Beneficial effect of amrinone on myocardial oxygen consumption during acute left ventricular failure in dogs

Beneficial Effect of Amrinone on Myocardial Oxygen Consumption During Acute Left Ventricular Failure in Dogs

JOHN H . JENTZER, MD THIERRY H . LEJEMTEL, MD EDMUND H . SONNENBLICK, MD, FACC EDWARD S . KIRK, PhD Bronx, New York

From the Department of Medicine, Division of Cardiology, Albert Einstein College of Medicine, Bronx, New York . This study was supported in pan by Grant HL 23171 from the National Institutes of Health, Bethesda, Maryland . Manuscript received August 20, 1980 ; revised manuscript received February 2, 1981, accepted February 11, 1981 . Address for reprints: Edward S . Kirk, PhD, Department of Medicine . Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461 .

In 11 dogs Ischemic left ventricular failure characterized by a 30 percent reduction In cardiac output and a left ventricular end-diastolic pressure of 18 mm Hg or more was produced by proximal occlusion of the left anterior descending coronary artery followed by serial occlusions of the distal left circumflex coronary artery . Administration of amrinone in an Intravenous bolus Injection followed by a constant Infusion produced improvements In cardiac output (from 1 .62 f 0 .50 to 2.19 f 0.52 Iiters/min [mean f standard deviation], p <0 .05), left ventricular end-diastolic pressure (from 21 .6 ± 3 .5 to 11 .0 ± 5 .4 mm Hg, p <0 .05) and peak positive rate of rise of left ventricular pressure [dP/dt] (from 1,264 ± 241 to 1,800 f 458 mm Hg-s-1 , p < 0 .05) . These Improvements were maintained throughout the 20 minute period of therapy . No significant alteration in heart rate or arterial pressure was noted . In parallel with the hemodynamic improvement myocardial oxygen consumption Improved to 0 .094 ± 0.0$ and 0 .092 ± 0 .04 vol-min -1-g -1 after 2 and 20 minutes ; respectively, of amrinone compared with 0 .124 ± 0 .05 during left ventricular failure (both p <0.05) . The effects of amrinone on left ventricular failure are due to augmented contractility and mild systemic vasodilatation . The reduction in myocardial oxygen consumption during amrinone-treated left ventricular failure presumably results from a reduction In ventricular wall tension that more than offsets the effect of an Increase In contractility.

Treatment of left ventricular failure precipitated by myocardial ischemia remains a major therapeutic challenge . In this setting the use of positive inotropic agents remains controversial because it is feared that inotropic stimulation may worsen the balance of oxygen supply and demand . A better understanding of the use of inotropic agents in left ventricular failure may be achieved by considering the factors determining myocardial oxygen consumption . Myocardial oxygen consumption is dependent on both the tension generated in the ventricular wall during systole and ventricular contractility .' Ventricular wall tension is in turn dependent on the pressure generated during systole and the left ventricular volume according to the Laplace relation . In heart failure ventricular volume may be increased and with inotropic stimulation ventricular volume and wall tension may decrease . Thus, the overall effect of a positive inotropic agent on myocardial oxygen consumption in the setting of acute myocardial ischemia is highly dependent on whether heart failure and ventricular dilatation are present . 2 Information based on experiments in nonfailing hearts may therefore be misleading . The evaluation of newer positive inotropic agents in acute ischemic left ventricular failure has been hampered by the lack of a model of acute ischemic left ventricular failure that is simple to prepare, stable and reproducible and in which the failure is primarily the result of myocardial ischemia . Prior models of left ventricular failure have been limited by the complexity of the procedure , 3 hemodynamic instability, 4 lack of uniformity in the hemodynamic indexes of left ventricular failures or

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AMRINONE

IN

LEFT VENTRICULAR FAILURE-JENTZER ET AL .

the use of additional agents to supplement myocardial ischemia in the induction of left ventricular failure . In this study we chose to investigate the hemodynamic and metabolic effects of amrinone, a nondigitalis, noncatecholamine positive inotropic agent, 7 on a new canine model of acute ischemic left ventricular failures

Methods Experimental preparation: Seventeen consecutive mongrel dogs of either sex weighing 17 to 26 kg were anesthetized with intravenous sodium pentobarbital, 30 mg/kg, and anesthesia was maintained thereafter with intravenous pentobarbital as needed . After tracheostomy, the dogs were intubated with a cuffed endotracheal tube and ventilated with an intermittent positive pressure respirator with 100 percent oxygen . The chest was opened through the left fifth intercostal space and the heart was exposed by excising the pericardium parallel to the phrenic nerve . The left anterior descending coronary artery was isolated below its first diagonal branch and the left circumflex coronary artery was isolated distal to its first major branch . Loose ligatures were placed around each isolated coronary vessel . A femoral venous catheter was used to administer drugs and a left atrial catheter was used to administer microspheres . A 7F balloon-tipped triple lumen thermodilution catheter (Gould Inc ., Oxnard, California) was introduced into the pulmonary artery through a femoral vein . Proper position of the catheter was verified by direct palpation of the catheter in the pulmonary artery and by the characteristic pulmonary arterial pressure tracing . Cardiac output was determined by thermodilution using a Gould Statham thermodilution cardiac output computer (model SP 1425) . Calculations were performed in duplicate using 5 cc of iced saline injectate. Pulmonary arterial and left ventricular pressures were recorded through cannulas connected to Statham P23Db strain gauge

transducers; systemic pressures was monitored with use of a femoral arterial cannula connected to another transducer . A second femoral arterial cannula was used for blood withdrawal during radioactive microsphere injection . All pressures were measured with reference from the mid chest position . Heart rate was obtained from the blood pressure recording . All recordings were made on a Beckman type SII oscillographic recorder . Heparin, 1 .0,000 U, was given intravenously to achieve anticoagulation . Lidocaine was given by intravenous bolus injection as needed to control ventricular ectopic activity . A polyethylene catheter was introduced through the left external jugular vein into the coronary sinus . Simultaneous central aortic and coronary sinus blood samples were analyzed for oxygen content in duplicate using a LEX 02 Con-TL (Lexington Instrument Corporation, Waltham, Massachusetts) . Amrinone (Win 40680) was kindly supplied by Dr . Adawia Alousi of the Sterling-Winthrop Research Institute Rensselaer, New York . A stock solution of 5 percent amrinone was prepared in 0 .5N lactic acid and was prepared fresh for each experiment ; subsequent dilutions were made with 0 .9 percent saline solution . Induction of isehemic left ventricular failure : This was done using the method of LeJemtel et als (Fig . 1) . Briefly, 15 to 20 minutes after permanent occlusion of the left anterior descending artery, the left ventricular end-diastolic pressure was adjusted, if necessary, to a level of 7 to 9 mm Hg by infusion of normal saline solution . A distal left circumflex arterial occlusion was then performed . If by 10 minutes after the left circumflex artery occlusion, the left ventricular end-diastolic pressure did not exceed 18 mm Hg an additional occlusion was performed slightly proximal to the original left circumflex artery occlusion . This procedure was repeated, as necessary, until the left ventricular end-diastolic pressure exceeded 18 mm Hg and cardiac output decreased by 30 percent . Once the initial left circumflex arterial occlusion was performed no

LEFT VENTRICULAR PRESSURE

CORONARY SINUS 02 CONTENT

AORTIC PRESSURE

THERMODILUTION CARDIAC OUTPUT

FIGURE 1 . Experimental preparation . LAD = left anterior descending coronary artery ; LCF = left circumflex coronary artery .

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additional pentobarbital or volume infusions were given . Stable left ventricular failure (more than 30 minutes) was achieved in 11 of the original 17 dogs, and these animals constitute the basis for this report. Amrinone administration : Once stable left ventricular failure was achieved, amrinone was administered as a 1 mg . kg - ' intravenous bolus dose, immediately followed by an infusion of 30 4g-kg -1 -min'' (three dogs) or 100 µg-kg-1-min-1 (eight dogs) that was maintained by a calibrated infusion pump (Harvard Apparatus) . Regional myocardial blood flow: Standard carbonized microspheres of 9 .0 t 1 µm in diameter labeled with the nuclides iodine-125, cerium-141, chromiun-51, strontium-85 and niobium-95 (3M Company) were used to measure regional myocardial blood flows The microspheres were suspended in a 63 percent sucrose solution and were dispersed before injection by mechanical agitation and sonication for 5 minutes in an ultrasonic bath. Ten ml of the solution, containing 106 beads, was injected over a period of 20 to 25 seconds through the left atrial cannula which was subsequently flushed with 10 ml of 0.9 percent saline solution . Usually there were no changes in the recorded hemodynamic variables after the injection, but occasionally a decrease in aortic pressure of 10 to 20 mm Hg and lasting about 10 to 15 seconds was noted . Arterial blood was withdrawn, starting just before the injection of microspheres and continuing for 30 seconds after the end of the injection, using a calibrated pump with a withdrawal rate of 19.4 ml/min (Harvard Apparatus) . This permitted the calculation of absolute tissue flows . 10 Gamma ray spectrometry was used to measure radioac-

tivity in all tissues and the corresponding blood samples using an ND 60 multichannel gamma ray counter (Nuclear Data Inc ., Schaumburg, Illinois) with a 3 inch (7 .6 cm) Nal (TI) crystal (Searle Analytic) . The number of microbeads present per gram of tissue averaged 1,134 ± 330 for the microspheres labeled with iodine-125, 1,484 1481 for those labeled with cerium-141, 2,193 ± 601 for those labeled with chromium-51, 2,113 ± 755 for those labeled with strontium-85 and 1,819 ± 812 for those labeled with niobium-95 in the samples from the normal myocardium, whereas the number was proportionally less in the samples from the ischemic tissue . The data were corrected for background and crossover counts on a Wang Laboratories model 2200S computer, which calculated the tissue flows in absolute units and the number of microspheres in each sample. Measurements of the aortocoronary sinus oxygen difference and microsphere administration were performed during a control period, 10 minutes after occlusion of the left anterior descending artery, during stable left ventricular failure and 2 and 20 minutes after the initiation of amrinone therapy . Before each of these measurements cardiac output was determined in duplicate to verify the stability of the preparation . Myocardial samples : In the anesthetized animal ventricular fibrillation was induced by an intravenous injection of potassium chloride after which the heart and various tissue samples (liver, stomach, spleen, diaphragm, hind limb skeletal muscle, kidney) were obtained . Immediately postmortem under equal pressure, simultaneous infusion of 0 .9 percent saline solution into the left main coronary artery, Evans blue dye into the left anterior descending artery at the site of its occlusion and acridine orange dye at the site of the most proximal left circumflex arterial occlusion was performed . The ischemic myocardium in areas supplied by the descending and left circumflex arteries as well as nonischemic myocardium were identified with the use of direct lighting and ultraviolet illumination . Myocardial samples were taken from the center of the areas stained with Evans blue dye and acridine orange

dye and from the center of the area perfused with 0 .9 percent saline solution. Transmural samples were then divided into endocardial and epicardial samples . The kidneys were sectioned along the sagittal plane and the cortex was separated from the medulla along their gross anatomic boundary. Calculations : Oxygen consumption per gram of nonischemic myocardium was calculated by multiplying the aortocoronary sinus oxygen difference by the transmural myocardial blood flow from the nonischemic myocardium . Systemic vascular resistance was calculated by dividing the mean aortic pressure by the cardiac output and converted to dynes s cm 5. Control dogs : In order to verify the stability of our model, acute left ventricular failure was induced in five control dogs . Once left ventricular failure was achieved no intervention was performed and the dogs were monitored for 60 minutes. Statistical analysis : All results are expressed as mean f standard deviation . Data were analyzed using the analysis of variance. The model was a single factor, repeated measures design. A maximum of five states were analyzed : (1) baseline ; (2) after ligation of the left anterior descending coronary artery ; (3) control left ventricular failure ; (4) amrinone infusion at 2 minutes ; and (5) amrinone infusion at 20 minutes . Hemodynamic data (aortic pressure, heart rate, thermodilution, cardiac output, left ventricular end-diastolic pressure, peak positive rate of rise of left ventricular pressure (dP/dt), pulmonary arterial pressure, systemic vascular resistance) in 11 dogs and tissue blood flow data in 9 dogs were obtained for all five states . Myocardial blood flow and myocardial oxygen consumption were obtained in 7 dogs for the baseline state and in 10 dogs for the subsequent four states. Analysis of variance was applied to the 10 animals for the latter four states . Results

Induction of heart failure : Stable left ventricular failure was achieved in 11 of the 17 animals in this study . Of the six dogs in which stable left ventricular failure was not induced, two died with primary ventricular fibrillation and four died with rapidly progressive, intractable left ventricular failure that terminated in fatal ventricular arrhythmias. Four of the experimental 11 animals were judged to be hypovolemic (left ventricular end-diastolic pressure less than 5 mm Hg) after occlusion of the left anterior descending artery and immediately given an infusion of approximately 150 ml of 0 .9 percent saline solution to raise the left ventricular end-diastolic pressure to the normal range (7 to 9 mm Hg) . Immediately before the first occlusion of the left circumflex artery the mean left ventricular end-diastolic pressure for the 11 animals was 8 .3 ± 1 .0 mm Hg compared with 7 .3 ± 2 .3 10 minutes after occlusion of the left anterior descending artery (difference not significant [NS]) . The time from occlusion of the left anterior descending artery to the first occlusion of the left circumflex artery averaged 30 ± 10 minutes ; the time from occlusion of the left anterior descending artery to achievement of stable left ventricular failure averaged 59 ± 17 minutes . On average, two occlusions of the left circumflex artery (range one to three) were required to induce left ventricular failure . The indexes of left ventricular function were significantly altered by the induction of left ventricular failure (Table I, Fig. 2) . Occlusion of the left circumflex

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TABLE I Hemodynamic Values Before and After Amrinone (mean ± standard deviation)

Control Cardiac 2 .79 output ±0.51 (liters/min) 107 .8 Mean aortic ±17 .8 pressure (mm Hg) Heart 160 rate ±27 (min'') LVEDP 4 .3 (mm Hg) ±2.4 Mean 19 .7 pulmonary ±5 .3 arterial pressure (mm Hg) 1706 Peak positive ±433 dP/dt (mm Hg/s) Systemic 2984 vascular ±423 resistance (dynes s cm 5 )

Amrinone At 2 At 20 Minutes Minutes

LAD Occlusion

LVF

2 .53 ±0.59

1 .62 1 ±0 .50

2 .19' ±0 .52

2 .23` +0 .68

102 .6 ±15 .8

91 .9 1 ±13 .2

84.6 ±16 .6

73 .8' ±17 .4

161 ±28

153 ±24

161 ±32

160 ±27

7 .3 ±2.3 18 .8 ±2 .4

21 .6 1 ±3 .5 26.9 1 ±10 .0

11 .0' ±5 .4 20 .2' ±3 .3

7 .6' ±1 .9 17 .1' ±2 .0

1580 ±453

1264r ±241

1800' ±458

1637' 1-404

3199 ±854

4537` ±1063

2901' 2629' ±598 ±556

' • 1 probability (p) values: ' p <0 .05 compared with values during left ventricular failure; 1 p < 0 .05 compared with control values . LAD = left anterior descending coronary artery ; LVEDP = left ventricular end-diastolic pressure ; LVF = left ventricular failure .

artery caused a significant reduction in cardiac output (from the normal values of 2 .79 ± 0 .51 in the control period to 1 .62 ± 0 .50 liters/min) and peak positive dP/d1(from 1,706 ± 433 to 1,264 ± 241 mm Hg s - ') and a significant elevation of left ventricular end-diastolic pressure (from 4.34:2 .4 to 21 .6 ± 3 .5 mm Hg) (p <0 .05) . Depressed left ventricular function was stable for the 20 minute period before the initiation of amrinone therapy . Heart rate and mean arterial pressure were not significantly altered by the induction of left ventricular failure . Figure 3 shows a transverse section of the left ventricle below the levels of the left anterior descending and left circumflex coronary arterial occlusions in a representative dog . The photograph was taken with multiple exposures using direct lighting and ultraviolet illumination . The blue- and orange-stained areas show the relative amount of left ventricular myocardium at this level rendered ischemic with this preparation . Amrinone therapy The administration of amrinone resulted in a dramatic alleviation of left ventricular failure that was both rapid and sustained (Fig . 2 and 4) . Two minutes after initiation of amrinone treatment, there were improvements in cardiac output (from 1 .62 ± 0.50 to 2 .19 t 0 .521iters/min, p <0 .05) peak positive dP/dt (from 1,264 ± 241 to 1,800 ± 458 mm Hg-s-1, p <0.05) and left ventricular end-diastolic pressure (from 21 .6 ± 3 .5 to 11 .0 ± 5 .4 mm Hg, p <0 .05) . These improvements were present throughout the 20 minute amrinone infusion . Mean arterial pressure declined to 73.8 ± 17 .4 mm Hg at the end of the amrinone infusion from a value of 91 .9 ± 13 .2 mm Hg during left ventricular failure (p <0 .05) .

20 LVEDP (mmHg)

10D

3 .0 -1

2 .0

C0 (L/min)

+

_l

10 * P . .05 Compared to LVF at T=20 minutes + P' .05 compared to Control

0

3000

dP/dT (mmHg/sec)

2000 1000-

+Amrinone Ima/kg IN Amrinone Inrutica



0-

1

aE y

20 22

40

TIME AFTER LVF (min)

FIGURE 2 . Hemodynamic results before and after administration of amrinone . C .O . = cardiac output ; dP/dT = peak positive rate of rise of left ventricular pressure ; I .V. = intravenously ; L = liters ; LAD, = occlusion of the left anterior descending coronary artery ; LVEDP = left ventricular end-diastolic pressure ; LVF = left ventricular failure ; T = time after amrinone .

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FIGURE 3 . Transverse section of the left ventricle of a representative dog . The blue- (top) and orange-(bottom left) stained areas are the areas rendered ischemic by occlusion of, respectively, the left anterior descending and the left circumflex artery .



AMRINONE IN LEFT VENTRICULAR FAILURE--IENTZER ET AL .

Myocardial blood flow : Myocardial blood flow in the nonischemic myocardium (Table II) rose slightly from a control value of 0.632 ± 0 .30 to 0 .677 ± 0.30 ml-min t -g - I after occlusion of the left anterior descending artery . The induction of left ventricular function elicited a dramatic increase in myocardial blood flow to 1 .04 ± 0 .34 ml-min -1 -g -1 . The administration of amrinone produced a gradual reduction in myocardial blood flow to 0 .836 ± 0 .33 ml-min-'-g' at 20 minutes. Amrinone produced no consistent alterations in ischemic myocardial blood flow or endocardial/epicardial blood flow ratios . The extremely low ischemic myocardial blood flow reflects the interruption of coronary collateral vessels subsequent to legations in both the left anterior descending artery and left circumflex artery arterial beds. Myocardial oxygen consumption : Oxygen consumption of nonischemic myocardium (Fig . 5, Table III) was measured in seven animals during the control period and did not differ from that measured after occlusion of the left anterior descending coronary artery (paired t test) . For the subsequent four states, measurements were made in 10 animals . Oxygen consumption of nonischemic myocardium was 0 .075 ± 0.03 Vol-min -, -g - 1 after occlusion of the left anterior descending artery and increased dramatically by 74 percent during left ventricular failure to 0 .124 ± 0 .05 (p <0.05) . Amrinone decreased oxygen consumption of the nonischemic myocardium to 0.094 :L 0 .05 vol-min-'-g 1 at 2 minutes (p <0 .05) and the reduction was maintained 20 minutes after the infusion was begun . The variation among animals in oxygen consumption was primarily due to variations in myocardial blood flow whereas oxygen extraction showed less variation under all experimental conditions . The changes in oxygen

TABLE II Myocardial Blood Flow (ml-min -1 -g -1 [mean ± standard deviation]) Myocardial Site

Control

Normal Endo

0 .615 ±0 .23 Epi 0 .649 ±0 .28 Trans 0 .632 ±0 .30 LAD-ischemic Endo Epi Trans LCx-ischemic Endo 0 .628 ±0.32 Epi 0 .707 10.36 Trans 0.668 ±0 .34

Amrinone At 20 At 2 Minutes Minutes

LAD Occlusion

LVF

0.632 ±0 .28 0 .724 ±0 .32 0.677 ±0 .30

1 .056 1 ±0 .39 1 .023 1 ±0 .33 1 .040 1 ±0 .34

0.924 10 .41 1 .0041 ±0 .33 0.964t ±0 .36

0 .785 ±0 .32 0 .886 ±0 .35 0 .836 ±0 .33

0 .034 ±0 .029 0 .113 ±0 .09 0 .073 ±0.04

0 .011t 10 .01 0 .057 1 ±0 .07 0 .0341 ±0 .03

0.0081 ±0 .01 0 .053t ±0.07 0 .0311 ±0 .03

0 .007 1 ±0.01 0 .0561 10 .07 0 .034t ±0.03

0 .689 ±0 .36 0 .733 ±0 .40 0 .711 ±0 .38

0 .11191 ' ±0 .03 0 .0751 • ±0.06 0 .0471 ' ±0.03

0 .018 1 * ±0.03 0 .0751' ±0 .07 0 .047t' ±0 .04

0 .0201 • ±0 .03 0.0721 • ±0 .07 0 .046 1 ' ±0 .03

'

.1 p values ; ' p <0 .05 compared with left ventricular failure ; t p <0 .05 compared with occlusion of the left anterior descending arteryEndo = endocardial ; Epi = epicardial ; trans = transmural; other abbreviations as in Table I .

consumption were also primarily due to variation in myocardial blood flow (Table III) . Tissue flow (Table IV) : The induction of left ventricular failure caused a reduction in splanchnic blood flow ; renal, hepatic, gastric, splenic and diaphragmatic blood flow all decreased . The administration of amrinone was associated with a sustained increase in the

200 AP (mmHg)

100 0

LVP (mm Hg)

20-1

liU~

0 -I

2 sec

dP/dT (mm Hg)

j J~

Al

2min. after Amrinone

20min.after Amrinone

L1

20 sec

000 2000 Lmerol

LADX

LVF IAmrinone lng kgHI .V.

~Anrinone I0O

kg-l-mm - ' I .Va

FIGURE 4. Original record from a representative dog . AP = aortic pressure; LVP = left ventricular pressure on an expanded scale ; other abbreviations as in Figure 2 .

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AMRINONE IN LEFT VENTRICULAR FAILURE-JENTZER ET AL.

30 25-

2020-

LVEDP

I

I

(mmHg)

0 Untreated n=5

15-

10

4-

41 Treated

LVEDP (mmHg)

-F-

n=Il

a..

10-

0

\i *P< .05 Compared to LVF + P- .05 Compared to Control

I

5-

)

Amrinon Imp/k9 IV . riAene

a

0

1

0

2SP0" 00

.15

20

40

60

TIME AFTER LVF (min) FIGURE 6 . Stability of experimental preparation in control dogs . Abbreviations as in Figure 2.

.10 MVO 21,i,_ , Vol-91 am .05

f-

-+

Amrinon, mg/kg IV. Amrrnons Infusion

0 11 ji 2

persistently elevated left ventricular end-diastolic pressure for at least 60 minutes (Fig . 6) .

I

1

20


co` TIME (min) FIGURE 5 . Effect of amrinone on myocardial oxygen consumption (MV02). Abbreviations as in Figure 2 .

blood flow to the renal medulla, the liver and an initial increase in the blood flow to the spleen and diaphragm . As a result of large statistical variation, none of these changes reached statistical significance . Control dogs: The five dogs in which acute left ventricular failure was induced had a hemodynamic profile similar to that of the 11 dogs given amrinone : a 30 percent reduction in cardiac output, a marked depression in peak positive dP/dt and a significantly elevated left ventricular end-diastolic pressure . The hemodynamic stability of these dogs is illustrated by the

Discussion

Ischemic left ventricular failure: One of the major difficulties in the in vivo evaluation of inotropic agents for the treatment of acute ischemic left ventricular failure has been the notable absence of a suitable model in which to evaluate new drugs . Such a model would be characterized by depression in indexes of contractility, a significant reduction in cardiac output and an elevation of left ventricular end-diastolic pressure" produced solely by acute myocardial ischemia. Such a preparation should be reliable, stable and easy to perform . The model developed in our laboratorys appears to have these properties. In open chest dogs ligation of the proximal left anterior descending artery followed b' serial ligations of the distal left circumflex artery will reliably produce acute left ventricular failure manifested by elevation of left ventricular end-diastolic pressure and depression of peak positive dP/dt and cardiac output .

TABLE III Myocardial Oxygen Consumpllon •

LAD Control Occlusion Arteriovenous

11 .86

11 .37

LVF 11 .48

Amrinon At 2 At 20 Minutes Minutes 10.21

Tissue Blood Flow (n = 9)

11 .16

oxygen ±3 .1 ±2.7 ±3 .4 ±2 .2 *2 .6 difference (vol/100 m) 0.677 1 .0401 0 .964: 0 .836 Myocardial 0.632 blood flow ±0.30 ±0 .34 ±0 .36 ±0 .33 ±0 .30 (mil-min-1 0-1 ) Myocardial 0 .071 0.075 0.124= 0 .094* 0 .092* ±0.05 oxygen ±0 .03 ±0 .03 ±0.05 ±0 .04 consumption (Vol-min- l0-1 ) Control measurements for 7 animals ; n = 10 for all other measurements . Statistical significance by analysis of variance on meaurements with n = 10 . T .t p values: 1 <0 .05 compared with left vens' tricular failure ; t <0 .05 compared with occlusion of the left anterior descending artery . Abbreviations as in Table I.

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TABLE IV

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LAD Tissue Liver Stomach Spleen Skeletal muscle Diaphragm Renal cortex

Renal medulla

Control

Occlusion

LVF

0 .722 0 .704 0 .442 ±0 .39 ±0 .37 ±0.21 0 .264 0 .158 0 .086 ±0 .25 ±0 .16 ±0.05 1 .702 2.424 1 .459 ±1 .27 ±1 .41 ±1 .06 0 .094 0 .027 0 .034 ±0 .15 ±0 .01 ±0.02 0 .184 0 .142 0 .083 ±0 .21 ±0 .11 ±0.07 5 .907 5 .876 5 .087 ±1 .07 ±1 .81 ±1 .08 1 .277 1 .477 1 .076 ±0 .81 ±1 .24 ±0 .7

Abbreviations as in Table I.

Amrinon At 2 At 20 Minutes Minutes 0 .680 ±0 .26 0 .077 ±0 .04 1 .801 ±1 .15 0 .037 ±0 .031 0 .098 ±0 .08 4 .671 ±1 .48 1 .085 ±0.85

0 .522 ±0 .18 0.084 ±0 .04 1 .078 ±1 .06 0 .031 ±0 .02 0 .08 ±0 .06 5 .018 ±1 .22 1 .261 ±0 .86



AMRINONE IN LEFT VENTRICULAR FAILURE-JENTZER ET AL .

Effects of inotropic agents in ischemic heart disease: The use of inotropic agents to augment myocardial contractility has been central in the treatment of chronic left ventricular failure .' 2 Conversely, in the setting of acute myocardial ischemia the use of inotropic agents has been controversial and has yielded conflicting results . 13-15 These discordant results are partly explained by the differences in the various studies in left ventricular end-diastolic pressure, which indirectly reflects left ventricular volume. Inotropic agents tend to increase myocardial oxygen consumption through an augmentation of myocardial contractility . 16,17 Myocardial oxygen consumption is

proportional to systolic wall tension, which is the product of intraventricular pressure and volume . With the administration of an inotropic agent, systolic wall tension increases to the extent that intraventricular pressure is increased, but decreases to the degree that the ventricular volume is reduced .18 In the nonfailing heart, inotropic agents increase contractility, which in turn increases oxygen consumption . Because systolic intraventricular pressure is minimally altered and ventricular volume is not greatly reduced, wall tension is not reduced and overall oxygen consumption increases . 2 In contrast, in the presence of increased ventricular volume and intraventricular pressure, the tendency for inotropic agents to augment oxygen consumption may be offset by the reduction of ventricular volume and the concomitant reduction in ventricular wall tension .' Response of ischemic myocardium to inotropic agents: During acute myocardial ischemia it has been suggested that the ischemic segment of myocardium has residual contractility 19 that contributes to overall left ventricular function 2 0 Furthermore, this segment of ischemic myocardium may respond to positive inotropic agents. 21,22 Thus, it can be anticipated that inotropic agents may increase the oxygen demand of ischemic myocardium by augmenting its contractile state . Despite the possible increases in the contractility of the ischemic myocardium, inotropic agents can cause a paradoxical systolic expansion in the area of ischemia .21 This is due to the differential augmentation in the contractility of the normal and the ischemic myocardium . Paradoxical systolic expansion of the ischemic myocardium results in a wasteful expenditure of ventricular pressure energy and increases myocardial oxygen consumption . 23 In myocardium that is not receiving enough blood flow to meet its metabolic needs, the oxygen consumption is proportional to the amount of blood flow to that area. Therefore, an increase in actual oxygen consumption of ischemic myocardium may not reflect further energy demand but rather an increased utilization derived from increased blood flow . Conversely, a decrease in oxygen consumption in this same ischemic area may reflect diminished blood flow, with possible deepening of ischemia. Unfortunately our model of ischemic left ventricular failure is not suitable for the evaluation of collateral blood flow because the ligation of both the left anterior descending and left circumflex arteries limits collateral blood flow severely .

Under conditions of nearly zero myocardial flow a satisfactory measure of local oxygen extraction is not available . For this reason we did not attempt to calculate oxygen consumption for the ischemic areas . Beneficial hemodynamic effects of amrinone : Amrinone is a noncatecholamine, nondigitalis glycoside agent that has considerable positive inotropic properties in vitro7 and in vivo . 24 Several clinical trials have shown it to he efficacious in patients with chronic left ventricular failure when administered intravenously 25,26 and orally . 27 In the setting of acute myocardial ischemia any possible beneficial effect of a positive inotropic agent on myocardial oxygen consumption will depend on the balance between augmentation in contractility and reduction in ventricular wall tension . 28 In this study we focused our attention on the ability of amrinone to improve the hemodynamic alterations and the concomitant changes in myocardial oxygen consumption in acute ischemic left ventricular failure . Treatment of stable left ventricular failure was begun simultaneously with a bolus injection and an infusion of amrinone . The effects of amrinone on this

model of left ventricular failure are increased cardiac output, decreased left ventricular end-diastolic pressure and augmented peak positive dP/dt . The first two effects may be due to reduction in afterload or an increase in myocardial contractility . The third effect, augmentation of peak positive dP/dt, may be due to an increase in myocardial contractility but is not consistent with simply a reduction in preload or afterload . Peak positive dP/dt is proportional to changes in inotropic state, 29 and in open chest canine preparations is directionally sensitive to changes in preload . 29-3 ' Provided that peak positive dP/dt occurs before aortic valve opening, it is largely independent of changes in afterload . 32 .33 The induction of left ventricular failure caused a marked increase in systemic vascular resistance and a reduction in splanchnic blood flow . Systemic vascular resistance decreased from 4,537 ± 1063 dynes s cm 5 during left ventricular failure to 2,901 ± 598 2 minutes after initiation of amrinone therapy and declined a small additional amount during the period of amrinone administration . Similarly, there was a partial restitution of splanchnic blood flow, most marked in the liver and renal medulla. Concurrent with the changes in systemic vascular resistance peak positive dP/dt increased significantly . The decline in systemic vascular resistance is most probably due to the improvement in myocardial contractility resulting in improved systemic circulation and probable withdrawal of sympathetic tone . 34 Therefore, the reduction in afterload seen with amrinone administration may be secondary to the improvement in left ventricular function. A direct effect of amrinone at the arteriolar level cannot be excluded, however. Alterations in vasomotor tone due to amrinone may occur directly as a response to the drug and indirectly through withdrawal of sympathetic tone resulting from improved myocardial contractility34 or peripheral pooling of the blood. Direct vasodilatory effects of amrinone are suggested from studies in normal dogs in

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AMRWONE IN LEFT VENTRICULAR FAILURE-JENTZER ET AL .

which very large doses of amrinone induced hypotension 35 The possibility that amrinone has vasodilatory properties was raised by the authors of two clinical trials25,26 in which amrinone was used for chronic congestive heart failure . Although the decrease in mean aortic pressure between the control period of left ventricular failure and 2 minutes after the amrinone bolus injection did not obtain statistical significance, the mean aortic pressure obtained after 20 minutes of amrinone treatment was reduced from the control period value (from 91 .9 ± 13 .2 to 73 .8 ± 17 .8 mm Hg, p <0 .05) . The gradual decrease in mean aortic pressure during treatment with amrinone was accompanied not by a decrease in cardiac output but by a similar decrease in left ventricular end-diastolic pressure (from 11 .0 t 5 .4 mm Hg 2 minutes after the amrinone bolus injection to 7 .6 ± 1 .9 mm Hg 20 minutes after amrinone treatment) . These changes are consistent with a reduction in both preload and afterload of the heart resulting in decreased cardiac filling combined with greater ejection fraction . The preload reduction may be due to spontaneous shifts in fluid or to a progressive venous vasodilatation caused by the amrinone . The former is unlikely because all hemodynamic variables were stable for up to 60 minutes in five control dogs in which no intervention was performed once stable left ventricular failure was induced (Fig . 6) . The striking increase in peak positive dP/dt noted within 2 minutes of the amrinone bolus injection indicates the inotropic effect of amrinone whereas the persistence of an elevated peak positive dP/dt throughout the 20 minute period of amrinone treatment in spite of a decrease in left ventricular end-diastolic pressure reveals that tachyphylaxis to the inotropic effect did not occur . We therefore believe that the salutory hemodynamic effects of amrinone on this model of left ventricular failure are due primarily to its isotropic activity with some possible additional benefit from a gradual reduction in preload and afterload . The hemodynamic changes seen 2 minutes after the amrinone bolus injection reflect blood levels due primarily to the bolus dose . As the levels of amrinone due to the bolus injection declined, the levels due to the infusion of amrinone rose and might account for some of the changes observed during amrinone treatment . Determination of blood levels of amrinone would assess this possibility but was not performed in this study . However, even if amrinone blood levels were in the socalled therapeutic range there would he no certainty that amrinone levels at the tissue receptor were unchanged . Myocardial oxygen consumption after amrinone : During the period of treatment with amrinone, myocardial oxygen consumption decreased significantly, indicating that the change in ventricular volume pre-

dominated over the augmentation in myocardial contractility . The samples of coronary sinus blood that were analyzed for oxygen content are a mixture of all left ventricular effluent 3 637 The use of coronary sinus blood samples as representative of venous blood from only normal areas neglects the contribution of the venous drainage of the ischemic areas . There is no error if extraction of oxygen by ischemic myocardium is equal to that of normal myocardium . Myocardial blood flow from the nonischemic myocardium was much greater than that from the ischemic areas supplied by the left anterior descending or left circumflex arteries (Table III) . It can therefore be expected that the contribution of the nonischemic myocardium to coronary sinus drainage would overshadow that from the ischemic areas of myocardium and that the effect of differences in oxygen extraction would be minimal . To quantitate this difference the free wall of the left ventricle in five dogs was dissected and then divided into the areas of nonischemic myocardium, left anterior descending arterial ischemia and left circumflex arterial ischemia, respectively . Although the amount of ischemic myocardium was large, its contribution to the total coronary sinus drainage was calculated to be less than 5 percent as a result of the severity of ischemia in the tissue . This small contribution is unlikely to influence our results significantly . An estimate of total left ventricular myocardial oxygen consumption was calculated using the estimates of the masses of ischemic and nonischemic myocardium and an assumed oxygen extraction of 100 percent for the ischemic area . Total left ventricular myocardial oxygen consumption was calculated to be 336 vol-min -1 during left ventricular failure, 220 at 2 minutes of amrinone therapy and 219 at 20 minutes of amrinone therapy . Conclusion : This study introduced a canine model of ischemic left ventricular failure that is stable, reproducible and simple to perform . In this model, amrinone, a new inotropic agent, was shown to improve dramatically the hemodynamic sequelae of left ventricular failure and the energy balance of the left ventricle . The net improvement in myocardial oxygen consumption during amrinone-treated left ventricular failure is caused by a reduction in ventricular wall tension, offsetting the increase in myocardial contractility due to amrinone . This exemplifies the multifactorial control of oxygen utilization in the heart .

Acknowledgment We extend our thanks to Walter Leon, Herbert Parker and Louis W arshaw for technical assistance and to Toni Maio and Annette Ingoglia for secretarial assistance . We also thank Calvin Eng, MD for his advice and review of the manuscript . Adawia Alousi, MD, in addition to generously supplying the amrinone for this study, provided essential advice on the use of the drug in the dog preparation .

References 1 . Covell JW, Braunwald E, Ross J Jr, Sonnenblick EH . Studies on digitalis. XVI . Effects on myocardial oxygen consumption . J Olin Invest 1966 ;45 :1535-42 . 2. Graham TIP Jr, Covell JW, Sonnenbllck EH, Ross J Jr, Braunwald

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281 . 21 . Purl PS, Bing RJ. Effects of drugs on myocardial contractility in the intact dog and in experimental myocardial Infarction . Basis for their use In cardiogenic shock . Am J Cardiol 1968 ;21 :886-93 . 22 . Vatner SF, Baig H, Manders WT, Murray PA. Effects of a cardiac glycoside on regional function, blood flow, and electrograms in conscious dogs with myocardial ischemia . Clrc Res 1978 ;43 : 413-23 . 23. Tennant R, Wiggers CJ . The effect of coronary occlusion on myocardial contraction . Am J Physiol 1935 ;112:351-61 . 24. Aloust AA, Farah AE, Lesher GY, Opalka CJ Jr. Cardiotonic activity of amrinone-WIN 40680 (5-amino-3,4'-bipyridin-6(1H)one . Circ Res 1979 ;45:666-77 . 25 . LeJemtel TH, Keung E, Sonnsnblick EH, et al . Amrinone: a new non-glycosidic, non-adrenerglc cardiotonic agent effective in the treatment of intractable myocardial failure in man, Circulation 1979 ;59:1098-104. 26 . Bennottl JR, Grossman W, Braunwaid E, Devotes DD, Alo ul AA . Hemodynamic assessment of amrinone : a new inotropic agent . N Engl J Mod 1978:299 :1373-7 . 27 . LeJemtel TH, Keung E, Rlbmr HS, et al . Sustained beneficial effects of oral amrinone on cardiac and renal function in patients with severe congestive heart failure . Am J Cardiol 1980 ;45 : 123-9 . 28 . Kirk ES, LeJemel TH, Nelson OR, Sonnenblidc EM . Mechanisms of beneficial effects of vasodilators and inotropic stimulation in the experimental failing ischemic heart . Am J Mod 1978 ;65 : 189-96 . 29 . Wallace AG, Skinner NS, Mitchell JH . Hemodynamic determinants of the maximal rate of rise of left ventricular pressure . Am J Physiol 1963;205:30-6 . 30 . Veragut UP, Krayenbuhl HP . Evaluation and quantification of myocardial contractility in the closed-chest dog . Cardiologia 1965 ;47 :96-112 . 31 . Burns JW, Covell JM, Roes J. Mechanics of isotonic left ventricular contractions . Am J Physlol 1973;224 :725-32 . 32. Ross J Jr, Covel JW, Sonrunbllck EH, Braunwaid E . Contractile state of the heart characterized by force-velocity relations in variably afterloaded and Isovolumic beats . Circ Res 1966 ;18: 149-63 . 33. Mason DT, Braunwald E, Covell JW, Sonnenbllck EH, Rose J . Assessment of cardiac contractility. The relation between the rate of pressure rise and ventricular pressure "rig isovolumic systole. Circulation 1971 ;44 :47-58 . 34. Mason DT, Braunwald E . Studies on digitalis . X . Effects of oubain on forearm vascular resistance and venous tone in normal subjects and in patients in heart failure . J Clin Invest 1964 ;43 :532-43 . 35 . Farah AE, Al usl AA. New cardiotonic agents: a search for digitalis substitute . Life Sci 1978 :22 :1139-48 . 36. Weam JT, Mettler Sit, Klumpp TO, Zschiesche U . The nature of the vascular communications between the coronary arteries and the chambers of the heart . Am Heart J 1933 ;9 :143-64 . 37 . Nakmawa HK, Roberts DL, Kiocke FJ . Quantification of anterior descending vs circumflex venous drainage In the canine great cardiac vein and Coronary sinus . Am J Physiol 1978;234:H1636.

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