Heart 1996;75:363-368 Cardiac hypertrophy as a result of long-term thyroxine therapy and thyrotoxicosis Gordon W Ching, Jayne A Franklyn, Terence J Stallard, Jacquie Daykin, Michael C Sheppard, Michael D Gammage Department of Cardiovascular Medicine, University of Birmingham, Queen Elizabeth Hospital, Birmingham G W Ching T J Stallard M D Gammage Department of Medicine, University of Birmingham, Queen Elizabeth Hospital, Birmingham J A Franklyn J Daykin M C Sheppard Correspondence to: Dr M D Gammage, Department of Cardiovascular Medicine, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH. Accepted for publication 10 October 1995 Abstract Objectives-To define the effects of long- term thyroxine treatment upon heart rate, blood pressure, left ventricular sys- tolic function, and left ventricular size, as well as indices of autonomic function, and to compare findings with those in patients with thyrotoxicosis before and during treatment. Design-Cross sectional study of patients prescribed thyroxine long term (n = 11), patients with thyrotoxicosis studied at presentation (n = 23), compared with controls (n = 25); longitudinal study of patients with thyrotoxicosis studied at presentation and serially after beginning antithyroid drug treatment (n = 23). Methods-24 h ambulatory monitoring of pulse and blood pressure, echocardiogra- phy, forearm plethysmography, and auto- nomic function tests. Results-Long-term thyroxine treatment in doses that reduced serum thyrotrophin to below normal had no effect on blood pressure, heart rate, left ventricular sys- tolic function or stroke volume index, but was associated with an 18-4% increase in left ventricular mass index (mean (SEM) 101'9 (3.09) g/m' v controls 86-1 (4.61), P < 0.01). Thyroxine treatment, like thyro- toxicosis, had no effect on tests of auto- nomic function. Untreated thyrotoxicosis resulted in pronounced changes in sys- tolic and diastolic blood pressure and an increase in heart rate during waking and sleep. Patients with thyrotoxicosis at pre- sentation had an increase in left ventricu- lar systolic function (ejection fraction 70 5 (1P66)% v 65 4 (1.79), P < 0 01; fractional shortening 40 4 (1.54)% v 35 6 (1.46), P < 0.01), increased stroke volume index (45.9 (2.4) mu/m2 v 36-6 (1.7), P < 0.001), and an increase in forearm blood flow, and decrease in vascular resistance. They had a similar degree of left ventricular hyper- trophy to that associated with thyroxine treatment (99.3 (4.03) glm2); all changes were corrected within 2 months by antithyroid drugs. Conclusions-The development of left ventricular hypertrophy in patients receiving thyroxine in the absence of sig- nificant changes in heart rate, blood pres- sure, and left ventricular systolic function is consistent with a direct trophic effect of thyroid hormone on the myocardium. The presence of left ventricular hypertro- phy determines that further studies are essential to assess cardiovascular risk in patients taking thyroxine long term. (Heart 1996;75:363-368) Keywords: thyroxine; thyrotoxicosis; left ventricular function; left ventricular hypertrophy The clinical effects of thyroid disease on the cardiovascular system have been recognised for many years, one of the first descriptions of hyperthyroidism reporting the association of toxic goitre and palpitation.' It has been shown that untreated thyrotoxicosis results in increases in heart rate, systolic blood pressure, and ventricular systolic and diastolic func- tion;2-4 changes which are largely corrected by antithyroid treatment.25 Furthermore, thyro- toxicosis has been reported to cause left ven- tricular hypertrophy in humans and the cat,67 while restoration of euthyroidism has been shown to reduce left ventricular mass.6 The similarity between the cardiovascular features of thyrotoxicosis and those of a hyperadrener- gic state has led to debate regarding the relative contributions of direct effects of excess thyroid hormones on the heart and indirect effects mediated by a change in adrenergic sensitivity.8 While it is clear from the studies described above that overt hyperthyroidism is associated with marked changes in cardiovascular func- tion, the cardiovascular effects of thyroxine replacement treatment are much less well defined. Thyroxine treatment, in doses which suppress serum thyrotrophin to below normal, has been reported to be associated with an increase in nocturnal heart rate9 and shorten- ing of the systolic time interval of the pre- ejection period,'0 while a recent study has demonstrated a change in left ventricular sys- tolic function and dimensions in patients given thyroxine. II Thyroxine treatment is widely pre- scribed, surveys indicating that approximately 1% of the general population'2 and 4% of those aged 60 years and above are receiving long- term thyroxine treatment.'3 Up to 21% of those in the general population prescribed thy- roxine are taking a dose sufficient to suppress serum thyrotrophin to below the lower limits of normal, indicating a degree of hyperthy- roidism,'4 and further indicating that a large population is at risk of any cardiovascular com- plication of this thyroid hormone excess. These facts determine that it is important to define further the cardiovascular consequences of thy- roxine treatment, especially in doses which suppress serum thyrotrophin to below normal. 363 on June 26, 2020 by guest. Protected by copyright. http://heart.bmj.com/ Heart: first published as 10.1136/hrt.75.4.363 on 1 April 1996. Downloaded from
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Heart 1996;75:363-368
Cardiac hypertrophy as a result of long-termthyroxine therapy and thyrotoxicosis
Gordon W Ching, Jayne A Franklyn, Terence J Stallard, Jacquie Daykin,Michael C Sheppard, Michael D Gammage
Department ofCardiovascularMedicine, UniversityofBirmingham, QueenElizabeth Hospital,BirminghamG W ChingT J StallardM D GammageDepartment ofMedicine, UniversityofBirmingham, QueenElizabeth Hospital,BirminghamJ A FranklynJ DaykinM C SheppardCorrespondence to:DrM D Gammage,Department ofCardiovascular Medicine,University of Birmingham,Queen Elizabeth Hospital,Edgbaston, BirminghamB15 2TH.
Accepted for publication10 October 1995
AbstractObjectives-To define the effects of long-term thyroxine treatment upon heartrate, blood pressure, left ventricular sys-tolic function, and left ventricular size, as
well as indices ofautonomic function, andto compare findings with those in patientswith thyrotoxicosis before and duringtreatment.Design-Cross sectional study of patientsprescribed thyroxine long term (n = 11),patients with thyrotoxicosis studied atpresentation (n = 23), compared withcontrols (n = 25); longitudinal study ofpatients with thyrotoxicosis studied atpresentation and serially after beginningantithyroid drug treatment (n = 23).Methods-24 h ambulatory monitoring ofpulse and blood pressure, echocardiogra-phy, forearm plethysmography, and auto-nomic function tests.Results-Long-term thyroxine treatmentin doses that reduced serum thyrotrophinto below normal had no effect on bloodpressure, heart rate, left ventricular sys-
tolic function or stroke volume index, butwas associated with an 18-4% increase inleft ventricular mass index (mean (SEM)101'9 (3.09) g/m' v controls 86-1 (4.61), P< 0.01). Thyroxine treatment, like thyro-toxicosis, had no effect on tests of auto-nomic function. Untreated thyrotoxicosisresulted in pronounced changes in sys-tolic and diastolic blood pressure and an
increase in heart rate during waking andsleep. Patients with thyrotoxicosis at pre-
sentation had an increase in left ventricu-lar systolic function (ejection fraction 70 5(1P66)% v 65 4 (1.79), P < 0 01; fractionalshortening 40 4 (1.54)% v 35 6 (1.46), P <0.01), increased stroke volume index (45.9(2.4) mu/m2 v 36-6 (1.7), P < 0.001), andan increase in forearm blood flow, anddecrease in vascular resistance. They hada similar degree of left ventricular hyper-trophy to that associated with thyroxinetreatment (99.3 (4.03) glm2); all changeswere corrected within 2 months byantithyroid drugs.Conclusions-The development of leftventricular hypertrophy in patientsreceiving thyroxine in the absence of sig-nificant changes in heart rate, blood pres-
sure, and left ventricular systolic functionis consistent with a direct trophic effect ofthyroid hormone on the myocardium.The presence of left ventricular hypertro-phy determines that further studies are
essential to assess cardiovascular risk inpatients taking thyroxine long term.
(Heart 1996;75:363-368)
Keywords: thyroxine; thyrotoxicosis; left ventricularfunction; left ventricular hypertrophy
The clinical effects of thyroid disease on thecardiovascular system have been recognised formany years, one of the first descriptions ofhyperthyroidism reporting the association oftoxic goitre and palpitation.' It has been shownthat untreated thyrotoxicosis results inincreases in heart rate, systolic blood pressure,and ventricular systolic and diastolic func-tion;2-4 changes which are largely corrected byantithyroid treatment.25 Furthermore, thyro-toxicosis has been reported to cause left ven-tricular hypertrophy in humans and the cat,67while restoration of euthyroidism has beenshown to reduce left ventricular mass.6 Thesimilarity between the cardiovascular featuresof thyrotoxicosis and those of a hyperadrener-gic state has led to debate regarding the relativecontributions of direct effects of excess thyroidhormones on the heart and indirect effectsmediated by a change in adrenergic sensitivity.8
While it is clear from the studies describedabove that overt hyperthyroidism is associatedwith marked changes in cardiovascular func-tion, the cardiovascular effects of thyroxinereplacement treatment are much less welldefined. Thyroxine treatment, in doses whichsuppress serum thyrotrophin to below normal,has been reported to be associated with anincrease in nocturnal heart rate9 and shorten-ing of the systolic time interval of the pre-ejection period,'0 while a recent study hasdemonstrated a change in left ventricular sys-tolic function and dimensions in patients giventhyroxine. II Thyroxine treatment is widely pre-scribed, surveys indicating that approximately1% of the general population'2 and 4% of thoseaged 60 years and above are receiving long-term thyroxine treatment.'3 Up to 21% ofthose in the general population prescribed thy-roxine are taking a dose sufficient to suppressserum thyrotrophin to below the lower limits ofnormal, indicating a degree of hyperthy-roidism,'4 and further indicating that a largepopulation is at risk of any cardiovascular com-plication of this thyroid hormone excess. Thesefacts determine that it is important to definefurther the cardiovascular consequences of thy-roxine treatment, especially in doses whichsuppress serum thyrotrophin to below normal.
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We have employed a series of non-invasivemethods to define changes in heart rate, bloodpressure, left ventricular function and size, aswell as peripheral vascular resistance andindices of autonomic function in patientsreceiving long-term thyroxine treatment.Results were compared with those frompatients with thyrotoxicosis investigated at pre-sentation and serially after beginning antithy-roid treatment, and with normal controls.
Patients and methodsPATIENTSThe thyroxine treated group comprised 11women (mean (range) age 44-5 (35-65) years,mean body mass index 24-4 kg/M2) who wereall receiving long-term thyroxine treatment(mean (range) dose 210 (100-300) ,ug/day) fora mean (range) of 9*6 (3-21) years because of apast history of thyroidectomy for differentiatedthyroid cancer. All patients had received con-stant doses of thyroxine with the intention ofmaintaining serum thyrotrophin below thenormal range. None had evidence of recurrentor metastatic disease at any time since totalthyroidectomy. Findings from this group werecompared with those from 23 women withovert thyrotoxicosis (mean (range) age 38-8(22-65) years, mean body mass index 22-3kg/M2) who were investigated at presentationand serially at 1 and 2 months after beginningantithyroid treatment with carbimazole.Findings were also compared with those from25 normal healthy women (mean (range) age42X9 (21-65) years, mean body mass index23X7 kg/mi2). Exclusion factors for patient andcontrol groups included a previous or presenthistory of cardiovascular disease, the presenceof atrial fibrillation, symptoms or signs sugges-tive of cardiac failure and treatment with anycardiovascular drug. All patients and controlsgave written consent to the studies which wereapproved by the South Birmingham HealthAuthority Research Ethics Committee.
ASSESSMENT OF THYROID STATUSThyroid function was determined in patientsand controls by measurement of serum freethyroxine, free tri-iodothyronine (AmerlexM radioimmunoassays, Kodak ClinicalDiagnostics, Amersham, UK) and thy-rotrophin using a sensitive immunometricmethod (IDS Gamma-BCT, Boldon, UK).Normal ranges were free thyroxine 9-24pmol/l, free tri-iodothyronine 2 0-9 0 pmol/l,and thyrotrophin 0 4-4 5 mU/l, determined asdescribed previously.'3 The limit of sensitivityof the thyrotrophin assay was 0 05 mU/l.
AMBULATORY MONITORING OF PULSE ANDBLOOD PRESSURE AND ECHOCARDIOGRAPHICSTUDIES
An automatic cuff sphygmomanometer (TM2420; A&D, Tokyo, Japan) was used to deter-mine 24 h ambulatory heart rate and bloodpressure.'5 M mode and cross sectional echo-cardiography (Hewlett-Packard Sonos 500,2-5 MHz transducer) were performed by thesame operator for all participants to measure
cardiac dimensions, as described previously;'6measurements included left ventricular endsystolic and end diastolic dimensions, left ven-tricular diastolic posterior wall thickness,interventricular diastolic septal thickness, andright ventricular diastolic diameter. Fractionalshortening and ejection fractions were deter-mined from echocardiographic data as indicesof systolic cardiac function, and left ventricu-lar mass index (left ventricular mass/body sur-face area) was calculated using the method ofDevereux.'7 Stroke volume index (stroke vol-ume/body surface area) was calculated usingthe formula of Teicholz et al.'8 '9
MEASUREMENT OF BLOOD FLOW ANDVASCULAR RESISTANCEForearm blood flow was measured by plethys-mography, using methods established in ourown unit,20 and forearm resistance calculatedas a function of mean blood pressure andblood flow as described.2'
TESTS OF AUTONOMIC FUNCTIONResponses of heart rate and blood pressure to600 upright tilt with footplate for 40 min, iso-metric forearm exercise, a cold pressor test,and Valsalva's manoeuvre were determined22to provide measures of autonomic activity.Beat to beat blood pressure was measuredduring autonomic testing using a Finapres fin-ger cuff (Ohmeda 2300 Finapres, BOC HealthCare, Denver, Colorado, USA) positioned atheart level.
STATISTICAL ANALYSISResults from patients receiving thyroxine andfrom those with thyrotoxicosis were comparedwith those from normal controls using theMann-Whitney U test. Linear regressionanalysis was used to relate heart rate andblood pressure results to measures of thyroidfunction.
ResultsTESTS OF THYROID FUNCTIONThe serum free thyroxine concentration wassignificantly raised in women treated with thy-roxine and to a greater extent in those withuntreated thyrotoxicosis compared with that incontrols (thyroxine treatment mean (SEM)28-0 (2 6) pmol/l (P < 0 005), thyrotoxicosis51-6 (2 2) (P < 0.0001), and controls 15-0(0 4)), while serum free tri-iodothyronine wassignificantly raised only in those with thyrotox-icosis (thyroxine treatment 6-6 (0 5) pmol/l,thyrotoxicosis 24-6 (2-1) (P < 0 005), andcontrols 5-6 (0.2)). Treatment of thyrotoxicosiswith antithyroid drugs resulted in a decrease inserum free thyroxine and free tri-iodothyro-nine concentrations by 1 month after startingtreatment and all had free thyroid hormoneconcentrations within the normal range by 2months after antithyroid treatment (free thy-roxine at 1 month 25-6 (5 9) pmol/l (P < 0 05v controls) and at 2 months 17-2 (3-1); freetri-iodothyronine at 1 month 15 1 (2 6) pmol/l(P < 0 05 v controls) and at 2 months 6-7(1 0)). Serum thyrotrophin values were below
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Cardiac hypertrophy as a result of long-term thyroxine therapy and thyrotoxicosis
Table 1 Systolic and diastolic blood pressure (BP), and heart rate in patients receiving long-term thyroxine treatment,patients with thyrotoxicosis before and after antithyroid drug treatment for 1 or 2 months, and controls
Thyroxine Thyrotoxicosis (n = 23)treatment Controls(n = 11) At presentation At 1 month At 2 months (n = 25)
Values are means (SEM). *P < 0-01; tP < 0-001 v controls.
the limit of assay sensitivity (< 0-05 mU/1) infive patients receiving long-term thyroxinetreatment, while the remainder in the grouphad detectable serum thyrotrophin concentra-tions below the normal range (0 05-0 5mU/l). All patients with overt thyrotoxicosishad a serum thyrotrophin measurement belowthe limit of assay sensitivity at presentation,while all controls had a normal serum thy-rotrophin value (mean 2-38 mU/l).
24 H AMBULATORY MONITORING OF PULSE ANDBLOOD PRESSUREThere were no significant differences in mean24 h systolic and diastolic blood pressures inpatients receiving long-term thyroxine treat-ment compared with those in controls. In con-trast, mean systolic blood pressure was
significantly increased in patients withuntreated thyrotoxicosis compared with that incontrols, while mean diastolic blood pressurewas reduced (table 1). These differences insystolic and diastolic blood pressure inpatients with thyrotoxicosis were abolished by 2months after starting antithyroid drug treat-ment (table 1). Linear regression analysis ofblood pressure results in patients with thyro-toxicosis at presentation showed a significantrelation between 24 h systolic blood pressureand mean heart rate with circulating concen-trations of free thyroxine (P < 0 05); a similarrelation was not observed in the thyroxinetreated group. Mean heart rate was not differ-ent from controls in those receiving thyroxine,in contrast to a significant increase in patientswith thyrotoxicosis which was no longer evi-dent 1 month after antithyroid treatment(table 1).
Analysis of waking and sleeping blood pres-sure and heart rate measurements showed thatsimilar findings for systolic and diastolic bloodpressure and heart rate were evident whenwaking and sleeping values were analysed sep-arately (table 1). Despite differences in systolicand diastolic blood pressure and heart rate inpatients with thyrotoxicosis at presentation,there was no change in diurnal variation in
blood pressure or heart rate in either patientswith thyrotoxicosis or those treated with thy-roxine compared with that in controls (datanot shown).
ECHOCARDIOGRAPHIC DETERMINATION OFLEFT VENTRICULAR SYSTOLIC FUNCTION ANDCARDIAC DIMENSIONSAnalysis of results of echocardiography (table2) showed no significant difference in left ven-tricular systolic and diastolic dimensions in thegroup receiving long-term thyroxine treat-ment. There was, however, a significantincrease in the interventricular septal thicknessand calculated left ventricular mass index inpatients treated with thyroxine. The left ven-tricular mass index was similarly increased inpatients with thyrotoxicosis at presentationcompared with that in controls; a difference nolonger evident by 1 month after antithyroidtreatment. There was no significant differencein the mean fractional shortening or systolicejection fraction in patients treated with thy-roxine, although these measures of systolicfunction were increased in patients with thyro-toxicosis before antithyroid treatment (table2). These abnormalities in thyrotoxicosis wereagain corrected within 2 months by antithy-roid drug treatment.
Table 2 Echocardiographic data in patients receiving long-term thyroxine treatment, patients with thyrotoxicosis beforeand after antithyroid drug treatment for 1 or 2 months, and controls
Thyroxine Thyrotoxicosis (n = 23)treatment Controls(n = 11) At presentation At 1 month At 2 months (n = 25)
INDICES OF CARDIAC OUTPUTCalculation of the stroke volume index inpatients treated with long-term thyroxineshowed no significant difference comparedwith that in controls, in contrast to an increasein patients with thyrotoxicosis at presentation,which was corrected by antithyroid drug treat-ment (table 2). Linear regression analysis of thestroke volume index results in patients withthyrotoxicosis at presentation showed a signifi-cant relation with the left ventricular mass
index (P < 0-01), but no significant relationwas found in the thyroxine treated group.
Measurement of forearm blood flow showedno significant change in the thyroxine treatedgroup, although there was a significant increasein flow in those with untreated thyrotoxicosis; a
finding that was corrected by antithyroid drugtreatment (mean (SEM) thyrotoxic group atpresentation 3-89 (0.23) ml/min/100 g (P <005), at 1 month 2-32 (0 35), and at 2 months2-5 (026), and controls 1-87 (029)).Calculation of forearm resistance showed a
reduction in vascular resistance in those withthyrotoxicosis compared with that in controlsbut again there was no significant difference inthe thyroxine treated patients (mean (SEM)thyroxine treated group 34-8 (4 9) units ofresistance, thyrotoxicosis at presentation 25-7(3 2) (P < 0 05), and controls 47 9 (5-6)).
TESTS OF AUTONOMIC FUNCTIONAssessment of increases in systolic and diastolicblood pressure and heart rate in response totilting, isometric forearm exercise, and a coldpressor stimulus failed to show any differencebetween patients receiving thyroxine or thosewith untreated thyrotoxicosis compared withthose in normal controls. Responses to theValsalva manoeuvre were similarly unaffectedby thyroxine treatment or thyrotoxicosis (datanot shown).
DiscussionIn the present study we have shown that long-term thyroxine treatment has no significanteffect on systolic or diastolic blood pressure or
heart rate when determined by ambulatorymonitoring over a 24 h period. Thyroxinetreatment was, however, associated with a sig-nificant increase in left ventricular mass indexof 18-4% compared with that in normal con-
trols. Untreated thyrotoxicosis resulted in morepronounced cardiovascular changes than thy-roxine treatment, including an increase in sys-tolic blood pressure, a reduction in diastolicblood pressure, and an increase in heart rate,changes evident throughout a 24 h period ofmonitoring and during waking and sleep.Patients with thyrotoxicosis at presentationshowed a similar degree of left ventricularhypertrophy to that observed in patients receiv-
ing long-term thyroxine treatment, as well as
an increase in left ventricular systolic functionindicated by measures of fractional shorteningand ejection fraction, an increase in the strokevolume index, and an increase in forearmblood flow, and decrease in vascular resistance.Treatment of thyrotoxicosis with antithyroid
drugs was effective not only in reducing circu-lating free thyroid hormone values to the nor-mal range but also in correcting abnormalitiesof blood pressure, heart rate, left ventricularmass, and left ventricular systolic function by 2months after starting treatment.The finding of increased left ventricular
mass in patients treated with long-term thyrox-ine treatment is in accord with a recent study"which included 10 patients (eight female andtwo male) who had undergone thyroidectomyfor thyroid cancer and who had subsequentlyreceived thyroxine in thyrotrophin suppressivedoses for a mean of 5 years. We, like Biondi etal," showed an increase in interventricular sep-tal thickness but in contrast to that study, wefailed to show a significant increase in heartrate or left ventricular fractional shortening inour thyroxine treated group. We found no sig-nificant difference in either waking or sleepingmeasurements of blood pressure and heart ratecompared with those in controls, in contrast toa report describing no change in blood pressurebut an increase in nocturnal heart rate in nor-mal controls treated short term with incremen-tal doses of thyroxine until thyrotrophinsuppression was achieved.9
Several previous studies have examined theeffect of untreated thyrotoxicosis on cardiovas-cular function and have described similarchanges in blood pressure and heart rate.2' Ourfinding of an increase in left ventricular systolicfunction is in agreement with the results of astudy using radionuclide ventriculography,which showed an increase in resting left ven-tricular ejection fraction in patients with hyper-thyroidism and a decrease when euthyroidismwas restored.24 Our findings of an increasedstroke volume index, an increase in forearmblood flow, and a decrease in vascular resis-tance are also consistent with a previous studyof patients with thyrotoxicosis providing evi-dence for peripheral vasodilatation.'5 Reportedstudies have compared cardiovascular functionin thyrotoxic subjects before treatment andafter restoration of euthyroidism but serialassessment of patients at frequent intervalsafter beginning antithyroid treatment has notbeen described before. It is notable thatantithyroid drug treatment abolished differ-ences in diastolic blood pressure and left ven-tricular mass index by 1 month after treatment,at a time point before circulating free thyroidhormone concentrations had been restored tonormal, and that all changes in the cardiovas-cular variables examined (except the IVS dias-tolic dimensions) were eliminated by only 2months of antithyroid treatment. This wouldsuggest that the cardiovascular risks ofpromptly treated thyrotoxicosis are minimal.Our finding of significant left ventricular
hypertrophy in patients treated with long-termthyroxine treatmlent in the absence of signifi-cant changes in heart rate, stroke volume,blood pressure, and left ventricular systolicfunction provides evidence for a direct effect ofthyroid hormones on the heart. This directeffect is supported by evidence indicating theexpression of functional receptors for thyroidhormone in the myocardium,'6 as well as direct
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Cardiac hypertrophy as a result of long-term thyroxine therapy and thyrotoxicosis
effects of thyroid hormones on myocardialgenes, including that encoding the cardiac spe-cific sarcoplasmic calcium adenosine triphos-phatase, an enzyme which affects the velocityof diastolic relaxation.27 Other evidence in sup-port of direct actions of thyroid hormones onthe myocardium comes from studies of patientswith hyperthyroidism. Forfar et al24 reportedthat /B adrenergic blockade did not affect anexercise induced change in left ventricular ejec-tion fraction, while a further study5 demon-strated that increases in left ventricular ejectionfraction in thyrotoxicosis were not associatedwith changes in ventricular loading conditions,and further, these loading conditions were notaltered by restoration of euthyroidism.The similarity between the clinical manifes-
tations of thyroid hormone excess and those of ahyperadrenergic state has led to extensiveinvestigation of the relation between thyroidstatus and the autonomic nervous system. It iswell recognised that thyrotoxicosis is not asso-ciated with an increase in circulating cate-cholamines28 and the mechanism by whichthyroid hormones might alter the responsive-ness to catecholamines is unknown. It has beenreported that hyperthyroidism is associatedwith an increase in the sensitivity of heart rateand left ventricular shortening velocity to stim-ulation by isoprenaline29 and some, but not all,studies have suggested an increase in adrener-gic receptor density in various tissues.3031Nonetheless, the absence of change inresponses in blood pressure or heart rate to tilt-ing, a cold pressor stimulus, or the Valsalvamanoeuvre, which all provide indirect mea-sures of sympathetic activity, provides strongevidence against a change in adrenergic sensi-tivity in either patients receiving thyroxine longterm or those with untreated thyrotoxicosis.The most notable finding in the present
study was significant left ventricular hypertro-phy in patients receiving long-term thyroxinetreatment and those with untreated thyrotoxi-cosis. Left ventricular hypertrophy was rapidlyreversed by treatment of thyrotoxicosis butdespite a considerably less noticeable increasein serum free thyroxine in the thyroxine treatedgroup, an 18% increase in left ventricular massindex was present in these patients, presumablyreflecting the duration of thyroxine treatment.The pathophysiological significance of thisincrease in left ventricular mass is unknown,although left ventricular hypertrophy is a wellrecognised risk factor for cardiac morbidity andmortality.3233 A recent report described anincreased incidence of atrial fibrillation withsuppression of serum thyrotrophin in patientsin the Framingham population (some of whomwere treated with thyroxine);34 however, nodata were provided for left ventricular mass inthis study. Further studies are essential todetermine whether cardiac hypertrophy associ-ated with long-term administration of thyrox-ine in doses that suppress serum thyrotrophinto below normal, as documented in the presentstudy, is itself associated with an increase incardiac events.We are grateful to Miss T Ryan for performing the echocardio-graphic measurements described. This study was supported by
the British Heart Foundation through award of a JuniorResearch Fellowship to GWC.
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30 Belzikian JP, Loeb JN. The influence of hyperthyroidism andhypothyroidism on a- and ,B-adrenergic receptor systemsand adrenergic responsiveness. Endocr Rev 1983;414:378-87.
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SHORT CASES IN CARDIOLOGY
Migration of an implantable cardioverter-defibrillator generator into the small bowel
Paul A Broadhurst, Jeremy Sayer, AnthonyW Nathan
Department ofCardiology, StBartholomew'sHospital, WestSmithfield, LondonP A BroadhurstJ SayerAW NathanCorrespondence to:Dr AW Nathan, Departmentof Cardiology, StBatholomew's Hospital, WestSmithfield, LondonEClA 7BE.
Accepted for publication9 October 1995
In February 1992, a previously fit man of 64experienced an out of hospital cardiac arrestwithout any prodromal symptoms. The para-medical team found him to be in ventricular fib-rillation from which he was successfullydefibrillated. There was no evidence of myocar-dial infarction and no neurological sequelae. Hewas transferred to our hospital where cardiaccatheterisation showed a chronically occludedleft anterior descending coronary artery as theonly abnormality. An exercise test was normaland there were no inducible ventricular arrhyth-mias at electrophysiological study. We decidedto implant a cardioverter-defibrillator.Under general anaesthesia, a CPI Endotak
0062 electrode was positioned in the right ven-tricular apex and a subcutaneous patch (0063)was implanted in the left sub-axillary area. A10 J, biphasic shock successfully terminated ven-tricular fibrillation. The leads were tunnelleddown into a subcostal pouch. The left rectusmuscle was dissected to make a pocket for thegenerator (CPI Ventak P2) which fitted satisfac-torily behind the muscle but still within the rectussheath. The generator pocket and wound wereclosed and the patient made a good recovery.He continued to do well without any shocks
and had only one episode of non-sustained ven-tricular tachycardia detected by the device. Hewas admitted in December 1994 for a replace-ment generator. He did not report any symp-toms and physical examination showed thegenerator to be deep to the original incision.
At operation, the original scar was resected
Photograph of implantable cardioverter-defibrillator generator placed in the surgicalyresected specimen ofjejunum, showing how the bowel conforms to the shape of the generator.
and after careful dissection of the leads the gen-erator was found to have migrated to the peri-toneum. With the assistance of a general surgeona midline incision was made and the defibrillatorwas found intraluminally within a loop ofjejunum and eroding the bowel wall (figure).The posterior walls of the bowel loops adheredto one another as in a surgically created anasto-mosis. The box was removed, 25 cm of jejunumresected, and the ends of the bowel were anasto-mosed. Peritoneal lavage was performed and thewound was closed. Because the electrodes weredeeply embedded in scar tissue they were notremoved. He was treated with intravenousantibiotics and did well postoperatively; it wasdecided not to reimplant another device. Bothleads and the subcutaneous patch had to beremoved five months later because he had a dis-charging abdominal wound sinus. He made agood recovery.
Although migration of a cardioverter-defibril-lator into the peritoneum has been described,'we believe that this is the first report of migra-tion into the bowel. Although the patient initiallydenied any gastroenterological symptoms, afterthe operation he did report some occasionalunexplained vomiting episodes in the monthsbefore the generator explantation. Had thedevice not been removed the small bowel wouldprobably have become obstructed.
It is not clear how the device migrated fromthe subrectus sheath into the jejunum but pre-sumably the device eroded through the posteriorwall of the sheath, passed into the peritoneum,and was encompassed by loops of small bowelonto which it became stuck. The device theneroded through the walls of the jejunum. It isfortunate that the outcome was not more seri-ous. It is important to remember that bowel orurinary tract symptoms in patients with anabdominally placed generator could be causedby device migration. Newer generators aresmaller and can usually be implanted sub-pectorally2 so such complications may becomeeven rarer.We thank Mr George Geroulakos for his help in this patient'smanagement.
1 Brune S, Gonska BD, Fleischman C, Herse B, Kreuzer H.Perforation of an automatic implantable cardioverter-defib-rillator into the peritoneal cavity. Z Kardiol 1991;80:59-61.
2 Bardy GH, Johnson G, Poole JE, Dolack GL, Kudenchuk PJ,Kelso D, et al. A simplified, single-lead unipolar trans-venous cardioversion-defibrillation system. Circulation1 993;88:543-7.
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