Control of cardiac output in thyrotoxic calves Evaluation of changes in the systemic circulation

Control of cardiac output in thyrotoxic calves.

Evaluation of changes in the systemic

circulation.

S Goldman, … , M Olajos, E Morkin

J Clin Invest.

1984;

73(2)

:358-365.

https://doi.org/10.1172/JCI111220

.

The contribution of peripheral vascular factors to the high output state in thyrotoxicosis was

examined in 11 calves treated with daily intramuscular injections of L-thyroxine (200

micrograms/kg) for 12-14 d. Thyroxine treatment increased cardiac output from 14.1 +/- 1.4

to 24.7 +/- 1.4 liters/min (P less than 0.001) and decreased systemic vascular resistance

from 562 +/- 65 to 386 +/- 30 dyn-s/cm5 (P less than 0.01). Blood volume was increased

from 65 +/- 4 ml/kg in the euthyroid state to 81 +/- 6 ml/kg when the animals were thyrotoxic

(P less than 0.05). The role of low peripheral vascular resistance in maintenance of the high

output state was evaluated by infusion of phenylephrine at two dosages (2.5 and 4.0

micrograms/kg per min). In the euthyroid state, no significant decrease in cardiac output was

observed at either level of pressor infusion. In the thyrotoxic state, the higher dosage of

phenylephrine increased peripheral resistance to the euthyroid control level and caused a

small (6%) decrease in cardiac output (P less than 0.05). This small decrease in cardiac

output probably could be attributed to the marked increase in left ventricular afterload

caused by the pressor infusion as assessed from measurements of intraventricular pressure

and dimensions. Changes in the venous circulation were evaluated by measurement of

mean circulatory filling pressure and the pressure gradient […]

Research Article

Control

of

Cardiac Output

in

Thyrotoxic

Calves

Evaluation of Changes in the

Systemic

Circulation

Steven Goldman, MarceyOlajos, and EugeneMorkin

Department of Internal Medicine, VeteransAdministration Medical Center, Tucson, Arizona 85723;Departments ofInternal Medicine and Pharmacology, University ofArizona College of Medicine, Tucson,Arizona85724

Abstract. The contribution of

peripheral

vas-cular factors

to

the

high output

state in

thyrotoxicosis

was

examined in

11

calves treated

with daily

intramus-cular

injections

of

L-thyroxine (200

,lg/kg)

for 12-14 d.

Thyroxine

treatment

increased cardiac output from

14.1±1.4 to 24.7±1.4

liters/min

(P

<

0.001) and decreased

systemic

vascular resistance from 562±65

to

386±30

dyn-s/cm5 (P

<

0.01). Blood volume

was

increased

from 65±4

ml/kg in the

euthyroid

state to

81±6

ml/kg when the

animals

were

thyrotoxic

(P

<

0.05).

The role

of low

pe-ripheral vascular resistance in maintenance of the

high

output

state was

evaluated

by infusion

of

phenylephrine

at two

dosages (2.5

and 4.0

,Ag/kg

per

min).

In

the

eu-thyroid

state,

no

significant

decrease

in

cardiac output

was

observed at

either level of pressor infusion.

In

the

thyrotoxic

state,

the

higher

dosage of

phenylephrine

in-creased

peripheral

resistance

to

the

euthyroid

control

level

and caused

a

small

(6%) decrease in cardiac output (P

<

0.05).

This small decrease in

cardiac

output

probably

could be

attributed

to

the marked increase in left

ven-tricular

afterload caused

by

the pressor

infusion

as

assessed

from measurements

of

intraventricular pressure and

di-mensions. Changes in the

venous

circulation

were

eval-uated

by

measurement

of

mean

circulatory filling

pressure

and

the pressure

gradient

for

venous return

in six animals

during

cardiac

arrest

induced

by

injection

of

acetylcholine

into the pulmonary artery. Mean circulatory

filling

pres-sure

increased from 10±1 mmHg in the euthyroid

state

These studies were presented in part at the Annual Meetings of the

AmericanPhysiological Society, New Orleans, 23,April1982. Addressreprintrequests to Dr. Goldman, Veterans Administration

Hospital.

Receivedfor publication 15 June 1983 and in revisedform 19 Sep-tember1983.

TheJournalof ClinicalInvestigation, Inc. Volume73, February 1984, 358-365

to

16±2 mmHg (P

<

0.01) during thyrotoxicosis,

while

pressure

gradient for venous return increased

from 10±1 to

14±2 mmHg

(P

<

0.02).

These

changes

in venous

return curves were

not

affected

significantly by ganglionic

blockade with

trimethapan (2.0 mg/kg per

min)

before

cardiac

arrest.

Thus, the

high output

stateassociated with

thyrotoxicosis is

not

dependent upon

a low

systemic

vas-cular

resistance,

but is associated with

increases in blood

volume,

mean

circulatory filling pressure,

and

pressure

gradient for

venous return.

Introduction

The cardiac output is often increased two to three times in

thyrotoxic subjects (1) and in animals (2, 3) treated with

ex-ogenousthyroid hormone.Avariety of mechanisms havebeen

postulatedto explain the augmentation in cardiac output,

in-cluding chronotropic and inotropic stimulation ofthe heart, increasedblood volume, and decreased systemic arterial

resis-tance (4). However, recent experiments and analyses suggest thatnoneof these factorsarelikelyto account for an increase

incardiacoutputof this magnitude. Forinstance,anincrease in heart rateinduced by electrical pacing failsto increase the resting cardiac outputbymorethanafew percent(5). Also, a

chronic increase in blood volumecauseshardly any increasein

cardiacoutput, butrather,usuallycauses anincreaseinarterial pressure(6, 7).

Beginningwith Guyton and co-workers (8), the importance ofvenousfactors intheregulation of cardiac output have been recognized. Their studies demonstrated that the pressure dif-ferencebetweentheperipheral veins and right atrium, the so-called pressuregradient for venous return

(PGVR),'

is a major determinant of blood flow returning to the heart. When this concept is combined with the classical formulationfor control of cardiac outputasafunction of right atrial (RA) pressure and

1. Abbreviations usedinthis paper: LA,leftatrial;LV, leftventricular; MCFP, meancirculatory fillingpressure;PGVR,pressuregradientfor

inotropicstate,thatis,as afamily of ventricular function

(Frank-Starling) curves, a framework is provided for evaluating the

relative importance of changes in the heart and peripheral

cir-culation inalterated hemodynamic states.

In thepresentstudy,wehave examinedtheeffects ofexcess

thyroid hormoneonthesystemic circulation in consciouscalves,

someofwhichwereinstrumented with sonomicrometercrystals

andpressurecatheterstopermit simultaneous evaluation of left ventricular (LV) performance. The effects on cardiac output

produced bynormalizingthesystemicvascular resistance with

phenylephrine,arelativelypurealpha-adrenergicagonist,were

determined before and aftertreatment with thyroid hormone.

Inaddition,changesinthevenousreturncurve weremonitored

bymeasuring the systemicvenous pressureduring

acetylcholine-induced cardiacarrest,that is, themeancirculatory filling

pres-sure(MCFP). The results indicate that the highoutput statein thyrotoxicosis is not dependent upon maintenance ofa low

systemic vascular resistance, butmayresultfromashiftin the

venous return curve such that thenew curve crossesthe new

cardiac function curveat a higher intercept on the flow axis,

resulting inamarked increasein cardiacoutput. Methods

Animal experiments. Experimentswereperformedon 11 calvesabout

5-6 mo ofage (90-130 kg). In six animals, sonomicrometer crystals

andpressuretransducerswereimplanted into theLV byusing the

op-erativetechniques described earlier (3).Ahigh fidelity micromanometer (Konigsberg Instruments, Pasadena, CA, P-7)wasinserted into theLV

chamberthroughastab incision in theapexof the heart. Pacing electrodes were suturedtothe left atrial (LA) appendage. Two pairs of5-MHz

sonomicrometercrystals, measuring either 4or5mmin diameter,were

placed in the LV walltocontinuouslymeasureLV wallthicknessand

LVminordiameter. For LV minor diametermeasurements,onecrystal

wasplaced throughadiagonally directed stabwoundcreatedbyaNo.

16gaugeneedleontothe posterior endocardial surface of the ventricle

neartheminorequator.The other endocardial crystalwasplaced slightly

lateraltothe left anterior descendingcoronaryartery.The second pair ofcrystalswasplacedoneither surface of the LV free wall in thesame

plane. This crystal pairwasused formeasurementofLVwall thickness.

Aortic Pressure (mm Hg)

58.2

LVDiameter (mm)

225

L

26.7

LVP

(mmHg)

0_

ECG

A c

Allcrystalswerepositionedsoastoprovide the shortest possible ultrasonic transit time. The position of the crystalswasverifiedatnecropsy.

Insix animals, aorticpressures wererecorded through 3-mm silastic

tubingintheright carotidarterywhichwasconnectedtoaP23IDstrain gauge(Statham Instruments, Inc., Oxnard, CA). Thegaugewaspositioned

atthemid-chestlevel and referencedtoatmosphericpressure.LV

me-chanical and hemodynamicmeasurementswere madein thestanding position without sedation. Datawere'recordedon anoscillographic

re-corder(VR-6, ElectronicsforMedicine,Inc., Pleasantville, NY). The

sonomicrometer crystalswereattachedtoanelectronicsystem(Triton Technology, San Diego, CA) which has been described earlier (9). Cardiac

outputwasmeasuredintriplicate usingaflow-directed thermal dilution pulmonaryarterycatheter andaminicomputer (No. 9510-A, Edwards Laboratories, Santa Ana, CA).

Control measurements ofheart rate, aorticpressure, LVpressure, andwall motionweremadedaily from7 to 10 daftersurgeryinthe conscious, unsedatedstatewith the heart beatingspontaneously.When

stable values had been achieved, the effects ofelevation ofsystemic bloodpressureby phenylephrine infusiononLVfunction and cardiac

output weredetermined. The animals then were lightly anesthetized

withamixture of halothane, nitrous oxide, and oxygenandacontrol value of MCFP was obtained. Thyrotoxicosis was induced by daily intramuscular injection of L-thyroxine (200 jg/kg). Allmeasurements

wererepeated 12-14 d after the initial dose of thyroxine.

Phenylephrine infusion. Phenylephrinewasadministered by

con-tinuous intravenous infusionat an initial rateof 2.5 jig/kg per min.

Thisdosewassufficienttoincrease peak systolic bloodpressureto - 175

mmHg. Heart ratewas heldconstantby electronic atrial pacingata

value slightlygreaterthan the sinus ratein orderto insure complete

capture. A small doseofatropine (0.1 mg)wasused,ifnecessary,to

maintain 1:1 atrioventricular conduction. After the bloodpressurehad

beenmaintainedatthis level for 10 min, recordings of cardiacoutput,

aortic pressure, and LV wall motion were made. The phenylephrine infusionratethenwasincreasedto4.0 jg/kgpermin, which increased

arterialsystolicpressureto-200mmHg and all recordingswererepeated

(Fig. 1).

MeasurementofMCFP. MCFPwasmeasuredinthecontrolstate

andafter2wkofthyroid hormone by the method described by Young

etal. (10). Animals were lightly anesthetized with halothane, nitrous

oxide, andoxygen.Acetylcholine (150 mg)wasadministeredas abolus injection throughapercutaneously introduced pulmonaryarterycatheter. Aortic and RApressures wererecorded during asystole.

D

04-I

0.

Figure 1.Recordingsof

electrocardiogram,LVpressure, LV

diameter,and aorticpressure ina

consciouseuthyroid calfat rest(A)and

duringintravenous infusionof

phenylephrine(4 jg/kgpermin)(B).

On the leftareshown similartracings

fromthesameanimal after2 wkof

treatmentwiththyroxineat rest(C)

andduringphenylephrineinfusion(D).

It

t

, A/ ,t'

Id\ A~s

V\Ifj

, .1

. ,N. . 0- V. .'. N _.' N\

N

A

,n'

AVtzf/\Af\ns

11 1

i-/.f

/

Calculations. LVpressures were recorded with a Konigsberg

In-struments P-7solid state pressure transducer. The value for maximum

LVdP/dt was obtained from an electronic differentiating circuit in the oscillographic recorder. Wall stress (WSt) was calculated from LV pressure

(F),

internal minor diameter (D), and wall thickness (WTh) as described earlier (3, 11), assuming aspherical model of theventricle: WSt =P XD/(4XWTh). Measurements were made at 40-ms intervals and peak wall stress values are reported.

Total vascular resistance was calculated as given below. Systemic vascularresistance=(mean aortic pressure-meanRApressure)/cardiac output.

MCFPwascalculated fromthesystemic arterial andRApressures

afteracetylcholinearrest asdescribed earlier (10):

MCFP=RA pressure+[(Arterial pressure-RApressure)/30].

ThePGVR was calculatedas theMCFPminus the RA pressure obtainedjust before cardiac arrest (10).

Blood volume determinations. Blood volumes were measured in six animals before and after thyroid administration using radioactive

"3'I-serum albumin (RISA) according to the method described by Blahd(12).

Statistics. Statistical analysis of the significance of differences

be-tween meanvalueswasmadeusing thet testfor paired values. Intergroup comparisons between control values and thoseobtained after infusion ofphenylephrineweremadeby Dunnett'stestformultiple comparisons

vs. acontrol, after analysisof variance had demonstrated statistically significant changes.

Results

Effectsof thyroxineonLVperformance. Heart rate, RA pres-sure, aortic pressure,cardiac output,peripheral vascular resis-tance, and LV dimensional measurements before and after treatment withthyroxine for 12-14 d are given in Table I.Mean

aortic pressure and cardiac output were significantly greater than control (P< 0.001) while peripheral vascular resistance wasdiminished. LVdP/dtwasincreased by -85% compared with the euthyroid value (P< 0.02). LVsystolic and diastolic

diatmeters

also were significantly increased (P <0.05). These increasesinLVdimensionscorresponded to anincrease in stroke volumefrom an average value of 150±16 ml in the euthyroid stateof 174±13mlafter thyroxine treatment. AverageLVwall thicknessatend-diastole wassomewhat less than control after treatmentwiththyroid hormone (P<0.05). RA pressure and

LVfractional shortening were unchanged in the thyrotoxic state. Thesebase-line measurements of hemodynamics and LV me-chanical functionineuthyroid and thyrotoxic calves are similar

tothosewehave reported earlier (3).

Effect

ofphenylephrine. The hemodynamic effects of two dose levels of phenylephrine in the euthyroid state and after2 wkofthyroxine treatment are represented graphically in Fig.

2 to illustrate the similarities in the effects on arterial blood pressure and cardiac output in both thyroid states. Statistical analysis of the

phenylephrine

datais presented in Table II.

Phenylephrine produced dose-related increases in the average

meanaortic pressures of both groups. The increments in

pres-sures in the thyrotoxic state, however, were not appreciably

Table I.Hemodynamic and LV Wall Motion Measurements in Euthyroid and Thyrotoxic Calves

Euthyroid Thyrotoxic P Values

Heartrate(beats/min) 96±5 146±6 <0.01

RApressure(mmfg) 1±1 1±1 NS LVsystolic pressure(mmHg) 114±4 148±6 <0.02

LVend-diastolic pressure (mmHg) 6±1 6±2 NS LVdP/dt(mmHg/s) 1,454±121 2,691±307 <0.02 Systolic aortic pressure(mmHg) 113±4 150±5 <0.001 Diastolic aortic pressure(mmHg) 73±7 94±5 <0.01 Mean aortic pressure(mmHg) 90±4 115±3 <0.001 Cardiac output(liters/min) 14.1±1.4 24.7±1.4 <0.001 Stroke volume(ml) 150±16 174±13 NS Systemic vascular resistance

(dyn-s/cm5) 563±65 386±30 <0.01

LVdiastolic diameter(mm) 45±4 53±4 <0.05

LVsystolic diameter(mm) 36±4 43±4 <0.05

LVwall thicknesssystole(mm) 13±2 12±2 NS

LVwallthickness diastole(mm) 11±2 11±2 <0.05 Peak wallstress(103 dyn/cm2) 143±12 232±27 <0.01 ValuesforLVdimensions and wallstress aremean±SE for sixcalves;

thehemodynamicdataarefrom 11 calves.

different from those in the euthyroidstate.Heartratewas held constantduring these experiments byatrialpacingandatropine

to prevent the reflex bradycardia that otherwise would have occurred.

Phenylephrine produced noappreciable change in cardiac

outputduring theeuthyroidstate. Inthethyrotoxic state, only

aslightdecrease incardiac output occurredatthehighestdose

level.Although theincrementalincreasesinperipheralvascular resistance were less in thethyrotoxic state, the absolute value forresistanceatthehighestphenylephrine dosage levelexceeded

that in theeuthyroid control state (602±34 vs. 562±65 dyn-s-cm5). Thus,despite normalizationofsystemicvascular resis-tanceby the pressor effects ofphenylephrine, cardiac outputin

thethyrotoxicstateremained almost twice theeuthyroidvalue. Changes inLVend-diastolic pressure and wall motion during thephenylephrine infusions alsowereobserved(Table II). LV

end-diastolic pressure and systolic and diastolic diameterswere

increased after administration of phenylephrineinboththyroid

stateswhilefractional shortening declined,aswouldbeexpected in response to the increase in afterload. Because of the larger initial dimensions and higher aortic pressures in thyrotoxic

an-imals, values for peak wall stresswere markedly increasedat

both dosages ofphenylephrine.

Effects of thyroxineon thevenoussystem. Representative tracings obtained during determination ofMCFP in the same

E 0

._

C,1

B

35

30_ 25- I

20 15 10 E 370-D

~290-I/I

'n 210

I

F

E _6-F T

_i T

E

5 50_

._?

>

-J ₄₀ T

Codc Phenyok Rwhbphrine

12.5pjg/kg/mn1 WO.p~g/kg/min)

Figure 2. Effects of increasingsystemicvascular resistance by infusion of graded doses ofphenylephrineinsix calves before (0) and after (0) 2wkoftreatmentwiththyroxine.(A)Meanaortic

pressure,(B) cardiacoutput,(C) peripheral vascular resistance, (D) LV wallstress,(E)LVend-diastolicpressure,(F)LVdiastolic diameter, and (G)LVsystolicdiameter. Means±SEareindicated.

heart for -7-8 s.During this period ofarrest,thearterialand venouspressuresreached plateaus,andthe arterialpressure

re-mained -20 mmHg above venous pressure. In these intact

animals, bloodcould notbepumped from the arterial to the

venous side ofthecirculation, as described byGuyton (8), to

reach the equilibriumpressureorMCFP.Therefore,MCFPwas

calculated byuseofthetwopressureplateausandthefact that the compliance of thevenous side of thesystem is estimated

to be 30 times greater than the arterial side (see Methods).

However, theamountaddedtothevenousplateau bythis

pro-cedure did notexceed 1 mmHginanyexperiment.

Afterthyroxine treatment, therewas an increase in aortic

pressures and heart rate (Fig. 3, right). During acetylcholine-induced cardiacarrest,aorticpressureswereessentiallythesame asintheeuthyroid state, butthevenouspressure plateauwas

5 mmHg higher than in the euthyroid state, resulting in an

increase in MCFPand PGVR.

Shown in Table IIIare group mean

values±SE

forRAand aortic pressures aftercardiacarrest in boththyroidstates. Cal-culated values for MCFP and PGVR alsoareshown. The average values for aortic pressure did not change after thyroxine treat-ment, while the RA pressure, MCFP, and PGVR were increased significantly(P<0.01). Values for MCFP and PGVR averaged -6 and 4 mmHg, respectively, greater during

thyrotoxicosis

than in theeuthyroidstate.

Todeterminewhether or notactivation of sympathetic

va-somotorreflexesplayed a role in the increase in MCFP,

mea-surements of MCFPwererepeatedin three calvesafter

ganglionic

blockade with trimethaphan (2.0

mg/kg

per min). In the eu-thyroidstate after

acetycholine-induced

arrest, RApressurewas

8±2

mmHg,aorticpressure,

26±4

mmHg; MCFP,8±2mmHg; and PGVR,

9±1

mmHg. Comparable values in thethyrotoxic state were: RA pressure,

12±1

mmHg; aortic pressure,

21±1

mmHg; MCFP,

12±1

mmHg; and

PGVR,

12+1

mmHg. Thus,

there werecomparable decreases in MCFP of -25 and 20%, respectively, afteracetylcholine-inducedarrest in theeuthyroid andthyrotoxic states.

Blood volumes changes. In six animals, blood volumes were measured by RISA before and after treatment with thy-roxine (Table IV). Mean blood volume was65±4ml/kg in the euthyroidstate and increased to

81±6

ml/kg afterthyroid hor-mone (P<0.05). On the average, plasma volume and erythrocyte mass also were greater in the thyrotoxic state.

Discussion

The results present the firstsystematicattempt to evaluate the role of changes in the arterial and venous compartments in maintainingthe high output stateassociatedwiththyrotoxicosis. These results deserve further comment in terms ofearlier studies of theperipheral circulationinthyrotoxicosisandtheusefulness of venous return curves andcardiac functioncurves in under-standing thisunique high output state.

Theilen and Wilson

(13)

suggested that

phenylephrine,

a

relatively pure

alpha-adrenergic

agonist, might be used to

sep-aratecentralvs.peripheral mechanismsin

thyrotoxicosis.

They reasoned that if the increase incardiac output was secondary

toperipheral vasodilation,thenapurely

vasoconstricting

drug shouldcause a

disproportionate

decrease in thecardiacoutput ofthyrotoxic patients. Conversely, if the higher output were

causedprimarilybyadirect action ofthyroidhormoneon myo-cardialperformance, vasoconstriction shouldnot cause an ap-preciable change incardiac output. They found that increases in meanarterial pressure of -50 mmHg caused

insignificant

changesin thecardiac index ofeuthyroid subjects. However,a

similarincreaseinarterialpressure inthyrotoxic patients pro-ducedanaverage decrease in cardiac index of -34%. The

re-sultant cardiac index was identical to the value obtained in euthyroid subjects.However, these workers failedto

appreciate

that"normalizing"vascular resistance inthe two

thyroid

states

would produce a disportionately greater increase in afterload

inthethyrotoxicheart, which is illustrated bythepresentstudy.

I -A

165

145-125

105-85

1150-C

1060 _

950

-850-

X

750-/

450- /

350_

E

E

12

I

.S8 0:

Table ILEffects ofPhenylephrine inEuthyroid andThyrotoxic Calves

Euthyroid Thyrotoxic

Phenylephrine Phenylephrine Phenylephrine Phenylephrine Control (2.5yg/kg/min) (4.0yg/kg/min) Control (2.5jsg/kg/min) (4.0$&g/kg/min)

Heart rate(beats/min) 95±5 91±9 91±9 146±6 146±6 146±6

LVsystolicpressure

(mmHg) 114±4 154±4* 201±4§ 148±6 174±8 206±10*

LVend-diastolic pressure

(mmHg) 6±1 13±1* 22±3* 7±2 18±4* 25±2*

Aorticpressuresystolic

(mmHg) 113±4 154±5t

200±5*

150±5 178±9 208±9t

Aorticpressurediastolic

(mmHg) 73±7 103±6* 140±5* 94±5 140±6* 146±9*

Aorticpressure mean

(mmHg) 90±4

131±9*

161±5t 115±6 152±6t 171±5f

Cardiacoutput 14.1±1.4 14.6±1.4 13.2± 1.2 24.7±1.4 23.3±2.1 23.2±1.6* Stroke volume(ml) 150±16 157±15 141±13 174±13 163±17 163±16 Systemic vascular resistance

(dyn/cm5) 563±65 814±92 1,046±118* 386±30 550±53* 602±34*

LVdiastolicdiameter(mm) 45±4 47±5* 47±4t 53±4 56±6* 57+5*

LVsystolic diameter (mm) 36±4 39±5* 41±4t 43±4 47±6* 47±4t

Fractional shortening 0.21±0.02 0.18±0.02 0.15±0.01 0.21±0.02 0.18±0.02 0.16±0.01 Peak wallstress

(XI03dyn/cm2) 143±12 193±24* 274±27* 232±27 284±44 315±50

Valuesrepresentmean±SE for sixcalvesbeforeandaftertreatmentwith thyroxine (200Ag/kg/d)for 12-14 d. Pvalueswerecalculatedonthe

basis of Dunnett'stestfor multiplecomparisons withacontrol. *P < 0.05 Referstocomparison between phenylephrine infusionand control

thyroidstate.tP<0.01. §P<0.001.

Shown in Table II aretheresultsofintravenous infusions ofphenylephrine before andafter2 wkofthyroxinetreatment. In the euthyroid state, an increment of70 mmHg in mean arterial pressure producednosignificant changeincardiac

out-put. This isexplainedby the fact thatLVdimensionsand end-diastolic pressure were increased during the pressor infusion, which would tend to maintain forward blood flow by the Frank-Starling mechanism. Because of these compensatory adjust-ments,peripheral vascular resistance isnot amajor determinant of cardiac output within the the normalphysiological operating range of the heart (14). On the other hand, as increases in afterload approach the ability ofthemyocardium to develop tension, cardiac output will decline. In thyrotoxic animalsat

thehigher level of phenylephrine infusion (4.0 gg/kg/per min), cardiac output decreased by 6%, but peakwallstress was 120% greater than the euthyroid control value. Smaller, but quali-tativelysimilar effectson LVfunction wereobservedin euthyroid animals. Thus, the high cardiac output in thyrotoxicosis is rel-ativelyindependent of changes in peripheral resistance and the slight decrease obtaineduponnormalizing resistanceisprobably related to the marked increase in afterload produced by the pressorinfusion.

Comparedwith the normalyounganimals used in thisstudy, manyof thepatients studied byTheilen andWilson (13) also mayhavehad some reduction inmyocardial functional capacity associated withaging,theduration of theirillness,orthe presence of other forms of heart disease. This may have contributedto

the greatereffect of pressor infusiononcardiac output observed

intheir study.

The partplayed bythe systemicvenoussystem in thehigh output state associated with thyrotoxicosis has received little attention. Frey (15) studied hand blood flowand venomotor

toneinnineuncomplicated casesof thyrotoxicosis beforeand after therapy. Venomotor tone (Apressure/Avolume) was as-sessed during changes in hand volume produced by inflation ofanoccluding cuff and recorded withahandplethysmograph. Despite a 50% reduction in hand blood volume after treatment,

nosignificant changes were found in venomotortoneor inthe initial peripheral venous pressure. This result was somewhat unexpected, since it hadbeenhypothesizedthat constrictionof capacitance vessels might beafactor inincreasingvenous return.

Inthe presentstudy, we have evaluated the role ofthevenous

18ri 1,.

AorticPressure ,i

(mmHg) i,,

15

RightAtrial I.

Pressure

(mmHg) .Ziv +.'.iS,'v.>stiJ_'v.'s'9'is 0 1''lI''i;'*'' ;'''

ECG \* '*" " " - * ''

2 s

Figure3.Representativerecords of MCFP determinations froma

single calf before(left)andafter(right)treatmentwiththyroxinefor2 wk. Shown arearterialpressure andrightatrial pressure. Cardiac

arrest wasinducedbyrapid injection (arrow) of 150mgacetylcholine

into the pulmonaryartery. Ineachcase,theheart wasstopped for

beenarrested and pressures in all the compartments are in equi-librium. This measurement is a function of the unstressed vol-ume,compliance, and the volume of blood in the system. The unstressed volume is the volume of blood in the system when MCFP equals zero and represents -85% of the normal blood volume in anesthetized dogs (16, 17). The hemodynamic im-portance of MCFP is that it, minus RA pressures, determines the PGVR. Because under steady state conditions venous return must be equal to cardiac output, MCFP is a major determinant of cardiac output.

Theaverage value for MCFP obtained here in lightly anes-thetized euthyroidcalves (10±1 mmHg) is similar to that ob-tained using acetylcholine arrest by Young et al. (10) in sedated dogs (9.9±1.6 mmHg). Sinceacetylcholinehasavariety of ac-tions on the circulation and nervous system that potentially

TableIII. Pressure Measurements in Euthyroid and Thyrotoxic

CalvesafterAcetylcholine-inducedCardiacArrest

Euthyroid Thyrotoxic PValues

RApressure(mmHg) 8±2 13±3 <0.01 Aorticpressure(mmHg) 28±2 26±2 NS Meancirculatory filling

pressure

(mmHg)

10±1 16±2 <0.01

Pressure gradientfor

venous return(mmHg) 10±1 14±2 <0.02 Values are mean±SE for six calvesbefore and after treatment with

thyroxine(200

,tg/kg)

for 12-14 d.

-7-8 s,during which theRApressure rose to aplateauvalue.This

value was -5 mmHg higher aftertreatment with thyroxine. During the sameperiod, arterial pressure fellto -30 mmHg.Equilibrium

valuesforthe twopressures, which istheMCFP,wasobtained using

theformulagiven in Methods.

could affect values for MCFP, these workers also measured MCFP in

pentobarbital-anesthetized

dogs in which the heart

had been arrested byacetylcholine or by electrical fibrillation. Nodifferences in values for MCFPwerefound between thetwo

methods forproducingarrest.

In the thyrotoxic state, an average increase of 6 mmHg in MCFP was observed (Table

III).

The relatively small increase in blood volume (20%) found in thyrotoxicosis, which is similar

tothatreported in thyrotoxic subjects (18), probably is not an adequate explanation for the large increase in MCFP. Chronic increases in blood volume of 20% in otherwise normal dogs have been reported to have little effect on MCFP (19). In the normal situation,stress-relaxationoccurs in the veins, increasing theircapacity sufficientlytoaccommodate theextrablood

vol-ume. In

thyrotoxicosis,

venous

compliance apparently

doesnot increasetothe same extent,

producing

an increasein MCFP. This is not related

primarily

to an increase in autonomic

ve-TableIV.Body Weight, Blood Volume, Plasma Volume, and

ErythrocyteMass inEuthyroidandThyrotoxic Calves

Euthyroid Thyrotoxic PValue

Bodyweight(kg) 120.6±9.3 99.6±7.7 <0.001

Bloodvolume

(ml/kg)

65±4 81±6 <0.05

Plasma volume

(ml/kg)

47±4 65±3 <0.01

Erythrocytemass

(ml/kg)

18±1 21±1 <0.05

Values are mean±SE for six calves before andafter treatment with thyroxine (200 Ag/kg) for 12-14 d.

18

r-1. v

iI

/

I"X

/

II I. .1 _.1I -4 -2 0 2 4 6 8 10 12 14 16 18

RAPressure(mmHg)

Figure4.Cardiac function andvenousreturncurvesforthe

euthyroidandthyrotoxicstates. Hypotheticalcardiac functioncurves wereconstructedtofitthroughmeasuredvalues from Tables I and IIIfor RApressureand cardiacoutputin theeuthyroid (0)and

thyrotoxic (0)statesbefore and afteracetylcholine-inducedcardiac

arrest.Theaveragevalue for the normal cardiacoutputis represented

bytheintersection ofthe cardiac function andvenousreturncurves.

Theincreased cardiacoutputobserved inthyrotoxic animals is the

result ofacombination of increasedmyocardialcontractilityand alterations in the characteristics of theperipheralvenous

compartment. This isrepresented bythe intersectionofthevenous

returncurvein thethyrotoxicstatewitha newcardiacfunction

curvewhich isdisplaced upwardandtothe left.

nomotor tone sinceMCFP decreasedonly-25%afterganglionic

blockade inthyrotoxicosis,whichwassimilar to the 20% decrease

observed ineuthyroid animals.

Tointegratetheobserved changesinthevenouscirculation

andheart,thegraphic approach originally described by Guyton (8)wouldseemuseful.Applicationof thisanalysis by

construc-tionofvenousreturn and cardiac function curvesisshown in

Fig. 4. Average values for euthyroid and thyrotoxic animals

from TableIII have been usedto construct these graphs. The

venous pressure at zero blood flow or MCFP was measured

when the circulationwasstopped byinjectionofacetylcholine. By recordingRApressureand cardiacoutputjust priorto

ace-tylcholine injection, the second point neededto construct the

venous return curve wasobtained.

Hypothetical cardiac function curves, whichare given for illustrativepurposesinFig. 4,weredrawnso as topassthrough measured valuesofRA pressureand cardiacoutput.Thepoint

atwhich thevenous return curveintersects the cardiac function

curve defines the cardiac output that would be produced by that set of curves. In the euthyroid state, the venous return curveintersects the cardiac functioncurve toproduceanormal cardiacoutputfor the calf of- _{14liters/minatanRApressure}

of -1 mmHg. Aftertreatment with thyroxine for 2

wk,

the MCFPwasincreased, shifting the venous return curve tothe right along the pressure axis. RA pressure before arrest was

changed verylittlesoin thyrotoxicosis the slope of thevenous return curve,which is inversely relatedto venousresistance, is essentially normal. The increase in MCFP observed after thy-roxinetreatmentis similartothat described in other highoutput states,suchasarteriovenous fistula (20) and anemia (21).

How-ever, in the latter conditions, the slope of the venous return

curveis markedly increased because of the decrease in venous

resistance.

Inprinciple, displacement of the venous return curve to the right shouldcause someincreaseincardiac output because the

venous curve would intersect the cardiac function curve at a

higher level. This effect is illustrated as the pointatwhich the venousreturn curve in thyrotoxicosis intersects the normal

car-diac functioncurveinFig.4.Thetheoretical increase in cardiac

output in this circumstance would be -40%. However, the positive inotropic action of thyroid hormone (3) causes the

car-diacfunction curve tobedisplaced upward and to the left. The

newvenousreturncurve thenintersects the new cardiac function

curve at a twofold higher value for cardiac output. Thus, the

characteristic high cardiacoutputassociatedwith thyrotoxicosis is produced byadifferent combination of actions on the systemic venouscirculation and heart than those found in other high output states.

Acknowledgments

The authorswish to thankGwen Roskefor technical assistance and EvelynEnglish for assistancewithpreparation ofthemanuscript.

Thiswork wassupported in part bythe VeteransAdministration,

theGustavus and Louis Pfeiffer Research Foundation, andNational Institutes ofHealthgrant HL-20984.

References

1. Merillon,J.P.,P.Passa, J.Chastre,A.Wolf,and R.Gourgon.

1982.Left ventricular functionandhyperthyroidism.Br. Heart J.

46:137-143.

2. Stauer, B. E., and A. Scherpe. 1975. Experimental hyperthy-roidism.I. Hemodynamicsandcontractilityinsitu. Basic Res.Cardiol.

70:115-129.

3. Goldman, S., M. Olajos,H. Friedman, W. R. Roeske, andE.

Morkin. 1982. Left ventricular performance inconscious thyrotoxic

calves.Am.J.Physiol. 242:Hl 13-121.

300r

270

-

240p-C ._

E

C)

0

210k

180

-150k

1201-

90g60

4. Freedberg,A. S., and M. W. Hamolsky. 1974. Effects ofthyroid

hormones on certain nonendocrine organ systems. In Handbook of

Physiology, Endocrinology. M. A. Greer and D. H. Solomon, editors.

American PhysiologicalSociety, Washington,DC. 3(Sect.7):435-468.

5. Cowley, A. W., Jr., and A. C. Guyton. 1971. Heart rate as a

determinant of cardiac output indogswitharteriovenous fistula. Am. J. Cardiol. 28:321-325.

6. Guyton, A. C. 1981. The relationship of cardiac outputcontrol

andarterialpressurecontrol. Circulation. 64:1079-1088.

7. Conway,J. 1962.Hemodynamicconsequences of induced changes

inblood volume. Circ. Res. 18:190-198.

8. Guyton,A. C., C. E. Jones, and T. G. Coleman. 1973.Circulatory Physiology: CardiacOutput and itsRegulation. W. B.Saunders Co.,

Philadelphia. 1-556.

9. Theroux,P., D.Franklin,J. Ross, Jr., and W. S. Kemper.Regional myocardial function duringacutecoronary occlusionanditsmodification bypharmacologicagents inthedog. 1974. Circ. Res. 35:896-908.

10. Young, D. B., R. H. Murray, R. G.Bergis, andA. K. Markov. 1980. Experimental angiotensin II hypertension. Am. J. Physiol. 239:H391-H398.

11. Sasayama, S., J. Ross, Jr., D.Franklin,C. M. Bloor, S.Bishop,

and R. B. Dilley. 1976. Adaptations ofthe left ventricle to chronic pressure overload. Circ. Res.38:176-178.

12. Blahd, W. H. 1971. Bloodvolume.InNuclearMedicine. P. K.

Schneiderand B.Benjamin, editors.McGraw Hill Book Co., New York.

593-602.

13. Theilen,E.O., and W. R.Wilson. 1967.Hemodynamic effects of peripheral vasocontriction in normal and thyrotoxic subjects. J.Appi.

Physiol. 22:207-210.

14. Herndon, C. W., and K. Sagawa. 1969. Combined effects of aorticandright atrialpressures onaortic flows.Am.J.Physiol. 217:65-72.

15. Frey, H. M. M. 1967. Peripheral circulation and metabolic con-sequencesofthyrotoxicosis. VII.Venomotor tone at restinthyrotoxic patients before and after treatment.Scand.J. Clin. Lab.Invest. 19:346-350.

16. Guyton, A. C., G. G. Armstrong, and P. L. Chipley. 1956.

Pressure volume curvesofthearterialand venous systemsinlive dogs.

Am.J.Physiol. 184:253-256.

17. Richardson, T. Q.,J. 0. Stallings, and A. C. Guyton. 1961.

Pressure volume curves in live, intact dogs. Am. J. Physiol. 201:471-474.

18. Herbert, V. 1978. Blood. In The Thyroid. S. C. Wernerand

S. H. Ingbar,editors.Harper&Row,Publishers,Inc., NewYork.

773-778.

19. Prather,J. W., and A.C. Guyton. 1969.Effect of blood volume,

meancirculatory pressure,and stressrelaxationoncardiacoutput. Am. J.Physiol.216:467-472.

20. Guyton, A.C.,and K.Sagawa. 1961. Compensations of cardiac

outputand other circulatory functions in areflex dogs with large A-V

fistulae.Am.J.Physiol. 200:1157-1163.

21. Guyton, A.C.,and T.Q. Richardson. 1961.Effectofhematocrit