Thyroid hormones and thermogenesis: a microcalorimetric study of overall cell metabolism in lymphocytes from patients with different degrees of thyroid dysfunction

We used microcalorimetry to measure lymphocyte heat production rate in patients with clinical and laboratory hyperthyroidism (serum TSH decreases, serum FT4 increases, serum FT3 increases), subclinical hyperthyroidism (serum TSH decreases, serum FT1 increases, serum FT3 =), and subclinical hypothyroidism (serum TSH increases, serum FT4 decreases, serum FT3 =) compared with healthy controls (N = 13). The lymphocyte heat production rate was significantly correlated to the free thyroxine level (r = 0.53, p less than 0.01) and to the free triiodothyronine level (r = 0.51, p less than 0.01) when calculated from pooled data for the three patients groups. The hyperthyroid patients (N = 8) had a significantly increased lymphocyte heat production rate, 3.43 +/- 0.25 pW/cell, as compared with 2.31 +/- 0.12 pW/cell in the control group (p less than 0.001). The groups with subclinical hyperthyroidism (N = 7) and subclinical hypothyroidism (N = 9) had lymphocyte heat production rates of 2.14 +/- 0.11 and 2.56 +/- 0.15 pW/cell, respectively, not significantly different from that in the controls. Consistently, there was no significant difference between patients with subclinical hyperthyroidism (N = 5) and controls (N = 5) with regard to lymphocyte energy production as calculated from separately measured oxygen consumption rates in vitro, 1.36 +/- 0.20 and 1.56 +/- 0.12 pW/cell, respectively. Thus microcalorimetry seems to be suitable for studying the influence of thyroid hormones on cellular metabolism. Subclinical thyroid dysfunction does not seem to alter the overall rate of lymphocyte metabolism.     

Erythrocyte thermogenesis in hyperthyroid patients: microcalorimetric investigation of sodium/potassium pump and cell metabolism

Erythrocyte thermogenesis was studied by microcalorimetry in 11 patients before and after treatment for hyperthyroidism. Cell heat production rate and intracellular Na+ and K+ levels were measured in plasma suspensions of erythrocytes with and without specific inhibition of Na/K ATPase by ouabain. The ouabain induced change in the heat production rate (the Na/K pump thermal power); the erythrocyte intracellular Na+ content and the ouabain sensitive Na+ transport were used to estimate the Na/K pump function. The mean value for heat production rate was 131 +/- 4 mW/L erythrocytes before treatment, which is significantly higher than in euthyroid subjects. A significant decrease (P less than 0.01) to normal levels was recorded following therapy. This decrease, as determined in samples with ouabain, correlated to changes in serum levels of triiodothyronine, T3, (r = .74, P less than 0.01). The Na/K pump thermal power was 11 +/- 2 mW/L erythrocytes (8 +/- 2% of total heat production rate) before and 9 +/- 2 mW/L erythrocytes (8 +/- 2%) after treatment. These two values were not different from those obtained in euthyroid subjects. The erythrocyte Na+ content decreased from 9.9 +/- 2.1 to 4.9 +/- 0.5 mmol/L erythrocytes (P less than 0.001) following normalization of thyroid function. The decrease in intracellular Na+ concentration correlated to the decrease in serum T3 levels, but only when calculated from the data obtained in samples with ouabain (r = .60, P less than 0.05). The relative increase in intracellular Na+ concentrations following addition of ouabain was significantly lower (P less than 0.05) before than after treatment for hyperthyroidism, 37 +/- 10% and 61 +/- 5%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Na+K+ATPase activity and ouabain binding sites in erythrocytes in hyperthyroidism before and after treatment.

Erythrocyte sodium pump is decreased in hyperthyroid patients. We described the effect of untreated hyperthyroidism on Na+K+ATPase activity, ouabain binding sites and intracellular sodium concentration. We found a reduction in Na+K+ATPase activity and in number of ouabain binding sites with a concomitant increase in intracellular sodium. B-blockade therapy failed to restore normal pump activity and sodium concentration, where only thionamide treatment was successful when it was able to decrease free T3.     

Erythrocyte sodium fluxes, ouabain binding sites, and Na+,K(+)-ATPase activity in hyperthyroidism

Erythrocyte sodium pump activity, in contrast to other tissues, is decreased in hyperthyroidism. In order to examine whether the effect of thyroid hormones on erythrocytes is part of a generalized effect on other transport pathways, we measured sodium pump activity, Na+,K(+)-adenosine triphosphatase (ATPase) activity, ouabain binding sites, bumetanide-sensitive sodium potassium cotransport (SPC), sodium lithium countertransport (SLC), and ouabain- and bumetanide-insensitive passive efflux of sodium (sodium "leak") in erythrocytes from 20 healthy subjects and 18 untreated hyperthyroid subjects. Sodium pump activity (ouabain-sensitive sodium efflux rate constant), Na+,K(+)-ATPase activity, and the number of ouabain binding sites were lower and the erythrocyte sodium content was higher in hyperthyroid subjects. The rate constants of erythrocyte SPC (P less than .05), SLC (P less than .001), and sodium "leak" (P less than .05) were also significantly lower in hyperthyroidism. In 11 of the hyperthyroid subjects, sodium flux measurements were repeated after 20 weeks of treatment. Sodium pump activity, the number of ouabain binding sites, and the rate constant for SLC increased. These results suggest that the effect of thyroid hormones on the erythrocyte sodium pump is part of a generalized effect on membrane proteins, rather than a specific effect.     

Peripheral bone density in women with untreated multinodular goitre

OBJECTIVES: We wished to determine whether women with multinodular goitre and spontaneous subclinical hyperthyroidism have decreased bone density. DESIGN AND SUBJECTS: Bone density was measured at the distal and proximal forearm. Data were expressed as Z-scores relative to the mean values out of 125 control subjects matched for age and menopause. The Z-scores of 23 women with subclinical hyperthyroid goitre (TSH < 0.1 mU/l and normal values for FT4 and total T3) and of 54 women with euthyroid goitre were compared. MEASUREMENTS: Bone density was measured by single photon absorptiometry. TSH was measured by IRMA, FT4 by RIA. RESULTS: Relative to the euthyroid goitre subjects the mean +/- SEM Z-scores of both the distal and proximal forearm density were lower (-0.69 +/- 0.17 vs -0.1 +/- 0.18, P < 0.05 and -0.5 +/- 0.18 vs 0.07 +/- 0.18, P < 0.05, respectively). Median (range) FT4 in the subclinical hyperthyroid goitre subjects was significantly higher than euthyroid goitre subjects (15.6 (11-23.2) pmol/l vs 11.9 (8.3-18.3) pmol/l, P < 0.001) although still within the normal range. FT4 correlated inversely with Z-scores of both distal and proximal forearm bone density in the subjects with subclinical hyperthyroidism (r = -0.42, P < 0.05 and r = -0.43, P < 0.05, respectively), but not in the euthyroid goitre subjects. CONCLUSION: These findings indicate that women with untreated multinodular goitre and subclinical hyperthyroidism have reduced bone density in the forearm.     

Mechanism of Thyroid Calorigenesis: Role of Active Sodium Transport

The hypothesis that thyroid calorigenesis is mediated by stimulation of active Na(+) transport was tested by measuring the Q(o2) of liver slices and skeletal muscle (diaphragm) from thyroxine- and triiodothyronine-injected thyroidectomized and normal rats in media fortified with ouabain (10(-3) M) and/or free of Na(+) or K(+). In both tissues, more than 90% of the increase in Q(o2) produced by injections of thyroid hormone in euthyroid rats was derived from increased energy utilization by the Na(+) pump. In triiodothyronine-treated thyroidectomized rats, activation of Na(+) transport accounted for 90% or more of the increment in Q(o2) in liver and 40% or more of the increment in diaphragm. Intracellular Na(+), K(+), and Cl(-) concentrations were measured in euthyroid and hyperthyroid liver and diaphragm. The transmembrane Na(+) and K(+) concentration differences were significantly increased in both tissues by the administration of triiodothyronine. These results indicate that thyroid hormone activates Na(+) extrusion and K(+) accumulation either by increasing the local concentration of ATP or by direct stimulation of the Na(+) pump.     

The effect of hyperthyroidism on in vivo aging of erythrocyte ouabain-binding sites and intracellular sodium and potassium

The sodium pump activity of erythrocytes is inhibited in hyperthyroidism, whereas in all other cells it is increased. To examine the possibility that thyroid hormones cause an accelerated loss of membrane proteins during in vivo aging, we determined the number of ouabain-binding sites (OBS) in young and old erythrocytes from 13 hyperthyroid and 13 euthyroid subjects. Erythrocytes were separated according to their cell age by centrifugation. In euthyroid subjects, the median number of OBS decreased from 415 (range, 341-551; mean +/- SEM, 440 +/- 19.1) in young cells to 336 (range, 287-453; mean, 340 +/- 13.6) in old cells. In hyperthyroid subjects the median number of OBS decreased from 290 (range, 190-370; mean, 280 +/- 13.3) in young cells to 207 (range, 155-244; mean, 208 +/- 7.5) in old cells. In hyperthyroid subjects the number of OBS of erythrocytes of all ages was lower than that in euthyroid subjects. The ratio of OBS between young and old cells in hyperthyroid subjects (median, 1.27; mean +/- SD, 1.34 +/- 0.16) was similar to that in euthyroid subjects (median, 1.29; mean, 1.30 +/- 0.12). We conclude that these results do not support the hypothesis that in hyperthyroidism there is accelerated loss of sodium pump sites during the lifespan of erythrocytes in circulation.     

Effect of thyroid status on ouabain binding to the human lymphocyte

Lymphocyte Na-K ATPase was evaluated as an index of thyroid status in man. Lymphocytes from 24 untreated hypothyroid patients and 11 hyperthyroid subjects were sampled in parallel with normal lymphocytes, and Na-K ATPase activity was assessed by measurements of ouabain binding to a plasma membrane fraction or to whole cells. In both systems, ouabain bound saturably and specifically, resulting in linear Scatchard plots. Normal lymphocyte plasma membranes bound 2.30 +/- 0.16 pmol ouabain/mg protein (mean +/- SEM; n = 11), with a Kd of 68 +/- 12 nM. Intact normal lymphocytes bound 3.24 +/- 0.30 pmol ouabain/10(7) cells (n = 14), representing 189,000 sites/cell. In hypothyroidism, ouabain binding, when compared with normal cells sampled on the same day, was reduced by 22.0 +/- 5.3% (n = 11; P less than 0.001) in plasma membranes and by 29.1 +/- 3.5% (n = 14) in whole lymphocytes (P less than 0.001), but there was no significant change in the Kd in the membrane fraction. In 6 subjects, the decrease in ouabain binding to lymphocytes was reversed by thyroid hormone replacement. Red cells from hypothyroid subjects showed normal ouabain binding. Ouabain binding to hyperthyroid plasma membranes (2.42 +/- 0.18 pmol/mg protein) was not significantly different from normal. The results in hypothyroid subjects are consistent with the hypothesis that lymphocyte Na-K ATPase is regulated by thyroid hormones. However, lymphocyte Na-K ATPase does not increase in parallel with elevated thyroid hormone levels in hyperthyroidism. The mechanisms underlying these observations remain to be clarified.     

Evaluation of sodium and potassium pump activity and number in diabetic erythrocytes

The Na+,K+-ATPase (= Na pump), which produces the concentration gradient of Na+ and K+ across the cell membrane, was studied in diabetic erythrocytes. The activity and number of Na pumps, which are functional and quantitative expression of the Na+,K+-ATPase in erythrocytes, were measured by ouabain-sensitive 42K or 43K influx and by [3H]ouabain binding, respectively. The turnover rate of the pumps was calculated from the two measurements to evaluate in situ activity of the pump. The Na pump activity was found to be higher in the diabetic (193 +/- 12 nmol K+/h . 10(9) cells) than in the normal group (164 +/- 6) (P less than 0.05), though the affinities of the pump for extracellular K+ were not different. The number of Na pumps and the Kd of the pumps for ouabain in the diabetic group were not significantly different from those in the normal group (354 +/- 12 site/cell and 4.33 +/- 0.20 nM). The turnover rate of the diabetic group tended to be higher than that of the normal group. The rate was about one third of the molecular activity reported for Na+,K+-ATPase under optimum conditions. These results indicate that the enzymatic properties as well as the number of Na pumps were not altered in diabetic erythrocytes despite the increased Na pump activity. Therefore the increased activity of the erythrocyte Na pump in diabetes mellitus suggests an increase of cation permeability associated with a possible disorder in the diabetic membrane.     

Erythrocyte metabolism in hyperthyroidism: a microcalorimetric study on changes in the Embden-Meyerhof and the hexose monophosphate pathways

Erythrocyte metabolism was studied in vitro by microcalorimetry in 10 hyperthyroid subjects before and after treatment. By inhibiting the enzyme enolase in the Embden-Meyerhof pathway with sodium fluoride (NaF) we have recorded the anaerobic and aerobic contributions in erythrocyte thermogenesis. The decrease in heat production rate in samples with NaF corresponds to the anaerobic contribution, whereas the values from samples with NaF reflect aerobic processes. Before treatment, total heat production rate was 120 +/- 2 mW/l erythrocytes which was higher than the post-treatment value of 99 +/- 2 (P less than 0.001) as well as the value for 14 euthyroid subjects, 108 +/- 2 mW/l (P less than 0.001). The NaF inhibitable rate was 73 +/- 2 before and 63 +/- 1 mW/l after therapy (P less than 0.01). These values correspond to 61 +/- 1 and 64 +/- 1% (n.s.) of the total heat production rate, and were similar to that of 61 +/- 2% for the controls. Heat production rates in the presence of NaF were 47 +/- 1 before and 36 +/- 1 mW/l after therapy (P less than 0.001), representing 39 +/- 1 and 36 +/- 1% of total values, respectively. The present results show that overall metabolism is increased in erythrocytes from hyperthyroid subjects before treatment and returns to normal after normalization of the thyroid function. Moreover, by using microcalorimetry we found that the metabolic activity along the Embden-Meyerhof anaerobic pathway as well as along the hexose monophosphate aerobic pathway in erythrocytes is stimulated by thyroid hormones.     

Lipolytic and ketogenic fluxes in human hyperthyroidism

The effect of hyperthyroidism on lipolytic and ketogenic fluxes was determined by measuring simultaneously (stable isotope methodology) glycerol, nonesterified fatty acids (NEFA), and ketone body (KB) kinetics in euthyroid and hyperthyroid subjects. In the postabsorptive state hyperthyroid patients had normal concentrations of insulin and glucagon, but increased concentrations (P less than 0.01) and turnover rates (P less than 0.01) of glycerol, NEFA, and KB. The ratio of NEFA appearance rate to glycerol appearance rate was decreased in hyperthyroid subjects (2.34 +/- 0.23 vs. 3.15 +/- 0.22; P less than 0.05), indicating that intracellular cycling between triglycerides and fatty acids was increased. The percentage of NEFA flux used for KB production, calculated from NEFA disappearance rates and KB appearance rates, was increased in hyperthyroid patients (21.20 +/- 2.75% vs. 13.37 +/- 0.63%; P less than 0.05), suggesting a diversion during hyperthyroidism of hepatic fatty acid metabolism toward ketogenesis. However, when the plasma NEFA levels of control subjects were raised by the infusion of a triglyceride emulsion to levels comparable to those observed in hyperthyroid patients their percentage of NEFA flux used for ketogenesis rose to values slightly higher (26.30%) than those of hyperthyroid subjects. In conclusion, 1) hyperthyroidism results not only in increased lipolysis, but also in enhanced triglyceride-fatty acid cycling, which could contribute to the excessive energy expenditure; and 2) the increased KB production of hyperthyroid patients results more from an increase in NEFA availability than from a direct stimulation of hepatic ketogenesis.     

Platelet Na,K-adenosine triphosphatase as a tissue marker of hyperthyroidism

Platelet Na(+),K(+)-adenosine triphosphatase (ATPase) activity was measured in 34 (15 males, 19 females) healthy subjects, 89 (35 males, 54 females) hyperthyroid patients, and 34 (7 males, 27 females) treated hyperthyroid patients to assess the potential of this measurement as a tissue marker and diagnostic test for hyperthyroidism. Platelet Na(+),K(+)-ATPase activity was measured in platelet lysates by the rate of release of phosphate from adenosine triphosphate (ATP) in the presence and absence of ouabain. Platelet Na(+),K(+)-ATPase activity (median and range) in the hyperthyroid group (271, 169 to 821 pmol/h/g protein) was significantly higher compared with the healthy group (125, 74 to 185 micromol/h/g protein, P <.001 by Mann-Whitney U test). The treated hyperthyroid group had slightly, but significantly higher, free triiodothyronine (FT3) and free thyroxine (FT4), as well as platelet Na(+),K(+)-ATPase activity (147, 98 to 246 micromol/h/g protein, P <.05). If a platelet Na(+),K(+)-ATPase activity of 190 micromol/h/g protein was used as a cut off value, the specificity and sensitivity were 90% and 93%, respectively. We conclude that platelet Na(+),K(+)-ATPase may be a useful tissue marker of hyperthyroidism.     

Evaluation of endothelial function in subclinical hypothyroidism and subclinical hyperthyroidism.

Subclinical hypothyroidism and subclinical hyperthyroidism are two frequently occurring conditions for which exact therapeutic approaches have not yet been established. The aim of this study was to compare the endothelial function and carotid artery intimae-media thickness (IMT) of these two groups of patients to euthyroid subjects and to assess the effects of these conditions on endothelial function. Study groups comprised of 25 subclinical hypothyroid patients (mean age, 32.28 +/- 9.67 years), 13 subclinical hyperthyroid patients (mean age, 35.69 +/- 9.67 years), and 23 euthyroid subjects (mean age, 35.87 +/- 7.93 years). They were evaluated for flow-mediated dilatation (FMD), and carotid artery IMT. The groups were matched strictly for atherosclerotic risk factors. The subclinical hypothyroid group was found to have significantly lower FMD values. No significant differences were observed between the groups with respect to other vascular parameters. The only discriminative factor between the groups was the state of their thyroid function. Therefore, subclinical hypothyroidism may have adverse effects on endothelial function independent from other well-known atherosclerotic risk factors.     

Status of the red cell Na,K-pump in hyper- and hypothyroidism

To investigate the status of the sodium-potassium pump in cells of human subjects with abnormal thyroid function, we measured the number of pump units as well as the cation transport activity of the pump in erythrocytes from 23 hyperthyroid and 7 hypothyroid patients. It was found that the number of Na+-K+-ATPase units in erythrocytes (as measured by ouabain binding) was significantly reduced in hyperthyroidism (mean 36% below controls, p less than 0.001). The rate of rubidium uptake by the same cells was also reduced, but to a smaller extent (mean 9%, p less than 0.02). These changes were reversible with control of the hyperthyroidism. Hypothyroid individuals showed changes in erythrocyte Na+-K+ pump which were in the opposite direction to those seen in hyperthyroidism. It is concluded that thyroid hormone exerts a marked negative influence on the number of Na+-K+ pump units in one easily available human cell type. The direction of the effect suggests a complex relationship between thyroid hormone and the level of the Na,K-ATPase in any one tissue. Whatever the cellular mechanism responsible for the effects observed in the red cell, these changes should provide a measure of thyroid hormone action at a cellular level and this may prove useful in the study of thyroid hormone physiology in man.     

Role of thyrotropin receptor antibodies in the development of hyperthyroidism: follow-up studies on nine patients with Graves' disease

TSH binding inhibitor immunoglobulin (TBII) and thyroid-stimulating antibody (TSAb) activities were measured serially for 4-32 months in nine patients before and during development of hyperthyroidism due to Graves' disease. Initially, all were euthyroid, seven had thyroid enlargement, one had proptosis, and seven had high serum titers of antithyroid microsomal antibodies. The occurrence of hyperthyroidism was preceded by detection of both TBII and TSAb in four patients and detection of TSAb alone in four patients. One patient had neither TBII nor TSAb when euthyroid. The mean initial TBII and TSAb activities were 10.2 +/- 15.2% (+/- SD) and 2677 +/- 4620%, respectively, when these patients were euthyroid. When they became hyperthyroid, both TBII and TSAb activities increased in all patients. At that time, TBII was detected in all but one (eight of nine subjects; 88.9%), with a mean activity of 58.8 +/- 23.4% (+/- SD), and TSAb was detected in all nine patients, with a mean value of 4508 +/- 4429%. These findings not only indicate the crucial role of TSH receptor antibodies in the development of hyperthyroidism due to Graves' disease, but also suggest that a certain period of subclinical Graves' disease exists before the onset of overt hyperthyroidism in most patients, in the sense that they have TSH receptor antibodies, especially TSAb, in their serum even though they are euthyroid.     

Therapeutic response to canrenone of patients with essential hypertension as a function of sodium transport anomalies and ouabain sensitivity of erythrocytes

The presence of Na+ transport abnormalities (decreased affinity of the Na+/K+ pump or the Na+, K+ cotransport for internal Na+, increased Na+:Li+ countertransport, increased Na+ leak), Na+ content, Na+/K+ pump activity and sensitivity to ouabain were investigated in erythrocytes from 13 patients with essential hypertension. According to the presence or absence of Na+ transport abnormalities, the patients were divided into two groups: TrNa(+) (n = 9) and TrNa(-) (n = 4) respectively. Compared with TrNa(-) patients, TrNa(+) patients were characterized by: (i) a higher arterial pressure (131.4 +/- 11.8 vs 110.0 +/- 13.2 mmHg, p less than 0.05), (ii) an increased erythrocyte Na+ content (8.9 +/- 1.0 vs 6.3 +/- 0.8 mmol/l.cells, p less than 0.01) associated with (iii) a decreased rate constant of Na+/K+ pump activity (235 +/- 26 vs 309 +/- 45 h-1, p less than 0.05) and (iv) a higher sensitivity to ouabain (0.76 +/- 0.23 vs 1.12 +/- 0.26 microM, p less than 0.05). Oral administration of canrenone 50 mg per day during 7 weeks decreased mean arterial pressure by 10-30 mmHg in 6 out of the 9 TrNa(+) patients. Conversely, it decreased mean arterial pressure in only one out of the 4 TrNa(-) patients. The hypotensive effect of canrenone in TrNa(+) patients was not associated with normalization of their Na+/K+ pump activity. Canrenone did not modify the sensitivity to ouabain of either the TrNa(+) or the TrNa(-) patients. Before treatment, acute injection of ouabain provoked an inhibition of the erythrocyte Na+/K+ pump, without any change in Na+ content.(ABSTRACT TRUNCATED AT 250 WORDS)     

Catecholamines metabolism in thyroid diseases. I. Epinephrine secretion rate in hyperthyroidism and hypothyroidism.

We have measured the secretion rate of epinephrine in 6 euthyroid, 6 hyperthyroid, and 6 hypothyroid subjects infused at a constant rate for a one hour period with tritiated epinephrine (.01 muc/kg/min) (New England Nuclear Inc.). Plasma and urinary levels of epinephrine were measured by modifying the fluorometric method of Anton and Sayre. Plasma levels of epinephrine were 3.0 +/- 3.0 ng/100 ml (mean +/- SD) in normal subjects, compared to 4.4 +/- 3.5 ng/100 ml (mean +/- SD) in hyperthyroid subjects. In urine, epinephrine values ranged from 1.3 mug/day to 6.1 mug/day in normal subjects. Mean value observed in hyperthyroidism was 4.9 +/- 2.6 mug/day and 3.8 +/- 1.0 mu/day in hypothyroidism. Plasma secretion rates averaged 48 +/- 27 mug/kg/day in normal subjects, compared to 54 +/- 18 mu/kg/day in hyperthyroidism and 43 +/- 20 mug/kg/day in hypothyroidism. Likewise, the mean urinary secretion rate was 55 +/- 27 mug/kg/day in normal subjects compared to 60 +/- 22 mug/kg/day in hyperthyroidism and 50 +/- 28 mug/kg/day in hypothyroidism. There is no statistical difference between the values found in the three groups of subjects (plasma and urine). Therefore, these results would indicate that the signs and symptoms encountered in hyperthyroidism are not secondary to a high secretion rate of epinephrine.     

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

The effect of hyperthyroidism on cardiac sensitivity to beta-adrenergic stimulation in humans is controversial. To determine whether heart rate and left ventricular contractile sensitivity to beta-adrenergic 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 micrograms of triiodothyronine (T3). The rate and extent of left ventricular shortening were determined by Doppler and two-dimensionally guided M-mode echocardiography. In the hyperthyroid state, heart rate at rest was faster (57 +/- 3 vs. 68 +/- 4 beats/min; p less than 0.001) and the slope of the relation of heart rate to the rate of isoproterenol infusion was 36% steeper (1,538 +/- 126 vs. 1,131 +/- 95; p less than 0.05). The left ventricular ejection time was shorter and the mean velocity of left ventricular circumferential fiber shortening (mVcf) was greater during all stages of isoproterenol infusion in the hyperthyroid versus the euthyroid state (p less than 0.01). After adjustment for the faster heart rate after T3 administration, left ventricular ejection time and mVcf were similar in the euthyroid and hyperthyroid states at baseline and during maximal beta-adrenergic stimulation but shortened and enhanced, respectively, during stages 1 and 2 of isoproterenol infusion (p less than 0.05). There was no effect of T3 administration on left ventricular mass, dimensions, end-systolic wall stress or stroke volume at rest or during any stage of isoproterenol infusion. These results indicate that in human subjects hyperthyroidism of short duration increases the sensitivity of heart rate and left ventricular shortening velocity to beta-adrenergic stimulation in the absence of changes in left ventricular mass, loading conditions or extent of shortening.     

Enhancement of endothelium-dependent flow-mediated vasodilation in hyperthyroidism

OBJECTIVE: Vascular responsiveness changes in hyperthyroid patients remains controversial. This study attempts to determine whether the vasomotor activity can be influenced by hyperthyroid conditions, and, if so, whether changes induced by hyperthyroidism may be restored to normal during the euthyroid state after treatment. DESIGN: A case-control clinical study. PATIENTS AND MEASUREMENTS: Forty-five pretreated hyperthyroid patients (mean age 36.62 +/- 10.12 years, 36 female) were compared with 45 gender- and age-matched control subjects (mean age 38.98 +/- 11.17 years, 40 female). Brachial artery endothelium-dependent flow-mediated vasodilation (FMD) and endothelium-independent nitroglycerin-mediated vasodilation (NMD) responses were assessed noninvasively by high-resolution ultrasound imaging. Among the 45 hyperthyroid patients, 27 patients underwent the same procedures prospectively in the post-treatment euthyroid state. RESULTS: The FMD values were significantly increased in hyperthyroid patients vs. those of controls (8.94 +/- 5.65%vs. 3.77 +/- 3.42%, P < 0.001), whereas NMD levels were not significantly different (18.17 +/- 7.76%vs. 17.28 +/- 6.63%, P = 0.560). Multiple regression analysis revealed that the presence of hyperthyroidism was the only significant factor associated with FMD. In the follow-up study of 27 hyperthyroid patients, the FMD values were significantly decreased in the post-treatment euthyroid state compared with those in the pretreated hyperthyroid state (6.40 +/- 4.27%vs. 8.83 +/- 4.61%, P = 0.021), although these values were still higher than those of controls. CONCLUSIONS: This study demonstrated that endothelium-dependent FMD was increased in the hyperthyroid patients, and could be partially restored by treatment with antithyroid agents.