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Relative contribution of inotropic and vasodilator effects to amrinone-induced hemodynamic improvement in congestive heart failure
RelativeContributionof lnotropic and Vasodilator Effectsto Amrinone-Induced Hemodynamic Improvementin CongestiveHeart Failure MARVIN A. KONSTAM, MD, STEVEN R. COHEN, MD, DAVID S. WEILAND, MD, TAMI T. MARTIN, RN, DHIRENDRA DAS, MD, JEFFREY M. ISNER, MD, and DEEB N. SALEM, MD
The relative contribution of inotropk and vasodilator effect to amrinone-induced hemodynamk improvement in congestive heart failure (CHF) is unknown. In 9 patients with CHF, the effects of amrinone and nitroprusside on hemodynamic and radlonuclide measurements were compared to determine whether reduced afterload accounts for the amrinoneinduced decrease in left ventricular end-systolic volume. In each patient, the end-systolic pressurevolume relation was derived using nitroprusside. After terminating nitroprusside treatment, intravenous amrinone (3 mg/kg) caused end-systolic volume to decrease from 148 f 35 ml/m* (mean f standard deviation) to 133 f 32 ml/m* (p <0.05), causing an increase in cardiac index from 1.9 f 0.8 to 2.7 f 0.8 iiters/min/m* (p
tance. Niiroprusside doses needed to match the decrease in LV end-systolic volume induced by amrtnone caused significantly greater decreases in arterial end-systolic pressure than did amrinone (p
T
tractility or reduced afterload contributes to changes in ventricular systolic volume and cardiac output in patients with CHF after bipyridine therapy remains unknown. We compared the effect of amrinone with that of nitroprusside on relative changes in left ventricular (LV) end-systolic volume and on arterial end-systolic pressure to test the hypothesis that the amrinone-induced decrease in LV end-systolic volume exceeds that predicted for a pure vasodilator, indicating inotropit effect.
he bipyridine agents, amrinone and milrinone, aug ment myocardial contractility in isolated tissue preparations.l-4 In patients with congestive heart failure (CHF), these drugs increase cardiac output and reduce ventricular filling pressure.s-14 In some studies, changes in isovolumic phase indexes have suggested that amrinone and milrinone exert at least part of their clinical hemodynamic effect through augmented contractility.5Jl However, direct bipyridine-induced vasodilatation likewise has been demonstrated in in vitro preparations1JJ5 The degree to which increased con-
Methods
From the Departments of Medicine and Radiology, Tufts University and New England Medical Center, Boston, Massachusetts. This study was supported in part by grants from the American Heart Association, Dallas, Texas, and the American Lung Association, New York, New York. Manuscript received May 13. 1985: revised manuscript received June 18, 1985, accepted June 21.1985. Address for reprints: Marvin A. Konstam. MD, Division of Cardiology, Tufts University-New England Medical Center, Box 108.171 Harrison Avenue, Boston, Massachusetts 02111.
Study population: The study group consisted of 9 patients (6 men, 3 women], aged 26 to 72 years (mean 59). All were in New York Heart Association functional class III or IV. Four patients had dilated cardiomyopathy and 5 had coronary artery disease with healed myocardial infarcts. All gave written, informed consent. Study protocol: All patients underwent simultaneous hemodynamic-radionuclide study in the postab242
February
TABLE
I
Effects
of Nitroprusside --
and Amrinone _.--..-..
Baseline ----Heart rate (min-‘) Arterial ESP (mm Hg) Mean PCW pressure (mm Hg) Mean PA pressure (mm Hg) Mean RA pressure (mm Hg) Cardiac index (liters/min/m2) SW (dynes+cm-5) LVESVI (ml/mz) LVEDVI (ml/m2) LVEF
I, 1986
.--_
-
--.-
Nitroprusside’ -_---_l-
94f
THE AMERICAN
--.
12
.-
JOURNAL
._ .---
OF CARDIOLOGY
95f
10
99f
10
91 f 21
63 f
90
96 f
22
84 f
19+*
28 f 7
17f89
31 f 5
19 f
105
43 f 9
27 f
47f
34 f
15t
2.2 f 1,971 f
7 f 39 0.8 1,085
2.9 f 0.85 1,113 f
4835
10
16f8
8 f 59
1.9 f 0.8 2,170
f
1,031
2.7 f 0.85 1,472 f
5585
153 f
38
135 f 345
148 f 35
133 f 32t
181 f
41
173*37t
176 f 36
168 f
0.16 f 0.05
0.23 f 0.07+
0.16 f
0.05
34
0.21 f 0.06t
Values are mean f standard deviation. * Maximal dose of nitroprusside administered. t p <0.005 vs nitroprusside effect: $ p <0.05 vs baseline; 5 p
sorptive state. Diuretic and vasodilator drugs were discontinued at least 12 hours before study, and no patient received sedative premeditation. Right-sided cardiac catheterization was performed through an antecubital or femoral vein, using a balloon-tipped thermodilution catheter, and systemic arterial pressure was monitored using a brachial or radial arterial cannula. Simultaneously with hemodynamic measurements, sequential equilibrium-gated radionuclide ventriculograms were performed as previously described.16J7 Red blood cells were labeled in vivo by intravenous injection of stannous pyrophosphate followed 20 minutes later by 15 to 20 mCi of technetium99m (Tc-99m) pertechnetate. A portable gamma camera was positioned in the modified left anterior oblique view using a caudally tilted 25” slant-hole collimator, with the degree of obliquity chosen to maximize interventricular and right atrioventricular separation. Scans were acquired for 8 minutes in a 64 X 64 matrix mode on magnetic disk using a nuclear medicine computer, with a 15% window centered at the Tc99m photopeak. Data acquisition was gated to the patient’s electrocardiogram, with each cardiac cycle separated into 24 frames. Pressure measurements and heart rates were recorded during the first 2 minutes and last 2 minutes of each radionuclide acquisition with each pair of measurements averaged. Systemic arterial dicrotic notch pressure was taken as an estimate of end-systolic pressure.18-21 Thermodilution cardiac output [average of 3 recordings with less than 10% variation] was also measured simultaneously with each scan acquisition. After baseline hemodynamic and radionuclide recordings,
243
Amrinone
12
12f6
57
-.--_----
Repeat Baseline .- - _ ..-.-_-.-----
93f
109
Volume
ejection capillary
nitroprusside was infused intravenously at an initial rate of 0.3 pg/kg/min, with the dose increased in increments of 0.3 pg/kg/min until either mean arterial pressure had fallen to 80% of baseline, or a dose of 5 pg/kg/min was reached. Radionuclide and hemodynamic measurements were made in each patient during nitroprusside infusion at 1 or more infusion rates to achieve several data points for deriving the end-systolic pressure-volume relationship in each patient. Before each radionuclide scan, the drug infusion rate was held constant, and systemic arterial pressure and cardiac output were observed to remain stable for at least 5 minutes. After terminating nitroprusside infusion, systemic arterial pressure and cardiac output were permitted to return to baseline, at which time repeat baseline hemodynamic and radionuclide recordings were made. Amrinone was then infused intravenously, with an initial bolus of 1 mg/kg, followed by 0.5 mg/kg every 10 minutes to a total of 3 mg/kg. After stabilization of arterial pressure and cardiac output for at least 10 minutes, final hemodynamic and radionuclide recordings were performed. During each scan acquisition, variation in arterial end-systolic pressure was 10% or less and variation in heart rate was 5% or less. Radionuclide analysis: Radionuclide studies were analyzed using previously described methods.16J7f22 End-diastolic LV perimeter was drawn using a computer joystick, and background regions were defined automatically using a previously described computer algorithm.‘” The LV region was redrawn, if necessary, on an ejection fraction image, and background regions were redefined as before. Background was subtracted from the LV region of interest using average counts per
244
AMRINONE:
INOTROPIC
AND VASODILATOR
NITROPRUSSIDE Rest N
EFFECTS
AMRINONE Rest A
FIGURE 1. Hemodynamic effects of nitroprusside (N) and amrinone (A). Both drugs decreased arterial endsystolic pressure in all patients, although this effect was significantiy more pronounced with nitroprusside. Cardiac Index increased comparably with both drugs. Both drugs decreased systemic vascular resistance (SVR) in ail patients.
NITROPRUSSIDE Rest N
AMRINONE
Rest 4 \
I
0
0
%zk
8 0
FIGURE 2. EAects ot nitroprusside (N) and amrinone (A) on left ventricular (LV) end-systolic volume and election fraction. Both drugs caused a signiticant decrease in end-systolic volume, resuiting in an Increase in ejection fraction.
pixel in the background region at the end-systolic frame, and LV ejection fraction was calculated as (end-diastoliccounts - end-systolic counts)/end-diastolic counts. LV end-systolic and end-diastolic volumes were calculated by a counts-basedmethod.2zA value for LV countsper secondwas derived by dividing end-systolicor end-diastolic countsby total acquisition time per frame. Activity in 5-ml heparinized blood samples, drawn at the midpoint of each scan acquisition,was counted using the same gammacamera and collimator as were used for cardiac imaging, and counts were corrected for decay occurring between the times of cardiac and blood sample scan acquisitions.LV volumes were then calculated from the ratio of ventricular counts per secondto simultaneous counts per milliliter in the peripheral blood sample,with correction made for count attenuationas previously described.22 Intraobserver variability of our radionuclide measurementshas been tested by analysis of duplicate scanswith duplicate blood sample acquisitionsin a seriesof 10 patients.Coefficients of variation for LV ejection fractions and end-diastolic and end-systolicvolumes were 3.9% (percentof measured ejection fraction], 3.4% and %I%, respectively. Statistical methods: We comparedbaseline hemodynamic and radionuclide measurementswith those performed after drug administration using paired t
February
test. We evaluated the relation between nitroprussideinduced changes in pressure and ventricular volume in each individual using linear regression analysis, The significance of linear LV end-systolic pressurevolume relations for the entire population was tested using stepwise linear regression. Comparison of fractional changes in hemodynamics and ventricular volumes achieved in each patient with nitroprusside vs amrinone was performed using a paired t test.
Results Table I shows the effect of amrinone and of maximal nitroprusside doses on hemodynamic and volumetric measurements. Heart rate was not significantly influenced by either drug. Both nitroprusside and amrinone significantly decreased pulmonary capillary wedge pressure (p <0.005 and p
N
1, 1966
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OF CARDIOLOGY
Volume
57
245
that predicted for a pure vasodilator. First, in each patient we retrospectively identified doses of nitroprusside that had caused reduction in end-systolic volume most closely matching that induced by amrinone. We compared the effects of these nitroprusside doses and of amrinone on arterial end-systolic pressure to determine whether similar reduction in end-systolic volume accompanied a similar reduction in afterload. The doses of nitroprusside selected in attempt to match amrinone effect on LV end-systolic volume caused a slightly smaller mean decrease in end-systolic volume than did amrinone and a slightly smaller mean increase in cardiac output than did amrinone (Fig. 31, although these differences between amrinone and nitroprusside effects were not statistically significant, Although these nitroprusside doses effected similar or less pronounced improvement in LV end-systolic volume and in cardiac output than did amrinone, nitroprusside caused a greater decrease in arterial endsystolic pressure than did amrinone in 7 of 9 patients [Fig, 4). End-systolic pressure decreased an average of 13 f 6% [k standard deviation) with amrinone vs 21 f 7% with nitroprusside (p
A 1.
Nitroprusside
FIGURE 3. Response to nltroprusslde (N) doses selected to match the effect of amrinone (A) on left ventricular end-systolic volume (LVESV). Amrlnone caused a slightly greater mean decrease In end-systolic volume and a slightly greater mean Increase In cardiac output than did these nltroprusslde doses, although the differences between amrlnone and nltroprusslde were not statistically slgnlflcant (NS).
Amrinone
FIGURE 4. Amrlnone-Induced percent reduction In arterial endsystolic pressure compared wlth that caused by the nltroprusslde dose that achieved a comparable decrease In end-systolic volume. Patients with cardiomyopathy are Indicated by circles and those wlth coronary artery disease by squares Although amrlnone reduced end-systolic pressure In all patients, this decrease was exceeded by that Induced by nltroprusslde In 7 of g patients. The mean decrease in end-systolic pressure was slgnlftcantly greater wlth nitroprusslde than with amrlnone, lndlcatlng that afterload reduction was not the sole cause of the decrease in end-systolic volume.
246
AMRINONE:
INOTROPIC
AND VASODILATOR
EFFECTS
fractional reduction in arterial end-systolic pressure. In 6 of 9 patients,the amrinone-induced decreasein end-systolicvolume exceededthat expectedfrom the degree of afterload reduction, suggesting that improved contractility contributed to amrinone effect (Fig. 6). In contrast,in 3 patients, the changein endsystolic volume was no more than that expectedfrom the amrinone reduction in arterial end-systolicpressure, failing to indicate inotropic effect in these patients. There was no discernible difference between the responsesof patients with coronary artery disease vs those with cardiomyopathy (Fig. 4 and 6).
Discussion In patientswith CHF, amrinone acutelyreducesLV filling pressureand increasescardiac outputwith minimal effect on heart rate.5-10J3 Amrinone possesses both myocardial inotropic and direct vasodilatorproperties,lJJ5and the contribution of augmentedcontractility to improved ejection function in CHF has not previously been demonstrated.In our study,with amrinone administration, afterloadreduction occurredin all patientsand was the sole effect in some.However, overall, the relation between arterial end-systolic pressure and LV end-systolic volume differed from that observed with nitroprusside, indicating that improved contractility contributed to amrinone’s reduction in end-systolic volume and increase in cardiac output.
Both amrinone’s inotropic and vasodilator effects have been demonstratedin in vitro preparations.QJ5 In somepatients,evidencefor amrinone effect on contractility hasbeenderived from isovolumic phasecontractile indexes.5However, even assuming the load independenceof thesevariables,a,changein isovolumic phase indexes does not ensure that augmented contractility contributes to improved ejection performance.Other studieshave failed to demonstrateconsistentchangesin isovolumic phasecontractileindexeswith amrinone.‘OJ3In normal subjects,Borow et al23 showed the inotropic effect of milrinone, another bipyridine agent,as indicated by shifts in the LV endsystolic pressure-dimension and stress-shortening relations. To distinguishinotropic from vasodilatorproperties of amrinone in severe CHF, we compared amrinone and nitroprussidewith regardto the relative effectson pressureand volume to test the hypothesis that the amrinone-induced decreasein LV end-systolic volume exceedsthat predicted for a pure vasodilator.In somepatients,inotropic action was demonstratedby a decreasein end-systolic volume disproportionate to the effect on afterload;that is, the amrinone pressurevolume point was shifted to the left of the nitroprusside-derived end-systolic pressure-volume line. We did not manipulate afterload after amrinone administration; therefore,we cannot comment on the effect of amrinone on the end-systolicpressure-volumeslope,a
0 Boseline 0 Nifroprusside
FIGURE
5.
Relation
bhweeri
pressure and left ventrlcu!ar In lndlvldual patients durlng gression lines are shown.
100
I30
160
LV END-SYSTOLIC
200
130
VOLUME (ml/m2)
160
arterial
end-systolic
(LV) end-systolic volume nitroprusslde lnfuslon. Re-
Februarv
measureof systolic elastance.The leftward shift of the amrinone pressure-volumepoint may representeither an increasein slope or a parallel displacement of the pressure-volumeline. Regardless,a decreasein LV end-systolic volume exceeding that observed for a pure vasodilator, for a given reduction in afterload, indicates augmentedinotropic state. Several reservationsmust be discussed.First, radionuclide volumetric measurementsaresubjectto error, particularly resulting from estimations of background and attenuation. Our methods have been validated againstthe standardof contrastventriculography in patientswith a wide rangeof LV function and volume.22Using thesemethods,we observedlinearity of the end-systolic pressure-volume relation in patients with CHF,21and have observedslopescomparable to thosedescribedby Grossmanet al,19using contrast ventriculography in a similar population. Errors in the attenuation estimate would affect all measurements in an individual proportionally and should not alter our conclusions,which are based on displacement of the amrinone data point from the pressurevolume line and on comparisonof amrinone and nitroprusside effects, using each individual as his own control. The second concern relates to the use of changesin end-systolicpressureasan index for differencesin afterload. Although measurementof systolic wall stresswould be desirable,the validity of geometric assumptionsimplicit in wall stressestimates are questionable in diseasedventricles, which are variably deformed. Characteristics of pressure-volume and stress-volumerelations, including linearity, preload independenceand responsivenessto contractility changes,are similar. ~ExOJ~-~~ Stressis related directly to pressureand cavity dimension and inversely to wall thickness. At comparable end-systolic volumes, our finding of greaterend-systolicpressuresfor amrinone than for nitroprusside therefore supportsthe conclusion of a significant difference betweenthe 2 drugs in the relation betweenchangesinduced in afterloadand systolic emptying. The possibility of reflex autonomic inotropic changesinduced by amrinone and nitroprussiderepresentsan additional concern.In previous studiesno evidencehasbeen found for reflex responsesthat significantly alter contractility with nitroprusside doses achieving the degree of blood pressurereduction efOur lack of changein fected during our study.1gs27-2g heart rate supports this conclusion. Any reflex increasesin inotropic state occurring during nitroprusside infusion would only have servedto mask our observed differences between nitroprusside and amrinone. With amrinone, we likewise observed no heart rate changeto support the possibility of significant reflex effects.Such effects were even less likely than with nitroprusside, which causedgreater blood pressurereduction than did amrinone. Clinical implications: Although hemodynamic and functional improvement are major goalsin CHF management,regardlessof mechanisms,the contribution of significant inotropic effect implies that a given improvement in LV end-systolic volume, and therefore
1.‘%@6’
WE
AMEQ!CAN
JO’JPNAL
OF CARDIOLOGY
Volume 57
247
0
30 aI .E 5 g m E e 3; w 203
.E % 8 b 0” 8 8 IO-
8
0
h % z + 0’
/
/
/
/
8 =
/
/
8 /
/
/
/
/ /
/
/
1 IO
I 20
PREDICTED % Decrease in LVESV Based on Nitroprusside and Amrinone Effect on Arterial End-Systolic
P-V
Relation Pressure
FIGURE 6. Observed amrlnone-induced decrease In left ventrkular end-systolic volume (LVESV) vs effect predkted for a pure vasodllator. Circles lndlcate patients wlth cardiomyopathy and equares lndlcate patlents wlth coronary artery dlseaw. Predkted percent decrease In volume was estlmated from lndlvldual nltroprurrklederived end-systolic pressure-volume relatkru and amrlnone-lnduced fractional red&Ion In arterial end-systolic pressure. In 6 of 9 patlents, observed effect exceeded predkted effect, 8uggestlng Improved contractlllty. In 3 patients, effects could be explatned solely by afterload changes, lndkated by data pofnfs at or to the right of the line of ldentlty.
cardiac output,may be achievedwith lessreduction in arterial perfusion pressurethan would otherwise occur. The inotropic contribution of amrinone that we observedgenerallyprovides a rationale for combining therapy with a pure vasodilator,althoughin somepatients amrinone exhibited only vasodilator effects. Further work may elucidate characteristicsof suchpatients to facilitate choosinga rational courseof therapy. Our approachfor identifying the relevant mechanisms of amrinone action may be valuable in comparingdrugsand in selectingtheir most appropriate role in managing CHF.
References 1. Alousi AA, Farah AE, Lesher GY. Opalka CJ Jr. Cardiotonic activity of omrinoneWin 40680 (5-Amino-3,4’bipyridine-6(IHJ-one]. Circ Res 1979;45:666-667. 2. Millard RW, Dube G, Grupp I, Alousi A, Schwartz A. Direct vosodilotor and positive inotropic actions of omrinone. J Mol Cell Cardiol 1980;12:647-652. 3. Alousi AA. Canter JM, Montenaro MJ, Fort DJ, Ferrari RA. Cardiotonic activity of milrinone, a new and potent cardiac bipyridine. on the normal and foiling heart of experimental animals. J Cordiovasc Phormacol 1983; 5:792-603. 4. Alousi AA, Stankus GP, Stuart JC, Walton LH. Characterization of the
248
AMRINONE:
INOTROPIC
AND VASODILATOR
EFFECTS
cardiotonic effects of milrinone, a new and potent cardiac bipyridine, on isolated tissues from several animal species. J Cardiovasc Pharmacol 1983;5:804-811. 6. Benotti JR, Grossman W, Braunwald E, Davolos DD, Alousi AA. Hemodynamic assessment of amrinone. N EngI I Med 1978;299:1373-1377. 6. LeJemtel TH. Keung E, Sonnenblick EH, Ribner HS, Matsumoto M, Davis R. Schwartz W, Alousi AA, Davolos D. Amrinone: a new non-glycoside. nonadrenergic cardiotonic agent effective in the treatment of intractable myocardial failure in man. Circulation 1979;59:1098-1104. 7. Klein NA, Siskind SJ. Frishman WH, Sonnenblick EH, LeJemtel TH. Hemodynamic comparison of intravenous amrinone and dobutamine in patients with chronic congestive heart failure. Am J Cardiol 1981;48:170-175. 6. Wynne J, Malacoff RF, Benotti JR, Curfman GD, Grossman W, Holman BL, Smith TW, Braunwald E. Oral amrinone in refractory congestive heart failure. Am J Cardiol 1980;45:1245-1249. 9. Weber KT, Andrews V, Janicki JS, Wilson JR, Fishman SP. Amrinone and exercise performance in patents with chronic heart failure. Am J Cardiol 1981;48:184-189. 10. Wilmshurst PT. Thompson DS, Jenkins BS. Coltart DJ, Webb-Peploe MM. Haemodynamic effects of intravenous amrinone in patients with impaired Ieft ventricular function. Br Heart J 1983;49:77-82. 11. Bairn DS, McDowell AV, Cheniles J, Monrad ES, Parker JA. Edelson J, Braunwald E, Grossman W. Evaluation of a new bipyridine inotropic agent-milrinone-in patients with severe congestive heart failure. N Engl J Med 1983;309:748-758. 12. Maskin CS, Sinoway L, Chadwick B, Sonnenblick EH. Lejemtel TH. Sustained hemodynamic and clinical effects of a new cardiotonic agent, WIN 47203. in patients with severe congestive heart failure. Circulation 1983; 67:1085-1070. 13. Firth BG, Ratner
AV, Grassman ED, Winniford Assessment of the inotropic and vasodilator effects terenoI. Am J Cardiol 1984;54:1331-1336. 14. Kubo SH. Cody RJ, ChatterJee K, Simonton Acute dose range study of milrinone in congestive 1985;55:728-730. 15. Hill NS, Rounds S. Amrinone dilates pulmonary ic vasoconstriction in isolated rat lungs. Proc
MD, Nicod P, Hillii LD. of amrinone versus isoproC, Rutrnen H, Leonard D.. heart failure. Am J Cardiol vessels and blunts hypoxSot Exp BioI Med 1983;
173:205-212.
16. Maddox DE, Holman BL, Wynne J. Idoine J, Parker JA, Uren R, Neil1 JM, Cohn PP. Ejection fraction image; a non-invasive index of regionaI left ventricular WaII motion. Am 1 Cardiol 1978;41:1230-1238. 17. Holman BL, Wynne J, Idoine J, Zielonke J. Neil1 J. The paradox image: a
noninvasive
index
of regional
left ventricular
dyskinesis.
J Nucl
Med
1979;20:1237-1242.
16. Borow KM, Neumann A, Wynne J. Sensitivity of end-systolic pressuredimension and pressure-volume relations to the inotropic state in humans. Circulation 1982;853988-99Y. 19. Grossman W, Braunwald E. Mann T. McLaurin LP, Green LR. Contractile state of the left ventricle in man as evaluated from end-systolic pressurevolume reIations. Circulation 1977;56:845-852. 20. Mehmel HC, Stockins B. Ruffmann K, Olshausen K, Schuler G, Kubler W. The linearity of the end-systolic pressure-volume relationship in man and its sensitivity for assessment of left ventricular Junction. Circulation 1981; 63:1216-1222.
21. Konstam MA, Cohen SR, Salem DN. Conlon TP, Isner JM. Das D, Zile MR, Levine HJ. Kahn PC. Comparison of left and right ventricular endsystolic pressure-volume relations in congestive heart failure. JACC 1985; 5:1326-1334.
22. Konstam MA, Wynne J. Holman BL, Brown EJ, Neil1 JM. Kozlowski J. Use of equilibrium (gated) radionuclide ventriculography to quantitate left ventricular output in patients with and without left-sided valvular regurgitation. Circulation 198X64578-585. 23. Borow KM, Come PC, Neumann A, Bairn DS, Braunwald E, Grossman W. Physiologic assessment of the inotropic, vasodilator and afterload reducing effects of milrinone in subjects without cardiac disease. Am J Cardiol 1985;55:1204-1209.
24. 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. 26. Weber KT, Janickl JS, Hefner LL. Left ventricular force-length relations of isovolumic and ejecting contractions. Am J Physiol 1978;231:337-343. 26. Marsh JD. 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. 27. Yin FCP, Guzman PA, Brin KP, Ma&en WL, Brlnker JA, Trail1 TA. Weiss 1L. Weisfeldt ML. Effect of nitroprusside on hvdraulic vascular loads on the right .and left ventricle of patients with heart failure. Circulation 1983:67:1330-1339.
26. Brodie BR, Grossman W, Mann T. McLaurln LP. Effects of sodium nitroprusside on left ventricular diastolic pressure-volume relations. J Clin Inves 1977;59:59-88.
29. Franciose JA, Dunkman WB. Wilen M. Silverstein ventricular filling pressure during nitroprusside infusion failure. Am J Med 1963:74:457-464.
SR. “Optimal” left for congestive heart
The relative contribution of inotropk and vasodilator effect to amrinone-induced hemodynamk improvement in congestive heart failure (CHF) is unknown. In 9 patients with CHF, the effects of amrinone and nitroprusside on hemodynamic and radlonuclide measurements were compared to determine whether reduced afterload accounts for the amrinoneinduced decrease in left ventricular end-systolic volume. In each patient, the end-systolic pressurevolume relation was derived using nitroprusside. After terminating nitroprusside treatment, intravenous amrinone (3 mg/kg) caused end-systolic volume to decrease from 148 f 35 ml/m* (mean f standard deviation) to 133 f 32 ml/m* (p <0.05), causing an increase in cardiac index from 1.9 f 0.8 to 2.7 f 0.8 iiters/min/m* (p
tance. Niiroprusside doses needed to match the decrease in LV end-systolic volume induced by amrtnone caused significantly greater decreases in arterial end-systolic pressure than did amrinone (p
T
tractility or reduced afterload contributes to changes in ventricular systolic volume and cardiac output in patients with CHF after bipyridine therapy remains unknown. We compared the effect of amrinone with that of nitroprusside on relative changes in left ventricular (LV) end-systolic volume and on arterial end-systolic pressure to test the hypothesis that the amrinone-induced decrease in LV end-systolic volume exceeds that predicted for a pure vasodilator, indicating inotropit effect.
he bipyridine agents, amrinone and milrinone, aug ment myocardial contractility in isolated tissue preparations.l-4 In patients with congestive heart failure (CHF), these drugs increase cardiac output and reduce ventricular filling pressure.s-14 In some studies, changes in isovolumic phase indexes have suggested that amrinone and milrinone exert at least part of their clinical hemodynamic effect through augmented contractility.5Jl However, direct bipyridine-induced vasodilatation likewise has been demonstrated in in vitro preparations1JJ5 The degree to which increased con-
Methods
From the Departments of Medicine and Radiology, Tufts University and New England Medical Center, Boston, Massachusetts. This study was supported in part by grants from the American Heart Association, Dallas, Texas, and the American Lung Association, New York, New York. Manuscript received May 13. 1985: revised manuscript received June 18, 1985, accepted June 21.1985. Address for reprints: Marvin A. Konstam. MD, Division of Cardiology, Tufts University-New England Medical Center, Box 108.171 Harrison Avenue, Boston, Massachusetts 02111.
Study population: The study group consisted of 9 patients (6 men, 3 women], aged 26 to 72 years (mean 59). All were in New York Heart Association functional class III or IV. Four patients had dilated cardiomyopathy and 5 had coronary artery disease with healed myocardial infarcts. All gave written, informed consent. Study protocol: All patients underwent simultaneous hemodynamic-radionuclide study in the postab242
February
TABLE
I
Effects
of Nitroprusside --
and Amrinone _.--..-..
Baseline ----Heart rate (min-‘) Arterial ESP (mm Hg) Mean PCW pressure (mm Hg) Mean PA pressure (mm Hg) Mean RA pressure (mm Hg) Cardiac index (liters/min/m2) SW (dynes+cm-5) LVESVI (ml/mz) LVEDVI (ml/m2) LVEF
I, 1986
.--_
-
--.-
Nitroprusside’ -_---_l-
94f
THE AMERICAN
--.
12
.-
JOURNAL
._ .---
OF CARDIOLOGY
95f
10
99f
10
91 f 21
63 f
90
96 f
22
84 f
19+*
28 f 7
17f89
31 f 5
19 f
105
43 f 9
27 f
47f
34 f
15t
2.2 f 1,971 f
7 f 39 0.8 1,085
2.9 f 0.85 1,113 f
4835
10
16f8
8 f 59
1.9 f 0.8 2,170
f
1,031
2.7 f 0.85 1,472 f
5585
153 f
38
135 f 345
148 f 35
133 f 32t
181 f
41
173*37t
176 f 36
168 f
0.16 f 0.05
0.23 f 0.07+
0.16 f
0.05
34
0.21 f 0.06t
Values are mean f standard deviation. * Maximal dose of nitroprusside administered. t p <0.005 vs nitroprusside effect: $ p <0.05 vs baseline; 5 p
sorptive state. Diuretic and vasodilator drugs were discontinued at least 12 hours before study, and no patient received sedative premeditation. Right-sided cardiac catheterization was performed through an antecubital or femoral vein, using a balloon-tipped thermodilution catheter, and systemic arterial pressure was monitored using a brachial or radial arterial cannula. Simultaneously with hemodynamic measurements, sequential equilibrium-gated radionuclide ventriculograms were performed as previously described.16J7 Red blood cells were labeled in vivo by intravenous injection of stannous pyrophosphate followed 20 minutes later by 15 to 20 mCi of technetium99m (Tc-99m) pertechnetate. A portable gamma camera was positioned in the modified left anterior oblique view using a caudally tilted 25” slant-hole collimator, with the degree of obliquity chosen to maximize interventricular and right atrioventricular separation. Scans were acquired for 8 minutes in a 64 X 64 matrix mode on magnetic disk using a nuclear medicine computer, with a 15% window centered at the Tc99m photopeak. Data acquisition was gated to the patient’s electrocardiogram, with each cardiac cycle separated into 24 frames. Pressure measurements and heart rates were recorded during the first 2 minutes and last 2 minutes of each radionuclide acquisition with each pair of measurements averaged. Systemic arterial dicrotic notch pressure was taken as an estimate of end-systolic pressure.18-21 Thermodilution cardiac output [average of 3 recordings with less than 10% variation] was also measured simultaneously with each scan acquisition. After baseline hemodynamic and radionuclide recordings,
243
Amrinone
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-.--_----
Repeat Baseline .- - _ ..-.-_-.-----
93f
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nitroprusside was infused intravenously at an initial rate of 0.3 pg/kg/min, with the dose increased in increments of 0.3 pg/kg/min until either mean arterial pressure had fallen to 80% of baseline, or a dose of 5 pg/kg/min was reached. Radionuclide and hemodynamic measurements were made in each patient during nitroprusside infusion at 1 or more infusion rates to achieve several data points for deriving the end-systolic pressure-volume relationship in each patient. Before each radionuclide scan, the drug infusion rate was held constant, and systemic arterial pressure and cardiac output were observed to remain stable for at least 5 minutes. After terminating nitroprusside infusion, systemic arterial pressure and cardiac output were permitted to return to baseline, at which time repeat baseline hemodynamic and radionuclide recordings were made. Amrinone was then infused intravenously, with an initial bolus of 1 mg/kg, followed by 0.5 mg/kg every 10 minutes to a total of 3 mg/kg. After stabilization of arterial pressure and cardiac output for at least 10 minutes, final hemodynamic and radionuclide recordings were performed. During each scan acquisition, variation in arterial end-systolic pressure was 10% or less and variation in heart rate was 5% or less. Radionuclide analysis: Radionuclide studies were analyzed using previously described methods.16J7f22 End-diastolic LV perimeter was drawn using a computer joystick, and background regions were defined automatically using a previously described computer algorithm.‘” The LV region was redrawn, if necessary, on an ejection fraction image, and background regions were redefined as before. Background was subtracted from the LV region of interest using average counts per
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NITROPRUSSIDE Rest N
EFFECTS
AMRINONE Rest A
FIGURE 1. Hemodynamic effects of nitroprusside (N) and amrinone (A). Both drugs decreased arterial endsystolic pressure in all patients, although this effect was significantiy more pronounced with nitroprusside. Cardiac Index increased comparably with both drugs. Both drugs decreased systemic vascular resistance (SVR) in ail patients.
NITROPRUSSIDE Rest N
AMRINONE
Rest 4 \
I
0
0
%zk
8 0
FIGURE 2. EAects ot nitroprusside (N) and amrinone (A) on left ventricular (LV) end-systolic volume and election fraction. Both drugs caused a signiticant decrease in end-systolic volume, resuiting in an Increase in ejection fraction.
pixel in the background region at the end-systolic frame, and LV ejection fraction was calculated as (end-diastoliccounts - end-systolic counts)/end-diastolic counts. LV end-systolic and end-diastolic volumes were calculated by a counts-basedmethod.2zA value for LV countsper secondwas derived by dividing end-systolicor end-diastolic countsby total acquisition time per frame. Activity in 5-ml heparinized blood samples, drawn at the midpoint of each scan acquisition,was counted using the same gammacamera and collimator as were used for cardiac imaging, and counts were corrected for decay occurring between the times of cardiac and blood sample scan acquisitions.LV volumes were then calculated from the ratio of ventricular counts per secondto simultaneous counts per milliliter in the peripheral blood sample,with correction made for count attenuationas previously described.22 Intraobserver variability of our radionuclide measurementshas been tested by analysis of duplicate scanswith duplicate blood sample acquisitionsin a seriesof 10 patients.Coefficients of variation for LV ejection fractions and end-diastolic and end-systolicvolumes were 3.9% (percentof measured ejection fraction], 3.4% and %I%, respectively. Statistical methods: We comparedbaseline hemodynamic and radionuclide measurementswith those performed after drug administration using paired t
February
test. We evaluated the relation between nitroprussideinduced changes in pressure and ventricular volume in each individual using linear regression analysis, The significance of linear LV end-systolic pressurevolume relations for the entire population was tested using stepwise linear regression. Comparison of fractional changes in hemodynamics and ventricular volumes achieved in each patient with nitroprusside vs amrinone was performed using a paired t test.
Results Table I shows the effect of amrinone and of maximal nitroprusside doses on hemodynamic and volumetric measurements. Heart rate was not significantly influenced by either drug. Both nitroprusside and amrinone significantly decreased pulmonary capillary wedge pressure (p <0.005 and p
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that predicted for a pure vasodilator. First, in each patient we retrospectively identified doses of nitroprusside that had caused reduction in end-systolic volume most closely matching that induced by amrinone. We compared the effects of these nitroprusside doses and of amrinone on arterial end-systolic pressure to determine whether similar reduction in end-systolic volume accompanied a similar reduction in afterload. The doses of nitroprusside selected in attempt to match amrinone effect on LV end-systolic volume caused a slightly smaller mean decrease in end-systolic volume than did amrinone and a slightly smaller mean increase in cardiac output than did amrinone (Fig. 31, although these differences between amrinone and nitroprusside effects were not statistically significant, Although these nitroprusside doses effected similar or less pronounced improvement in LV end-systolic volume and in cardiac output than did amrinone, nitroprusside caused a greater decrease in arterial endsystolic pressure than did amrinone in 7 of 9 patients [Fig, 4). End-systolic pressure decreased an average of 13 f 6% [k standard deviation) with amrinone vs 21 f 7% with nitroprusside (p
A 1.
Nitroprusside
FIGURE 3. Response to nltroprusslde (N) doses selected to match the effect of amrinone (A) on left ventricular end-systolic volume (LVESV). Amrlnone caused a slightly greater mean decrease In end-systolic volume and a slightly greater mean Increase In cardiac output than did these nltroprusslde doses, although the differences between amrlnone and nltroprusslde were not statistically slgnlflcant (NS).
Amrinone
FIGURE 4. Amrlnone-Induced percent reduction In arterial endsystolic pressure compared wlth that caused by the nltroprusslde dose that achieved a comparable decrease In end-systolic volume. Patients with cardiomyopathy are Indicated by circles and those wlth coronary artery disease by squares Although amrlnone reduced end-systolic pressure In all patients, this decrease was exceeded by that Induced by nltroprusslde In 7 of g patients. The mean decrease in end-systolic pressure was slgnlftcantly greater wlth nitroprusslde than with amrlnone, lndlcatlng that afterload reduction was not the sole cause of the decrease in end-systolic volume.
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fractional reduction in arterial end-systolic pressure. In 6 of 9 patients,the amrinone-induced decreasein end-systolicvolume exceededthat expectedfrom the degree of afterload reduction, suggesting that improved contractility contributed to amrinone effect (Fig. 6). In contrast,in 3 patients, the changein endsystolic volume was no more than that expectedfrom the amrinone reduction in arterial end-systolicpressure, failing to indicate inotropic effect in these patients. There was no discernible difference between the responsesof patients with coronary artery disease vs those with cardiomyopathy (Fig. 4 and 6).
Discussion In patientswith CHF, amrinone acutelyreducesLV filling pressureand increasescardiac outputwith minimal effect on heart rate.5-10J3 Amrinone possesses both myocardial inotropic and direct vasodilatorproperties,lJJ5and the contribution of augmentedcontractility to improved ejection function in CHF has not previously been demonstrated.In our study,with amrinone administration, afterloadreduction occurredin all patientsand was the sole effect in some.However, overall, the relation between arterial end-systolic pressure and LV end-systolic volume differed from that observed with nitroprusside, indicating that improved contractility contributed to amrinone’s reduction in end-systolic volume and increase in cardiac output.
Both amrinone’s inotropic and vasodilator effects have been demonstratedin in vitro preparations.QJ5 In somepatients,evidencefor amrinone effect on contractility hasbeenderived from isovolumic phasecontractile indexes.5However, even assuming the load independenceof thesevariables,a,changein isovolumic phase indexes does not ensure that augmented contractility contributes to improved ejection performance.Other studieshave failed to demonstrateconsistentchangesin isovolumic phasecontractileindexeswith amrinone.‘OJ3In normal subjects,Borow et al23 showed the inotropic effect of milrinone, another bipyridine agent,as indicated by shifts in the LV endsystolic pressure-dimension and stress-shortening relations. To distinguishinotropic from vasodilatorproperties of amrinone in severe CHF, we compared amrinone and nitroprussidewith regardto the relative effectson pressureand volume to test the hypothesis that the amrinone-induced decreasein LV end-systolic volume exceedsthat predicted for a pure vasodilator.In somepatients,inotropic action was demonstratedby a decreasein end-systolic volume disproportionate to the effect on afterload;that is, the amrinone pressurevolume point was shifted to the left of the nitroprusside-derived end-systolic pressure-volume line. We did not manipulate afterload after amrinone administration; therefore,we cannot comment on the effect of amrinone on the end-systolicpressure-volumeslope,a
0 Boseline 0 Nifroprusside
FIGURE
5.
Relation
bhweeri
pressure and left ventrlcu!ar In lndlvldual patients durlng gression lines are shown.
100
I30
160
LV END-SYSTOLIC
200
130
VOLUME (ml/m2)
160
arterial
end-systolic
(LV) end-systolic volume nitroprusslde lnfuslon. Re-
Februarv
measureof systolic elastance.The leftward shift of the amrinone pressure-volumepoint may representeither an increasein slope or a parallel displacement of the pressure-volumeline. Regardless,a decreasein LV end-systolic volume exceeding that observed for a pure vasodilator, for a given reduction in afterload, indicates augmentedinotropic state. Several reservationsmust be discussed.First, radionuclide volumetric measurementsaresubjectto error, particularly resulting from estimations of background and attenuation. Our methods have been validated againstthe standardof contrastventriculography in patientswith a wide rangeof LV function and volume.22Using thesemethods,we observedlinearity of the end-systolic pressure-volume relation in patients with CHF,21and have observedslopescomparable to thosedescribedby Grossmanet al,19using contrast ventriculography in a similar population. Errors in the attenuation estimate would affect all measurements in an individual proportionally and should not alter our conclusions,which are based on displacement of the amrinone data point from the pressurevolume line and on comparisonof amrinone and nitroprusside effects, using each individual as his own control. The second concern relates to the use of changesin end-systolicpressureasan index for differencesin afterload. Although measurementof systolic wall stresswould be desirable,the validity of geometric assumptionsimplicit in wall stressestimates are questionable in diseasedventricles, which are variably deformed. Characteristics of pressure-volume and stress-volumerelations, including linearity, preload independenceand responsivenessto contractility changes,are similar. ~ExOJ~-~~ Stressis related directly to pressureand cavity dimension and inversely to wall thickness. At comparable end-systolic volumes, our finding of greaterend-systolicpressuresfor amrinone than for nitroprusside therefore supportsthe conclusion of a significant difference betweenthe 2 drugs in the relation betweenchangesinduced in afterloadand systolic emptying. The possibility of reflex autonomic inotropic changesinduced by amrinone and nitroprussiderepresentsan additional concern.In previous studiesno evidencehasbeen found for reflex responsesthat significantly alter contractility with nitroprusside doses achieving the degree of blood pressurereduction efOur lack of changein fected during our study.1gs27-2g heart rate supports this conclusion. Any reflex increasesin inotropic state occurring during nitroprusside infusion would only have servedto mask our observed differences between nitroprusside and amrinone. With amrinone, we likewise observed no heart rate changeto support the possibility of significant reflex effects.Such effects were even less likely than with nitroprusside, which causedgreater blood pressurereduction than did amrinone. Clinical implications: Although hemodynamic and functional improvement are major goalsin CHF management,regardlessof mechanisms,the contribution of significant inotropic effect implies that a given improvement in LV end-systolic volume, and therefore
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PREDICTED % Decrease in LVESV Based on Nitroprusside and Amrinone Effect on Arterial End-Systolic
P-V
Relation Pressure
FIGURE 6. Observed amrlnone-induced decrease In left ventrkular end-systolic volume (LVESV) vs effect predkted for a pure vasodllator. Circles lndlcate patients wlth cardiomyopathy and equares lndlcate patlents wlth coronary artery dlseaw. Predkted percent decrease In volume was estlmated from lndlvldual nltroprurrklederived end-systolic pressure-volume relatkru and amrlnone-lnduced fractional red&Ion In arterial end-systolic pressure. In 6 of 9 patlents, observed effect exceeded predkted effect, 8uggestlng Improved contractlllty. In 3 patients, effects could be explatned solely by afterload changes, lndkated by data pofnfs at or to the right of the line of ldentlty.
cardiac output,may be achievedwith lessreduction in arterial perfusion pressurethan would otherwise occur. The inotropic contribution of amrinone that we observedgenerallyprovides a rationale for combining therapy with a pure vasodilator,althoughin somepatients amrinone exhibited only vasodilator effects. Further work may elucidate characteristicsof suchpatients to facilitate choosinga rational courseof therapy. Our approachfor identifying the relevant mechanisms of amrinone action may be valuable in comparingdrugsand in selectingtheir most appropriate role in managing CHF.
References 1. Alousi AA, Farah AE, Lesher GY. Opalka CJ Jr. Cardiotonic activity of omrinoneWin 40680 (5-Amino-3,4’bipyridine-6(IHJ-one]. Circ Res 1979;45:666-667. 2. Millard RW, Dube G, Grupp I, Alousi A, Schwartz A. Direct vosodilotor and positive inotropic actions of omrinone. J Mol Cell Cardiol 1980;12:647-652. 3. Alousi AA. Canter JM, Montenaro MJ, Fort DJ, Ferrari RA. Cardiotonic activity of milrinone, a new and potent cardiac bipyridine. on the normal and foiling heart of experimental animals. J Cordiovasc Phormacol 1983; 5:792-603. 4. Alousi AA, Stankus GP, Stuart JC, Walton LH. Characterization of the
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EFFECTS
cardiotonic effects of milrinone, a new and potent cardiac bipyridine, on isolated tissues from several animal species. J Cardiovasc Pharmacol 1983;5:804-811. 6. Benotti JR, Grossman W, Braunwald E, Davolos DD, Alousi AA. Hemodynamic assessment of amrinone. N EngI I Med 1978;299:1373-1377. 6. LeJemtel TH. Keung E, Sonnenblick EH, Ribner HS, Matsumoto M, Davis R. Schwartz W, Alousi AA, Davolos D. Amrinone: a new non-glycoside. nonadrenergic cardiotonic agent effective in the treatment of intractable myocardial failure in man. Circulation 1979;59:1098-1104. 7. Klein NA, Siskind SJ. Frishman WH, Sonnenblick EH, LeJemtel TH. Hemodynamic comparison of intravenous amrinone and dobutamine in patients with chronic congestive heart failure. Am J Cardiol 1981;48:170-175. 6. Wynne J, Malacoff RF, Benotti JR, Curfman GD, Grossman W, Holman BL, Smith TW, Braunwald E. Oral amrinone in refractory congestive heart failure. Am J Cardiol 1980;45:1245-1249. 9. Weber KT, Andrews V, Janicki JS, Wilson JR, Fishman SP. Amrinone and exercise performance in patents with chronic heart failure. Am J Cardiol 1981;48:184-189. 10. Wilmshurst PT. Thompson DS, Jenkins BS. Coltart DJ, Webb-Peploe MM. Haemodynamic effects of intravenous amrinone in patients with impaired Ieft ventricular function. Br Heart J 1983;49:77-82. 11. Bairn DS, McDowell AV, Cheniles J, Monrad ES, Parker JA. Edelson J, Braunwald E, Grossman W. Evaluation of a new bipyridine inotropic agent-milrinone-in patients with severe congestive heart failure. N Engl J Med 1983;309:748-758. 12. Maskin CS, Sinoway L, Chadwick B, Sonnenblick EH. Lejemtel TH. Sustained hemodynamic and clinical effects of a new cardiotonic agent, WIN 47203. in patients with severe congestive heart failure. Circulation 1983; 67:1085-1070. 13. Firth BG, Ratner
AV, Grassman ED, Winniford Assessment of the inotropic and vasodilator effects terenoI. Am J Cardiol 1984;54:1331-1336. 14. Kubo SH. Cody RJ, ChatterJee K, Simonton Acute dose range study of milrinone in congestive 1985;55:728-730. 15. Hill NS, Rounds S. Amrinone dilates pulmonary ic vasoconstriction in isolated rat lungs. Proc
MD, Nicod P, Hillii LD. of amrinone versus isoproC, Rutrnen H, Leonard D.. heart failure. Am J Cardiol vessels and blunts hypoxSot Exp BioI Med 1983;
173:205-212.
16. Maddox DE, Holman BL, Wynne J. Idoine J, Parker JA, Uren R, Neil1 JM, Cohn PP. Ejection fraction image; a non-invasive index of regionaI left ventricular WaII motion. Am 1 Cardiol 1978;41:1230-1238. 17. Holman BL, Wynne J, Idoine J, Zielonke J. Neil1 J. The paradox image: a
noninvasive
index
of regional
left ventricular
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J Nucl
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16. Borow KM, Neumann A, Wynne J. Sensitivity of end-systolic pressuredimension and pressure-volume relations to the inotropic state in humans. Circulation 1982;853988-99Y. 19. Grossman W, Braunwald E. Mann T. McLaurin LP, Green LR. Contractile state of the left ventricle in man as evaluated from end-systolic pressurevolume reIations. Circulation 1977;56:845-852. 20. Mehmel HC, Stockins B. Ruffmann K, Olshausen K, Schuler G, Kubler W. The linearity of the end-systolic pressure-volume relationship in man and its sensitivity for assessment of left ventricular Junction. Circulation 1981; 63:1216-1222.
21. Konstam MA, Cohen SR, Salem DN. Conlon TP, Isner JM. Das D, Zile MR, Levine HJ. Kahn PC. Comparison of left and right ventricular endsystolic pressure-volume relations in congestive heart failure. JACC 1985; 5:1326-1334.
22. Konstam MA, Wynne J. Holman BL, Brown EJ, Neil1 JM. Kozlowski J. Use of equilibrium (gated) radionuclide ventriculography to quantitate left ventricular output in patients with and without left-sided valvular regurgitation. Circulation 198X64578-585. 23. Borow KM, Come PC, Neumann A, Bairn DS, Braunwald E, Grossman W. Physiologic assessment of the inotropic, vasodilator and afterload reducing effects of milrinone in subjects without cardiac disease. Am J Cardiol 1985;55:1204-1209.
24. 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. 26. Weber KT, Janickl JS, Hefner LL. Left ventricular force-length relations of isovolumic and ejecting contractions. Am J Physiol 1978;231:337-343. 26. Marsh JD. 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. 27. Yin FCP, Guzman PA, Brin KP, Ma&en WL, Brlnker JA, Trail1 TA. Weiss 1L. Weisfeldt ML. Effect of nitroprusside on hvdraulic vascular loads on the right .and left ventricle of patients with heart failure. Circulation 1983:67:1330-1339.
26. Brodie BR, Grossman W, Mann T. McLaurln LP. Effects of sodium nitroprusside on left ventricular diastolic pressure-volume relations. J Clin Inves 1977;59:59-88.
29. Franciose JA, Dunkman WB. Wilen M. Silverstein ventricular filling pressure during nitroprusside infusion failure. Am J Med 1963:74:457-464.
SR. “Optimal” left for congestive heart