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Bedside technics for the evaluation of ventricular function in man
Bedside
Technics
of Ventricular ARNOLD M. WEISSLER, M.D., F.A.c.c.,
for the Evaluation Function
WILLARD S. HARRIS, M.D. and CLYDE D. SCHOENFELD, M.D. Columbus,
S
in Man*
Ohio
and abbreviation of the ejection phase of systole in patients with heart failure. Studies from this laboratory revealed that the systolic interval changes in heart failure may yield a measure of the decrease in stroke volume and cardiac output.g~‘0 On the basis of these observations it appeared that the determination of the systolic phases of the cardiac cycle by indirect means may offer a convenient, noninvasive approach to detecting changes in cardiac performance. The present studies were designed to test further the validity of such application of the systolic time intervals.
THE EARLIEST investigations of cardiovascular physiology interest has been focused on the pulsatile movements of the arteries, the veins, the precordium, the cardiac apex and, indeed, the movements of the body as a whole, in order to derive meaningful clinical measures of the heart’s performance in man. Despite a large body of information on changes in contour of these pulsations, no consistently useful expression of cardiac performance which can be applied at the bedside has evolved. As early as 1874, Garrod’ expressed interest in the temporal phenomena of the cardiac contraction cycle as a measure of cardiac performance in man and demonstrated the inverse relation between the duration of left ventricular ejection and heart rate. Later, Bowen and Lombard and Cope3 affirmed these observations and demonstrated that the systolic intervals vary not only with heart rate but with sex and posture as well. In the now classic studies by Frank4 and Wigger9 marked alterations in the phases of the cardiac cycle were found to accompany changes in other performance characteristics of the cardiac chambers. Thus, it was early appreciated that changes in the more usual expressions of cardiac function in volume, pressure and flow were accompanied by easily detectable alterations in the temporal course of the cardiac cycle. Clinical application of these observations in man was introduced by Katz and Feil,6 who established the method of simultaneously recording the heart sounds, the central arterial pulse tracing and the electrocardiogram to define the intervals in the cardiac cycle. Employing this approach, Blumberger’ and later Jezeka demonstrated prolongation of the pre-ejection period INCE
METHOD The systolic time intervals of left ventricular systole were measured from simultaneous recordings of the electrocardiogram, phonocardiogram, carotid arterial pulse tracing and a chest pneumogram employing a multichannel photographic system (Electronics for Medicine DR-8).1° The recordings were obtained at a paper speed of 100 mm./sec. The electrocardiographic lead most clearly demonstrating the onset of ventricular depolarization (usually lead II or a precordial lead) was employed. A microphone (Peiker) was placed over the upper part of the precordium in a position optimal for recording the initial high frequency vibrations of the first and second heart sounds. Two microphones were sometimes necessary to define the initial vibrations of both sounds. The carotid arterial pulsation was recorded with a funnelshaped pickup attached by polyethylene tubing (length, 8 cm.; internal diameter, 4 mm.) to a Statham P23Db strain gauge. The system was airfilled and was amplified to maximal gain. The funnel was placed firmly over the carotid artery with the gauge vented to air. The vent was then closed manually to record the pulse.
* From the Department of Medicine, Ohio State University College of Medicine, Columbus, Ohio. This invcstigation was supported in part by Research Grants H-6737, FR-34 (General Clinical Research Center), HE-09884 and a Career Program Award HE-K-3-13,971 from the U. S. Public Health Service and Research Grant 64-G-127 from the American Heart Association. Address for reprints: Arnold M. Weissler, M.D., Department of Medicine, Ohio State University College of Medicine, 410 W. Tenth Ave., Columbus, Ohio 43210. VOLUME
23,
APRIL 1969
577
Weissler
PHONO
AORTIC PRESSURE
LV PRESSURE
ECG
Figure 1. Relation of the measured systolic time interval, tu the cardiac cycle. Simultaneous registration of phonocardiogram (phono), aortic pressure tracing, left ventricular (LV) pressure tracing and electrocardiogram. PEP = pre-ejection phase; LVET = left ventricular ejection time; QSs = total electromechanical systole. The following phases of the cardiac cycle were measured: (1) total electromechanical systole (QSs), measured from the onset of the QRS complex to the hrst high frequency vibrations of the second heart sound; (2) left ventricular ejection time (LVET), measured from the beginning upstroke to the trough of the incisural notch on the carotid arterial pulse tracing; and (3) left ventricular pre-ejection period (PEP), derived by subtracting the left ventricular ejection time from total electromechanical systole (QS, - LVET). Ail intervals were calculated as the mean of measurements on 20 to 30 consecutive beats, each read to the nearest 5 msec. Care was taken to begin and end a series of consecutive readings with the same phase of the respiratory cycle. The relation of the measured systolic time intervals to the cardiac cycle are illustrated in Figure 1. Normal regression equations relating heart rate and the QSs, LVET and PEP were derived from observations on 121 normal male and 90 normal female subjects and have been published previously.10 The determination of the systolic intervals were made with the subjects supine and fasting between 8:00 and 10:00 A.M. The normal regression equations relating heart rate and the three systolic intervals, expressed in msec. and corrected for sex (M or F) are as follows: Q&(M) Q&(F) PEP(M) PEP(F) LVET(M) LVET(F)
= = = = = =
HR -2.0 HR -0.4 HR -0.4HR -1.7 HR -1.6 HR -2.1
+ + + + + +
546 549 131 133 413 418
et al. ‘I’he differences in the regression equations for the sexes was significant (p < 0.01) for the QS, and LVET, but not for the PEP. Deviations from these normal data were calculated as the difference between the observed interval and that predicted from the normal regression line for heart rate. The appropriate regression equation for sex was used for calculating the deviation from normal in QSs and LVET. Since the regression equations for PEP did not differ significantly according to sex, the male equation was used for calculation of the deviations from normal. The ratio of PEP to LVET (PEP/LVET) was measured directly from the uncorrected values for these two intervals. In the present studies, cardiac output and stroke volume were measured and correlated with the systolic time intervals in 34 patients with heart disease. The types of heart disease were coronary artery disease (11 patients), hypertensive heart disease (17 patients) and primary myocardial disease (6 patients). Eleven of the patients were in functional class I-II and 23 in functional class III-IV, according to the New York Heart Association classification. All observations were made between 8:OO and 10:00 A.M. with the subjects supine and fasting. The patients had received no digitalis for four weeks prior to the study, and all other medication was curtailed for 48 hours before the study. All patients had a normal QRS (less than 100 msec.) and were in sinus rhythm at the time of the study. Cardiac output was determined by the indicator-dilution technic employing central injection of indocyanine dye and continuous sampling from a brachial artery. Stroke volume was calculated by dividing cardiac output by heart rate. Since the hemodynamic measurements and the systolic intervals can bc influenced by the laboratory procedure, 24 normal subjects (14 male, 10 female) were studied under the same conditions and their data compared with those of the patients. The average cardiac output for this group of normal subjects was 3.15 L./min./M.2 (SE. 0.09). and heart rate averaged 70 (S.E. 2.2). Statistical analysis was performed according to Snedecor by IBM 7094 and Wang 360 computers. RESULTS
The mean deviations in the systolic intervals from the normal regression data among the patients with functional
class
I-II
and
III-IV
heart
disease
are
2. In both groups a similar pattern of deviation in the systolic intervals was apparent. Total electromechanical systole (QS,) was not significantly altered, but the pre-ejection period (PEP) was lengthened and left ventricular ejection time (LVET) was abbreviated. The magnitude of the deviation in the PEP and LVET was significantly greater among the patients with functional class III-IV disease. The mean deviation in PEP averaged summarized
in
THE
Figure
AMERICAN
JOURNAL
OF CARDIOLOGY
Bedside +19
1nsec.
Evaluation
of Ventricular FUNCTIONAL
(p < 0.001) among patients in func-
tional class I-II and f44 msec. (p < 0.001) among patients in functional class III-IV. The deviations in LVET averaged -21 msec. (I < 0.002) among patients in functional class I and II and -39 msec. (p < 0.001) among patients in functional class III-IV. Among the patients in functional class I-II cardiac output averaged 2.71 L./min./M.* (SE. 0.18) and heart rate averaged 67 (S.E. 2.9); in the patients in functional class III-IV cardiac output averaged I .93 L./rnit~./M.~ (S.E. 0.10) and heart rate averaged 86 (S.E. 3.1). In normal subjects who underwent cardiac catheterization under identical laboratory conditions to those of the patients there was slight diminution in QS2 (- 9 msec., SE. 3.2), PEP (- 5 msec., SE. 2.6) and LVET (-4 msec., S.E. 2.0). The relation of the deviation in the pre-injection period (PEP) from the normal regression equation to the cardiac output and stroke volume among the patients with heart disease is summarized in Figure 3. Prolongation of the PEP was significantly correlated with the cardiac output (T = -0.72, p < 0.01) and the stroke volume (r = -0.80, p < 0.01). The greatest proiongation in PEP accompanied lowest cardiac output and stroke volume levels. Patients with functionally mild disease (class I-II) demonstrated least deviation from normal in both the PEP and the flow measurements. The relation of the deviation in the left uentricular ejection time (LVET) from the normal regression
+eo
.
.
l
t60 ’
.
CLASS I-n
FUNCTIONAL
bPEP
Figure 2. Systolic time intervals in heart disease. Mean deviations from normal in QS,, PEP and LVET in 11 patients with functional class I-II and 23 patients with functiona class III--IVheart disease (arteriosclerotic heart disease, hypertensive cardiovascular disease and primary myocardial disease). CI = cardiac index; HR = heart rate; SI = stroke index.
equation to the cardiac output and stroke volume among the patients is summarized in Figure 4. Abbreviation in LVET was significantly correlated with cardiac output (r = +0.62,p < 0.01) and stroke volume (I = +0.60, p < 0.01). The correlations were not as close as those for the PEP. The greatest shortening of LVET occurred
+00.
:
t60.
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.
+40*
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--.____--.-_
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__
-20. i 0
I CARMC
2
“SC-
OUTPUT L/MlNfY2
4
0
15
30
STROKE “OLUME
45
60
mm2
Figure 3. The relation of the deviation in PEP from the normal regression equation to cardiac output (left) and stroke volume (right) among 34 patients with heart disease. VOLUME
23,
APRIL
1969
CLASS II[-Ip
m*ac
zq
. .
579
Function
Weissler
580
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o.-
et al.
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-1
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-
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._. m
45
60
STROKE VOLUME ml/M2
CARDIAC OUTPUT L/MINIM*
Figure 4. The relation of the deviation in LVET from the normal regression equation to cardiac output (left) and stroke volume (right) among 34 patients with heart disease.
2 CARDlAC
1 CWPUT
4
LIYIN/YZ
IS
SD
45
so
STROKE VOLUME ml/MS
Figure 5.
The relation of PEP/LVET to the cardiac output (left) and stroke volume (right) among 34 patients with heart disease. Bars represent 1 S.D. from the mean for the PEP/LVET and the flow measurements.
among the patients with lowest cardiac output and stroke volume. The patients with functionally mild disease (class I-II) demonstrated least deviation from normal in both the LVET and the flow measurements. Mean PEP/LVET Ratio: The pattern of the deviation from normal in the PEP and LVET in patients with heart disease suggested use of the ratio of the two intervals as a composite expression of these changes. This ratio affords the practical convenience that it varies within narrow limits without correction for heart rate or sex. The mean PEP/LVET for the 2 11 normal subjects studied in the basal state was 0.345 (S.D. 0.036). Among the 24 normal subjects who
underwent cardiac catheterization the PEP/’ LVET averaged 0.334 (SD. 0.046). Thus, the state of arousal associated with preparation for the hemodynamic measurements did not significantly alter the ratio. The relation of the uncorrected PEP/LVET to tile cardiac output and stroke volume among the patients with heart disease is illustrated in Figure 5. The PEP/LVET was closely correlated with cardiac output (r = -0.72, p < 0.01) and stroke volume (r = -0.82, p < 0.01). The patients with functionally mild disease (class I-II) demonstrated least deviation in PEP/LVET. Separation of the patients from the normal range of data was more clearly evident in the PEP/LVET THE
AMERICAN
JOURNAL
OF CARDIOLOGY
Bedside
Evaluation
than in the measurement of cardiac output and stroke volume. Only 1 subject in functional class I-II and none in functional class III-IV fell lvithin 1 S.D. of the normal mean value for PEP,‘LVET. DISCUSSION The duration of the systolic time intervals in man can be conveniently determined by noninvasive technics from simultaneous recordings of the electrocardiogram, phonocardiogram and carotid arterial pulsation. In normal subjects studied under basal conditions the systolic intervals vary inversely and linearly with heart rate. The normal regression equations relating heart rate and the systolic intervals, corrected for the slight differences between the sexes, provide a basis for the study of alterations induced by heart disease. In previous studies on undigitalized patients in sinus rhythm the presence of conspicuous heart failure was found to be associated with a characteristic pattern of deviation in the systolic intervals. This consisted of a prolongation of the pre-ejection period and an abbreviation of the left ventricular ejection time, while total electromechanical systole remained unaltered.lO These abnormalities occurred in the absence of a measurable abnorlnality in the duration of ventricular depolarization. The present observations demonstrate that the pattern of deviation in the systolic intervals can be identified among patients with functionally mild heart disease. The deviations in the pre-ejection period and the left ventricular ejection time were significantly correlated with the stroke volume and cardiac output. Thus, the systolic time intervals offer not only a useful index of the presence of a diminished cardiac output and stroke volume but a semiquantitative expression of the degree of impairment in the flow measures as well. Since the pre-ejection period (PEP) lengthens and the ejection time (LVET) shortens, but total electromechanical systole is unchanged, the ratio of the two intervals encompasses a single expression of the changes in heart failure. &4pplication of the PEP/LVET is facilitated by the observation that this ratio tends to remain within narrow limits among normal subjects even when uncorrected for heart rate and sex. In other words, the normal variation in LVET with heart rate and sex is minimized by inclusion of the PEP measurement in the ratio. The PEPXVET was found to be increased among VOLUME
23,
APRIL
1969
of Ventricular
Function
582
patients with heart disease. The magnitude of the deviations in the ratio permitted a clear separation of subjects with heart disease from the normal subjects. Since the PEP/LVET was found to be closely correlated with the cardiac output and stroke volume, it yields a simplified semiquantitative measure of the circulatory impairment in arteriosclerotic and hypertensive heart disease and in primary myocardial disease. Influence of Other Hemodynamic Factors: III applying the PEP/LVET to the detection of impaired cardiac performance it is 0: importance to recognize that hemodynamic influences other than heart failure may alter the ratio. Studies in this laboratory have demonstrated that an increase in the PEP/LVET occurs during the assumption of the upright posture and during peripheral pooling of blood with venous occlusive tourniquets.” The PEP/LVET is also increased with increases in peripheral resistance induced pharmacologically by angiotensin and methoxamine, with beta receptor blockade with propranolol(l0 mg. intravenously) and with norepinephrine infusion after beta receptor blockade. l2 The presence of sustained diastolic hypertension tends to increase the PEP and the PEP/LVET slightly in patients with heart failure.‘O However, among the patients with chronic arterial hypertension and minimal functional impairment (Class I-II) no independent effect of arterial pressure on the systolic intervals or the PEP/LVET could be demonstrated. Patients with aortic stenosis or aortic regurgitation in the absence of heart failure demonstrate an abbreviation in the pre-ejection period and a lengthening of the ejection period.7-g The changes in systolic intervals induced by heart failure may, therefore, be masked in aortic valvular disease. Prolongation of the pre-ejection period has been observed in patients with left bundle branch blocks and an increase in the PEP/LVET is observed among such patients in the absence of heart failure. Diminution in the PEP/LVET ratio can be induced by beta receptor stimulation with isoproterenol and after administration of the digitalis glycosides.12 It is apparent, therefore, that the PEP,/LVET must be interpreted relative to the hemod~namic setting. The finding of an increase m the PEP/LVET does not of itself constitute definite evidence for a failing left ventricle. In applying the measure of PEP/LVET to patients with heart disease it is most important to snake the observations with the patient srlpinc and as
Weissler
582
AORTIC PRESSURE
L
IPRESSURE
-NORMAL ---CHF Figure 6. Schematic refiresentation of the changes in the cardiac cycle responsible for the altered systolic intervals in heart disease. Normal aortic and ventricular pressure curves
compared to those in congestive heart failure (CHF). close to a basal state as is feasible. The contribution of digitalis therapy must also be recognized. Altered Systolic Intervals in Heart Failure and Ventricular Performance: In interpreting the mechanisms accounting for the prolongation of the PEP and the abbreviation of the LVET, and, hence, for the increase in PEP/LVET in heart failure, the effects of hemodynamic influences accompanying this circulatory state must be considered. It is pertinent that in normal persons pharmacologically induced increases in peripheral resistance to levels comparable to that in severe heart failure result in increases in the PEP/LVET which are small relative to those observed among patients with conspicuous heart failure. Similarly, beta receptor blockade with propranolol induces only slight increases in PEP/LVET in normal subjects. Thus, although such factors as elevated peripheral resistance and depletion of myocardial catecholamines might contribute to the increased PEP/LVET in heart failure, it would appear that primary alterations in ventricular performance play the dominant role. Previous studies have demonstrated that the maximal rate of isovolumic systolic pressure rise is reduced in patients with left heart failure.13 During laboratory-induced depression of myocardial function a similar decrease in the maximal rate of rise of left ventricular pressure has been observed.” Recent studies by Spann and associates16 on the length-tension and force-
et al. velocity relations in papillary muscles from the failing right ventricle of the cat have demonstrated a significant diminution in the intrinsic contractile performance of the myocardiurn, at a time when the duration of the active state of contraction remained unaltered. Present evidence, therefore, favors the hypothesis that a defect in the contractile performance of the ventricle is primarily responsible for the altered systolic intervals in heart failure. It would appear that at any level of end-diastolic volume, prolongation of the pre-ejection period in heart failure results from a deficient rate of myocardial force development early in systole. There is a consequent decrease in the rate of rise of intraventricular pressure throughout the preejection period. This results in a lengthening in the time required for intraventricular pressure to reach arterial diastolic pressure levels (Fig. 6). Since the duration of total electromechanical systole is unaltered, the lengthening of the preejection period results in abbreviation of the subsequent systolic ejection period, both events being associated with a diminished left ventricular stroke volume. SUMMARY Characteristic changes in the systolic intervals of the left ventricle have been demonstrated among patients with arteriosclerotic, hypertensive and primary myocardial disease. These consist of a prolongation of the pre-ejection period and an abbreviation in the ejection time, while total electromechanical systole remains unaltered. The changes in the pre-ejection period and the left ventricular ejection time correlate well with the level of cardiac output and stroke volume. The ratio of the pre-ejection period to the left ventricular ejection time (PEP/LVET) lends a convenient expression of these changes in the systolic intervals. The ease with which these measures can be obtained, using a noninvasive technic, suggests their use in the bedside evaluation of cardiac performance in man. REFERENCES 1. GARROD, A. H. On some points connected with circulation of the blood arrived at from a study of the ;;ylFgraph. Proc. Roy. Sot. London, 23: 140, 2. BOWEN, W. P. Changes in heart rate, blood pressure and duration of systole from bicycling. Am. J. Physiol., 11: 59, 1904. 3. LOMBARD, W. P. and COPE, 0. M. Duration of the systole of the left ventricle of man. Am. J. Physiol., 77: 263, 1926. THE
AMERICAN
JOURNAL
OF CARDIOLOGY
Bedside Evaluation of Ventricular 4. FRANK, 0.
On
the dynamics
of cardiac
muscle.
by CHAPMAN, C. B. and WASSERMAN, E. Am. Heart .J., 58: 282, 467, 1959. 5. WIGGERS, C. J. Studies on the consecutive phases of the cardiac cycle. IL The laws governing the relative duration of ventricular systole and diastole. Am. J. Physic& 56: 439, 1921. 6. KATZ, L. N. and FEIL, H. S. Clinical observations on the dynamics of ventricular systole: I. Auricular fibrillation. Arch. Znt. Med., 32: 672, 1923. 7. BLUMBERGER, K. Die Untersuchung der Dynamik des Herzens beim Menschen. Ergebn. inn. Med. u. Translated
Kinderhk., 62: 424, 1942. 8. JEZEK, V. Clinical value of the polygraphic
tracing in the study of the sequence of events during cardiac contraction. Cardiologia, 43: 298, 1963. 9. WEISSLER, A. M., PEELER, R. G. and ROEHLL, W. H. Relationships between left ventricular ejection time, stroke volume, and heart rate in normal individuals and patients with cardiovascular disease. Am. Heart J., 62: 367, 1961.
583
10. WEISSLER, A. M., HARRIS, W. S. and SCHOENFELD, C. D. Systolic time intervalsin heart failure in man.
Circulation, 37, 149, 1968. 11. STAFFORD, R. W., HARRIS, W. S., WEISSLER, A. M. and WARREN, J. V. The systolic time intervals as indices of gravitational circulatory stress in man (Abstr.). Am. J. Cardiol., 19: 152, 1967. 12. HARRIS, W. S., SCHOENFELD, C. D. and WEISSLER, A. M. Personal observations. 13. GLEASON, W. L. and BRAUNWALD, E. Studies on the first derivative of the ventricular pressure pulse in man. J. Clin. Invest., 41: 80, 1962. 14. MASON, D. T. Usefulness and limitations of the rate of rise of intraventricular pressure (dp/dt) for the evaluation of myocardial contractility in man.
Am. J. Cardiol., 23: 516, 1969. 15. QPANN, .J. F., JR., BUCCINO, R. A., SONNENBLICK, E. H. and BRAUNWALD, E. Contractile state of cardiac muscle obtained from cats with experimentally produced ventricular hypertrophy and heart failure. Circulation Res., 21: 341, 1967.
End of Symposium
VOLUME 23, APRIL 1969
Function
Technics
of Ventricular ARNOLD M. WEISSLER, M.D., F.A.c.c.,
for the Evaluation Function
WILLARD S. HARRIS, M.D. and CLYDE D. SCHOENFELD, M.D. Columbus,
S
in Man*
Ohio
and abbreviation of the ejection phase of systole in patients with heart failure. Studies from this laboratory revealed that the systolic interval changes in heart failure may yield a measure of the decrease in stroke volume and cardiac output.g~‘0 On the basis of these observations it appeared that the determination of the systolic phases of the cardiac cycle by indirect means may offer a convenient, noninvasive approach to detecting changes in cardiac performance. The present studies were designed to test further the validity of such application of the systolic time intervals.
THE EARLIEST investigations of cardiovascular physiology interest has been focused on the pulsatile movements of the arteries, the veins, the precordium, the cardiac apex and, indeed, the movements of the body as a whole, in order to derive meaningful clinical measures of the heart’s performance in man. Despite a large body of information on changes in contour of these pulsations, no consistently useful expression of cardiac performance which can be applied at the bedside has evolved. As early as 1874, Garrod’ expressed interest in the temporal phenomena of the cardiac contraction cycle as a measure of cardiac performance in man and demonstrated the inverse relation between the duration of left ventricular ejection and heart rate. Later, Bowen and Lombard and Cope3 affirmed these observations and demonstrated that the systolic intervals vary not only with heart rate but with sex and posture as well. In the now classic studies by Frank4 and Wigger9 marked alterations in the phases of the cardiac cycle were found to accompany changes in other performance characteristics of the cardiac chambers. Thus, it was early appreciated that changes in the more usual expressions of cardiac function in volume, pressure and flow were accompanied by easily detectable alterations in the temporal course of the cardiac cycle. Clinical application of these observations in man was introduced by Katz and Feil,6 who established the method of simultaneously recording the heart sounds, the central arterial pulse tracing and the electrocardiogram to define the intervals in the cardiac cycle. Employing this approach, Blumberger’ and later Jezeka demonstrated prolongation of the pre-ejection period INCE
METHOD The systolic time intervals of left ventricular systole were measured from simultaneous recordings of the electrocardiogram, phonocardiogram, carotid arterial pulse tracing and a chest pneumogram employing a multichannel photographic system (Electronics for Medicine DR-8).1° The recordings were obtained at a paper speed of 100 mm./sec. The electrocardiographic lead most clearly demonstrating the onset of ventricular depolarization (usually lead II or a precordial lead) was employed. A microphone (Peiker) was placed over the upper part of the precordium in a position optimal for recording the initial high frequency vibrations of the first and second heart sounds. Two microphones were sometimes necessary to define the initial vibrations of both sounds. The carotid arterial pulsation was recorded with a funnelshaped pickup attached by polyethylene tubing (length, 8 cm.; internal diameter, 4 mm.) to a Statham P23Db strain gauge. The system was airfilled and was amplified to maximal gain. The funnel was placed firmly over the carotid artery with the gauge vented to air. The vent was then closed manually to record the pulse.
* From the Department of Medicine, Ohio State University College of Medicine, Columbus, Ohio. This invcstigation was supported in part by Research Grants H-6737, FR-34 (General Clinical Research Center), HE-09884 and a Career Program Award HE-K-3-13,971 from the U. S. Public Health Service and Research Grant 64-G-127 from the American Heart Association. Address for reprints: Arnold M. Weissler, M.D., Department of Medicine, Ohio State University College of Medicine, 410 W. Tenth Ave., Columbus, Ohio 43210. VOLUME
23,
APRIL 1969
577
Weissler
PHONO
AORTIC PRESSURE
LV PRESSURE
ECG
Figure 1. Relation of the measured systolic time interval, tu the cardiac cycle. Simultaneous registration of phonocardiogram (phono), aortic pressure tracing, left ventricular (LV) pressure tracing and electrocardiogram. PEP = pre-ejection phase; LVET = left ventricular ejection time; QSs = total electromechanical systole. The following phases of the cardiac cycle were measured: (1) total electromechanical systole (QSs), measured from the onset of the QRS complex to the hrst high frequency vibrations of the second heart sound; (2) left ventricular ejection time (LVET), measured from the beginning upstroke to the trough of the incisural notch on the carotid arterial pulse tracing; and (3) left ventricular pre-ejection period (PEP), derived by subtracting the left ventricular ejection time from total electromechanical systole (QS, - LVET). Ail intervals were calculated as the mean of measurements on 20 to 30 consecutive beats, each read to the nearest 5 msec. Care was taken to begin and end a series of consecutive readings with the same phase of the respiratory cycle. The relation of the measured systolic time intervals to the cardiac cycle are illustrated in Figure 1. Normal regression equations relating heart rate and the QSs, LVET and PEP were derived from observations on 121 normal male and 90 normal female subjects and have been published previously.10 The determination of the systolic intervals were made with the subjects supine and fasting between 8:00 and 10:00 A.M. The normal regression equations relating heart rate and the three systolic intervals, expressed in msec. and corrected for sex (M or F) are as follows: Q&(M) Q&(F) PEP(M) PEP(F) LVET(M) LVET(F)
= = = = = =
HR -2.0 HR -0.4 HR -0.4HR -1.7 HR -1.6 HR -2.1
+ + + + + +
546 549 131 133 413 418
et al. ‘I’he differences in the regression equations for the sexes was significant (p < 0.01) for the QS, and LVET, but not for the PEP. Deviations from these normal data were calculated as the difference between the observed interval and that predicted from the normal regression line for heart rate. The appropriate regression equation for sex was used for calculating the deviation from normal in QSs and LVET. Since the regression equations for PEP did not differ significantly according to sex, the male equation was used for calculation of the deviations from normal. The ratio of PEP to LVET (PEP/LVET) was measured directly from the uncorrected values for these two intervals. In the present studies, cardiac output and stroke volume were measured and correlated with the systolic time intervals in 34 patients with heart disease. The types of heart disease were coronary artery disease (11 patients), hypertensive heart disease (17 patients) and primary myocardial disease (6 patients). Eleven of the patients were in functional class I-II and 23 in functional class III-IV, according to the New York Heart Association classification. All observations were made between 8:OO and 10:00 A.M. with the subjects supine and fasting. The patients had received no digitalis for four weeks prior to the study, and all other medication was curtailed for 48 hours before the study. All patients had a normal QRS (less than 100 msec.) and were in sinus rhythm at the time of the study. Cardiac output was determined by the indicator-dilution technic employing central injection of indocyanine dye and continuous sampling from a brachial artery. Stroke volume was calculated by dividing cardiac output by heart rate. Since the hemodynamic measurements and the systolic intervals can bc influenced by the laboratory procedure, 24 normal subjects (14 male, 10 female) were studied under the same conditions and their data compared with those of the patients. The average cardiac output for this group of normal subjects was 3.15 L./min./M.2 (SE. 0.09). and heart rate averaged 70 (S.E. 2.2). Statistical analysis was performed according to Snedecor by IBM 7094 and Wang 360 computers. RESULTS
The mean deviations in the systolic intervals from the normal regression data among the patients with functional
class
I-II
and
III-IV
heart
disease
are
2. In both groups a similar pattern of deviation in the systolic intervals was apparent. Total electromechanical systole (QS,) was not significantly altered, but the pre-ejection period (PEP) was lengthened and left ventricular ejection time (LVET) was abbreviated. The magnitude of the deviation in the PEP and LVET was significantly greater among the patients with functional class III-IV disease. The mean deviation in PEP averaged summarized
in
THE
Figure
AMERICAN
JOURNAL
OF CARDIOLOGY
Bedside +19
1nsec.
Evaluation
of Ventricular FUNCTIONAL
(p < 0.001) among patients in func-
tional class I-II and f44 msec. (p < 0.001) among patients in functional class III-IV. The deviations in LVET averaged -21 msec. (I < 0.002) among patients in functional class I and II and -39 msec. (p < 0.001) among patients in functional class III-IV. Among the patients in functional class I-II cardiac output averaged 2.71 L./min./M.* (SE. 0.18) and heart rate averaged 67 (S.E. 2.9); in the patients in functional class III-IV cardiac output averaged I .93 L./rnit~./M.~ (S.E. 0.10) and heart rate averaged 86 (S.E. 3.1). In normal subjects who underwent cardiac catheterization under identical laboratory conditions to those of the patients there was slight diminution in QS2 (- 9 msec., SE. 3.2), PEP (- 5 msec., SE. 2.6) and LVET (-4 msec., S.E. 2.0). The relation of the deviation in the pre-injection period (PEP) from the normal regression equation to the cardiac output and stroke volume among the patients with heart disease is summarized in Figure 3. Prolongation of the PEP was significantly correlated with the cardiac output (T = -0.72, p < 0.01) and the stroke volume (r = -0.80, p < 0.01). The greatest proiongation in PEP accompanied lowest cardiac output and stroke volume levels. Patients with functionally mild disease (class I-II) demonstrated least deviation from normal in both the PEP and the flow measurements. The relation of the deviation in the left uentricular ejection time (LVET) from the normal regression
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.
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.
CLASS I-n
FUNCTIONAL
bPEP
Figure 2. Systolic time intervals in heart disease. Mean deviations from normal in QS,, PEP and LVET in 11 patients with functional class I-II and 23 patients with functiona class III--IVheart disease (arteriosclerotic heart disease, hypertensive cardiovascular disease and primary myocardial disease). CI = cardiac index; HR = heart rate; SI = stroke index.
equation to the cardiac output and stroke volume among the patients is summarized in Figure 4. Abbreviation in LVET was significantly correlated with cardiac output (r = +0.62,p < 0.01) and stroke volume (I = +0.60, p < 0.01). The correlations were not as close as those for the PEP. The greatest shortening of LVET occurred
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Figure 3. The relation of the deviation in PEP from the normal regression equation to cardiac output (left) and stroke volume (right) among 34 patients with heart disease. VOLUME
23,
APRIL
1969
CLASS II[-Ip
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579
Function
Weissler
580
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Figure 4. The relation of the deviation in LVET from the normal regression equation to cardiac output (left) and stroke volume (right) among 34 patients with heart disease.
2 CARDlAC
1 CWPUT
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LIYIN/YZ
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Figure 5.
The relation of PEP/LVET to the cardiac output (left) and stroke volume (right) among 34 patients with heart disease. Bars represent 1 S.D. from the mean for the PEP/LVET and the flow measurements.
among the patients with lowest cardiac output and stroke volume. The patients with functionally mild disease (class I-II) demonstrated least deviation from normal in both the LVET and the flow measurements. Mean PEP/LVET Ratio: The pattern of the deviation from normal in the PEP and LVET in patients with heart disease suggested use of the ratio of the two intervals as a composite expression of these changes. This ratio affords the practical convenience that it varies within narrow limits without correction for heart rate or sex. The mean PEP/LVET for the 2 11 normal subjects studied in the basal state was 0.345 (S.D. 0.036). Among the 24 normal subjects who
underwent cardiac catheterization the PEP/’ LVET averaged 0.334 (SD. 0.046). Thus, the state of arousal associated with preparation for the hemodynamic measurements did not significantly alter the ratio. The relation of the uncorrected PEP/LVET to tile cardiac output and stroke volume among the patients with heart disease is illustrated in Figure 5. The PEP/LVET was closely correlated with cardiac output (r = -0.72, p < 0.01) and stroke volume (r = -0.82, p < 0.01). The patients with functionally mild disease (class I-II) demonstrated least deviation in PEP/LVET. Separation of the patients from the normal range of data was more clearly evident in the PEP/LVET THE
AMERICAN
JOURNAL
OF CARDIOLOGY
Bedside
Evaluation
than in the measurement of cardiac output and stroke volume. Only 1 subject in functional class I-II and none in functional class III-IV fell lvithin 1 S.D. of the normal mean value for PEP,‘LVET. DISCUSSION The duration of the systolic time intervals in man can be conveniently determined by noninvasive technics from simultaneous recordings of the electrocardiogram, phonocardiogram and carotid arterial pulsation. In normal subjects studied under basal conditions the systolic intervals vary inversely and linearly with heart rate. The normal regression equations relating heart rate and the systolic intervals, corrected for the slight differences between the sexes, provide a basis for the study of alterations induced by heart disease. In previous studies on undigitalized patients in sinus rhythm the presence of conspicuous heart failure was found to be associated with a characteristic pattern of deviation in the systolic intervals. This consisted of a prolongation of the pre-ejection period and an abbreviation of the left ventricular ejection time, while total electromechanical systole remained unaltered.lO These abnormalities occurred in the absence of a measurable abnorlnality in the duration of ventricular depolarization. The present observations demonstrate that the pattern of deviation in the systolic intervals can be identified among patients with functionally mild heart disease. The deviations in the pre-ejection period and the left ventricular ejection time were significantly correlated with the stroke volume and cardiac output. Thus, the systolic time intervals offer not only a useful index of the presence of a diminished cardiac output and stroke volume but a semiquantitative expression of the degree of impairment in the flow measures as well. Since the pre-ejection period (PEP) lengthens and the ejection time (LVET) shortens, but total electromechanical systole is unchanged, the ratio of the two intervals encompasses a single expression of the changes in heart failure. &4pplication of the PEP/LVET is facilitated by the observation that this ratio tends to remain within narrow limits among normal subjects even when uncorrected for heart rate and sex. In other words, the normal variation in LVET with heart rate and sex is minimized by inclusion of the PEP measurement in the ratio. The PEPXVET was found to be increased among VOLUME
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APRIL
1969
of Ventricular
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582
patients with heart disease. The magnitude of the deviations in the ratio permitted a clear separation of subjects with heart disease from the normal subjects. Since the PEP/LVET was found to be closely correlated with the cardiac output and stroke volume, it yields a simplified semiquantitative measure of the circulatory impairment in arteriosclerotic and hypertensive heart disease and in primary myocardial disease. Influence of Other Hemodynamic Factors: III applying the PEP/LVET to the detection of impaired cardiac performance it is 0: importance to recognize that hemodynamic influences other than heart failure may alter the ratio. Studies in this laboratory have demonstrated that an increase in the PEP/LVET occurs during the assumption of the upright posture and during peripheral pooling of blood with venous occlusive tourniquets.” The PEP/LVET is also increased with increases in peripheral resistance induced pharmacologically by angiotensin and methoxamine, with beta receptor blockade with propranolol(l0 mg. intravenously) and with norepinephrine infusion after beta receptor blockade. l2 The presence of sustained diastolic hypertension tends to increase the PEP and the PEP/LVET slightly in patients with heart failure.‘O However, among the patients with chronic arterial hypertension and minimal functional impairment (Class I-II) no independent effect of arterial pressure on the systolic intervals or the PEP/LVET could be demonstrated. Patients with aortic stenosis or aortic regurgitation in the absence of heart failure demonstrate an abbreviation in the pre-ejection period and a lengthening of the ejection period.7-g The changes in systolic intervals induced by heart failure may, therefore, be masked in aortic valvular disease. Prolongation of the pre-ejection period has been observed in patients with left bundle branch blocks and an increase in the PEP/LVET is observed among such patients in the absence of heart failure. Diminution in the PEP/LVET ratio can be induced by beta receptor stimulation with isoproterenol and after administration of the digitalis glycosides.12 It is apparent, therefore, that the PEP,/LVET must be interpreted relative to the hemod~namic setting. The finding of an increase m the PEP/LVET does not of itself constitute definite evidence for a failing left ventricle. In applying the measure of PEP/LVET to patients with heart disease it is most important to snake the observations with the patient srlpinc and as
Weissler
582
AORTIC PRESSURE
L
IPRESSURE
-NORMAL ---CHF Figure 6. Schematic refiresentation of the changes in the cardiac cycle responsible for the altered systolic intervals in heart disease. Normal aortic and ventricular pressure curves
compared to those in congestive heart failure (CHF). close to a basal state as is feasible. The contribution of digitalis therapy must also be recognized. Altered Systolic Intervals in Heart Failure and Ventricular Performance: In interpreting the mechanisms accounting for the prolongation of the PEP and the abbreviation of the LVET, and, hence, for the increase in PEP/LVET in heart failure, the effects of hemodynamic influences accompanying this circulatory state must be considered. It is pertinent that in normal persons pharmacologically induced increases in peripheral resistance to levels comparable to that in severe heart failure result in increases in the PEP/LVET which are small relative to those observed among patients with conspicuous heart failure. Similarly, beta receptor blockade with propranolol induces only slight increases in PEP/LVET in normal subjects. Thus, although such factors as elevated peripheral resistance and depletion of myocardial catecholamines might contribute to the increased PEP/LVET in heart failure, it would appear that primary alterations in ventricular performance play the dominant role. Previous studies have demonstrated that the maximal rate of isovolumic systolic pressure rise is reduced in patients with left heart failure.13 During laboratory-induced depression of myocardial function a similar decrease in the maximal rate of rise of left ventricular pressure has been observed.” Recent studies by Spann and associates16 on the length-tension and force-
et al. velocity relations in papillary muscles from the failing right ventricle of the cat have demonstrated a significant diminution in the intrinsic contractile performance of the myocardiurn, at a time when the duration of the active state of contraction remained unaltered. Present evidence, therefore, favors the hypothesis that a defect in the contractile performance of the ventricle is primarily responsible for the altered systolic intervals in heart failure. It would appear that at any level of end-diastolic volume, prolongation of the pre-ejection period in heart failure results from a deficient rate of myocardial force development early in systole. There is a consequent decrease in the rate of rise of intraventricular pressure throughout the preejection period. This results in a lengthening in the time required for intraventricular pressure to reach arterial diastolic pressure levels (Fig. 6). Since the duration of total electromechanical systole is unaltered, the lengthening of the preejection period results in abbreviation of the subsequent systolic ejection period, both events being associated with a diminished left ventricular stroke volume. SUMMARY Characteristic changes in the systolic intervals of the left ventricle have been demonstrated among patients with arteriosclerotic, hypertensive and primary myocardial disease. These consist of a prolongation of the pre-ejection period and an abbreviation in the ejection time, while total electromechanical systole remains unaltered. The changes in the pre-ejection period and the left ventricular ejection time correlate well with the level of cardiac output and stroke volume. The ratio of the pre-ejection period to the left ventricular ejection time (PEP/LVET) lends a convenient expression of these changes in the systolic intervals. The ease with which these measures can be obtained, using a noninvasive technic, suggests their use in the bedside evaluation of cardiac performance in man. REFERENCES 1. GARROD, A. H. On some points connected with circulation of the blood arrived at from a study of the ;;ylFgraph. Proc. Roy. Sot. London, 23: 140, 2. BOWEN, W. P. Changes in heart rate, blood pressure and duration of systole from bicycling. Am. J. Physiol., 11: 59, 1904. 3. LOMBARD, W. P. and COPE, 0. M. Duration of the systole of the left ventricle of man. Am. J. Physiol., 77: 263, 1926. THE
AMERICAN
JOURNAL
OF CARDIOLOGY
Bedside Evaluation of Ventricular 4. FRANK, 0.
On
the dynamics
of cardiac
muscle.
by CHAPMAN, C. B. and WASSERMAN, E. Am. Heart .J., 58: 282, 467, 1959. 5. WIGGERS, C. J. Studies on the consecutive phases of the cardiac cycle. IL The laws governing the relative duration of ventricular systole and diastole. Am. J. Physic& 56: 439, 1921. 6. KATZ, L. N. and FEIL, H. S. Clinical observations on the dynamics of ventricular systole: I. Auricular fibrillation. Arch. Znt. Med., 32: 672, 1923. 7. BLUMBERGER, K. Die Untersuchung der Dynamik des Herzens beim Menschen. Ergebn. inn. Med. u. Translated
Kinderhk., 62: 424, 1942. 8. JEZEK, V. Clinical value of the polygraphic
tracing in the study of the sequence of events during cardiac contraction. Cardiologia, 43: 298, 1963. 9. WEISSLER, A. M., PEELER, R. G. and ROEHLL, W. H. Relationships between left ventricular ejection time, stroke volume, and heart rate in normal individuals and patients with cardiovascular disease. Am. Heart J., 62: 367, 1961.
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10. WEISSLER, A. M., HARRIS, W. S. and SCHOENFELD, C. D. Systolic time intervalsin heart failure in man.
Circulation, 37, 149, 1968. 11. STAFFORD, R. W., HARRIS, W. S., WEISSLER, A. M. and WARREN, J. V. The systolic time intervals as indices of gravitational circulatory stress in man (Abstr.). Am. J. Cardiol., 19: 152, 1967. 12. HARRIS, W. S., SCHOENFELD, C. D. and WEISSLER, A. M. Personal observations. 13. GLEASON, W. L. and BRAUNWALD, E. Studies on the first derivative of the ventricular pressure pulse in man. J. Clin. Invest., 41: 80, 1962. 14. MASON, D. T. Usefulness and limitations of the rate of rise of intraventricular pressure (dp/dt) for the evaluation of myocardial contractility in man.
Am. J. Cardiol., 23: 516, 1969. 15. QPANN, .J. F., JR., BUCCINO, R. A., SONNENBLICK, E. H. and BRAUNWALD, E. Contractile state of cardiac muscle obtained from cats with experimentally produced ventricular hypertrophy and heart failure. Circulation Res., 21: 341, 1967.
End of Symposium
VOLUME 23, APRIL 1969
Function