10 {\texttimes} 10(-7) in EAs and P = 3.88 {\texttimes} 10(-3) in AAs) and VWF rs7962217 (Gly2705Arg,P = 6.30 {\texttimes} 10(-9) in EAs and P = 2.98 {\texttimes} 10(-2) in AAs. Significant associations for FVIII :C were also observed with F8/TMLHE region SNP rs12557310 in EAs (P = 8.02 {\texttimes} 10(-10) ), with VWF rs1800380 in AAs (P = 5.62 {\texttimes} 10(-11) ), and with MAT1A rs2236568 in AAs (P51.69 {\texttimes} 10(-6) ). We replicated previously reported associations of FVIII :C and VWF :Ag with the ABO blood group, VWF rs1063856(Thr789Ala), rs216321 (Ala852Gln), and VWF rs2229446 (Arg2185Gln). Findings from this study expand our understanding of genetic influences for FVIII :C and VWF :Ag in both EAs and AAs.

}, keywords = {Adult, African Americans, Aged, European Continental Ancestry Group, Factor VIII, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Methionine Adenosyltransferase, Middle Aged, Polymorphism, Single Nucleotide, Venous Thromboembolism, von Willebrand Factor}, issn = {1096-8652}, doi = {10.1002/ajh.24005}, author = {Tang, Weihong and Cushman, Mary and Green, David and Rich, Stephen S and Lange, Leslie A and Yang, Qiong and Tracy, Russell P and Tofler, Geoffrey H and Basu, Saonli and Wilson, James G and Keating, Brendan J and Weng, Lu-Chen and Taylor, Herman A and Jacobs, David R and Delaney, Joseph A and Palmer, Cameron D and Young, Taylor and Pankow, James S and O{\textquoteright}Donnell, Christopher J and Smith, Nicholas L and Reiner, Alexander P and Folsom, Aaron R} } @article {6863, title = {HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials.}, journal = {Lancet}, volume = {385}, year = {2015}, month = {2015 Jan 24}, pages = {351-61}, abstract = {

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{\textperiodcentered}06 mmol/L (95\% CI 0{\textperiodcentered}05-0{\textperiodcentered}07) lower LDL cholesterol and higher body weight (0{\textperiodcentered}30 kg, 0{\textperiodcentered}18-0{\textperiodcentered}43), waist circumference (0{\textperiodcentered}32 cm, 0{\textperiodcentered}16-0{\textperiodcentered}47), plasma insulin concentration (1{\textperiodcentered}62\%, 0{\textperiodcentered}53-2{\textperiodcentered}72), and plasma glucose concentration (0{\textperiodcentered}23\%, 0{\textperiodcentered}02-0{\textperiodcentered}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{\textperiodcentered}02, 95\% CI 1{\textperiodcentered}00-1{\textperiodcentered}05); the rs12916-T allele association was consistent (1{\textperiodcentered}06, 1{\textperiodcentered}03-1{\textperiodcentered}09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0{\textperiodcentered}92 mmol/L (95\% CI 0{\textperiodcentered}18-1{\textperiodcentered}67) at 1-year of follow-up, increased bodyweight by 0{\textperiodcentered}24 kg (95\% CI 0{\textperiodcentered}10-0{\textperiodcentered}38 in all trials; 0{\textperiodcentered}33 kg, 95\% CI 0{\textperiodcentered}24-0{\textperiodcentered}42 in placebo or standard care controlled trials and -0{\textperiodcentered}15 kg, 95\% CI -0{\textperiodcentered}39 to 0{\textperiodcentered}08 in intensive-dose vs moderate-dose trials) at a mean of 4{\textperiodcentered}2 years (range 1{\textperiodcentered}9-6{\textperiodcentered}7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1{\textperiodcentered}12, 95\% CI 1{\textperiodcentered}06-1{\textperiodcentered}18 in all trials; 1{\textperiodcentered}11, 95\% CI 1{\textperiodcentered}03-1{\textperiodcentered}20 in placebo or standard care controlled trials and 1{\textperiodcentered}12, 95\% CI 1{\textperiodcentered}04-1{\textperiodcentered}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.

}, keywords = {Aged, Body Mass Index, Body Weight, Cholesterol, HDL, Cholesterol, LDL, Diabetes Mellitus, Type 2, Female, Genetic Testing, Humans, Hydroxymethylglutaryl CoA Reductases, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Male, Middle Aged, Polymorphism, Single Nucleotide, Randomized Controlled Trials as Topic, Risk Factors}, issn = {1474-547X}, doi = {10.1016/S0140-6736(14)61183-1}, author = {Swerdlow, Daniel I and Preiss, David and Kuchenbaecker, Karoline B and Holmes, Michael V and Engmann, Jorgen E L and Shah, Tina and Sofat, Reecha and Stender, Stefan and Johnson, Paul C D and Scott, Robert A and Leusink, Maarten and Verweij, Niek and Sharp, Stephen J and Guo, Yiran and Giambartolomei, Claudia and Chung, Christina and Peasey, Anne and Amuzu, Antoinette and Li, KaWah and Palmen, Jutta and Howard, Philip and Cooper, Jackie A and Drenos, Fotios and Li, Yun R and Lowe, Gordon and Gallacher, John and Stewart, Marlene C W and Tzoulaki, Ioanna and Buxbaum, Sarah G and van der A, Daphne L and Forouhi, Nita G and Onland-Moret, N Charlotte and van der Schouw, Yvonne T and Schnabel, Renate B and Hubacek, Jaroslav A and Kubinova, Ruzena and Baceviciene, Migle and Tamosiunas, Abdonas and Pajak, Andrzej and Topor-Madry, Roman and Stepaniak, Urszula and Malyutina, Sofia and Baldassarre, Damiano and Sennblad, Bengt and Tremoli, Elena and de Faire, Ulf and Veglia, Fabrizio and Ford, Ian and Jukema, J Wouter and Westendorp, Rudi G J and de Borst, Gert Jan and de Jong, Pim A and Algra, Ale and Spiering, Wilko and Maitland-van der Zee, Anke H and Klungel, Olaf H and de Boer, Anthonius and Doevendans, Pieter A and Eaton, Charles B and Robinson, Jennifer G and Duggan, David and Kjekshus, John and Downs, John R and Gotto, Antonio M and Keech, Anthony C and Marchioli, Roberto and Tognoni, Gianni and Sever, Peter S and Poulter, Neil R and Waters, David D and Pedersen, Terje R and Amarenco, Pierre and Nakamura, Haruo and McMurray, John J V and Lewsey, James D and Chasman, Daniel I and Ridker, Paul M and Maggioni, Aldo P and Tavazzi, Luigi and Ray, Kausik K and Seshasai, Sreenivasa Rao Kondapally and Manson, JoAnn E and Price, Jackie F and Whincup, Peter H and Morris, Richard W and Lawlor, Debbie A and Smith, George Davey and Ben-Shlomo, Yoav and Schreiner, Pamela J and Fornage, Myriam and Siscovick, David S and Cushman, Mary and Kumari, Meena and Wareham, Nick J and Verschuren, W M Monique and Redline, Susan and Patel, Sanjay R and Whittaker, John C and Hamsten, Anders and Delaney, Joseph A and Dale, Caroline and Gaunt, Tom R and Wong, Andrew and Kuh, Diana and Hardy, Rebecca and Kathiresan, Sekar and Castillo, Berta A and van der Harst, Pim and Brunner, Eric J and Tybjaerg-Hansen, Anne and Marmot, Michael G and Krauss, Ronald M and Tsai, Michael and Coresh, Josef and Hoogeveen, Ronald C and Psaty, Bruce M and Lange, Leslie A and Hakonarson, Hakon and Dudbridge, Frank and Humphries, Steve E and Talmud, Philippa J and Kivimaki, Mika and Timpson, Nicholas J and Langenberg, Claudia and Asselbergs, Folkert W and Voevoda, Mikhail and Bobak, Martin and Pikhart, Hynek and Wilson, James G and Reiner, Alex P and Keating, Brendan J and Hingorani, Aroon D and Sattar, Naveed} } @article {6616, title = {Prospective association of fatty acids in the de novo lipogenesis pathway with risk of type 2 diabetes: the Cardiovascular Health Study.}, journal = {Am J Clin Nutr}, volume = {101}, year = {2015}, month = {2015 Jan}, pages = {153-63}, abstract = {

BACKGROUND: Experimental evidence suggests that hepatic de novo lipogenesis (DNL) affects insulin homeostasis via synthesis of saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs). Few prospective studies have used fatty acid biomarkers to assess associations with type 2 diabetes.

OBJECTIVES: We investigated associations of major circulating SFAs [palmitic acid (16:0) and stearic acid (18:0)] and MUFA [oleic acid (18:1n-9)] in the DNL pathway with metabolic risk factors and incident diabetes in community-based older U.S. adults in the Cardiovascular Health Study. We secondarily assessed other DNL fatty acid biomarkers [myristic acid (14:0), palmitoleic acid (16:1n-7), 7-hexadecenoic acid (16:1n-9), and vaccenic acid (18:1n-7)] and estimated dietary SFAs and MUFAs.

DESIGN: In 3004 participants free of diabetes, plasma phospholipid fatty acids were measured in 1992, and incident diabetes was identified by medication use and blood glucose. Usual diets were assessed by using repeated food-frequency questionnaires. Multivariable linear and Cox regression were used to assess associations with metabolic risk factors and incident diabetes, respectively.

RESULTS: At baseline, circulating palmitic acid and stearic acid were positively associated with adiposity, triglycerides, inflammation biomarkers, and insulin resistance (P-trend < 0.01 each), whereas oleic acid showed generally beneficial associations (P-trend < 0.001 each). During 30,763 person-years, 297 incident diabetes cases occurred. With adjustment for demographics and lifestyle, palmitic acid (extreme-quintile HR: 1.89; 95\% CI: 1.27, 2.83; P-trend = 0.001) and stearic acid (HR: 1.62; 95\% CI: 1.09, 2.41; P-trend = 0.006) were associated with higher diabetes risk, whereas oleic acid was not significantly associated. In secondary analyses, vaccenic acid was inversely associated with diabetes (HR: 0.56; 95\% CI: 0.38, 0.83; P-trend = 0.005). Other fatty acid biomarkers and estimated dietary SFAs or MUFAs were not significantly associated with incident diabetes.

CONCLUSIONS: In this large prospective cohort, circulating palmitic acid and stearic acid were associated with higher diabetes risk, and vaccenic acid was associated with lower diabetes risk. These results indicate a need for additional investigation of biological mechanisms linking specific fatty acids in the DNL pathway to the pathogenesis of diabetes.

}, keywords = {Aged, Biomarkers, Cohort Studies, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Female, Follow-Up Studies, Humans, Incidence, Lipogenesis, Liver, Male, Palmitic Acid, Phospholipids, Prevalence, Proportional Hazards Models, Risk Factors, Stearic Acids, United States, Up-Regulation}, issn = {1938-3207}, doi = {10.3945/ajcn.114.092601}, author = {Ma, Wenjie and Wu, Jason H Y and Wang, Qianyi and Lemaitre, Rozenn N and Mukamal, Kenneth J and Djouss{\'e}, Luc and King, Irena B and Song, Xiaoling and Biggs, Mary L and Delaney, Joseph A and Kizer, Jorge R and Siscovick, David S and Mozaffarian, Dariush} } @article {6660, title = {Urine Collagen Fragments and CKD Progression-The Cardiovascular Health Study.}, journal = {J Am Soc Nephrol}, volume = {26}, year = {2015}, month = {2015 Oct}, pages = {2494-503}, abstract = {

Tubulointerstitial fibrosis is common with ageing and strongly prognostic for ESRD but is poorly captured by eGFR or urine albumin to creatinine ratio (ACR). Higher urine levels of procollagen type III N-terminal propeptide (PIIINP) mark the severity of tubulointerstitial fibrosis in biopsy studies, but the association of urine PIIINP with CKD progression is unknown. Among community-living persons aged >=65 years, we measured PIIINP in spot urine specimens from the 1996 to 1997 Cardiovascular Health Study visit among individuals with CKD progression (30\% decline in eGFR over 9 years, n=192) or incident ESRD (n=54) during follow-up, and in 958 randomly selected participants. We evaluated associations of urine PIIINP with CKD progression and incident ESRD. Associations of urine PIIINP with cardiovascular disease, heart failure, and death were evaluated as secondary end points. At baseline, mean age ({\textpm}SD) was 78{\textpm}5 years, mean eGFR was 63{\textpm}18 ml/min per 1.73 m(2), and median urine PIIINP was 2.6 (interquartile range, 1.4-4.2) μg/L. In a case-control study (192 participants, 231 controls), each doubling of urine PIIINP associated with 22\% higher odds of CKD progression (adjusted odds ratio, 1.22; 95\% confidence interval, 1.00 to 1.49). Higher urine PIIINP level was also associated with incident ESRD, but results were not significant in fully adjusted models. In a prospective study among the 958 randomly selected participants, higher urine PIIINP was significantly associated with death, but not with incident cardiovascular disease or heart failure. These data suggest higher urine PIIINP levels associate with CKD progression independently of eGFR and ACR in older individuals.

}, keywords = {Aged, Cardiovascular Diseases, Case-Control Studies, Disease Progression, Female, Heart Failure, Humans, Kidney Failure, Chronic, Male, Peptide Fragments, Procollagen, Prospective Studies, Renal Insufficiency, Chronic}, issn = {1533-3450}, doi = {10.1681/ASN.2014070696}, author = {Ix, Joachim H and Biggs, Mary L and Mukamal, Kenneth and Djouss{\'e}, Luc and Siscovick, David and Tracy, Russell and Katz, Ronit and Delaney, Joseph A and Chaves, Paulo and Rifkin, Dena E and Hughes-Austin, Jan M and Garimella, Pranav S and Sarnak, Mark J and Shlipak, Michael G and Kizer, Jorge R} } @article {7117, title = {Cardiovascular Disease, Mortality Risk, and Healthcare Costs by Lipoprotein(a) Levels According to Low-density Lipoprotein Cholesterol Levels in Older High-risk Adults.}, journal = {Clin Cardiol}, volume = {39}, year = {2016}, month = {2016 Jul}, pages = {413-20}, abstract = {

BACKGROUND: The value of lipoprotein(a) (Lp[a]) for predicting cardiovascular disease (CVD) across low-density lipoprotein cholesterol (LDL-C) is uncertain.

HYPOTHESIS: In older high-risk adults, higher LDL and Lp(a) combined would be associated with higher CVD risk and more healthcare costs.

METHODS: We included 3251 high-risk subjects (prior CVD, diabetes, or 10-year Framingham CVD risk >20\%) age >=65 years from the Cardiovascular Health Study and examined the relation of Lp(a) tertiles with incident CVD, coronary heart disease (CHD), and all-cause mortality within LDL-C strata (spanning <70 mg/dL to >=160 mg/dL). We also examined 1-year all-cause and CVD healthcare costs from Medicare claims.

RESULTS: Over a 22.5-year follow-up, higher Lp(a) levels predicted CVD and total mortality (both standardized hazard ratio [HR]: 1.06, P < 0.01), whereas higher LDL-C levels predicted higher CHD (standardized HR: 1.09, P < 0.01) but lower total mortality (standardized HR: 0.94, P < 0.001). Adjusted HRs in the highest (vs lowest) tertile of Lp(a) level were 1.95 (P = 0.06) for CVD events and 2.68 (P = 0.03) for CHD events when LDL-C was <70 mg/dL. One-year all-cause healthcare costs were increased for Lp(a) ($771 per SD of 56 {\textmu}g/mL [P = 0.03], $1976 for Lp(a) 25-64 {\textmu}g/mL vs <25 {\textmu}g/mL [P = 0.02], and $1648 for Lp(a) >=65 {\textmu}g/mL vs <25 {\textmu}g/mL [P = 0.054]) but not LDL-C.

CONCLUSIONS: In older high-risk adults, increased Lp(a) levels were associated with higher CVD risk, especially in those with LDL-C <70 mg/dL, and with higher healthcare costs.

}, issn = {1932-8737}, doi = {10.1002/clc.22546}, author = {Zhao, Yanglu and Delaney, Joseph A and Quek, Ruben G W and Gardin, Julius M and Hirsch, Calvin H and Gandra, Shravanthi R and Wong, Nathan D} } @article {8095, title = {Galectin-3 and Soluble ST2 and Kidney Function Decline in Older Adults: The Cardiovascular Health Study (CHS).}, journal = {Am J Kidney Dis}, volume = {67}, year = {2016}, month = {2016 06}, pages = {994-6}, keywords = {Aged, Cohort Studies, Creatinine, Cystatin C, Female, Galectin 3, Glomerular Filtration Rate, Humans, Interleukin-1 Receptor-Like 1 Protein, Logistic Models, Longitudinal Studies, Male, Prognosis, Renal Insufficiency, Chronic}, issn = {1523-6838}, doi = {10.1053/j.ajkd.2015.12.022}, author = {Bansal, Nisha and Katz, Ronit and Seliger, Stephen and DeFilippi, Christopher and Sarnak, Mark J and Delaney, Joseph A and Christenson, Robert and de Boer, Ian H and Kestenbaum, Bryan and Robinson-Cohen, Cassianne and Ix, Joachim H and Shlipak, Michael G} } @article {7242, title = {Longitudinal assessment of N-terminal pro-B-type natriuretic peptide and risk of diabetes in older adults: The cardiovascular health study.}, journal = {Metabolism}, volume = {65}, year = {2016}, month = {2016 Oct}, pages = {1489-97}, abstract = {

INTRODUCTION: Natriuretic peptides have a well-recognized role in cardiovascular homeostasis. Recently, higher levels of B-type natriuretic peptide (BNP) have also been associated with decreased risk of diabetes in middle-aged adults. Whether this association persists into older age, where the pathophysiology of diabetes changes, has not been established, nor has its intermediate pathways.

METHODS: We investigated the relationship between N-terminal (NT)-proBNP and incident diabetes in 2359 older adults free of cardiovascular disease or chronic kidney disease in the Cardiovascular Health Study.

RESULTS: We documented 348 incident cases of diabetes over 12.6years of median follow-up. After adjusting for age, sex, race, body mass index, systolic blood pressure, anti-hypertensive treatment, smoking, alcohol use, and LDL, each doubling of NT-proBNP was associated with a 9\% lower risk of incident diabetes (HR=0.91 [95\% CI: 0.84-0.99]). Additional adjustment for waist circumference, physical activity, estimated glomerular filtration rate or C-reactive protein did not influence the association. Among putative mediators, HDL and triglycerides, adiponectin, and especially homeostasis model assessment of insulin resistance, all appeared to account for a portion of the lower risk associated with NT-proBNP.

CONCLUSION: In older adults without prevalent cardiovascular or kidney disease, higher NT-proBNP is associated with decreased risk of incident diabetes even after adjustment for traditional risk factors. These findings suggest that the metabolic effects of natriuretic peptides persist late in life and offer a potential therapeutic target for prevention of diabetes in older people.

}, issn = {1532-8600}, doi = {10.1016/j.metabol.2016.06.002}, author = {Brutsaert, Erika F and Biggs, Mary L and Delaney, Joseph A and Djouss{\'e}, Luc and Gottdiener, John S and Ix, Joachim H and Kim, Francis and Mukamal, Kenneth J and Siscovick, David S and Tracy, Russell P and de Boer, Ian H and deFilippi, Christopher R and Kizer, Jorge R} } @article {7244, title = {Risk Factors for Incident Carotid Artery Revascularization among Older Adults: The Cardiovascular Health Study.}, journal = {Cerebrovasc Dis Extra}, volume = {6}, year = {2016}, month = {2016 Nov 16}, pages = {129-139}, abstract = {

BACKGROUND: Population-based risk factors for carotid artery revascularization are not known. We investigated the association between demographic and clinical characteristics and incident carotid artery revascularization in a cohort of older adults.

METHODS: Among Cardiovascular Health Study participants, a population-based cohort of 5,888 adults aged 65 years or older enrolled in two waves (1989-1990 and 1992-1993), 5,107 participants without a prior history of carotid endarterectomy (CEA) or cerebrovascular disease had a carotid ultrasound at baseline and were included in these analyses. Cox proportional hazards multivariable analysis was used to determine independent risk factors for incident carotid artery revascularization.

RESULTS: Over a mean follow-up of 13.5 years, 141 participants underwent carotid artery revascularization, 97\% were CEA. Baseline degree of stenosis and incident ischemic cerebral events occurring during follow-up were the strongest predictors of incident revascularization. After adjustment for these, factors independently associated with an increased risk of incident revascularization were: hypertension (HR 1.53; 95\% CI: 1.05-2.23), peripheral arterial disease (HR 2.57; 95\% CI: 1.34-4.93), and low-density lipoprotein cholesterol (HR 1.23 per standard deviation [SD] increment [35.4 mg/dL]; 95\% CI: 1.04-1.46). Factors independently associated with a lower risk of incident revascularization were: female gender (HR 0.51; 95\% CI: 0.34-0.77) and older age (HR 0.69 per SD increment [5.5 years]; 95\% CI: 0.56-0.86).

CONCLUSIONS: Even after accounting for carotid stenosis and incident cerebral ischemic events, carotid revascularization is related to age, gender, and cardiovascular risk factors. Further study of these demographic disparities and the role of risk factor control is warranted.

}, issn = {1664-5456}, doi = {10.1159/000452426}, author = {Garg, Parveen K and Koh, Willam J H and Delaney, Joseph A and Halm, Ethan A and Hirsch, Calvin H and Longstreth, William T and Mukamal, Kenneth J and Kucharska-Newton, Anna and Polak, Joseph F and Curtis, Lesley} } @article {6932, title = {Study of Cardiovascular Health Outcomes in the Era of Claims Data: The Cardiovascular Health Study.}, journal = {Circulation}, volume = {133}, year = {2016}, month = {2016 Jan 12}, pages = {156-64}, abstract = {

BACKGROUND: Increasingly, the diagnostic codes from administrative claims data are being used as clinical outcomes.

METHODS AND RESULTS: Data from the Cardiovascular Health Study (CHS) were used to compare event rates and risk factor associations between adjudicated hospitalized cardiovascular events and claims-based methods of defining events. The outcomes of myocardial infarction (MI), stroke, and heart failure were defined in 3 ways: the CHS adjudicated event (CHS[adj]), selected International Classification of Diseases, Ninth Edition diagnostic codes only in the primary position for Medicare claims data from the Center for Medicare \& Medicaid Services (CMS[1st]), and the same selected diagnostic codes in any position (CMS[any]). Conventional claims-based methods of defining events had high positive predictive values but low sensitivities. For instance, the positive predictive value of International Classification of Diseases, Ninth Edition code 410.x1 for a new acute MI in the first position was 90.6\%, but this code identified only 53.8\% of incident MIs. The observed event rates for CMS[1st] were low. For MI, the incidence was 14.9 events per 1000 person-years for CHS[adj] MI, 8.6 for CMS[1st] MI, and 12.2 for CMS[any] MI. In general, cardiovascular disease risk factor associations were similar across the 3 methods of defining events. Indeed, traditional cardiovascular disease risk factors were also associated with all first hospitalizations not resulting from an MI.

CONCLUSIONS: The use of diagnostic codes from claims data as clinical events, especially when restricted to primary diagnoses, leads to an underestimation of event rates. Additionally, claims-based events data represent a composite end point that includes the outcome of interest and selected (misclassified) nonevent hospitalizations.

}, keywords = {Blood Glucose, Cardiovascular Diseases, Female, Follow-Up Studies, Health Surveys, Hospitalization, Hospitals, Veterans, Humans, Insurance Claim Review, International Classification of Diseases, Lipids, Male, Managed Care Programs, Medicare, Risk Factors, Sampling Studies, Treatment Outcome, United States}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.115.018610}, author = {Psaty, Bruce M and Delaney, Joseph A and Arnold, Alice M and Curtis, Lesley H and Fitzpatrick, Annette L and Heckbert, Susan R and McKnight, Barbara and Ives, Diane and Gottdiener, John S and Kuller, Lewis H and Longstreth, W T} } @article {8486, title = {Characterization of cardiac mechanics and incident atrial fibrillation in participants of the Cardiovascular Health Study.}, journal = {JCI Insight}, volume = {5}, year = {2020}, month = {2020 Oct 02}, abstract = {

BACKGROUND: Left atrial (LA) and left ventricular (LV) remodeling are associated with atrial fibrillation (AF). The prospective associations of impairment in cardiac mechanical function, as assessed by speckle-tracking echocardiography, with incident AF are less clear.

METHODS: In the Cardiovascular Health Study, a community-based cohort of older adults, participants free of AF with echocardiograms of adequate quality for speckle tracking were included. We evaluated the associations of indices of cardiac mechanics (LA reservoir strain, LV longitudinal strain, and LV early diastolic strain rate) with incident AF.

RESULTS: Of 4341 participants with strain imaging, participants with lower LA reservoir strain were older, had more cardiometabolic risk factors, and had lower renal function at baseline. Over a median follow-up of 10 years, 497 (11.4\%) participants developed AF. Compared with the highest quartile of LA reservoir strain, the lowest quartile of LA reservoir strain was associated with higher risk of AF after covariate adjustment, including LA volume and LV longitudinal strain (heart rate [HR], 1.80; 95\% CI, 1.31-2.45; P < 0.001). The association of LA reservoir strain and AF was stronger in subgroups with higher blood pressure, NT-proBNP, and LA volumes. There were no associations of LV longitudinal strain and LV early diastolic strain rate with incident AF after adjustment for LA reservoir strain.

CONCLUSION: Lower LA reservoir strain was associated with incident AF, independent of LV mechanics, and with stronger associations in high-risk subgroups. These findings suggest that LA mechanical dysfunction precedes the development of AF. Therapies targeting LA mechanical dysfunction may prevent progression to AF.

FUNDING: This research was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086 and grants KL2TR001424, R01HL107577, U01HL080295, and U01HL130114 from the NIH{\textquoteright}s National Center for Advancing Translational Sciences, and National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org.

}, issn = {2379-3708}, doi = {10.1172/jci.insight.141656}, author = {Patel, Ravi B and Delaney, Joseph A and Hu, Mo and Patel, Harnish and Cheng, Jeanette and Gottdiener, John and Kizer, Jorge R and Marcus, Gregory M and Turakhia, Mintu P and Deo, Rajat and Heckbert, Susan R and Psaty, Bruce M and Shah, Sanjiv J} } @article {8403, title = {Innate and adaptive immune cell subsets as risk factors for coronary heart disease in two population-based cohorts.}, journal = {Atherosclerosis}, volume = {300}, year = {2020}, month = {2020 05}, pages = {47-53}, abstract = {

BACKGROUND AND AIMS: Cell-mediated immunity is implicated in atherosclerosis. We evaluated whether innate and adaptive immune cell subsets in peripheral blood are risk factors for coronary heart disease.

METHODS: A nested case-cohort study (n~=~2155) was performed within the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS). Cases of incident myocardial infarction (MI) and incident angina (n~=~880 total cases) were compared with a cohort random sample (n~=~1275). Immune cell phenotypes (n~=~34, including CD14 monocytes, natural killer cells, γδ T cells, CD4, CD8 and CD19 lymphocyte subsets) were measured from cryopreserved cells by flow cytometry. Cox proportional hazards models with adjustment for cardiovascular disease risk factors were used to evaluate associations of cell phenotypes with incident MI and a composite phenotype of incident MI or incident angina (MI-angina) over a median 9.3 years of follow-up. Th1, Th2, Th17, T regulatory (CD4CD25CD127), naive (CD4CD45RA), memory (CD4CD45RO), and CD4CD28 cells were specified as primary hypotheses. In secondary analyses, 27 additional cell phenotypes were investigated.

RESULTS: After correction for multiple testing, there were no statistically significant associations of CD4 naive, memory, CD28, or T helper cell subsets with MI or MI-angina in MESA, CHS, or combined-cohort meta analyses. Null associations were also observed for monocyte subsets, natural killer cells, γδ T cells, CD19 B cell and differentiated CD4 and CD8 cell subsets.

CONCLUSIONS: The proportions of peripheral blood monocyte and lymphocyte subsets are not strongly related to the future occurrence of MI or angina in adults free of autoimmune disease.

}, issn = {1879-1484}, doi = {10.1016/j.atherosclerosis.2020.03.011}, author = {Olson, Nels C and Sitlani, Colleen M and Doyle, Margaret F and Huber, Sally A and Landay, Alan L and Tracy, Russell P and Psaty, Bruce M and Delaney, Joseph A} } @article {8833, title = {Adverse cardiac mechanics and incident coronary heart disease in the Cardiovascular Health Study.}, journal = {Heart}, year = {2021}, month = {2021 Jul 13}, abstract = {

OBJECTIVES: Speckle-tracking echocardiography enables detection of abnormalities in cardiac mechanics with higher sensitivity than conventional measures of left ventricular (LV) dysfunction and may provide insight into the pathogenesis of coronary heart disease (CHD). We investigated the relationship of LV longitudinal strain, LV early diastolic strain rate (SR) and left atrial (LA) reservoir strain with long-term CHD incidence in community-dwelling older adults.

METHODS: The association of all three strain measures with incidence of non-fatal and fatal CHD (primary outcome of revascularisation, non-fatal and fatal myocardial infarction) was examined in the population-based Cardiovascular Health Study using multivariable Cox proportional hazards models. Follow-up was truncated at 10 years.

RESULTS: We included 3313 participants (mean (SD) age 72.6 (5.5) years). During a median follow-up of 10.0 (25th-75th percentile 7.7-10.0) years, 439 CHD events occurred. LV longitudinal strain (HR=1.25 per SD decrement, 95\% CI 1.09 to 1.43) and LV early diastolic SR (HR=1.31 per SD decrement, 95\% CI 1.14 to 1.50) were associated with a significantly greater risk of incident CHD after adjustment for potential confounders. By contrast, LA reservoir strain was not associated with incident CHD (HR=1.06 per SD decrement, 95\% CI 0.94 to 1.19). Additional adjustment for biochemical and echocardiographic measures of myocardial stress, dysfunction and remodelling did not meaningfully alter these associations.

CONCLUSION: We found an association between echocardiographic measures of subclinically altered LV mechanics and incident CHD. These findings inform the underlying biology of subclinical LV dysfunction and CHD. Early detection of asymptomatic myocardial dysfunction may offer an opportunity for prevention and early intervention.

}, issn = {1468-201X}, doi = {10.1136/heartjnl-2021-319296}, author = {Massera, Daniele and Hu, Mo and Delaney, Joseph A and Bartz, Traci M and Bach, Megan E and Dvorak, Stephen J and deFilippi, Christopher R and Psaty, Bruce M and Gottdiener, John S and Kizer, Jorge R and Shah, Sanjiv J} } @article {9175, title = {Association of immune cell subsets with incident heart failure in two population-based cohorts.}, journal = {ESC Heart Fail}, year = {2022}, month = {2022 Sep 12}, abstract = {

AIMS: Circulating inflammatory markers are associated with incident heart failure (HF), but prospective data on associations of immune cell subsets with incident HF are lacking. We determined the associations of immune cell subsets with incident HF as well as HF subtypes [with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF)].

METHODS AND RESULTS: Peripheral blood immune cell subsets were measured in adults from the Multi-Ethnic Study of Atherosclerosis (MESA) and Cardiovascular Health Study (CHS). Cox proportional hazard models adjusted for demographics, HF risk factors, and cytomegalovirus serostatus were used to evaluate the association of the immune cell subsets with incident HF. The average age of the MESA cohort at the time of immune cell measurements was 63.0~{\textpm}~10.4~years with 51\% women, and in the CHS cohort, it was 79.6~{\textpm}~4.4~years with 62\% women. In the meta-analysis of CHS and MESA, a higher proportion of CD4+ T helper (Th) 1 cells (per one standard deviation) was associated with a lower risk of incident HF [hazard ratio (HR) 0.91, (95\% CI 0.83-0.99), P~=~0.03]. Specifically, higher proportion of CD4+ Th1 cells was significantly associated with a lower risk of HFrEF [HR 0.73, (95\% CI 0.62-0.85), <0.001] after correction for multiple testing. No association was observed with HFpEF. No other cell subsets were associated with incident HF.

CONCLUSIONS: We observed that higher proportions of CD4+ Th1 cells were associated with a lower risk of incident HFrEF in two distinct population-based cohorts, with similar effect sizes in both cohorts demonstrating replicability. Although unexpected, the consistency of this finding across cohorts merits further investigation.

}, issn = {2055-5822}, doi = {10.1002/ehf2.14140}, author = {Sinha, Arjun and Sitlani, Colleen M and Doyle, Margaret F and Fohner, Alison E and B{\r u}zkov{\'a}, Petra and Floyd, James S and Huber, Sally A and Olson, Nels C and Njoroge, Joyce N and Kizer, Jorge R and Delaney, Joseph A and Shah, Sanjiv S and Tracy, Russell P and Psaty, Bruce and Feinstein, Matthew} } @article {9240, title = {Circulating differentiated and senescent lymphocyte subsets and incident diabetes risk in older adults: The Cardiovascular Health Study.}, journal = {Endocrinol Diabetes Metab}, volume = {6}, year = {2023}, month = {2023 Jan}, pages = {e384}, abstract = {

INTRODUCTION: Cellular senescence is a feature of aging implicated in the pathophysiology of diabetes mellitus (DM). Whether senescent lymphocytes are associated with the future occurrence of DM is uncertain.

METHODS: We used cryopreserved peripheral blood mononuclear cells collected from 1860 Cardiovascular Health Study participants (average age 80.2 years) and flow cytometry immunophenotyping to evaluate the longitudinal relationships of naive (CD45RA ), memory (CD45RO ), senescent (CD28 ), and T effector memory RA (TEMRA) (CD28 CD57 CD45RA ) CD4 and CD8 T cells, and memory B cells (CD19 CD27 ), with the risk of incident DM. In exploratory analyses we evaluated the relationships of 13 additional innate lymphocyte and CD4 and CD8 subsets with incident DM risk.

RESULTS: Over a median follow-up time of 8.9 years, 155 cases of incident DM occurred. In Cox models adjusted for demographic variables (age, sex, race, study site and flow cytometry analytical batch) or diabetes risk factors (demographic variables plus education, body mass index, smoking status, alcohol use, systolic blood pressure, hypertension medication use and physical activity), no significant associations were observed for any CD4 , CD8 or CD19 cell phenotypes with incident DM.

CONCLUSIONS: These results suggest the frequencies of naive, memory and senescent T cells and memory B cells are not strongly associated with incident DM risk in older adults.

}, keywords = {CD28 Antigens, CD8-Positive T-Lymphocytes, Cellular Senescence, Diabetes Mellitus, Leukocytes, Mononuclear, Lymphocyte Subsets}, issn = {2398-9238}, doi = {10.1002/edm2.384}, author = {Olson, Nels C and Doyle, Margaret F and B{\r u}zkov{\'a}, Petra and Huber, Sally A and de Boer, Ian H and Sitlani, Colleen M and Tracy, Russell P and Psaty, Bruce M and Mukamal, Kenneth J and Delaney, Joseph A} }