Effect of hyperthyroidism of short duration on cardiac sensitivity to beta-adrenergic stimulation

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Effect of Hyperthyroidism of Short Duration on Cardiac Sensitivity to Beta-Adrenergic Stimulation WADE H . MARTIN III, MD, FACC, ROBERT J . SPINA, PHD . ELLEN KORTE, MA Saint Louis,

Missouri

The effect of hyperthyroidism on cardiac sensitivity no betaadrenergic stimulation in humans is controversial. To determine whether heart rate and left ventricular contractile sensitivity to betaadrenergic stimulation are altered by hyperthyroidism in human subjects, the frequency, velocity and extent of left ventricular shortening at rest and during a 4-stage graded dose isoproterenol infusion were characterized in eight young healthy subjects before and after 2 weeks of daily administration of 100 Jag of triiodothyronine (Ts). The rate and extent of left ventricular shortening were determined by Doppler add two-dimensionally guided M-mode echocardiography . In the hyperthyroid state, heart rate at rest was faster (57 ± 3 vs. 68 t 4 beats/min; p < 0.001) and the slope of the relation of hurt rate to the rate of isoproterenol infusion was 36% steeper (1,538 t 126 vs. 1,131 t 95 ; p < 0 .05) . The left ventricular ejection lime was shorter and the mean velocity of left ventricular circumferential fiber shortening (mVcf) was greater during all

Hyperthyroidism increases beta-adrenergic receptor density and agonist sensitivity in the myocardium of several species of experimental animals (1-8). However, in humans the effect of altered thyroid status on cardiac sensitivity to beta-adrenergic stimulation is highly controversial (9-15). Although beta-adrenergic blockade is used therapeutically to treat thyrotoxicosis, most previous investigations (11-15) in human subjects have failed to detect evidence of enhanced left ventricular contractile or heart rate sensitivity to catecholamines in the hyperthyroid state . Possible explanations for this paradox include the fact that earlier investigations of cardiac responses to beta-adrenergic antagonists (13,14) or epinephrine (11,12) either did not permit analysis of the dose-agonist response relation or were confounded by other effects of catecholamines such as alpha-adrenergic stimulation . The latter are of major physiologic importance, but

From the Section of Applied Physiology . Department of Medicine and the been Walter Johnson Institute of Rehabilitation, Washington University School of Medicine, Saint Louis, Missouri . This study was supported by Grant HLA1290 and by Institutional National Research Service Award AG-00078 from the National Institutes of Health, Bethesda . Maryland . Manuscript received September 13 . 1991: revised manuscript received November 11 . 1991, accepted November 21 .1991 . Addressforreprints: Wade H. Martin 111. MD, Washington University School of Medicine, Department of Medicine . 4566 Scott Avenue . Campus Box 8113, Saint Louis, Missouri 63110 . ®1992 by

the American College

of Cardiology

stages of isoprotereewl infusion in the hyperthyroid versus the euthyraid state (p < 0 .01). After adjanent far the faster heart rate after T a administration, left ventricular ejection time and mVef were similar in the enthyroid and hyperthyroid states at baseline and diving maximal beta-adrenergic stimulation but shurtened and enhanced, respectively, during stages 1 and 2 of isoproterenol infusion (p < 0 .05). There was no et el of Ts administration on left ventricular mass, dimensions, endaystolic wag stress or stroke volume at rest ar during any stage of isoprokreaol infusion. These results indicate that in ban= subjects hyperlhyroidism of short duration increases the sensitivity of hurt rate and left ventricular shettenhr; velocity to beta-ardrenergic stimulation in the absence of changes in left ventricular mass, goading conditions or extent of shortening. (J Am Call Candied 1943;19 :1195-97)

epinephrine elicits only a modest increase in heart rate in comparison with selective beta-adrenergic agonises such as isoproterenol (16). The cardiac stroke volume response to isoproterenol was also found to be unaltered in the hyperthyroid state (15). However, hyperthyroidism enhances the velocity rather than the extent of myocardial shortening in experimental animals (17) and stroke volume is not a sensitive or specific index of myocardial contractility . Therefore, we hypothesized that the discrepant effects of hyperthyroidism on cardiac beta-adrenergic sensitivity in humans and experimental animals could be explained by different effects on the velocity and extent of left ventricular shortening during beta-adrenergic stimulation . Because left ventricular loading conditions and mass influence cardiac performance (18), are often altered by hyperthyroidism (19,20) and were frequently not evaluated in earlier studies of the effect of hyperthyroidism on left ventricular contractile responses to beta-adrenergic agonises or antagonists, a second objective was to assess whether altered cardiac ; loading conditions could account for the absence of increased left ventricular beta-adrenergic sensitivity in patients with thyrotoxicosis . To test our hypotheses in human subjects, we characterized the effect of mild to moderate hyperthyroidism induced by short-term administration of triiodothyronine on the velocity, extent and frequency of left ventricular shortening and on simultaneous noninvasive 6735-1097I5LS5 .00



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MARTIN ET AL. HYPERTHYROIDISM AND BETA-ADRENERGIC RESPONSES

estimates of left ventricular mass and loading conditions during a graded dose isoproterenol infusion . Methods Study subjects. Eight euthyroid subjects (four men and four women) with a mean age (±SE) of 25 ± I years were studied . Results of a medical history, physical examination, rest electrocardiogram (ECG) and maximal exercise stress test were normal in all participants . None took regular medications, consumed caffeine-containing beverages or smoked on days of laboratory visits . Subjects were studied before and after a 2-week regimen of 100 pglday of oral triiodothyronine (T5) . The protocol for this investigation was approved on October 22, 1987 by the Human Studies Committee of Washington University with a yearly renewal since that time . All subjects gave voluntary written informed consent for participation in the study . isoproterenol infusion protocol . This protocol was conducted in the morning after an overnight fast at a similar time of day in the euthyroid and hyperthyroid states . Doppler and two-dimensional echocardiographic examinations were performed after 15 to 30 min of supine rest and during the latter 5 min of each of 4 stages of a graded dose isoproterenol infusion, A calibrated model 22 Harvard infusion pump was used to infuse isoproterenol into a forearm vein at rates of 0 .01, 0.02, 0.03 and 0.04 cg/kg per min, respectively, in stages I to 4 (21) . The infusion was terminated after stage 3 at the request of one subject because of palpitation associated with sinus tachycardia . However, there were no arrhythmias or other adverse cardiac effects of the study . During infusions, cardiac rhythm was monitored continuously by oscilloscope . Heart rate was determined every 2 min from at least three consecutive RR intervals of the ECG . Blood pressure was measured with a cuff sphygmomanometer at 3, 6 and 10 min of each stage. Heart rate and blood pressure remained stable between 6 and 10 min . Therefore, data from these time intervals were averaged and reported in the results . Doppler and two-dimensional echocardiographic studies. Two-dimensionally guided M-mode echocardiograms of the left ventricle were obtained from the parasternat short-axis view with use of a Hewlett-Packard model 77020A ultrasound imaging system equipped with a 2 .5-MHz model 21200B transducer. Recordings were made on light-sensitive paper with the transducer positioned in the third or fourth left intercostal space . The transducer position was documented and maintained constant during each stage and before and after T5 administration . After echocardiograms of the left ventricle were obtained, continuous wave Doppler tracings of the ascending aorta were recorded from the supracternal notch with use of a .19-MHz Hewlett-Packard model 21221A transducer to characterize aortic flow velocity and left ventricular ejection time . Subsequently, the aortic outflow tract and root were visualized from the parasternal long-axis position. Two-dimensional images of this view

(ccc

V .I. 19, No. b

May 19911!85-91

were used to obtain M-made echocardiograms of the aortic root and valve . Left ventricular end-diastolic and end-systolic dimensions (LVEDD and LVESD, respectively) were determined according to recommendations of the American Society of Echocardiography (22) . The coefficient of variation for measurements of left ventricular dimensions during catecholamine infusion or exercise is <5% in our laboratory (23,24) . At each stage of isoproterenol infusion, measurements were made of at least five cardiac cycles that were consecutive except for occasional exclusions for technical quality . The extent of left ventricular shortening was quantified as fractional shortening (FS%) by using the relation FS% = I(LVEDD - LVESD)ILVEDD)] x 10001o. Left ventricular ejection time (LVET) was measured from the onset to the termination of at least five continuous wave Doppler tracings of the ascending aorta. These beats were again consecutive except in occasional instances . To assess the rate of left ventricular shortening, the mean velocity of circumferential fiber shortening (mVcf) was calculated as mVcf = FS%/ LVET. Because measurements of fractional shortening and left ventricular ejection time were made on nonsimultaneous beats, the heart rate of cardiac cycles used for echocardiographic and Doppler measurements was determined and compared . Differences in hear rate during the same stage of isuproterenol infusion averaged 3 beats/min and were significant only during stage 2, in which echocardiographic and Doppler study heart rates were 86 and 91 beats/min, respectively (p < 0 .05) . In the hyperthyroid state, heart rate was considerably faster than in the euthyroid state (p < 0.001). To adjust for these differences, the left ventricular ejection time was corrected for heart rate (LVETC), as described by Colon et al. (25), by using the relation LVETC = LVET/\R-R . The mean velocity of left ventricular circumferential fiber shortening was also corrected for heart rate by calculating the quotient of fraction shortening and the left ventricular ejection time corrected for heart rate . To account for the effect of changes in q/tertoad, the mean velocity of left ventricular circumferential fiber shortening was expressed as a function of left ventricular endsystolic meridional wall stress . The latter was estimated from cuff measurements of systolic blood pressure and echocardiographic measurements of left ventricular dimensions and posterior wall thickness at end-systole as described by Reichek et al . (26). Left ventricular mass was assessed from baseline short-axis M-mode echocardiograms with the method of Troy et al . (27). Stroke volume was determined as the difference between left ventricular enddiastolic and end-systolic volume where both volumes were estimated from respective linear dimensions of M-made echocardiograms (27) . Statistics, The statistical significance of effects of hyperthyroidism and isoproterenol infusion on left ventricular function and other physiologic variables was evaluated by tw -way analysis of variance. Differences between specific



MARTIN ET AL. HYPERTHYROIDISM AND BETA-ADRENERGIC RESPONSES

JACC Vol. I9 . No. 6 May 1992:11X5-91

04

1197

4.0

aZ V 3 2 .0 0 0 175 ~= 125 E

s00 Figure .1 Effect of experimental hyperthyroidism on heart rate during supine rest and in response to a graded dose isoproterenol infusion . Data are mean values ± SE . *`p < 0.01 ; ***p < 0 .001 versus euthyroid values at the same stage.

means were identified by Student i tests for paired observations . The slope and intercept of equations describing heart rate responses to isoproterenol in each subject before and afterT3 administration were determined by linear regression analysis . The effect of hyperthyroidism on these values was then assessed by Student t tests for paired observations . Differences in results were considered statistically significant at p < 0.05 . Data are expressed as mean values .0 SE .

Results Thyroid indexes . During initial studies, subjects were cuthyroid as assessed by plasma T, and thyroid-stimulating hormone levels (112 ± 10 ng/ml and 1 .7 ± 0 .3 µU/ml, respectively). Two weeks of daily T3 administration increased plasma T, concentration by 401% (564 ± 141 ng/ml ; p < 0.001) and resulted in a decrease in thyroid-stimulating hormone to 0.5 1AUlml in two subjects and to undetectable levels in the other six subjects (p < 0 .001). Physiologic manifestations of hyperthyroidism included a faster heart rate at supine rest (68 ± 4 vs . 57 ± 3 beats/min; p < 0.001), a higher oxygen uptake at rest (0 .25 m 0.02 vs. 0.22 m 0.02 liters/min ; p = 0.05) as measured by automated respiratory gas adalysis (28), and a tendency to lose weight (715 . 5 vs. 72 .9 ± 5.4 kg ; p = 0.08) . Heart rate (Fig. 1). isoproterenol elicited a progressive increase in heart rate with no evidence of desensitization during the 4 stages of infusion . By linear regression analysis the correlation between isoproterenol infusion rate and heart rate averaged 0.97 ± 0 .01 before T3 administration and 0.98 ± 0.03 afterward. In the hyperthyroid state, the slope of the regression line was 36% greater than in the euthyroid state (1,538 ± 126 vs . 1,131 ± 95; p < 0.05), consistent with enhanced heart rate sensitivity or responsiveness to betaadrenergic stimulation, or both . Peak heart rate in stage 4 of isoproterenol infusion was 102 ± 4 beats/min in the euthyroid state and 129 ± 5 beats/min after T 3 administration .

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0r 0 001 0.02 003 004 ISOPROTERENOL (trortt /nen) Figure 2. Effect of experimental hyperthyroidism on audiac dimensions (upper panel, A) . stroke volume (middle pod, B) and systolic blood pressurefeft ventricular rod-systolic dimension (SBPI LVESD) relation (lower panel, C) during supine rest and in response to a graded dose isoproterenol infusion . Cardiac dimensions in diastole and systole and stroke volume were determined echocardiographically . Data are mean values m SE.

dam,

Left ventricah r fianctilina and mass (Fig. 2). Baseline left ventricular dimensions, fractional shortening and stroke volume were within the normal range and did not change significantly after T3 administration (33 .3 ± 1 .7% vs . 33 .9 x 1 .3% for fractional shortening before vs. after T3 administration ; p = NS) . Aortic diameter, measured at the level of the aortic valve, and baseline peak aortic flow velocity also remained similar (2 .9 ± 0.2 vs. 2.9 ± 0.1 cm and 102 .1 *_ 4.2 vs. 109 .8 ± 4.2 ends, respectively ; p = NS). Similarly, baseline systolic blood pressure and left ventricular afterload, defined as end-systolic meridional wall stress, were not altered by hyperthyroidism (112 ± 4 vs . 114 4 mm Hg and 58.6 ± 4.2 vs. 58.9 ± 4.9 g/cm2, respectively ; p = NS) . Finally, there was no evidence of left ventricular hypertrophy in these subjects after 2 weeks of excess T3 administration (left ventricular mass = 137 .4 ± 13 .8 vs . 132 .9 '_ 12 .9 g before vs . after Ts; p = NS). In contrast to these findings, baseline left ventricular ejection time was shorter and the mean velocity of left ventricular circumferential fiber shortening was faster after than before T, administration (0.28 ± 0.02 vs. 0.32 ± 0.02 s and 1 .23 ± 0.1 vs . 1 .06 0.06 diameters/s. respectively; p < 0.001 and p < 0 .05), consistent with an increased left ventricular contractile state. However, when the baseline left ventricular ejection time and the mean velocity of circumferential fiber shortening were adjusted for the faster heart rate induced by hyperthyroidism, mesa differences were no longer significant (0.31 ± 0.02 vs. 0.3 ± 0 .02 s and 1 .09 ± 0 .08 vs . 1 .18



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MARTIN ET AL. HYPERTHYROIDISM AND META.ADRENEROIC RESPONSES

JACC Vul . 19, Nn, E May 19911185-91

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of

f~ Emhymid o-b Hs enaneid 08 D

ISOPROTERENOL (p9/kg/min) Figum3. Effect of experimental hyperthyroidism on left venticWar ejection time (LVET) (upper panel, A) determined by Doppler echocardiography and the mean velocity of left ventricular circumferenlial fiber shortening (mVcf) (lower panel, B) determined by lwodimersionally guided M-mode and Doppler echocardiography during supine rest and in response to a graded dose isoproterenol infusion . ?iota are mean values ± SE . •p < 0.05; r*rp < 0.001 versus euthyroid values at the same stage .

0 .09 diameters/s, respectively, before and after Te administration ; p = NS) . Effects of hyperthyroidism on left venlricular eantraelite responses to heta.adrenergic stimulation (Fig. 2 to 5) . Graded dose isoproterenol infusion markedly augmented the left ventricular contractile state. This effect was demonstrated by decreases in left ventricular end-systolic dimensions (Fig . 2), ejection time (Fig . 3) and ejection time currnUed fur heart rate (Fig . 4) and by large increases in left ventricular fractional .shortening, stroke volume (Fig . 2), mean velocity of circumferential fiber shortening (Figs . 3 and 4 . respectively; for results before and after correction for heart rate) and the ratio of systolic blood pressure to left ventricular end-systolic dimension (Fig . 2) . These effects weru not accompanied by a change in preload, defined as left ventricular end-diastolic dimension (Fig- 2)- but they may have been related in part to a decrease in afterload, quantified as left ventricular end-systolic meridional wall stress (Fig, 5) . The increase in left ventricular contractile state in response to isoproterenol attained a plateau in stage 2 or 3 as assessed by the absence of further changes in mean velocity of circumferential fiber shortening, end-systolic dimension and stroke volume (Fig . 2 to 4), consistent with achievement of a maximal left ventricular contractile response to belaadrenergic stimulation . The magnitude of enhancement affruclional shortening and stroke volume with tsaproterenol infusion was similar before arrd after ingestion of T3 (Fig. 2) . Thus, experimental

r

, 0.02 0 .03 0.04 0 0.01 ISOPROTERENOL IJig/kg/min)

Fgure 4. Effect of experimental nyperthynoidism on the left ventricular ejection time corrected for heart rate (LV£TO) (upper panel, A) determined by Doppler echocardiography and the mean velocity of left ventricular circumferntial fiber shortening corrected for heart rate (mVcfr) flower panel, B) determined by two-dimensionally guided N-mode and Doppler echocardiography during supine rest and in response to a graded dose isoproterenol infusion . Data are mean values . SE . "p < 0.05 versus euthyroid values at the same stage .

hyperthyroidism did not influence the extent of left ventricular shortening in response to selective beta-adrenergic stimulation . Aortic root diameter under these conditions was also not altered by hyperthyroidism . In contrast, peak aortic flow velocity during isoproterenol infusion tended to be higher in the hyperthyroid state (p = 0 .10). The left ventric ular ejection time, uncorrected for the faster heart rate after T, administration, was significantly reduced (Fig . 3) and the rate of left ventricular shortening, quantified as the mean velocity of circumferential fiber shortening (Fig . 3), was increased in the hyperthyroid versus the euthyroid state at

More 5. Efect of experimental hyperthyroidism on the mean velocity of left venaicular (LV) circumferential fiber shortening (mVefl expressed as a function of aferload, defined as left ventricutarend-sysroRc wall stress . Data am mean values r SE . ep < 0A5 ;

r"'p < 0.001 versus values for circumferential fiber shortening in the euthyroid state. 3-2 .

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1 .6

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H e,e., h o--O Hranthno;d

0fd 25 35 45 55 65 LV END SYSTOLIC WALL STRESS Igm/gmr )



tact Yd. 19, No. 6 Muy 1992'.1195-91

MARTIN Er At. HYPERTHYROIDISM AND BETA-ADRENERGIC RESPONSES

baseline and at all stages of isoproterenol infusion, even though concurrent changes in afterload (Fig . 5) and preload (Fig. 2) during the infusion were similar in both studies . However, after adjustment of the left ventricular ejection time and shortening velocity for the faster heart rate in the hyperthyroid state, both measurements were similar before and after T5 administration at baseline and at maximally stimulating rates (stages 3 and 4) of isoproterenol infusion (Fig . 4). In contrast, the left ventricular ejection time corrected for heart rate was shorter during stages I and 2 and the mean velocity of circumferential fiber shortening corrected for heart rate was greater during stage I after T, administration, providing evidence that isotropic sensitivity to selective beta-adrenergic stimulation is increased by experimental hyperthyroidism even in the absence of a change in the extent of left ventricular shortening. Discussion Major findings in relation to previous studies. In our study 2 weeks of excess triiodothyronine (T 5) administration resulting in mild to moderate hyperthyroidism increased the sensitivity of both heart rate and left ventricular shortening velocity to beta-adrenergic stimulation in human subjects . These effects occurred even though the extent of left ventricular shortening was not enhanced and there were no significant differences between the euthyroid and hyperthyroid states in left ventricular dimensions, mass or loading conditions . Our results are consistent with studies in experimental animals demonstrating that thyroid hormones increase myocardial beta-adrenergic receptor density (2,3,7,8), amplify the cyclic adenosine monophosphate response of cultured heart cells to epinephrine (41. enhance the tachycardic response of isolated mouse hearts to submaximally stimulating doses of isoproterenol (I) and augment the contractile response of isolated rat myocardium to low dose beta-adrenergic stimulation (6). Paradoxically, other investigations (11-15) have suggested that results of these studies are not applicable to human subjects. No augmentation of human cardiovascular responses to catecholamines was observed during T,-induced thyrotoxicosis (11 .12) and no difference was found in the effect of beta-adrenergic blockade on heart rate or myocardial function of spontaneously thyrotoxic and normal persons (13,14) . Similar to findings in experimental animals, however, our data demonstrate that hyperthyroidism increases the sensitivity of heart rate and left ventricular shortening velocity to beta-adrenergic stimulation in humans. Effect of Ta administration on cardiac responses to isopro. terenol. Most earlier studies (11-14) of the effect of hyperthyroidism on left ventricular function in humans either did not examine the dose-response relation to beta-adrenergic agonist administration or reported responses to epinephrine or norepinephrine, Although these catecholamines are of major physiologic importance, they also stimulate alpha-

1189

adrenergic receptors, evoke parasympathetic reflex activity, alter cardiac loading conditions and elicit only a slight increase or a decrease in heart rate in comparison with isoproterenol (16)- Investigations of human cardiovascular responses to isoproterenol(15) were performed before sensitive noninvasive methods were available to quantify both the velocity and the extent of left ventricular shortening under physiologic conditions . In our subjects, the response of left ventricular shortening velocity to low dose isoproterenol infusion was enhanced after T5 administration, a finding similar to previous observations in the myocardium of experimental animals (1,6.8) . At higher levels of beta-adrenergic stimulation that elicited a plateau in the left ventricular contractile response, increases in heart rate and in the absolute (uncorrected for heart rate) velocity of left ventricular shortening were greater in the hyperthyroid than in the euthyroid state . However, after normalization of left ventricular shortening velocity for the faster heart rate in the hyperthyroid state, no difference between pre- and post-T, studies was found at maximally stimulating isoproterenol infusion rates . The latter results are in agreement with in vitro studies demonstrating no T,-induced increase in the maximal velocity or extent of myocardial shortening in response to catecholamines (6,17) . Our findings are also consistent with previous data in humans showing no effect of induced hyperthyroidism on stroke volume responses to the selective beta-adrenergic agonist isoproterenol (15) and with the well known abbreviation of left ventricular ejection time by spontaneous thyrotoxicosis (29) . Left ventricular leading conditions. Hyperthyroidism often results in reduced peripheral vascular resistance and enhanced cardiac preload (19,20) . Such changes could confound interpretation of effects of T, on left ventricular contractile function. Subjects who participated in the present investigation were found to have a lower total peripheral resistance (higher heart rate and cardiac output at a similar mean blood pressure) after than before T, administration . However, tree myocardial afterload is thought to be most accurately quantified in terms of end-systolic meridional wall stress (18). Reliable and reproducible techniques to estimate wall stress noninvasively have been developed (26). In our subjects, left ventricular afterload, quantified in this manner, was not significantly altered by T, administration either in baseline studies or during isoproterenol infusion . Thus, the effect of T 3 on the sensitivity of left ventricular shortening velocity to isoproterenol is unlikely to be related to decreased afterload in the hyperthyroid state . Similarly, there was no influence of T, on preload, defined as left ventricular end-diastolic dimension . Although we did not measure end-diastolic pressure, the absence of a change in left ventricular end-diastolic diameter provides evidence that myocardial fiber length was not increased in the hyperthyroid state (18). The conclusion that the T3 induced increase in velocity of left ventricular shortening is not related to effects on cardiac loading conditions is also consistent with



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data of Goldman et al. (30) obtained in conscious thyrotoxic calves . Other cardiac effects of hyperthyroidism in experimental animals. In addition to altering responses to beta-adrenergic stimulation, T3 elicits other cardiac effects in experimental

animals . These include tachycardia at rest, cardiac enlargement, hypertrophy, an enhanced contractile state and myosin isoenzyme transformation (8,19). In our subjects experimental hyperthyroidism induced tachycardia and an augmented rate of left ventricular shortening, but hypertrophy, cardiac enlargement and an increased extent of left ventricular contraction did not occur . Furthermore, the reduction of left ventricular ejection time was partly related to a faster heart rate. The explanation for the absence of cardiac hypertrophy and enlargement in these human subjects is unclear. However, considerable variation in thyroid hormone-induced effects on the heart has been observed in studies of different species of mammals (1,6-8,19). In addition, there were differences in the dosage and duration of thyroid hormone treatment in those studies (1,6-8,19) and very high doses were often given . Thus, it is not surprising that some effects of T 3 reported in experimental animals were not found in the present study . Contrasting effects of hyperthyroidism on cardiac and skeletal muscle. In a previous investigation (31), we ob-

JACC Vol. 19, No . 6 May 1992:1185-91 otherwise healthy young patients with thyrotoxicosis of recent onset . It is unclear whether our findings are also applicable to older persons, patients with more prolonged hyperthyroidism or those with coexistent illnesses . A control group would have been useful to completely exclude effects of methodologic and biologic variability . However, reproducibility data from previous studies (23) indicate that methodologic and biologic variability are not great enough to explain the change in left ventricular shortening velocity observed in the current investigation after T, administration . Conclusions. This study indicates that in human subjects, hyperthyroidism of short duration increases the responses of heart rate and left ventricular shortening velocity to low dose beta-adrenergic agonist (isoproterenol) infusion . At higher levels of beta-adrenergic stimulation that elicit a plateau consistent with maximization of the left ventricular contractile response, the heart rate-adjusted velocity of left ventricular shortening is not augmented by hyperthyroidism. Thus, hyperthyroidism of short duration increases heart rate and left ventricular contractile sensitivity to beta-adrenergic stimulation in human subjects . We thank Ali A. Ehsani, MD and Peter B . Con, PhD for constructive suggestions and Phyllis Anderson for preparation of the typescript .

served that the same T 3 administration protocol used in the

current study to induce thyrotoxicosis resulted in skeletal muscle atrophy and accelerated whole body protein catabolism . In addition, beta-adrenergic receptor density in skeletal muscle fibers was increased without a change in metabolic or peripheral vascular sensitivity to isoproterenol (32). These findings are in contrast to the maintenance of left ventricular mass and enhancement of left ventricular sensitivity to beta-adrenergic stimulation observed in the present investigation. However, disparate effects on skeletal and cardiac muscle are consistent with evidence in experimental animals (33,34) that hyperthyroidism enhances skeletal muscle protein breakdown while simultaneously increasing cardiac mass. Previous controversies regarding physiologic effects of hyperthyroidism may be related in part to disparities such as these . Results of our studies emphasize the importance of characterizing specific effects of hyperthyroidism in pertinent human target tissue. Limitations. Patients with spontaneous hyperthyroidism may have a variety of cardiac manifestations of thyrotoxicosis including atrial tachyarrhythmias, cardiomegaly and congestive heart failure (20) . The lack of these findings in our subjects is probably due to their young age, the relatively short duration of thyrotoxicosis and the absence of coexistent cardiovascular disorders such as hypertension or coronary artery disease . For ethical reasons we did not consider it appropriate to induce a hyperthyroid state for more than a few weeks . Nevertheless . our subjects were clearly hyperthyroid on the basis of marked changes in plasma T3 and thyroid-stimulating hormone concentrations and an increased rest metabolic rate . Thus, our data are relevant to

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415-64. 20. Klein I . Thyroid hormmte and doe cardiovascuar system. Am J Sled 1990 .86:631-7. .21. Martin WH 111, Spina RJ, Kone E, 0650 C . BI&crsatchronic and m- an cardiovascular pi adrenergic responses . I Appl Physiol 1991 : 71 :1523-8 . 52 . Snhn O1, Dehtarie A, Ktsslo J . Weyman A . Recommendatootrs regarding

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