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Serum thyroid hormone levels may not accurately reflect thyroid tissue levels and cardiac function in mild hypothyroidism

¹Cardiovascular Research Center, Sanford Research/University of South Dakota; ²Metabolism and Nutrition Research Center, Sanford Research/University of South Dakota, Sioux Falls, South Dakota; ³Endocrinology, Instituto de Investigaciones Biomédicas Alberto Sols, Autonomous University of Madrid and Spanish Research Council, Madrid, Spain

Submitted 29 November 2007 ; accepted in final form 26 February 2008

	ABSTRACT

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The link between thyroid dysfunction and cardiovascular diseases has been recognized for more than 100 years. Although overt hypothyroidism leads to impaired cardiac function and possibly heart failure, the cardiovascular consequences of borderline low thyroid function are not clear. Establishment of a suitable animal model would be helpful. In this study, we characterized a rat model to study the relationship between cardiovascular function and graded levels of thyroid activity. We used rats with surgical thyroidectomy and subcutaneous implantation of slow release pellets with three different T₄ doses for 3 wk. In terminal experiments, cardiac function was evaluated by echocardiograms and hemodynamics. Myocardial arteriolar density was also quantified morphometrically. Thyroid hormone levels in serum and heart tissue were determined by RIA assays. Thyroidectomy alone led to cardiac atrophy, severe cardiac dysfunction, and a dramatic loss of arterioles. The low T₄ dose normalized serum T₃ and T₄ levels, but cardiac tissue T₃ and T₄ remained below normal. Low-dose T₄ failed to prevent cardiac atrophy or restore cardiac function and arteriolar density to normal values. All cardiac function parameters and myocardial arteriolar density were normalized with the middle dose of T₄, whereas the high dose produced hyperthyroidism. Our results show that thyroid hormones are important regulators of cardiac function and myocardial arteriolar density. This animal model will be useful in studying the pathophysiological consequences of mild thyroid dysfunction. Results also suggest that cardiac function may provide valuable supplemental information in proper diagnosis of mild thyroid conditions.

thyroidectomy; thyroxine; myocardial arterioles

Although overt hypothyroidism leads to impaired cardiac function and possibly heart failure, the cardiovascular consequences of borderline low thyroid function (e.g., subclinical hypothyroidism, sick euthyroid syndrome, etc.) are not clear. A growing body of clinical evidence suggests that these conditions lead to increased cardiovascular risk and mortality (24, 30). Although reports on the incidence of borderline low thyroid function vary widely, one study suggested a 4–10% prevalence of subclinical hypothyroidism in the general population and an incidence of 20% in women over age 60 (18). When considering the number of individuals at risk, it is surprising that only one animal study to date has examined the effects of subclinical hypothyroidism and heart disease (12). In that study, we demonstrated dramatic improvement in cardiac function and remodeling in cardiomyopathic hamsters treated with TH. It is clear that a major impediment to research in this area is the lack of a suitable animal model to systematically study the cardiovascular consequences of graded levels of thyroid function. In particular, it would be most useful to examine cardiac risk at various levels of thyroid function between euthyroidism and hypothyroidism. In this study, we have characterized a rat model that will enable such studies to be conducted safely and effectively. Results suggest that cardiac functional measures may provide valuable supplemental information in treatment decisions regarding mild thyroid dysfunction.

	MATERIALS AND METHODS

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Animal model and study design. Rats used in this study were purchased from Charles River Laboratories (Wilmington, MA). Fourteen 6-wk-old male Sprague-Dawley rats served as controls, and 35 age- and sex-matched thyroidectomized Sprague-Dawley rats were divided into different experimental groups as follows: eight each in placebo, 1.65-mg, and 3.3-mg groups; and 11 in an 8.25-mg group. Subcutaneous placebo and pellets with various doses [1.65, 3.3, and 8.25 mg of thyroxine (T₄) were prepared in 60-day release rate pellets; Innovative Research of America (IRA), Sarasota, FL] were implanted in the neck 1 wk after surgery. All animals were exposed to a 12:12-h light-dark cycle and given standard rat chow and water ad libitum. After 3 wk of T₄ treatment, echocardiographic and hemodynamic measurements were collected. Changes in arteriolar density were quantified morphometrically. Serum was collected for total triiodothyronine (T₃) and T₄ assays. Additionally, myocardial T₃ and T₄ were determined from animals in each group. All procedures in this study were approved by the University of South Dakota Animal Care and Use Committee and followed institutional guidelines for animals.

Echocardiography and hemodynamics. In terminal experiments, echocardiographic and hemodynamic data were collected. Rats were anesthetized with 1.5% isofluorane. After the chest was shaved, each animal was placed on an isothermal pad that was maintained at 40°C with echocardiographic gel applied to the left hemithorax. M-mode images were obtained from the short axis of the left ventricle (LV) at the level of the papillary muscle and used to measure left ventricular internal dimensions and posterior/anterior wall thickness (PWT/AWT). A VisualSonic Vevo 660 high-resolution imaging system with a 25-MHz RMV-710 transducer (Toronto, ON, Canada) was used in this study.

After the echocardiograms were completed, the right carotid artery was dissected, isolated, and cannulated with a Millar (Houston, TX) ultraminature pressure transducer catheter. This pressure catheter was inserted into the right carotid artery and advanced through the aorta into the LV. When the pressure was stable, measurements were recorded and processed electronically by a Digi-Med Heart Performance Analyzer (Micro-Med, Louisville, KY). Left ventricular systolic pressure, heart rate (HR), maximal rate of pressure rise (dP/dT), and maximal rate of pressure decline (NdP/dT) were collected (11, 17).

Quantification of arterioles. A transverse slice midway between the base and apex of the LV (3 mm thickness) was collected and fixed in 10% neutral buffered formalin. Frozen formalin-fixed tissue specimens were sectioned at 5 µm by cryostat (Leica CM1800 Cryostat; North Central Instruments, Polymouth, MN) at –20°C. Mouse anti--smooth muscle actin Cy3-conjugated monoclonal antibody (C6198; Sigma, St. Louis, MO) was used to label arterioles. Data were collected from approximately 25 randomly selected fields from each animal at x20 magnification. On the basis of the minor diameter, arterioles between 5 and 30 µm with at least one layer of smooth muscle were used to quantify numerical density (ND) and length density (LD) in each animal. Arteriolar data were referenced to myocyte area rather than tissue section area to eliminate errors due to shrinkage or separation artifacts. Additionally, myocytes account for 95% of the tissue solid mass (10) and nearly all of the tissue oxygen needs. Arteriolar ND was calculated from average number of arterioles per unit myocyte area. Arteriolar LD (average length of arterioles/unit myocyte volume) was calculated based on the following formula: LD (mm/mm³) = (a/b)/M, where a and b are the maximum and minimum external arteriolar diameters, respectively, and M is the area of myocytes (1).

Determinations of T₃ and T₄ in serum and rat heart tissue. Serum T₃ and T₄ were measured with specific and highly sensitive RIAs as described (22). For the T₃ and T₄ RIA assays, 250 µl of serum per tube was used. T₃ and T₄ levels in the rat heart tissue were also measured by RIAs after extraction and purification of the iodothyronines as described previously (19, 20). In brief, methanol was added to the frozen tissue sample and homogenized. Tracer amounts of [¹²⁵I]T₃ and [¹³¹I]T₄ were added to the homogenate. Chloroform-methanol (2:1) was added to extract endogenous and added iodothyronines. The iodothyronines were then back extracted into an aqueous phase and purified through resin columns. Iodothyronines were then eluted and evaporated to dryness. RIA buffer was added and measured by highly sensitive RIAs to detect T₃ and T₄ levels. Concentrations were calculated using the amount of T₃ and T₄ found in the RIAs, the individual recovery of the [¹²⁵I]T₃ and [¹³¹I]T₄ added to each sample, and the weight of the tissue sample that was to be extracted.

Statistical analyses. To model weight gain, the mean response profile was examined over time by treatment groups with the use of locally weighted regression and scatter plot smoothing, which suggested that a piecewise general linear model would fit well. Akaike's information criterion was used to compare models with different time point breaks, and joining the line segments together at 5 days produced the best fit. An unstructured covariance matrix was implemented for the repeated measurements. Temperature was measured as often as weight. However, due to severely skewed raw responses, a longitudinal model was not appropriate. Instead, the change from baseline to final measurement prior to the rats being killed (15 or 16 days) was modeled in a good-fitting simple linear regression.

To model the nonlinear responses of ND and LD, different transformations were conducted on the dosage level. Modeling dosage fits quadratically as well as categorically by Akaike's information criterion method. The dosage level was mean centered to avoid multicollinearity issues in the polynomial terms.

One-way ANOVA models were implemented for all responses not addressed above. Left ventricular systolic pressure was log transformed for analysis. If homogeneity or normality were not satisfactory even after considering natural log transformations, i.e., heart rate, serum T₃ and T₄, heart T₄, AWT in diastole (AWTd), and PWT in diastole (PWTd), a nonparametric one-way ANOVA (Kruskal-Wallis) was performed on the ranked measurements.

Diagnostics were conducted to verify model assumptions. Dunnett adjustment was used to compare all treatment groups with the unaffected control group and for 95% confidence intervals. A P value of <0.05 was considered statistically significant. Analyses were performed using SAS version 9.1 (SAS Institute, Cary, NC).

	RESULTS

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Physical data. One week after surgery, rats were supplemented with the T₄ doses indicated in MATERIALS AND METHODS. Body weight (BW) and body temperature were monitored every 3 or 4 days and reported in Fig. 1, A and B. Body temperature was significantly reduced in the placebo group, normalized in the low-dose (1.65 mg) and middle-dose (3.3 mg) groups, and significantly increased in the 8.25-mg group. Placebo rats failed to gain weight, whereas weight gain was slightly but significantly attenuated in the 1.65-mg group (Fig. 1C). Rats treated with the 3.3-mg pellets gained weight normally, whereas 8.25-mg T₄ treatment significantly increased BW. Upon arrival to our facility, surgery rats had slightly but significantly higher BW than controls before treatments started despite being age matched (Fig. 1B). However, there was no significant difference in weight 5 days after T₄ treatment. Rats with placebo and low-dose T₄ (1.65 mg) treatments showed a significant heart atrophy compared with the controls, whereas high-dose (8.25 mg) T₄ treatment led to a significant hypertrophy (Fig. 1D). The 3.3-mg dose normalized both heart weight (HW) and BW, whereas the 8.25-mg dose resulted in a significantly higher HW/BW (Fig. 1E).

View larger version (45K): [in this window] [in a new window]   Fig. 1. Physical changes from all animals included in the study. A: changes in body temperature. Dashed lines are 95% confidence bands for the linear regression lines. [Temp(C) = –1.35 + 0.40 x Dose(mg); r2 = 0.88]. B: changes in body weight over time shown with locally weighted regression and scatter plot smoothing [dotted line, placebo (P); short-dashed line, 1.65 mg; medium-dashed line, 3.3 mg; long-dashed line, 8.25 mg; solid line, control (C)]. C: body weight gain rate from day 5 to day 22 after treatment. aDunnett adjustment for 95% confidence intervals of treatment minus control group; 0.00 (mg) T4 indicated P group. D: heart weight. E: heart weight/body weight ratio (HW/BW). Thyroidectomized rats treated with 3 different doses of T4 are labeled as 1.65, 3.3, and 8.25 (in mg). Values are means ± SE. **P < 0.01 vs. control; *P < 0.05 vs. control.

View larger version (31K): [in this window] [in a new window]   Fig. 2. Echocardiographic data. Values are means ± SE. **P < 0.01 vs. control; *P < 0.05 vs. control. LVFS, left ventricle fractional shortening; AWTd, anterior wall thickness in diastole; AWTs, anterior wall thickness in systole; PWTd, posterior wall thickness in diastole; PWTs, posterior wall thickness in systole; LVIDd, LV internal dimension in diastole.

View larger version (39K): [in this window] [in a new window]   Fig. 3. Hemodynamics data. Values are means ± SE. **P < 0.01 vs. control; *P < 0.05 vs. control. HR, heart rate; LVSP, left ventricle systolic pressure; dP/dT, maximal rate of pressure rise; NdP/dT, maximal rate of pressure decline; bpm, beats/min.

View larger version (27K): [in this window] [in a new window]   Fig. 4. Arteriolar length density in myocardium. Dashed lines are 95% confidence bands for the quadratic regression lines. , Small arterioles range 5–15 µm; , large arterioles range 15–30 µm. **P < 0.01 vs. control for small arterioles. There was no significant overall effect for large arterioles.

View larger version (35K): [in this window] [in a new window]   Fig. 5. Triiodothyronine (T3) and throxine (T4) levels in serum and heart tissue. A: serum T4 levels. B: serum T3 levels. C: rat heart tissue T4 levels. D: rat heart tissue T3 levels. Values are means ± SE. **P < 0.01 vs. control; *P < 0.05 vs. control.

	DISCUSSION

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Many studies have examined hyperthyroidism and hypothyroidism (15, 26, 32). The purpose of this study, however, was quite different. Our intention was to demonstrate the feasibility of using an animal model to study borderline or mild thyroid dysfunction safely and effectively for the first time. In the current experiments, we were able to show that thyroid function can be controlled in a graded manner using slow pellet release of T₄ in thyroidectomized rats. These excellent results were achieved without the use of radioactive iodine, thus markedly improving the safety of the animal model. Nearly 20% of women over age 60 and 4–10% of the general population have subclinical hypothyroidism (18). Although the importance of treating subclinical hypothyroidism remains debatable, clinical epidemiological studies have shown that this condition may be an independent risk factor for coronary heart disease (30) and is also associated with an increased risk of chronic heart failure in older adults when serum thyrotropin (TSH) level is 7.0 mIU/l or higher (24). To our knowledge, no basic research related to this important topic has been conducted, likely due to the lack of an established animal model.

Data collected from echocardiography, hemodynamics, and arteriolar morphometry from placebo rats with surgical thyroidectomy were very similar to previously reported values from rats treated with PTU (26). Placebo rats developed cardiac atrophy, severe systolic dysfunction, and a dramatic loss of arterioles. We found the 1.65-mg T₄ dose most interesting because of the disconnection between serum hormone levels and cardiac indicators of thyroid function. Although serum T₃ and T₄ were normalized, cardiac T₃ and T₄ were significantly below normal and cardiac function remained impaired in this group. All measured cardiac parameters were normalized with the 3.3-mg dose. However, serum hormone levels were above normal, again suggesting that a similar disconnection between serum hormones and cardiac function can occur in mild hyperthyroidism. This is not surprising considering the known difficulties in proper diagnosis of mild thyroid dysfunction. Our results also confirm previous work by Escobar-Morreale et al. (7) showing elevated serum T₄ levels with a T₄ dose that normalized TH in most organs. Indeed, there is a clinical controversy regarding the concept that euthyroidism may be best obtained with combination T₃ plus T₄ treatment. The general consensus, however, suggests that combination treatment is not substantiated by available information related to risk and/or benefit at this time. Results from the current experiment suggest that a T₄ dose between 1.65 and 3.3 mg in rats of this size will likely normalize serum and cardiovascular parameters. Indeed, a recent experiment in male rats that were 1 mo older showed that a 2.7-mg pellet resulted in normal serum T₃, T₄, and cardiac function (Gerdes AM, unpublished observation).

Clinical diagnosis and treatment of mild thyroid dysfunction is not an exact science. Many factors can also complicate the situation. There is a rather wide range in the currently accepted range for normal values in serum TH and TSH. Seasonal and daily fluctuations contribute to within-individual variations, whereas genetic variability may be considerable in normal individuals (2). Additionally, clinicians rarely know what normal hormone values were for a typical patient who develops thyroid dysfunction. If a given individual was high normal to begin with, low-normal hormone values may represent overt hypothyroidism for that particular patient. Noninvasive cardiac echo data may prove helpful. For instance, if an individual with mild hypothyroidism has bradycardia, increased LV systolic dimension, and impaired ejection fraction with no other apparent indications for heart disease, one might be more comfortable with initiating treatment. Clearly, more clinical studies are needed to confirm that such an approach will lead to improved outcome.

It seems logical that cardiac functional measures would provide a more reliable indicator of TH function at the tissue level than would serum hormone levels. Cardiac function represents the end output of TH action on the heart. At the tissue level, many changes can occur downstream of serum hormone levels. There may be alterations in hormone membrane transporters, activation or deactivation of hormones by intracellular deiodinases, changes in thyroid nuclear receptors, posttranslational modification of gene products, etc.

TH is well known as a regulator of vascular remodeling in the heart. TH can induce cardiac hypertrophy as well as capillary angiogenesis, which has been proven in many animal models such as rat, pig, and rabbit (6, 27, 31). Tomanek and colleagues (28, 29) have shown that TH, as well as its analog 3,5-diiodothyropropionic acid, can promote coronary angiogenesis in physiological hypertrophy and after myocardial infarction. However, the mechanism of myocardial arteriolar loss in hypothyroidism is not clear. A similar reduction in arterioles, known as rarefaction, occurs in hypertension (5, 14). Reduced arteriolar density was also observed in the current experiment. However, hypertension-associated rarefaction is a completely different phenomenon than observed here in hypothyroidism. With arteriolar rarefaction from hypertension, hypertrophying cardiac myocytes push vessels further apart, resulting in reduced vascular density. In the case of hypothyroidism, there is actually atrophy of myocyte cross-sectional area associated with cardiac atrophy (16). In this case, one might expect an increase in vascular density. However, metabolic needs are significantly reduced in hypothyroidism so that fewer vessels may be needed. Rate pressure product (RPP = HR x systolic blood pressure) is an index of myocardial oxygen consumption. RPP was lower in placebos than in controls, suggesting that reduced metabolic needs may play an important role. It is for this reason that we suspect arteriolar loss in hypothyroidism is likely related to disuse; arterioles are simply not needed and die off. Since hypothyroidism leads to arteriolar vasoconstriction (13, 23), it is possible that sustained vasoconstriction leads to arteriolar loss from either hypoxia or apoptosis. Vascular endothelial growth factor and nitric oxide may also play a role. Reduced vascular endothelial growth factor and nitric oxide, known to occur in hypothyroidism, have been implicated in microvascular rarefaction in metabolic syndrome (9).

Whether arteriolar loss occurs in other important vascular beds during low-thyroid states is unknown but could be of considerable clinical consequence. For instance, it is possible that this condition leads to neurovascular loss when one considers the neurological consequences of low thyroid function (25). The model characterized here should be of considerable use to study organ and systemic consequences of thyroid dysfunction and borderline thyroid dysfunction.

The surgical thyroidectomy with T₄ replacement model described here is modified from a similar model used by Escobar-Morreale et al. (7). In their experiments, surgical thyroidectomy was followed by ¹³¹I to ablate thyroid remnants. T₃ and/or T₄ were delivered by Alzet minipumps to provide fine adjustment in TH activity. In their studies, serum hormone levels did not always reflect myocardial tissue hormone levels in borderline thyroid conditions, suggesting that serum hormone levels alone may be insufficient for proper diagnosis in borderline conditions. Cardiac function was not assessed in their experiments, so it was not clear how well tissue hormone levels coincided with cardiac function. We found that surgically thyroidectomized rats provided by Charles River Laboratories consistently demonstrated low thyroid function. When male rats are used, rare surgical failures are readily detected by the rats' ability to gain weight normally. An important safety concern was eliminated by deleting the radioactive iodine component from the protocol of Escobar-Morreale et al. (e.g., disposal of contaminated feces, urine, and carcasses was not needed) (7).

It should be noted that we have observed batch-related inconsistencies in TH activity of the manufactured pellets used in this experiment. When graded doses were manufactured at the same time, as in the current experiment, an excellent dose-related response was obtained in serum hormone levels and thyroid functional changes. This has been confirmed in another recent experiment in addition to the current report. However, when new delivery dose rates were ordered based on the current experimental results, we observed a batch-related discrepancy in hormone activity on two occasions. Consequently, one may consider having all doses prepared at the same time or the use of osmotic pumps as an alternative. However, Alzet minipumps are much larger and have more limited maximum time release rates than the slow-release pellets used here (6 wk for Alzet pumps vs. 90 days for IRA pellets).

	GRANTS

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This work was supported by Grant No. 5-P20-RR-017662 from the National Institutes of Health/National Center for Research Resources and the South Dakota 2010 Initiative Research Centers Program.

	ACKNOWLEDGMENTS

 
We thank Drs. Dajun Wang and Yuefeng Chen for their technical assistance. Sanford Research/University of South Dakota is a partnership between the Sanford School of Medicine at the University of South Dakota and Sanford Health (formerly Sioux Valley Hospital and Health Systems) in Sioux Falls, SD.

	FOOTNOTES

 

Address for reprint requests and other correspondence: A. M. Gerdes, Cardiovascular Research Center, Sanford Research/Univ. of South Dakota, 1100 East 21st St., 7th Floor, Sioux Falls, SD 57105 (e-mail: Martin.Gerdes{at}usd.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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