Computer analysis of the orthogonal electrocardiogram and vectorcardiogram in 939 cases with hypertensive cardiovascular disease

Computer and

analysis

of the orthogonal

vectorcardiogram

hypertensive

in 939

cardiovascular

electrocardiogram

cases with disease

D. McCaugh-an, M.D. D. Littmann, M.D. H, V. Pifiberger, M.D. Washington, D. C.

A

ny pathological state which increases left ventricular work may be expected to lead eventually to left ventricular hypertrophy (LVH). At least in the early stages of LVH, cardiac enlargement may not be present radiologically, but the increase in muscle mass caused by concentric hypertrophy may produce electrocardiographic (ECG) changes. The term left ventricular overload (LVO) is used in this communication whether LVH is detectable or not. The value of the electrocardiogram in the diagnosis of LVO has been established.‘e4 However, several studies5eg indicate that the sensitivity of the ECG criteria used may be as low as 33 per cent with a specificity of 65 per cent (false positive rate of 3.5 per cent). The introduction of the vectorcardiogram has been claimed to increase sensitivity.‘O-l7 However, most of these studies have included cases from a wide variety of etiologies and the number

of false positives (FP) in age, race, and sexmatched normal control groups has not been examined in many reports. Left ventricular work is increased by hypertension,18j1s and it is known that ECG changes may occur in patients with hypertension without radiological evidence of cardiac enlargement.20 Correlations have been shown between the blood pressure level and ECG changes.21 With the advent of digital computers for ECG analysis, it has become possible to test complex multivariate classification techniques which might lead to earlier recognition of electrocardiographic changes due to LVO. At the same time, large numbers of conventional ECG and VCG parameters can be tested for their efficiency in the separation of normal and abnormal in order to arrive at a set of optimal diagnostic discriminators. It appeared indicated, therefore, to evaluate ECG changes presumably due to LVO in a single etiological group and

From

the Veterans Administration Cooperative Study on Automatic Cardiovascular Data Processing. Veterans Ad ministration Hospitals: Birmingham. Ala.; Dallas, Texas; Durham. N. C.; Minneapolis, Minn.; San Francisco Calif.; Sepulveda. Calif.; Washington. D. C.; West Roxbury, Mass.; and the Department of Medicine, Harvard University, Boston. Mass., and the Departments of Medicine and Clinical Engineering. George Washington University, \?-ashington. D. C. Supported in part by Research Grant HL 15047-01 from the National Heart and Lung Institute. National Institutes of Health, United States Public Health Service. Received for publication June 5. 1972. Reprint requests to: Hubert V. Pipberger. M.D., Veterans Administration Hospital, 50 Irving Street. N. W.. Washington. D. C. 20422.

Vol. 85, No. 4, #p.467-482

April, 1973

American Heart Journal

467

468

McCaughan,

Littmann,

compare the findings with an age, race, and sex-matched normal control group of large size. The present study represents a comprehensive computer analysis of the orthogonal ECG in 939 patients with hypertensive cardiovascular disease (HCVD) compared with a group of 229 “normals.” Patients

AWL Hcort .I. Ajvil, 1973

and Pipberger

and methods

The records used in the present study were obtained from a cooperative study of eight Veterans Administration hospitals. Caseswere selected at each hospital according to study protocol specifications. The population of patients selected in this study is comparable to the population which is to be diagnosed in a general hospital with an adult male population. The authors had no influence on the choice of casesat the different hospitals. The geographic distribution assures a representative sample of cases. The diagnosis of hypertension was based on the finding of an average blood pressure of at least 150/90 mm. Hg, using blood pressures obtained in the sitting position four times a day during a three-day period following the day of admission. It is assumed that many such patients have some degree of LVO. The only ECG criterion used for exclusion of patients was a QRS duration of 0.126 sec. or more. Although the upper limit for simultaneously recorded leads in normals was found to be 0.112 sec., this range was arbitrarily extended by 14 msec. because it is well known that LVH by itself may lead in some cases to QRS prolongation. After elimination of 34 records with a QRS duration of more than 0.126 sec., the 96th percentile range proved to be 0.123 sec. for Group 3, indicating that LVH leads to only moderate prolongation of the QRS. In addition to this single ECG criterion used in the selection of patients, all patients who had a clinical history consistent with coronary heart disease--i.e., angina pectoris and/or a history of myocardial infarction, were excluded. Patients with coronary heart disease and hypertension will be reported separately. Records of 939 patients were available for analysis. These were subdivided into three clinical categories as follows: (1) 394 patients without cardiac enlargement on

x-ray and no history of congestive heart failure, (2) 242 patients with chest x-ray evidence of cardiac enlargement and no history of congestive heart failure, and (3) 303 patients with cardiac enlargement on x-ray and a history of one or more episodes of congestive heart failure. As the majority of these patients was over 40 years old, 229 control records from normal subjects between 40 and 78 years old were chosen for comparison. Black and white subjects were included: 33 per cent of the normals, 29 per cent of Group 1, 39 per cent of Group 2, and 39 per cent of Group 3 were black. At the time the ECG was recorded, the percentage of cases in each of the three groups that was taking a digitalis preparation was: 3 per cent of Group 1, 10 per cent of Group 2, and 81 per cent of Group 3. The patients in Group 1 presumably have the mildest or least advanced form of LVH, essentially of the concentric type. The patients in Group 2, exhibiting cardiomegaly by x-ray, have probably some degree of cardiac dilatation in addition to LVH. Group 3 patients may have, in addition to LVH and cardiomegaly, some degree of right ventricular hypertrophy (RVH) as a consequence of left ventricular failure. Most of these patients exhibit biventricular hypertrophy (BVH) with predominance of the left ventricle when they come to autopsy.22 Patient protocols were recorded on FOSDIC forms which can be transcribed directly onto digital tapes for computer correlations. Data

acquisition

and

analysis

Orthogonal ECG’s were recorded on magnetic tape, using the Frank systemz3 with the chest electrodes at the level of fourth intercostal space, as recommended for subjects in the supine position.24 Positive polarity of the three leads was as follows: X leftward, Y inferiorly, and Z posteriorly. The recording equipment which was standardized by similar procedures at the various participating hospitals had an over-all frequency response from 0.05 to 1,250 I-Iz (3 db. down at the lower end of this range). Details of the analog-to-digital conversion process and computer analysis have been reported previously.25 A Control

Computer analysis

Data Corporation 3200 digital computer was used for this study. A total of 333 different scalar and vectorial measurements was computed for each record, comprising practically all parameters previously advocated for ECG analysisz6 The purpose of computing such a large number of measurements was to search for optimal discriminators between ECG’s in patients with hypertension and in normal subjects. Statistical procedures used in this search have been described in detail previously.22v27 Since most ECG measurements are not normally distributed, 96 percentile ranges are used rather than means and standard deviations. This is accomplished by eliminating 2 per cent of the cases at each end of the distribution according to the method originally suggested by Simonson2* Thus, “outliers” are eliminated in a fashion comparable to that used with means f two standard deviations when data are normally distributed. Frank ECG measurements of the three different groups with HCVD were ranked according to the percentage of cases which exceeded 96 percentile ranges of normal. With this procedure, a set of candidates for optimal discrimination between normal and HCVD was obtained. Since most abnormal cases exceed normal ranges on one end the upper or lower limit, the only-i.e., number of normals exceeding this limit is 2 per cent. These cases are considered as “false positives” (FP) since they are incorrectly labelled as abnormal. When several criteria are used, the rate of false positives increases also. Once a list of the best discriminators has been established, the records of all patients, both normals and the disease groups, are compared side by side to test the efficiency of these discriminators. Many of them that individually appear to be efficient in separating the disease group from normals are then found to be redundant as they do not add additional cases not found by other measurements already. Such measurements may then be eliminated. At the same time, measurements which contribute new cases are retained. Thus, sets of criteria are found which separate the maximum number of abnormal records from the normal controls. In order to test their specificity, cumulative FP rates need to be determined also.

of ECG and VCG in LVO

469

This type of evaluation was performed for both scalar and vectorial measurements which can be easily obtained by hand. Subsequently, a set of optimal measurements, regardless of complexity, was obtained strictly for computer analysis. Thirty criteria which were found most efficient were subjected to linear discriminant function analysis using an approach described previously in detail. 22 With this procedure, all measurements simultaare considered neously and weight factors are determined for each parameter. The best discriminators are then combined to form a multidimensional vector for each patient record. Subsequently, mean vectors are calculated for each diagnostic entity-i.e., normal subjects or patients with hypertension. Unknown records are then classified by use of a likelihood ratio test by which the vector differences between the unknown and the various means are determined. The smaller this vector difference, the greater the likelihood that the record belongs to this group. The total number of measurements used in multidimensional analysis proved critical because a number that is too large leads to overly optimistic results which cannot be duplicated on new and independent case material. Cornfieldzg has reported that this number should not exceed 1/20th of the number of cases under study in a two-group comparison. Correlation coefficients for systolic and diastolic blood pressures were determined for each of the 333 measurements. Minnesota coding30 of the standard 12lead ECG was available for all patients with HCVD. Cumulative results of all cases with abnormal voltage (Code 3.1) and ST-T wave changes (Codes 4.1, 4.2, 4.3, 5.1, 5.2 and 5.3) were determined. Standard 12-lead ECG’s were not available for the normal group of 229 cases for the Frank ECG analysis. As previously shown,31 a group of 150 normal ECG’s demonstrated statistical stability in means and distributions when compared with other similarly sized samples. Thus, a group of 192 normals, selected according to the same criteria, in which 12-lead ECG’s were available, was analyzed to determine the FP rate for the Minnesota Code criteria used. There were 31 per cent black subjects in this group.

470

McCatlghan,

Littmann,

and Pipberger

Am. Heart .I. Ajwii, 1973

Fig. 1. Averaged Frank scalar leads based on 229 normal control subjects and three groups of hypertensives. QRS and ST-T complexes were normalized in time by dividing the duration of each into eight equal parts. Each point represents l/8, 2/8, and so on, of QRS and ST-T. Calibration is 0.5 mv. For further description, see text.

Results

ECG and

VCG conjigzLration.

The mean configuration of the scalar X, Y, and Z leads and the vector loop projections in the transverse planes are shown in Figs. 1 and 2. These mean values were derived from the total sample for each group and from the normal control sample. The QRS complexes and the time interval from the end of QRS to the end of the T wave (ST-T) were each normalized in time by division into eight equal parts. The mean values of each eighth were calculated and then used for the display of the average scalar leads and vector loops. The average transverse plane projections shown in Fig. 2 indicate that point J (junction of QRS and ST-T) is carried progressively anteriorly and rightward from the normal group to Group 3. Although the percentage of cases taking digitalis preparations increases significantly from Group 1

to Group 3, only 3 per cent of Group 1 and 10 per cent of Group 2 were taking digitalis at the time the ECG was recorded; thus this J point alteration cannot be attributed to digitalis alone and must also be an effect of increasing LVO. As this displacement of the J junction is similar to that seen in coronary artery disease, relative coronary insufficiency as a concomitant cause could not be excluded. The changes which occur in the initial part of the QRS may he seen in the normalized transverse plane and Lead Z (Figs. 1 and 2). Lead Z shows a reduction in the Q wave duration and voltage. The Q, was less than 0.02 sec. (96 percentile limit of normal) in 5 per cent of Group 1, 10 per cent of Group 2, and 14 per cent of Group 3. The QZ was absent in S per cent of Group 1, 10 per cent of Group 3, and 15 per cent of Group 3. The mean azimuth angles of the instan-

Y&me Number

85 4

Computer analysis

of ECG and VCG in LVO

471

Fig. 2. Averaged Frank transverse planar projections based on 229 normal control subjects and three groups of hypertensives. The QRS complexes were normalized in time by dividing the duration of each into eight equal parts. Therefore, each point represents l/8, 2/8, and so on, of the QRS. The final point on each projection is the J point. All QRS loops rotate counterclockwise. Note the progressive reduction in duration and voItage of the initial anterior forces accompanied by increase in posterior and leftward directed mid-QRS forces. There is also a progressive shift of the initial l/8 QRS vector toward the left, together with a shift of point J in rightward and anterior direction. Note also the relative narrowing of the QRS loop in the most advanced Group 3. For further description, see text.

taneous vectors from the beginning of the QRS were as follows: 0.01 sec.: Normal, 96’; Group 1, 100”; Group 2, 102O; Group 3, 100’. 0.02 sec.: Normal, 52’; Group 1, 51’; Group 2, 51”; Group 3, 50”. 0.03 sec.: Normal, 11’; Group 1, 6”; Group 2, 6’; Group 3, 349”. Thus the directions of the mean initial QRS vectors up to 0.02 sec. are practically unchanged, while the mean 0.03 sec. vector has a slightly more posterior direction in the three hypertensive groups. QRS voltage. As expected and as shown in Fig. 1, there was a mean increase in QRS voltage in leftward (R,) and posterior (R,) direction, corresponding to the anatomic location of the left ventricle. The over-all increase of the QRS magnitude is best expressed by the spatial time integral of QRS (S A QRS). As compared to a normal mean of 34 pv sec., the means for Groups 1 to 3 were 40, 45, and 52 pv sec., in this order. Although the mean direction of S A QRS in the transverse plane was

almost the same as in normals, its mean elevation angle decreased progressively from 40’ in Group 1 to 11’ in Group 3 (normal mean 36’). R peak time. The mean R peak time (intrinsicoid deflection) of each of the three scalar leads increased with a more advanced degree of LVO. When compared with normal, this mean increase was relatively small; however, with a maximum of 7 msec. in Lead X for the most severe, Group 3. When the number of caseswhich exceeded the 96 per cent limit of normal in Lead X of 48 msec. was determined, the percentages in each group increased substantially from 6 per cent in -Group 1 to 13 per cent in Group 2 and 32 per cent in Group 3. Although this criterion proved relatively efficient for the separation of LVO from normal, by itself it did not contribute independent diagnostic information not already provided by the criteria given in Tables I to III. QRS duration. The QRS duration increased progressively with advancing de-

472

McCaughan,

Table I. Discriminators

Littmann,

Am. Heart I. Afwil, 1973

and Pipberger

between normals and three groups of patients with hypertension*

Measurementt

Normal limits (96% range)

RX R. Rx+ S, Rx+ FL Q/R, ratio Maximal QRS vector (transverse) Maximal QRS vector (sagittal) Maximal spatial magnitude TX 6/8 ST-T,

1.9 mv. 1.5 mv. 2.1 mv. 3.1 mv. 0.1 mv. 2.1 mv. 2.1 mv. 2.5 mv. -0.06 mv. 0.02 mv. -0.08 mv. 8"82'$ 91”-186”$

JI Transverse T angle Sagittal T angle

*The upper limit of the normal range is tAll measurements are amplitudes unless tAngular measurements greater than 82’ $Angular measurements greater than 91’

Group

1

20%

15% 9% 11% 14%

16% 14%

6% 9% 24% 32% 17% 37% 25%

Group

19% 15% 24% 23% 23%

8% 18% 50% 57% 31% 64% 41%

2

False positives (cumulative)

Group3

All

16%

17% 17% 13%

ig 5%

21%

6%

27% 15% 29% 35%

24%

28%

21%

14% 19% 71% 75% 54%

9% 15% 46%

81% 66%

58%

52% 33% 42%

9% 9% 10%

10% 13% 13% 15%

18% 20%

shown (Frank). indicated othenvise. or less than 8’. or less than 186”.

grees of LVO. In Group 1 the mean duration was 91 msec., in Group 2, 94 msec., and in Group 3, 98 msec. The upper limits of the 96 per cent ranges for the three groups were 115, 119, and 123 msec., respectively. The gradual increase from an upper limit of normal of 112 msec. to 123 msec. in the most severe group of LVO confirms the belief that ventricular hypertrophy alone can lead to a moderate QRS prolongation in the absence of a ventricular conduction defect of the bundle branch block type. Frank scalar and vector discriminators. Table I shows the 13 Frank ECG measurements which were the best discriminators between the normal and the hypertensive groups. Apart from the maximal spatial QRS magnitude, all these measurements can be conveniently obtained from scalar and vectorcardiographic plane displays. Six-eighths ST-T in X corresponds closely to the maximum T,. As only one end of the 96 per cent range was used, the number of false positives for each measurement individually was 2 per cent. The cumulative FP rate is shown with a total for all measurements of 20 per cent. This FP rate of 20 per cent precludes practical use of all 13 criteria since every fifth normal record would be misclassified as LVO with this set of measurements.

For all measurements except R,, there is an increase in number of cases exceeding normal limits with increasing severity of LVO from Group 1 to 3. A decrease in R, amplitude in the most advanced cases was described previously13 when a correlation between radiologic heart size and LVO was attempted. In cases with substantial cardiomegaly, R, amplitudes continue to increase with a concomitant decrease of R,. This phenomenon leads to narrow, posteriorly directed QRS loops in the transverse plane which sometimes form a figure eight. Table II shows a more practical selection of seven diagnostic LVO criteria. Even with this smaller number of measurements, the cumulative FP rate is 13 per cent-i.e., a misclassification of every eighth normal record would have to be expected. At this level of specificity, 50, 74, and 89 per cent of Groups 1 to 3 respectively, would be correctly classified as LVO. If the FP rate of 13 per cent is considered intolerably high, the number of criteria may be decreased by selecting only the first four measurements. Such a choice would be accompanied by a substantial decrease in correct classifications with 25 per cent for Group 1, 38 per cent for Group 2, and 46 per cent for Group 3. These first four QRS measurements prob-

L’ohne

85

Number

4

Computer

analysis

II. Selected Frank scalar measurements that records and three groups of patients with hypertension

Table

Measurement*

Group 1

(cumulative) RX

15%

RE Rx+ Rx+ Y/k

21% S, Rz

24%

25% 3690 4670

J: *All

measurements

unless

indicated

discriminate

Grou# 3 (cumulative)

w%

1Wo

3370 37% 38%

37% 44% 46 %

50%

62%

7157* 74%

W% are amplitudes

Grcu~5 2 (cumulative)

of ECG and VCG in LVO

e$ciently

All (cumulative) 17% 29% 34% 35Yo 45%

473

between

normal

False pm&es (cumulative)

270 5% 5%

6% 9%

SS%

65%

11%

89%

69%

13%

otherwise.

ably are the least controversial discriminators for LVO. The subsequent measurements including the Q/R, amplitude ratio are not specific for LVO. It should be noted that after the first three QRS measurements are applied, the measurement R, + R, only adds new cases at the same rate as false positives. Table III shows seven QRS measurements which were applied in a similar manner as the seven measurements in Table II. The first four are identical in both tables. If the three measurements, maximal transverse QRS amplitude, maximal sagittal QRS amplitude, and the more complicated maximal spatial amplitude are added, the percentage of newly diagnosed cases increases at the same rate as the false positives. Thus, these three vector measurements which are excellent discriminators between normais and each of the three HCVD groups individually, do not contribute significantly to the number of correctly classified records if the four scalar variables are used first. They appear completely redundant. Correlation of Frank ECG criteria with blood pressure. Out of the 333 ECG measurements tested, 34 led to a correlation coefficient of more than 0.2 with systolic pressure and 22 with diastolic pressure (P < 0.01). The great majority of these consisted of ST and T measurements with the highest values at point J in Lead X and at S/8 ST-T,. Systolic blood pressure and QRS variables correlated best with the spatial magnitude of the 0.05 sec. QRS vector (r =

0.211), the spatial 6/8 QRS (r= 0.231), and 7/8 QRS vectors (r = 0.262). Diastolic pressures correlated most significantly with R, amplitudes (r = 0.232) and the S/8 QRS amplitude in the same lead (r = 0.228). M&variate analysis. Table IV shows 13 measurements which were found best for the separation of normal vs. LVO when discriminant function analysis was applied. The methods used for the selection of these measurements have been described in detail elsewhere.22Each variable is multiplied by its discriminant function coefficient or weight factor and the products are added in order to obtain a single patient vector. The last column gives an indication of the individual contributions of the different variables. These products were obtained by multiplying mean measurements with the weight factors. It becomes obvious that the first measurement, the maximal QRS vector in the transverse plane, exceeds all others in discrimination power by a wide margin. Seven out of the 13 variables, including the first, are vector measurements. The contributions of the last variables appear very small and three or four could probably be eliminated without changing classification results significantly, It should be noted that only one measurement is in the ST-T segment. Tables V and VI show the classification results by discriminant function analysis and a likelihood ratio test for the three hypertensive groups vs. normal. They were compared with results obtained by use of optimal discriminators listed in Table III at nearly identical levels of specificity-i.e.,

474

McCaughan,

Littmann,

Am. Heurt J. Afiril, 1973

and Pipberger

Table III. Selected Frank scalar and vector measurements records and three groups of patients with hypertension

Group 1 (cumulative)

Measurement*

15% 2190 2490 2590 25% 26% 26Y0

RX

R. Rx+

S,

Rx+ Rz Transverse magnitude (maximum) Sagittal magnitude (maximum) Spatial magnitude (maximum) *All

measurements

Table

are amplitudes

unless

indicated

Discriminant function

Productt

coejicients Max QRS,.

6/g QR%,s 2/g QRSz 51% QRSx,z S/8 ST-T, 5/g QRS,.

618 QRSx, RX 6/g RZ 318 4/g 418

QRSx. QRS, QRSx. QRSz

*AU measurements tProduct of means plied by 1,000.

are amplitudes and discriminant

0.23 -0.25 0.52 -0.10 1.00 0.09 0.25 -0.04 0.10 0.03 -0.22 -0.02 -0.01

(cumulative)

2OY* 33% 377,

3890 38% 38%’

38%

between normal

3 All (cumulative) j (cumulative) Group

16% 3770 44 70 46’% 47% 47% 47%

17%

w%

False pxitives (cumulative)

2%

34%

22

3590

690

35%

7% 7%

36% 36%

8%

otherwise.

IV. Disc&m&ant function analysis

Measurements*

2

Group

that discriminate

329 - 109 -100 - 97 84 83 69 - 47 44 32 - 30 - 26 - 5

unless indicated otherwise. function coeficients multi-

5 per cent FP in Table V and 9 to 10 per cent FP in Table VI. The multivariate analysis led to a substantial improvement in correct classifications by 29, 38, and 43 per cent for Groups 1, 2, and 3, respectively, when the specificity was kept constant at 95 per cent (Table V). When the FP rate was allowed to rise to 9 and 10 per cent (Table VI), the improvement in correct classification was somewhat less but still impressive with 24, 31, and 30 per cent for Groups 1, 2, and 3, respectively. Results were also expressed in the form of performance scores (PS) where sensitivity and specificity are combined in a single term, PS= M (sensitivity+ specificity). Whereas the scores for multivariate

analysis remained practically unchanged with a decrease in specificity from Table V to VI, the scores for conventional LVO criteria increased to 7 per cent with this decrease in specificity. Standard lZ-lead ECG. Table VII shows the results using the Minnesota Code. Twenty-one per cent of Group 1,34 per cent of Group 2, and 43 per cent of Group 3 were correctly classified by the voltage criteria of Code 3.1. Comparison of Tables II and VII shows that the four Frank voltage ECG discriminators are superior to the voltage discriminators of the Minnesota Code 3.1 by 4 per cent in Group 1, 4 per cent in Group 2, and 3 per cent in Group 3, at identical FP rates (6 per cent). Discussion The electrocardiogram is well recognized as an indicator of LVO. However, the large number of reports which have appeared in the literature advocating various criteria indicates that the sensitivity and specificity of these criteria are still very much in question. The introduction of corrected orthogonal lead systems appeared to improve the sensitivity of criteria, but the specificity of these was frequently not investigated. The influence of age, sex, and race should also be taken into consideration.32,33Furthermore, the number of cases required to obtain reproducible results needs to be determined. Previously, it had been found that 300 records from patients with LVO are insufficient to achieve reproducibility in the separation from normal.31 However, when the present sample of 939

Computer analysis

Table V. Results of multivariate‘analysis Mdhariate

analysis

Groufi

Group 1 N

Group 2 N

in comparison

of ECG and VCG in LVO

with Frank

N

5370 5%

47% 950/,

Group 2

N

75% 5%

95%

Grou$

II II

25%

ECG measurements criteria (Frank)*

Conventional

I

475

1

N

24To 5%

76%

Grouti 2

N

37%

63% 95%

WO

95%

II

Group 3 N

Group 3

N

87%

1370 95 %

5%

Performance scoresi Multivariate analysis Group 1 Group 2 Group 3 *Criteria 1 to 3 of Table II. tPerformance score = M (sensitivity

74% 85% 91%

/I

Group 3

N

4470

5670

5%

Conventional Group 1 Group 2 Group 3

95%

analysis (Frank)

60% 66% 70%

+ specificity).

records was subdivided at random into two halves (469 and 470), mean results of maximal QRS vector and R wave amplitudes differed only by less than 3 per cent between the two groups. Differences in ST-T amplitudes were less than 0.02 mv. in angles less than 2’, and in wave durations less than 2 msec. The remarkable stability of results indicated that record samples of 470 are sufficiently large to be considered representative of HCVD. It indicated at the same time that HCVD as an ECG entity is more inhomogeneous than most others.26,*7,31This is probably due to the variable influence of many different factors such as increase in LV muscle mass,cardiac dilatation, development of biventricular hypertrophy, and probably others. Since they are not necessarily developing in parallel, effects on the ECG cannot be expected to be very uniform. In order to collect such large numbers of records, it was necessary to organize a cooperative study with eight hospitals par-

ticipating. The main goal was to re-evaluate ECG performance in single diseaseentities and to test automated means for possible enhancement of this performance. Such studies have the advantage of uniform data collection according to strict study protocols and uniform recording techniques. The number of hospitals involved assures large representative record samplescollected over a reasonable period of time. Use of a digital computer for record analysis allows a great number of comparisons and correlations in order to arrive at optimal criteria for diagnostic discrimination. Complex classification techniques can be tested at the same time to improve such discrimination. In the present study, only hypertensive subjects without other known heart disease were evaluated. The division into the three groups was based on the natural history of hypertensive cardiovascular disease. As in previous studies,22~27~34J5 the most striking finding was the redundancy of many ECG measurements for the separation of a given

476

McCaughan,

Littmann,

Table VI. Results of multivariate

analysis

Multivariate Group

Group 1 N

Group 2

N

Group 3 N

Am

and Pipberger

in comparison

analysis

with conventional ECG measurements

Conventional __-----N

I

Group

criteria

1

(Frank)*

N

6070 1%

4070

Group2

N

I

Group2

8170 1070

19% 9070

Ii

50%1 9%

Group3

N

/I

Group3

N

890 90%

Ii

62% 9Yc

3890 91%

927*

10%

3670

990

907c

Hcarf J. April, 1973

6470 91% N 5090 91%

II Performance scores? Multivariate analysis Group 1 Group 2 Group 3 *Criteria 1 to 3 of Table 11. tPerf0rmance xO*e = S (sensitivity+

‘)

75%

86% 91%

Conventional Group 1 Group 2 Group 3

criteria (Frank) 64%

71% 77%

specificity).

group from normal. Although a large number of discriminators may be individually of great value, many of these discriminators are found to be redundant when used in conjunction with others. Vectorcardiographic measurements which individually have a high discriminatory value were almost completely redundant when used together with scalar measurements. Vector directions were found to have a low level of specificity, which is in agreement with the studies of Romhilt and associates” and Murata and associates.14More complicated measurements, such as maximal spatial magnitude and time integrals, were also found to be redundant when used together with scalar parameters. In all studies aimed at exploring the diagnostic information content of the ECG more thoroughly, it is always amazing how rapidly this information is exhausted when a few judiciously selected criteria are used first. Comparisons between the diagnostic performance of different ECG criteria for LVO, as reported in the literature, are always

difficult because methods of patient selection in different studies are frequently not the same, the type and severity of disease leading to LVO may differ, or the number of casesreported may be too small to be truly representative for a given disease catewry. 36 For these reasons we believe it is preferable to study a reasonably welldefined diseaseentity such as HCVD rather than a variety of cardiac disorders which may lead to LVO but which may differ in many other characteristics. As expected, the results for the 394 patients in Group 1, without cardiac enlargement and without history of congestive heart failure, were not very encouraging. Using simple hand measurements at a FP rate of 5 per cent, only 24 per cent of the records could be classified correctly (Table II). This number could be raised to 50 per cent when Q/R,, T,, and JX were added to the criteria. To base a definite LVO diagnosis solely on these rather nonspecific criteria raises the FP rate not only for normals but even more for a host of other

Computer analysis

Table VI I. Standard

1Z-lead elettrocardiogram

Measurement

R 2 2.6 mV. VS or Vs or R 2 2.0 mV. 1, 2, 3 aVF or R 2 1.2 mV. aVL (Code 3.1) ST-J depression F 1 mm. 1, 2, aVL, aVF, VI.6 (Code 4.1) ST-J depression OS-O.9 mm. and ST segment horizontal or downward sloping 1, 2, aVL, aVF, VI-S (Code 4.2) ST downward sloping to 0.5 mm. below P-R baseline (Code 4.3) T amplitude 7 - 5 mm. with R 2 0.5 mm. 1, 2, Vt-6, aVL, aVF (Code 5.1) T amplitude - 1 to - 5 mm. (Code 5.2) T flat or diphasic 1, 2, V3-6, aVL, aVF (Code 5.3)

of ECG and VCG in LVO

477

results

(cumulative)

21%

34%

43%

32%

6%

25%

42%

59%

40%

6%

36%

56%

75%

54%

6%

41%

59%

80%

58%

6%

41% 45%

60% 68%

82% 87%

59% 65%

7% 10%

57%

75%

91%

73%

16%

entities accompanied by changes in Q/R, ratio and ST-T abnormalities. Using multivariate analysis, the recognition rate for Group 1 rose to 53 per cent at the same specificity level, still leaving, however, almost 50 per cent false negatives. The degree of LVH in this group is difficult to estimate and when present, it has to be of the concentric type. Although not entirely satisfactory, the performance of the ECG for this group is particularly helpful since in none of these patients does the chest x-ray contribute to the diagnosis of cardiac disease. When cardiac enlargement became evident (Group 2), the recognition rate for conventional criteria rose to 37 per cent and by multivariate analysis to 75 per cent. For Group 3, with a history of one or more episodes of congestive heart failure, recognition rates increased further to 87 per cent for multivariate criteria and only 44 per cent for the more conventional hand measurements on the same Frank ECG’s. As mentioned earlier, comparisons of performance characteristics of different LVH criteria as reported in the literature are relatively difficult because of differences in patient material, differences in the type of underlying disease, and probably more often lack of indications on sensitivity and specificity. The use of performance scores (PS) which takes into account both false

Group

2

All

False positives

Group 3 (cumu4htive)

Group I (cumulative)

(cumulatie)

(cumulative)

positives and negatives represents, however, a relatively efficient method for comparisons. They were used extensively by Holt and co-workers37 in very careful correlations of their own material with that of other authors. An extension of their compilation including data from the present study is given in Table VIII. As in most previous studies, the assumption was made that high voltage criteria are a fair indicator of LVO or of an increase in left ventricular muscle mass. One of the most important factors in comparisons of the difference in severity of LVO becomes obvious immediately when the first four studies listed in this table are considered where the same ECG criterion was used (maximal QRS,,, vector). When applied to records from patients with congenital aortic stenosis, Hugenholtz and Gamboa38 and Reeve and associates3sobtained scores of 80 and 66, respectively. A difference in the severity of LVO can explain such a discrepancy in results. Using the same criterion, Holt and associates3’ obtained a score of 76 in a series of 72 patients whose left ventricular muscle mass had been determined angiocardiographitally. With few exceptions, their diagnosis was valvular heart disease. In the most severe casesof the present study, Group 3, the same ECG criterion resulted in a score of only 59, indicating a significantly lesser

478

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Performance

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scores for left ventricular

overload (LVO)* Performance

Bagnosis

Author

1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Hugenholtzrs Reeveas HoIF Present study Romhiltrr Present study Holtrr Holt3’ Present study Present study

(Group 3) (Group 3) (Group 3) (Group 3)

ASt AS AS, AI HCVD Autopsies with LVH HCVD AS, AI AS, AI HCVD HCVD

ECG

measurement

Max QRSxyz Max QRSxyz Max QRSxyz Max QRSxyz Max QRSxz Max QRSxz .%I+ Rv6 or vg 12 dipole model Rx, Rz, Rx + Sy Multivariate analysis

scares

80 66 76 59 81 63 77 91 77 91

*Performance scores for LVO reported in the literature compared with those obtained in Group 3 of the present study. Kate that the latter group appears considerably milder when identical ECG measurements are compared. In spite of this difference in severity of disease, multivariate analysis resulted in the best performance score, and compares favorably with the 12 dipole method. trlbbreviations: AS = aortic stenosis; AI = aortic insufficiency; HCVD = hypertensive cardiovascular disease; LVH = left ventricular hypertrophy.

degree of LVO than in the samples with valvular heart disease. The maximal QRS vector in the transverse plane resulted in a slightly higher PS for the severe group of HCVD, namely 63. A comparison of the performance of this measurement with that obtained in a study of autopsied LVH cases by Romhilt and associatesr7shows again very clearly a significant discrepancy in the severity of LVO. This, of course, had to be expected in records from patients in a terminal stage of disease. Holt and co-workers37 also tested the LVH criteria of Sokolow and Lyon’ on their relatively severe cases,which resulted in a score of 77. The same score of 77 was obtained by using a combination of R,, R,, and R, + S, on the significantly milder cases of LVO in Group 3 of the present study. These results suggest that the orthogonal lead criteria exceed those of Sokolow and Lyon’ by a substantial margin. In the study of Holt and co-workers,37 a novel method of computing time histories of 12 dipole equivalents, representing the total electrical output of the heart, was described. Time integrals of each dipole were obtained and were compared with those from normal hearts. The computations were based on 126 body surface leads. In their differentiation between normal and LVO, a PS of 91 was obtained which exceeded substantially all other scores based on orthogonal or 12-lead ECG criteria from

the same patients. However, the PS based on their method with 126 leads was exactly the same as that obtained in the present study when multivariate analysis was applied to records from patients with a substantially milder form of LVO. These results suggest that the performance of multivariate ECG analysis is at least equal to that based on a multiple dipole model derived from 126 surface leads. It should be noted, however, that one ST-T measurement was used in the multivariate analysis while the multiple dipole model was based on QRS data alone. Although the improvements in ECG classification through multivariate techniques appear quite impressive, one should not lose sight of the fact that for ECG’s of HCVD patients, a sizable number of false negatives still remain. When false positives are kept at a tolerable level of 5 per cent, the ECG of only one out of two of the patients without cardiac enlargement and without signs or symptoms of cardiac failure will be diagnosed correctly. Once cardiac enlargement becomes recognizable, the number of false negatives is still one out of four. Only when the heart begins to fail is the number of false negatives reduced to one out of eight. It is mainly in comparison with conventional criteria that multivariate techniques excel. Even when optimized sets of such criteria were used, their sensitivity was only half of that ob-

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mined by multivariate analysis; and the numbers of false negatives was three out of four for Group 1, two out of three for Group 2, and almost one out of two for the most severe Group 3 (Table V). Performance scores proved a very useful tool for comparing different ECG measurements on the same record material. When different record samples are compared and the same criteria are used at a similar level of specificity, an estimate of the severity of disease in various samples can be made. It should also be kept in mind that similar to most studies on LVO, classification results reported here refer only to the question LVO or normal. In most clinical situations, this question has to be extended to all other possible ECG abnormalities. This leads practically always to a deterioration of results. When this was done in a sevengroup classification40 which included three types of myocardial infarcts, LVO, RVO, pulmonary emphysema, and normal, the PS for Group 3 of the present study decreased from 91 to 80 and for Group 2 from 85 to 78. When all possible ECG diagnoses are considered simultaneously, a similar deterioration of diagnostic scores has to be expected for all results reported in the literature since none of the proposed LVO criteria is truly pathognomonic. Comparison of the results between orthogonal and 12-lead ECG is difficult mainly because of the multiplicity of diagnostic criteria which has been advocated for the latter. The Minnesota Code30 is gaining increasing acceptance for :he standardization of ECG data, but observer variability and coding difficulties must be borne in mind.41 In the present study, orthogonal lead measurements proved slightly superior to the standard 12-lead ECG, Code 3.1, 4 per cent in Group 1, 4 per cent in Group 2, and 3 per cent in Group 3. Multivariate analysis gave substantially better results at approximately the same FP rate, 32 per cent for Group 1, 41 per cent for Group 2, and 44 per cent for Group 3. It would appear that four simple orthogonal lead measurements give at least equal performance to the standard 12-lead ECG in recognizing LVO in HCVD. Although both systolic and diastolic blood pressures correlated highly significantly with a number of ECG measure-

of ECG and VCG in LVO

479

ments, the level of correlations was not sufficiently high to allow useful predictions of blood pressure levels on the basis of ECG parameters. This situation could not be greatly improved by application of multiple regression analysis. Dern and associates42 had reported previously on similar correlations between blood pressure and ECG. Attempts were also made to identify specific ECG indicators for cardiac enlargement by applying t tests between the cases without cardiac enlargement (Group 1) and those with enlargement (Groups 2 and 3). The t values for comparisons increased considerably more from Group 2 to Group 3 than they did from Group 1 to 2 where cardiomegaly was the only clinical feature for differentiation. Several other factors besides cardiomegaly must have therefore contributed to the widening gap between Groups 2 and 3, since both of the latter groups were characterized by cardiac enlargement, although possibly of different degree. The most consistent feature to indicate an advanced stage of HCVD was the progressive narrowing of the QRS loop in the transverse plane accompanied by an increase in R, amplitude with a relative decrease in RX.r3 In this phase of the disease, multiple factors such as BVH,22 cardiac dilatation with an increase of the intracavitary blood mass,43 together with a progressively dominating increase in left ventricular muscle mass need to be considered simultaneously. From the present data, it did not seem possible to differentiate clearly between these factors and considerably more study is needed to arrive at more precise indicators for each of these variables. When the LVO criteria proposed in this study are applied, some limitations should be kept in mind. They were based on a male veteran population above the age of 40. Approximately one third of the patients with HCVD and of the normal controls were black. As reported previously,32 age, race, torso geometry, and sex all exert an influence on the ECG, leading to different limits of normal when data are stratified according to these variables. The limits indicated in the present study apply strictly only to a racially-mixed male population of 40 years of age and older. Upper limits of normal for QRS voltages tend to be

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somewhat lower in white subjects and in females. Higher voltage values may be found in younger normal subjects.32 Reliable stratification according to all constitutional variables requires even larger samples than those available for the present study. Such a stratification will be attempted when more material becomes available. From the present study, it became quite obvious that it is preferable to study a single, well-defined disease entity leading to LVO rather than a variety of diseases which have LVO in common. The number of reports dealing specifically with the ECG in HCVD have been rather limited.44-46 In general, the degree of LVO found was considerably less than that encountered in most other studies based on patients with different forms of congenital or rheumatic heart disease. Part of this difference may be due to antihypertensive therapy received by practically all patients in the present study. Performance scores for a variety of LVO criteria proved a very practical means, not only for identifying optimal criteria but also for arriving at estimates of the severity of LVO when different studies were compared. In the most severe Group 3 of the present study where the degree of LVO appeared considerably less than that in other studies, it was still possible, however, to achieve a score of 70 with four simple scalar measurements. This result could still be exceeded by a considerable margin through multivariate analysis when a PS of 74, 85, and 91 was obtained for the mild, moderate, and severe groups, respectively, with the exception of the multiple dipole model system. The main disadvantage of this method, however, lies in the fact that it can hardly be used without access to computer facilities. Furthermore, it remains somewhat unsatisfactory that once a diagnostic decision has been made by computer for a given case, it is not intuitively obvious which ones of the multiple ECG measurements used contributed most to this classification. Identifying the most significant variables for each single case would require additional computations which may be desirable for teaching purposes. For the diagnostic decision per se, it is irrelevant. A major difficulty in developing multi-

variate analysis procedures derives from the need of relatively large “training samples” for establishment of criteria and methods which then need to be checked with “testing samples” of approximately equal size. 2g This problem can be overcome best through cooperative studies by several hospitals, such as the present study. With few exceptions, the promising initial studies on multivariate classification techniques of the sixties had to be discontinued because of lack of sufficient record material. Only after data collection of more than 10 years has it become possible now to take full advantage of the computer’s capability to handle multiple variables simultaneously, based on studies with sufficiently large record numbers. The improvements obtained in diagnostic accuracy of the ECG appear to amply justify the joint efforts of the participating investigators. Summary

Orthogonal ECG’s (Frank system) were recorded from 939 male patients with hypertensive cardiovascular disease (HCVD) and were compared with records from 229 normal subjects, matched for age, race, and sex. The hypertensive subjects were divided into three clinical groups: (1) patients without cardiac enlargement by chest x-ray and no history of congestive heart failure (CHF), (2) patients with cardiac enlargement but without past or present CHF, and (3) patients with cardiac enlargement and one or more episodes of CHF. A sustained blood pressure level of 150/90 mm. Hg or more was present in all cases. First an attempt was made to identify optimal scalar and vectorial ECG measurements for discriminating between HCVD and normal, testing a total of 333 variables, With four scalar measurements at a specificity level of 95 per cent, 24 per cent of Group 1,37 per cent of Group 2, and 44 per cent of Group 3 could be correctly classified. Vector measurements were found mostly redundant. Using linear discriminant function analysis and a likelihood ratio test with 13 different ECG variables at a level of specificity of 95 per cent, it was possible to identify correctly 53 per cent, 75 per cent, and 87 per cent of Groups 1, 2, and 3, respectively.

l~‘olame .Vwnber

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Comparison of results with other reports on ECG changes caused by left ventricular overload (LVO) suggested that the degree of LVO in HCVD, even in the most advanced Group 3, was considerably less than that reported in patients with valvular heart disease with the only exception of terminal cases with HCVD who had come to autopsy. Antihypertensive therapy was considered as one factor which might have contributed to this finding. Multivariate ECG analysis was found an efficient means for diagnostic classification, leading to results which equalled those reported for multiple dipole analysis. As compared to scalar or vector measurements, either used individually or in combination, the multivariate technique exceeded all of these methods for LVO diagnosis by a wide margin when specificity was kept at a constant level. The authors gratefully acknowledge the valuable assistance of Mrs. Ruby C. Harris, B.S. REFERENCES 1. Sokolow, M., and Lyon, T. P.: Ventricular complex in left ventricular hypertrophy as obtained by unipolar precordial and limb leads, AM. HEART J. 37:161, 1949. 2. Scott, R. C., Seiwert, V. J., Simon, D. L., and McGuire, J.: Left ventricular hypertrophy: A study of the accuracy of current electrocardiographic criteria when compared with autopsy findings in 100 cases, Circulation 11:89, 1955. 3. Scott, R. C.: The correlation between the electrocardiographic patterns of ventricular hypertrophy and the anatomic findings, Circulation 21:256,

1960.

Soloff, L. A., and Lawrence, J. W.: The electrocardiographic findings in left ventricular hypertrophy and dilatation, Circulation 26:553, 1962. 5. Griep, A. H.: Pitfalls in the electrocardiographic diagnosis of left ventricular hypertrophy: A correlative study of 200 autopsied patients, Circulation 20:30, 1959. 6. Allenstein, B. J., and Mori, H.: Evaluation of electrocardiographic diagnosis of ventricular hypertrophy based on autopsy comparison, Circulation 21:401, 1960. 7. Chou, T. C., Scott, R. C., Booth, R. W., and McWhorter, H. B.: Specificity of the current electrocardiographic criteria in the diagnosis of left ventricular hypertrophy, AM. HEART J. 4.

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tion of LVH in 364 unselected autopsy cases, HEART J. 76:596, 1968. 10. Bristow, J. D., Porter, G. A., and Griswold, H. E.: Observations with the Frank system of vectorcardiography in left ventricular hypertrophy, AM. HEART J. 62:621, 1961. 11. Hugenholtz, P. G., Lees, M. M., and Nadas, A. S.: The scalar electrocardiogram, vectorcardiogram, and exercise electrocardiogram in the assessment of congenital aortic stenosis, Circulation 26:79, 1962. 12. Binaghi, G., Neri, G., Recalcati, P., and Obbiassi, M. : Valutazione dell’ipertrofia ventricolare sinistra mediante I’elettrocardiogramma registrato con il sistema di Frank, Folia Cardiol. AM.

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Kaneko, S.: A quantitative analysis of the vectorcardiogram in normal and left ventricular hypertrophy groups using the Frank and the Takayasu lead system, Jap. Circ. J. 31:1157, 1967. 16. Toshima, H., Cueto, J., and Lillehei, C. W.: Vectorcardiographic studies in acquired valvular disease with reference to the diagnosis of left ventricular hypertrophy, Circulation 35:132, 1967. 17. Romhilt, D. W., Greenfield, J. C., Jr., and Estes, E. H., Jr.: Vectorcardiographic diagnosis of left ventricular hypertrophy, Circulation 37:15, 15.

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