Usefulness of systolic time intervals in coronary artery disease

Usefulness Coronary

RICHARD HARISIOS THOMAS WILBUR Columbus

of Systolic

Time Intervals in

Artery Disease

P. LEWIS,

MD,

BOUDOULAS,

FACC MD,

G. WELCH, MD+ F. FORESTER, MS,

FACC’ PE’

and Toledo, Ohio

This review summarizes current knowledge concerning the value of systolic time intervals in coronary artery disease. Although the usual pattern of prolongation of the preejection period (PEP) and shortening of the left ventricular ejection time (LVET) characteristic of left ventricular failure is seen in acute myocardial infarction, the systolic time intervals (as well as all other measures) are profoundly influenced by adrenergic hyperactivity characteristics of this disorder. Adrenergic stimulation normally shortens both the PEP and LVET indexes and decreases the PEP/LVET ratio. The degree of shortening of electromechanical systole (QS,) is directly related to the excessive adrenergic tone. Patients with the greatest systolic time interval abnormalities have a poorer prognosis, a greater incidence of congestive heart failure and more abnormalities of directly measured indexes of left ventricular performance. The systolic time intervals are useful for assessing left ventricular performance in chronic coronary artery disease as well. In chronic coronary artery disease the PEP/LVET ratio and angiographically determined left ventricular ejection fraction are closely correlated (r = -0.76), but the level of this correlation is less than that in other forms of left ventricular disease. The left ventricular ejection time index is prolonged after exercise in patients with angina pectoris when compared with findings in normal subjects. Failure of the ischemic ventricle to respond to adrenergic

From the Department of Medicine, Division of Cardiology, The Ohio State University College of Medicine, Columbus, Ohio* and the Department of Medicine, Medical College of Ohio, Toledo, Ohio.f This study was supported in part by U. S. Public Health Service Cardiovascular Training Grant 5 TO1 HL5968-01 from the National Heart and Lung Institute, Bethesda, Md., Research Grant 64-G-127 from the American Heart Association, Dallas, Texas and by a grant from the Central Ohio Chaoter of the American Heart Association, Columbus, Ohio. Address for reprints: Richard P. Lewis, MD, Division of Cardiology, Ohio State University Hospital, 466 W. Tenth Ave., Columbus, Ohio 43210.

stimulation is the most likely mechanism. Addition of the postexercise left ventricular ejection time to standard treadmill stress testing identifies a significant number of patients (23 percent) who would have had false negative results by electrocardiographic criteria alone. In addition, this index provides confirmatory evidence in those with apparently positive electrocardiographic test data. The systolic time intervals have been useful in assessing both medical and surgical therapy in coronary artery disease. The test can be performed repeatedly and provides a measure of both left ventricular performance and extent of adrenergic hyperactivity. Thus, evaluation of therapy represents the most useful future application of systolic time intervals.

This review summarizes the results of recent studies of the systolic time intervals in coronary artery disease and presents additional supplementary data from our laboratory. The reader is referred to recent reviews for a more detailed discussion of methodology and pathophysiology.1-3 The evaluation of coronarv arterv disease nresents uniaue challenges when compared with e;aluati& of otheriypes of heart disease. Left ventricular performance may change dramatically from moment to moment depending upon the presence of myocardial ischemia. Tests of ventricular performance such as the systolic time intervals

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may well be normal at rest in a patient who is severely disabled during exercise. Another unique characteristic bearing upon the interpretation of hemodynamic data in coronary artery disease is the presence of a hyperadrenergic state in many patients.*-lo This introduces an important variable in the interpretation of all measures of ventricular performance including the systolic time intervals. Finally, the very methods by which one validates noninvasive techniques may have major limitations in coronary artery disease. The left ventricular ejection fraction, a standard measure in other forms of left ventricular disease, may be incorrectly estimated when regional contraction abnormalities distort the ellipsoid configuration of the ejecting ventricle.11~12 This review of the application of the systolic time intervals in coronary artery disease was undertaken with these factors in mind. Methodology Technique The technique of measurement of the systolic time intervals has been described in detail elsewhere,1-3J3J4 but certain methodologic points bear reemphasis. Although the basic concept of the systolic time intervals is simple, their measurement requires great care. Faulty technique may completely obscure results since values as small as 20 to 30 msec represent significant deviations from normal. It is imperative to use a recorder that can faithfully achieve a paper speed of 100 mm/set. The measurement error is f3 msec at this range but increases significantly at slower paper speeds.15 An optical recorder is the most desirable. It has a better frequency response than most direct-writing systems. In addition, it allows amplification of the carotid pulse to at least 5 cm, thus providing significantly improved delineation of the upstroke and incisura.2J5 A proper transducer for recording the carotid pulse is essential. It must have a time constant greater than 2.5 seconds and a flat frequency response to 30 hertz or the signal will be distorted.16 Most piezoelectric devices do not meet these criteria. The air-filled Statham strain gauge and carrier preamplifier remain the most satisfactory system.13 Finally, the phonocardiographic system must have an adequate filter to define precisely the initial high frequency vibrations of the aortic closure sound. Therefore, to assure

quality tracings, equipment of high quality is required. Many commercially available recording systems do not meet one or more of these standards.15 Other common errors in technique include failure to average enough cycles to account for respiratory variation (at least 10 are required) and failure to select the best electrocardiographic lead for delineation of the onset of electrical systole. It is an obvious but often unheeded fact that the systolic time intervals should not be calculated when tracings are inadequate. In our laboratory we have found that in approximately 2 percent of patients complete systolic time intervals cannot be measured because of technically inadequate tracings. Measurements The three systolic time intervals most commonly employed are the preejection period (PEP), left ventricular ejection time (LVET) and electromechanical systole (QS,). All three are calculated from easily defined landmarks. The preejection period is composed of two subintervals: electromechanical delay (30 to 40 msec) and isovolumic systole (60 to 80 msec). In the absence of a significant left ventricular conduction delay (QRS duration less than 100 msec) little is gained by determining the subintervals of the PEP. When left bundle branch block is present, the electromechanical delay is variably prolonged. In such instances the onset of isovolumic systole determined from the apex cardiogram is useful to define the extent of the PEP prolongation related to the conduction defect.2 Common factors influencing the PEP and LVET in patients with coronary disase are listed in Table I. The underlying mechanism responsible for change in the PEP is a change in the rate of rise of left ventricular pressure (dP/ dt).lJ7 The LVET unlike the PEP is shortened by nearly all variables.* For this reason the LVET is the most consistent of the systolic time intervals to reflect deviations from normal function. The LVET is shortened either by a decreased stroke volume relative to end-diastolic volume (heart failure, negative inotropic drugs and decreased preload) or by a more rapid rate of ejection (positive inotropic agents). The QS2 best reflects the presence of positive inotropic stimulation since both the PEP and LVET are shortened.182o This is true for both normal and abnormal ventricles.20

TABLE

II

Calculation TABLE

I Time

Intervals

Indexes*

in

Period Index

Low left ventricular isovolumic pressure Positive tnotropic agents

1. 2. 3. 4.

Left Ventricular

Ejection

Time

(PEPI)

Preejection

Left ventricular failure Left ventricular conduction delay Diminished preload Negative inotropic agents Index

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Index (QS,I) $96: + It

Period Index

(PEPI)

M PEPI = 0.4 HR t PEP F PEPI = 0.4 HR + PEP Left Ventricular M F

(LVETI)

1. Left ventricular failure 2. Diminished preload 3. Positive inotropic agents 4. Negative inotropic agents

Systole

M QS,I = 2.1 HR + QS, F QS,I = 2.0 HR + QS,

Prolonged Preejection

788

Interval

Normal Index i 1 SD (msec)

Electromechanical

Shortened

2.

Time

Equation

Factors Influencing the Systolic Coronary Artery Disease

1.

of Systolic

LVETI LVETI

Ejection

= 1.7 HR + LVET = 1.6 HR + LVET

131 k IO 1332 11 Time

Index

(LVETI) 413 + 10 418i 10

*Data based on findings in 121 normal male (M) and 90 female (F) subjects studied in the fasting state between 8:00 and IO:00 AM. HR = heart rate; SD = standard deviation.

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The PEP and LVET are less useful for this purpose in patients with left ventricular dysfunction because these variables are also influenced by hemodynamic changes induced by the positive inotropic agent.20 Previous studies from this laboratory have defined the regression equations for the PEP, LVET and QS2 with heart rate in a large population of normal subjects.‘sJ4 Experience indicates that it is easiest to report the rate-corrected interval as an “index” value. The systolic time interval indexes (in milliseconds) are obtained by transposition of terms of the regression equation and in fact represent the Y intercept of the regression at zero heart rate. The equations are listed in Table II. By calculation of the index value (for either men or women) an immediate estimate of the deviation from normal is obtained. For example if a QSs index is 516 msec it is immediately clear that it is 30 msec shorter than expected for a normal man. Because the PEP index prolongs and the LVET index shortens when left ventricular dysfunction is present it has become customary to employ the PEP/LVET ratio as a single measure of left ventricular performance by the systolic time intervals.14v2’ In this manner patients with borderline changes in the PEP or LVET index are identified as abnormal. Because the PEP and LVET normally shorten proportionally with increased heart rate, the PEP/LVET ratio is not influenced by heart rate.2 All systolic time interval measurements from our laboratory presented in the review were performed according to techniques previously reported.isJ4 The results of angiographic studies of left ventricular contraction were also performed as reported previously.22-24 Cardiac output determinations by the radioiodinated serum albumin (RISA) method were performed according to techniques reported by others. 25-27 The RISA cardiac output measurements were validated in our laboratory by simultaneous injection of RISA and indocyanine green in the right atrium in 12 subjects. The correlation between the values for cardiac index obtained from the two methods was 0.96 (P
of Acute

Myocardial

Infarction

In spite of numerous studies, reports vary concerning the value of the systolic time intervals in acute myocardial infarction.8,28-38 In fact, because of adrenergic hyperactivity so commonly present in patients with this condition, the systolic time intervals in acute myocardial infarction represent a special circumstance. The pattern of prolongation of the PEP index and shortening of the LVET index and increase in the PEP/LVET ratio typical of left ventric, ular dysfunction is somewhat masked by the presence of excessive adrenergic stimulation. Failure to account for this phenomenon has been directly responsible for much of the confusion in the reported studies. Saltzman et a1.3g employed various rates of infusion of epinephrine in normal subjects and measured the systolic time intervals.3g An infusion rate of 0.1 wg/kg per min shortened the QSs index by 30 msec which is similar to that seen in patients with acute myocardial infarction. Of note, the PEP/LVET ratio at this infusion rate decreased to a value of 0.20. This is the result of marked shortening of the PEP index associated with a relatively unchanged LVET index. In the case of the LVET index, the increase in cardi-

TIME

INTERVALS

IN

CORONARY

DISEASE-LEWIS

ET

AL.

ac output and stroke volume produced by catecholamines counterbalances the shortening of the LVET produced by inotropic stimulation.18 The result is no net change in the LVET index. The PEP index is shortened by an increase in the rate of rise of left ventricular pressure in isovolumic systole.i7J8 Thus, in the presence of significant adrenergic hyperactivity, the PEP/LVET ratio of the normal ventricle is well below the mean normal value of 0.34. This must be kept in mind when the systolic time intervals are interpreted in this setting. Previous

Studies

In spite of a variety of conclusions by previous investigators, the major series in which serial studies were performed reveal a remarkable similarity of data. Virtually all investigators have noted that the QSs and LVET indexes are greatly shortened. The shortening reaches its peak 3 to 7 days after infarction. The shortened LVET index has been attributed both to a diminished stroke volume and to adrenergic stimulation.30-3s The duration of the PEP index is variable but is often “normal.” In fact, it should be shortened if left ventricular performance were normal in the presence of excess adrenergic activity.37 Thus, the finding of a normal PEP in this setting reflects an abnormality in left ventricular performance. In almost all instances patients who are judged to have more severe left ventricular dysfunction clinicaIly or by direct measurement with cardiac catheterization techniques have a more abnormal PEP/ LVET ratio.30,31,33T34,38 Those patients who die usually have greater deviations in the LVET index and PEP/LVET ratio.30,31,38 Most investigators have stressed the value of serial measurements in predicting outcome and magnitude of hemodynamic derangement. The LVET index has been suggested as the most useful of the various systolic time intervals for this purpose, although we believe that the PEP/ LVET ratio is just as useful. The systolic time intervals have been criticized because they do not separate patients with and without myocardial infarction and because they show a wide overlap among patients with acute myocardial infarction.“‘j It should be stressed that the systolic time intervals are a test of left ventricular performance and as such are not necessarily useful for the diagnosis of myocardial infarction. Furthermore, a wide overlap is also noted in various direct measures of left ventricular performance such as the cardiac output, left ventricular dP/dt, and left ventricular end-diastolic pressure.33’38,40 Indeed, as will be discussed, patients with acute myocardial infarction are not a homogeneous group, and many have relatively well preserved left ventricular performance. Rahimtoola et a1.4c performed several hemodynamic studies in the early days and several weeks after infarction and correlated these measurements with the systolic time intervals. They showed that improvement in the systolic time intervals is associated with improvement in the cardiac index and re-

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nine green (no. = 15) method. Figure 1 shows the high correlations between the PEP/LVET ratio and the cardiac and stroke indexes. The PEP/LVET ratio was less abnormal for any level of cardiac index or stroke index than is the case in chronic heart disease.14 We believe that this finding represents the effect of excessive adrenergic activity upon the systolic time intervals. It became apparent during the analysis of our series that the state of the left ventricle before infarction was a major determinant of the degree of abnormality of systolic time intervals.43 Twenty-eight patients (Group I) with prior abnormality of the left ventricle produced either by infarction or by longstanding hypertension requiring therapy had a significantly increased PEP/LVET ratio on admission (mean f standard error of the mean 0.48 f 0.02). The PEP/LVET ratio was abnormal (greater than 0.42) in 23 of 28 patients (82 percent). In contrast, in the 25 patients (Group II) who had no evidence of left ventricular disease before the infarction, the mean initial PEP/LVET ratio was normal in 90 percent and significantly different from that of patients with prior disease (0.34 f 0.02, P
duction in left ventricular end-diastolic pressure.40 In addition, administration of ouabain in either the early or late phase of acute myocardial infarction was associated with reduction in the left ventricular enddiastolic pressure and improvement in left ventricular dP/dt and the PEP/LVET ratio.41,42 The cartliac index was not significantly changed. The systolic time intervals are probably of less value in patients with cardiogenic shock. They are technically difficult to determine in such patients. Furthermore, the low isovolumic pressure may result in a normal PEP index in spite of a poor rate of rise of left ventricular pressure.37 However, the measurement of the LVET index may well be useful if it is performed in a serial manner.30,31,34 Recently the PEP index has been combined with systemic arterial pressure data and pressure measurements obtained with a Swan-Ganz catheter to provide a contractility index that may prove highly usefu1.3s Present Series

We have performed serial studies in 53 consecutive patients with acute myocardial infarction. Patients with left bundle branch block or those who did not survive were excluded from the analysis. There were 41 men and 12 women with a mean age of 58 years. All but three of the patients had a transmural infarction; half of the infarctions were inferior and half anterior in location. All patients were studied 2 to 4 days after admission and at discharge; 25 patients underwent serial studies for up to 9 months. We noted abnormalities in the systolic time intervals similar to those mentioned in previous reports. In addition, we were able to relate the shortening of the QSs index directly to catecholamine excretion in these patients.s Acute phase: Cardiac output studies were performed in 30 patients during the 1st or 2nd week of hospitalization by the RISA (no. = 15) or indocya-

ACUTE

INFARCTION

MYOCARDIAL (n=30)

1.20 r = -0.81 1.00

I

I

. .80

PEP

. 60

PEp LVET’

.

LVET ’

. 0.:

St, -

,

I

04 0

2

4

6

0

20

40

7

60

80

STROKE INDEX CARDIAC INDEX between PEP/LVET ratio and cardiac index (liters/min per m*) (left) and stroke index (ml/m’) (right) in 30 patients with acute myocardial infarction. Horizontal lines indicate upper limit of normal for PEP/LVET ratio and vertical lines indicate lower limit of normal for cardiac and stroke index.

FIGURE 1. Relation

790

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SYSTOLIC

x

* T

_

PRE”lcusLY

NoliMAL

_

PREblousLY

Amcembl.

DISEASE-LEWIS

ET AL

cardial infarction. Apex phonocardiograms were used to determine gallop rhythm. Congestive heart failure was judged from both chest X-ray films and physical examination. All patients had a fourth sound gal10p.sl*~~Patients with a normal PEP/LVET ratio had a smaller incidence of clinical congestive failure than patients with an abnormal ratio (12 versus 59 percent, P
LVET ratio did not change significantly from admission to discharge in either subgroup of these 25 patients or during the 9 month follow-up period in patients with presumably normal left ventricular function before the infarction. In patients with abnormal left ventricular function before infarction, the PEP/ LVET ratio gradually returned to the normal range over 3 to 6 months and decreased significantly between the time of discharge and the observation at 6 months (P <0.03). Data in the two subgroups were significantly different until 6 months after infarction (P <0.05). The QSs index was significantly shortened in both groups during hospitalization but had returned to normal by 3 months in both subgroups and remained normal subsequently. Figure 3 shows the change in PEP/LVET ratio that occurred in seven patients in this series who either had an extension of their infarction (five patients) or a second infarction within 3 months (two patients). It is clear that the second insult to the myocardium had a significant deleterious effect on the PEP/LVET ratio. This information suggests that patients with acute myocardial infarction should not be grouped together for purposes of analysis of left ventricular performance since performance during the infarction is substantially influenced by the prior state of the ventricle. In addition, this study provides a possible basis for differential rates of rehabilitation. Patients with a first infarction and a “normal” PEP/LVET ratio during their infarction may well be candidates for early rehabilitation. Those with an abnormal PEP/LVET ratio during their infarction may require up to 6 months for recovery. Further studies are required to clarify this observation. Clinical correlations: We also investigated the relation between the PEP/LVET ratio and other clinical variables in the 53 patients with acute myo-

.50

TIME INTERVALS IN CORONARY

Relation of Systolic Time Intervals to Other Measures of Left Ventricular Performance in Chronic Coronary Artery Disease The data from Figure 1 indicate a close correlation between the PEP/LVET ratio and cardiac index and stroke index in the setting of acute myocardial infarction. Similar close correlations have been reported for patients with overt congestive heart failure due to coronary artery disease, hypertensive heart disease or primary myocardial disease-l4 However, when less symptomatic ambulatory patients with chronic left ventricular disease are studied, many patients are encountered who have a normal cardiac and stroke index but significantly abnormal systolic time intervals.2 Ahmed et a1.46 also pointed out the poor correlation that may exist between cardiac output and the systolic time intervals. However, more direct measures of left ventricular performance correlate closely with the systolic time intervals, particularly in patients with left ventricular myocardial dysfunction.46

I_” L”

*

,45 PEP LVET

----__-_____

-_

-------__-_ .62 ,

.4o

1

0

BEFORE

m

AFTER

*+_ I SEM -II

‘35 .30

’

. AOM

PEP 46 LVET’

3Mo 6 MO 9 MO changes in PEPILVET ratio after acute myocardial infarction: serial mean values for 12 patients with a previously normal left ventricle (open circles) and 13 patients with a previously abnormal left ventricle (closed circles). The horizontal bars indicate ranges for f 1 standard error of the mean, the dashed line the upper limit of normal for the PEP/LVET ratio (0.42). The dissimilarity between the two groups is striking: asterisks indicate significant differences between the two groups (P <0.05). ADM = 1st 3 days after admission; DIS = day before discharge (usually 2 to 3 weeks after admission study); LV = left ventricle: MO = months. DIS

FlGlJRE 2. Long-term

.30

1, OC

p
FIGURE 3. The PEP/LVET

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Adequacy of preload: Another factor that must be considered when evaluating the systolic time intervals in chronic coronary artery disease is the adequacy of the preload. Patients with old myocardial infarction usually have diminished left ventricular diastolic distensibility and therefore are more sensitive to diminished preload. In a recent study, one third of patients with chronic left ventricular disease hospitalized for therapy of congestive heart failure showed a worsening of the systolic time intervals after treatment.47 This abnormality could be reversed by salt repletion. With modern potent diuretic agents, overdiuresis and the resultant suboptimal preload are not uncommon and are reflected by the systolic time intervals (as opposed to many common bedside signs). When the PEP/LVET ratio is higher than expected, diminished preload should be suspected as a contributing factor. Correlation of systolic time intervals and ejection fraction: As a result of these considerations Garrard et a1.21 compared the systolic time intervals with various other direct measures of left ventricular performance in patients with a wide variety of chronic left ventricular disorders.*l They found the highest correlation between the PEP/LVET ratio and the left ventricular ejection fraction (r = -0.90) and concluded that both variables, while measuring different phenomena, were fundamental measures of myocardial performance and as such were highly correlated. However, their series contained only a limited spectrum of patients with coronary artery disease. Subsequent studies48,4g suggested that the correlation between the PEP/LVET ratio and left ventricular ejection fraction was less close when only patients with coronary artery disease were considered.

I001

\

I

o

80 \

\

ANGINAle.391

.

PRIOR MI (Il.761

.

DEVELOPED PRESSURE c4OmmHp (n-12) Y.

60

99-ll.lx

I

EJECTION FRACTION

\

0 0

.20

.40

.60

.80

1.00

PEP/f-VET

FIGURE 4. Relation between left ventricular ejection fraction and PEP/LVET in 127 patients with angiographically established significant coronary artery disease. The symbols designate various categories within the group. All patients with an isovolumic systolic pressure of less than 40 mm Hg had a prior myocardial infarction (Ml). The dashed lines represent 95 percent confidence intervals from a previous study*’ (see text).

792

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Accordingly, we examined the relation between the PEP/LVET ratio and left ventricular ejection fraction in 127 patients with stable coronary artery disease documented by cardiac catheterization (Fig. 4). The ejection fraction was measured by single plane right anterior oblique left ventricular cineangiogram in 112 patients and by biplane angiogram in 15. All patients had at least 70 to 80 percent stenosis of one major coronary vessel. The correlation of -0.76 is smaller than that reported for the series of Garrard et a1.21 but better than that previously reported for coronary disease alone when either resting or postexercise values of PEP/LVET ratio were employed.47T48 When the 95 percent confidence intervals from Garrard’s series are superimposed on the data from the present study, it is clear that the lesser correlation in coronary artery disease is predominantly related to patients with prior infarction who have a better PEP/LVET ratio than would have been predicted from the ejection fraction. Correlations in coronary artery disease versus other disorders: Several explanations may be advanced for the lesser correlation of the PEP/LVET ratio and ejection fraction in coronary artery disease than for other disorders of the left ventricle. First, it is not uncommon for patients with old myocardial infarction to have increased left ventricular end-diastolic pressure associated with a normal or somewhat reduced systemic diastolic pressure. Hence, the pressure that must be developed during isovolumic contraction is small and the preejection period index may be normal in the presence of a poor rate of rise of left ventricular pressure. This phenomenon has clearly been documented in patients with acute myocardial infarction37 (see earlier section). Nearly half of those patients whose data fell outside the 95 percent confidence intervals of our previous series had a greatly reduced isovolumic pressure (less than 40 mm Hg). A second explanation is that the single view right anterior oblique cineangiocardiogram often underestimates the left ventricular ejection fraction when significant localized contraction abnormalities are present.llJ* This is related to the fact that the areas of the left ventricle that are least likely to be involved by ischemic damage are not seen in the right anterior oblique view. A third explanation is that some patients were experiencing angina pectoris during left ventriculography.50 In our laboratory this occurs in 5 to 10 percent of patients and is usually overlooked unless the patient is questioned. It is well known that the ejection fraction may acutely deteriorate during angina pectoris.51 Thus, the lesser correlation of PEP/LVET ratio and left ventricular ejection fraction in chronic coronary artery disease has a variety of causes, only one of which represents an error in the systolic time interval estimate of left ventricular performance. Clinical implications: Close inspection of the data in Figure 4 reveals that a PEP/LVET ratio

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greater than 0.50 is associated with an ejection fraction of less than 40 percent in 95 percent of cases. An ejection fraction less than 40 percent is a commonly employed lower limit of ventricular performance used to determine the feasibility of coronary bypass surgery. Thus, the systolic time intervals remain a useful screening test for identifying patients with left ventricular dysfunction of severe enough nature to compromise the result of coronary bypass surgery. It can also be seen in Figure 4 that the majority of patients with angina pectoris without documented prior infarction have a normal ejection fraction and normal systolic time intervals. Patients with documented old myocardial infarction may have normal or abnormal systolic time intervals and left ventricular ejection fraction depending on the size and number of prior infarctions. Systolic time intervals and segmental contraction abnormalities: Although patients with angina pectoris usually have a normal ejection fraction, segmental analysis of the ventricular contraction pattern may reveal several types of mild localized contraction abnormalities.24*52 In this series only 26 percent of the patients with angina pectoris had a normal left ventricular contraction pattern. The mean ejection fraction and PEP/LVET ratio for 11 patients with no localized contraction abnormalities were identical to the values for normal subjects in our laboratory (Table III). In 30 patients there were one or more hypokinetic segments, and both the PEP/ LVET ratio and ejection fraction were significantly different from values in those with normal contraction patterns. Thus the PEP/LVET ratio and ejection fraction are equisensitive to the presence of mild localized contraction abnormalities. Systolic Time Intervals as Adjunct to Exercise Testing The systolic time intervals have also been employed as an adjunct to exercise testing.4s,53-56 Of all approaches employed, measurement of the postexercise left ventricular ejection time index to identify patients with angina pectoris appears the most promising. Pouget found that this index was significantly prolonged after exercise in patients with angina compared with the value in normal subjects.5” The mechanism of this prolongation was not clear. Failure of the ischemic myocardium to respond to catecholamines has been suggested. The differential response is abolished by pretreatment with propranolol, which prolongs the left ventricular ejection time index in normal subjects, and nitroglycerin, which shortens it in patients with heart disease.54,55 Prospective study of LVET after submaximal exercise test: These investigators did not employ a treadmill test. In addition, their postexercise left ventricular ejection time was corrected for heart rate by employing the preexercise resting regression data. We therefore studied prospectively 75 patients with angina-like chest pain by means of multistage tread-

TIME INTERVALS IN CORONARY

DISEASE-LEWIS

ET AL.

mill testing and pre- and postexercise systolic time intervals.56 Twenty-one patients with normal coronary arteries by coronary arteriography served as control subjects. Of all the systolic time intervals the left ventricular ejection time (LVET) 4 minutes after exercise proved the most useful index in separating normal subjects from those with coronary artery disease. The 4 minute postexercise regression relating LVET to heart rate for the 21 normal subjects was used to correct the LVET for heart rate in the 54 patients with coronary artery disease. The deviations in LVET from the normal regression (A LVET) before and after exercise were employed to calculate the net A LVET 4 minutes after exercise. A net increase in LVET of 30 msec was not observed in any normal subject and was therefore considered an abnormal response. Fifty-two percent of the 53 patients with significant coronary artery disease had a positive exercise test result by electrocardiographic criteria (more than 1.0 mm flat S-T depression at 60 msec), 18 percent had an indeterminate result and 28 percent a negative result. Among the normal subjects, 14 percent had false positive test results. Forty-six percent of those with coronary artery disease had a prolonged postexercise LVET. Thus, an approximately equal number of patients had positive test results by either electrocardiographic criteria or LVET prolongation. However, because the composition of the groups was different, the combination of the two criteria identified 74 percent of the patients. Potential applications: Since a recent large prospective study57 indicated that at best only 65 percent of patients with coronary artery disease are identified with submaximal treadmill testing employing electrocardiographic criteria alone, measurement of the 4 minute postexercise A LVET may increase the usefulness of treadmill testing as a screening test. It allows identification of a significant percentage of patients with a negative or equivocal electrocardiographic response. In addition, and perhaps equally useful, it can provide independent evidence that significant coronary artery disease is present in patients with positive electrocardiographic test results, which in some cases (10 to 15 percent) are false positive results.

TABLE

III

Relationship Between the PEP/LVET Ratio and Ejection Fraction in 41 Patients with Angina Pectoris”

Group

PEPiLVET Ratio

No segmental contraction abnormality (11 patients) One or more hypokinetic segments (30 patients) P

0.35 to.01 0.38 i 0.01
April 1976

* Values expressed

The American

as mean t 1 standard

Journal

of CARDIOLOGY

Ejection Fraction (%I 68.5 ?I.8 62.3 il.0 10.005

error of the mean.

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Another potential application of the systolic time intervals is in evaluation of the effects of an exercise program in patients with coronary artery disease. One report58 suggests that among normal subjects there is a difference in the resting systolic time intervals of physically active and sedentary persons. Another study.5g in which the systolic time intervals were measured before and after exercise suggeste;d that left ventricular performance was better in active than in sedentary patients with heart disease. This is another area for future research. Detection of Adrenergic Hyperactivity Coronary Artery Disease by Systolic Time Intervals

error of the mean] versus 543 msec f 1.8, P
in

Patients who have sustained an acute myocardial infarction have increased adrenergic activity.*-” Adrenergic hyperactivity had also been shown to be present in the early weeks after coronary bypass surgery and in some patients with chronic stable angina pectoris. g,10 The basis for this adrenergic hyperactivity is not clear since it can occur in the absence of significant hemodynamic abnormality. In many instances emotional stress undoubtedly plays a role.4,s Recent studies60-s4 suggest that adrenergic hyperactivity may have certain deleterious effects and be an important pathophysiologic factor in the acute manifestations of coronary artery disease. QS, index as identifier of adrenergic hyperactivity: The evidence suggests that the systolic time intervals may prove useful for identification of adrenergic hyperactivity in coronary artery disease.s,lT2o This is manifested by shortening of all the intervals but is best seen in the QS2 index. It is most clearly seen in patients with acute myocardial infarctioqs although we have also noted it in those with chronic stable angina. When 93 patients with angina pectoris and significant coronary arterial narrowing were compared with 60 patients with chest pain but normal coronary arteries, the mean &ST index was significantly shorter in the group with coronary disease (527 f 1.6 [standard

Use of Systolic

PCOOOl

pccJcJol

P’OOOI

FIGURE 5. Effect of propranolol: Deviation of the mean QSz index from the normal value of 546 msec (.1C&l) before and 10 minutes after administration of 2.5 mg of propranolol in four groups of patients. Normal subjects have normal values before and after administration of propranolol. Patients with stable chronic coronary artery disease (ASHD) or acute myocardial infarction (AMI) and those studied 2 weeks after aortocoronary saphenous vein bypass grafting (SVG) have initially short values that are significantly prolonged by propranolol. Vertical bars indicate ranges for 1 standard error of the mean. N.S. = not significant.

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Coronary bypass surgery: Perhaps one of the most promising uses of the systolic time intervals in coronary artery disease is to aid in the evaluation of therapy-both medical and surgical. Johnson et al.@ reported that if significant left ventricular dysfunction were present preoperatively, improvement of the systolic time intervals occurred after coronary bypass surgery if the vein graft remained patent.@ Our previous study9 indicated that perioperative myocardial infarction results in a deterioration of the PEP/ LVET ratio in the early postoperative period, but, as in spontaneous myocardial infarction, the ratio returns to control levels by 3 months. In both studies there was marked shortening of the QS2 index in the early postoperative period consistent with adrenergic hyperactivity so that the systolic time intervals must be interpreted accordingly (see previous sections). Beta adrenergic blockade: This is becoming a major form of therapy for all manifestations of coronary artery disease-stable angina, intermediate syndrome, and selected cases of acute myocardial infarction. Since the systolic time intervals not only provide a measure of left ventricular performance but also provide a clue to the presence of adrenergic hyperactivity, their serial measurement after beta blocking drug therapy appears to have great prom-

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ise.67 Indeed, a recent repor@ confirms the usefulness of the PEP/LVET ratio as a guide to the dosage of propranolol in angina pectoris. Other factors affecting measurements: If serial measurements of the systolic time intervals are to be useful in following up patients with coronary artery disease, the extent of day to day variation must be considered. A previous study has shown that a change of f0.07 (2 standard deviations) indicates significant improvement or deterioration in left ventricular performance.2 Finally, attention must be paid to factors such as the temporal relation between the administration of the medication under study and mea-

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surement of the systolic time intervals, the clinical state of the patient at the time of study, and the presence of other cardioactive medications. Combination with other noninvasive techniques: Evaluation of therapy represents an area wherein the combined use of several noninvasive techniques should prove more useful than the use of one technique alone.6g,70 Thus, echocardiography and treadmill testing, and perhaps some of the newer radioisotope techniques, can be combined with the systolic time intervals to provide a rather complete quantitative analysis of the results of a specific therapeutic intervention.

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