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Experimental Studies

The Effect of Experimental Hypothyroidismon Coronary Blood Flow andHemodynamic Factors*

J OHN C. SCOTT, PH.D., THEODORE A. BALOURDAS,M.D. and MILL ARD N. CROLL, M.D.Philadelphia, Pennsylvania

T HE EFF ECTSUPON cardiodynamics of hyper-and hypothyroidism, particularly the for-mer, have been studied by many investigators.Hypothyroidism in man has been shown to beassociated with a reduction in heart rate, cardiacoutput and arterial pressure.2 n vi tro studiesof experimentally induced hypothyroidism havedemonstrated a reduction in oxygen consump-tion of the myocardium. However, few reportshave appeared describing the relationshipbetween myocardial consumption of oxygen,coronary blood flow and cardiac efficiency inthe animals with experimentally producedhypothyroidism. A somewhat comparable situa-tion of hypothermia has been studied in detail.3

Since controlled inactivation of the thyroidhas been used in recent years as a therapeutictool in the treatment of angina, more informa-tion concerning the effects on myocardialmetabolism would seem desirable. The presentreport deals with results obtained in the dogbefore and after the experimental production ofhypothyroidism by the use of I131.

METHODSBlood flow in the coronary sinus was measured bythe nitrous oxide desaturation method as describedby Goodale et aL4 Cardiac output, arterial bloodpressure, left ventricular oxygen consumption, etc.,were measured or calculated by methods describedearlier.6 The protein bound iodine PBI) conversionratio was estimated by using an anion exchange resinto remove iodide I.

The observations were made under morphine,chloralose anesthesia on a series of fourteen dogsweighing 17 to 24 kg. The routine experimentalprocedure for all of the dogs consisted of two sets ofobservations on each dog on the same day, the twoexperiments being separated by an interval of aboutone hour. During this period depth of anesthesiaand other factors were kept as nearly constant aspossibIe. This approach double runs) was appliedto the following experimental categories: 1) nor-mal dogs, 2) normal followed by atropine, 3)dogs with hypothyroidism. 4) hypothyroid followedby atropine. The dosage of atropine was 0.2 mg.per kg. given intravenously. A few days after thenormal experiment the dog was given 30 to 35mc. I13rby stomach tube. Four to eight weeks later asecond double run was performed, i.e., the samemeasurements were repeated both before and afteradministration of 13r.

RESULTSTable I lists the average values of the data

in the normal and in the hypothyroid stateboth before and after the administration ofatropine. The average per cent change forthe several categories is also listed. It is im-portant to note that the per cent change iscalculated for each individual difference andthen averaged, i.e., the calculation of per centwas based on the average of the differences, noton the difference of the averages. P value forthe average per cent change of several factorsconsidered to be of special interest is alsoincluded.

From the Department of Physiology and the Institute for Cardiovascular Research, Hahnemann Medical Collegeand Hospital, Philadelphia, Pennsylvania. This study was supported by Grant No. H-3815 of the National HeartInstitute, U. S. Public Health Service.

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Effect of Experimental HypothyroidismTABLEI

Mean and Average Per Cent Change of Measured Values

Factors*

No. of caseCSBFCVRMABPCILVWLV 02 consLV effic.HRA. 02cs. 02Cor. A-VMZ&SystemicA-V 01Rect. temp.Respiratory

rateMin. vol.BMR

1) 2)Normal HYPO-thyroid

13 1461 7 43.3

1 8 2.6110 105

22 1.522 1.68 46 5.8

16 3 17.160 4421 2 20.572 6.9

14 0 13.20 81 0.787 06 7.32

37 0 36.1123 4843 1

--

103.0731.4

(3)AveragePer Cent

Change ofsroups (1) to (2

14-27p

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692 Scott, Balourdas and Crollconsumption, heart rate, respiratory rate andrespiratory minute volume showed markedincreases.

Efects of Atrojine on the Dog with Hypothyroidism:The increases noted previously also occurred inthe animal with hypothyroidism. The absolutevalues for coronary sinus blood flow and heartrate were approximately the same but since thepre-atropine values were smaller the percent-age change with atropine was greater in thehypothyroid. Both the absolute and percent-age change in cardiac index were somewhatsmaller. A considerably greader reduction incalculated left ventricular efficiency wasproduced by atropine in the dog with hypo-thyroidism again as a result of the higherefficiency in the pre-atropine state.

OMMENTSHeart Rate: The increase or decrease in heart

rate associated with hyperthyroidism or hypo-thyroidism, respectively, has been attributedto the specific effects of the thyroid hormoneson the myocardial tissue. Thyroxine acceler-ates the rate in perfused hearts6 or even in theembryonic heart before the development ofneural tissue. In our experiments the percent increase in heart rate following atropinewas greater in the hypothyroid than in thenormal group but the actual rates in the twogroups were approximately the same. Thereduction in heart rate with hypothyroidismappears to be associated with an increased vagaltone or possibly with a reduction in the thresholdto vagal stimulation, since the blocking of vagalactivity with atropine produced similar heartrates in both groups. If one considers atropinein the dosage used in these experiments as astress stimulus, the hypothyroid heart seems tohave lost little of its rate-adaptive capacity.This is significant because the ability of theheart to change its rate is an important cardiacreserve mechanism.

Myocardial Oxygen Consumption: Both thetotal body oxygen consumption and the leftventricular oxygen consumption were reducedin the hypothyroid state. A comparison of theratio of left ventricular to body oxygen consump-tion in the normal with the hypothyroid groupfailed to show a significant difference. This isin agreement with Light et al.,s who noted aproportional increase in myocardial oxygen con-sumption in clinical hyperthyroidism. Sincethe influence of the thyroid upon myocardialoxygen consumption has been demonstrated

with cardiac tissue slices,9 it might be assumedthat the regulation is primarily at the cellularlevel rather than by means of heart rate. Onthe other hand, the regulation in the intactanimal may be effected to a significant degreethrough control of the heart rate. Recentevidence strongly supports the close associationbetween myocardial oxygen consumption andheart rate in the dog in a variety of experimentalsituations.5~10~11

This relationship also is borne out in thepresent data by the results obtained whenatropine was given to the normal and to thehypothyroid dog. Here there were extremeincreases in heart rate associated with markedincreases in myocardial oxygen consumption.In the hypothyroid state the oxygen consump-tion of the left ventricle increased over 150per cent in association with a 350 per cent in-crease in rate. The important point, however,is that the relatively low oxygen consumption ofthe hypothyroid heart equaled the value of thenormal group when both were subjected to theinfluence of atropine. Thus the influence ofrate upon left ventricular oxygen consumptionappears to be of the same order of magnitude inthe hypothyroid and the normal heart underthese experimental conditions.

Coronary Sinus Blood Flow: The changes incoronary sinus blood flow paralleled those forleft ventricular oxygen consumption. The flowdecreased in the hypothyroid state and increasedwith atropine in both groups, reaching aboutthe same value in spite of starting at a lower levelin the hypothyroid group. Again the explana-tion rests on the evidence of a close associationbetween coronary flow and heart rate.5J0v11

Cardiac Index: The reduction in cardiac indexin the hypothyroid dog agrees with the findingsof Stewart et a1.2 in patients with myxedema.They also reported an increase in the systemicA-V oxygen difference which was associatedwith an increase in circulation time. Althoughnot statistically significant, the increase in A-Voxygen difference is present in our data alsoand probably indicates correctly the direction ofchange. This increase should be considered inrelation to the total body oxygen consumption.The decrease in cardiac index is associated witha decrease in total oxygen consumption butan increased A-V oxygen difference. Since

A-V O2 difference = oxygen consumptioncardiac outputit appears that the cardiac index decreased rela-

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Effect of Experimental Hypothyroidism 693tively more than the oxygen consumption or, thatthe oxygen consumption was maintained in thehypothyroid at the expense of an increased A-Voxygen difference. ,This state is referred to asclass 2 a) in a previous publication.s Atropineincreased the cardiac index and decreased thesystemic A-V oxygen difference in both the nor-mal and the hypothyroid animals but here alsothe cardiac index remained at a lower level andthe A-V oxygen dilfference was consistently higherthan in the normal group.

The lower ca:rdiac index in the dog withhypothyroidism is due to either a reduction inthe contractile strength of the myocardium or toa raised threshold to stimuli which increase thecardiac output. Evidence from our experi-ments can not differentiate between these twopossibilities although all of the experimentalprocedures for the normal and the hypothyroiddogs were as nearly identical as possible.Studies6 demonstrating an increased cardiacoutput in the perfused heart with thyroid sub-stances suggest that the former explanation ismore likely to be the correct one.

SUMMARYA reduction in the basal metabolism rate and

protein bound iodine conversion ratio in agroup of dogs following the administration ofP was accepted as evidence of experimentallyinduced hypothyroidism. Observations of car-diac functions were made in the normal controlgroup and in the hypothyroid group. Thelatter group was characterized by a reductionin coronary sinus blood flow, left ventricularoxygen consumption and heart rate. Atropineincreased each of these values in the hypothyroidanimals to a level approximately equal to thatinduced by atropine in the normal controlgroup. The ability of the hypothyroid heartto raise coronary sinus blood flow and leftventricular oxygen consumption to the levelof the normal heart in response to atropine isexplained in terms of changes in heart ratebecause a close association between heart rateand these two Sunctions has been establishedunder a wide variety of experimental conditions.The capacity of the hypothyroid heart to changeits rate appears to be unimpaired.

The cardiac index of the hypothyroid heartis also reduced but fails to return to the normalcontrol levels in response to atropine. This re-duction is probably associated with an increasein A-V oxygen difference, indicating a relativelygreater reduction in cardiac output than intotal oxygen consumption.

ACKNOWLEDGMENTWe wish to express our appreciation to L. Miller forhis technical advice and assistance.

REFERENCES1. ANDRUS, E. The thyroid and the circulation. Cir-

culation 7: 437, 1953.2. STEWART, H. J ., DEI TRICK, . E. and CRANE , N. F.

Studies of the circulation in patients sufferingfrom spontaneous myxedema. J. Clin. Invest. 17 :237, 1938.3. The Physiology of Induced H ypothermia, p. 146.Edited by Dripps, R. D. Washington, D. C.,1956. National Academy of Sciences, NationalResearch Council.

4. GOODALE,W. T. and HACK EL, D. B. Measurementof coronary blood flow in dogs and man fromrate of myocardial nitrous oxide desaturation.Circul&n Res. 1 : 502, 1953.

5. SCOTT J . C. and BALOURDAS,T. A. An analysisof coronary flow and related factors followingvagotomy, atropine and sympathectomy. Cir-culati on Res. 7: 162, 1959.

6. KL EI NFELD, M., ROSENTHAL, A. and STEIN, E.Comparative effects of DL -thyronine, L-triiodo-thyronine and L-thyroxine on the isolated per-fused frog heart. Am. J. Physiol. 195: 63 1958.

7. MARKOWITZ C. and YATER, W. M. Response ofexplanted cardiac muscle to thyroxine. Am. J.Physiol. 100: 162 1932.

8. LI GHT, L., DEFAZIO, V., TALMERS, F. N., RECAN,T. R. and HELL EMS, H. K . Coronary bloodflow, myocardial oxygen consumption and myo-cardial metabolism in normal and hyperthyroidhuman subjects. Circul ation 14: 90 1956.

9. GOH, K. 0. and DAL LAM, R. D. Oxygen consump-tion of the auricles, right and left ventricles of thenormal hypothyroid and hyperthyroid rat heart.Am. J. Physiol. 188 514 1957.

10. SCOTT J. C. and BAL OURDAS, T. A. Effect ofatropine and of chronic A-V block on coronaryblood flow in the dog. Am. J. Physiol. 198 1451960.

11. LAURENT, D., WILLI AMS-B ENE, C., WILLI AMS, F.L., and KATZ, L. N. Effects of heart rate oncoronary flow and cardiac oxygen consumption.Am. J. Physiol. 185: 355 1956.

MAY1961