Computer analysis of the orthogonal electrocardiogram in pulmonary emphysema

Computer Analysis of the Orthogonal Electrocardiogram in Pulmonary Emphysema

ANDREW

KERR, Jr.,

ARNOLD

ADICOFF,

JACK and

MD* MD,

D. KLINGEMAN, HUBERT

Washington,

FACC MS

V. PIPBERGER,

MD,

FACC

D. C.

From the Veterans Administration Cooperative Study on Automatic Cardiovascular Data Processing, Veterans Administration Hospitals, Batavia, N. Y., Birmingham, Ala., Durham, N. C., Houston, Texas, Minneapolis, Minn., San Francisco, Calif., Washington, D. C. and West Roxbury, Mass., and the Department of Medicine. Georgetown University School of Medi: tine, Washington, D. C. This study was supported in part by Research Grant HE 09696 from the National Heart Institute, U. S. Public Health Service. Manuscript received February 14, 1969, accepted April 24, 1969. * Present address: Akron City Hospital, Akron, Ohio. Address for reprints: Hubert V. Pipberger, MD, Veterans Administration Hospital, 50 Irving St., N.W., Washington, D. C.

34

Orthogonal electrocardiograms (Frank system) were recorded from 405 patients with pulmonary emphysema of moderate and severe degree. The diagnosis was based on clinical and radiologic or pulmonary function studies, or both, according to uniform study protoco1s. Of 333 electrocardiographic measurements computed from each record, different sets of diagnostic criteria were selected for optimal separation of records of patients with pulmonary emphysema from those of normal subjects, using a variety of statistical techniques. The first set consisted of five scalar and vector measurements which can be easily obtained and which do not require access to computer facilities. With these criteria, 80 percent of the records of patients with pulmonary emphysema could be correctly classified, with a false positive rate of 11 percent. With a second set of 14 more complex measurements intended for computer use, 81 percent of pulmonary emphysema tracings were classified correctly, with a reduction in false positives to 5 percent. With the use of additional criteria, a series of 140 records from patients with right ventricular hypertrophy due to pure mitral stenosis could be differentiated from records of patients with pulmonary emphysema in 80 percent of cases. Reduction of the R wave and the R:S ratio in lead X proved to be the best discriminators between records of normal subjects and those of patients with pulmonary emphysema. Correlations with arterial pC0, showed progression of R, changes, a QRS shift in a superior direction and a rightward shift of the P wave as the best indicators of deteriorating pulmonary function. Classification procedures were tested on independent record samples including 1 sample of 22 autopsy cases of pulmonary emphysema. Results were nearly identical. They exceeded those reported in the literature, which may be attributed to the use of more reliable electrocardiographic leads and to application of more efficient multivariate classification procedures. With the increasing frequency of pulmonary emphysema in the aging population, the need for simple screening tests for disease detection is becoming more urgent. The electrocardiographic changes accompanying the disease have been described by many authors.‘-lo In the majority of reports, however, the number of cases was limited, the control subjects were often obtained from different age groups or the data analysis lacked indications about sensitivity and specificity of the electrocardiographic criteria applied. To reevaluate quantitatively diagnostic electrocardiographic performance for this disease entity, corrected orthogonal electrocardiograms were recorded from 4Q5 patients with pulmonary emphysema

The American Journal of CARDIOLOQY

ELECTROCARDIOGRAM

in eight Veterans Administration hospitals, in the framework of a Cooperative Study on Cardiovascular Data Processing. The diagnosis was based on clinical, radiologic and pulmonary function criteria obtained from uniform patient protocols designed for the study. Electrocardiographic findings did not enter into the case selection process. Record analysis was performed by digital computer, which allowed tIesting of large numbers of electrocardiographic measurements to identify the most efficient parameters for diagnostic discrimination. A control analysis was performed on 229 tracings ohtained from normal subjects between the ages of 40 and 78 years.

Materials and Methods Patient Selection The 405 patients included in the present study were selected from a larger group of 935 on the basis of severity of the disease and completeness of patient protocols. Three clinical degrees were used for classification of cases: mild, moderate and severe. Patients with a mild degree of emphysema were excluded from the study because evidence for the diagnosis was frequently considered inadequate. The problem of early recognition of the disease with mild manifestations will be covered in a separate investigation. In addition to the latter cases, patients were excluded when their study protocols were incomplete, that is, when essential data were missing. Of the patients in the 405 remaining cases classified as moderate or severe, all had a history of excessive cough and dyspnea on exertion. In 249 (61 percent) shortness of breath was also present at rest. Exercise tolerance was moderately reduced in 363 (90 percent) ; the remaining 42 patients were incapacitated. Patients with only mild reduction in exercise tolerance were not included. The diagnosis of pulmonary emphysema was supported by radiologic findings in 97 percent, and confirmed by pulmonary function studies in 43 percent. In only 3 percent was the diagnosis considered well enough established by history and physical examination alone. Of t’he 175 patients with a timed vital capacity (1 set), 170 showed a reduction below 75 percent and 121 below 50 percent. Arterial pC0, was elevated above 50 mm Hg in 99 patients tested. In 197 examinations of arterial pOs, results were distributed as follows: 95 to 100 mm Hg (2 cases) ; 90 to 95 (16 cases) ; 80 to 90 (138 cases) ; 70 to 80 (37 cases) ; below 70 (2 ca.ses). In 23 percent of the pat’ients, chest roentgenograms showed moderate, and in 28 percent marked enlargement of the heart. One or more episodes of congestive heart failure were reported in 187 (46 percent) of the patients. The age d&rib&ion of the patients with emphysema is given in Table I. Since the patients were, with 3 exceptions, above age 40 years, 229 control records were obtained from normal subjects between 40 and 78 years old.2o The only electrocardiographic criterion used for ex-

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1970

TABLE

IN PULMONARY

EMPHYSEMA

I

Age Distribution of 405 Patients with Pulmonary Emphysema Patients

(vr)

no.

%

30-39 40-49 50-59 60-69 270

3 35 90 152 125

1 8 22 38 31

Total

405

Age

elusion of pafients was a QRS duration of 0.126 set or more. Although the normal limit for simultaneously recorded orthogonal leads was found to be 0.112 set, the range was arbitrarily extended by 14 msec because right ventricular hypertrophy might have led in some cases to a QRS prolongation in the absence of a conduction defect of the bundle branch block type. To test the separation between records from patients with emphysema and those assumed to have right ventricular hypertrophy, records were selected from 140 patients with hemodynamically significant mitral stenosis, evidenced by right heart catheterization. Patient protocols were recorded on FOSDIC forms21 which can be transcribed directly onto digital tapes for computer correlations. Data Acquisition and Analysis Orthogonal electrocardiograms were recorded on magnetic tape, using the Frank system,“2 with the chest electrodes at the level of the fourth intercostal space, as recommended for the supine position.2” The recording equipment, which was uniformly calibrated at the various participating hospitals, had an overall frequency response of 0.05 to 1,250 Hz (3 clb down at the lower end of this range). Details of the analog to digital conversion process and computer analysis have been reported previously.21 A Control Data Corporation 3200 digital computer was used in the study. A total of 333 different scalar and vectorial measurements were computed for each record, comprising practically all parameters previously advocated for electrocardiographic analysis. The purpose of computing such a large number of measurements was to search for optimal discriminators between electrocardiograms from patients with emphysema and normal subjects. Statistical procedures used in this search have been described in detail previous1y.z” First, t tests between the record samples under study are performed for all measurements. Since electrocardiographic data are sometimes not normally distributed, t values can serve as only a crude guide for selecting the best measurements. They lead, however, to a smaller set of candidates from the original number (333). These candidates are then compared side by side by determining the number of abnormal records that exceed 96 percentile ranges of normal. Two aims are

35

KERR ET AL

achieved in this side by side comparison: (1) It is possible to identify parameters that contribute independently to the separation of normal from abnormal. If such measurements are omitted, the percentage of correctly classified cases decreases. (2) Redundant measurements are identified at the same time. They may appear relatively efficient when considered as single discriminators, but the cases separated by such parameters are already identified by some other measurement. These measurements can be safely omitted without decreasing the total number of correctly classified records. This type of evaluation was performed for both scalar and vectorial measurements which can be obtained easily by hand measurements. Subsequently a set of optima1 measurements, regardless of complexity, was obtained strictly for computer analysis. Thirty candidate criteria were subjected to linear discriminant function analysis, using an approach described previously in detai1.25 With this procedure all measurements are considered simultaneously and weight factors are determined for each parameter. The best discriminators are then combined to a multidimensional vector for eaeh patient record. Subsequently, mean vectors are calculated for each diagnostic entity, for example, normal subjects or patients with pulmonary emphysema. Unknown records are then classified by use of a likelihood ratio test by which vector differences between the unknown and the various means are determined. The smaller this vector difference, the greater is 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. Empirically it was found that this number should not exceed the square root of the number of cases under study. To test the repeatability and reliability of the various statistical analyses, all procedures were performed first on a smaller sample of 224 patients (55 percent of the total) and repeated later for the remaining 45 percent. Furthermore, all procedures were performed separately for the following subgroups: (1) Patients classified as having moderately severe pulmonary emphysema and those with a severe degree. (2) Patients with and without a history of congestive heart failure. (3) Patients grouped according to arterial pOz and pC0, levels. Finally, electrocardiographic records from 22 patients with advanced pulmonary emphysema who had died and come to autopsy were used as independent control tracings.

Results ECG and VCG Configuration The mean configurations of the scalar X, Y and Z leads and the vector loop projections in the frontal,

36

left sagittal and transverse planes are shown in Figure 1. These means were derived from the total sanlplc of 405 records and the normal control sample. The QRS duration and the time interval from the end of the QRS to the end of T (ST-T) wave were each normalized in time by being divided into eight equal parts. The means of each eighth were calculated and then used for t’he display of the average scalar leads and vector loops. Mean results and distribution of data are shown for the most common electrocardiographic and vectorcardiographic measurements in Tables II and III. When compared with normal records, the most striking feature of the records from patients with pulmonary emphysema was the reduction in voltage of the R wave in lead X. In almost half of the pulmonary emphysema group this finding was associated with a shift of QRS toward the right, as shown by the decreasing R:S, ratio. Of lesser significance appeared t.he overall decrease in QRS and T voltage, a shift of the P wave toward the right and an increasing elevation of the S-T segment in lead Z.

Scalar and Vector Discriminators Of a total of 333 different electrocardiographic measurements tested, the most efficient discriminators between the normal subjects and those with pulmonary emphysema were selected as described in the section on methods (Table IV). Only those are listed which can be conveniently obtained from generally available scalar and vectorcardiographic plane displays. Several interesting features are revealed in this tabulation. Five scalar QRS measurements already led to identification of 77 percent of pulmonary emphysema records with a false positive rate of 8 percent. Addition of four vector measurements of QRS increased the percentage of correct classifications by 5 percent, but the false positive rate increased at the same time to 19 percent. This small gain in sensitivity was completely offset by the larger loss in specificity. The seven scalar and vectorial P and T measurements listed brought the recognition up to 94 percent, but the false positive rate rose at the same time to a prohibitive 29 percent. As shown in Tables II and III, many of these parameters separated patients with pulmonary emphysema from normal subjects relatively well when the criteria were considered singly. Their true contribution is realized only when many measurements are viewed together. The specificity of t,he T criteria was extremely poor, as shown by the greater rise in recognition rate for cases with mitral stenosis. The fact that most criteria contributed only redundant information is also shown in the last column of Table IV. Here the number of records is listed

The American Journal of CARDIOLOGY

ELECTROCARDIOGRAM

IN

PULMONARY

EMPHYSEMA

5mV

TRANSVERSE

which would not have been classified as pulmonary emphysema if a given measurement had been omitted. As can be seen from the small numbers, independent contributions of diagnostic information are extremely small when many parameters are jointly analyzed. A more practical and extremely efficient set of five criteria is .given in Table V. With as few as five measurements, 80 percent of the patients with pulmonary emphysema could be identified, with a false positive rate of 11 percent. The three scalar measurements alone led to recognition of 68 percent. The number of false positives may be considered tolerable, particularly since most commonly used conventional electrocardiographic criteria have substantially higher false positive rates.% Computer Classification The 30 best discriminators according to t tests were selected first as candidates for computer classification. They were subjected to linear discriminant function analysis, and 14 measurements with the highest dis-

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1970

Averaged scalar leads and Figure 1. vector loops based on 405 records from patients with pulmonary emphysema .(dashed linesj and 229 normal control subiects fsolid lines). ORS and ST-T 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 QRS or ST-T. Note the reduction in voltage in all three leads, particularly in lead X. (To maintain clarity of presentation, the low voltage T loops have been omitted.)

criminant scores were chosen for multivariate analysis. The criteria together with their discriminant function coefficients and classification results are list.ed in Table VI. Of the total of 405 pulmonary emphysema records, 329 (81 percent) were correctly classified, with a false positive rate of only 5 percent.. Of the QRS measurements listed, amplitudes of 3/8 QRS in the transverse plane and of R, contributed most to t.he separation of records of patients with pulmonary emphysema from normal records. The criteria are listed in the order of their normalized discriminant function coefficients and show a sizable contribution of S-T and T measurements. Their relatively high coefficients may be misleading, however, because the product between electrocardiographic measurements and coefficients determines their contribution to the discriminant scores. Since ST-T amplitudes are smaller than those of QRS, their coefficients tend to be higher. Compared to record classification by a series of individual measurements, a substantial gain in sensitiv-

37

2

B 5 6

e

S

i

? e

ii

TABLE II

0.21

0.035 0.016

0.21

2.13

0.27 0.05

0.08 -0.19

7.02

1.90

0.60 1.27

0.13 0.35

--+ f 0.009 0.060

+

f

f +

f +

f

---t 0.068

0.041

0.013

0.97

0.016

*

+

0.33

+ 0.37 --+ 1.48

0.07

0.53 0.08

f

-+ 0.000

0.012

0.016

f 0.08 -+ 0.38

f 0.03 -+ 0.12

0.021

0.11 0.05

0.06 0.02

(99q6,

(65%)

(20%)

(100%)

(85%)

(65%)

(100%)

(22%)

(22%)

(89q6)*

41%

..

7%

16%

14%

8%

57%

2%

1%

6%


<1.43:

>0.17:

< -0.06:

>0.052:

>0.60:

<0.51:

>0.024:

>0.19:

<0.03:

Normal Limits (96%) and Percentage of Records of Pulmonary Emphysema Outside These Limits

* The percentages in parentheses indicate the number of cases in which a given wove was present. In the second, fourth and sixth columns normal limits and the percentage of patients with pulmonary emphysema outside these limits ore shown. In places without entry, all pulmonary emphysema records were within normal limits. In 11 percent of the patients without P wove measurements, atriol Abrillation was present.

Time from beginning of QRS to largest R peak (set)

R:S amplitude rotio

Q:R amplitude ratio

T amplitude lmv)

S duration (set)

S amplitude +I

R amplitude (mv)

Q duration (ret)

Q amplitude (mv)

(mv)

P amplitude

Mean, Standard Deviation and 96% Range

Lead X

Means, Standard Deviations and 96 Percentile Ranges Derived from 405 Records of Patients with Pulmonary Emphysema

0.13

2.55

0.27 0.06

0.07 24

0.016 0.038

-0

0.012

0.037

0.07

0.31

0.60 0.09

0.012

0.024

0.14 0.05

0.15 0.05

+

f

+

9.87

2.77

0.41 1.33

--* f 0.060 0.011

f

0.076

0.015

0.97

0.21

0.36 1.57

0.004

0.018

0.13 0.55

f 0.17 --t 0 37

-+

f

+

f

f +

+

f

f +

f 0.06 -+ 0.29

(100%)

(56%)

(56%)

(100%)

(50%)

(50%)

(89%)

(97%)

(56%)

.-

(47%)

Mean, Standard Deviation and 96% Range

Lead Y

<0.028:

<0.80:

>0.32:

<-0.10:

>0.056:

>0.56;

<0.24:

>0.028:

>0.24:

>0.23:

4%

16%

8%

23%

6%

5%

15%

6%

4%

8%

Normal Limits (96%) and Percentage of Records of Pulmonary Emphysema Outside There limits

0.032 0.048

0.23

2.71

0.39 0.06

-0.11 -0.44

0.012

0.033

0.06

0.21

0.69 0.14

0.012

0.028

0.20 0.06

bipharic -0.12

0.013

0.15 0.55

+f

+

f

f +

f +

+

f

+

f

f -+

0.068 0.010

5.90

2.12

0.46 1.93

0.14 0.20

0.064

0.15

0.52

0.15

0.36 1.61

--f 0.052

f

f +

--+ 0.15

(99%)

(Eye,)

(79%)

(100%)

(8%)

(8%)

(100%)

(SO%1

(80%)

(89%)

Mean, Standard Deviation ond 96% Range

<0.33:

<0.016:

<0.08:

<-0.07: >O.ll:

14%

6yo

12%

7% 5%

Normal limits (96%) and Percentage of Records of Pulmonary Emphysema Outside These Limits

10%

2aajo


44/,

No S present in normal subjects


>-0.05:

No S present in normal subjects

No S present in normal subjects

Lead 2

$ 1

z

;;

(“)

(“1

standard

and

rcole

Angular

used

ranges

are

indicated

is that

limits.

96

+Z

percentile

1 OE”

El0

0.31

0.06

--124O

El0

0.19

0.03

-cl370

35’

0.30

0.06

+169O

36O*

0.31

0.06

by

_

-.

limits

900:

970:

Heart

with

+82O:

-

+113O:

+92’?

shown

_

(96%)

16%

32%

31%

4070

31%

of Records Emphysema

These

American

are

-+

-

5%

+

9%

-+

7%

+

7%

rotation.

the

ranges

+I50

265*

>0.28:

+81°

<0.05:

+32O

>0.25:

Pulmonary Outside

+24O

>0.25:

of

limits

Emphysema

Percentage

Normal

P Vector

Pulmonary

and

in clockwise

recommended

ond

normal

deviations

f

+

-46O

1450

+60°

f

+

309’

f

-+

0.17

f

+

+4E0

-14E”

0.07

f

-+

--+

-340

0.09

f

f790

0.04

f

-+

0.16

-90

0.06

f

+

+82*

f

-+

0.06

Range

0.16

96%

and

with

Maximal

Patients

Standard

of 405

Deviation

Mean,

T Vectors

of cases outside

angular

Association.

The

the number

(‘1

orientation

* Means,

Elevation

(“1

(mv)

amplitude

azimuth

Spatial

(mv)

Spatial

Direction

amplitude

Transverse

Direction

(mv)

plane

plane

(‘1

amplitude

Sagittal

Direction

amplitude

(mv)

P, QRS

plane

Maximal

;;

Frontal

TABLEIll

5

c’

0.87

-63O

+210

204O

294O

0.44

1.07

-169*

+770

0.30

0.87

-74*

+29O

0.31

0.93

-126O

+42O

0.31

96%

f

+

f

+

f

---f

f

-+

f

--t

f

+

f

+

f

-+

f

+ 71°

1.79

0.39

+:::

29O

52O

2.29

0.45

-310

550

1.84

0.41

+12E”

49*

1.92

0.40

-173O

Range

and

Standard

Deviation

Mean,

Maximal

+S”

-40

260’

<0.84:

-+117o

<0.64:

-200

<0.48:


of

and

QRS

-+

-+

33%

-+

32yo

-+

10%

+

47%

Outside

Pulmonary

+72O:

limits

+61°

210:

-32*;

+124O:

These

50%

32%

36%

26%

21%

Records

(96%) of

Emphysema

limits

Percentage

Normal

Vector

0.21

f

i

f -+

+140 -750

& --t

53O 284O

f --f

+750

0.25

f --t

-490

0.08

f --)

0.20

-+

*

+

0.05

t150

+157*

0.06

0.22

f +

+I20

0.10 0.46

1940

63’

0.54

0.12

.l”,‘,“.

0.50

0.11

-540

710

0.48

0.11

.lZ

Ronge

--t

-1500

0.07

96%

and

Standard

Deviation

Mean,

of

12:

20

+30

<0.15:

-8O


f91°


+20

+

+

18%

+

24yo

-+

Records

-

limits

81 O:

82O:

+57O:

-

1740:

j-750:

These

15Yo

+

8%

Outside

Pulmonary

(96%) of

Emphysema

limits Percentage

Normal

T Vector

and

<0.09:

Maximal

46q7,

47%

47%

62%

44%

KERR

ET

AL.

TABLE IV Selected Subjects

Scalar and

and

Vector

Patients

with

Measurements Pulmonary

That

Discriminate

Efficiently

Between

Records

of

Normal

Emphysema*

cases

of

cases

Pulmonary Emphysema Out

of

Number

Mitral

of Normal Range

Stenosis of

of Out

Emphysema

Normal

F&e

Range

(Cunw$tive)

(Cumulative)

of Cases

Pulmonary

Out

Positives (Cumulative)

of

Range

(%I

scalar leads RX

57

31

2

R:Sx ratio

63

38

3

One

Measurement

(%I

0

Normal by

Only

QRS measurements

R, peak QT R:S,

time

interval

(uncorrected)

ratio

Vectorcardiographic

42

6

44

7

77

46

8

planes

QRS,,

angle

80

50

12

2

Maximal

QRS,,

amplitude

81

50

13

3

Maximal

QRS,,

amplitude

82

50

14

1

Maximal

QRSx.

angle

82

52

19

84 88

65 72

20 21

2

89

72

21

1

P:Ry ratio

Vectorcardlographic

planes

angle

90

99

22

7

TX, angle

92

99

25

1

P,,

angle

92

99

28

1

P,,

angle

94

99

29

T,,

* To evaluate stenosis.

Note

specitlcity

of the criteria

they

the increase

in the number

of false

ity was obtained. As shown in Table IV, the percentage of correct classifications was only 66 percent when the false positive rate was kept at 6 percent (using the first three criteria). When an equally large record number of 81 percent was correctly classified, the false positive rate had more than doubled and reached 13 percent (using the first seven criteria). Clinical

Correlations

Severity of disease: To determine whether the severity of the disease was expressed in the electrocardiogram, several comparisons between various subcategories were made together with correlations between pulmonary function data and electrocardiographic measurements. First, electrocardiographic data of 296 patients whose condition was classified clinically as moderate were compared by t tests with the 109 remaining patients whose condition was classified as severe. The highest t value was found to be 3.1 for the spatial magnitude of point J, which was increased in the severe cases. Comparison of mean results revealed a clear trend toward decreasing R, amplitudes (0.55 vs. 0.49 mv) together with an increasing shift of QRS toward the right, as expressed in the mean R:S, ratios (2.3 vs. 1.7). Because of the large spread of findings no efficient separation of

40

4

Maximal

P and T measurements scalar leads T, TY _

66 71

3

were

also applied positives

when

to records large

from

numbers

patients

with

mitral

are

used

of criteria

moderate and severe cases was possible, however, and it was decided to merge the two groups. Congestive failure: Since it is frequently assumed that one or more episodes of congestive heart failure lead to biventricular hypertrophy, the patients were separated into those with and without a history of cardiac decompensation. The latter may have normal hearts or right ventricular hypertrophy. The t values between these two groups were slightly higher than in the previous comparison, reaching 3.9. The most useful electrocardiographic characteristic, however, proved to be an increasing QRS shift in superior direction with a decrease of the R:S, ratio. This was mainly due to larger S,. waves in patients wit,h a history of congestive heart failure. The spatial magnitude of the maximal QRS vector and of the 3/8 and 4/8 ST-T vectors increased at the same time. The latter electrocardiographic characteristics have previously been used successfully in differentiations between biventricular and right ventricular hypertrophy.“” Arterial p& and pC0,: In 85 patients with arterial pOz values below 90 mm Hg and in 87 patients with pC0, levels above 50 mm Hg, blood gas data and electrocardiographic measurements were correlated. Correlation coefficients up to 0.35 indicated only a

The

American

Journal of CARDIOLOQY

ELECTROCARDIOGRAM

TABLP

IN

PULMONARY

EMPHYSEMA

v

Reduced

Set

Use in the

of

Diagnostic

Recognition

Electrocardiographic

of Pulmonary

Criteria

Which

Can

Be Recommended

for

Practical

Emphysema*

Cases Pulmonary Out

of

of Emphysema

Normal

False

Range

Positives (Cumulative)

(Cumulative) (%I

r%r

Scalar leads RX

57

2

R:Sx

63

4

T.

68

7

VsctorcardioBraphic Maximal

QRS,,

Maximal

Pxy angle

* For normal cardiographic

limits,

planer

amplitude

see Table

measurements

IV.

os the

Note

that

most

practical

these

slight to moderate interdependence of the data. With increasing pC0, values R waves in lead X tended to decrease, while S waves in lead Y increased. The Q-T interval became shorter at the same time. Low pO? values were accompanied primarily by changes in time intervals, such as prolongation of the R, peak time and decrease of the Q-T interval. Stability and Repeatability

of Results

In previous studiesZ7, Z+ it was found that in clinical investigations a minimal sample size is necessary if the data are to become sufficiently stable so that investigations can be repeated without a substantial change in results. This appeared to be true even when case material was chosen according to stringent uniform selection criteria. For this reason, data analysis in the present study was performed first on 226 records (55 percent of the total) while the data collection was continued until a second sample of 179 records became available. Data analysis was then repeated for the second group and results and variances compared. The differences encountered were small and did not exceed 5 percent of the mean amplitudes of spatial vectors or 7 percent of the mean scalar deflections. The largest difference in standard deviations was 3.7 percent. Both increases and decreases of results were found. In view of the remarkable stability of the data it was assumed that approximately 200 electrocardiographic records from patients with pulmonary emphysema indicate a fair representation of the electrocardiographic data of the disease entity under study. It was therefore decided to merge the data of both samples. An additional test of the classification procedures was performed on 22 records from patients who had died and come to autopsy. Ten of these (45 percent) exhibited right ventricular hypertrophy and the remaining 12 (55 percent) biventricular hypertrophy. When the diagnostic matrix with the criteria of Table VI was used, 90 percent of the right ventricular

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74

9

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efficient

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o list of 333

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hypertrophy group and 67 percent of the biventricular hypertrophy group were classified correctly, with an overall accuracy of 77 percent. Mitral Stenosis vs. Pulmonary Emphysema It is safe to assume that at least part of the elcrtrocardiograpbic changes found in pulmonary emphysema are due to right, ventricular bypcrtrophy, particularly in patients in an advanced phase of the disease. The question arises, therefore, whether records from patients with pulmonary emphysema can be separated from those of patirntjs assumed to hare pure right ventricular hypertrophy. To investigate this problem, records from 140 patients with pure mitral stenosis confirmed by cardiac catheterization were selected for study.“!’ The record samples of pulmonary TABLE VI Electrocardiographic for

Computer

Patients

Criteria

Differentiation

with

Pulmonary

Selected

by

Between

Emphysema

Discriminant

and

Normal

Coefficients Discriminant

Measurements

1.

2/a ST-T, Maximal

3.

1 /B

4.

R,

spatial

2/0 QRS,

6.

Maximal

7.

3/0 ST-T.

QRS

0.

2/B

QRSx

9.

3/B

QRS

Maximal

vector,

transverse

transverse spatial

piane

plane

QRS

vector

11. S, 12. Maximal QRS vector, 13. QY 14. 4/8 QRS,

frontal

plane

Likelihood Correctly

positives

False

negatives

percentage

of

of false

Bl%, 5% 19%

represent

dircriminont

of Functions

Test

classified

False

* All measurements Coefficients

Ratio

from

1.00 -0.57 -0.33 -0.28 0.27 0.23 -0.19 0.18 -0.16 -0.13 -0.10 0.10 -0.08 -0.03

X component

QRS,

5.

10.

T vector,

Analysis

Records

Subjects*

Electrocardiographic

2.

Function

Electrocardiographic

amplitudes,

functions

were

expressed normalized.

in Note

millivolts. the

small

positives.

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KERR ET AL.

emphysema and mitral stenosis were t’ested against each other in a fashion similar to that described for testing records of pulmonary emphysema against records of normal subjects. Table VII lists the best discriminators. Keeping the percentage of false positives and false negatives equal, 80 percent of the records of mitral stenosis and puhnonary emphysema could be correctly classified, that is, a relatively efficient separation of the two groups could be achieved. The records of mitral stenosis were also tested against, the criteria for pulmonary emphysema which can be used without a computer (Table IV). Applying the first five QRS criteria, 46 percent of the records of mitral stenosis were classified as abnormal. With the same criteria, 77 percent of the records of pulmonary emphysema were correctly classified. When the records of mitral stenosis were tested against the criteria for pulmonary emphysema selected for computer use (Table VI), 58 percent were classified as showing pulmonary emphysema. Approximately 60 percent of cases of pure right ventricular hypertrophy may be expected to fall into the pulmonary emphysema group regardless of which of the two sets of criteria for pulmonary emphysema is used. To obtain a more efficient separation between pulmonary emphysema and mitral stenosis, an additional computer classificat’ion employing the criteria of Table VII seemed necessary.

Discussion Many different criteria have been proposed and used for the electrocardiographic diagnosis of pulmonary emphysema. l-19 In some of the earliest reports no clear distinction was made between car pulmonale TABLE

VII

Electrocordiogrophic Criteria Selected by Discriminant Function Analysis for Differentiation between Electrocardiographic Records from Patients with Pulmonary Emphysema and Mitral Stenosis* Electrocardiographic Measurements 1. 2. 3. 4. 5. 6. 7. a. 9. 10. 11. 12.

Coefficients of Discriminant Functions

0.02 ret S-T, 7/a ST-T, 3/a ST-T, J, 0.01 set QRS. l/a QRS. 2/a QRS. 0.05 set QRS, 0.02 set QRS. 4/a QRS,. 0.03 set QRS, R, amplitude likelihood Ratio Test Correctly classified False positives False negatives

1 .o -0.49 -0.44 -0.39 0.15 0.13 0.05 -0.04 0.03 -0.03 0.01 -0.01

aO% 20% 20%

* An equal error clossitlcation WQS programmed, that is, the number of false positives and negatives was being kept the some. All measurements represent amplitudes expressed in millivolts.

42

and specific electrocardiographic patterns of pulmonary emphysema. In more recent years, however, most investigators have apparently agreed that car pulmonale is not necessarily associated with pulmonary emphysema and that characteristic elect.rocardiographic changes may be found without significant right ventricular hypertrophy. Nevertheless, no agreement on sensitivity and specificity of electrocardiographic criteria for recognition *of pulmonary emphysema seems to prevail. For this reason, a large number of orthogonal electrocardiograms were collected from eight Veterans Administration hospitals in the framework of a Cooperative Study on Cardiovascular Data Processing with the goal of reevaluating electrocardiographic performance in this differentiation. Such studies have the advantage of uniform data collection according to strict study protocols and uniform recording techniques, together with relative ease of obtaining large representative record samples for statistical evaluation. Available computer facilities allowed a great variety of comparisons and correlations in order to arrive at optimal criteria for diagnostic discrimination. In the present as in previous studies,26,30 when a multitude of criteria were tested, redundancy of diagnostic information was the most striking finding. Many criteria, when viewed by themselves, may lead to rather efficient separation of normal from abnormal patterns. Side by side comparison with other measurements, however, may disclose that they identify only the same cases already recognized by other criteria. This finding makes it possible to keep the number of diagnostic criteria relatively small without loss of discriminatory power. At the same time it points out the limitations in diagnostic information yielded by the electrocardiogram. Redundancy of diagnostic information, however, is not limited to electrocardiographic data. It was found as prevalent when information from medical history, physical examination and laboratory tests was studied in a similar fashion.31 In the described search for optimal discriminators between normal subjects and patients with pulmonary emphysema, a hierarchy of criteria could be est,ablished both for electrocardiographic measurements which can be conveniently obtained from scalar lead or vector loop displays and also for electrocardiographic computer analysis in which complexity of measurements does not represent a limitation. The results were substantially better than those previously reported, particularly in light of the relatively low rate of false positive findings. The use of linear discriminant function analysis for record classification may be questioned because this method is based on the assumption of normal data distributions which are not always present in electrocardiographic data. Yasui et a1.32 investigated

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this problem but found that combinations of multiple electrocardiographic measurements lead to multivariate normal distributions which would justify the use of this technique. The highly satisfactory results obtained with this method in our laboratory25~30~31 seem to suggest at the same time that this procedure is relatively robust.

Factors contributing to electrocardiographic changes: The most characteristic feature of the records of pulmonary emphysema was the reduction in amplitude of R,, which by itself was found below normal limits in 57 percent of cases. Several factors may contribute to this finding. Overinflation of the lungs in pulmonary emphysema increases resistivity of the thorax, resulting in low voltage in all leads. The mean reduction was 55 percent for R,, 42 percent for R, and 26 percent for R, when compared to normal means for patients in the same age group. One factor contributing to the greater decrease of R, is probably the verticalization of the heart in pulmonary emphysema with flattening and lowering of the diaphragm. The spatial relations between heart and lung tissue are subject to complex changes in pulmonary overinflation which may contribute to differences in voltage reduction along the orthogonal lead axes. An additional factor, which applies to orthogonal leads X and Z but also to precordial leads of the conventional 12 lead electrocardiogram, is the relation between chest electrode levels and the position of the heart. Since the standard placement of electrodes is based on average heart levels along a vertical axis, their position would appear too high in patients with pulmonary emphysema. This can be easily demonstrated by lowering the chest or precordial electrodes by one or two intercostal spaces. This is usually accompanied by an increase in recorded potentials. Data of the present study, as well as those reported by others, are derived from standard chest electrode locations which are frequently incorrect for patients with pulmonary emphysema. It may be argued, however, that this recording error facilitates electrocardiographic diagnosis of pulmonary emphysema by accentuating the low voltage phenomenon in both the orthogonal and the standard 12 lead electrocardiograms. A fourth factor which is probably operative many patients with advanced pulmonary in emphysema is due to right ventricular hypertrophy, which develops late in the disease and is found in the great majority of patients who come to autopsy. An increase in right ventricular forces tends to decrease the normally predominating forces of the left ventricle which are directed toward the left and posteriorly. Thus, in the group of patients with mitral stenosis, used as the control group in the present study, the mean amplitude of R, was also decreased by 29 percent. The increasing amplitude of S, accompanied by a

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decreasing R:S, ratio is also typically seen in right ventricular hypertrophy. Which one of these factors predominates in a given case would be difficult to determine and probably varies considerably from one to another. hlthough most of the QR,S abnormalities encountered in pulmonary emphysema can be explained on the basis of increased resistivity of the thorax, position of the heart and the eventual development of right ventricular hypertrophy, some others are more difficult to understand. The shift of terminal QRS forces in a superior rightward and posterior direction in the later phases of the disease represents one of these puzzles. It may be due to a combination of right ventricular hypertrophy and a complex redistribution of current in the thorax with some pathways almost blocked by large air spaces and some others serving as preferential conductors. The QRS shift in an anterior direction, which is frequently seen in terminal cases, is probably a direct consequence of the right ventricular hypertrophy that is almost invariably present then. Differentiation from myocardial infarction : Many authors have commented that the electrocardiographic changes in pulmonary emphysema may mimic myocardial infarcts. Most striking in the present series was the complete loss of anterior forces in 21 percent of the cases and an abnormally low Q:R, ratio in an additional 10 percent. The Q:R, and Q:R, ratios were abnormally large in 28 and 32 cases, respectively, thus mimicking lateral and diaphragmatic infarcts. A significant but only moderately strong correlation was found between these Q wave changes and arterial pCO2 levels, suggesting that in patients with advanced pulmonary emphysema, patterns of pseudoinfarction are more prone to develop. A most difficult diagnostic problem still persists in those patients who have both pulmonary emphysema and significant coronary artery disease. Even without a history of chest pain or myocardial infarct, the latter cannot be ruled out completely in a population of which more than two thirds exceed the age of 60 years. Of the 22 patients who came to autopsy, 2 showed advanced, 8 moderate and 7 slight atheromatous changes of the coronary arteries. Atria1 fibrillation, found in 45 cases (11 percent), is also suggestive of t’he presence of coronary disease. P pulmonale: The frequency of P pulmonale in pulmonary emphysema differs considerably in published reports. In the present material the P, voltage exceeded normal limits in only 8 percent. In their relatively large series, Spodick et all2 and Chappell’” reported 14 and 11 percent, respectively. Spodick et al. were able to correlate the incidence of P pulmonale with advanced airway obstruction, which would agree with the higher frequency of 22 percent reported from autopsies by Phillips6 Right axis deviation of the

43

KERR ET AL.

P wave appeared to be a more sensitive criterion in the present material (19 percent). The amplitude ratio between the P wave and the following R wave exceeded normal limits in about as many cases (18 percent). In the side by side comparison of large numbers of different criteria and in multivariate discriminant analysis, P wave information proved almost completely redundant. Chou and Helm33 have also recently emphasized the low specificity of P pulmonale.

Correlations with arterial pC0,: Correlations between arterial pC0, and electrocardiographic measurements provided some insight into the development of the electrocardiographic changes associated with pulmonary emphysema. Although too low to be used as predictors, correlation coefficients between 0.25 and 0.35 were found very useful in identifying electrocardiographic characteristics that point toward deterioration of pulmonary function. As one might expect, the best discriminators between records of normal subjects and those with pulmonary emphysema led also the the highest correlations. The spatial magnitude of the initial 0.04 set and maximal QRS vector decreased with increasing pC0, levels and shifted at the same time toward the right. Both R and S waves in lead X increased in duration concomitantly with a decrease in Q duration in lead Y. The R wave in lead Y approached the base line and changed later into a deep S wave. A shift to the right of the maximal P vector was the only significant atria1 indicator of pC0, elevation. Since pulmonary and cardiac factors are inseparably intermixed in the genesis of the electrocardiographic features of pulmonary emphysema, conclusions on pulmonary function drawn from the electrocardiogram have to be interpreted with these limitations in mind.

References 1. Scott RW,

Garvin CF: Cor pulmonale. Observations in fifty autopsy cases. Amer Heart J 22:56, 1941 2. Zuckermann R, Cabrera E. Fishleder BL. et al: Electrocardiogram in chronic car pulmona.le. Amer Heart J 35:421, 1948 3. Mounsey JPD, Ritzman LW, Selverstone NJ: Cardiographic studies in severe pulmonary emphysema. Brit Heart J 14:442, 1952 4. Scott RC, Kaplan S, Fowler NO, et al: The electrocardiographic pattern of right ventricular hypertrophy in chronic car pulmonale. Circulation 11:927, 1955 5. Wasserburger RH, Ward VG, Cullen ER, et al: The T-a wave of the adult electrocardiogram. An expression of pulmonary emphysema. Amer Heart J 54875, 1957 6. Phillips RW: The electrocardiogram in car pulmonale secondary to pulmonary emphysema. A study of 18 cases proved at autopsy. Amer Heart J 56:352. 1958

44

Clinical implications: The results of the present study emphasize the need for quantitating electrocardiographic findings to improve diagnostic classification and correlations with other physiologic parameters. It appears particularly important to reconcile some of the discrepancies in normal limits which are being used in conventional electrocardiography for recognition of pulmonary emphysema. Low voltage criteria of limb leads *have been variously reported between 0.2 and 0.7 mv.15,26 A similar situation prevails for P direction in the frontal plane with normal limits between 60” and 80°.9v34 These and other discrepancies usually arise from normal control groups of inadequate size or from different age groups. Reported results, particularly false positive rates, are therefore often difficult to evaluate. Comparison of the clinical degree of the disease in material from different sources poses an even larger problem. For the patients in our study it appeared less critical than anticipated since group differences between the electrocardiographic expressions of pulmonary emphysema of moderate and severe degree were not very sharp. The described electrocardiographic changes can be considered typical for the patient who requires hospitalization because of respiratory difficulties and who presents objective evidence for the presence of pulmonary emphysema. Using the described criteria, about 80 percent of such cases can be recognized electrocardiographically. Whether typical electrocardiographic changes can be identified in an early phase of the disease remains to be investigated. The presented data may serve as end-point for such a study. Since the electrocardiogram represents one of the simpler clinical tools, its increasing usefulness in clinical evaluation of patients and screening of populations for pulmonary emphysema appears most promising.

7. Wasserburger RH, Kelly JR, Rasmussen HK, et al: The electrocardiographic pentalogy of pulmonary emphysema. A correlation of roentgenographic findings and pulmonary function studies. Circulation 20~831, 1959 8. Littmann D: The electrocardiographic findings in pulmonary emphysema. Amer J Cardiol 5:339, 1960 9. Scott RC: The electrocardiogram in pulmonary emphysema and chronic car pulmonale. Amer Heart J 61843. 1961 10. Butch GE, DePasquale NP. Electrocardiographic diagnosis of pulmonary heart disease. Amer J Cardiol 11:622, 1963 11. Phillips JH, Problems in the diagnosis of Burch GE: car pulmonale. Amer Heart J 66:818, 1963 12. Spodick DH, Hauger-Klevene JH, Tyler JM, et al: The electrocardiogram in pulmonary emphysema. Relationship of characteristic electrocardiographic findings to severity of disease as measured by degree of airway obstruction. Amer Rev Resp Dis 88:14, 1963

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Spatial magnitude, orientaPipberger HV: 13. Yano K, tion and velocity of the normal and abnormal QRS complex. Circulation 29:107, 1964 14. Fowler NO, Daniels C, Scott RC, et al: The electrocardiogram in car pulmonale with and without emphysema. Amer J Cardiol 16:500, 1965 15. Selvester RH, Rubin HB: New criteria for the electrocardiographic diagnosis of emphysema and COT pulmonale. Amer Heart J 69:437, 1965 The electrocardiogram in chronic bron16. Chappell AG: chitis and emphysema. Brit Heart J 28:517, 1966 Medrano GA et al: De Santana MMC, 17. Galland F, Diffuse obstructive pulmonary emphysema. An electrocardiographic and functional correlation. Arch lnst Cardiol Mex 36:225, 1966 The electrocardiogram in car pul18. Oran S, Davies P: monale. Progr Cardiovasc Dis 9:341, 1966 19. Millard FJC: The electrocardiogram in chronic lung disease. Brit Heart J 29:43, 1967 20. Pipberger HV, Goldman MJ, Littman D, et al: Correlations of the orthogonal electrocardiogram and vectorcardiogram with constitutional variables in 518 normal men. Circulation 35:536, 1967 21. Cosma J, Volk M, Greenough ML, et al: Automatic method for processing mass data in clinical medicine (FOSDIC). Meth Inform Med 2:125, 1963 An accurate, clinically practical system for 22. Frank E: spatial vectorcardiography. Circulation 13:737, 1956 23. Langner PH, Okada RH, Moore SR, et al: Com-

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parison of four orthogonal systems of vectorcardiography. Circulation 17:46, 1958 Pipberger HV: Computer analysis of the electrocardiogram, Computers in Biomedical Research, New York, Academic Press, 1965, Vol. 1, p. 337 Gamboa R, Klingeman JD, Pipberger HV: Computer diagnosis of biventricular hypertrophy from the orthogonal electrocardiogram. Circulation 39:72, 1969 Simonson E: Differentiation Between Normal and Abnormal in Electrocardiography. St. Louis, CV Mosby, 1961, p. 35-41, 142 Klingemann J, Pipberger HV: Computer classifications of electrocardiograms. Computers Biomed Res l:l, 1967 Pipberger HV, Schneiderman MA, Klingeman JD: The love-at-first-sight effect in research. Circulation 38:822, 1968 Harley A, Greenfield JC: Computer analysis of the orthogonal electrocardiogram in patients with mitral stenosis, in preparation. Goldman MJ, Pipberger HV: Analysis of the orthog onal electrocardiogram and vectorcardiogram in ventricular conduction defects with and without myocardial infarction. Circulation 39:243, 1969. Pipberger HV, Klingeman JD, Cosma J: Computer evaluation of statistical properties of clinical information in the differential diagnosis of chest pain. Meth Inform Med 7:79, 1968 Yasui S, Yokoi M, Watanabe Y. et al: Computer diagnosis of electrocardiograms by means of the joint probability. Jap Circ J 32:517, 1968 Chou T-C, Helm RA: The pseudo P-pulmonale. Circulation 32:96, 1965 Sodi-Pallares D, Calder RM: New Bases of Electrocardiography. St. Louis, CV Mosby, 1956, p. 83

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