03311nas a2200601 4500008004100000022001400041245020900055210006900264260001600333300001100349490000800360520151200368653001001880653002201890653000901912653002801921653001901949653004001968653001102008653001502019653003802034653001502072653001102087653000902098653001602107653001402123653003602137653001702173100002502190700002102215700002402236700002002260700002302280700002002303700001902323700002302342700002002365700001202385700001602397700002302413700001802436700002102454700001902475700002202494700002102516700002202537700002102559700002102580700001702601700003002618700002502648856003602673 2011 eng d a1528-002000aAssociation 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).0 aAssociation of genomic loci from a cardiovascular gene SNP array c2011 Jan 06 a268-750 v1173 a
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.
10aAdult10aAfrican Americans10aAged10aCardiovascular Diseases10aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aFibrinogen10aGenetic Predisposition to Disease10aHaplotypes10aHumans10aMale10aMiddle Aged10aPhenotype10aPolymorphism, Single Nucleotide10aRisk Factors1 aWassel, Christina, L1 aLange, Leslie, A1 aKeating, Brendan, J1 aTaylor, Kira, C1 aJohnson, Andrew, D1 aPalmer, Cameron1 aHo, Lindsey, A1 aSmith, Nicholas, L1 aLange, Ethan, M1 aLi, Yun1 aYang, Qiong1 aDelaney, Joseph, A1 aTang, Weihong1 aTofler, Geoffrey1 aRedline, Susan1 aTaylor, Herman, A1 aWilson, James, G1 aTracy, Russell, P1 aJacobs, David, R1 aFolsom, Aaron, R1 aGreen, David1 aO'Donnell, Christopher, J1 aReiner, Alexander, P uhttps://chs-nhlbi.org/node/156203101nas a2200493 4500008004100000022001400041245016400055210006900219260001600288300001200304490000700316520162000323653001001943653002201953653000901975653002801984653004002012653001502052653001102067653003802078653001102116653000902127653001602136653003602152100002002188700002102208700002102229700001702250700002402267700001802291700002302309700002302332700001802355700002102373700001902394700001902413700002202432700003002454700002102484700001702505700002402522700002502546856003602571 2011 eng d a1460-208300aA gene-centric association scan for Coagulation Factor VII levels in European and African Americans: the Candidate Gene Association Resource (CARe) Consortium.0 agenecentric association scan for Coagulation Factor VII levels i c2011 Sep 01 a3525-340 v203 aPolymorphisms 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.
10aAdult10aAfrican Americans10aAged10aCardiovascular Diseases10aEuropean Continental Ancestry Group10aFactor VII10aFemale10aGenetic Predisposition to Disease10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide1 aTaylor, Kira, C1 aLange, Leslie, A1 aZabaneh, Delilah1 aLange, Ethan1 aKeating, Brendan, J1 aTang, Weihong1 aSmith, Nicholas, L1 aDelaney, Joseph, A1 aKumari, Meena1 aHingorani, Aroon1 aNorth, Kari, E1 aKivimaki, Mika1 aTracy, Russell, P1 aO'Donnell, Christopher, J1 aFolsom, Aaron, R1 aGreen, David1 aHumphries, Steve, E1 aReiner, Alexander, P uhttps://chs-nhlbi.org/node/156802698nas a2200469 4500008004100000022001400041245009100055210006900146260001300215300001200228490000700240520141400247653001401661653000901675653001001684653002601694653002001720653001101740653001801751653001101769653001401780653002301794653000901817653001201826653003001838653003201868653002401900653001701924653001601941653001801957653002401975100001801999700002002017700001902037700002102056700002302077700002402100700002402124700002402148700002002172856003602192 2012 eng d a1930-739X00aAdiposity and incident heart failure in older adults: the cardiovascular health study.0 aAdiposity and incident heart failure in older adults the cardiov c2012 Sep a1936-410 v203 aWhile 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.
10aAdiposity10aAged10aAging10aBody Fat Distribution10aBody Mass Index10aFemale10aHeart Failure10aHumans10aIncidence10aIndependent Living10aMale10aObesity10aPredictive Value of Tests10aProportional Hazards Models10aProspective Studies10aRisk Factors10aSex Factors10aUnited States10aWaist Circumference1 aDjoussé, Luc1 aBartz, Traci, M1 aIx, Joachim, H1 aZieman, Susan, J1 aDelaney, Joseph, A1 aMukamal, Kenneth, J1 aGottdiener, John, S1 aSiscovick, David, S1 aKizer, Jorge, R uhttps://chs-nhlbi.org/node/134403050nas a2200505 4500008004100000022001400041245014600055210006900201260001300270300001100283490000700294520163200301653000901933653002201942653001501964653002501979653001902004653002302023653001102046653002002057653001102077653001402088653002002102653000902122653001302131653002202144653001502166653002402181653001202205653001702217653001802234100002002252700002102272700001702293700001902310700001802329700002102347700002802368700002302396700002402419700002702443700002202470700001602492856003602508 2014 eng d a1099-155700aEnhancing case ascertainment of Parkinson's disease using Medicare claims data in a population-based cohort: the Cardiovascular Health Study.0 aEnhancing case ascertainment of Parkinsons disease using Medicar c2014 Feb a119-270 v233 aPURPOSE: We sought to improve a previous algorithm to ascertain Parkinson'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.
10aAged10aAged, 80 and over10aAlgorithms10aAntiparkinson Agents10aCohort Studies10aDatabases, Factual10aFemale10aHospitalization10aHumans10aIncidence10aLogistic Models10aMale10aMedicare10aParkinson Disease10aPrevalence10aProspective Studies10aSmoking10aTime Factors10aUnited States1 aTon, Thanh, G N1 aBiggs, Mary, Lou1 aComer, Diane1 aCurtis, Lesley1 aHu, Shu-Ching1 aThacker, Evan, L1 aNielsen, Susan, Searles1 aDelaney, Joseph, A1 aLandsittel, Douglas1 aLongstreth, William, T1 aCheckoway, Harvey1 aJain, Samay uhttps://chs-nhlbi.org/node/618803165nas a2200505 4500008004100000022001400041245011400055210006900169260001300238300001000251490000800261520171800269653001001987653000901997653002802006653001802034653001302052653001102065653004302076653001502119653003202134653001302166653001102179653000902190653001602199653004402215653003602259653001602295100001802311700001802329700002102347700002302368700001902391700003002410700001702440700002502457700002302482700002202505700002302527700001802550700001602568700002102584700001802605856003602623 2014 eng d a1879-247200aA genetic association study of D-dimer levels with 50K SNPs from a candidate gene chip in four ethnic groups.0 agenetic association study of Ddimer levels with 50K SNPs from a c2014 Aug a462-70 v1343 aINTRODUCTION: 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<2.0×10(-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.
10aAdult10aAged10aCardiovascular Diseases10aEthnic Groups10aFactor V10aFemale10aFibrin Fibrinogen Degradation Products10aFibrinogen10aGenetic Association Studies10aGenotype10aHumans10aMale10aMiddle Aged10aOligonucleotide Array Sequence Analysis10aPolymorphism, Single Nucleotide10aYoung Adult1 aWeng, Lu-Chen1 aTang, Weihong1 aRich, Stephen, S1 aSmith, Nicholas, L1 aRedline, Susan1 aO'Donnell, Christopher, J1 aBasu, Saonli1 aReiner, Alexander, P1 aDelaney, Joseph, A1 aTracy, Russell, P1 aPalmer, Cameron, D1 aYoung, Taylor1 aYang, Qiong1 aFolsom, Aaron, R1 aCushman, Mary uhttps://chs-nhlbi.org/node/661103072nas a2200433 4500008004100000022001400041245012500055210006900180260001300249300001300262490000700275520183300282653000902115653001502124653003002139653002602169653003002195653002602225653001102251653001602262653001102278653000902289653001802298653002202316100001702338700002102355700001502376700001602391700002402407700001902431700001902450700001902469700002302488700002402511700001802535700002402553700002502577856003602602 2015 eng d a1935-554800aCirculating and dietary trans fatty acids and incident type 2 diabetes in older adults: the Cardiovascular Health Study.0 aCirculating and dietary trans fatty acids and incident type 2 di c2015 Jun a1099-1070 v383 aOBJECTIVE: 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 ± 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.
10aAged10aBiomarkers10aDiabetes Mellitus, Type 210aDiabetic Angiopathies10aDietary Fats, Unsaturated10aEpidemiologic Methods10aFemale10aFood Habits10aHumans10aMale10aPhospholipids10aTrans Fatty Acids1 aWang, Qianyi1 aImamura, Fumiaki1 aMa, Wenjie1 aWang, Molin1 aLemaitre, Rozenn, N1 aKing, Irena, B1 aSong, Xiaoling1 aBiggs, Mary, L1 aDelaney, Joseph, A1 aMukamal, Kenneth, J1 aDjoussé, Luc1 aSiscovick, David, S1 aMozaffarian, Dariush uhttps://chs-nhlbi.org/node/666403195nas a2200577 4500008004100000022001400041245014300055210006900198260001300267300001100280490000700291520150000298653001001798653002201808653000901830653004001839653001601879653001101895653001701906653003401923653001101957653000901968653003501977653001602012653003602028653002702064653002602091100001802117700001802135700001702153700002102170700002102191700001602212700002202228700002402250700001702274700002102291700002402312700001802336700002202354700002102376700002302397700002302420700001802443700002102461700003002482700002302512700002502535700002102560856003602581 2015 eng d a1096-865200aGene-centric approach identifies new and known loci for FVIII activity and VWF antigen levels in European Americans and African Americans.0 aGenecentric approach identifies new and known loci for FVIII act c2015 Jun a534-400 v903 aCoagulation 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 × 10(-7) in EAs and P = 3.88 × 10(-3) in AAs) and VWF rs7962217 (Gly2705Arg,P = 6.30 × 10(-9) in EAs and P = 2.98 × 10(-2) in AAs. Significant associations for FVIII :C were also observed with F8/TMLHE region SNP rs12557310 in EAs (P = 8.02 × 10(-10) ), with VWF rs1800380 in AAs (P = 5.62 × 10(-11) ), and with MAT1A rs2236568 in AAs (P51.69 × 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.
10aAdult10aAfrican Americans10aAged10aEuropean Continental Ancestry Group10aFactor VIII10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aMethionine Adenosyltransferase10aMiddle Aged10aPolymorphism, Single Nucleotide10aVenous Thromboembolism10avon Willebrand Factor1 aTang, Weihong1 aCushman, Mary1 aGreen, David1 aRich, Stephen, S1 aLange, Leslie, A1 aYang, Qiong1 aTracy, Russell, P1 aTofler, Geoffrey, H1 aBasu, Saonli1 aWilson, James, G1 aKeating, Brendan, J1 aWeng, Lu-Chen1 aTaylor, Herman, A1 aJacobs, David, R1 aDelaney, Joseph, A1 aPalmer, Cameron, D1 aYoung, Taylor1 aPankow, James, S1 aO'Donnell, Christopher, J1 aSmith, Nicholas, L1 aReiner, Alexander, P1 aFolsom, Aaron, R uhttps://chs-nhlbi.org/node/737608133nas a2201957 4500008004100000022001400041245012800055210006900183260001600252300001100268490000800279520256000287653000902847653002002856653001602876653002102892653002102913653003002934653001102964653002002975653001102995653004103006653005103047653000903098653001603107653003603123653004203159653001703201100002403218700001803242700003103260700002303291700002503314700001503339700001803354700002003372700002303392700002103415700002103436700001803457700002203475700001503497700002803512700002103540700001703561700002203578700001403600700001803614700001903632700002203651700001903673700001503692700001703707700002003724700002603744700002103770700002203791700002503813700002103838700003103859700002203890700002403912700002503936700002103961700002303982700002404005700001904029700002304048700002304071700002104094700002504115700002004140700001904160700001804179700002104197700001404218700001904232700002604251700002404277700002004301700001504321700002004336700003404356700002104390700002304411700002604434700002204460700002604482700001804508700001904526700001904545700002204564700002204586700002304608700002004631700002004651700002104671700002104692700002304713700002104736700002004757700002404777700002104801700002304822700002004845700002204865700001904887700001904906700003704925700002104962700002104983700002205004700002305026700002205049700002405071700002105095700002505116700002005141700002405161700001805185700001805203700002105221700002905242700001905271700002105290700002305311700002005334700002305354700001905377700001805396700001705414700001505431700001905446700002205465700002305487700001505510700002105525700002605546700002305572700002205595700001805617700001805635700002505653700002005678700002105698700002205719700002105741700002405762700002405786700001905810700002505829700002405854700002705878700002105905700001805926700001905944700002105963700002005984700002406004700002406028700001906052710002306071710002106094710002406115856003606139 2015 eng d a1474-547X00aHMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials.0 aHMGcoenzyme A reductase inhibition type 2 diabetes and bodyweigh c2015 Jan 24 a351-610 v3853 aBACKGROUND: 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.
10aAged10aBody Mass Index10aBody Weight10aCholesterol, HDL10aCholesterol, LDL10aDiabetes Mellitus, Type 210aFemale10aGenetic Testing10aHumans10aHydroxymethylglutaryl CoA Reductases10aHydroxymethylglutaryl-CoA Reductase Inhibitors10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aRandomized Controlled Trials as Topic10aRisk Factors1 aSwerdlow, Daniel, I1 aPreiss, David1 aKuchenbaecker, Karoline, B1 aHolmes, Michael, V1 aEngmann, Jorgen, E L1 aShah, Tina1 aSofat, Reecha1 aStender, Stefan1 aJohnson, Paul, C D1 aScott, Robert, A1 aLeusink, Maarten1 aVerweij, Niek1 aSharp, Stephen, J1 aGuo, Yiran1 aGiambartolomei, Claudia1 aChung, Christina1 aPeasey, Anne1 aAmuzu, Antoinette1 aLi, KaWah1 aPalmen, Jutta1 aHoward, Philip1 aCooper, Jackie, A1 aDrenos, Fotios1 aLi, Yun, R1 aLowe, Gordon1 aGallacher, John1 aStewart, Marlene, C W1 aTzoulaki, Ioanna1 aBuxbaum, Sarah, G1 avan der A, Daphne, L1 aForouhi, Nita, G1 aOnland-Moret, Charlotte, N1 aSchouw, Yvonne, T1 aSchnabel, Renate, B1 aHubacek, Jaroslav, A1 aKubinova, Ruzena1 aBaceviciene, Migle1 aTamosiunas, Abdonas1 aPajak, Andrzej1 aTopor-Madry, Roman1 aStepaniak, Urszula1 aMalyutina, Sofia1 aBaldassarre, Damiano1 aSennblad, Bengt1 aTremoli, Elena1 ade Faire, Ulf1 aVeglia, Fabrizio1 aFord, Ian1 aJukema, Wouter1 aWestendorp, Rudi, G J1 ade Borst, Gert, Jan1 ade Jong, Pim, A1 aAlgra, Ale1 aSpiering, Wilko1 avan der Zee, Anke, H Maitland1 aKlungel, Olaf, H1 ade Boer, Anthonius1 aDoevendans, Pieter, A1 aEaton, Charles, B1 aRobinson, Jennifer, G1 aDuggan, David1 aKjekshus, John1 aDowns, John, R1 aGotto, Antonio, M1 aKeech, Anthony, C1 aMarchioli, Roberto1 aTognoni, Gianni1 aSever, Peter, S1 aPoulter, Neil, R1 aWaters, David, D1 aPedersen, Terje, R1 aAmarenco, Pierre1 aNakamura, Haruo1 aMcMurray, John, J V1 aLewsey, James, D1 aChasman, Daniel, I1 aRidker, Paul, M1 aMaggioni, Aldo, P1 aTavazzi, Luigi1 aRay, Kausik, K1 aSeshasai, Sreenivasa, Rao Kondap1 aManson, JoAnn, E1 aPrice, Jackie, F1 aWhincup, Peter, H1 aMorris, Richard, W1 aLawlor, Debbie, A1 aSmith, George Davey1 aBen-Shlomo, Yoav1 aSchreiner, Pamela, J1 aFornage, Myriam1 aSiscovick, David, S1 aCushman, Mary1 aKumari, Meena1 aWareham, Nick, J1 aVerschuren, W, M Monique1 aRedline, Susan1 aPatel, Sanjay, R1 aWhittaker, John, C1 aHamsten, Anders1 aDelaney, Joseph, A1 aDale, Caroline1 aGaunt, Tom, R1 aWong, Andrew1 aKuh, Diana1 aHardy, Rebecca1 aKathiresan, Sekar1 aCastillo, Berta, A1 aHarst, Pim1 aBrunner, Eric, J1 aTybjaerg-Hansen, Anne1 aMarmot, Michael, G1 aKrauss, Ronald, M1 aTsai, Michael1 aCoresh, Josef1 aHoogeveen, Ronald, C1 aPsaty, Bruce, M1 aLange, Leslie, A1 aHakonarson, Hakon1 aDudbridge, Frank1 aHumphries, Steve, E1 aTalmud, Philippa, J1 aKivimaki, Mika1 aTimpson, Nicholas, J1 aLangenberg, Claudia1 aAsselbergs, Folkert, W1 aVoevoda, Mikhail1 aBobak, Martin1 aPikhart, Hynek1 aWilson, James, G1 aReiner, Alex, P1 aKeating, Brendan, J1 aHingorani, Aroon, D1 aSattar, Naveed1 aDIAGRAM Consortium1 aMAGIC Consortium1 aInterAct Consortium uhttps://chs-nhlbi.org/node/686303962nas a2200529 4500008004100000022001400041245014100055210006900196260001300265300001100278490000800289520248600297653000902783653001502792653001902807653002802826653003002854653001102884653002202895653001102917653001402928653001602942653001002958653000902968653001802977653001802995653001503013653003203028653001703060653001803077653001803095653001803113100001503131700001803146700001703164700002403181700002403205700001803229700001903247700001903266700001903285700002303304700002003327700002403347700002503371856003603396 2015 eng d a1938-320700aProspective association of fatty acids in the de novo lipogenesis pathway with risk of type 2 diabetes: the Cardiovascular Health Study.0 aProspective association of fatty acids in the de novo lipogenesi c2015 Jan a153-630 v1013 aBACKGROUND: 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.
10aAged10aBiomarkers10aCohort Studies10aCross-Sectional Studies10aDiabetes Mellitus, Type 210aFemale10aFollow-Up Studies10aHumans10aIncidence10aLipogenesis10aLiver10aMale10aPalmitic Acid10aPhospholipids10aPrevalence10aProportional Hazards Models10aRisk Factors10aStearic Acids10aUnited States10aUp-Regulation1 aMa, Wenjie1 aH Y Wu, Jason1 aWang, Qianyi1 aLemaitre, Rozenn, N1 aMukamal, Kenneth, J1 aDjoussé, Luc1 aKing, Irena, B1 aSong, Xiaoling1 aBiggs, Mary, L1 aDelaney, Joseph, A1 aKizer, Jorge, R1 aSiscovick, David, S1 aMozaffarian, Dariush uhttps://chs-nhlbi.org/node/661603025nas a2200469 4500008004100000022001400041245008200055210006900137260001300206300001300219490000700232520171300239653000901952653002801961653002501989653002402014653001102038653001802049653001102067653002802078653000902106653002202115653001602137653002402153653003302177100001902210700001902229700002102248700001802269700002102287700001902308700001602327700002302343700001802366700002002384700002602404700002502430700002002455700002402475700002002499856003602519 2015 eng d a1533-345000aUrine Collagen Fragments and CKD Progression-The Cardiovascular Health Study.0 aUrine Collagen Fragments and CKD ProgressionThe Cardiovascular H c2015 Oct a2494-5030 v263 aTubulointerstitial 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 (±SD) was 78±5 years, mean eGFR was 63±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.
10aAged10aCardiovascular Diseases10aCase-Control Studies10aDisease Progression10aFemale10aHeart Failure10aHumans10aKidney Failure, Chronic10aMale10aPeptide Fragments10aProcollagen10aProspective Studies10aRenal Insufficiency, Chronic1 aIx, Joachim, H1 aBiggs, Mary, L1 aMukamal, Kenneth1 aDjoussé, Luc1 aSiscovick, David1 aTracy, Russell1 aKatz, Ronit1 aDelaney, Joseph, A1 aChaves, Paulo1 aRifkin, Dena, E1 aHughes-Austin, Jan, M1 aGarimella, Pranav, S1 aSarnak, Mark, J1 aShlipak, Michael, G1 aKizer, Jorge, R uhttps://chs-nhlbi.org/node/666002367nas a2200217 4500008004100000022001400041245017300055210006900228260001300297300001100310490000700321520163400328100001701962700002301979700002102002700002202023700002202045700002602067700002002093856003602113 2016 eng d a1932-873700aCardiovascular Disease, Mortality Risk, and Healthcare Costs by Lipoprotein(a) Levels According to Low-density Lipoprotein Cholesterol Levels in Older High-risk Adults.0 aCardiovascular Disease Mortality Risk and Healthcare Costs by Li c2016 Jul a413-200 v393 aBACKGROUND: 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 µg/mL [P = 0.03], $1976 for Lp(a) 25-64 µg/mL vs <25 µg/mL [P = 0.02], and $1648 for Lp(a) ≥65 µg/mL vs <25 µg/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.
1 aZhao, Yanglu1 aDelaney, Joseph, A1 aQuek, Ruben, G W1 aGardin, Julius, M1 aHirsch, Calvin, H1 aGandra, Shravanthi, R1 aWong, Nathan, D uhttps://chs-nhlbi.org/node/711701271nas a2200433 4500008004100000022001400041245011500055210006900170260001200239300001000251490000700261653000900268653001900277653001500296653001500311653001100326653001500337653003100352653001100383653004200394653002000436653002500456653000900481653001400490653003300504100001800537700001600555700002100571700002700592700002000619700002300639700002400662700002000686700002200706700003000728700001900758700002400777856003600801 2016 eng d a1523-683800aGalectin-3 and Soluble ST2 and Kidney Function Decline in Older Adults: The Cardiovascular Health Study (CHS).0 aGalectin3 and Soluble ST2 and Kidney Function Decline in Older A c2016 06 a994-60 v6710aAged10aCohort Studies10aCreatinine10aCystatin C10aFemale10aGalectin 310aGlomerular Filtration Rate10aHumans10aInterleukin-1 Receptor-Like 1 Protein10aLogistic Models10aLongitudinal Studies10aMale10aPrognosis10aRenal Insufficiency, Chronic1 aBansal, Nisha1 aKatz, Ronit1 aSeliger, Stephen1 aDeFilippi, Christopher1 aSarnak, Mark, J1 aDelaney, Joseph, A1 aChristenson, Robert1 ade Boer, Ian, H1 aKestenbaum, Bryan1 aRobinson-Cohen, Cassianne1 aIx, Joachim, H1 aShlipak, Michael, G uhttps://chs-nhlbi.org/node/809502668nas a2200289 4500008004100000022001400041245014400055210006900199260001300268300001200281490000700293520175800300100002402058700001902082700002302101700001802124700002402142700001902166700001702185700002402202700002402226700002202250700002002272700003002292700002002322856003602342 2016 eng d a1532-860000aLongitudinal assessment of N-terminal pro-B-type natriuretic peptide and risk of diabetes in older adults: The cardiovascular health study.0 aLongitudinal assessment of Nterminal proBtype natriuretic peptid c2016 Oct a1489-970 v653 aINTRODUCTION: 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.
1 aBrutsaert, Erika, F1 aBiggs, Mary, L1 aDelaney, Joseph, A1 aDjoussé, Luc1 aGottdiener, John, S1 aIx, Joachim, H1 aKim, Francis1 aMukamal, Kenneth, J1 aSiscovick, David, S1 aTracy, Russell, P1 ade Boer, Ian, H1 adeFilippi, Christopher, R1 aKizer, Jorge, R uhttps://chs-nhlbi.org/node/724202682nas a2200253 4500008004100000022001400041245011600055210006900171260001600240300001200256490000600268520189400274100002102168700002102189700002302210700001902233700002202252700002702274700002402301700002702325700002102352700001902373856003602392 2016 eng d a1664-545600aRisk Factors for Incident Carotid Artery Revascularization among Older Adults: The Cardiovascular Health Study.0 aRisk Factors for Incident Carotid Artery Revascularization among c2016 Nov 16 a129-1390 v63 aBACKGROUND: 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.
1 aGarg, Parveen, K1 aKoh, Willam, J H1 aDelaney, Joseph, A1 aHalm, Ethan, A1 aHirsch, Calvin, H1 aLongstreth, William, T1 aMukamal, Kenneth, J1 aKucharska-Newton, Anna1 aPolak, Joseph, F1 aCurtis, Lesley uhttps://chs-nhlbi.org/node/724403259nas a2200481 4500008004100000022001400041245010400055210006900159260001600228300001100244490000800255520187600263653001802139653002802157653001102185653002202196653001902218653002002237653002402257653001102281653002702292653004502319653001102364653000902375653002602384653001302410653001702423653002102440653002202461653001802483100002002501700002302521700002102544700002202565700002802587700002302615700002202638700001602660700002402676700002102700700002002721856003602741 2016 ENG d a1524-453900aStudy of Cardiovascular Health Outcomes in the Era of Claims Data: The Cardiovascular Health Study.0 aStudy of Cardiovascular Health Outcomes in the Era of Claims Dat c2016 Jan 12 a156-640 v1333 aBACKGROUND: 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.
10aBlood Glucose10aCardiovascular Diseases10aFemale10aFollow-Up Studies10aHealth Surveys10aHospitalization10aHospitals, Veterans10aHumans10aInsurance Claim Review10aInternational Classification of Diseases10aLipids10aMale10aManaged Care Programs10aMedicare10aRisk Factors10aSampling Studies10aTreatment Outcome10aUnited States1 aPsaty, Bruce, M1 aDelaney, Joseph, A1 aArnold, Alice, M1 aCurtis, Lesley, H1 aFitzpatrick, Annette, L1 aHeckbert, Susan, R1 aMcKnight, Barbara1 aIves, Diane1 aGottdiener, John, S1 aKuller, Lewis, H1 aLongstreth, W T uhttps://chs-nhlbi.org/node/693203329nas a2200277 4500008004100000022001400041245012700055210006900182260001600251490000600267520248500273100001902758700002302777700001102800700001902811700002002830700002102850700002002871700002302891700002302914700001502937700002302952700002002975700002002995856003603015 2020 eng d a2379-370800aCharacterization of cardiac mechanics and incident atrial fibrillation in participants of the Cardiovascular Health Study.0 aCharacterization of cardiac mechanics and incident atrial fibril c2020 Oct 020 v53 aBACKGROUND: 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'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.
1 aPatel, Ravi, B1 aDelaney, Joseph, A1 aHu, Mo1 aPatel, Harnish1 aCheng, Jeanette1 aGottdiener, John1 aKizer, Jorge, R1 aMarcus, Gregory, M1 aTurakhia, Mintu, P1 aDeo, Rajat1 aHeckbert, Susan, R1 aPsaty, Bruce, M1 aShah, Sanjiv, J uhttps://chs-nhlbi.org/node/848602512nas a2200229 4500008004100000022001400041245012000055210006900175260001200244300001000256490000800266520180100274100001902075700002402094700002302118700002002141700002002161700002202181700002002203700002302223856003602246 2020 eng d a1879-148400aInnate and adaptive immune cell subsets as risk factors for coronary heart disease in two population-based cohorts.0 aInnate and adaptive immune cell subsets as risk factors for coro c2020 05 a47-530 v3003 aBACKGROUND 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.
1 aOlson, Nels, C1 aSitlani, Colleen, M1 aDoyle, Margaret, F1 aHuber, Sally, A1 aLanday, Alan, L1 aTracy, Russell, P1 aPsaty, Bruce, M1 aDelaney, Joseph, A uhttps://chs-nhlbi.org/node/840302650nas a2200241 4500008004100000022001400041245010200055210006900157260001600226520189900242100002102141700001102162700002302173700002002196700001902216700002302235700003002258700002002288700002402308700002002332700002002352856003602372 2021 eng d a1468-201X00aAdverse cardiac mechanics and incident coronary heart disease in the Cardiovascular Health Study.0 aAdverse cardiac mechanics and incident coronary heart disease in c2021 Jul 133 aOBJECTIVES: 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.
1 aMassera, Daniele1 aHu, Mo1 aDelaney, Joseph, A1 aBartz, Traci, M1 aBach, Megan, E1 aDvorak, Stephen, J1 adeFilippi, Christopher, R1 aPsaty, Bruce, M1 aGottdiener, John, S1 aKizer, Jorge, R1 aShah, Sanjiv, J uhttps://chs-nhlbi.org/node/883302657nas a2200289 4500008004100000022001400041245010000055210006900155260001600224520177800240100001702018700002402035700002302059700002202082700002102104700002002125700002002145700001902165700002202184700002002206700002302226700002002249700002202269700001702291700002302308856003602331 2022 eng d a2055-582200aAssociation of immune cell subsets with incident heart failure in two population-based cohorts.0 aAssociation of immune cell subsets with incident heart failure i c2022 Sep 123 aAIMS: 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 ± 10.4 years with 51% women, and in the CHS cohort, it was 79.6 ± 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.
1 aSinha, Arjun1 aSitlani, Colleen, M1 aDoyle, Margaret, F1 aFohner, Alison, E1 aBůzková, Petra1 aFloyd, James, S1 aHuber, Sally, A1 aOlson, Nels, C1 aNjoroge, Joyce, N1 aKizer, Jorge, R1 aDelaney, Joseph, A1 aShah, Sanjiv, S1 aTracy, Russell, P1 aPsaty, Bruce1 aFeinstein, Matthew uhttps://chs-nhlbi.org/node/917502516nas a2200325 4500008004100000022001400041245014100055210006900196260001300265300000900278490000600287520149900293653001801792653003101810653002401841653002201865653002801887653002301915100001901938700002301957700002101980700002002001700002002021700002402041700002202065700002002087700002402107700002302131856003602154 2023 eng d a2398-923800aCirculating differentiated and senescent lymphocyte subsets and incident diabetes risk in older adults: The Cardiovascular Health Study.0 aCirculating differentiated and senescent lymphocyte subsets and c2023 Jan ae3840 v63 aINTRODUCTION: 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.
10aCD28 Antigens10aCD8-Positive T-Lymphocytes10aCellular Senescence10aDiabetes Mellitus10aLeukocytes, Mononuclear10aLymphocyte Subsets1 aOlson, Nels, C1 aDoyle, Margaret, F1 aBůzková, Petra1 aHuber, Sally, A1 ade Boer, Ian, H1 aSitlani, Colleen, M1 aTracy, Russell, P1 aPsaty, Bruce, M1 aMukamal, Kenneth, J1 aDelaney, Joseph, A uhttps://chs-nhlbi.org/node/9240