Intrinsic left ventricular contractility in normal subjects

Intrinsic left Ventricular Contractility in Normal Subjects MARVIN W. KRONENBERG, MD, JACK P. UETRECHT, MD, PhD, WILLIAM D. DUPONT, PhD, MICHAEL H. DAVIS, MD, BRIAN K. PHELAN, MD, and GOTTLIEB C. FRIESINGER, MD

The influence of autonomic tone on left ventricular (LV) contractility, along with the range of normal values and the effects of exercise on contractile state, were studied in 12 normal volunteers. Serial reproducibility was examined in a subgroup of 6. LV contractility was estimated by the LV peak-systolic pressure to end-systolic volume relation (pressurevolume relation), and the ratio of peak-systolic pressure to end-systolic volume (pressure/volume ratio). The cuff blood pressure and radlonuclide ventriculogram were recorded at rest, during exercise and during pharmacologic pressure-afterloading with phenylephrine, before and after vagal and padrenergic “blockade.” Both the pressure/volume ratio and ejection fraction increased during the stlmulus of exercise (both p 50.006). After blockade, the pressure-volume relations were highly linear (r

= 0.95 $E 0.05 [standard deviation], n = 12), and there was no systematic difference in their slopes induced by blockade. The serial studies of pressurevolume relations showed no significant differences. The results demonstrated that vagal and sympathetic tone were not important in the support of LV contractility in normal subjects at rest, and that the pressure-volume relation and pressure/volume ratio are reproducible between studies. Also, the findings confirmed that both the pressure/volume ratlo and the ejection fraction were sensitive to exercise-induced changes in contractility. This demonstration of intrinsic LV contractility in normal subjects, plus the reproducibility of the measurements, supports the feasibility of serial study of LV contractility. (Am J Cardiol

T

1966;61:621-627)

umc relations,6~7~g-‘12 reproducibility13r14 or effects of autonomic tone.12L15 Autonomic tone might be important in setting the baseline [“intrinsic”] contractile state, because the heart is richly innervated. Previously, Jose and TaylorI studied “intrinsic cardiac function” using atropine and propranolol to produce “autonomic blockade.” In the present study, we employed the systolic pressure-volume concept and radionuelide ventriculography to evaluate “intrinsic: LV contractility” in normal subjects at rest, during exercise and during autonomic blockade to assess the influence of autonomic tone. The reproducibility of the data was investigated.

he left ventricular (LV] end-systolic pressure-volume relation and variations have been employed as estimates of LV contractility.1-12 However, there are few data to define the normal range of pressure-vol-

From the Departments of Medicine, Pharmacology and Preventive Medicine and Biostatistics, Vanderbilt IJniversity School of Medicine, Nashville, Tennessee. This study was supported in part by Research Career Development Award 1 K04 HLOO852 [Dr. Kronenberg), National Research Service Award 5T32 HL074ll and grant GM 313 04 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland, a faculty development award (Dr. Uetrecht] from the Pharmaceutical Manufacturers Association, Washington, D.C., and a research fellowship (Dr. Davis] from the Middle Tennessee Chapter, American Heart Association, Nashville, Tennessee. Manuscript received August 31,1987; revised manuscript received and accepted November 9, 1987. Address for reprints: Marvin W. Kronenberg, MD, Cardiology Division, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.

Methods Population and protocol: We studied 14 normal volunteers. They were untrained, asymptomatic adults (9 men, 5 women], ages 33 & 12 years (standard deviation), range 21 to 69. Each had a normal physical examination, took no medications and gave written informed consent on forms approved by our institutional review board. Serial studies were performed in 9. 621

622

LEFT VENTRICULAR

CONTRACTILITY

Intravenous cannulae were inserted in right and left forearm veins for blood sampling and drug infusion, respectively. The subjects lay supine and were studied while fasting. Radionuclide ventriculograms were collected to estimate LV volume (see later) and auscultatory blood pressure was measured simultaneously using an 8-stage protocol (Figure 1). Data were collected at rest (stage l], during supine bicycle ergometer exercise (stage 2) and after a recovery period of 20 to 30 minutes following exercise (stage 3). Then, the systolic blood pressure was increased in steps by a phenylephrine infusion (stages 4 and 5J. After discontinuing phenylcphrine, atropine and propranolol were infused iniravenously to produce vagal and /3-adrenergic “blockade.” Loading doses were followed by maintenance infusions. Data were reacquired when the systolic pressure was stable (stage 6). Then, the phenylephrine infusion was repeated to achieve 2 pressure increments and measurements were ‘repeated [stages 7 and 8). The protocol required 3 hours, with 45 minutes for stages 6 through 8. Imaging: Red blood cells were labeled in vivo17 using 25 mCi technetium-g9m pertechnetate. Electrocardiographic R-wave gated images of the cardiac blood pool in the left anterior oblique projection were collected by a PhoGamma IV scintillation camera (Sicmens) using a low-energy all-purpose collimator and a symmetrical 20% window. They were stored by a PDP ll/40 computer (Digital Equipment], using a 64 X, 64 image matrix, 30 ms per frame, 20 frames per cardiac cycle and variable hardware zoom for magnification. Images were collected for 2 million counts at rest (usually 5 minutes) and for 3 minutes on exercise. For estimating LV volume, with each image a 5-ml blood sample was drawn intro a heparinized syringe, transferred to a Petri dish using a pipette with 0.5% error at full scale (Oxford Macro-Set, Sherwood Medical), placed on the collimator and counted for 5 minutes afterwards. Blood pressure was assessed once a minute during imaging with an am,eroid cuff sphygmomanometeb. Drug infusion: Phenylephrine was infused with a calibrated pump (Harvard). After the initial rate of 0.2 pg/kg/min, the rate was increased to achieve an approximate 20 mm Hg increment in systolic pressure. Then, the radionuclide vcntriculogram was repeated and the rate increased for a similar pressure increment before another image. This sequence was repeated after vaga1 and P-tidrenergic “blockade.“16 For this, atropine (0.2 mg/ml] was infused over 10 to 15 minutes to a total loading dose of fl.b4 mg/kg. The maintenance

STUDY

STAGE

FIGURE

PROTOCOL

I

I

I

I

I

2

3

45

1. Protocol.

Stages

I

and conditions

are shown.

I

I

I

6

7

8

dose was 0.2 pg/kg/min. Propranolol was infused simultaneously, totalling 0.2 mg/kg. The maintenance dose was 1.1 pg/kg/min. Exercise protocol: Exercise was performed by pedaling a bicycle ergometer (Collins], supine at 60 rpm, beginning at 25 watts and increasing over 2 to 3 minutes to an individualized maximal load for a 3-minute exercise image. Serial studies: Two weeks to 3 months later, a second study was performed in 9 subjects following an identical protocol. All subjects able to return were studied without reference to their initial evaluation. Radionuclide ventriculography: %Veevaluated this method for estimating the LV ejection fraction and volume using software of our design.18 Among 18 patients, the correlation for ejection fraction between radionuclide and contrast ventriculography was 0.93 (p 0.98. Blood pressure: In 9 consecutive catheterized patients there was close correlation between the systolic blood pressure (mm Hg) by cuff and in the ascending aorta (cuff = -1.68 + 1.03 X aortic) (r = 0.991, p
March

Results Fourteen subjects had 1 study and 9 subjects had 2. Studies were excluded only for inadequate definition of the left ventricle, artifacts in blood sample counts or inadequate exercise electrocardiographic gating. For study 1, there were technically excellent rest-exercise pressure/volume ratios for 13 subjects and pressurevolume relations for 12. For study 2, there were pressure/volume ratios and pressure-volume relations for

1, 1988

THE AMERICAN

JOURNAL

OF CARDIOLOGY

Volume

623

81

2.2 f 1.1 mm Hg/ml (n = 12); after blockade it had become 2.5 f 1.6. These values were not significantly different. In that study, the extrapolated end-systolic volume for a systolic pressure of 0 averaged -30 ml before blockade and -28 ml after it. These values were not significantly different. In study 2, the extrapolated volume averaged -28 ml before blockade and -6 ml after (p = O.O51), approaching, but not achieving, standard statistical significance.

6.

Rest-exercise results: In study 1 the pressure/volume ratio increased from 3.6 f 2.7 mm Hg/ml “units” at rest to 7.9 f 3.5 during exercise (n = 13, p
I6

rA

12P/V RATIO

6

4-

I EXER I REST STUDY

I

STUDY

I

STUDY

2

FIGURE 2. Pressure/volume ratio. A, the ratio of peak-systolic pressure to end-systolic volume increased on exercise. /3, duplicate rest and exercise ratios were not significantly different in serial studies. The maximum difference in the exercise pressure/volume ratio was 2.5 units. P/V = pressure/volume.

SBP (mm Hg) 200-

A

B l

2~1201

.2

(1411

1805 (51) (109)

160-

7

140-

7(ll6, 155)

180)

(64)

4

Y .I

73)

d? (631

~

3

40

(76)

t

6 (811

801 20

*I

3ta4,

60

80

ESV

20

I

I

40

60

(ml)

FIGURE 3. Two patterns of pressure-volume relations. The numbers 1 through 8 denote stages in the protocol and the numbers in parentheses represent heart rate. A, subject 8: the systolic pressure-volume relation was linear before and after blockade. i3, subject 11: there was a marked leftward shift in the pressure-volume relation with a higher infusion rate of phenylephrine before autonomic blockade. The relation was more linear after blockade.

113 11 4

= 6)

9 37 27 29 45 38 31 57 32 67 46 48 42 39 15 4 31 13 5

ESV (ml)

12.3 3.4 3.9 3.7 2.2 3.3 3.4 2.0 3.3 1.7 2.5 2.4 2.6 3.6 2.7 0.8 4.8 3.7 1.5

P/V

84 70 73 61 71 72 68 53 72 65 64 64 67 68 7 2 72 7 3

(?) 66 75 56 73 55 70 56 63 46 56 78 77 60 64 10 3 66 9 4

(b:) 168 198 150 158 167 146 178 108 199 178 185 188 170 175" 17 5 165* 19 a

(m?zg)

1

* p SO.003 rest versus exercise;t p <0.05 rest versus exercise. Bpm = beats per minute; EF = ejection fraction; ESV = end-systolicvolume;.HR standard error.

8 2

111 125 106 107 100 126 106 113 105 112 114 116 111 112

F M F F F M M M M M M M M = 13)

2 3 4 5 6 7 8 9 10 11 12 13 Mean(n SD SE Mean(n SD SE

1

SBP (mmHg)

Sex

Subject

Rest

Study

12 19 38 39 31 23 15 32 22 33 33 14 22 26' 9 3 27 11 4

Fii

= heart

14.0 10.4 4.0 4.1 5.4 6.3 11.9 5.9 9.1 5.4 5.6 13.4 7.7 7.9" 3.5 1.0 7.4 4.0 1.6

P/V

Exercise

158 167 176 179 148 117 155 127 138 140 141 170 145 151" 19 5 158* 23 9

(E)

rate; P/V = ratio

85 84 66 64 80 79 83 66 83 74 80 84 81 78* 8 2 76 9 4

(T)

TABLE I Peak Syst@ic Blood Pressure and End-Systolic Volume at Rest and Durlng Exercise

of SBP/ESV;

1.7 7.0 0.1 0.4 3.2 3.0 8.5 3.9 5.8 3.7 3.1 11.0 5.1 4.3 3.2 0.9 2.6 2.6 1.0

AP/V

AP/V

112 10 4

109 124 103 110 102 124

SBP. (mmHg)

= change

32 13 5

12. 34 29 31 31 52

b-4

ESV

4.3 2.4 1.0

9.1 3.7 4.0 3.6 3.3 2.4

P/V

in P/V ratio;

Rest

SBP =

72 8 3

85 72 73 65 76 62

(7)00

peak-systolic

68' 13 5

65 68 67 93 54 61

(b$l)

2

164' 15 6

160 194 157 159 165 150

blood

(msmBpHg)

Study

pressure;

24+ a 3

13 17 24 26 27 37

ESV (ml)

SD

=

7.at 3.3 1.4

12.3 11.4 6.5 6.1 6.1 4.1

P/V

Exercise

standard

79+ 7 3

85 87 80 72 80 70

(?)

deviation;

146" 24 10

151 130 155 184 ‘142 114

(bz)

SE

3.4 2.2 0.9

3.2 7.7 2.5 2.5 2.8 1.7

AP/V

=

March

TABLE

II

End-Systolic

Pressure-Volume

Mean SD SE Mean (n = 6) SD SE

M = slope of linear SBP equals 0. Values

AMERICAN

JOURNAL

OF CARDIOLOGY

1

Study

Pre-blockade

1 2 3 4 5 7 8 9 10 11 12 13 (n = 12)

THE

Volume

81

625

Relations Study

Subject

I,1988

Post-blockade

2 Post-blockade

Pre-blockade

m

VO

m

VO

r

SE

m

VO

m

vo

r

SE

1.0 1.9 1.5 3.6 0.7 4.3 3.4 2.8 2.4 2.4 1.3 1.9 2.2 1.1 0.3 2.2 1.5 0.8

-104 -31 -37

2.7 2.3 2.8 1.1 1.6 6.8 1.9 3.3 1.6 2.5 0.8 2.0 2.5 1.6 0.5 2.9 2.0 0.8

-35 -15 -12 -58 -36

0.96 0.87 0.85

0.75 1.32 2.23 0.23 2.77 0.50 0.02 0.10 0.12 0.24 0.46 0.79 0.93 0.28 1.46 1.04 0.47

1.6 3.5 1.8 1.6 5.0 1.9

-64 -5 -30 -49 -26

2.8 2.8 4.2 3.1 4.1 3.7

32 -16 3 -8 11 8

0.98 0.99 0.98 0.99 0.92 0.99

0.56 0.43 0.89 d.28 1.72 0.35

2.6 1.4 0.8

-28 27 11

3.5 0.6 0.3

-6 16 7

0.98 0.03 0.01

0.71 0.51 0.22

1 -108 0 12 5 -11 -6 -49 -32 -30 40 12 -47 49 20

17 -9 -3 -38 -8 -104 -41 -28 32 9 -23 26 11

regression of end-systolic pressure-volume were not significantly different by paired

relations; ttests.

0.99 0.93 0.97 1. 0.99 0.99 0.96 0.97 0.95 0.05 0.02 0.92 0.06 0.63

r = Pearson

Reproducibility of pressure-volume relations: Pressure and volume were reproducible after autonomic blockade in the group of 6 serial studies (Figure 5). The individual pressure-volume data were quite similar visually (Figure 4), and statistically (Table II]. There were no significant differences in the pressurevolume slopes either before or after blockade, or in the volumes at zero-pressure. Also, the 95% confidence limits of the standard error of the slope estimates after blockade overlapped in every case.

Discussion End-systolic pressure volume relations reflect LV contractility. 1-7,1o-13We examined peak systolic pressure to end-systolic volume relations to assess in normal volunteers the importance of autonomic tone, the effects of exercise and the reproducibility of the data. We found no significant effect of autonomic tone on systolic pressure-volume relations or on pressure/volume ratios; reproducibility was generally good. The pressure/volume ratio increased during exercise, rcfleeting increased contractility. Prestiure-volume relations and pressure/volume ratio: The slope of the LV end-systolic pressure-volume relation equals the end-systolic pressure divided by the difference of the end-systolic volume minus a correction factor [the volume at zero pressure, termed Vo).2 Suga et al1 and Sagawa et al8 proposed the pr&sure/volume ratio as an estimate of contractility. This ratio may be considered as 1 related locus of the pressure-volume relation, but its absolute value differs from the slope value because of Vo. In the isolated heart, LV volume is altered by a compliant balloon. There, the systolic pressure-volume relation is linear and the V. usually has a positive

correlation

9

coefficient;

SE = standard

error

of estimate;

VO = ESV when

value.2~20 However, V. has yet to be determined directly in vivo. We confirmed that systolic pressure-volume relations were linear, but the extrapolated Vo was us& ally negative. This value has been reported both as positive3~4~6~7J1and negative.5J1 Such extrapolation assumes linearity, but negative values imply nonlinearity below the operating range. Thus, extrapolation of VO may be invalid and greater reliance should be placed on actual pressure and volume measurements. The pressure/volume ratio may change by altering pressure, volume, or both. An increase in pressure coupled to a decrease in volume is consistent with increased contractility, and this occurred during exercise in our study.

SBP (mm Hg)

PRE-BLOCKADE

POST-BLOCKADE

FiGURE 4. Pressure-volume relations for the study group. There was an overall similarity. Serial studies In 6 subjects were generally concordant. Data were more llnear after autonomic blockade ior reasons explalned In the text. Numbers above graphs specify subjects as listed in tables.

626

LEFT VENTRICULAR

CONTRACTILITY

180 -r

-Study --Study2

I

160 SBP (mmHg)

SEM t-f+ N=6

100 iIiI

II

II

II

40 40

60 ESV(mI)

80

FIGURE 5. Reproducib ‘lllty of pressure-volume relations. Stages 6 to 8 of studies 1 and 2 are shown. The mean pressure and volume were not significantly dffferent.

Autonomic blockade: Whereas others have examined contractility in transplanted hearts (denervated],12*22 the present study used a more direct approach by investigating the effects of autonomic tone on LV contractility and reproducibility in normal subjects. There was no difference in the slope of the pressure-volume relation before or after blockade after excluding stage 5, which was probably affected by phenylephrine’s ,f3-adrenergic effect.23v24Resting autonomic tone seems relatively unimportant for supporting normal LV contractility in dogs3 There are fewer data in normal humans. Borow et al found no differences between pressure-dimension relations in transplanted denervated hearts and in other normal subjects.12 Crawford et al found that end-systolic dimension was unchanged before and after oral propranolol.15 However, in heart failure,16 cardiac output decreased after blockade but not in normal subjects. Thus, sympathetic drive may support contractility in heart failure, but not in the normal population. Reproducibility: The duplicate, serial pressurevolume relations in 6 subjects were not significantly different. The greatest difference between duplicate pressure/volume ratios during exercise was 2.5 units and may represent the upper limit of normal variability. Potential limitations included the volume and blood pressure methods, the effect of heart rate and drugs. The radionuclide method is affected by attenuation25-27, but can quantitate vo1ume,3.1g,25-27 small changes in volume,27 pressure-volume loopsz8 and pressure-volume relations.27 Changes in the same sub-

ject should be assessed reliably, because attenuation should be constant. Using 3 points per pressure-volume curve and peak systolic pressure might cause errors. Although there are problems in using 3 points to define linearity, other Estistudies have proven this point. l-3.5-8,10-14.20.21,27,29 mates of contractility by peak and end-systolic pressure are quite similar, 4,5,21v2g but the former has steeper slopes. Tachycardia is a moderate, positive inotropic stim~1~~~2~~0~3~ and may decrease end-systolic volume.22r28 In our study, the mean heart rate increased 29 beats from stage 3 to 6, but in 1 of our subjects a go-beat increase did not affect pressure-volume relations in further studies [data not shown]. Baroreceptor-mediated bradycardia [as before blockade) has not been studied, but when pacing stops, end-systolic volume22 and end-systolic dimension30 change minimally. Reflexes, hormonal background and coronary perfusion pressure might modify the effect of rate alone.31 The available data favor our conclusion that vagal and P-adrenergic stimuli do not significantly alter normal LV contractility. Phenylephrine has cardiac /3-adrenergic effects23s24 and our data confirm this in some subjects [Figures 3 and 4). Less phenylephrine was required to raise the blood pressure after blockade, probably by attenuating P-adrenergic vasodilation.32 /3-adrenergic blockade seems necessary before using phenylephrine. Although methoxamine might be as usefu1,33 it also may affect contractility.24o34s35 Acknowledgment: We thank David E. Hansen, MD, for manuscript review, Jenny James and Joyce Semenya for technical assistance and Sue Warrington for manuscript preparation.

References 1. Suga H. Sagawa K, Shoukas AA. Load independence of the instantaneous pressure-volume ratio of the canine left ventricle and effects of epinephrine and heart rate on the ratio. Circ Res 1973;32:314-322. 2. Sagawa K. The end-systolic pressure-volume relation of the ventricle: definition, modifications and clinical use (editorial]. Circulation 1981;63:12231227.

3. Sodums MT, Radke FR. Starling MR. Little WC, O’Rourke RA. Evaluation of left ventricular contractile performance utilizing end-systolic pressurevolume relationships in conscious dogs. Circ Res 1984;54:731-739. 4. Grossman W. Braunwald E. Mann T, McLaurin LP, Green LH. Contractile state of the left ventricle in man as evaluated from end-systolic pressurevolume relations. Circulation 1977;56:845-852. 5. Mehmel HC, Stockins B. Ruffman K, Olshausen KV. Schuler G. Kubler W. The linearity of the end-systolic pressure-volume relationship in man and its sensitivity for assessment of left ventricular function. Circulation 1981;63: 1216-1222.

6. Marsh ID. Green LH, Wynne J, Cohn PF, Grossman W. Left ventricular end-systolic pressure-dimension and stress-length relations in normal human subjects. Am J Cardiol 1979;44:1311-1317. 7. Borow KM, Neumann A. Wynne J. Sensitivity of end-systolic pressuredimension and pressure-volume relations to the inotropic state in humans. Circulation 1982;65:988-997. 8. Sagawa K. Saga H, Shoukas AA, Bakalar KM. End-systolic pressure/ volume ratio: a new index of ventricular contractility. Am J Cardiol 1977; 40:748-753.

9. Dehmer GJ. Lewis SE, Hillis LD. Corbett J. Parkcy RW, Willerson JT. Exercise-induced alterations in left ventricular volumes and the pressurevolume relationship: a sensitive indicator of left ventricular dysfunction in patients with coronary artery disease. Circulation 1981;63:1008-1018. 10. Schuler G, van Olshausen K, Schwarz F. Mehmel II, IIofman M, Hcrmann H-J, Lange D, Kubler W. Noninvasive assessment of myocardiaf con-

March

tractility in asymptomatic patients with severe aortic regurgitation and normal left ventricular ejection fraction at rest. Am J Cardiol 1982;50:45-52. 11. Shen WF, Roubin GS, Choong CY-P, Hutton BF, Harris PJ, Fletcher PJ, Kelly DT. Evaluation of relationship between myocardial contractile state and left ventricular function ip patients with aortic regurgitation. Circulation 1985;71:31-38. 12. Borow KM, Neumann A. Arensman FW, Yacoub MH. Left ventricular contractility and contractile reserve in humans after cardiac transplantation. Circulation 1985;71:866-872. 13. Borow KM, Henderson IC, Newman A, Colan S, Grady S. Papish S, Goorin A. Assessment of left ventriculhr contractility in patients receiving doxorubicin. Ann Intern Med 1983;99:750-756. 14. Byrd BF III, Hartness WO, Collins HW, Phelan BK, Kronenberg MW. Intrinsic variability of left ventricular contractility and relaxation ljarameters [abstr). Circulation 1985;72:111-368. 15. Crawford MH, Lindenfeld J, O’Rourke RA. Effects of oral propranolol on left ventricular size and performance during exercise and acute pressure loading. Circulation 1980;61:549-554. 16. Jose AD, Taylot RR. Autonomic blockade by propranolol and atropine to study intrinsic myocardial function in man. J Clin Invest 1969;48:2019-2031. 17. Pave1 DG, Zimmer AM, Patterson VN. In vivo labeling of red blood cells with 99mTc: a new approach to blood pool visualization. J Nucl Med 1977;18:305-308. 18. Kronenberg MW, O’Comior JL, Higgins SB, Pederson RW, Friesinger GC. Analysis of variables affecting calculation of left ventricular ejection fraction using a new technique for border definition. In: Ripley RL, HC Ostrow, eds. Proceedings of Computers in Cardiology. New York: Institute of Electrical and Electronic Engineers, 1980:107-113. 19. Dehmer GJ, Lewis SE, Hillis LD, Tweig D, Falkoff M, Parkey RW, Willerson JT. Nongeometric determinatioli of left ventricular volumes from equilibrium blood pool scans. Am J Cardiol 1980;45:293-300. 20. Maughan WL, Sunagawa K, Burkhoff D, Sagawa K. Effect of arteiial impedance changes oil the end-systolic pressure-volume relation. Circ Res 1984;54:595-602. 21. McKay RG, Aroesty JM, Heller GV, Royal HD, Warren SE, Grossman W. Assessment of the end-systolic pressure-volume relationship in human beings with the use of a time-varying elastance model. Circulation 1986;74:97-104. 22. Ricci DR, Orlick AE, Alderman EL, Ingels NB Jr, Daughters GT II, Kusnick CA, Reitz BA, Stinson EB. Role of tachycardia as an inotropic stimulus in man. J Clin Invest 1979;63:695-703. 23. Govier WC. Myocardial alpha adrenergic receptors ancl their role in the production of a positive inotropic effect by sympathomimetic agents. J Phar-

1,1988

THE

AMERICAN

JOURNAL

OF CARDIOLOGY

Volume

61

627

macol Exp Ther 1968;159:82-90. 24. Kronenberg MW, Grambbw DW: McCain RW, Boucek RJ Jr, Moreau GA, Sagawa K, Friesinger GC. Both phenylephrine and methoxamine affect left ventricular contractile performance [abstr]. JACC 1986;7:122A. 25. Links JM, Becker LC, Shindledecker JG, Guzman P, Burow RD, Nickoloff EL, Alderson PO, Wagner HN. Measurement of absolute left ventricular volume from gated blood pool studies. Circtdation 1982;65:82-91. 26. Starling MR, Dell’Italia LJ, Nusynowitz NL, Walsh RA, Little WC, Benedetto AR. Estimates of left-ventricular volumes by equilibrium radionuclide angiography: importance of attenuation correction. J Nucl Med 1984;25:1420. 27. Kronenberg VW, Parrish MD, Jenkins DW Jr, Sandler MP, Friesinger GC. Accuracy of radionuclide ventriculography for estimation of left ventricular volume changes and end-systolic pressure-volume relations. JACC 1985; 6:106411072. 28. Magorien DJ, Shaffer P, Bush CA, Magorien RD, Kolibash AJ, Leier CV, Bcishore TM. Assessment of left ventricular pressure-volume relations using gated radionuclide angiography, echocardiograDhy and micromanometer pressure recordings. A new method for serial measurementS of systolic and diastolic function in man. Circulation 1983;67:844-853. 29. Kono A, Maughan WL, ,Sunagawa K, Hamilton K, Sagawa K, Weisfeldt ML. The use of left veritricular end-ejection pressure and peak pressure in the estimation of the end-systolic preiure-volume relationship. Circulation 1984;70:1057-1065. 30. Mahler F, Yo?an C, Ross J Jr. Inotropic effect of tachycardia and poststimulation potentiation in the conscious dog. Am J Physiof 1974;227:569-575. 31. Mauglian WL, Sunagawa K, Burkhoff D, Graves WL Jr, Hunter, WC, Sagawa K. Effect of heart rote on the canine end-systolic pressure-volume relationship. Circulation 1985;72:654-659. 32. Evans JE, Knapp CF, Lowery TR. Pressor response buffering by betaadrenergic cind cholinergic vasodilotion in tranquilized dogs. Am J Physiol 1979;236:H165-H173. 33. Goldberg LI, Bloodwell RD. Braunwald E, Morrow AG. The direct effects of noreoinephrine, epinephrihe and methoxamine on myocardial contractile force in man. Circulation 1960;22:1125-1131. 34. Endoh M, Shumann HJ. Frequency-dependence of the positive inotropic effect of methoxamine and naphazoline mediated by alpha-adrenoreceptors in the isolated rabbit papillary muscle. Nounyn Schmiedebergs Arch Pharmacol 1975;287:377-389. 35. Freeman GL, Little WC, O’Rourke RA. The effect of vasoactive agents on the left ventircular end-systolic pressure-volume relation in closed-chest dogs. Circulatiori 1986;74:1107-1113.