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Stress Echocardiography in Hyperthyroidism

Departments of Endocrinology/Metabolism, and Cardiology (S.W., S.M.K.), Gutenberg University Hospital, Mainz 55101, Germany; and the Echocardiography Laboratory, Division of Cardiology, Duke University Medical Center (T.J.R.), Durham, North Carolina 27710

Address all correspondence and requests for reprints to: Prof. George J. Kahaly, University Hospital, Building 303, Mainz 55101, Germany. E-mail: kahaly{at}endokrinologie.klinik.uni-mainz.de

	Abstract

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Exertion symptoms occur frequently in subjects with hyperthyroidism. Using stress echocardiography, exercise capacity and global left ventricular function can be assessed noninvasively. To evaluate stress-induced changes in cardiovascular function, 42 patients with untreated thyrotoxicosis were examined using exercise echocardiography. Studies were performed during hyperthyroidism, after treatment with propranolol, and after restoration of euthyroidism. Twenty- two healthy subjects served as controls. Ergometry was performed with patients in a semisupine position using a continuous ramp protocol starting at 20 watts/min. In contrast to control and euthyroidism, the change in end-systolic volume index from rest to maximal exercise was lower in hyperthyroidism. At rest, the stroke volume index, ejection fraction, and cardiac index were significantly increased in hyperthyroidism, but exhibited a blunted response to exercise, which normalized after restoration of euthyroidism. Propranolol treatment also led to a significant increase of delta () stroke volume index. Maximal work load and heart rate were markedly lower in hyper- vs. euthyroidism. Compared to the control value, systemic vascular resistance was lowered by 36% in hyperthyroidism at rest, but no further decline was noted at maximal exercise. The stroke volume index, ejection fraction, heart rate, and maximal work load were significantly reduced in severe hyperthyroidism. Negative correlations between free T₃ and diastolic blood pressure, maximal work load, heart rate, and ejection fraction were noted. Thus, in hyperthyroidism, stress echocardiography revealed impaired chronotropic, contractile, and vasodilatatory cardiovascular reserves, which were reversible when euthyroidism was restored.

	Introduction

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STRESS ECHOCARDIOGRAPHY compares two-dimensional echocardiography images obtained before, during, and after exercise and is an accurate technique for the evaluation and follow-up of global and regional left ventricular function (1, 2). In the normal subject, when cardiac performance is monitored during exercise, the most striking physiological changes are the increase in left ventricular contractility and the decrease in end-systolic volume. These alterations can be detected by analysis of left ventricular wall motion and measurement of the ejection fraction response to stress. Failure of these changes to occur during exercise is abnormal. Possible causes include cardiomyopathy, reduced exercise capacity, medications such as ß-blockers, and is-chemia (3, 4).

Some of the prominent symptoms and signs of hyperthyroidism are those involving the cardiovascular system (5, 6, 7). These changes arise both from alterations in systemic hemodynamics and from T₃-mediated effects on cardiac myocyte-specific gene expression (8, 9, 10). Exertion symptoms, dyspnea, and impaired effort tolerance are common complaints in patients with hyperthyroidism. Proposed explanations include high output left heart failure, ineffective oxygen utilization, and respiratory muscle weakness (5). Hyperthyroid subjects may not be able to meet the additional demand for increased work. Thus, to analyze the alterations of cardiovascular function and work capacity thought to occur in hyperthyroidism, we performed stress echocardiography in a large group of thyrotoxic patients before and during propranolol therapy and after restoration of euthyroidism. These results were compared to those in a group of healthy controls. We speculated that stress echocardiography would be a useful technique to quantify and monitor cardiac dysfunction during hyperthyroidism and subsequent therapy. We hypothesized that the resting cardiovascular changes associated with hyperthyroidism would lead to an abnormal functional response to exercise that could be reversed after restoration of the euthyroid state.

	Subjects and Methods

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Forty-two out-patients (32 females and 10 males; age, 42 ± 2 yr; range, 29–59 yr; body surface area, 1.75 ± 0.03 m² with untreated hyperthyroidism, 32 with Graves’ disease, and 10 with toxic goiter) participated in this prospective study. Twenty-two healthy euthyroid volunteers served as controls (11 females and 11 males; age, 40 ± 2 yr; range, 25–48 yr; body surface area, 1.87 ± 0.04 m²; TSH, 1.5 ± 0.9 mU/L). The reported investigations were approved by the responsible ethic committee, and informed consent was obtained from all patients and controls before participation. We selected hyperthyroid subjects with no history of arrhythmia, valvular or coronary heart disease, or neuromuscular or pulmonary disease that could contribute to their exercise intolerance. Diagnosis of hyperthyroidism was based on increased free T₃ (mean, 17.3 ± 1.4 pg/mL) and free T₄ (4.1 ± 0.3 ng/dL) levels as well as a suppressed TSH (0.03 ± 0.009 mU/L). According to an established clinical scale for hyperthyroidism (11), cardiovascular symptoms (nervousness, sweating, heat tolerance, weakness, tremor, etc.) were significantly more frequent and severe among 14 patients (33%) with a free T₃ level above 20 pg/mL (see Table 3). Clinical and biochemical data were recorded before and after therapy for hyperthyroidism. Serum free T₃ (range, 3–6 pg/mL), free T₄ (0.8–2 ng/dL), and TSH (0.23–4 mU/L) were measured using commercially available kits (Boehringer Mannheim, Mannheim, Germany). All patients were initially treated with propranolol (120 mg/day) for 1 week, then with methimazole (20 mg/day), and propranolol was gradually reduced.

A complete two-dimensional echocardiography and Doppler examination was performed in all thyrotoxic patients at the time of study entry, after 1 week of propranolol therapy, and then 6 months later using an ultrasound system (Vingmed CFM 800, Sonotron, Horton, Norway) equipped with a 2.5-MHz transducer and an integrated stress echocardiography digitizing system (Echo PAC, version 4.1.3, Horton, Norway). Patients performed the identical exercise protocol at baseline and after restoration of the euthyroid state (free T₃, 4.4 ± 0.1 pg/mL; free T₄, 1 ± 0.06 ng/dL; TSH, 2.5 ± 0.9 mU/L) and were free of cardiovascular medication. Images were stored on videotape and on magneto-optical disks in a digital format. Analysis of echographic and Doppler measurements was performed using an off-line work station (Echo-com, Fulda, Germany) by one experienced observer (S.W.). End-diastolic and end-systolic volume indexes were calculated from apical two- and four-chamber views using the modified biplane Simpson technique according to the guidelines of the American Society of Echocardiography (1, 2, 3, 4). Left ventricular diastolic function (deceleration and isovolumic relaxation times), right ventricular systolic pressure, and flow velocities (maximal aortic flow velocity, mitral E and A wave velocities) were recorded with continuous and pulsed wave Doppler. All measurements were made on three representative cardiac cycles, and mean values were calculated. Exercise testing was performed on an electromagnetically braked cycle ergometer (Ergometrics 900L, Ergoline, Bitz, Germany; with Marquette-Case 12, Marquette, WI) with the patient in a 45° semisupine position. A ramp protocol starting with 20 watts/min was employed. Work load was continuously increased by 20 watts/min up to a symptom-limited maximum. End points for exercise testing were chest pain, exhaustion, or ST segment depression greater than 0.3 mV. Evaluated variables included reason for termination of exercise, heart rate (beats per min), and rate-pressure product (heart rate x systolic blood pressure).

Systemic vascular resistance index (SVRI; dynes per s/cm^-5·M²) was calculated as follows: SVRI = (mean arterial pressure - mean right atrial pressure) x 80/cardiac index. Mean right atrial pressure was estimated as a constant of 5 mm Hg (12).

Statistics

Data are expressed as the mean ± SE. Statistical analysis was performed using SAS software (13). The Mann-Whitney U test for multiple comparison and the Wilcoxon signed-rank test were used as appropriate. Paired comparisons of more than two proportions were analyzed using the Bonferroni adjustment. The correlation coefficients were generated with the Pearson bivariate correlation test. Statistical significance was accepted at the 95% confidence level (P < 0.05).

	Results

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Hemodynamic data

In patients with hyperthyroidism, heart rate at rest was higher than in euthyroidism, but exhibited a smaller increase between rest and maximal exercise compared with euthyroidism and control values (Table 1). Systolic blood pressure at rest was significantly higher in hyperthyroidism compared with euthyroidism and control values, with no differences detected at maximal exercise. At rest, the rate-pressure product was increased in hyperthyroidism compared with euthyroidism and propranolol values. The magnitude of increase in rate-pressure product from rest to maximal exercise was lower in hyperthyroidism compared with euthyroidism and control values. In patients with thyrotoxicosis, maximal work load was markedly reduced. It increased slightly during propranolol therapy and was significant after restoring euthyroidism. Systemic vascular resistance was decreased by 36% in hyperthyroid patients and by 17% and 12% in propranolol and euthyroid subjects compared to control values. During exercise and in contrast to euthyroid subjects (-35%) and controls (-45%), no further decrease in vascular resistance index was noted (-5%). At maximal exercise, this parameter was higher (+12%) in hyperthyroid patients vs. controls.

In contrast to control and euthyroid subjects, end-systolic volume index was lower in hyperthyroidism (Table 2). In all states, the end-diastolic volume index was similar. Compared with euthyroid and control subjects, stroke volume index, ejection fraction, and cardiac index at rest were significantly higher in hyperthyroidism. During exercise, there was a blunted response of stroke volume index, ejection fraction, and cardiac index, all of which normalized in euthyroidism. Propranolol treatment also led to a significant increase in stroke volume index. Compared with euthyroid and control values, hyperthyroidism was associated with a shorter preejection period, a shorter isovolumic relaxation and deceleration time, a higher maximal aortic flow velocity, and higher mitral E and A wave velocities. These differences were noted at rest and partly during exercise and were significantly modified during propranolol therapy. At rest, right ventricular systolic pressure was normal. In hyperthyroidism, hyperkinetic left ventricular wall motion was noted, and no wall motion abnormalities developed with exercise. In 10 of 32 subjects (31%) with Graves’ disease but in none with toxic goiter, a myxomatous mitral valve prolapse was present. Prolapse was unchanged during propranolol treatment and/or when patients were made euthyroid.

In patients with a serum free T₃ level above 20 pg/mL, diastolic blood pressure, systemic vascular resistance index, heart rate, stroke volume index, ejection fraction, cardiac index, and maximal work load were lower than those in patients with a free T₃ level less than 20 pg/mL (Table 3). Positive correlations between free T₃ and heart rate at rest (r = 0.7; P = 0.0001) and maximal exercise (r = 0.58; P = 0.0009) were observed, whereas negative correlations between free T₃ and diastolic blood pressure at rest and maximal exercise (r = -0.67; P = 0.0006 and r = -0.58; P = 0.0008, respectively), maximal work load (r = -0.62; P = 0.0001), heart rate (r = -0.49; P = 0.0014), ejection fraction (r = -0.48; P = 0.0015), and maximal rate pressure product (r = -0.38; P = 0.013) were noted.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Cardiovascular function

Using stress echocardiography for the first time in a large group of subjects with untreated hyperthyroidism, this prospective, controlled study demonstrated marked changes in cardiovascular function and exercise capacity that were related to the severity of thyroid disease and confirmed the markedly lowered systemic vascular resistance at rest. The major findings were the diminished left ventricular chronotropic and contractile reserve demonstrated during exercise in hyperthyroid patients, their association with typical symptoms of thyrotoxicosis, and the reversibility of these changes after therapy. As previously shown (14), left ventricular diastolic function (e.g. isovolumic relaxation) was enhanced in hyperthyroidism, remained unchanged during ß-blockade, and returned to normal in the euthyroid state. In contrast to a recent report (15), neither echocardiographic signs of pulmonary hypertension nor features of right ventricular overload were noted.

In our study patients, cardiac output was potentially near maximal at rest and did not increase in response to exercise. The negative correlation between serum T₃ level and ejection fraction and the decrease in ejection fraction during exercise in severe thyrotoxicosis support the presence of impaired functional left ventricular reserve in hyperthyroid patients. These subjects had a less than expected increase in left ventricular contractility during exercise (markedly reduced end-systolic volume index), but showed the appropriate response after antithyroid treatment, which suggests a direct effect on the myocardium of an excess of circulating T₃. It may be that left ventricular dysfunction induced only by exercise represents an intermediate state between normal left ventricular function and dysfunction at rest, and that in the long run, untreated patients with hyperthyroidism could acquire a true thyroid-induced cardiomyopathy. A negative correlation between ejection fraction and T₃ levels has also been observed by Feldman et al. (16), who reported that changes in left ventricular contractility were not associated with alterations in heart rate and/or ventricular loading, providing in vivo evidence for a direct inotropic effect of thyroid hormones. Furthermore, using radionuclide ventriculography, impaired exercise-induced increases in left ventricular ejection fraction in thyrotoxic patients have been described, with these abnormalities being corrected by restoration of euthyroidism (17). Others using the nuclear medicine technique have reported normal left ventricular systolic function in hyperthyroidism both at rest and during exercise (18). An alternative explanation is that before treatment, resting systemic vascular resistance was already maximally reduced and therefore could not decline further with exercise (19). In the absence of such a decline, left ventricular afterload and contractility may not change, and so cardiac output would not increase. The lack of increase in the ejection fraction during exercise could simply be due to the imposition of an exercise-induced increase in afterload on a heart that is performing near its maximal capacity. Indeed, the systemic vascular resistance and diastolic blood pressure were substantially lower in our study patients with the higher serum free T₃ levels; therefore, the failure to alter ejection fraction with exercise in that group would be consistent with the hypothesis that changes in systemic vascular resistance, rather than changes in cardiac contractility, may explain the results observed (20). Further, although thought to reflect impaired cardiac performance, a decrement in maximum workload, exercise intolerance, and dyspnea on exertion may also be caused by weakness of skeletal and respiratory muscles. Using objective measures of muscle strength and endurance, reversible dysfunction of distal skeletal, proximal, and respiratory muscles was observed in hyperthyroid patients. Muscle function and exercise performance improved and attained control levels when the patients were chemically and clinically euthyroid (21).

Hemodynamic data

In contrast to values during the control period and euthyroid state, heart rate did not increase significantly during exercise in hyperthyroid patients as a sign of impaired chronotropic reserve. The current results are consistent with a described depression of the efferent activity of the vagal component of the autonomic nervous system during exercise in thyrotoxic subjects (22, 23). Furthermore, although the rate-pressure product was significantly higher in hyper- vs. euthyroidism, work load was markedly lower in thyrotoxic patients. This product is an index of cardiac work that correlates with myocardial oxygen consumption (24). During exercise, the lesser increase in rate-pressure product in hyperthyroid patients was most likely due to the higher resting heart rate and systolic blood pressure seen in thyrotoxicosis and was consistent with decreased contractile reserve and low efficiency of cardiac function. In concordance to this, ineffective cardiorespiratory function in hyperthyroidism has been shown; the oxygen pulse (oxygen uptake per heart beat) was decreased at the ventilatory anaerobic threshold. During exercise, increments of minute ventilation (respiratory rate x tidal volume), oxygen uptake, and oxygen pulse were lower in hyper- vs. euthyroidism (25).

Metabolic factors

Regarding possible metabolic causes of the impaired inotropic and chronotropic responses to incremental exercise in our study patients, hyperthyroidism increases fast myosin (26) and fast twitch fibers in skeletal muscle (27), which are less economic in oxygen utilization during contraction than slow twitch muscle fibers (28). Reduced exercise efficiency may also be induced by excessive heat production in thyrotoxicosis (29). Effort tolerance was also impaired in short duration experimental hyperthyroidism, because of decreased skeletal muscle mass and oxidative capacity related to accelerated protein catabolism (30). Thyroid hormones affect mitochondria mass and enzyme activities (31), and clinical symptoms of exercise intolerance in hyperthyroidism may be due to decreased, rather than increased, muscle oxidative capacity (32). Because elevated skeletal muscle blood flow during exercise was reported in thyrotoxic rats (33), cardiovascular dysfunction alone cannot explain exercise limitation.

ß-Blockade

The actions of thyroid hormones may be mediated by adrenergic receptor stimuli that can be blocked by ß-antagonists (19). This effect is plausible because there is a high cardiac sensitivity to ß-adrenergic stimulation in thyrotoxicosis (34). Furthermore, in contrast to the effects of ß-blockade in controls, propranolol partially improved skeletal muscle weakness in hyperthyroid patients (21) and reversed T₄-induced cardiac hypertrophy in both animals and humans (35, 36). Thyroid hormone and catecholamines in concert may mediate the muscle dysfunction in hyperthyroidism. Although older patients with hyperthyroidism may lack an appropriate peripheral circulatory response, propranolol therapy enhanced work load in our study and reduced the response of heart rate to exercise. Thus, ß-blockade led to more economical work and higher efficiency of cardiovascular function. This may explain clinical amelioration of symptoms in thyrotoxic patients during propranolol therapy (37, 38). As patients did not train or exercise regularly during the 6-month observation period, antithyroid treatment also explains the improvement in exercise capacity.

In conclusion, thyroid hormones may significantly decrease the strength of both respiratory and skeletal muscles and affect regulatory mechanisms of adaptation to incremental effort. In hyperthyroidism, stress echocardiography demonstrated a hyperdynamic cardiac function as well as a lowered systemic vascular resistance at rest and impaired chronotropic, contractile, and vasodilatatory reserves during exercise, which were reversible when euthyroidism was restored.

Received December 31, 1998.

Revised March 4, 1999.

Accepted March 30, 1999.

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