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Grace Ballas Research Unit, Cardiac Rehabilitation Institute, The Chaim Sheba Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Hashomer, Israel
Grace Ballas Research Unit, Cardiac Rehabilitation Institute, The Chaim Sheba Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Hashomer, Israel
Department of Epidemiology and Preventive Medicine, The Chaim Sheba Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Hashomer, Israel
Department of Internal Medicine D and the Hypertension Unit, The Chaim Sheba Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Hashomer, Israel
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.
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.
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.
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.
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).
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 1Flow diagram of study population selection. LBBB = Left bundle brunch block.
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.
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.
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.
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
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).
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
Variable
Coronary event
No (N = 531)
Yes (N = 35)
P value
Men
465 (88)
34 (97)
0.097
Age (years)
55 ± 7
59 ± 8
0.002
Body Mass Index (Kg/m2)
27 ± 3
27 ± 3
0.904
Systolic blood pressure (mm Hg)
126 ± 17
128 ± 15
0.437
Diastolic blood pressure (mm Hg)
79 ± 9
79 ± 8
0.794
Heart rate (beats/min)
78 ± 13
72 ± 9
0.012
Hypertension
205 (39%)
27 (77%)
<0.001
Diabetes Mellitus
70 (13%)
5 (14%)
0.852
Hypercholesterolemia
233 (45%)
18 (53%)
0.367
Smoker
88 (23%)
7 (28%)
0.535
Positive Family history
133 (25%)
9 (27%)
0.804
Framingham Score (%)
11.6 ± 3.2
12.8 ± 2.3
0.010
Low score
347(66%)
16(46%)
Intermediate score
144(27%)
17(49%)
High score
38 (7%)
2 (6%)
0.025
eGFR (ml/min)
77 ± 13
73 ± 10
0.057
Serum Glucose (mg/dL)
100 ± 24
98 ± 19
0.649
Serum Cholesterol (mg/dL)
200 ± 33
198 ± 34
0.717
Serum Triglyceride (mg/dL)
143 ± 80
142 ± 59
0.890
Serum HDL Cholesterol (mg/dL)
45 ± 12
43 ± 11
0.452
Serum LDL Cholesterol (mg/dL)
127 ± 29
126 ± 31
0.855
METS
11.8 ± 4.6
11.2 ± 2.5
0.433
Exercise time (minutes)
10.2 ± 4.8
9.6 ± 2.6
0.423
Maximal heart rate (beats/min)
157 ± 14
152 ± 11
0.083
Maximal systolic blood pressure (mm Hg)
181 ± 62
182 ± 39
0.931
Total calcium score (units)
82 ± 230
502 ± 597
<0.001
Total calcium score >0
255 (48%)
31 (89%)
<0.001
Abnormal exercise ECG
57 (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
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
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).
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,
Coronary risk stratification, discrimination, and reclassification improvement based on quantification of subclinical coronary atherosclerosis: the Heinz Nixdorf Recall study.
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.
Coronary heart disease morbidity and mortality in hypercholesterolemic men predicted from an exercise test: the Lipid Research Clinics Coronary Primary Prevention Trial.
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.
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.
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.
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.
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.
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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Heart disease and stroke statistics—2014 update: a report from the American Heart Association.
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.
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.
Correlation of coronary calcification and angiographically documented stenoses in patients with suspected coronary artery disease: results of 1,764 patients.
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).
Coronary risk stratification, discrimination, and reclassification improvement based on quantification of subclinical coronary atherosclerosis: the Heinz Nixdorf Recall study.
Coronary heart disease morbidity and mortality in hypercholesterolemic men predicted from an exercise test: the Lipid Research Clinics Coronary Primary Prevention Trial.
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.
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.
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