Asymptomatic coronary artery disease detection: Update 1996

Journal of Electrocardiology Vol. 29 Supplement

Asymptomatic Coronary Artery Disease D e t e c t i o n : U p d a t e 1996 A Screening Protocol Using 16-Lead High-resolution ECG, Ultrafast CT, Exercise Testing, and Radionuclear Imaging Ronald H. Startt Selvester, MD, Javed Ahmed, MD, and Gil D. Tolan, MD

Abstract: The authors have proposed a new four-step screening algorithm to detect asymptomatic coronary artery disease (CAD) in flight school candidates, cadets, and rated flyers of the Unites States Air Force (USAF). In step 1, the USAF Armstrong Laboratory (USAF/AL) risk profile and improved 16-lead high-resolution electrocardiogram/vectorcardiogram will be recorded at baseline. On routine follow-up evaluations, quantitative serial comparisons will be performed by the method of Komreich. In step 2, beginning with flight school candidates and cadets, all three groups will be studied by the ultrafast computed tomograph (CT) protocol. Those candidates positive for coronary calcium will be studied by coronary angiography and ventriculography, and their eligibility for continued rated flight status will be determined by present criteria. In step 3, those candidates negative for coronary calcium by ultrafast CT will then be screened by the newly defined and improved high-sensitivity treadmill exercise test criteria. In step 4, candidates with a positive treadmill exercise test result, or who are also found in the upper quintile of the USAF/AL risk profile, wild also have exercise nuclear wall motion studies and perfusion scans. If these are abnormal and suggestive of myocardial ischemia, this subset will also be studied by heart catheterization and coronary angiography, and their eligibility for continued rated flight status will be determined by present criteria. The incidence of coronary calcium/no calcium for each degree of stenosis in the 6,000 flyers in each quintile was used to develop the following projections: (1) that more than 3 of 4 rated flyers with unsuspected CAD, and (2) more than 9 of i0 with severe flow-limiting CAD can be identified by these upgraded screening procedures. Evidence is herein presented that these enhancements will result in a major (5-8-fold) increase in case finding of this disease. Based on the estimate of four lost high-performance aircrafts per year from sudden incapacitation of the pilot due to CAD, w h e n this four-step screen is fully operational, it can be expected to reduce the $80 million annual losses to the United States government from CAD by 85%, a savings of $68 million per year. K e y w o r d s : electrocardiography, coronary risk factors, coronary heart disease screening, coronary calcium, ultrafast C% treadmill exercise testing, radionuclear scintigraphy.

From the Department of Medicine, Division of Cardiology, University of Southern California, Los Angeles, and the Memorial Heart Institute of Long Beach, Long Beach, California.

Reprint requests: Ronald H. Startt Selvester, MD, JournaI of Electrocardiology, PO Box 90186, Long Beach, CA 90809-0186.

135

136

Journal of Electrocardiology

Vol. 29 Supplement

Background This report is an analysis of the incidence of asymptomatic coronary artery disease (CAD) and the presentation of enhanced screening procedures for its detection. Significant (_> 30% luminal diameter) atheromatous CAD was reported in 20% of Korean (1) and Vietnam (2) war casualties and was recently confirmed in young trauma victims (3). It is now well established (4-6) that such atheroma (_> 30%) are the precursor of plaque rupture, platelet aggregation, clot formation, acute coronary occlusion, and myocardial infarction (MI). Furthermore, the risk of acute plaque rupture and MI is increased twoto threefold during high physical stress. For every four clinically recognized acute MIs, there is another one with sudden death as the first sign or symptom, one clinically "silent" new Q wave MI identified later by a followup electrocardiogram (ECG) (7,8), and two non-Q wave MIs that are both clinically and electrocardiographically silent (7-10). Thus, in the 30,000 United States Air Force (USAF) rated flyers, for the 30-35 acute MIs recognized each year, another 30-35 are "silent" (60-70 MIs total). Each flyer logs 300 plus hr/y, 3% of the total hours in a year. Thus, 2 MIs/y (3% of the 60-70) would occur while the pilot is at the controls. As summarized by one of us (G.T.) in the USAF School of Aerospace Medicines (SAM) technical report (1 i), five to seven high-performance aircrafts crash each year with no apparent reason, no communication from the pilot, and no attempt to eject. Assuming the two- to threefold increased risk of plaque rupture and acute MI under high-stress maneuvers, it is conservatively estimated that at least four of these losses were from sudden incapacitation of the pilot due to unsuspected CAD. In addition to the loss of life, at the current cost of pilot training and aircraft procurement, it is estimated that losses to the United States government from this cause alone are at least $80 million per year. The reader is referred to previous reports (12-15) for details of the anatomic, physiologic, and statistical basis of computer simulations of the electrical activity of the h u m a n heart (ie, ECG). Summarized briefly, the heart is a muscular pump that depends on unobstructed coronary arteries for fuel and oxygen to deliver nutrition via the circulatory system to the rest of the body. Heart muscle cells are driven by an electrical excitation sequence that stimulates an efficient sequence of contraction of these working myocytes and a very efficient circulatory pump. The Selvester-Solomon digital computer simulation used here (15) is composed of a 1 m m 3 digitized normal adult male heart imbedded in a digitized normal male torso that includes all of the factors k n o w n to influence the h u m a n ECG. These include realistic anatomy and electrical conductivities of the heart, blood mass, lungs, and external torso boundary. Measured electrical properties and geometry of excitation and recovery were used in the modeling of the wavefront that stimulates the mechanical contraction of the heart. The recovery portion of the ECG (ie, the ST-T segment) is particularly important since recovery of working myocytes is especially sensitive to decreased blood supply. The specific

aim, from a detailed study of local heart excitationrecovery, was the enhanced early detection of coronary narrowing in asymptomatic pilots. The advantage of using a simulation based directly on k n o w n anatomy and electrophysiology is that the results of numerical experiments with the model can be immediately translatated to this anatomy, geometry, and electrophysiology. Changes in the model were easily accomplished. These included enlargement of any heart chamber, local damage (infarcts) of heart muscle (or damage to the conduction system producing conduction defects), or any combination of the above. Once an anatomically based model was validated, a large number of experiments, with combinations of infarct size, chamber enlargements, and conduction defects, was generated in a short time, creating an archive of the combined effects of the complex interactions (16-18). Key studies validating the accuracy of the model assumptions and results have been reported (i 9-23). This also included documentation (24) that model criteria applied to patients with CAD, serial angiograms, and high-resolution 18-simultaneous-lead ECGs were 97% reliable in predicting serial angiographic change or lack of it due to new heart attacks (Fig. 1). Since the 1985 USAF/SAM technical report, the computer model of h u m a n heart excitation (the QRS portion of the ECG) has been enhanced to include its recovery, the ST-T (25). A series of studies (26-28) was generated from this simulation relating to the detection,

14--

e

// ,o _

o ~

7--

'31-

.//

.,,,/

I l l

°Z/ /_y, C//f -

No ~^l~Imlrl ch~ncje°~l

i I I I I I I I I I I I T 2 3 4 5 ~ 7 8 9 io ~l ~2 f3 i4 VentricuLogram infarct, size {cm)

Fig. l. The new infarct size (including no change on the serial McFee vectorcardiograms (VCGs) and biplane ventriculograms) is plotted. Criteria for myocardial infarct size developed from the computer model of the h u m a n heart's electrical activity were applied to serial high-resolution digitized and signal-averaged ECGs and threedimensional VCGs in a blinded review by two readers. Serial coronary and biplane ventricular angiograms, with informed consent given by the patients, were recorded as part of a coronary progression study on 74 subjects at a m e a n interval of 22 months.

Asymptomatic CAD Detection localization, and quantitation of myocardial ischemia from decreased regional blood flow to the heart muscle due to narrowing of the coronary artery supplying the region.

Proposed Screening Algorithm This report presents both an analysis of the incidence of symptomatic CAD in rated USAF flyers and proposals for enhanced screening procedures for its detection. Based on the incidence of CAD in the pilot population, and the ECG forward model development of the last few years, evidence is presented herein that enhancements at three levels of the present screening procedures will result in a major (5-8-fold) increase in case finding of asymptomatic CAD. Step 1: upgrade the resting 12-lead ECG screening of flight school candidates and routine follow-up evaluation of cadets and rated aircrews to a 16-lead system with high-resolution three-dimensional presentation and quantitative serial comparison by the Kornreich method. Step 2: upgrade x-ray fluoroscopic screening for coronary calcium deposits to the use of ultrafast computed tomography (CT) for the screening of flight school candidates, cadets, and rated aircrews. Step 3: upgrade exercise testing using this 16-lead system, with enhancements that increase detection accuracy, to the role of a secondary screen for all subjects screened negative in step 2. Step 4: those candidates positive in step 3 (or those who are in the upper quintile of the USAF Armstrong Laboratory coronary risk profile [29] who are negative in steps 2 and 3) will have exercise nuclear perfusion and wall motion studies performed. If the nuclear studies suggest ischemia, ultrafast CT is positive for coronary calcium, or the high-resolution three-dimensional serial 16-lead ECG shows changes of silent MI, the presence and/or extent of CAD will be defined by heart catheterization and angiography. The specific screening enhancements will n o w be discussed.

Upgrade the Existing 12-Lead ECG to a 16-Lead High-resolution System Previous work with the Selvester-Solomon ECG simulation (30,31) have shown that local segments of the heart were reflected on local torso locations with variable lead field strengths between the heart segment and torso lead location. These are defined as variable transfer functions between the local heart segment and local surface locations. These transfer functions are usually related in normal subjects to the QRS amplitude at the torso location (1 I). A study of local coronary ischemia produced by balloon occlusion of individual coronary arteries at the time of coronary dilation or angioplasty (28) directly confirmed the predictions of the model with regard to the type of ECG changes and their location on the torso produced by well-defined local regions of ischemia. For this study, a total of 16 simultaneous leads were available.

•

Selvester et al.

137

At last year's International Society for Computerized Electrocardiology meeting, we proposed an upgrade of the 12-lead ECG systems currently in routine use by adding 4 extra leads to the existing 12, recording the 16 simultaneous leads at 500-1,000 samples per second, and displaying high-gain signal-averaged scalar ECGs and two three-dimensional displays (Cube and Frank vectorcardiograms [VCGs]). The 18-simultaneous-lead ECG system reported earlier (24) in the study of CAD patients with serial angiogram consisted of a 1,000 sampies per second signal-averaged, simultaneous 12-lead ECG and two three-dimensional VCG lead systems (ie, Cube and McFee). The modified Cube lead system recorded from leads on the right chest and on the back were essentially independent from the standard 12 leads. The McFee (like the Frank) lead set records information mainly from the anterior and left precordium and from the left leg. Therefore, it contains no statistically indep e n d e n t information from the standard 12 leads. The 18-lead set is, therefore, essentially equivalent to the proposed 16-Iead set. Commercially available software and hardware will need minor upgrading to accomplish this important task. The 18-lead array was 97% effective in predicting serial angiographic change or lack of it (24). This remarkable success is due in part to the three-dimensional VCG display of the surface ECG information, in part to the fact that new local information was being recorded from the right ventricle and posterior left ventricle in the back and right chest leads, and in part to the increased resolution of the high sampling rate of 1,000 samples/s with signal averaging to reduce the noise. The high correlation achieved in this blinded study is shown in Figure 1. Madrid et al. provided similar documentation of increased resolution using these lead systems in a group of posterior infarcts from left circumflex occlusion (32). The Cube three-dimensional VCG system with leads on the back and right chest produced significantly higher sensitivity (95%) and similar specificity (96%) for a 3-cm or larger posterior infarct than either the 12-lead ECG (80%/96%) or the McFee three-dimensional VCG (84%/96%). Serial comparison programs available on commercial systems fall short of optimizing the identification of serial changes just described. They use serial comparison of wave duration, amplitude measurements, and diagnostic statements. Appropriate software upgrading, however, that includes millisecond-by-millisecond comparisons of serial differences of the entire P-QRS-T-U complex by the method of Komreich (33-35) would essentially replicate the performance of the blinded visual readings. These differences can be plotted with 95% confidence limits that these changes are beyond those noted from day-to-day variability in ECG recordings. From the entire population of 30,000 rated flyers (36), there are 30-35 recognized acute myocardial infarcts plus six to eight k n o w n sudden deaths per year as a result of acute infraction. The five to seven high-performance aircrafts that crash each year with no apparent reason, no prior communication from the pilot, and no attempt to eject (11) are most likely due to sudden

138

Journal of Electrocardiology Vol. 29 Supplement

incapacitation of the pilot from an unrecognized acute coronary event, the most common cause of sudden incapacitation in American men. Based on the Framingham studies, including autopsy data (7,8), statistically, there is likely to have been another 40-50 asymptomatic silent myocardial infarcts: 15-20 with new Q waves on standard serial 12-lead ECGs, similar to that observed by Loecher et al. (36). Another 30-35 are clinically and electrocardiographically silent (7-10) or unrecognized asymptomatic non-Q wave infarcts (ie, no significant Q wave [or "Q-equivalent"] changes on serial ECGs). Kornreich-type quantitative serial comparison with the proposed 16-lead high-resolution ECG and three-dimensional VCG display would be expected to yield at least 30 more n e w recognized infarcts. This one upgrade alone would increase the case finding of n e w previously silent MI by a factor of 2.5-3 over current procedures.

Upgrade of Radiographic Screening for Coronary Calcium It has been recognized for years that the presence of calcium in the wall of the coronary artery is invariably an indication of intimal atherosclerosis (37-39). The extent of coronary calcification has been shown to correlate with the severity of coronary stenosis and the frequency of MI (40-43). There have been a n u m b e r of attempts to capitalize on this fact by cardiac fluoroscopy in multiple views using image intensifiers (44,45), including the report of the USAF/SAM experience by Loecher et al. (36). Although some studies (46,47) have semiquantified calcium, none have attempted a precise quantification similar to that reported in the pathologic literature. Detrano et al. (46,47) have reported on digital subtraction as superior to conventional fluoroscopy for the detection of coronary calcium, Reinmuller and Lipton (48) used conventional CT, and Tannenbaum et al. (49) used the low-resolution cine mode of ultrafast CT. This latter study reported good interobserver agreement

Fig. 2. The percent of coronary vessels with mild and severe stenosis and calcium seen by ultrafast computed tomography for asymptomatic ambulatory subjects by age groups. This is based on a survey of the literature and a review of the data on coronary calcium in asymptomatic rated flyers provided by Tolan et al. (26) and those suspected of coronary artery disease reported by Loecher et al.

(36).

100 90

for the detection of coronary calcium using eight 8-mm cuts with 4 - m m gaps between each level. Agatston et al. (50) reported improved spatial resolution and detection of coronary calcium using ultrafast CT that included 20 3-mm cuts with no gaps between slices. These authors also reported a scoring system for the quantitation of the amount of calcium in the wall of the coronary arteries and the extent in all vessels. Agaston et al. (50) also reported on 50 patients (mean age, 60 _+ 10) who had coronary angiographic studies in w h o m the ultrafast CT was superior to conventional cardiac fluoroscopy for detecting coronary calcium (96 vs 57% by patient and 65 vs 38% by vessel). They noted a marked difference in mean calcium scores (on ultrafast CT) between the patients with calcium detected only by ultrafast CT and those detected by both methods (99 vs 546) and noted that this "indicates that it is generally subjects with milder calcification who are undetected by fluoroscopy." They also reported a significant decrease in sensitivity for the detection of 50% CAD in the younger patients (mean age, 40 years). In more recent reports, Tannenbaum et al. (49) and Breen et al. (51) have reported 96-100% sensitivity for the detection of 50% CAD and 80-90% sensitivity for the detection of 10-49% CAD by this high-resolution mode in patients (mean ages, 54 and 47, respectively) being evaluated for suspected CAD. These data would be applicable to the oldest half of the USAF rated flyers. Fallivollita et aI. (52) reported decreasing sensitivity of coronary calcium by ultrafast CT in patients under the age of 50, noting that; 9 of 58 (16%) patients with greater than 50% obstruction on coronary angiography failed to show calcium by ultrafast CT. These relationships are summarized in Figure 2. In asymptomatic flyers with no clinical suspicion of CAD, Loecher et a]. (36) reported a sensitivity of coronary cap cium by fluoroscopy of 66% for those with 50% or greater coronary stenosis and 55% for those with 10% or greater stenosis (Fig. 3). W h e n the incidence of coronary calcium reported by Loecher et al. (36) (Fig. 3) is corrected for the increased sensitivity observed by Agatston et al. (50) (Fig. 2) and adjusted for age (Fig. 4), a sensitivity of 95-98% for

[ ] 30-49% [ ] _>50%

06

.....

70

P ~ c

60 50

e

t

,

40 30 20

lo 0

,[ 20-28

J t

!

- - J 30-39

k.

140-49

50-59

t 60-69

Asymptornatic CAD Detection Normal 325 ~

5

3

%

[]

Ca by fluoro

[]

Ca by Fsst-CT

50-100% 104

10-29% 49

30-49% 55

Fig. 3. Modified from published data for asymptomatic flyers by Loecher and associates to include the expected results based on the Agatston study of fluoroscopy versus ultrafast computed tomography and the incidence of coronary calcium in asymptomatic 40-year-old patients. The radii in each of the pie-shaped sections represent the percent of each of the subsets that are expected to show coronary calcium by each method. Data from Loceher et al. (36) and Agatston et al. (56).

detecting high-grade stenosis in older flyers (age > 50) becomes evident. Furthermore, this improved sensitivity w h e n coupled with the pathologic observation that coronary calcium is always associated with atheroma can now be used as a reliable (100% specificity) marker of coronary atheroma. Unfortunately, the sensitivity is

Fig. 4. Graphic summary of the incidence of coronary calciu1T1 expected in each decile of rated flyers based on the literature cited. This grape does not include those with ratable coronary disease who do not have calcium in their coronary arteries. The open diamonds relating the incidence in asymptomatic factory workers is probably most representative of the incidence in asymptomatic rated flyers. The line labeled Projected Fast CT was based on the fluoro versus fast CT studies of Agatston as projected from that observed at fluoro in the Armstrong Laboratory database provided by Tolan. CT, computed tomography; Fluoro, fluoroscopic. Data from Joseph et al. (3), Agatston et al. (50), Loceher et al. (36), and Tolan et aL (26).

Selvester et al.

139

decreased to 80% in the 50-59-year-old age group for tee detection of 30-49% coronary stenosis. Even so, these relationships suggest that in the oldest decile, primary screening for coronary calcium by ultrafast CT might be tEe preferred strategy. As reported above, for 50% or greater disease, the sensitivity is decreased to 70-75% in the 20-29-year-old age group; for 30-49% stenosis, the sensitivity is 45-55%. Strategies must be designed to detect high-grade CAD k n o w n to be present in this young age group, as shown in the Korean (1) and Vietnam (2) war casualties and recently again confirmed in young trauma victims by Joseph et al. (3). These latter studies, where an incidence of 9% was found for highgrade (>_ 50%) CAD and 21% for 30% or greater stenosis, are particularly relevant to the youngest quintiles of training and rated flyers. It is likewise most noteworthy that 1% of these young m e n and w o m e n had 90% or greater left main CAD. Data on the relative incidence of coronary calcium in the groups of ambulatory asymptomatic subjects, subjects with suspect CAD, and USAF rated flyers reported earlier were used to construct tee projected incidence of coronary calcium as a function of age by cluintiles in the USAF rated flyers (Fig. 5). The incidence of coronary calcium seen in the rated flyers undergoing work-up for problems other than suspect CAD provided by the Brooks USAF Armstrong Laboratory database was used to project a possible distribution of coronary calcium across the deciles of flyers. The relative relationship between fluoroscospic and ultrafast CT coronary calcium observed in the same (older) patients by Agatston et al. (50), along with their observation that the younger subjects with milder calcification were undetected by fluoroscopy, was used in weighting the projected incidence of calcium as shown in Figure 5. It will be noted that this

~

Inlimal Rough:ning

•

Fluoro Ca+ (Loecher) (possible CAD N=613) A Fluoro Ca+ (Tolan) (CAD not suspected N=1894)

• Autopsy >_30%CAD (Josephs) (trauma victims N=111) o Fast CT Ca+ (Projected) <> Fast CT Ca+ (Agatston) (non CAD N=475 90

Projecled (FasbCT)' ~

80

70

f

/-,~

60

/J~'~'/"/'% )-/

50 40

Observed

30 20 10 0

l 20

25

30

4" Loecher et al JACC 19:1167-72, • Josephs et al JACC 21:

'92 No2,267A,'93

35

40

45

~u^-e in Years

50

55

60

o Agatstonet al

JACC 15:827-32,

"90

140 100%

Journal of Electrocardiology Vol. 29 Supplement __Q_L_

Q2

_Q3

Q4

90%

Q5

severity of CAD by quintiles in rated flyers elucidates the basis and background for this report.

NON-CALCIFIED!

80%

Upgrade of Exercise Testing to a 16-Lead High-sensitivity Detection System

i

,, ,, ,, ._-

70%

60%

t

,

,, I :

f

50%

NOR

40% 1-29% 30% I ~ 30-49% 20%

m >=50% 10%

0% 26

30

34

40

46

MEDIAN AGE OF QUINTILE

Fig. 5. Bar graph of the 30,000 United States Air Force rated flyers by quintile (6,000 flyers). The projected distribution of coronary disease in each quintile (with and without coronary calcium) is represented by the shaded areas defined by the four boxes to the right of the figure, varying from angiographically normal to > 50% coronary artery disease (luminal diameter). The upper portion above the heavy line are those flyers projected to have no coronary calcium and the lower portion are those with calcium. The projections are a summary of data in Figures 2-4.

expected incidence, projected from that observed at the USAF Armstrong Laboratory, is less than that observed by Agatston et al. in the younger asymptomatic ambulatory factory workers. It is also less than that expected in this age group assuming that they are similar to the young trauma victims reported by Joseph et al. (3). The recent report by Janowitz et al. found an 11% incidence of coronary calcification in asymptomatic ambulatory subjects 20-29 years old (53). To confirm these relationships, we propose securing ultrafast CT studies on the specific flyers represented in the lower quintile of the observed (fluoro) line in Figure 4, both those with and those without coronary calcium observed at fluoroscopy. Also, ultrafast CT studies for coronary calcium should be done on a random sample of 200 flyers, representative of the lowest quintile, to verify the real incidence in these subsets. This is an important question since, according to Joseph et al. (3), there may be an incidence of significant disease as high as 20%, or more that, that by current criteria would make the young candidate/cadet ineligible for rated flyer status and the costly training this status entails. The summary bar graph (Fig. 5) showing the incidence and distribution of coronary calcium and the

The rationale for developing a model and criteria for regional ischemia is that identification of such ischemia would be expected to increase the sensitivity of ECG ST changes for detecting unsuspected CAD in asymptomatic aircrews. Based on our computer modeling of the QRST, exercise testing, and angioplasty studies, and on the prior work of Komreich et al. and Montague et al. (33-35), the presence of n e w and unique information in the extra leads beyond the standard 12 leads is expected to improve both the specificity and sensitivity of the ECG exercise test. A n u m b e r of investigators (35,54,55) have reported 16-150-lead ECG body surface maps at rest and during exercise in normal subjects and patients with documented ventricular hypertrophy or CAD. These data, along with our simulations and multilead exercise studies, are the basic building blocks for the establishment of multilead ECG criteria for ischemia in the USAF aircrew population. Only Montague et al. (35) have recorded these maps throughout the exercise and recovery period. The others have recorded exercise body surface maps early in the postexercise period. The relevance to the USAF ischemia detection in aircrews project is that these workers have established 95% confidence limits of norreal for ST depression (or elevation) over the torso surface. Predictably, they found that the breakpoint for optimal separation of normal from abnormal was quite variable over the torso. One way of systematizing these results is to normalize each ECG lead for lead field strength (transfer impedance) between the heart and the lead. Ellestad et al. (56) and Bonoris et aI. (57) have shown that these criteria are related, at least in part, to the QRS amplitude across a n u m b e r of precordial sites. Expressing the ST depression as a percentage of the R amplitude improves sensitivity, especially in those with smaller R waves, with no loss of specificity.

Observations of T Morphology Changes During the last several years, a high-fidelity 26-simultaneous-lead ECG recording system with median beats has been evaluated. In those patients with ischemic ST-T change with exercise, it was observed that the earliest change to appear during stress was the appearance of a downward displacement of the upslope and early portion of the peak of the T wave. At times, this resulted in a notched T wave and at other times, a movement of the peak of the T later in time (ie, an increase in the Q peaked T). This p h e n o m e n o n had been observed in the multicenter study (58) of random chamber exposure of patients with k n o w n ischemic heart disease to carbon

Asymptomatic CAD Detection monoxide (two exercise tolerance tests with differing ievels of carbon dioxide and two tests with clean air; both subjects and testers were blinded as to the contents of the test chamber). In the Rancho Los Amigos/USC Medical Center portion of this study, the ECG was recorded with a high-fidelity signal-averaged system. Similar changes had been noted in leads specific for the local ischemic region w h e n subendocardial ischemia was simulated with the computer model (25-27). O'Donnell et al. reported a related p h e n o m e n o n w h e n they observed an increased steepness of the downslope of the T wave as an added marker for early ischemia in treadmill testing (59). This finding is currently being followed up in the cIinicat treadmill exercise testing laboratory by Ellestad and associates with encouraging initial results (60).

Hemodynamic Changes With Myocardial Ischemia Myrianthefs et al. explored the probability that the k n o w n ischemic dysfunction, especially of the left side of the heart during exercise, would produce measurable changes in the left atrial component of the P wave of the ECG (61). It has been k n o w n for years that the end-diastolic pressure in the left ventricle is elevated during anginal episodes (62). Orlando et aI. demonstrated that the left atrial component of the P wave was quite responsive to the left ventricular end-diastolic pressure, as reflected in the pulmonary wedge pressure (63). As documented in the study of Myrianthefs et al. (61), a change in P wave duration during exercise and that persists into recovery was significantly more common in patients with ischemic heart disease than in normal subjects. Based on that work, this p h e n o m e n o n can be assumed to be due to an increase in left ventricular end-diastolic pressure secondary to ischemia in the patients with CAD in whom it occurred. Amon et al. (64) and Miyara et al. (65) reported that a prolonged hypertensive response, a slow return of the systemic blood pressure to normal in recovery, or both, was a marker of the autonomic alpha-adrenergic response to ischemic ventricular dysfunction and low stroke volume. This hemodynamic parameter needs to be revisited in a prospective study with special attention to carefully recorded blood pressure {66). The hypothesis, that a normal response of both this hemodynamic variable and the P wave change in patients with significant local coronary obstructions may represent little or no ischemia due to effective collateral flow to the involved vessel distal to the obstruction needs to be examined critically.

Ischemic ST Response as a Function of Cardiac Work: the ST/HR Slope The reasonable assumption, that the ischemic ST-segment shift on the ECG as an indicator of the disparity between oxygen supply and demand of the working myocardium and the heart rate as a measure of heart work could be used to quantify the degree of ischemia in CAD was tested by Eliam and associates (67). While it

•

Selvester et al.

141

was expected by workers in this field that this concept might improve the accuracy of interpretation of the exercise ECG, m a n y were surprised (68-70) at the phen o m e n a l accuracy of the maximal ST/HR slope method found in early reports. This has led to a spirited exchange in the literature (71-76} and a carefully crafted editorial by Sheffield (77). With gradual staging of the treadmill exercise load and computerized measurements of ST-segm e n t at ST60, sensitivities of 93-95% can be expected in the pilot populations with specificities of 80% or better. We propose that the existing 16-lead ECG recording system and treadmill exercise test be adapted by using commercially available computerized 16-lead ECG systems with signal averaging and digital measurements of ECG variables. We also propose using the more gradual Comell treadmill speed and grade protocol (69), using STsegments recorded at 60 ms after the J point (ST60) and paying meticulous attention to details in replicating the method of Okin and Kligfield for determining the maxim u m ST/HR slope and slope index. We further propose recording the resting preexercise ECG with the patient supine using the 16dead system, including limb leads on the extremities, the six standard precordial leads, and four additional leads at leads V4R, V8, V8R, and V8R-S(houlder) directly above V8R on the right posterior shoulder. The extremity leads will then be moved to the modified Mason-Likar lead locations and the 16-lead ECGs will be repeated with the patient supine for later comparison to the standard extremity locations. The upright MasonLikar 16-lead ECG is then recorded at baseline and with exercise. The treadmill test is conducted using the Comell protocol and careful blood pressure recording at baseline, during exercise, and during recovery. During the first year of the n e w protocol for treadmill testing, it is important to set cut-points for the ST60, Q peaked T, P wave duration, delta P wave duration, m a x i m u m ST60/HR slope, delta ST/HR index, blood pressure response, and treadmill time in order to establish regression coefficients in the 16-lead data set and exercise variables that will achieve the 93-95 % sensitivity standard in the pilot populations being worked up at the Armstrong Laboratory, including coronary angiography. A shift in strategy is also proposed for screening of the asymptomatic aircrew for evidence of CAD. After 1 year w h e n procedures, cut-points, regression coefficients, and/or criteria for the pilot population are established, we propose shifting the ultrafast CT scanning for coronary calcium to regional medical centers as a part of the primary screening. In flight surgeons' offices worldwide, the USAF/Armstrong Laboratory risk profile (29) will be updated along with recording the new high-resolution 16-lead ECG/three-dimensional VCG upgrade described earlier. Subjects who screen positive with the serial 16lead ECG/three-dimensional VCG upgrade for silent infarct will be referred directly for cardiology work-up and coronary angiography, as will all subjects who screen positive for calcium by ultrafast CT. Those subjects screening negative for calcium by ultrafast CT will have the high sensitivity treadmill exercise test done as part of the primary screening for ischemia and functional cardiac reserve. Those positive by the treadmill stress

142

Journal of Electrocardiology Vol. 29 Supplement

test, those with abnormal ST-T changes on the 16-lead ECG, and those who are negative by all prior screens, but in the upper quintile, by the risk profile, will also have exercise nuclear wall motion studies and tomographic perfusion scans. If these studies abnormal and suggestive of ischemia, this group will be referred for cardiology work-up and coronary angiography as described earlier. Projected from the prevalence and severity of CAD, the four-step screen can be expected: (1) in 25year-old cadets, to identify 60% of those with 30% or more CAD, 90% of those with 50% or more CAD, with 45% false positive results, and (2) in 45-year-old rated flyers, to identify 85% of those with 30% or more CAD and 95% of those with 50% or more CAD with 25% false positive results. This 4 step algorithm warrants controlled testing in this high occupational risk environment.

I2.

13.

14. 15.

16.

References 17. 1. Enos WE Holmes RH, Beger J: Coronary disease among United States soldiers killed in action in Korea. JAMA 52:1090, 1953 2. McNamara J J, Molot MA, Stemple JE Cutting RT: Coronary artery disease in combat casualties in Vietnam. JAMA 215:1185, I971 3. Joseph J, Ackerman D, Talley JD et al: Manefestations of coronary atherosclerosis in young trauma victims: an autopsy study. J Am Coil Cardiol 22:459, 1993 4. Brown BG, Galley CA, Badger RS et al: Incomplete lysis of thrombus in the moderate underlying atherosclerotic lesion during intracoronary infusion of streptokinase for acute myocardial infarction: quantitative angiographic observations. Circulation 73:653, 1986 5. Singh RN: Progression of coronary atherosclerosis: clues to pathogenesis from serial coronary arteriography. Br Heart J 52:451, 1984 6. Little WC, Conastantinescu M, Applegate RJ et al: Can coronary angiography predict the site of a subsequent myocardial infarction in patients with mildto-moderate coronary disease? Circulation 78:1157, 1988 7. Kannel WB, McNamara PN, Feinleib M, Dawber TR: The unrecognized myocardial infarction: fourteenyear follow-up experience in the Framingham Study. Geriatrics 25:75, 1970 8. Kannel WB, Abbott RD: The incidence and prognosis of unrecognized myocardial infarction: an update of the Eramingham Study. N Engl J Med 311:1144, 1984 9. Lindberg HA, Berkson DM, Stamler J, Poindexter A: Totally asymptomatic myocardial infarction. Arch Intern Med 106:628, I960 10. Johnson WJ, Achor RWP, Burchell HB, Edwards JE: Unrecognized myocardial infarction. Arch Intern Med 103:253, 1959 l l . Selvester RH, Solomon JC: Optimal ECG electrode sites and criteria for detection of asymptomatic coronary artery disease at rest and with exercise. Techni-

18.

19.

20.

21.

22.

23.

24.

cal report of the School of Aerospace Medicine, TRUSAFSAM-ETC. Brooks AFB, Texas, 1985 Selvester RH, Solomon JC, Gillespie TL: Digital computer model of a total body ECG surface map: an adult male torso simulation with lungs. Circulation 38:685, 1968 Selvester RH, Kirk WL, Pearson RB: Propagation velocities and voltage magnitudes in local segments of myocardium. Circ Res 27:619 1970 Solomon JC, Selvester RH: Current dipole m o m e n t density of the heart. Am Heart J 81:35 l, 1971 Solomon JC, Selvester RH: Simulation of measured activation sequence in the h u m a n heart. Am Heart J 85:518, 1973 Selvester RH, Solomon JC: Infarct size and QRS changes (QRS criteria applicable to computer diagnostic programs), p. 69. In Tolan GD, Pryor TA (eds): Proceedings of the Engineering Foundation conference on computerized interpretations of the ECG. Engineering Foundation, New York, 1980 Selvester RH, Solomon JC: Computer simulations of ventricular depolarization, QRS duration and quantitation of wall thickness. Computer ECG analysis: towards standardizations, p. 261. In Willems JL, van Bemmel JH, Zywietz C (eds): Proceedings of the 3rd international conference on c o m m o n standards for quantitative electrocardiography. North Holland, Amsterdam, 1986 Selvester RH, Solomon JC: Computer simulation of the h u m a n electrocardiogram--fascicular blocks and myocardial infarction, p. 215. In Leinberger J (ed): Computers in cardiology: proceedings of the IEEE Computer Society, Boston, MA, 1987 Palmeri ST, Harrison DG, Cobb F R e t ah A QRS scoring system for assessing left ventricuIar function after myocardial infarction. N Engl J Med 306:4, 1982 Ideker RE, Wagner GS, Ruth WK et ah EvaIuation of a QRS scoring system for estimating myocardial infarct size part II. Correlation with quatitative anatomic findings for anterior infarcts. A m J Cardiol 49:1604, 1982 Ward RM, White RD, Ideker RE et ah Evaluation of a QRS scoring system for estimating myocardial infarct size. Part IV. Correlation with quantitative anatomic findings for posterolateraI infarcts. Am J Cardiol 53:706, 1984 Bounous EP, Califf RM, Harrell F E e t al: Prognostic value of the simplified Selvester QRS score in patients with coronary artery disease. J Am Coil Cardiol 11:35, 1988 Sevilta DC, Wagner NB, White RD et ah Anatomic validation of electrocardiographic estimation of the size of acute and healed myocardial infarcts. Am J CardioI 65:1301, 1990 Selvester RH, Sanmarco ME: Infarct size in hi-gain, hi-fidelity serial VCGs and serial ventriculograms in patients with proven coronary artery disease. In Antaloczy A (ed): Proceedings of the 4th World Congress on Electrocardiography: Modern electrocardiology. Exerpta Medica, Amsterdam, 1978

Asymptomatic CAD Detection 25. Selvester RH, Solomon JC, Tolan GT: Fine grid computer simulation of QRS-T and criteria for quantitating regional ischemia. J Electrocardiol 20(suppl): l, 1987 26. Tolan GT, Selvester RH, Solomon JC: Optimal ECG electrode sites and criteria for detection of asymptomatic coronary artery disease. Computer ECG analysis: towards standardization, p. 255. In Willems JL, van Bemmel JH, Zywietz C (eds): 3rd International Conference on Common Standards for Quantitative Electrocardiography. North Holland, Amsterdam, 1986 27. Wagner NB, Sevilla DC, Krukoff MW et ah Transient alterations in the QRS complex and ST segment during balloon angioplasty of the left anterior descending coronary artery. Am J Cardiol 62:1038, 1988 28. Saetre HA, Selvester RHS, Solomon JC et al: Sixteen lead electrocardiographic changes with coronary angioplasty: location of STT changes with balloon occlusion of five arterial segments. J Electrocardiol 24(suppl):153, 1991 29. Clark DA, Tolan GD, Johnson R et ah The West Point study: 40 years of follow-up. Aviat Space Eviron Med 65(5 suppl):A71, 1994 30. Selvester RH, Solomon JC: Optimal ECG electrode sites and criteria for detection of asymptomatic coronary artery disease at rest and with exercise: update 1990. Technical Report of the School of Aerospace Medicine, TR-AL-1991-0029. Brooks AFB, Texas, 1992 31. Selvester RH, Gillespie TL: Simulated ECG surface map's sensitivity to local segments of myocardium: proceedings of Vermont conference on body surface mapping of cardiac fields. Adv Cardiol 10:xx, 1974 32. Madrid WL, Sanmarco ME, Gaarder TG, Selvester RH: Circumflex occlusion and posterior myocardial infarction, diagnostic criteria and automated ECG analysis programs, p. 37. In Bailey JJ (ed): Computerized interpretation of the ECG XI: proceedings of the Engineering Foundation conferences. Engineering Foundation, New York, 1986 33. Kornreich F, Montague TJ, Kavadias M e t al: Multigroup diagnosis of body surface potential maps. J Electrocardiol 22 (suppl): 169, 1989 34. Kornreich F, Montague TJ, Rautaharju PM et al: Identification of best electrocardiographic leads for the diagnosing anteior and inferior myocardial infarction by statistical analysis of bogy surface potential maps. Am J Cardiol 58:863, I986 35. Montague TJ, Witkowski FX, Miller RM et ah Exercise body surface mappinng in single and multiple coronary disease. Chest 97:1333, 1990 36. Loecher TH, Schwartz RS, Cotta CW, Hickman JR: Fluoroscopic coronary calcification and associated coronary disease in asymptomatic young men. J Am Coll Cardiol 19:1167, I992 37. Blankenhorn DH, Stern D: Calcification in the coronary arteries. A m J Roentgenol 5:772, 1959 38. Blankenhorn DH: Coronary arterial calcification: a review. Am J Med Sci 242:1, 1961 39. Eggan DA, Strong JP, McGill HC: Coronary calcification: relationship to clinically significant coronary

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

•

Selvesteret al.

143

lesions and race, sex, and topographical distribution. Circulation 32:948, 1965 Beadenkopf WG, Daoud AS, Love BM: Calcification of the coronary arteries and its relationship to arteriosclerosis and myocardial infarction. Am J Roentgenol 92:865, 1964 Warburton RK, Tampas JP, Soute AB, Taylor HC: Coronary artery calcification: its relationship to coronary artery stenosis and myocardial infarction. Radiology 9h109, 1968 Fink RJ, Achor RRWP, Kinkaid OW, Brandenberg RO: Significance of calcification of the coronary arteries. Am J Cardiol 26:241, 1970 Hamby RI, Tabrah E Wisoff BG, Hartstein ML: Coronary artery calcification: clinical implications and angiographic correlates. A m Heart J 87:565, 1974 Uretsky BE Rifkin RD, Sharma SC, Reddy PS: Value of fluoroscopy in the dectection of coronary stenosis: influence of age sex and n u m b e r of vessels calcified on diagnostic eficacy. Am Heart J 115:323, 1988 Margolis JR, Chert JTT, Kong Y e t al: The diagnostic and prognostic significance of coronary artery calcification. Radiology 137:609, 1980 Detrano R, Markovic D, Simpfendorfer C et al: Digital subtraction fluoroscopy: a n e w method of detecting coronary calcifications with improved sensitivity for the prediction of coronary disease. Circulation 71:725, 1985 Detrano R, Simpfindorfer C, Day K et al: Comparison of stress digital ventriculography, stress scintography, and digital fluoroscopy in the diagnosis of coronary artery disease in in subjects with and without myocardial infarction. Am J Cardiol 56:434, 1985 Reinmuller R, Lipton MJ: Detection of coronary artery calcification by computed tomography. Dynamic Cardiovascular Imaging 1:139, 1987 Tannenbaum SR, Dondon GT, Veselik KE et al: Detection of calcium deposits in coronary arteries by ultrafast computed tomography and correlation with angiography. Am J Cardiol 63:870, 1989 Agatston AS, Janowitz WR, Hildner FJ et al: Quantification of coronary artery calcium using ultrafast computed tomography. Am J Cardiol 15:827, 1990 Breen JE Sheedy PF, Schwartz RS et ah Coronary artery calcification detected with ultrafast-CT as an indication of coronary artery disease: work in progress. Radiology 185:435, 1992. Fatlavollita JA, Brody AS, Kumar K, Canty JM: Predictive value of fast CT coronary calcification as compared to angiography in patients under the age of 50. J An1 Coll Cardiol Suppl 21:267A, 1993 Janowitz WR, Agatston AS, Aizwa N e t al: Quantification of coronary calcium reflects the angiographic extent of coronary artery disease. Am J Cardiol 72:247, 1993 Ikeda K, Kawashima S, Kubota I e t ah Non-invasive detection of coronary artery disease by body surface electrocardiographic mapping after dipyridimole infusion. J Electrocardiol 19:213, 1986

144

Journal of Electrocardiology Vol. 29 Supplement

55. Fox KM, Richards M, Jonathan A et al: Precordial electrocardiographic mapping in the identification of patients with left main stem narrowing. Int J Cardiol 3:315, 1983 56. Ellestad MH, Crump R, Surber M: The significancance of lead strength on ST changes during treadmill stress test. J Electrocardiol 25 (suppl) :31, 1992 57. Bonoris PE, Greenberg PS, Castellanet M J, Ellestad MH: Significance of changes in R wave amplitude during treadmill stress testing: angiographic correlation. Am J Cardiol 41:846, 1978 58. Allred EN, Blecker RE, Chaitman RB et ah Shortterm effects of carbon monoxide exposure on the exercise performance of subjects with coronary artery disease. N Engl J Med 321:1426, 1989 59. O'Donnell J, Lovelace DE, Knoebel SB, McHenry PL: Behavior of the terminal T wave during exercise in normal subjects, patients with symptomatic coronary artery disease and apparently healthy subjects with abnormal ST depression. J Am Coll Cardiol 5:78, 1985 60. Ellestad MH, Queiroz JA, Selvester RHS, Shandling AH: Prolongation of corrected Q peak T with exercise testing provides improved diagnostic power, p. 91. In Congress of cardiac rehabilitation. A t h e n e u m Press, Newcastle u p o n Tyne, UK, 1993 6I. Myrianthefs MM, Ellestad MH, Selvester RHS, Crump R: Significance of signal-averaged P-wave changes during exercise in patients with coronary artery disease and correlation with angiographic findings. Am J Cardiol 68:1619, 1991 62. Wiener L, Dwyer EM Jr, Cox WJ: Left ventricular hemodynamics in exercise-induced angina pectoris. Circulation 38:240, 1968 63. Orlando J, Vicario Del M, Aronow WS, Cassidy J: Correlation of m e a n pulmonary wedge pressure left atrial dimensions, and PTF-V1 in patients with acute myocardial infarction. Circulation 55:750, 1977 64. Amon KW, Richards KL, Crawford MH: Usefulness of the post exercise systolic blood pressure in the diagnosis of coronary artery disease. Circulation 70:951, 1984 65. Miyara T, Yokota M, Iwase M e t al: Mechanism of abnormal postexerdse systolic blood pressure response and its diagnostic value in patients with coronary artery. Am Heart J 120:40, I990

66. Acanforo D, De Caprio L, Cuomo S e t ah Diagnostic value of the ratio of the recovery systolic blood pressure for the detection of coronary artery disease. Circulation 77:I306, 1988 67. Elamin M, Boyle R, Kardish M e t al: Accurate detection of coronary disease by a new exercise test. Br Heart J 48:311, 1982 68. Kligfield P, Okin PM, Ameisen O, Borer JS: EvaIuation of coronary artery disease by an inproved methods of exercise electrocardiography: the ST segment/ heart rate slope. Am Heart J 112:589, 1986 69. Okin PM, Ameisen O, Kligfield P: A modified treadmill exercise protocol for computer-assisted analysis of the ST segment/heart rate slope: methods and reproducibility. J Electrocardiol 19:31 l, 1986 70. Okin PM, Kligfield P, Milner MR et al: Heart rate adjustment of ST segment depression for reduction of false positive electrocardiographic responses to exercise in asymptomatic m e n screened for coronary artery disease. Am J Cardiol 62:i043, 1988 71. Iedigfield P, Ameisen O, Okin PM: Heart rate adjustment of ST segment depression for improved detection of coronary artery disease. Circulation 79:245, 1989 72. Lachterman B, Lehmann KG, Detrano R et al: Comparison of the ST segment/heart rate index to standard ST criteria for analysis of exercise electrocardiogram. Circulation 82:44, 1990 73. Okin PM, Bergman G, Kligfield P: Effect of ST segment measurement point on performance of standard and heart rate-adjusted ST segment criteria for identification of coronary artery disease. Circulation 84:57, 1991 74. Simoons M, Block P: Towards the optimaI lead system and optimal criteria for exercise electrocardiography. Am J Cardiol 47:I366, 198i 75. Rossi L, Carbonieri E, Castello C et al: Description and evaluation of the method for computer analysis of the exercise electrocardiogram. J Electrocardiol 20:77, 1987 76. Sievanen H: Development and evaluation of the multivariate ST/HR analysis for the assessment of myocardial ischemia. PhD thesis. Tampere University of Technology, Tampere, Finland, 1991 77. Sheffield LT: Upsloping ST segments: easy to measure, hard to agree upon, (editorial) Circulation 82:426, 1991