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Coronary Artery Calcium and Exercise Electrocardiogram as Predictors of Coronary Events in Asymptomatic Adults

Published:January 05, 2015DOI:https://doi.org/10.1016/j.amjcard.2014.12.039
      Early identification of patients at risk for coronary heart disease is crucial to formulate effective preventive strategies. The elevated risk of coronary artery calcium (CAC) for coronary heart disease is well established. Our aim was to estimate the relative risk of abnormal exercise electrocardiography (Ex ECG) in the presence of CAC. During the year 2001, 566 asymptomatic subjects performed a treadmill exercise test and consented to perform an unenhanced computed tomography to assess CAC. Patients were followed until December 2012. The relative risk for coronary events (acute myocardial infarction, hospitalization for unstable angina or coronary catheterization that resulted in angioplasty or coronary artery bypass surgery), of abnormal Ex ECG and presence of CAC were analyzed. An abnormal Ex ECG was found in 71 subjects (12.5%), and CAC was found in 286 subjects (50.5%). During a mean follow-up of 6.5 ± 3.3 years, 35 subjects experienced a first coronary event. In those without CAC, the rate of coronary events was low (4 of 280; 1.4%) regardless of the Ex ECG results. Subjects with both CAC and abnormal Ex ECG had the highest rate of coronary events (13 of 39; 33%). The adjusted hazard ratio for coronary events, in subjects with CAC, was 5.16 (95% confidence interval 2.52 to 10.60) in those with abnormal Ex ECG compared with those with normal Ex ECG. In conclusion, in subjects with CAC, further risk stratification can be achieved by an Ex ECG, whereas in those without CAC, an Ex ECG has less additional value in predicting coronary events.
      Coronary heart disease (CHD) still remains a leading cause of death in the Western world.
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      Heart disease and stroke statistics—2014 update: a report from the American Heart Association.
      Approximately 50% of coronary deaths occur in previously asymptomatic subjects.
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      • Rajakangas A.M.
      • Pajak A.
      Myocardial infarction and coronary deaths in the World Health Organization MONICA Project. Registration procedures, event rates, and case-fatality rates in 38 populations from 21 countries in four continents.
      Thus, early and accurate identification of subjects at risk for coronary events is important to institute effective preventive strategies. Conventional risk factors are only partially adequate in achieving this goal as 40% to 70% of patients with myocardial infarction (MI) would not have been recognized as patients at risk using conventional models such as the Framingham score or Prospective Cardiovascular Munster score.
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      Preventing myocardial infarction in the young adult in the first place: how do the National Cholesterol Education Panel III guidelines perform?.
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      Simple scoring scheme for calculating the risk of acute coronary events based on the 10-year follow-up of the prospective cardiovascular Munster (PROCAM) study.
      Coronary artery calcium (CAC) has been shown to be a sensitive marker of early stages of atherosclerosis.
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      • Simons D.B.
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      • Sheedy P.F.
      • Schwartz R.S.
      Coronary artery calcium area by electron-beam computed tomography and coronary atherosclerotic plaque area. A histopathologic correlative study.
      Computed tomography (CT) is an accurate tool for the detection and quantification of CAC and is suggested in the diagnosing of subclinical CHD.
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      • Bruning R.
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      • Steinbeck G.
      Correlation of coronary calcification and angiographically documented stenoses in patients with suspected coronary artery disease: results of 1,764 patients.
      The role of an exercise electrocardiogram (Ex ECG) as a screening technique in asymptomatic subjects is controversial. Low exercise capacity and heart rate recovery during exercise tests have been found to predict mortality in several studies.
      • Gianrossi R.
      • Detrano R.
      • Mulvihill D.
      • Lehmann K.
      • Dubach P.
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      • Froelicher V.
      Exercise-induced ST depression in the diagnosis of coronary artery disease. A meta-analysis.
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      • Maki M.
      • Yachi Y.
      • Asumi M.
      • Sugawara A.
      • Totsuka K.
      • Shimano H.
      • Ohashi Y.
      • Yamada N.
      • Sone H.
      Cardiorespiratory fitness as a quantitative predictor of all-cause mortality and cardiovascular events in healthy men and women: a meta-analysis.
      Other studies have demonstrated that ST depression on an Ex ECG does not predict CHD.
      • Goraya T.Y.
      • Jacobsen S.J.
      • Pellikka P.A.
      • Miller T.D.
      • Khan A.
      • Weston S.A.
      • Gersh B.J.
      • Roger V.L.
      Prognostic value of treadmill exercise testing in elderly persons.
      • Lin E.
      • Hwang W.
      Imaging assessment of cardiovascular risk in asymptomatic adults.
      Currently, exercise testing is not advocated for diagnostic purposes in healthy subjects because of its low specificity and sensitivity.
      • Gibbons R.J.
      • Balady G.J.
      • Bricker J.T.
      • Chaitman B.R.
      • Fletcher G.F.
      • Froelicher V.F.
      • Mark D.B.
      • McCallister B.D.
      • Mooss A.N.
      • O'Reilly M.G.
      • Winters Jr., W.L.
      • Antman E.M.
      • Alpert J.S.
      • Faxon D.P.
      • Fuster V.
      • Gregoratos G.
      • Hiratzka L.F.
      • Jacobs A.K.
      • Russell R.O.
      • Smith Jr., S.C.
      ACC/AHA 2002 guideline update for exercise testing: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1997 Exercise Testing Guidelines).
      However, exercise tests have been suggested for prognostic use in healthy subjects.
      • Ashley E.A.
      • Myers J.
      • Froelicher V.
      Exercise testing in clinical medicine.
      The aim of this prospective study was to assess the CHD risk of abnormal Ex ECG in relation with CAC.

      Methods

      We included subjects examined in our annual check-up clinic between January 2001 and January 2002. Of 1,850 subjects, 745 asymptomatic consecutive subjects who fulfilled the inclusion criteria and consented to perform a screening cardiac CT for CAC evaluation were included. The inclusion criteria were men >40 and women >50 years who were free of CV disease. Of this group, 609 subjects performed a treadmill exercise test and assessment of CAC on the same day. Baseline clinical and laboratory data were also reported. Seventy-seven patients were lost to follow-up, 34 of them were re-contacted and completed telephone questioning regarding coronary events (Figure 1). Thus, 566 asymptomatic subjects constituted our study group. The research protocol was approved by the local institutional review board and complies with the Declaration of Helsinki.
      Figure thumbnail gr1
      Figure 1Flow diagram of study population selection. LBBB = Left bundle brunch block.
      Treadmill exercise testing was conducted in a fasting state using the Bruce protocol.
      • Bruce R.A.
      • Kusumi F.
      • Hosmer D.
      Maximal oxygen intake and nomographic assessment of functional aerobic impairment in cardiovascular disease.
      Before stress testing, the 12-channel electrocardiogram at rest was analyzed. According to the protocol, the velocity of the treadmill is accelerated every 3 minutes; the gradient of the treadmill is gradually elevated until the subject reaches his targeted heart rate. The target heart rate was determined according to the following formula: (220 − age). ECG was recorded, and blood pressure (BP) measurements were continued until values returned to baseline levels after discontinuation of the treadmill. Ex ECG was performed with the patient in an upright position. ECG was continuously monitored throughout the test and BP measured every 3 minutes during the load increment stage. Reasons for terminating the exercise was a decrease in BP of 10 mm Hg or more compared with BP at rest, systolic BP >230 mm Hg or diastolic BP >130 mm Hg, horizontal and downsloping ST-segment depressions of >0.3 mV or ST-segment elevations of >0.1 mV, ventricular tachycardia persisting for >30 seconds, an increasing number or polytypic premature beats, disturbed intraventricular or atrioventricular transition, exhaustion of the patient, severe dyspnea, and angina pectoris.
      For this study, Ex ECG was considered abnormal when an unequivocal ST depression >0.1 mV (horizontal or downsloping) was recorded during the exercise. Additional non-ST parameters were metabolic equivalents, exercise time, maximal heart rate, and maximal systolic BP. The physician who analyzed the Ex ECG was blinded to the results of the coronary CT.
      All CT scans were performed in a single center and analyzed by an experienced physician on a dual-detector spiral CT without ECG gating and without contrast injection; scanning protocol and CAC measuring were implemented according to a previously published protocol using the modified Agatston method.
      • Shemesh J.
      • Apter S.
      • Rozenman J.
      • Lusky A.
      • Rath S.
      • Itzchak Y.
      • Motro M.
      Calcification of coronary arteries: detection and quantification with double-helix CT.
      Total CAC score (TCS) was the sum of all the individual calcific lesions identified within the area of the coronary arteries. The reproducibility of calcification scoring by this method is high with intraclass correlation and interobserver agreement coefficients of 0.99 and of 0.94, respectively.
      • Shemesh J.
      • Apter S.
      • Rozenman J.
      • Lusky A.
      • Rath S.
      • Itzchak Y.
      • Motro M.
      Calcification of coronary arteries: detection and quantification with double-helix CT.
      A TCS >0 was considered positive for the presence of CAC.
      Height and weight were measured with participants wearing light clothing without shoes. Body mass index was calculated as weight (kg)/height (m2). Blood pressure was measured in a seated position after 3 minutes of rest. Hypertension was defined when 2 separate BP readings were ≥140 mm Hg for systolic BP and/or ≥90 mm Hg for diastolic BP, a history of hypertension was reported, or the subject had taken antihypertensive medications.
      Diabetes mellitus was defined when fasting plasma glucose was >126 mg/dl (7.0 mmol/L) on 2 separate readings, a history of diabetes mellitus was reported, or the subject had taken insulin or oral hypoglycemic medications. Hypercholesterolemia was defined when measured total cholesterol was >250 mg/dl or when the patient reported taking cholesterol-lowering medications. Smoking status was determined according to the questionnaire; participants were divided into current smokers or nonsmokers.
      Estimated glomerular filtration rate (eGFR) was calculated according to the Chronic Kidney Disease Epidemiology Collaboration equation.
      • Levey A.S.
      • Stevens L.A.
      • Schmid C.H.
      • Zhang Y.L.
      • Castro III, A.F.
      • Feldman H.I.
      • Kusek J.W.
      • Eggers P.
      • Van Lente F.
      • Greene T.
      • Coresh J.
      A new equation to estimate glomerular filtration rate.
      Framingham score estimating the 10-year cardiovascular risk was calculated for each subject.
      • Wilson P.W.
      • D'Agostino R.B.
      • Levy D.
      • Belanger A.M.
      • Silbershatz H.
      • Kannel W.B.
      Prediction of coronary heart disease using risk factor categories.
      Subjects were divided into 3 subgroups: <10% (low score), 11% to 20% (moderate score), and >20% (high score).
      Subjects' files were reviewed through 2012. Subjects who were lost to follow-up were contacted, and the coronary end points were assessed by a telephone interview. The end point was delineated as first coronary events, such as acute MI, hospitalization for unstable angina, or coronary catheterization, that resulted in angioplasty or coronary artery bypass surgery.
      Data were analyzed by the Statistical Package for the Social Sciences (IBM SPSS Statistics), software version 21.0. Clinical characteristics of study subjects were compared between the following groups: patients with normal and abnormal Ex ECG and according to the presence or absence of CAC. Continuous variables were expressed as mean ± SD. Categorical variables were expressed as frequencies (percentage). Clinical characteristics of study subjects were compared by chi-square tests for categorical variables and independent t tests or analysis of variance tests for continuous variables. Length of follow-up was calculated as time from screening until development of the first coronary event or until the last follow-up date. Incidence of the CHD was analyzed in relation to Ex ECG and the CAC results using the chi-square test with Ex ECG layers. CHD rate was analyzed according to the presence or absence of CAC and normal or abnormal Ex ECG. Hazard ratios (HRs) and 95% confidence intervals (CIs) for incident coronary event by CAC and Ex ECG were estimated by the Cox proportional hazard model adjusting for potential confounders. Conventional risk factors were selected for the model based on previous studies and an association with coronary events in the univariate analysis. Model discrimination was assessed by the C statistics of Harrell et al. The c index is a probability of concordance between predicted and observed survival with c = 0.5 for random predictions and C = 1 for a perfect discriminating model. The c index is relatively unaffected by the amount of censoring. The Kaplan-Meier procedure compared time-to-event models in the presence of censored cases between those with CAC and normal or abnormal Ex ECG. Differences were considered statistically significant at p <0.05.

      Results

      The study population consisted of 566 subjects (88% men) with a mean age of 55.5 ± 7.3 years. Seventy-one (12.5%) subjects had abnormal Ex ECG. Those with abnormal Ex ECG had similar characteristics as those with a normal Ex ECG (Table 1).
      Table 1Baseline characteristics of study population according to calcium score and stress test results
      VariableCoronary Artery Calcium
      No (N = 280)Yes (N = 286)
      P value = between those with and without CAC.
      P value
      Normal Ex ECG (N – 248)Abnormal Ex ECG (N = 32)P ValueNormal Ex ECG (N – 247)Abnormal Ex ECG (N = 39)P value
      Men205 (83%)25 (78%)0.496232 (94%)37 (95%)0.887<0.001
      Age (years)53 ± 753 ± 60.99658 ± 759 ± 80.247<0.001
      Body Mass Index (Kg/m2)27.0 ± 3.526.1 ± 3.50.15127.2 ± 3.127.4 ± 3.80.6350.351
      Systolic blood pressure (mm Hg)123 ± 16124 ± 210.849128 ± 15130 ± 150.4950.001
      Diastolic blood pressure (mm Hg)78 ± 977 ± 100.56179 ± 977 ± 60.1240.309
      Heart rate (beats/min)79 ± 1378 ± 120.72576 ± 1277 ± 110.6640.056
      Hypertension43 (17%)6 (19%)0.85180 (33%)18 (43%)0.096<0.001
      Diabetes Mellitus12 (5%)0 (0)0.20226 (11%)6 (15%)0.3810.002
      Hypercholesterolemia102 (42%)10 (31%)0.239118 (49%)21 (55%)0.4850.031
      Smoker31 (12%)4 (12%)0.99956 (23%)4 (10%)0.0770.007
      Positive Family history57 (23%)10 (31%)0.32166 (27%)9 (24%)0.7270.497
      Framingham Score (%)10.9 ± 3.310.8 ± 3.40.95012.5 ± 2.812.9 ± 2.60.388<0.001
      Low score198 (80%)25 (78%)123 (50%)17 (44%)
      Intermediate score45 (18%)5 (16%)96 (39%)17 (44%)
      High score5 (2%)2 (6%)0.34828 (11%)5 (13%)0.7580.499
      eGFR (ml/min)78 ± 1378 ± 110.98675 ± 1274 ± 120.6330.002
      Serum Glucose (mg/dL)97 ± 1992 ± 1140.197104 ± 29102 ± 200.633<0.001
      Serum Cholesterol (mg/dL)201 ± 34195 ± 280.389199 ± 34201 ± 310.7200.731
      Serum Triglyceride (mg/dL)146 ± 78161 ± 1130.359138 ± 76146 ± 680.5230.181
      Serum HDL Cholesterol (mg/dL)45 ± 1249 ± 170.11344 ± 1044 ± 130.9120.202
      Serum LDL Cholesterol (mg/dL)127 ± 28119 ± 270.164127 ± 30128 ± 280.9470.590
      METS12.0 ± 6.311.8 ± 2.60.87712.0 ± 6.411.5 ± 2.10.6270.309
      Exercise time (minutes)10.5 ± 6.610.1 ± 2.90.8739.9 ± 2.210.2 ± 2.10.9170.193
      Maximal heart rate (beats/min)159 ± 13159 ± 150.973154 ± 13151 ± 140.166<0.001
      Maximal systolic blood pressure (mm Hg)175 ± 22176 ± 190.892189 ± 86179 ± 460.5290.021
      Total calcium score (units)00202 ± 371281 ± 3830.218
      eGFR = estimated glomerular filtration rate; Ex ECG = exercise electrocardiography; HDL = high density lipoprotein; LDL = low density lipoprotein; METS = metabolic equivalents; Positive family history = first degree relative with premature cardiovascular disease (man under age 55 or a woman under age 65).
      P value = between those with and without CAC.
      Two hundred and eighty-six (50.5%) subjects had CAC (TCS >0). Subjects with CAC were older (p <0.001) and more likely to be men and smokers; had a higher systolic BP, serum glucose, and Framingham score (p <0.001) and lower eGFR; and were more likely to have hypertension, diabetes mellitus, and hypercholesterolemia than those without CAC (Table 1).
      During a follow-up of 11 years (mean 6.5 ± 3.3), 35 subjects experienced a first coronary event, 12 experienced an acute MI, 4 unstable angina pectoris, and 19 subjects underwent coronary catheterization resulting in percutaneous coronary intervention (n = 13) or coronary artery bypass surgery (n = 6).
      Subjects who experienced coronary events were older, had a higher Framingham risk score, and were more likely to have hypertension, CAC, and an abnormal Ex ECG than those without events (Table 2). In those with an abnormal Ex ECG, 14 (19.7%) experienced a coronary event; in those with CAC, 31 (11%) experienced a coronary event.
      Table 2Baseline characteristics of study population according to events
      VariableCoronary event
      No

      (N = 531)
      Yes

      (N = 35)
      P value
      Men465 (88)34 (97)0.097
      Age (years)55 ± 759 ± 80.002
      Body Mass Index (Kg/m2)27 ± 327 ± 30.904
      Systolic blood pressure (mm Hg)126 ± 17128 ± 150.437
      Diastolic blood pressure (mm Hg)79 ± 979 ± 80.794
      Heart rate (beats/min)78 ± 1372 ± 90.012
      Hypertension205 (39%)27 (77%)<0.001
      Diabetes Mellitus70 (13%)5 (14%)0.852
      Hypercholesterolemia233 (45%)18 (53%)0.367
      Smoker88 (23%)7 (28%)0.535
      Positive Family history133 (25%)9 (27%)0.804
      Framingham Score (%)11.6 ± 3.212.8 ± 2.30.010
      Low score347(66%)16(46%)
      Intermediate score144(27%)17(49%)
      High score38 (7%)2 (6%)0.025
      eGFR (ml/min)77 ± 1373 ± 100.057
      Serum Glucose (mg/dL)100 ± 2498 ± 190.649
      Serum Cholesterol (mg/dL)200 ± 33198 ± 340.717
      Serum Triglyceride (mg/dL)143 ± 80142 ± 590.890
      Serum HDL Cholesterol (mg/dL)45 ± 1243 ± 110.452
      Serum LDL Cholesterol (mg/dL)127 ± 29126 ± 310.855
      METS11.8 ± 4.611.2 ± 2.50.433
      Exercise time (minutes)10.2 ± 4.89.6 ± 2.60.423
      Maximal heart rate (beats/min)157 ± 14152 ± 110.083
      Maximal systolic blood pressure (mm Hg)181 ± 62182 ± 390.931
      Total calcium score (units)82 ± 230502 ± 597<0.001
      Total calcium score >0255 (48%)31 (89%)<0.001
      Abnormal exercise ECG57 (11)14 (40)<0.001
      eGFR = estimated glomerular filtration rate; HDL = high density lipoprotein; LDL = low density lipoprotein; METS = metabolic equivalents; Positive family history = first degree relative with premature cardiovascular disease (man under age 55 or a woman under age 65).
      Of 286 subjects with CAC, 247 subjects (86.4%) had a normal Ex ECG and 39 (13.6%) an abnormal Ex ECG. Of 71 subjects with an abnormal Ex ECG, 32 subjects (45%) had no CAC. Subjects without CAC had a very low rate of coronary events, 1.2% in those with a normal Ex ECG and 3% in those with an abnormal Ex ECG (Table 3). In those with CAC, the rate of events was 7.3% (18 of 247) in those with a normal Ex ECG and 33% (13 of 39) in those with an abnormal Ex ECG. Subjects with CAC and an abnormal Ex ECG experienced the highest rate of coronary events.
      Table 3Coronary events rate according to stress test results and presence of Coronary Artery Calcium
      Stress test resultsCoronary Calcium
      YesNoTotal
      Normal18/247 (7.3%)3/248 (1.2%)21/495 (4.2%)
      Abnormal13/39 (33%)1/32 (3%)14/71 (19.7%)
      Total31/286 (11%)4/280 (1.4%)35/566 (6.2%)
      In subjects without CAC, the HR for coronary events of abnormal Ex ECG was not calculated because only 4 events occurred during the follow-up. Ex ECG affected long-term coronary events only in subjects with CAC. Compared with those with CAC and a normal Ex ECG, the unadjusted HR was 5.23 (95% CI 2.56 to 10.69) in those with CAC and an abnormal Ex ECG. The effect of Ex ECG in those with CAC remained significant even after adjustment for age, gender, hypercholesterolemia, proteinuria, and eGFR, with an adjusted HR of 5.16 (95% CI 2.52 to 10.60; Table 4). For sensitive analysis, we further analyzed the results separately using only the hard end points (MI and unstable angina pectoris; n = 16). Age- and gender-adjusted HR was 2.47 (p = 0.119), and Framingham score–adjusted HR was 2.37 (p = 0.136). The adjusted Kaplan-Meier survival curve to a first coronary event in subjects with CAC according to the results of Ex ECG is presented in Figure 2. Those with CAC and an abnormal Ex ECG had a significant worse outcome than those with normal Ex ECG (p <0.01).
      Table 4rates and HR for coronary events by Exercise electrocardiography for study population with Coronary artery Calcium
      VariableNormal Ex ECG

      (N = 247)
      Abnormal Ex ECG

      (N = 39)
      Event rate18 (7.3%)13 (33.3%)
      Unadjusted HR1.05.23 (95% CI; 2.56-10.69)
      Age and gender adjusted HR
      The C index = 0.69.
      1.04.98 (95% CI; 2.43-10.23)
      Framingham score adjusted HR
      The C index = 0.67.
      1.05.16 (95% CI; 2.52-10.60)
      CI = confidence interval; Ex ECG = exercise electrocardiography; HR = hazard ratios.
      The C index = 0.69.
      The C index = 0.67.
      Figure thumbnail gr2
      Figure 2Kaplan-Meier survival curves to first coronary event in subjects with CAC according to results of exercise tests (Ex ECG). Those with CAC and an abnormal Ex ECG had a significant worse outcome than the other groups (p <0.01).

      Discussion

      The main finding of our study is that an abnormal Ex ECG in asymptomatic subjects produced an incremental prognostic value for coronary events in only those with CAC. This is the first study of asymptomatic subjects comparing the predictive value for coronary events of Ex ECG and coronary CT. In asymptomatic subjects, the emphasis is on the assessment of long-term risk and primary prevention of future clinical coronary disease.
      There is clear evidence that the presence and degree of CAC, as measured by CT, increases the risk of cardiac events,
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      Coronary calcium by spiral computed tomography predicts cardiovascular events in high-risk hypertensive patients.
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      Coronary artery calcification predicts long-term mortality in hypertensive adults.
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      Coronary risk stratification, discrimination, and reclassification improvement based on quantification of subclinical coronary atherosclerosis: the Heinz Nixdorf Recall study.
      and lack of CAC is associated with a low rate of CV events even in diabetic hypertensive patients.
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      Relation of coronary artery calcium to cardiovascular risk in patients with combined diabetes mellitus and systemic hypertension.
      The exercise test has been considered a potential useful technique for coronary disease screening.
      • Greenland P.
      • Smith Jr., S.C.
      • Grundy S.M.
      Improving coronary heart disease risk assessment in asymptomatic people: role of traditional risk factors and noninvasive cardiovascular tests.
      It is simple to administer, inexpensive, and safe. Nevertheless, the role of Ex ECG as a screening technique in asymptomatic subjects is inconclusive. A number of studies have shown that exercise-induced ischemia in healthy subjects is associated with an increased risk of future MI and sudden death.
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      One large report confirmed the prognostic value of Ex ECG in 25,927 men, who were free of clinical disease and who had undergone maximal exercise testing during a screening evaluation.
      • Gibbons L.W.
      • Mitchell T.L.
      • Wei M.
      • Blair S.N.
      • Cooper K.H.
      Maximal exercise test as a predictor of risk for mortality from coronary heart disease in asymptomatic men.
      Other studies have demonstrated that ST depression on Ex ECG is not predictive of CHD.
      • Goraya T.Y.
      • Jacobsen S.J.
      • Pellikka P.A.
      • Miller T.D.
      • Khan A.
      • Weston S.A.
      • Gersh B.J.
      • Roger V.L.
      Prognostic value of treadmill exercise testing in elderly persons.
      • Lin E.
      • Hwang W.
      Imaging assessment of cardiovascular risk in asymptomatic adults.
      Moreover, the use of an Ex ECG for the purpose of diagnosing coronary disease in asymptomatic patients has been criticized because it has low sensitivity and low specificity in subjects with low risk. Therefore, the US Preventive Services Task Force recommended against using exercise testing as a screening tool.
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      • Benjamin E.J.
      • Budoff M.J.
      • Fayad Z.A.
      • Foster E.
      • Hlatky M.A.
      • Hodgson J.M.
      • Kushner F.G.
      • Lauer M.S.
      • Shaw L.J.
      • Smith Jr., S.C.
      • Taylor A.J.
      • Weintraub W.S.
      • Wenger N.K.
      • Jacobs A.K.
      2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
      It seems that the low accuracy of Ex ECG in predicting coronary events is because of its inability to detect early stages of coronary atherosclerosis in the form of nonobstructive lesions. The main advantage of measuring CAC is the ability to detect and quantify subclinical atherosclerosis in the coronary artery walls much before it reduces the lumen to the level of flow limitation.
      The presence of CAC identifies asymptomatic subjects with coronary risk.
      • Greenland P.
      • LaBree L.
      • Azen S.P.
      • Doherty T.M.
      • Detrano R.C.
      Coronary artery calcium score combined with Framingham score for risk prediction in asymptomatic individuals.
      In these subjects, an abnormal Ex ECG predicts coronary events. In our study, approximately 50% of the asymptomatic subjects had CAC, and in these subjects, an abnormal Ex ECG produced an incremental prognostic value for coronary events. In contrast, about half of the asymptomatic subjects had no CAC. These subjects had a low rate of coronary events even when the Ex ECG was abnormal. Subjects without CAC had a low coronary risk, and as has been previously shown in low-risk subjects, the Ex ECG exhibited low sensitivity and specificity.
      • Gibson R.S.
      The diagnostic and prognostic value of exercise electrocardiography in asymptomatic subjects and stable symptomatic patients.
      According to the current guidelines, CAC assessment is mainly beneficial in subjects with moderate or mild-to-moderate CV risk as assessed by the Framingham or the European SCORE.
      • Goff Jr., D.C.
      • Lloyd-Jones D.M.
      • Bennett G.
      • Coady S.
      • D'Agostino R.B.
      • Gibbons R.
      • Greenland P.
      • Lackland D.T.
      • Levy D.
      • O'Donnell C.J.
      • Robinson J.G.
      • Schwartz J.S.
      • Shero S.T.
      • Smith Jr., S.C.
      • Sorlie P.
      • Stone N.J.
      • Wilson P.W.
      2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American heart association task force on practice guidelines.
      Most subjects included in our study had a low or moderate risk, and the Framingham score was similar in those with normal or abnormal Ex ECG. In these subjects, screening for CAC is justified. Therefore, we suggest performing a low-dose chest CT as a screening tool and perform an Ex ECG only in those with CAC.
      An important clinical application of our study is that in subjects without CAC, an abnormal Ex ECG is probably false positive, and further imaging such as stress echo or nuclear perfusion can be avoided. Thus, it seems that an Ex ECG is unwarranted in those without CAC.
      We suggest beginning coronary risk screening with a low-dose chest CT and avoid an Ex ECG in those without CAC. Alternatively, if during a screening procedure in an asymptomatic subject, an abnormal Ex ECG is observed, and it may be worthwhile to assess the CAC score by a low-dose chest CT rather than performing a coronary angiography.
      Our study group represented a population that participates in an annual screening program with a low and/or moderate Framingham score. These subjects represented a distinct population, highly willing and motivated, to assess and treat their coronary risk and may not represent the general population. Second, our study group was relatively small, and <10% of the subjects were lost to follow-up. However, we were able to identify some subjects lost to follow-up and were able to carry out a long-term follow up with enough end points to draw clear conclusions.

      Acknowledgments

      Shay Ehrlich performed this work in partial fulfillment of the MD thesis requirements of the Sackler Faculty of Medicine, Tel Aviv University.

      Disclosures

      The authors have no conflicts of interest to disclose.

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