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Relative insensitivity of isovolumic phase indices in the assessment of left ventricular function
Relative insensitivity of isovolumic phase indices in the assessment of left ventricular function S. Z. Naqvi, M.D., F.R.C.P.(C) A. W. Chisholm, M.D., F.R.C.P.(C) J. R. Standen, M.D., F.R.C.P.(C) S. J. Shane, M.D., F.R.C.P.(C) Toronto, Ontario, Canada
Several recent publications 1-~' '~' ~ have emphasized the value of derived isovolumic phase indices (contractility indices) in the measurement of ventricular performance. Since ventricular function curves ("pump-function" indices) have widely recognized limitations in the assessment of myocardial performance, it has generally been considered that the isovolumic phase indices are more sensitive than such curves in the distinction between normal and impaired myocardial function. In an attempt to test this thesis, we compared indices derived from high-fidelity left ventricular pressure recordings and left ventricular cineangiograms, with left ventricular function curves. The latter were constructed from measurements of left ventricular end-diastolic pressure (LVEDP) and stroke work index (SWI) obtained both at rest and after isometric handgrip exercise. Methods and materials
In this study, 20 patients underwent full-dress right and left heart catheterization, with intramuscular diazepam 5 mg. as premedication. Retrograde left heart catheterization was performed by the Seldinger technique. Left ventricFrom the Division of Cardiology, the Department of Radiology, and the Cardiovascular Investigation Unit, Sunnybrook Hospital, Toronto, Ontario, Canada. Financial assistance was rendered to this project by the Ontario Heart Foundation, Grant No. 3-242-276-33, and Sunnybrook Hospital Research Foundation, Grant No. 73-21. Received for publication April 16, 1975. Reprint requests: Dr. S. J. Shane, Cardiovascular Unit, Sunnybrook Hospital, 2075 Bayview Ave., Toronto, Ontario, Canada M4N 1A9.
May, 1976, Vol. 91, No. 5, pp. 577-583
ular pressures were recorded by a S t a t h a m SF 1 catheter, standardized against signals from a Statham P 23 Db Pressure Transducer connected to the fluid-filled lumen of the same SF 1 catheter. Simultaneous left brachial artery pressures were recorded using a short No. 5 Fr. Teflon catheter. The first derivative of the left ventricular pressure (dp/dt) was recorded by a Resistance/Capacitance differentiating circuit (Electronics for Medicine, White Plains, N. Y.) with a corner frequency of 160 Hz. All pressures were recorded at a paper speed of 200 mm. per second. Cardiac output was determined by the dye-dilution technique, injecting 5 mg. of indocyanine green into the pulmonary artery, and sampling from the left brachial artery catheter. The patients then did 3 minutes of isometric handgrip exercise, using a J a m a r Hand Dynamometer PC 5033) at one third maximum voluntary effort,4 being at the same time discouraged from performing a simultaneous Valsalva maneuver. Pressure recordings and cardiac output determinations were repeated at the end of 3 minutes. The SF 1 catheter was then replaced by a No. 8 Ducor-Cordis pigtail catheter and a left ventriculogram was performed in the RAO projection at 60 frames per second. Renografin 76 (18 ml.) was injected during the diastolic filling period for three consecutive cycles, with a Viamonte-Hobbs Model 2000 Pressure Injector. The QRS complex of the electrocardiogram (ECG) was used to trigger the pressure injector. The ejection fraction (EF) was calculated from the uniplane ventriculogram by the method of Green and associates2 Only the first three beats were used in this calculation, since Carleton ~ had
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Vmax at rest
Vmax c exercise
EF% at rest
120 100 -
80-
60-
O
2-
9
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O
$
$
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Fig.
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m
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1. Ejection fractions, Groups I and II.
shown changes in the left ventricular volume after the second cardiac cycle following opacification. The presence of akinetic segments was taken into account and corrections were made for the EF by the method of Kitamura and associatesY Percentage shortening of t h e minor axis was calculated as the change from diastole to systole in those patients free of localized abnormalities of left ventricular function. Peak d p /d t was calculated by multiplying the height of the curve obtained through the R.C. circuit by the constant (K) of t h a t particular SGM pressure channel and the SF1 transducer. Velocity of contractile element (VCe) was calculated from the expression d p / d t / 3 2 P during the period of isovolumic contraction at 5 msec. intervals. VCe was then plotted against simultaneous left ventricular pressure and the descending limb extrapolated to obtain Vmax in muscle lengths per second (M.L./sec.) at zero load. VCe and peak d p / d t (Vpm) were calculated using a constant K of 32 at rest and, in 15 patients, under the stress of 3 minutes of isometric handgrip exercise. P a t i e n t g r o u p s . Of the 20 patients studied, four were found to b e normal as judged by resting
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20
LVEDP, EF, Vmax, left ventricular function curves, and the left ventriculogram. These were placed in Group I. Group II consisted of two patients with elevated resting LVEDP. One of these had a normal Vmax at rest, as well as a normal VCe, peak dp/dt, and EF, but responded to exercise by an 8 mm. Hg rise in LVEDP, thus increasing the stroke volume index and the stroke work index. The left ventriculogram showed left ventricular hypertrophy. T he second patient in this group had a n elevated L V E D P, low normal EF and VCe at peak dp/dt, and a decreased Vmax. His response to exercise was a decrease in the stroke volume index, despite a 7 mm. Hg rise in LVEDP. The left ventriculogram showed generalized hypokinesia. These two patients had normal coronary arteries and a diagnosis of cardiomyopathy was made. Group III consisted of 14 patients with proved coronary artery disease. Results Ejection f r a c t i o n
(EF). Of these 20 patients, the
left ventriculogram was of unsatisfactory quality for the determination of EF because of runs of VPB's in only two.
May, 1976, Vol. 91, No. 5
Isovolumic phase indices in L V function
0 NORMAL
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9 CAD ~, CARDIOMYOPATHY 60
1.5
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1.0 o
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.5
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~
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|
9
I
-5
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Fig. 2. Per cent minor axis shortening.
P a t i e n t s in G r o u p s I a n d I I h a d n o r m a l ejection fractions {Fig. 1). Only five of the 14 p a t i e n t s w i t h coronary a r t e r y disease h a d decreased E F ' s . T h e r e was also considerable overlap b e t w e e n t h e groups and the difference b e t w e e n the m e a n s was not statistically significant. Only three of the p a t i e n t s with c o r o n a r y a r t e r y disease showed less t h a n 30 per cent s h o r t e n i n g of the m i n o r axis. T h e r e was considerable o v e r l a p between the values of G r o u p s I, II, a n d I I I (Fig. 2). V m a x a t r e s t . W h e n c o m p a r e d to the n o r m a l value of 1.85 _+ 0.26 M.L./sec., all p a t i e n t s in G r o u p I and one of t h e two p a t i e n t s in G r o u p I I h a d n o r m a l values at rest. Only four of t h e p a t i e n t s in G r o u p I I I had decreased values at rest. T h e r e was considerable overlap b e t w e e n the n o r m a l subjects a n d the p a t i e n t s with c o r o n a r y a r t e r y disease, w i t h no statistically significant difference in the mean values (Fig. 1). V m a x w i t h e x e r c i s e . In 16 patients, V m a x was obtained following isometric h a n d g r i p exercise. I n three patients, c a t h e t e r m o v e m e n t a r t i f a c t , resulting f r o m t a c h y c a r d i a , p r e v e n t e d a c c u r a t e analysis of isovolumic c o n t r a c t i o n . I n one patient, the resting L V E D P was very high, a n d t h e response to exercise was n o t studied. All patients in the n o r m a l group showed an increase in V m a x with no m o r e t h a n a 4 m m . increase in L V E D P . One of the p a t i e n t s in t h e c a r d i o m y o p a t h y group was able to increase t h e V m a x by 0.5 muscle lengths (M.L./sec.) with t h e assistance of an 8 m m . increase in L V E D P . T h e second patient in this group showed an increase in
American Heart Journal
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MYOPATHY
Fig. 3. V m a x E-R.
0 NORMAL
1.1
9 CAD CARDIO MYOPATHY 1.0
0.9
0.8
s, ~S~
~.0
0.7
0.6
./\.
(max. dp/dt/32.P) (0.743 + .056) (0.687- .819)
0.5
0.4
R;ST
EXERCISE
Fig. 4. VCe at peak dp/dt.
V m a x by 0.15 M.L./sec., following a 7 m m . increase in L V E D P . P a t i e n t s in G r o u p I I I d e m o n s t r a t e d differing responses to exercise, e.g., an inability to increase V m a x despite i n o r d i n a t e rises in L V E D P . One patient had a small increase in V m a x , despite a 1 m m . fall in resting L V E D P . T h e o t h e r p a t i e n t s in this group who were able to increase their Vmax, however, did so with the assistance of an
579
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1.1
\
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9 CAD 0 NORMAL
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CAROIOMYOPATHu
1800
9 CAD CARDIOMYOPATHY
0.9 1600
0.8
u=J 0.7
0.6
2 /4
1400
\
1200
0.5
0.4
I 20
I 30
LVEDP
l 40
I000
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Fig. 5. LVEDP plotted against VCe at peak dp/dt. 800
increase in LVEDP greater than 4 mm. Hg {average, 9.6 mm.). Although some overlap occurred between the various groups in the mean values of Vmax with exercise, there was a significant difference in the values for Vmax with exercise minus rest. This aided in separating patients with coronary disease from normal subjects (Fig. 3). V C e at peak dp/dt. Only five patients with Coronary artery disease had a clearly abnormal VCe at peak dp/dt. Two of these were able to produce minimal increases in this parameter with isometric handgrip exercise, one of them showing 9a very good response. All the remaining patients with coronary artery disease had a fall in the stress-induced VCe when compared with their resting values. The same was true for the two patients with primary myocardial disease {Fig. 4). Left ventricular function curves were constructed with VCe at peak d p / d t plotted against L V E D P and the separation among the three groups became still more striking (Fig. 5).
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Fig. 6. Peak dp/dt resting.
Peak dp/dt. As seen in Fig. 6, peak d p / d t itself is not a very sensitive index for the separation of normal subjects from patients with cardiomyopathy and coronary artery disease. The construction of left ventricular function curves by plotting peak d p / d t against LVEDP did not make this index any more sensitive than when viewed alone (Fig. 7). Left v e n t r i c u l a r f u n c t i o n c u r v e s . Separation was possible among the three groups by the construction of left ventricular function curves {Fig. 8). The sole exception was one patient in the normal group in whom catheter entrapment occurred following exercise, causing the exercise LVEDP to be spuriously elevated. This patient increased his Vmax from 2.5 to 4.3 M.L./sec. and had a resting LVEDP of 12 mm. Hg with an ejection fraction of 76 per cent.
May, 1976, Vol. 91, No. 5
Isovolumic phase indices in L V function
o
3000
sviQ
o
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2500
2000
,fi~
9
fi
i..
1500
;I 1000 -
500 -
///r 50
I 10
L 20 LVEDP
l 30 (ram
I 40
Hg)
Fig. 7, L V E D P plotted against peak d p / d t .
Discussion M a n y excellent papers h a v e been published in recent years, p u r p o r t i n g to differentiate reduced h e m o d y n a m i c p e r f o r m a n c e as a result of m e c h a n ical lesions from t h a t due to depressed m y o c a r d i a l function.2 3.9. 19. . . . ~ While these h a v e u n d o u b t edly added to our u n d e r s t a n d i n g of this subject, they h a v e raised m a n y f u n d a m e n t a l questions. I t seems t h a t m a n y o t h e r factors h a v e to be t a k e n into a c c o u n t when concepts of m u s c l e m e c h a n i c s are used to assess c o n t r a c t i l i t y in the i n t a c t heart, TM and some of our present a s s u m p t i o n s a p p e a r to be unjustified or unproved. T h i s applies to the values for K a n d c in t h e f o r m u l a for VCe. Similarly, d o u b t has been raised concerning the original conclusion t h a t V m a x is i n d e p e n d e n t of fiber length./7 Moreover, v a r i a t i o n s in h e a r t r a t e alter p e r f o r m a n c e per stroke a n d the inotropic state directly via force-frequency relations2 ~ Further, alterations in aortic pressure alone can greatly influence left v e n t r i c u l a r p e r f o r m a n c e . T h e value of isovolumic phase indices was initially believed to reside in t h e fact t h a t t h e y were relatively uninfluenced b y a l t e r a t i o n s in
American Heart Journal
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:::::::::::::::::::::: CORONARYDISEASE
i!~ili!i!i!iiCARDIOMYOPATHY Fig. 8, Distribution of LV function curves in three groups of patients. Figures in open circles denote n u m b e r of paLients m each group.
preload and afterload, b u t were sensitive to alterations in the inotropic state. In our experience, peak d p / d t was not sufficiently sensitive in separating n o r m a l subjects f r o m p a t i e n t s w i t h coronary a r t e r y disease or c a r d i o m y o p a t h y (Fig. 6). Ross a n d associates 11 h a d previously s h o w n t h a t d p / d t was m o r e sensitive to changes in inotropic s t a t e t h a n d p / d t / 4 0 , or peak d p / d t / developed pressure. In an a t t e m p t to n a r r o w t h e "gray" zone where overlap was n o t e d in the values of p e a k d p / d t , we i n t r o d u c e d the stress resulting f r o m isometric h a n d g r i p exercise. As seen in Fig. 7, left v e n t r i c u l a r f u n c t i o n curves were constructed. T w o p a t i e n t s with coronary a r t e r y disease increased their p e a k d p / dt with only m i n i m a l changes in L V E D P , overlapping the response shown b y n o r m a l subjects. All the o t h e r patients with c o r o n a r y a r t e r y disease and the two p a t i e n t s with c a r d i o m y o p a t h y were able to increase their p e a k d p / d t only by very significant increases in L V E D P . T h e technique of plotting VCe against L V E D P (Fig. 5} is m u c h more helpful in s e p a r a t i n g the three groups of patients. T h e a b n o r m a l respond-
581
Naqvi et al.
ers showed either a m i n i m a l increase in VCe with significant increase in L V E D P , or an a c t u a l decrease following isometric h a n d g r i p e x e r c i s e - a finding previously r e p o r t e d by K r a y e n b u h l a n d associates. 2~ T h a t worker suggested t h a t this finding m a y be the result of the absence of i m m e d i a t e changes in c o n t r a c t i l i t y in p a t i e n t s with c o r o n a r y a r t e r y disease. Falsetti a n d associates 3 h a d previously r e p o r t e d an a b s e n c e of significant correlation b e t w e e n VCe a t p e a k stress and the clinical state. In o u r hands, resting values were not helpful in the distinction b e t w e e n n o r m a l subjects a n d p a t i e n t s with c o r o n a r y a r t e r y disease or c a r d i o m y o p a t h i e s : however, the difference between exercise minus resting Vmax was of discriminative value. Peterson a n d associates 1~ had found t h a t V m a x c a l c u l a t e d from total pressure was quite sensitive in s e p a r a t i n g n o r m a l from a b n o r m a l subjects, a l t h o u g h he too noted an overlap w h e n the individual cases were compared. Falsetti a n d associates 3 f o u n d V m a x to be a sensitive and consistent indicator of m y o c a r dial performance. In our experience, ejection fraction has n o t been sufficiently sensitive to s e p a r a t e n o r m a l from a b n o r m a l subjects (Fig. 1). I t h a s been reported t h a t the ejection fraction m a y r e m a i n n o r m a l while the m e a n Vcf is diminished in m i t r a l regurgitation. ~1 Earlier studies h a d i n d i c a t e d t h a t velocity of wall m o t i o n provides a sensitive index of m y o c a r d i a l c o n t r a c t i l i t y in the presence of aortic valve disease. Peterson and associates2 ~ using e l e c t r o m a g netic probes, found t h a t peak velocity of shortening provided the best index for the identification of depressed m y o c a r d i a l function. In our hands there was considerable overlap in p e r c e n t age of m i n o r axis shortening b e t w e e n v a r i o u s groups of patients, and this has also been the experience of K a r l i n e r and associates. 2-~ Benzing and associates ~ h a v e r e c e n t l y shown t h a t c o n t r o l of preload a n d afterload is an indispensable prerequisite in the assessment of the ability of velocity of fiber s h o r t e n i n g (Vcf) to reflect changes in the contractile s t a t e of t h e left ventricle. As seen in Fig. 8, left v e n t r i c u l a r f u n c t i o n curves were a d e q u a t e for the s e p a r a t i o n of n o r m a l subjects f r o m p a t i e n t s with c a r d i o m y o p a t h y and c o r o n a r y a r t e r y disease, an experience shared by S w a n 4 a n d b y Gorlin and associates. ~ I t m u s t be r e m e m b e r e d , however, t h a t t h e y do
582
n o t provide a m e a s u r e of the inotropic s t a t e of the m y o c a r d i u m , a n d t h a t t h e y are influenced by resting fiber length (preload) a n d by a l t e r a t i o n in wall forces during ejection (afterload). T h e relative independence of b o t h t o t a l a n d t o t a l - p r e s s u r e isovolumic indices from t h e effect of a c u t e changes in preload remain s o m e w h a t c o n t r o v e r sial. T h e experience of Peterson and associates TM is similar to ours in t h a t we b o t h h a v e f o u n d isovolumic phase c o n t r a c t i o n indices to be u n r e liable for c o m p a r i n g p a t i e n t s w i t h n o r m a l h e a r t s from those with m y o c a r d i a l disease. S o m e observers consider t h a t the overlap seen in these isovolumic indices m a y be r e l a t e d in p a r t to as y e t u n s u p p o r t e d a s s u m p t i o n s concerning h e a r t size and series elasticity. S o m e of t h e o t h e r p r o b l e m s at present disregarded in t h e d e t e r m i n a t i o n of contractility h a v e been elegantly s u m m a r i z e d b y Noble. 1~ and m u c h f u r t h e r w o r k needs to be done.
Summary 1. T h e a u t h o r s c o m p a r e d t h e sensitivity of t h e isovolumic phase indices (contractility indices) against LV function curves ( " p u m p - f u n c t i o n " indices) in assessing v e n t r i c u l a r p e r f o r m a n c e . 2. Certain modifications of the usual isovolumic phase indices, especially those i n t r o d u c i n g t h e concept of c o m p a r i s o n of exercise with rest, seemed to us to be slightly m o r e helpful in separating n o r m a l subjects f r o m the p a t i e n t s with coronary a r t e r y disease or c a r d i o m y o p a thies, but these differences were n o t striking w h e n statistically evaluated, and could not be utilized in the assessment of left v e n t r i c u l a r function in individual patients. 3. T h e construction of left v e n t r i c u l a r function curves, in our hands, yielded equally as satisfactory information and, in addition, was m u c h simpler to perform. 4. It is concluded t h a t c o n t r a c t i l i t y indices are relatively insensitive in the a s s e s s m e n t of left ventricular function, and t h a t they offer little a d v a n t a g e over " p u m p - f u n c t i o n " indices for this purpose.
REFERENCES 1. Mason, D. T., Spann, J. F., Jr., and Zelis, R.: Quantification of the contractile state of the intact human heart, Am. J. Cardiol. 26:248, 1970. 2. Mason, D. T., Spann, J. F., Jr., Zelis R., et al.: Comparison of the cardiac contractile state in patients with
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Isovolumic phase indices in L V function
3. 4. 5. 6. 7. 8. 9.
i0. 11. 12.
idiopathi c myocardial disease and in ventricular hypertrophy 2 ~ to prolonged systolic pressure overloading (abst.), J. Clin. Invest. 4:61a, 1970. Falsetti, H. L., Mates, R. E., Green, D. G., et al.: Vmax as an index of contractile state in man, Circulation 43:467, 1971. Kovowitz, C., et al.: Effects of isometric exercise on cardiac performance, Circulation 44:944, 1971. Green, D; G., et aI.: Estimation of left ventrieular volume by one-plan e cineangiograms, Circulation 25:61, 1967. Carleton, R. A.: Changes in left ventricular volume during angiography, Am. J. Cardiol. 27:460, 1971. Kitamura, S., et al.: Geometric and functional abnormalities of the left ventricle with a chronic localized noncontractile area, Am. J. Cardiol. 31:701, 1973. Katz, L. N., editor: Symposium on t h e regulation of the performance of the heart, Physiol. Rev. 35:90, 1955. Zelis, R., Amsterdam, E. A., and Mason, D. T.: Isometric Vmax as an index of contractility independent of series elastic and fibre shortening. Implication concerning pressure-volume data in myocardial fibrosis, valvular regurgitation, ventricular aneurysm and ventricular septal defect, Circulation 2[Suppl: 2]:89, 1971. Mirsky, I., et al.: General index of assessment of cardiac function, Am. J. Cardiol. 30:483, 1973. Ross, R. S., et al.: Effect of pacing-induced tachycardia and myocardial ischaemia on Ventricular pressurevelocity relationship in man, Circulation 44:74, 1972. Rackley, C. E., et al.: Regional left ventricular performance in the year following myocardial infarction, Circulation 44:679, 1972.
American Heart Journal
13. Gorlin, R., et al.: Effect of angiographic material on left ventricular function in man, Am. J. Cardiol. 32:21, 1973. 14. Peterson, K. L., et al.: Comparison of isovolumic and ejection phase indices of myocardial performance in man, Circulation 44:1088, 1974. 15. Eckberg, D. L., et al.i Mechanics of left ventricular contraction in chronic severe mitral regurgitation, Circulation 47:1252, 1973. 16. Noble, M. I. M.: Problems concerning the applications of mechanics to the determination of contractile state in man, Circulation 45:252, 1972. 17. Pollock, G. H.i Maximum velocity as an index of contractility in cardiac muscle. A critical evaluation, Circ. Res. 26:111, 1970. 18. Cove[l, J. W., et at.: The effect of increasing frequency of contraction on the force-velocity relation in the left ventricle, Cardiovasc. Res. 1:2, 1967. 19. Ross, J., Jr., and Sobel, B. E.i Regulation of cardiac contraction, Ann. Rev. Physiol. 34:47, 1972. 20. Krayenbuhl, H. P., et aL: Evaluation of L. V. function from isov01umic pressure measurements during isometric exercise, Am. J. Cardiol. 29:323, 1972~ 21. Gault, J. H., Covell, J. W:; et al.: L. V: performance following correction of free aortic regurgitation, Circulation 42:773, 1970. 22. Karliner, J. S,, Gault, J. H., et al.: Mean velocity of fibre shortening, Circulation 44:323, 1971. 23. Benzing, G., III, et al.: Evaluation of left ventricular performance, Circulation 49:925~ 1974.
583
Several recent publications 1-~' '~' ~ have emphasized the value of derived isovolumic phase indices (contractility indices) in the measurement of ventricular performance. Since ventricular function curves ("pump-function" indices) have widely recognized limitations in the assessment of myocardial performance, it has generally been considered that the isovolumic phase indices are more sensitive than such curves in the distinction between normal and impaired myocardial function. In an attempt to test this thesis, we compared indices derived from high-fidelity left ventricular pressure recordings and left ventricular cineangiograms, with left ventricular function curves. The latter were constructed from measurements of left ventricular end-diastolic pressure (LVEDP) and stroke work index (SWI) obtained both at rest and after isometric handgrip exercise. Methods and materials
In this study, 20 patients underwent full-dress right and left heart catheterization, with intramuscular diazepam 5 mg. as premedication. Retrograde left heart catheterization was performed by the Seldinger technique. Left ventricFrom the Division of Cardiology, the Department of Radiology, and the Cardiovascular Investigation Unit, Sunnybrook Hospital, Toronto, Ontario, Canada. Financial assistance was rendered to this project by the Ontario Heart Foundation, Grant No. 3-242-276-33, and Sunnybrook Hospital Research Foundation, Grant No. 73-21. Received for publication April 16, 1975. Reprint requests: Dr. S. J. Shane, Cardiovascular Unit, Sunnybrook Hospital, 2075 Bayview Ave., Toronto, Ontario, Canada M4N 1A9.
May, 1976, Vol. 91, No. 5, pp. 577-583
ular pressures were recorded by a S t a t h a m SF 1 catheter, standardized against signals from a Statham P 23 Db Pressure Transducer connected to the fluid-filled lumen of the same SF 1 catheter. Simultaneous left brachial artery pressures were recorded using a short No. 5 Fr. Teflon catheter. The first derivative of the left ventricular pressure (dp/dt) was recorded by a Resistance/Capacitance differentiating circuit (Electronics for Medicine, White Plains, N. Y.) with a corner frequency of 160 Hz. All pressures were recorded at a paper speed of 200 mm. per second. Cardiac output was determined by the dye-dilution technique, injecting 5 mg. of indocyanine green into the pulmonary artery, and sampling from the left brachial artery catheter. The patients then did 3 minutes of isometric handgrip exercise, using a J a m a r Hand Dynamometer PC 5033) at one third maximum voluntary effort,4 being at the same time discouraged from performing a simultaneous Valsalva maneuver. Pressure recordings and cardiac output determinations were repeated at the end of 3 minutes. The SF 1 catheter was then replaced by a No. 8 Ducor-Cordis pigtail catheter and a left ventriculogram was performed in the RAO projection at 60 frames per second. Renografin 76 (18 ml.) was injected during the diastolic filling period for three consecutive cycles, with a Viamonte-Hobbs Model 2000 Pressure Injector. The QRS complex of the electrocardiogram (ECG) was used to trigger the pressure injector. The ejection fraction (EF) was calculated from the uniplane ventriculogram by the method of Green and associates2 Only the first three beats were used in this calculation, since Carleton ~ had
American Heart Journal
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N a q v i et al.
Vmax at rest
Vmax c exercise
EF% at rest
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m
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MYOPATHY
1. Ejection fractions, Groups I and II.
shown changes in the left ventricular volume after the second cardiac cycle following opacification. The presence of akinetic segments was taken into account and corrections were made for the EF by the method of Kitamura and associatesY Percentage shortening of t h e minor axis was calculated as the change from diastole to systole in those patients free of localized abnormalities of left ventricular function. Peak d p /d t was calculated by multiplying the height of the curve obtained through the R.C. circuit by the constant (K) of t h a t particular SGM pressure channel and the SF1 transducer. Velocity of contractile element (VCe) was calculated from the expression d p / d t / 3 2 P during the period of isovolumic contraction at 5 msec. intervals. VCe was then plotted against simultaneous left ventricular pressure and the descending limb extrapolated to obtain Vmax in muscle lengths per second (M.L./sec.) at zero load. VCe and peak d p / d t (Vpm) were calculated using a constant K of 32 at rest and, in 15 patients, under the stress of 3 minutes of isometric handgrip exercise. P a t i e n t g r o u p s . Of the 20 patients studied, four were found to b e normal as judged by resting
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20
LVEDP, EF, Vmax, left ventricular function curves, and the left ventriculogram. These were placed in Group I. Group II consisted of two patients with elevated resting LVEDP. One of these had a normal Vmax at rest, as well as a normal VCe, peak dp/dt, and EF, but responded to exercise by an 8 mm. Hg rise in LVEDP, thus increasing the stroke volume index and the stroke work index. The left ventriculogram showed left ventricular hypertrophy. T he second patient in this group had a n elevated L V E D P, low normal EF and VCe at peak dp/dt, and a decreased Vmax. His response to exercise was a decrease in the stroke volume index, despite a 7 mm. Hg rise in LVEDP. The left ventriculogram showed generalized hypokinesia. These two patients had normal coronary arteries and a diagnosis of cardiomyopathy was made. Group III consisted of 14 patients with proved coronary artery disease. Results Ejection f r a c t i o n
(EF). Of these 20 patients, the
left ventriculogram was of unsatisfactory quality for the determination of EF because of runs of VPB's in only two.
May, 1976, Vol. 91, No. 5
Isovolumic phase indices in L V function
0 NORMAL
70
2.0
9 CAD ~, CARDIOMYOPATHY 60
1.5
50
1.0 o
9 40
30
.5
t
9
~
o
9
|
9
I
-5
20
NORMAL
Fig. 2. Per cent minor axis shortening.
P a t i e n t s in G r o u p s I a n d I I h a d n o r m a l ejection fractions {Fig. 1). Only five of the 14 p a t i e n t s w i t h coronary a r t e r y disease h a d decreased E F ' s . T h e r e was also considerable overlap b e t w e e n t h e groups and the difference b e t w e e n the m e a n s was not statistically significant. Only three of the p a t i e n t s with c o r o n a r y a r t e r y disease showed less t h a n 30 per cent s h o r t e n i n g of the m i n o r axis. T h e r e was considerable o v e r l a p between the values of G r o u p s I, II, a n d I I I (Fig. 2). V m a x a t r e s t . W h e n c o m p a r e d to the n o r m a l value of 1.85 _+ 0.26 M.L./sec., all p a t i e n t s in G r o u p I and one of t h e two p a t i e n t s in G r o u p I I h a d n o r m a l values at rest. Only four of t h e p a t i e n t s in G r o u p I I I had decreased values at rest. T h e r e was considerable overlap b e t w e e n the n o r m a l subjects a n d the p a t i e n t s with c o r o n a r y a r t e r y disease, w i t h no statistically significant difference in the mean values (Fig. 1). V m a x w i t h e x e r c i s e . In 16 patients, V m a x was obtained following isometric h a n d g r i p exercise. I n three patients, c a t h e t e r m o v e m e n t a r t i f a c t , resulting f r o m t a c h y c a r d i a , p r e v e n t e d a c c u r a t e analysis of isovolumic c o n t r a c t i o n . I n one patient, the resting L V E D P was very high, a n d t h e response to exercise was n o t studied. All patients in the n o r m a l group showed an increase in V m a x with no m o r e t h a n a 4 m m . increase in L V E D P . One of the p a t i e n t s in t h e c a r d i o m y o p a t h y group was able to increase t h e V m a x by 0.5 muscle lengths (M.L./sec.) with t h e assistance of an 8 m m . increase in L V E D P . T h e second patient in this group showed an increase in
American Heart Journal
CAD
MYOPATHY
Fig. 3. V m a x E-R.
0 NORMAL
1.1
9 CAD CARDIO MYOPATHY 1.0
0.9
0.8
s, ~S~
~.0
0.7
0.6
./\.
(max. dp/dt/32.P) (0.743 + .056) (0.687- .819)
0.5
0.4
R;ST
EXERCISE
Fig. 4. VCe at peak dp/dt.
V m a x by 0.15 M.L./sec., following a 7 m m . increase in L V E D P . P a t i e n t s in G r o u p I I I d e m o n s t r a t e d differing responses to exercise, e.g., an inability to increase V m a x despite i n o r d i n a t e rises in L V E D P . One patient had a small increase in V m a x , despite a 1 m m . fall in resting L V E D P . T h e o t h e r p a t i e n t s in this group who were able to increase their Vmax, however, did so with the assistance of an
579
N a q v i et al.
1.1
\
NORMAL
NORMAL
9 CAD 0 NORMAL
1.0
CAROIOMYOPATHu
1800
9 CAD CARDIOMYOPATHY
0.9 1600
0.8
u=J 0.7
0.6
2 /4
1400
\
1200
0.5
0.4
I 20
I 30
LVEDP
l 40
I000
(mm Hg)
Fig. 5. LVEDP plotted against VCe at peak dp/dt. 800
increase in LVEDP greater than 4 mm. Hg {average, 9.6 mm.). Although some overlap occurred between the various groups in the mean values of Vmax with exercise, there was a significant difference in the values for Vmax with exercise minus rest. This aided in separating patients with coronary disease from normal subjects (Fig. 3). V C e at peak dp/dt. Only five patients with Coronary artery disease had a clearly abnormal VCe at peak dp/dt. Two of these were able to produce minimal increases in this parameter with isometric handgrip exercise, one of them showing 9a very good response. All the remaining patients with coronary artery disease had a fall in the stress-induced VCe when compared with their resting values. The same was true for the two patients with primary myocardial disease {Fig. 4). Left ventricular function curves were constructed with VCe at peak d p / d t plotted against L V E D P and the separation among the three groups became still more striking (Fig. 5).
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Fig. 6. Peak dp/dt resting.
Peak dp/dt. As seen in Fig. 6, peak d p / d t itself is not a very sensitive index for the separation of normal subjects from patients with cardiomyopathy and coronary artery disease. The construction of left ventricular function curves by plotting peak d p / d t against LVEDP did not make this index any more sensitive than when viewed alone (Fig. 7). Left v e n t r i c u l a r f u n c t i o n c u r v e s . Separation was possible among the three groups by the construction of left ventricular function curves {Fig. 8). The sole exception was one patient in the normal group in whom catheter entrapment occurred following exercise, causing the exercise LVEDP to be spuriously elevated. This patient increased his Vmax from 2.5 to 4.3 M.L./sec. and had a resting LVEDP of 12 mm. Hg with an ejection fraction of 76 per cent.
May, 1976, Vol. 91, No. 5
Isovolumic phase indices in L V function
o
3000
sviQ
o
NORMAL
9
CAD
:'
CARDIOMYOPATHY
2500
2000
,fi~
9
fi
i..
1500
;I 1000 -
500 -
///r 50
I 10
L 20 LVEDP
l 30 (ram
I 40
Hg)
Fig. 7, L V E D P plotted against peak d p / d t .
Discussion M a n y excellent papers h a v e been published in recent years, p u r p o r t i n g to differentiate reduced h e m o d y n a m i c p e r f o r m a n c e as a result of m e c h a n ical lesions from t h a t due to depressed m y o c a r d i a l function.2 3.9. 19. . . . ~ While these h a v e u n d o u b t edly added to our u n d e r s t a n d i n g of this subject, they h a v e raised m a n y f u n d a m e n t a l questions. I t seems t h a t m a n y o t h e r factors h a v e to be t a k e n into a c c o u n t when concepts of m u s c l e m e c h a n i c s are used to assess c o n t r a c t i l i t y in the i n t a c t heart, TM and some of our present a s s u m p t i o n s a p p e a r to be unjustified or unproved. T h i s applies to the values for K a n d c in t h e f o r m u l a for VCe. Similarly, d o u b t has been raised concerning the original conclusion t h a t V m a x is i n d e p e n d e n t of fiber length./7 Moreover, v a r i a t i o n s in h e a r t r a t e alter p e r f o r m a n c e per stroke a n d the inotropic state directly via force-frequency relations2 ~ Further, alterations in aortic pressure alone can greatly influence left v e n t r i c u l a r p e r f o r m a n c e . T h e value of isovolumic phase indices was initially believed to reside in t h e fact t h a t t h e y were relatively uninfluenced b y a l t e r a t i o n s in
American Heart Journal
NORMAL
:::::::::::::::::::::: CORONARYDISEASE
i!~ili!i!i!iiCARDIOMYOPATHY Fig. 8, Distribution of LV function curves in three groups of patients. Figures in open circles denote n u m b e r of paLients m each group.
preload and afterload, b u t were sensitive to alterations in the inotropic state. In our experience, peak d p / d t was not sufficiently sensitive in separating n o r m a l subjects f r o m p a t i e n t s w i t h coronary a r t e r y disease or c a r d i o m y o p a t h y (Fig. 6). Ross a n d associates 11 h a d previously s h o w n t h a t d p / d t was m o r e sensitive to changes in inotropic s t a t e t h a n d p / d t / 4 0 , or peak d p / d t / developed pressure. In an a t t e m p t to n a r r o w t h e "gray" zone where overlap was n o t e d in the values of p e a k d p / d t , we i n t r o d u c e d the stress resulting f r o m isometric h a n d g r i p exercise. As seen in Fig. 7, left v e n t r i c u l a r f u n c t i o n curves were constructed. T w o p a t i e n t s with coronary a r t e r y disease increased their p e a k d p / dt with only m i n i m a l changes in L V E D P , overlapping the response shown b y n o r m a l subjects. All the o t h e r patients with c o r o n a r y a r t e r y disease and the two p a t i e n t s with c a r d i o m y o p a t h y were able to increase their p e a k d p / d t only by very significant increases in L V E D P . T h e technique of plotting VCe against L V E D P (Fig. 5} is m u c h more helpful in s e p a r a t i n g the three groups of patients. T h e a b n o r m a l respond-
581
Naqvi et al.
ers showed either a m i n i m a l increase in VCe with significant increase in L V E D P , or an a c t u a l decrease following isometric h a n d g r i p e x e r c i s e - a finding previously r e p o r t e d by K r a y e n b u h l a n d associates. 2~ T h a t worker suggested t h a t this finding m a y be the result of the absence of i m m e d i a t e changes in c o n t r a c t i l i t y in p a t i e n t s with c o r o n a r y a r t e r y disease. Falsetti a n d associates 3 h a d previously r e p o r t e d an a b s e n c e of significant correlation b e t w e e n VCe a t p e a k stress and the clinical state. In o u r hands, resting values were not helpful in the distinction b e t w e e n n o r m a l subjects a n d p a t i e n t s with c o r o n a r y a r t e r y disease or c a r d i o m y o p a t h i e s : however, the difference between exercise minus resting Vmax was of discriminative value. Peterson a n d associates 1~ had found t h a t V m a x c a l c u l a t e d from total pressure was quite sensitive in s e p a r a t i n g n o r m a l from a b n o r m a l subjects, a l t h o u g h he too noted an overlap w h e n the individual cases were compared. Falsetti a n d associates 3 f o u n d V m a x to be a sensitive and consistent indicator of m y o c a r dial performance. In our experience, ejection fraction has n o t been sufficiently sensitive to s e p a r a t e n o r m a l from a b n o r m a l subjects (Fig. 1). I t h a s been reported t h a t the ejection fraction m a y r e m a i n n o r m a l while the m e a n Vcf is diminished in m i t r a l regurgitation. ~1 Earlier studies h a d i n d i c a t e d t h a t velocity of wall m o t i o n provides a sensitive index of m y o c a r d i a l c o n t r a c t i l i t y in the presence of aortic valve disease. Peterson and associates2 ~ using e l e c t r o m a g netic probes, found t h a t peak velocity of shortening provided the best index for the identification of depressed m y o c a r d i a l function. In our hands there was considerable overlap in p e r c e n t age of m i n o r axis shortening b e t w e e n v a r i o u s groups of patients, and this has also been the experience of K a r l i n e r and associates. 2-~ Benzing and associates ~ h a v e r e c e n t l y shown t h a t c o n t r o l of preload a n d afterload is an indispensable prerequisite in the assessment of the ability of velocity of fiber s h o r t e n i n g (Vcf) to reflect changes in the contractile s t a t e of t h e left ventricle. As seen in Fig. 8, left v e n t r i c u l a r f u n c t i o n curves were a d e q u a t e for the s e p a r a t i o n of n o r m a l subjects f r o m p a t i e n t s with c a r d i o m y o p a t h y and c o r o n a r y a r t e r y disease, an experience shared by S w a n 4 a n d b y Gorlin and associates. ~ I t m u s t be r e m e m b e r e d , however, t h a t t h e y do
582
n o t provide a m e a s u r e of the inotropic s t a t e of the m y o c a r d i u m , a n d t h a t t h e y are influenced by resting fiber length (preload) a n d by a l t e r a t i o n in wall forces during ejection (afterload). T h e relative independence of b o t h t o t a l a n d t o t a l - p r e s s u r e isovolumic indices from t h e effect of a c u t e changes in preload remain s o m e w h a t c o n t r o v e r sial. T h e experience of Peterson and associates TM is similar to ours in t h a t we b o t h h a v e f o u n d isovolumic phase c o n t r a c t i o n indices to be u n r e liable for c o m p a r i n g p a t i e n t s w i t h n o r m a l h e a r t s from those with m y o c a r d i a l disease. S o m e observers consider t h a t the overlap seen in these isovolumic indices m a y be r e l a t e d in p a r t to as y e t u n s u p p o r t e d a s s u m p t i o n s concerning h e a r t size and series elasticity. S o m e of t h e o t h e r p r o b l e m s at present disregarded in t h e d e t e r m i n a t i o n of contractility h a v e been elegantly s u m m a r i z e d b y Noble. 1~ and m u c h f u r t h e r w o r k needs to be done.
Summary 1. T h e a u t h o r s c o m p a r e d t h e sensitivity of t h e isovolumic phase indices (contractility indices) against LV function curves ( " p u m p - f u n c t i o n " indices) in assessing v e n t r i c u l a r p e r f o r m a n c e . 2. Certain modifications of the usual isovolumic phase indices, especially those i n t r o d u c i n g t h e concept of c o m p a r i s o n of exercise with rest, seemed to us to be slightly m o r e helpful in separating n o r m a l subjects f r o m the p a t i e n t s with coronary a r t e r y disease or c a r d i o m y o p a thies, but these differences were n o t striking w h e n statistically evaluated, and could not be utilized in the assessment of left v e n t r i c u l a r function in individual patients. 3. T h e construction of left v e n t r i c u l a r function curves, in our hands, yielded equally as satisfactory information and, in addition, was m u c h simpler to perform. 4. It is concluded t h a t c o n t r a c t i l i t y indices are relatively insensitive in the a s s e s s m e n t of left ventricular function, and t h a t they offer little a d v a n t a g e over " p u m p - f u n c t i o n " indices for this purpose.
REFERENCES 1. Mason, D. T., Spann, J. F., Jr., and Zelis, R.: Quantification of the contractile state of the intact human heart, Am. J. Cardiol. 26:248, 1970. 2. Mason, D. T., Spann, J. F., Jr., Zelis R., et al.: Comparison of the cardiac contractile state in patients with
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Isovolumic phase indices in L V function
3. 4. 5. 6. 7. 8. 9.
i0. 11. 12.
idiopathi c myocardial disease and in ventricular hypertrophy 2 ~ to prolonged systolic pressure overloading (abst.), J. Clin. Invest. 4:61a, 1970. Falsetti, H. L., Mates, R. E., Green, D. G., et al.: Vmax as an index of contractile state in man, Circulation 43:467, 1971. Kovowitz, C., et al.: Effects of isometric exercise on cardiac performance, Circulation 44:944, 1971. Green, D; G., et aI.: Estimation of left ventrieular volume by one-plan e cineangiograms, Circulation 25:61, 1967. Carleton, R. A.: Changes in left ventricular volume during angiography, Am. J. Cardiol. 27:460, 1971. Kitamura, S., et al.: Geometric and functional abnormalities of the left ventricle with a chronic localized noncontractile area, Am. J. Cardiol. 31:701, 1973. Katz, L. N., editor: Symposium on t h e regulation of the performance of the heart, Physiol. Rev. 35:90, 1955. Zelis, R., Amsterdam, E. A., and Mason, D. T.: Isometric Vmax as an index of contractility independent of series elastic and fibre shortening. Implication concerning pressure-volume data in myocardial fibrosis, valvular regurgitation, ventricular aneurysm and ventricular septal defect, Circulation 2[Suppl: 2]:89, 1971. Mirsky, I., et al.: General index of assessment of cardiac function, Am. J. Cardiol. 30:483, 1973. Ross, R. S., et al.: Effect of pacing-induced tachycardia and myocardial ischaemia on Ventricular pressurevelocity relationship in man, Circulation 44:74, 1972. Rackley, C. E., et al.: Regional left ventricular performance in the year following myocardial infarction, Circulation 44:679, 1972.
American Heart Journal
13. Gorlin, R., et al.: Effect of angiographic material on left ventricular function in man, Am. J. Cardiol. 32:21, 1973. 14. Peterson, K. L., et al.: Comparison of isovolumic and ejection phase indices of myocardial performance in man, Circulation 44:1088, 1974. 15. Eckberg, D. L., et al.i Mechanics of left ventricular contraction in chronic severe mitral regurgitation, Circulation 47:1252, 1973. 16. Noble, M. I. M.: Problems concerning the applications of mechanics to the determination of contractile state in man, Circulation 45:252, 1972. 17. Pollock, G. H.i Maximum velocity as an index of contractility in cardiac muscle. A critical evaluation, Circ. Res. 26:111, 1970. 18. Cove[l, J. W., et at.: The effect of increasing frequency of contraction on the force-velocity relation in the left ventricle, Cardiovasc. Res. 1:2, 1967. 19. Ross, J., Jr., and Sobel, B. E.i Regulation of cardiac contraction, Ann. Rev. Physiol. 34:47, 1972. 20. Krayenbuhl, H. P., et aL: Evaluation of L. V. function from isov01umic pressure measurements during isometric exercise, Am. J. Cardiol. 29:323, 1972~ 21. Gault, J. H., Covell, J. W:; et al.: L. V: performance following correction of free aortic regurgitation, Circulation 42:773, 1970. 22. Karliner, J. S,, Gault, J. H., et al.: Mean velocity of fibre shortening, Circulation 44:323, 1971. 23. Benzing, G., III, et al.: Evaluation of left ventricular performance, Circulation 49:925~ 1974.
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