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Leukocyte Telomere Length and Coronary Artery Calcium

      Patients with histories of myocardial infarction display shortened leukocyte telomere length (LTL), but conflicting findings have been reported on the relation between LTL and subclinical coronary artery atherosclerosis, as expressed by coronary artery calcium (CAC). The aim of this study was to examine the relation between LTL, measured by Southern blots, and CAC in 3,169 participants in the National Heart, Lung, and Blood Institute Family Heart Study. Participants consisted of 2,556 whites, 613 blacks, 1,790 women, and 1,379 men. The odds of having CAC ≥100 for the shortest LTL tertile versus the longest LTL tertile were 1.95 (95% confidence interval [CI] 1.28 to 3.16) in white men and 1.76 (95% CI 1.18 to 2.45) in white women, after adjusting for multiple covariates of CAC. The corresponding odds ratios for blacks were 1.53 (95% CI 0.67 to 3.50) and 0.87 (95% CI 0.37 to 2.00). Significance levels of tests for trend across LTL tertiles were p = 0.002 in white men, p = 0.006 in white women, p = 0.32 in black men, and p = 0.74 in black women. The associations, or lack of associations, were independent of C-reactive protein levels and other risk factors for CAC. As previously shown in other studies, whites displayed shorter LTLs than blacks (p <0.0001). In conclusion, the higher the coronary artery atherosclerotic burden in whites, the shorter the LTL. This LTL-atherosclerosis connection is not found in blacks. The mechanisms for the racial difference in LTL, CAC, and their interrelations do not seem to be related to inflammation and merit further research.
      Cardiovascular disease, principally in the form of atherosclerosis, and leukocyte telomere length (LTL) are associated with aging and ostensibly with each other.
      • Aviv A.
      Genetics of leukocyte telomere length and its role in atherosclerosis.
      A recent meta-analysis, although confirming that patients who have had myocardial infarctions have shorter LTLs than their peers, failed to show a significant association of LTL with coronary artery disease, the root cause of most cases of myocardial infarction.
      • D'Mello M.J.
      • Ross S.A.
      • Briel M.
      • Anand S.S.
      • Gerstein H.
      • Pare G.
      Association between shortened leukocyte telomere length and cardiometabolic outcomes: systematic review and meta-analysis.
      Coronary artery calcium (CAC) is a highly sensitive and specific index of coronary artery disease risk, because arterial calcium is pathognomonic of atherosclerosis and also a sensitive indicator of atherosclerotic plaque burden in the coronary arteries.
      • Budoff M.J.
      • Achenbach S.
      • Blumenthal R.S.
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      • Guerci A.D.
      • Lima J.A.
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      • Rubin G.D.
      • Shaw L.J.
      • Wiegers S.E.
      American Heart Association Committee on Cardiovascular Imaging and InterventionAmerican Heart Association Council on Cardiovascular Radiology and InterventionAmerican Heart Association Committee on Cardiac Imaging, Council on Clinical Cardiology
      Assessment of coronary artery disease by cardiac computed tomography: a scientific statement from the American Heart Association Committee on Cardiovascular Imaging and Intervention, Council on Cardiovascular Radiology and Intervention, and Committee on Cardiac Imaging, Council on Clinical Cardiology.
      A body of research indicates that independent of traditional risk factors, CAC predicts myocardial infarction.
      • Hopkins P.N.
      • Ellison R.C.
      • Province M.A.
      • Pankow J.S.
      • Carr J.J.
      • Arnett D.K.
      • Lewis C.E.
      • Heiss G.
      • Hunt S.C.
      Association of coronary artery calcified plaque with clinical coronary heart disease in the National Heart, Lung, and Blood Institute's Family Heart Study.
      • Church T.S.
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      • McGuire D.K.
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      Coronary artery calcium score, risk factors, and incident coronary heart disease events.
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      Coronary calcium as a predictor of coronary events in four racial or ethnic groups.
      • Shaw L.J.
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      • Callister T.Q.
      Coronary artery calcium as a measure of biologic age.
      Even in the presence of multiple cardiac risk factors, subjects with no evidence of CAC have low near-term risk for myocardial infarction.
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      • Gibbons L.W.
      • Nichaman M.Z.
      Coronary artery calcium score, risk factors, and incident coronary heart disease events.
      Here we present the relation of LTL with CAC on the basis of a cohort comprising 3,169 participants in the National Heart, Lung and Blood Institute Family Heart Study. This work has also examined whether gender, ethnicity (black or white), and high-sensitivity serum C-reactive protein (CRP) affect the association of LTL with CAC.

      Methods

      The NHLBI Family Heart Study is a multicenter investigation of the genetic and epidemiologic basis of cardiovascular disease.
      • Higgins M.
      • Province M.
      • Heiss G.
      • Eckfeldt J.
      • Ellison R.C.
      • Folsom A.R.
      • Rao D.C.
      • Sprafka J.M.
      • Williams R.
      NHLBI Family Heart Study: objectives and design.
      From January 2002 to January 2004, 3,359 subjects were examined (2,737 whites, 622 blacks). These subjects had either participated in previous clinic visits from February 1994 to March 1996 or were newly recruited blacks from the Hypertension Genetic Epidemiology Network field center in Birmingham, Alabama.
      • Williams R.R.
      • Rao D.C.
      • Ellison R.C.
      • Arnett D.K.
      • Heiss G.
      • Oberman A.
      • Eckfeldt J.H.
      • Leppert M.F.
      • Province M.A.
      • Mockrin S.C.
      • Hunt S.C.
      NHLBI family blood pressure program: methodology and recruitment in the HyperGEN network. Hypertension Genetic Epidemiology Network.
      The study protocol was approved by the institutional review board at each of the participating centers, and each participant gave written informed consent.
      Ethylenediamine tetra-acetic acid blood was stored at −70°C until shipment to the Center of Human Development and Aging at the New Jersey Medical School, Rutgers, for LTL measurement. Deoxyribonucleic acid (DNA) was extracted using the Gentra Puregene Blood Kit (Qiagen, Valencia, California), and samples were subjected to DNA integrity tests. LTL was derived from the mean length of the terminal restriction fragments, determined by Southern blot analysis.
      • Kimura M.
      • Stone R.C.
      • Hunt S.C.
      • Skurnick J.
      • Lu X.
      • Cao X.
      • Harley C.B.
      • Aviv A.
      Measurement of telomere length by the Southern blot analysis of terminal restriction fragment lengths.
      The interassay coefficient of variation for duplicate samples, which were resolved on different gels on different occasions, was 2.4%.
      CAC measurements were obtained from 5 field centers using 4-slice multidetector computed tomographic systems without contrast (GE Health Systems LightSpeed Plus and LightSpeed Ultra, Siemens Volume Zoom, or Philips MX 8000). The protocol and scoring (Agatston score) at a central reading laboratory have been previously described and were consistent across centers.
      • Hopkins P.N.
      • Ellison R.C.
      • Province M.A.
      • Pankow J.S.
      • Carr J.J.
      • Arnett D.K.
      • Lewis C.E.
      • Heiss G.
      • Hunt S.C.
      Association of coronary artery calcified plaque with clinical coronary heart disease in the National Heart, Lung, and Blood Institute's Family Heart Study.
      Measurements of glucose and lipid levels were performed on fasting blood samples. Thirty-six subjects who were fasting for <6 hours were excluded from all analyses. High-sensitivity serum CRP was measured at the Laboratory for Clinical Biochemistry Research, University of Vermont, using an enzyme-linked immunosorbent assay method calibrated with World Health Organization reference material.
      • Folsom A.R.
      • Pankow J.S.
      • Tracy R.P.
      • Arnett D.K.
      • Peacock J.M.
      • Hong Y.
      • Djousse L.
      • Eckfeldt J.H.
      Association of C-reactive protein with markers of prevalent atherosclerotic disease.
      The New Jersey and Vermont laboratories were blinded to the identities of the subjects.
      Pack-years of smoking were obtained by a questionnaire. An automated blood pressure device (Dinamap Monitor Pro 100) was used to record 3 measurements of blood pressure, 1 minute apart. Hypertension was defined as currently taking antihypertensive medications or an untreated blood pressure of ≥140/90 mm Hg. Medication use for hypertension or dyslipidemia was obtained from each subject and coded as current or not for this analysis.
      Subject characteristics were compared across gender and race categories using generalized estimating equations and an exchangeable correlation matrix to model the relatedness of the subjects (PROC GENMOD; SAS Institute Inc., Cary, North Carolina). To examine the mean LTL by 4 different CAC categories (0, 1 to 99, 100 to 399, and ≥400 Agatston units), we first adjusted LTL for age and analyzed the means of the residuals after the overall mean was added back to each residual. A test for a linear trend across the categories was performed using contrasts in this same model. Tertiles of LTL were analyzed for the primary association tests so that a linear relation between LTL and CAC did not need to be assumed.
      To predict the risk for developing significant coronary atherosclerotic calcium, CAC was modeled as a dichotomous dependent variable (CAC ≥100 vs CAC <100) in a logistic general linear model that incorporated the effects of LTL nested within gender and race categories as the independent variable, the relatedness of the sample, and multiple covariates that have been shown to be related to the development of CAC. Two sets of covariates were used for additional statistical adjustment. First, adjustment was performed using age and body mass index (BMI) only as covariates. The second set of covariates included age, BMI, pack-years of smoking, glucose, low-density lipoprotein cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, mean arterial blood pressure, blood pressure medication status, and CRP. Gender-combined models included an adjustment for gender.

      Results

      A total of 3,169 of 3,359 subjects had LTL measurements. The 190 subjects without LTL measurements were those who did not provide blood samples to obtain DNA, those who had too little DNA for LTL measurement, and whose samples failed the DNA integrity tests. Table 1 lists the characteristics of the subjects. Women were slightly older and had lower diastolic blood pressure, higher CRP and HDL cholesterol, but lower fasting glucose and triglycerides compared with men. Blacks were younger and displayed higher BMIs, systolic and diastolic blood pressures, higher CRP, fasting glucose and HDL cholesterol, and lower triglycerides than whites. Fewer women than men were smokers. Compared with whites, more blacks were current smokers and taking antihypertensive medications, and fewer were taking lipid-lowering drugs.
      Table 1Subject characteristics in the NHLBI Family Heart Study
      VariableBlackWhitep-value
      p-value from two-way ANOVA test for gender and race, after adjusting for age.
      Men

      (N=215)
      Women (N=398)Men (N=1164)Women (N=1392)Gender Effect
      p-value from two-way ANOVA test for gender and race, after adjusting for age.
      Race Effect
      p-value from two-way ANOVA test for gender and race, after adjusting for age.
      Age (year)52±0.754±0.657±0.458±0.40.01<0.0001
      Body mass index (kg/m2)30.4±0.433.8±0.429.3±0.228.4±0.20.47<0.0001
      Systolic blood pressure (mmHg)132±1.4133±1.2122±0.5119±0.6<0.0001<0.0001
      Diastolic blood pressure (mmHg)79±0.874±0.673±0.367±0.3<0.0001<0.0001
      Coronary arterial calcium (Agatston)342±44166±19521±29125±13<0.00010.09
      Leukocyte telomere length (kb)6.85±0.047.11±0.036.73±0.026.87±0.02<0.0001<0.0001
      C-reactive protein (mg/l)4.6±0.47.6±0.52.8±0.14.1±0.2<0.0001<0.0001
      Glucose (mg/dl)116±3.0111±2.2103±0.897±0.6<0.0001<0.0001
      Low density lipoprotein cholesterol (mg/dl)113±2.6116±1.8109±1.0112±1.10.010.03
      High density lipoprotein (mg/dl)47±1.157+0.742±0.454±0.5<0.0001<0.0001
      Triglycerides (mg/dl)117±5.7110±3.9152±3.2136±2.4<0.0001<0.0001
      Pack-years of smoking15.4±1.47.0±0.615.9±0.87.6±0.5<0.00010.49
      Antihypertensive drugs56%70%33%30%0.37<0.0001
      Lipid lowering drugs20%15%26%21%<0.00010.16
      Data are presented as mean ± SEM.
      p-value from two-way ANOVA test for gender and race, after adjusting for age.
      Age-adjusted LTL was longer in women than in men (6.98 ± 0.02 vs 6.81 ± 0.02, p <0.0001) and in blacks than in whites (7.01 ± 0.03 vs 6.78 ± 0.02, p <0.0001). Shorter LTL was significantly related to increased CAC category, but only in whites (Table 2). Blacks with either CAC = 0 or CAC ≥400 had longer LTLs than those in the 2 intermediate CAC categories, resulting in more of a quadratic relation between the 2 variables. When age-adjusted LTL was divided into tertiles, shorter LTL predicted increased probability of CAC ≥100 in white men and women after adjustment for age and BMI (Figure 1). Odds ratios for CAC ≥100 for the shorter LTL tertile versus the longer LTL tertile were 2.08 (95% confidence interval [CI] 1.38 to 3.13) for white men and 1.55 (95% CI 1.06 to 2.28) for white women after age and BMI adjustment. After including other covariates that have been related to CAC in the model (mean arterial pressure, low-density lipoprotein cholesterol, HDL cholesterol, triglycerides, pack-years of smoking, and CRP), the previous odds ratios were only slightly reduced and remained significant (1.95 [95% CI 1.28 to 3.16] for white men and 1.76 [95% CI 1.18 to 2.45] for white women). Significance levels of tests for linear trend across the 3 LTL tertiles were p = 0.002 for white men and p = 0.006 for white women. The odds ratios for blacks (Figure 1) were not significant (1.53 [95% CI 0.67 to 3.50] for black men and 0.87 [95% CI 0.37 to 2.00] for black women) in the fully adjusted model. Results of tests for linear trends across the LTL tertiles in blacks were p = 0.32 for men and p = 0.74 for women.
      Table 2Age-adjusted leukocyte telomere length (kb) by coronary arterial calcium (CAC, Agatston score) category, sex, and race
      CACBlackWhite
      MenWomenBothMenWomenBoth
      06.98±0.08 (82)7.20±0.04 (205)7.08±0.04 (287)6.78±0.04 (300)6.85±0.03 (721)6.80±0.02 (1021)
      1-996.92±0.07 (71)7.16±0.06 (127)7.04±0.05 (198)6.78±0.03 (371)6.88±0.03 (380)6.81±0.02 (751)
      100-3996.90±0.10 (29)7.15±0.09 (36)7.02±0.07 (65)6.57±0.04 (154)6.77±0.05 (147)6.69±0.04 (301)
      ≥4006.97±0.10 (33)7.23±0.10 (30)7.10±0.07 (63)6.61±0.04 (339)6.74±0.06 (144)6.70±0.03 (483)
      p
      Test for linear trend across CAC categories.
      0.910.800.900.00030.0360.002
      Sample size is given for each category in parentheses. Mean leukocyte telomere length adjusted for age and sex when combining men and women. Data are presented as mean ± SEM.
      Test for linear trend across CAC categories.
      Figure thumbnail gr1
      Figure 1Odds ratios of coronary calcium (≥100 vs <100 Agatston units) by tertile of LTL: (A) white men and women and (B) black men and women. The longest LTL tertile is used as the referent group. Odds ratios and 95% CIs are shown after adjustment for either age and BMI or adjustment for age, BMI, mean arterial pressure, low-density lipoprotein cholesterol, HDL cholesterol, triglycerides, pack-years of smoking, CRP, and use of antihypertensive or lipid-lowering medications.
      CRP was not significantly associated with CAC in the fully adjusted models for either race, and in addition, CRP was also not related to LTL (p = 0.65 in whites and p = 0.40 in blacks, after adjusting for gender, age, BMI and pack-years). Age and pack-years of smoking were significantly related to CAC for both genders in the whites, with BMI also associated in white women and mean arterial pressure associated in white men.

      Discussion

      Longer LTLs in women than men
      • Gardner M.
      • Bann D.
      • Wiley L.
      • Cooper R.
      • Hardy R.
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      Halcyon study team
      Gender and telomere length: systematic review and meta-analysis.
      and in blacks than whites
      • Hunt S.C.
      • Chen W.
      • Gardner J.P.
      • Kimura M.
      • Srinivasan S.R.
      • Eckfeldt J.H.
      • Berenson G.S.
      • Aviv A.
      Leukocyte telomeres are longer in African Americans than in whites: the National Heart, Lung, and Blood Institute Family Heart Study and the Bogalusa Heart Study.
      • Elbers C.C.
      • Garcia M.E.
      • Kimura M.
      • Cummings S.R.
      • Nalls M.A.
      • Newman A.B.
      • Park V.
      • Sanders J.L.
      • Tranah G.J.
      • Tishkoff S.A.
      • Harris T.B.
      • Aviv A.
      Comparison between southern blots and qPCR analysis of leukocyte telomere length in the Health ABC Study.
      have been consistently observed when LTL measurements are performed by Southern blots. In the present study, these gender and race differences in LTL were confirmed. Furthermore, we observed an inverse relation between LTL and CAC for only whites, whose age-adjusted LTL between individuals (men and women) with CAC scores <100 Agatston units versus those with CAC scores ≥100 Agatston units amounted to about 110 base pairs (Table 2). This compares with average differences of 170 base pairs between men and women and 230 base pairs between whites and blacks. Thus, factors that affect LTL dynamics (LTL at birth and age-dependent shortening afterward) and their relation with CAC may differ in nature and magnitude between blacks and whites. However, the nature of these factors is poorly understood.
      A recent meta-analysis has confirmed that subjects who experienced myocardial infarctions were likely to have shorter LTLs than their peers.
      • D'Mello M.J.
      • Ross S.A.
      • Briel M.
      • Anand S.S.
      • Gerstein H.
      • Pare G.
      Association between shortened leukocyte telomere length and cardiometabolic outcomes: systematic review and meta-analysis.
      However, the meta-analysis failed to show a significant association of short LTL with coronary artery disease, the principal cause of myocardial infarction. In addition, 2 studies
      • Kark J.D.
      • Nassar H.
      • Shaham D.
      • Sinnreich R.
      • Goldberger N.
      • Aboudi V.
      • Bogot N.R.
      • Kimura M.
      • Aviv A.
      Leukocyte telomere length and coronary artery calcification in Palestinians.
      • Mainous 3rd, A.G.
      • Codd V.
      • Diaz V.A.
      • Schoepf U.J.
      • Everett C.J.
      • Player M.S.
      • Samani N.J.
      Leukocyte telomere length and coronary artery calcification.
      observed an inverse relation of LTL with CAC, while a third study
      • Kroenke C.H.
      • Pletcher M.J.
      • Lin J.
      • Blackburn E.
      • Adler N.
      • Matthews K.
      • Epel E.
      Telomerase, telomere length, and coronary artery calcium in black and white men in the CARDIA Study.
      did not. One of the studies examined whites and blacks.
      • Mainous 3rd, A.G.
      • Codd V.
      • Diaz V.A.
      • Schoepf U.J.
      • Everett C.J.
      • Player M.S.
      • Samani N.J.
      Leukocyte telomere length and coronary artery calcification.
      It observed a lower strength of the association between LTL and CAC in blacks than in whites; in blacks, this association was not statistically significant. These studies comprised relatively small sample sizes. The findings of the present study clearly establish that in whites, LTL is inversely associated with CAC, a finding that is not observed in blacks.
      CAC scores are typically lower in women than men and in blacks than whites.
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      Racial differences in coronary artery calcification are not attributed to differences in lipoprotein particle sizes: the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) Study.
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      Early adult risk factor levels and subsequent coronary artery calcification: the CARDIA Study.
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      • Post W.
      • Kronmal R.A.
      Distribution of coronary artery calcium by race, gender, and age: results from the Multi-Ethnic Study of Atherosclerosis (MESA).
      • Yan L.L.
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      • Kiefe C.I.
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      • Matthews K.A.
      • Greenland P.
      Education, 15-year risk factor progression, and coronary artery calcium in young adulthood and early middle age: the Coronary Artery Risk Development in Young Adults study.
      Previous studies have also found that CRP levels are lower in men than women and in whites than blacks.
      • Lakoski S.G.
      • Cushman M.
      • Criqui M.
      • Rundek T.
      • Blumenthal R.S.
      • D'Agostino Jr., R.B.
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      Gender and C-reactive protein: data from the Multiethnic Study of Atherosclerosis (MESA) cohort.
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      Distribution and metabolic syndrome correlates of plasma C-reactive protein in biracial (black-white) younger adults: the Bogalusa Heart Study.
      • Rosen B.D.
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      • Lai S.
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      • Lima J.A.
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      These gender- and race-related differences in CAC and CRP were observed in the present work. The ultimate trigger of myocardial infarction is often the disruption of the atherosclerotic plaque, a process that is prompted by inflammation and thrombosis.
      • Hansson G.K.
      • Libby P.
      The immune response in atherosclerosis: a double-edged sword.
      • Virmani R.
      • Burke A.P.
      • Farb A.
      • Kolodgie F.D.
      Pathology of the vulnerable plaque.
      Accordingly, CRP has been the focus of studies that have examined the ability of inflammatory biomarkers to predict this eventuality, but its value for clinical practice is a matter of debate.
      • Virmani R.
      • Burke A.P.
      • Farb A.
      • Kolodgie F.D.
      Pathology of the vulnerable plaque.
      • Kinlay S.
      • Egido J.
      Inflammatory biomarkers in stable atherosclerosis.
      • Yousuf O.
      • Mohanty B.D.
      • Martin S.S.
      • Joshi P.H.
      • Blaha M.J.
      • Nasir K.
      • Blumenthal R.S.
      • Budoff M.J.
      High-sensitivity C-reactive protein and cardiovascular disease: a resolute belief or an elusive link?.
      CRP appears to predict myocardial infarction,
      • Yousuf O.
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      • Blaha M.J.
      • Nasir K.
      • Blumenthal R.S.
      • Budoff M.J.
      High-sensitivity C-reactive protein and cardiovascular disease: a resolute belief or an elusive link?.
      but it is a weak index of coronary atherosclerosis, especially as represented by CAC.
      • Khera A.
      • de Lemos J.A.
      • Peshock R.M.
      • Lo H.S.
      • Stanek H.G.
      • Murphy S.A.
      • Wians Jr., F.H.
      • Grundy S.M.
      • McGuire D.K.
      Relationship between C-reactive protein and subclinical atherosclerosis: the Dallas Heart Study.
      In the present study, we found no relations between LTL and CRP and between CRP and CAC.
      The large sample size of the present study and the use of the more precise Southern blot method to measure LTL,
      • Aviv A.
      • Hunt S.C.
      • Lin J.
      • Cao X.
      • Kimura M.
      • Blackburn E.
      Impartial comparative analysis of measurement of leukocyte telomere length/DNA content by Southern blots and qPCR.
      we suggest, provide confidence in the validity of the findings. Nevertheless, we would like to underscore the study limitations. First, this was a cross-sectional analysis. A longitudinal study that monitors LTL and CAC score over many years might be more informative. Second, there were fewer blacks than whites and, on average, blacks were younger than whites. Therefore, there was less chronological time for LTL to shorten and CAC to develop in blacks. That being said, the sample size for the blacks was much larger than previously published studies, and the odds ratios were much lower and more inconsistent across LTL tertiles than for whites. Nevertheless, we cannot rule out smaller risks in blacks compared with whites of high CAC levels with shorter telomeres.

      Disclosures

      The authors have no conflicts of interest to disclose.

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