Associations between Blood Lead Levels and Coronary Artery Stenosis Measured Using Coronary Computed Tomography Angiography
2021; National Institute of Environmental Health Sciences; Volume: 129; Issue: 2 Linguagem: Inglês
10.1289/ehp7351
ISSN1552-9924
AutoresSuwhan Kim, Wonyang Kang, Seunghyeon Cho, Dae-Young Lim, Yeongjae Yoo, Ryoung Jin Park, Byung-Chan Lee, Jai-Dong Moon, Won-Ju Park,
Tópico(s)Cardiac electrophysiology and arrhythmias
ResumoVol. 129, No. 2 ResearchOpen AccessAssociations between Blood Lead Levels and Coronary Artery Stenosis Measured Using Coronary Computed Tomography Angiography Suwhan Kim, Wonyang Kang, Seunghyeon Cho, Dae-Young Lim, Yeongjae Yoo, Ryoung Jin Park, Byung Chan Lee, Jai-Dong Moon, and Won-Ju Park Suwhan Kim Department of Occupational and Environmental Medicine, Chonnam National University (CNU) Medical School and CNU Hwasun Hospital, Hwasun, Republic of Korea , Wonyang Kang Department of Occupational and Environmental Medicine, Chonnam National University (CNU) Medical School and CNU Hwasun Hospital, Hwasun, Republic of Korea Institute of Occupational and Environmental Health, Korea Workers' Compensation & Welfare Service, Incheon, Republic of Korea , Seunghyeon Cho Department of Occupational and Environmental Medicine, Chonnam National University (CNU) Medical School and CNU Hwasun Hospital, Hwasun, Republic of Korea , Dae-Young Lim Department of Occupational and Environmental Medicine, Chonnam National University (CNU) Medical School and CNU Hwasun Hospital, Hwasun, Republic of Korea , Yeongjae Yoo Department of Occupational and Environmental Medicine, Chonnam National University (CNU) Medical School and CNU Hwasun Hospital, Hwasun, Republic of Korea , Ryoung Jin Park Department of Occupational and Environmental Medicine, Gwangyang Sarang General Hospital, Gwangyang, Republic of Korea , Byung Chan Lee Department of Radiology, CNU Medical School and CNU Hwasun Hospital, Republic of Korea , Jai-Dong Moon Department of Occupational and Environmental Medicine, Chonnam National University (CNU) Medical School and CNU Hwasun Hospital, Hwasun, Republic of Korea , and Won-Ju Park Address correspondence to Won-Ju Park, Department of Occupational and Environmental Medicine, Chonnam National University Hwasun Hospital, 322 Seoyang-ro, Hwasun-gun, Jeollanam-do 58128, Republic of Korea. Telephone: 82-61-379-7788. Email: E-mail Address: [email protected] Department of Occupational and Environmental Medicine, Chonnam National University (CNU) Medical School and CNU Hwasun Hospital, Hwasun, Republic of Korea Published:23 February 2021CID: 027006https://doi.org/10.1289/EHP7351AboutSectionsPDF Supplemental Materials ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InRedditEmail AbstractBackground:Lead exposure is a risk factor for increased blood pressure and cardiovascular disease, even when blood lead levels (BLLs) are within the normal range.Objective:This study aimed to investigate the association between BLL and coronary artery stenosis (CAS) in asymptomatic adults using 128-slice dual-source coronary computed tomography (CT) angiography.Methods:We analyzed medical records data from 2,193 adults (1,461 men and 732 women) who elected to complete a screening health examination, coronary CT angiography, and BLL measurement during 2011–2018 and had no history of CAS symptoms, cardiovascular disease, or occupational exposure to lead. Logistic regression models were used to estimate associations between moderate-to-severe CAS (≥25% stenosis) and a 1-μg/dL increase in blood lead, with and without adjustment for age, sex, hypertension, diabetes mellitus, dyslipidemia, body mass index, regular exercise, smoking status, and alcohol drinking.Results:BLLs ranged from 0.12 to 10.14μg/dL, with an arithmetic mean of 2.71±1.26μg/dL. The arithmetic mean was higher for men than for women (2.98±1.26μg/dL vs. 2.18±1.08μg/dL, p<0.001) and higher in the moderate-to-severe CAS group than in the no-CAS or <25% stenosis group (3.02±1.44μg/dL vs. 2.67±1.23μg/dL, p<0.001). Moderate-to-severe CAS was significantly associated with BLL before and after adjustment, with an adjusted odds ratio for a 1-μg/dL increase in BLL of 1.14 (95% CI: 1.02, 1.26), p=0.017.Conclusions:BLL was positively associated with the prevalence of moderate-to-severe CAS in Korean adults who completed an elective screening examination for early cardiovascular disease, 94% of whom had a BLL of 20 years of age who completed voluntary medical examinations at the Chonnam National University (CNU) Hwasun Hospital in South Jeolla Province, South Korea, between January 2011 and December 2018 and consented to the collection and use of their personal information for research purposes, in accordance with the Personal Information Protection Act of South Korea. Medical records data were anonymized and stored in the CNU Hwasun Hospital Clinical Data Warehouse, and the study protocol was approved by the institutional review board (IRB) of CNU Hwasun Hospital (IRB number CNUHH-2020-150).Participants (or their employers) were responsible for the costs of the health examinations, which were not prompted by any symptoms or clinical indications. Of the 11,846 consenting participants who completed a health examination, 3,417 underwent elective coronary artery CT angiography to screen for early cardiovascular disease; of these, 2,316 also elected to have blood lead measurement (Figure 1). Contraindications for the screening coronary CT scan were a history of severe adverse reactions to iodinated radiocontrast media or a glomerular filtration rate of 10 min. Total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein cholesterol, triglycerides, and blood glucose levels were measured in blood samples collected after 12 h of fasting.Regular exercise was defined as performing regular physical activity for more than 30 min per day and more than once a week. Participants who had smoked less than five packs of cigarettes in their life were classified as nonsmokers, whereas those who had stopped smoking or who smoked currently were classified as ex-smokers and current smokers, respectively. Participants who ingested more than 20 g of alcohol more than once a week were classified as alcohol drinkers. Obesity was defined as a body mass index (BMI; kg/m2) of ≥25, according to guidelines set by the South Korean Ministry of Health and Welfare (Seo et al. 2019). Participants who were taking antihypertensive medications or had a systolic blood pressure of ≥140 mmHg or a diastolic blood pressure of ≥90 mmHg at the time of the examination were classified as hypertensive. Participants who were being treated for diabetes mellitus or had fasting glucose levels ≥126mg/dL or glycated hemoglobin (HbA1c) levels ≥6.5% at the time of the health examination were classified as having diabetes. Participants with total cholesterol levels of ≥240mg/dL, LDL cholesterol levels of ≥160mg/dL, or triglyceride levels of ≥500mg/dL at the time of the health examination, were classified as having dyslipidemia.Blood Lead MeasurementsWhole blood (3mL) was collected using a disposable syringe and placed in a K2 ethylenediaminetetraacetic acid vacuum tube. The syringe and tube were made of metal-free products. After collection, samples were mixed well and stored in a refrigerator at 4°C (2–8°C) for up to 3 d before analysis. BLLs were analyzed according to Korea Occupational Safety and Health Agency (KOSHA) guidelines (KOSHA 2017) using an atomic absorption spectrometer (Shimadzu) attached to a graphite furnace atomizer (GFA-EX7; Shimadzu). Stored samples were mixed for ≥30 min, and 0.1mL of whole blood was diluted with 0.8mL of 1% Triton X-100. All BLL measurements conducted during the study period (2011–2018) were performed by a single analyst under identical laboratory conditions. To verify the validity and reliability of the analysis, external quality control was performed, and laboratory conditions and the proficiency of the analyst were assessed every 2 y by KOSHA, and internal quality control was performed using standard reference material. The limit of detection (LOD) was 0.01μg/dL. No samples had lead levels below the LOD.Coronary Artery StenosisCoronary CT angiography was performed using 128-slice dual-source CT equipment (SOMATOM Definition Flash). To assess CAS, electrocardiographically gated axial images of the heart were obtained after intravascular administration of a contrast medium (Ultravist; Schering AG). The intensity of the contrast-enhanced portion of the coronary lumen at the site of maximal stenosis was measured and compared with the mean values obtained for the proximal and distal sites. After imaging, two experienced and certified cardiovascular radiology specialists evaluated the degree of narrowing of the inner diameter of the coronary artery. When there was a discrepancy in the readings recorded by the radiology specialists, the final values were decided by consensus. All analyses were performed by the same two radiology specialists during the study period. Both were qualified by the Certification Board of Cardiovascular Computed Tomography. The Korean Society of Cardiovascular Imaging recognizes this qualification, and training and evaluation are required for renewal of the certification every 5 y. In the evaluations conducted, the degree of stenosis was described as the percentage of narrowing. The degree of stenosis was classified according to the guidelines of the Coronary Artery Disease-Reporting and Data System (Ramanathan et al. 2019) as follows: a) no stenosis (0% narrowing); b) mild stenosis (>0% and <25% narrowing); c) moderate stenosis (≥25% and <70% narrowing); and d) severe stenosis (≥70% narrowing) (Figure 2). In the present study, for the purpose of statistical analyses, moderate-to-severe coronary artery narrowing (≥25% stenosis) was defined as moderate-to-severe CAS (MSCAS).Figure 2. Coronary artery stenosis visualized using 128-slice dual-source coronary computed tomography angiography. (A) Mild stenosis in left circumflex artery, (B) moderate stenosis in left anterior descending artery, and (C) severe stenosis in right coronary artery.Statistical AnalysisDifferences in the prevalence of CAS according to categorical variables were evaluated using the Pearson chi-square test. BLLs exhibited a right-skewed distribution (Figure 3); therefore, differences in natural log-transformed BLLs according to participant characteristics were compared using a Student's t-test or analysis of variance (Table S1). Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for MSCAS (≥25% stenosis) in association with a 1-μg/dL increase in BLL in the population as a whole and after stratification by sex. Models were adjusted for covariates that were significant predictors of MSCAS in bivariate models (Table S2), with increasing levels of adjustment for Model 1 [adjusted for age (continuous) and sex]; Model 2 [age, sex, BMI (continuous), regular exercise (yes/no), smoking (ever/never), and alcohol consumption (yes/no)]; and Model 3 [Model 2 covariates plus hypertension (yes/no), diabetes mellitus (yes/no), dyslipidemia (yes/no)]. Given the importance of cigarette smoking as a potential confounder, we repeated Models 2 and 3 after replacing smoking (ever/never) with pack-years of smoking (continuous, with never smokers assigned a value of 0). All statistical analyses were performed using SPSS (version 26.0; SPSS Inc.), and the significance level was defined as p 25) was 46% among men and 31% among women (Table 1), and the average BMI was also higher in men than women (24.8±2.8 vs. 23.9±2.9, respectively). Men were also more likely than women to consume alcohol (79% vs. 38%), be current or former smokers (77% vs. 3%), and be classified as having hypertension (30% vs. 27%) and diabetes mellitus (19% vs. 14%). Regular exercise was reported by 54% of men and women, and the prevalence of dyslipidemia was 23% in men and women. Of the total number of participants, 296 (14%) had mild CAS (>0 and <25% stenosis), and 250 (11%) had MSCAS (≥25% stenosis) (Table 1).Table 1 General characteristics of study participants.Table 1 has three main columns, namely, Variables, lowercase italic n (percentage), and lowercase italic p value. The lowercase italic n (percentage) column is subdivided into three columns, namely, Total, lowercase italic n equals 2,193; Men, lowercase italic n equals 1,461; and Women, lowercase italic n equals 732.Variablesn (%)p-ValueaTotal (n=2,193)Men (n=1,461)Women (n=732)Age (y)<0.001 <4080 (3.6)54 (3.7)26 (3.5) ≥40 to <50641 (29.2)480 (32.9)161 (22.0) ≥50 to <60962 (43.9)624 (42.7)338 (46.2) ≥60510 (23.3)303 (20.7)207 (28.3)BMI (kg/m2)<0.001 <251,291 (58.9)786 (53.8)505 (69.0) ≥25902 (41.1)675 (46.2)227 (31.0)Smoking<0.001 Nonsmoker1,053 (48.0)344 (23.5)709 (96.9) Ex-smoker529 (24.1)526 (36.0)3 (0.4) Current smoker611 (27.9)591 (40.5)20 (2.7)Alcohol drinking<0.001 No760 (34.7)308 (21.1)452 (61.7) Yes1,433 (65.3)1,153 (78.9)280 (38.3)Regular exercise0.823 No999 (45.6)668 (45.7)331 (45.2) Yes1,194 (54.4)793 (54.3)401 (54.8)Hypertension0.104 No1,554 (70.9)1,019 (69.7)535 (73.1) Yes639 (29.1)442 (30.3)197 (26.9)Dyslipidemia0.952 No1,691 (77.1)1,126 (77.1)565 (77.2) Yes502 (22.9)335 (22.9)167 (22.8)Diabetes mellitus0.002 No1,817 (82.9)1,185 (81.1)632 (86.3) Yes376 (17.1)276 (18.9)100 (13.7)Degree of CAS 0% and <25%)296 (13.5)222 (15.2)74 (10.1) Moderate (≥25% and <70%)184 (8.4)148 (10.1)36 (4.9) Severe (≥70%)66 (3.0)52 (3.6)14 (1.9)Note: BMI, body mass index; CAS, coronary artery stenosis.aComparison by Pearson chi-square test between men and women.Overall, BLLs ranged from 0.12 to 10.14μg/dL. The arithmetic mean was 2.71±1.26μg/dL overall and was significantly higher in men (2.98±1.26μg/dL) than women (2.18±1.08μg/dL, p<0.001) (Table 2). Mean BLL was highest in the 50- to 59-y age group (2.78±1.24μg/dL) (Table S1). Other significant predictors of higher BLL were BMI, smoking, and alcohol consumption, whereas diabetes was associated with lower BLL. With respect to CAS, mean BLL was significantly higher in the group with ≥25% stenosis than in participants with 0 to<25% stenosis (3.02±1.44μg/dL vs. 2.67±1.23μg/dL).Table 2 Blood lead level distribution of study participants.Table 2 has three main columns, namely, Variables, lowercase italic n, and Blood lead level (micrograms per deciliter). The Blood lead level (micrograms per deciliter) column is subdivided into seven columns, namely, Arithmetic mean plus or minus Standard Deviation, Minimum, twenty-fifth percentile, fiftieth percentile, seventy-fifth percentile, Maximum, and Geometric mean (geometric standard deviation).VariablesnBlood lead level (μg/dL)Arithmetic mean±SDMin.25th percentile50th percentile75th percentileMax.Geometric mean (GSD)All participants2,1932.71±1.260.121.842.533.3810.142.43 (1.64)Men1,4612.98±1.260.122.112.783.6410.012.72 (1.56)Women7322.18±1.080.201.442.032.6810.141.93 (1.67)Note: GSD, geometric standard deviation; max., maximum; min., minimum; SD, standard deviation.The prevalence of MSCAS was higher in men (n=200, 13.7%) than in women (n=50, 6.8%). Older age, hypertension, dyslipidemia, and diabetes mellitus were significant predictors of MSCAS overall, and in men and women. Obesity, smoking, pack-years of smoking, alcohol consumption, and a lack of regular exercise were also significant predictors of MSCAS in the overall population (Table S2).Because the general characteristics of the participants differed significantly according to sex, the association between MSCAS and BLL was analyzed after stratification by sex. In all participants, the fully adjusted (Model 3) OR for a 1-μg/dL increase in BLL was 1.14 (95% CI: 1.02, 1.26) (Table 3). Corresponding ORs for men and women were 1.14 (95% CI: 1.01, 1.28) and 1.10 (95% CI: 0.86, 1.41), respectively. Model estimates were very similar when adjusted for pack-years of smoking instead of smoking (ever/never); for example, for all participants, the Model 3 OR was 1.13 (95% CI: 1.02, 1.26) (Table S3).Table 3 Odds ratios for moderate-to-severe coronary artery stenosis (≥25% stenosis) in association with a 1-μg/dL increase in blood lead level.Table 3 has seven columns, namely, Variables; Total, lowercase italic n; Cases, lowercase italic n (percent), begin superscript lowercase a end superscript; Model; Odds ratio; 95 percent confidence intervals; and lowercase italic p value.VariablesTotal (n)Cases [n (%)]aModelOdds ratio95% CIp-ValueAll participants2,193250 (11.4)Unadjusted1.221.11–1.34 10μg/dL. In a prospective cohort of U.S. men, the risk of ischemic heart disease was 1.73 times higher (95% CI: 1.05, 2.87) in men with a BLL of ≥5μg/dL vs. men with a BLL of <5μg/dL (Jain et al. 2007). Mortality was higher among U.S. residents with BLLs of 10–19 and 20–29μg/dL, respectively, compared with <10μg/dL, based on NHANES BLL data from 1976–1980 and mortality follow-up through 1992 (Lustberg and Silbergeld 2002). A subsequent NHANES study based on BLL data from 1988–1994, with mortality follow-up through 2000, also reported higher mortality with increasing BLLs, though BLL categories were reduced to 5–9μg/dL and ≥10μg/dL compared with 50% stenosis) in 103 patients (mean age: 61.5±9.7y), segment-based sensitivity, specificity, and positive and negative predictive values of the 16-slice CT were 95%, 98%, 87%, and 99%, respectively (Hoffmann et al. 2005). In other studies of patients, the sensitivity, specificity, and positive and negative predictive values of the 16- to 64-slice CT were 82–95%, 95–98%, 87–93%, and 93–99%, respectively (Kuettner et al. 2005; Leschka et al. 2005; Mollet et al. 2005; Raff et al. 2005). In a study of 168 high-risk asymptomatic patients (≥1 major risk factor: hypertension, diabetes, hypercholesterolemia, family history, or smoking), the sensitivity, specificity, and positive and negative predictive values of the 16-slice CT were 100%, 98%, 95%, and 100%, respectively (Romeo et al. 2007). A significant association between BLLs and CAS was found through multislice imaging study in this study. This manuscript could be used as valuable data on the association of lead to cardiovascular disease. Another strength of this study was that as a routine part of the health examination, and to ensure that the use of contrast media was not contraindicated, each participant was interviewed by a physician using a structured questionnaire that was consistent throughout the study period (2011–2018).In conclusion, BLL was associated with MSCAS in an asymptomatic population, 94% of whom had BLLs below the recommended standard of 5μg/dL. To prevent and reduce the global burden of cardiovascular diseases, our results suggest that BLLs should be maintained as low as possible.AcknowledgmentsWe thank all the members of the Health Promotion Center at Chonnam National University Hwasun Hospital. We also thank Editage ( https://www.editage.co.kr) for English language editing.ReferencesBenjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, et al.2018. Heart disease and stroke statistics—2018 update: a report from the American Heart Association. Circulation 137(12):e67–e492, PMID: 29386200, 10.1161/CIR.0000000000000558. Crossref, Medline, Google ScholarCDC (Centers for Disease Control and Prevention).2018. About ABLES. https://www.cdc.gov/niosh/topics/ables/description.html [accessed 25 September 2020]. Google ScholarCheng Y, Schwartz J, Vokonas PS, Weiss ST, Aro A, Hu H. 1998. Electrocardiographic conduction disturbances in association with low-level lead exposure (the Normative Aging Study). 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