hemodynamic determinants of the maximal rate of rise of left ...€¦ · i - maximal rate of left...

Hemodynamic determinants of the maximal rate of rise of left ventricular pressure

ANDREW G. WALLACE, N. SHELDON SKINNER, JR., AND JERE H. MITCHELL’ La borutory of Curdiovascular Physiology, National Heart Institute, National Institutes of Health, Bethesdu, Murylund

WALLACE, ANDREW G., N. SHELDON SKINNER, JR., AND JERE H. MITCHELL. Hemodynamic determinants of the maximal rate of rise of left ventricular pressure. Am, J. Physiol. 205 (I) :

30-36. 1963. -The maximal rate of left ventricular pressure development (max. dp/dt) was measured in an arenexic preparation which permitted independent control of stroke volume, heart rate, and aortic pressure. Max. dp/dt increased as a result of elevating ventricular end-diastolic pressure. Elevating mean aortic pressure and increasing heart rate each resulted in a higher max. dp/dt without a change in ventricular end-diastolic pressure. Aortic diastolic pressure was shown to influence max. dp/dt in the absence of changes in ventricular end-diastolic pressure or contractility. Increasing contractility increased max. dp/dt while changing the manner of ventricular activation decreased max. dp/dt. These findings demonstrate that changes in max. dp/dt can and frequently do reflect changes in myocardial contractility. These data also indicate that max. dp/dt is a complex function, subject not only to extrinsically induced changes in contractility, but also to ventricular end-diastolic pressure, aortic diastolic pressure, the manner of ventricular activation, and intrinsic adjustments of contractility.

0 UR PRESENT UNDERSTANDING of myocardial muscle mechanics suggests that the maximal rate of contraction, from any given initial fiber length, is a sensitive index of the inotropic state of the muscle (I, 2). This view has been extended to the intact heart and preliminary measurements have indicated that the rate of development of ventricular pressure (dp/dt) may be a useful indicator of the heart’s performance (3-8). The object of this investigation was to examine as systematically as possible the effects of ‘ventricular end- diastolic pressure (LVEDP), aortic pressure, heart rate and extrinsic inotropic influences on the maximal rate of rise of left ventricular pressure (max. dp/dt). The results of this study help to define more clearly

Received for publication 30 December 1962. 1 Present address: Established Investigator, American Heart

Association, University of Texas, Southwestern Medical School, Dallas, Texas l

those circumstances which should obtain for max. dp/dt to indicate reliably changes in the basic contractility of the myocardium, as well as to determine those influences other than changes in contractility which can alter max. dp/dt. The term myocardial contractility will be used to describe the performance of the heart. When from any given end-diastolic pressure the ventricle performs more external stroke work or stroke power, without a decrease of either, or when the ventricle is able to perform a constant amount of external work or power from a lower end-diastolic pressure, an increase of myocardial contractility is considered to have occurred. A preliminary report of this material has been presented elsewhere (9).

METHODS

Mongrel dogs (avg. wt. 19.5 kg) were anesthetized with a warmed mixture of chloralose (60 mg/kg) and urethan (600 mg/kg). Coagulation was prevented by an initial dose of 75 mg heparin followed by IO-mg

doses hourly. Respiration was maintained by a Starling Ideal pump.

A right heart bypass preparation which has been described in detail elsewhere was used (IO). Briefly, all venous blood was drained from the right heart into a reser.voir and pumped back into the cannulated main pulmonary artery. Inflow to the pulmonary artery (cardiac output) was continuously metered and could be controlled by altering pump rate. Aortic pressure was controlled or varied by a mechanical resistance on the descending thoracic aorta. Heart rate was controlled by pacing from the right atrium. All animals were rendered areflexic by confirmed ganglionic blockade with mec- amylamine (Tnversine) 20 mg/kg plus bilateral va- gotomy. This preparation permitted independent control of stroke volume, mean aortic pressure, and heart rate.

Aortic and left ventricular diastolic pressures were measured through short metal sounds connected directly to Statham strain-gauge transducers. The frequency response of these recording systems was linear from o

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HEMODYNAMIC DETERMINANTS OF VENTRICULAR PRESSURE RISE

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FIG. I - Maximal rate of left ventricular pressure development panel) and mean aortic pressure (right panel). The regression (dp/dt) in mm Hg/sec. is plotted on the vertical axis of each lines, regression equations, and coefficients of correlation are graph, and related to LVEDP (left panel), heart rate (middle given in each panel.

to 30 cycles/set. The full left ventricular pressure pulse was measured with a catheter-tip micromanometer introduced into the ventricle through the apex. The frequency response of this system was uniform to 70 cycles/set. The first derivative of the full ventricular pressure pulse was continuously computed by an R-C differentiating circuit, the amplitude of which was a linear function of frequency to 70 cycles/set. The differ- entiator was calibrated by the method of Neal et al. (I I ). The aortic gauge and the micromanometer were both calibrated at an equal sensitivity of 0-250 mm Hg full scale before each experiment. Following introduc- tion, peak systolic pressure recorded by the micromanometer was set to equal peak aortic pressure. Ventricular diastolic pressure was recorded at a sensi-- tivity of 40 cm Hz0 equal 40 divisions of paper. Zero base line for the ventricular diastolic gauge was the level of the tip of the recording sound within the ventricle.

a representative experiment. At a stroke volume of IO

ml (panel A), LVEDP was 5 cm Hz0 and max. dp/dt was 2,200 mm Hg/sec. Stroke volume was then elevated to 30 ml (panel B); LVEDP rose to 1 I cm Hz0 and max. dp/dt increased to 3,500 mm Hg/sec.

When stroke volume was augmented at constant mean aortic pressure, aortic systolic pressure increased. The effect of increasing stroke volume at constant aortic systolic pressure was also observed* The results of such an experiment are shown in Fig. 2 (lower) l Stroke volume was increased from IO (panel A) to 30 ml (panel B) at an aortic systolic pressure of 130 mm Hg. LVEDP increased from 4.5 to 10.0 cm Hz0 and max. dp/dt increased from 2,650 to 3,350 mm Hg/sec.

RESULTS

In the experiments described in this report the effect was observed of varying independently stroke volume (and thus LVEDP), heart rate and mean aortic pressure on max. dp/dt of the left ventricle. The composite data from these studies illustrating the relation between max. dp/dt and each of the above hemodynamic variables are shown in Fig. I.

Effect of increasing heart rate (Fig. I, middle). In I 2

experiments on 5 dogs the relation between heart rate and max. dp/dt was examined. Mean aortic pressure was controlled at IOO mm Hg and stroke volume was maintained at 15 ml. In each study heart rate was increased in steps of approximately IO beats/min from the lowest possible pace rate. All animals showed an increase of max. dp/dt with increasing heart rate. No consistent change of LVEDP was observed as heart rate was increased. Figure 3 (upper) shows tracings from a representative experiment. In panel A heart rate was 120 beats/min and max. dp/dt was 2,050 mm Hg/sec. In panel B heart rate was increased to 188 beats/min and max. dp/dt increased to 2,680 mm Hg/sec.

Efect of ventricular end-diastolic j-v-essure (Fig. I, left) + In nine experiments on five dogs the relation between LVEDP and max. dp/dt was investigated. Mean aortic pressure was maintained constant at IOO mm Hg and heart rate was controlled at 150 beats/min in each experiment. Ventricular end-diastolic pressure was elevated by increasing stroke volume in steps of IO ml. All animals showed an increase of max. dp/dt with the elevation of LVEDP induced by the augmentation of stroke volume. Figure 2 (u#$er) illustrates tracings from

Efect of increasing aortic pressure (Fig. I, right). The effect of increasing mean aortic pressure on max. dp/dt was examined in I I experiments on 5 animals. In each study mean aortic pressure was elevated in steps of approximately IO mm Hg while stroke volume and heart rate were held constant. In all animals max. dp/dt increased as mean aortic pressure was elevated. The increase of max. dp/dt occurred whether or not LVEDP rose. Figure 3 (lower) shows tracings from an illustrative study. In panel A, mean aortic pressure was

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WALLACE, SKINNER, AND MITCHELL

FIG. 2. Upper: effect of augmenting stroke volume from IO ml (panel A) to 30 ml (panel B). Mean aortic pressure IOO mm Hg. Lower: effect of augmenting stroke volume from IO ml (panel A) to 30 ml (panel B). Aortic systolic pressure ISO mm Hg. AP = aortic pressure; LVP = left ventricular pressure; LVD = left ventricular diastolic pressure. Paper speed IOO mm/set.

g7 mm Hg and max. dp/dt was 3,480 mm Hg/sec. In panel B, mean aortic pressure was elevated to 145 mm Hg and max. dp/dt increased to 4,700 mm Hg/sec.

In four animals the influence of aortic diastolic pressure on max. dp/dt was investigated. Aortic resistance was abruptly increased between two heart beats. As a result, the ventricular contraction on the first beat subsequent to the increase was initiated from the same LVEDP as the preceding beat, but had to achieve a higher aortic diastolic pressure before ejection began. Figure 4 shows tracings from two such experiments. In panel A the resistance was elevated at such a time in the diastolic interval that aortic diastolic pressure was increased from 65 mm Hg to 87 mm Hg; on the

FIG. 3. Upper: effect of increasing heart rate from 120 (panel A) to 188 (panel B). Lower: effect of elevating mean aortic pressure from 97 mm Hg (panel A) to 145 mm Hg (panel B). Paper speed I 00 mm/set.

first beat after elevating aortic resistance max. dp/dt was 465 mm Hg/sec greater. In panel B aortic diastolic pressure was elevated from I I 5 mm Hg to I 27 mm Hg; max. dp/dt increased 200 mm Hg/sec. Aortic diastolic pressure was shown to influence max. dp/dt at diastolic pressures ranging from 50 to 130 mm Hg.

Figure 5 demonstrates the changes in max. dp/dt and LVEDP subsequent to a sudden maintained elevation of aortic pressure. In panel A max. dp/dt and LVEDP increased coincident with the elevation of aortic resistance. While aortic pressure was then held at the new level max. dp/dt remained constant despite a fall of LVEDP. In panel B max. dp/dt continued to increase while LVEDP fell. Figure 6 illustrates the time course of changes in max. dp/dt and LVEDP in high speed tracings. Panel A shows the control record prior to elevation of aortic resistance Mean aortic

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HEMODYNAMIC DETERMINANTS OF VENTRICULAR PRESSURE RISE 33

FIG. 4. Effect of abruptly increasing aortic resistance between two heart beats on max. dp/dt. See RESULTS section for description.

pressure was 80 mm Hg, LVEDP 6 cm H20 and max. dp/dt 1,900 mm Hg/sec. Panel B was taken IO set after mean aortic pressure was suddenly increased to 125 mm Hg; LVEDP increased to I I cm Hz0 and max. dp/dt to 2,300 mm Hg/sec. Panel C was taken I min later. Despite the fall in LVEDP to 8 cm HzO, max. dp/dt had increased further to 3,000 mm Hg/sec. Panel D shows two beats IO set after mean aortic pressure was abruptly returned to the original level of 80 mm Hg. Although LVEDP was 3 cm Hz0 less than control, max. dp/dt was 2, IOO mm Hg/sec.

Effect of altering inotropic background. In three animals the effect on max. dp/dt of a continuous infusion of

FIG. 5. Effects of sudden maintained elevation of aortic pressure on max. dp/dt and LVEDP. See RESULTS section for description.

norepinephrine was observed. Heart rate, stroke volume, and mean aortic pressure were held constant. In all animals max. dp/dt increased. A representative experiment is shown in Fig. 7 (upper). In the control record LVEDP was 5 cm Hz0 and max. dp/dt was 2,360 mm Hg/sec. During the norepinephrine infusion LVEDP fell to 3 cm Hz0 and max. dp/dt increased to 3.270 mm Hg/sec. Five animals were digitalized with acetyl strophanthidin. All showed an increased contractility (fall in LVEDP at constant heart rate, stroke

FIG. 6. Fast traces (IOO mm/set) illustrating the time course of changes in LVEDP and max. dp/dt subsequent to elevation of aortic resistance. See RESULTS section for further description.

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34 WALLACE, SKINNER, AND MITCHELL

both animals changing from atria1 to ventricular pacing resulted in a fall of max. dp/dt and an increase in LVEDP. Figure 8 shows tracings from one such experiment. During atria1 pacing, max. dp/dt was 2,280 mm Hg/sec while during ventricular pacing max. dp/dt was I ,800 mm Hg/sec in spite of a higher LVEDP.

FIG. 7. Upper: effects of norepinephrine infusion (0.5 rg/kg min). Heart rate 150, stroke volume 15 ml, mean aortic pressure IOO mm Hg. Lower: effects of acetyl strophanthidin (300 rg). Heart rate 156, stroke volume 15 ml, mean aortic pressure IOO mm Hg. A = control; B = intervention.

volume, and mean aortic pressure) (I 2) and an increase of max. dp/dt. Figure 7 (loser) shows the effect of acetyl strophanthidin. In the control record LVEDP was 4 cm Hz0 and max. dp/dt 3,090 mm Hg/sec. After acetyl strophanthidin LVEDP fell to 2.5 cm Hz0 and max. dp/dt increased to 4,000 mm Hg/sec.

Eject of altered ventricular activation. In two dogs the pathway of ventricular activation was abruptly changed and the effect on max. dp/dt was observed. During the control period the heart was paced from the right atrium. Ventricular activation was then altered by delivering a stimulus directly to the ventricular epi- cardium from a second impulse generator synchronized with the first, but at a delay of 60-70 msec (slightly less than the control P-R interval). Mean aortic pressure, heart rate, and stroke volume were held constant. In

DISCUSSION

The instantaneous rate of change of ventricular pressure (dp/dt) prior to opening of the aortic valve should be closely related to the rate of change of wall tension at any corresponding instant (7). Since max. dp/dt is reached before the onset of ejection (13) we felt that this measurement might be modified by changes of initial fiber length and contractility in a manner qualitatively similar to the effects of changing preload and inotropic background on the maximal rate of tension development by isolated cardiac muscle (2). The data presented in this paper support in several respects the view that max. dp/dt is influenced by mechanical conditions under which the heart is operating in a manner similar to the effects of analogous factors on the rate of tension development by isolated muscle. In addition, the experiments demonstrate that max. dp/dt is a complex function subject to the influence of hemodynamic variables other than initial fiber length and the external inotropic background. These observations help to define more clearly limitations which should be considered if max. dp/dt is to be used as a reliable index of changes in myocardial contractility.

Contraction of isolated heart muscle demonstrates two prominent characteristics. The first is that under constant load conditions, frequency of stimulation and inotropic state, the rate of force development increases as a result of increasing initial length (2). The maximal rate of tension development by an isometric segment of ventricular myocardium also has been shown to be a function of initial segment length (14). In the intact ventricle max. dp/dt increased as LVEDP was elevated. In addition, over the range of end-diastolic pressures studied the increase of max. dp/dt which resulted from elevating ventricular end-diastolic pressure clearly dominated the Laplace effect (15). That is, despite an increase in the radius of the ventricle, the greater rate of tension development consequent to the longer initial fiber length resulted in a higher max. dp/dt.

A second characteristic of heart muscle is that at constant initial length the rate of force development increases as a result of positive inotropic influences (I, 2). In the intact heart at constant stroke volume, aortic pressure and heart rate myocardial contractility was augmented by norepinephrine infusion and by digitalization. In each instance a marked increase of max. dp/dt occurred despite a fall of LVEDP.

It has been suggested that max. dp/dt is dependent only on ventricular end-diastolic fiber length and the existing level of myocardial contractility. In this study it was observed that on the first beat following an eleva-

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HEMODYNAMIC DETERMINANTS OF VENTRICULAR PRESSURE RISE 35

tion of aortic diastolic pressure max. dp/dt increased. This increase of max. dp/dt occurred with no change of LVEDP and was demonstrated over a wide range of pressures encompassing the normal diastolic levels. Since it is unlikely that any alteration of contractility occurred on the first beat (16), we have concluded that when the heart is operating from any given initial fiber length aortic diastolic pressure can influence max. dp/dt in the absence of changes in contractility.

The finding that max. dp/dt is higher on the first beat following elevation of aortic diastolic pressure is consistent with the observation that the rate of rise of ventricular pressure increases until just before the aortic valve opens (I 3). At least two factors could be operative in the increase of max. dp/dt which resulted from elevating aortic diastolic pressure and thereby delaying the onset of ejection. Although the biochemical events associated with shortening of the contractile element of each fiber are thought to reach full active state almost instantaneously, force is developed by the fiber at a much slower rate. The mechanical interaction between the contractile element and the series elastic structure of each fiber is thought to explain this delay (I 1). A second possible factor has to do with the degree to which contraction of the ventricle is asynchronous (18) and the effects of a lack of synchronous contraction on changes of ventricular compliance during early systole. During the isovolumic period more fibers are continually entering into the contracted state (19) and thus the rate of ventricular pressure development increases. Further, as more fibers contract the ventricular wall becomes less compliant (20) and, therefore, for any given

FIG. 8. Effect of changing from atria1 pacing (panel A) to ventricular pacing (panel B). Heart rate 158, stroke volume 14 ml, mean aortic pressure I oo mm Hg.

rate of fiber shortening the rate of rise of pressure increases. When the contraction of the heart was made less synchronous than normal by pacing from the ventricle rather than from the atrium, max. dp/dt decreased despite a higher LVEDP. This finding supports the view that the manner of ventricular activation can influence significantly the performance of the ventricle and its rate of pressure development (2 I).

Sarnoff and co-workers (22) have shown that several beats after a maintained elevation of aortic pressure, an increase of contractility occurs which has been called homeometric autoregulation. Similarly, a sustained increase of heart rate has been demonstrated to lead to an increase of contractility (22, 23). Following an elevation of aortic pressure max. dp/dt increased on the first few beats because of a transient increase of LVEDP and because of a higher aortic diastolic pressure. On subsequent beats, max. dp/dt remained constant or increased further despite a fall of LVEDP. In- creasing heart rate also resulted in a marked increase of max. dp/dt without any change of LVEDP. These findings offer additional support for the concept of homeometric autoregulation and demonstrate that intrinsic alterations of contractility can result in substantial changes of the relation between max. dp/dt and LVEDP.

It has been suggested that max. dp/dt may be a useful index of changes in myocardial contractility. Reeves and his associates (7) were the first to carefully evaluate this possibility. They demonstrated a close correlation between changes of contractile force measured with a strain-gauge arch and max. dp/dt from any given end- diastolic circumference. Gleason and Braunwald (8)

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36 WALLACE, SKINNER, AND MITCHELL

showed that max. dp/dt was increased by the inotropic agent Isuprel as well as by the tachycardia which followed atropine administration. Siegel and Sonnenblick (24) showed in an isovolumically contracting ventricle that the maximal rate of pressure rise divided by in- tegrated isometric tension was modified by changes of contractility, but not influenced by alterations of end- diastolic fiber length. The data presented in this report confirm the view that max. dp/dt can be a sensitive index of extrinsically induced changes in myocardial contractility. However, under the conditions of our experiments aortic diastolic pressure, the manner of ventricular activation and intrinsic adjustments of

REFERENCES

I.

2.

3.

4. 5.

6.

7.

8.

9.

10.

II.

12.

ABBOTT, B. C., AND W. F. H. M. MOMMAERTS. J. Gen. Physiol. 4* : 533, 1959. SONNENBLICK, E. H. Am. J. PhysioZ. 202 : 931, I 962.

FRANK, 0. (Translated by C. B. Chapman and E. Wasser- man) Am. Heart f. 58: 282, 19.59. WIGGERS, C. J. J. Pharmacol. Exptl. Therap. 30: 233, 1927.

WIGGERS, C. J., AND B. STI~~SON. J. Pharmacol. Exptl. Therap. 30: 251, 1927. TOUCAN, R. A., AND P, G. P. YOUNG. Federation Proc. 20: I 24, 1961. REEVES, T.J., 1;. L. HEFNER, W. B. ,JONES, C. COGHLAN, G. PRIETO, AND J. CARROLL. Am. Heart J. 60: 745, 1960. GLEASON, W. L., AND E. BRAUNWALD. J. CZin. Invest. 41 : 80, 1962. WALLACE, A. G., N. S. SKINNER, AND J. H. MITCHELL. Circulation 26: 798, I 962. WALLACE, A. G.,J. H. MITCHELL, N. S. SKINNER, AND S.J+ SARNOFF. Circulation Res. In press. NEAL, J-J., W. HALPERN, AND T.J. REEVES. J. A@. Physiol. 15: 74,7, 1960.

SARNOFF, S. J., AND J. H. MITCHELL. Am. J. Med. 30: 747, 1961.

contractility (i.e., homeometric autoregulation) each have been shown to influence importantly max. dp/dt. These considerations demonstrate that max. dp/dt is not a specific index of myocardial contractility and emphasize that changes of this measurement should be interpreted with caution if any significant alteration of aortic pressure or heart rate occurs.

The authors express their appreciation to Dr. Stanley J. Sarnoff for his interest and helpful criticisms throughout this study and to Mrs. Carrie Scott and Frank Perry for their valuable assist- ance. The catheter-tip micromanometer used for ventricular pulse measurement was kindly supplied by Statham Transducers, Inc.

‘30

14.

‘5* 16.

=7*

18.

19. 20.

21.

22.

23.

24.

ANGELAKOS, E. T., J. C. TORRES, AND M. L. TORCHIANA. Federation Proc. 2 I : 129, 1962. REEVES, T. J., AND L. L. HEFNER. Am. Heart J. 64: 525, rg6z.

BURTON, A. C. Am. Heart J. 54: 801, I 957. PIEPER, H. P. Circulation Res. I o : 285, I 962. SANDOW, A. In: Biophysics of Physiological and PharmacoZogicaZ

Actions edited by A. M. Shanes. Washington, D. C.: Am. Assoc. Advan. Science. 1961, p. 413. RUSHMER, R. F. Am. J. Physiol. 184: I 88, 1956.

WIGGERS, C. J. A m. J. Physiol. 80: 12. Igap FRY, D. L., D. M. GRIGGS, AND J. C. GREENFIELD. CircuZation

Res. In press. GILMORE, J. P., S. J. SARNOFF, J. H. MITCHELL, AND R. J. LINDEN. Brit. Heart J. In press. SARNOFF, S. J., J. H. MITCHELL, J. P. GILMORE, AND J. P. REMENSNYDER. Circulation Res. 8 : I 077, 1960.

MITCHELL, J.H., A. G. WALLACE, AND N. S. SKINNER. Am. J.

Physiol. In press. SIEGEL, J. H., AND E. I-L SONNENBLICK. Circulation Res. In press.

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