Thyroid hormone metabolism and cardiac gene expression after acute myocardial infarction in the rat

Kaie Ojamaa, Agnes Kenessey, Rajesh Shenoy, and Irwin Klein

Divisions of Endocrinology and Pediatric Cardiology, Departments of Medicine and Pediatrics, North Shore University Hospital/New York University School of Medicine, Manhasset, New York 11030


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

In a rat model of acute myocardial infarction (MI) produced by coronary artery ligation, thyroid hormone metabolism was altered with significant reductions (54%) in serum triiodo-L-thyronine (T3), the cellular active hormone metabolite. T3 has profound effects on the heart; therefore, rats were treated with T3 after acute MI for 2 or 3 wk, at either replacement or elevated doses, to determine whether cardiac function and gene expression could be normalized. Acute MI resulted in a 50% (P < 0.001) decrease in percent ejection fraction (%EF) with a 32-35% increase (P < 0.01) in compensatory left ventricle (LV) hypertrophy. Treatment of the MI animals with either replacement or elevated doses of T3 significantly increased %EF to 64 and 73% of control, respectively. Expression levels of several T3-responsive genes were altered in the hypertrophied LV after MI, including significant decreases in alpha -myosin heavy chain (MHC), sarcoplasmic reticulum calcium-activated ATPase (SERCA2), and Kv1.5 mRNA, whereas beta -MHC and phospholamban (PLB) mRNA were significantly increased. Normalization of serum T3 did not restore expression of all T3-regulated genes, indicating altered T3 responsiveness in the postinfarcted myocardium. Although beta -MHC and Kv1.5 mRNA content was returned to control levels, alpha -MHC and SERCA2 were unresponsive to T3 at replacement doses, and only at higher doses of T3 was alpha -MHC mRNA returned to control values. The present study showed that acute MI in the rat was associated with a fall in serum T3 levels, LV dysfunction, and altered expression of T3-responsive genes and that T3 treatment significantly improved cardiac function, with normalization of some, but not all, of the changes in gene expression.

triiodothyronine; left ventricular ejection fraction; myosin; calcium ATPase; cardiac gene expression


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

THYROID HORMONE has profound effects on cardiac contractile function as well as on cardiovascular hemodynamics, including blood pressure and systemic vascular resistance (7, 24, 39). The cellular-active metabolite of thyroid hormone, triiodo-L-thyronine (T3), regulates expression of specific cardiomyocyte genes independent of its effects on cardiac growth and protein synthesis (37, 40). Certain T3-responsive cardiac genes, including, but not limited to, the myosin heavy chains (MHC), phospholamban (PLB), and sarcoplasmic reticulum calcium-activated ATPase (SERCA2), are important determinants of cardiac contractility (14, 16, 19, 22). Their expression has been shown to be altered similarly in hypothyroidism and in various models of heart failure (1, 17, 28, 43).

Acute myocardial infarction (MI) is the major cause of heart failure in the adult American population (11). After acute MI, the remaining viable left ventricle (LV) undergoes hypertrophy and remodeling to compensate for the loss of the infarcted nonfunctional myocardium. Previous studies by Yue et al. (45) have reported alterations in cardiac phenotype after MI that may potentially contribute to the observed impairment in LV function. Ultimately, this compensation determines whether cardiac function is maintained or heart failure ensues.

Thyroid hormone metabolism has been reported to be abnormal in patients with chronic heart failure, with an impairment of L-thyroxine (T4)-to-T3 conversion resulting in a low T3 state (13, 15). A significant decrease in serum T3 was observed in humans after acute MI, which reached a nadir on the 4th day and persisted throughout the 10-day period of observation (8). Serum thyrotropin (TSH) levels remained unaltered during this period. Thus acute and chronic cardiac dysfunction can be characterized as nonthyroidal illnesses in which low serum T3 levels can alter the expression of cardiac genes (5). In the present study, we addressed the hypothesis that the low T3 state after acute MI may contribute to the changes in cardiac specific gene expression and further compromise the cardiac myocyte in its response to the ischemic injury. The low T3 syndrome has not previously been reported in an animal model of ischemic heart disease.


    MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Animal treatment protocols. MI was produced by ligation of the left coronary artery of adult male Sprague-Dawley rats weighing between 180 and 200 g (Charles River Laboratories, Raleigh, NC). To assess the extent of the infarct, at 1 wk after MI surgery, the animals were sedated (100 mg/kg ketamine, 1.5 mg/kg xylazine) to obtain electrocardiographic (EKG) tracings and two-dimensional echocardiographic analysis (7.5 mHz probe; Acuson, Mountain View, CA). Ejection fraction (EF) and percent fractional shortening were measured by use of M-mode analysis. Heart rates were obtained from the EKG tracings. At that time, a randomly assigned subgroup of the MI animals received T3 (Sigma, St. Louis, MO). T3 was delivered subcutaneously by constant infusion via a miniosmotic pump (Alza, Palo Alto, CA) set to deliver 1.2 µg/day for 2 wk. A subgroup of these animals received 10 µg of T3 delivered twice daily by subcutaneous injection for an additional 1 wk. Blood from all animals was obtained from the ocular space at 1, 3, and 4 wk after the coronary artery ligation surgery to measure serum levels of total T4 and T3 by radioimmunoassay (DiaSorin, Stillwater, MN). Animals were weighed weekly.

Immediately before animals were killed, at either 3 or 4 wk after the MI surgery, EKG and echocardiographic measurements were reassessed. At death, a midline thoracotomy exposed the heart, which was then removed; the atria and major vessels were removed, and the LV including the septum and the right ventricle (RV) were isolated, immediately frozen in liquid nitrogen, and then weighed. The area of infarct was visually identified and dissected away from the remaining LV and weighed. Blood was collected, and the serum was retained for analysis.

Tissue preparation and RNA analysis. Frozen LV and RV tissues were pulverized with a mortar and pestle placed in liquid nitrogen and then homogenized with a Potter-Elvehjen homogenizer in guanidinium thiocyanate for RNA extraction as previously described (2). RNA was quantified by A260 nm, and its integrity was verified by ethidium bromide intercalation of the ribosomal RNA resolved by denaturing gel electrophoresis. Conditions for Northern blot analysis of the alpha - and beta -MHC, SERCA2, and PLB mRNAs were as previously described (2, 32). Isoform-specific radiolabeled oligodeoxynucleotide probes were used for the MHC mRNA quantitation, whereas cDNA probes for SERCA2 and PLB were radiolabeled by random priming. Individual mRNA values were normalized by the amount of 18S rRNA in each sample measured on the same Northern blot. 18S rRNA was quantified by a radiolabeled oligodeoxynucleotide probe.

A competitive quantitative RT-PCR (QRT-PCR) method was developed to determine the copy number of Kv1.5 mRNA per microgram of total RNA from cardiac tissue, as previously described (36).

Statistical analysis. All results are expressed as means ± SE. Unpaired Student's t-test was used for statistical comparison of two groups.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Experimental myocardial infarction. All animals showed evidence of a significant area of MI as determined by the presence of a Q wave on standard EKG limb lead III and impaired systolic EF measured 1 wk after surgery (40 ± 5 vs. 81 ± 2% EF). Echocardiography using M-mode analysis showed that the mean percent ejection fraction (%EF) in the MI group was reduced significantly by ~50% compared with control or sham animals throughout the 4-wk period after coronary artery ligation (Fig. 1). EFs were not different between sham-operated and control animals, and their values have been combined. A trend toward an improvement in %EF in the MI group occurred over the 4 wk after surgery (40 ± 5 to 46 ± 4%), suggesting some compensation of LV function after infarction. The size of the infarct was determined at death by weighing the infarcted LV tissue and expressing its weight as a percentage of the weight of the total LV of body weight-matched control animals at the time of coronary artery ligation surgery. Although this measure, based on necrotic tissue weight, underestimated infarct size, the mean percent infarction of the 14 animals was 28 ± 6% (range 18-40%).


View larger version (27K):
[in this window]
[in a new window]
 
Fig. 1.   Effect of myocardial infarction (MI) and treatment with triiodo-L-thyronine (T3) on %ejection fraction measured at 1, 3, and 4 wk post-MI. * P < 0.05, MI vs. MI + T3; ** P < 0.05, sham vs. MI and MI + T3. See MATERIALS AND METHODS for experimental protocol.

Mean body weights, LV and RV weights, and heart rates at 3 and 4 wk after MI are summarized in Table 1. No significant differences were found in body weights among the groups, although the MI animals tended to have lower body weights than controls. The LV mass in the MI group was significantly increased by 32% compared with control (P < 0.01). The weight of the RV in the MI group was increased by about twofold (P < 0.001) at 4 wk after infarction compared with control animals. The observation that RV weight increased to a greater extent than the LV weight in the MI animals may be the result of increased left ventricular end-diastolic pressures leading to increased pulmonary pressures and edema, as reflected by increased lung weights (1.525 ± 0.66 and 1.175 ± 0.22 g, MI and control groups, respectively).

                              
View this table:
[in this window]
[in a new window]
 
Table 1.   Cardiac chamber sizes and heart rates after MI and with T3 treatment

Heart rates measured at the time of death were not significantly different among control and MI groups at 300 ± 1 vs. 283 ± 8 and 313 ± 22 beats/min, respectively (Table 1).

Thyroid hormone metabolism after acute MI and effects of T3 treatment. To assess changes in thyroid hormone metabolism after acute MI, serum total T3 and T4 levels were measured during the 4-wk period after coronary artery ligation. Serum T3 levels fell within 1 wk of the acute infarct, and remained >40% lower than control (62 ± 4 vs. 33 ± 5 ng/dl) 4 wk after the MI (P < 0.01; Table 3). Serum T4 levels were unchanged after acute MI and throughout the 4-wk study period (5.1 ± 0.2 and 4.6 ± 0.3 µg/dl, control and MI, respectively; Table 2). The observation that serum T4 was unaltered suggests that serum TSH was also normal. The low serum T3 in the presence of normal serum T4 levels is characteristic of the low T3 syndrome (5, 6).

                              
View this table:
[in this window]
[in a new window]
 
Table 2.   Serum total T3 and T4 in control/sham rats and rats with MI with and without T3 treatment

To determine whether normalization of serum T3 levels after MI would affect cardiac function and specific gene expression, animals were administered T3 by continuous infusion at a dose chosen to achieve normal serum T3 levels. This dose increased serum T3 to control levels at 60 ± 5 ng/dl and did not significantly inhibit endogenous production of T4 (3.9 ± 1.2 µg/dl), indicating that TSH was not suppressed. This replacement dose of T3 had no effect on heart rate (Table 1). A second T3 dosage regimen was administered to a subgroup of MI animals, in which the serum levels of T3 were increased 7.5-fold to 453 ± 20 ng/dl measured 3 h (peak level) after subcutaneous injection (Table 2). After 1 wk at this dose regimen of T3, serum T4 levels were significantly decreased to 1.8 ± 0.1 µg/dl. Because of the rapid half-life of T3, (68 ± 1 ng/dl at 10 h post-T3 injection), animals were injected with T3 every 12 h to maintain elevated serum levels. This dose of T3 significantly increased heart rate to 367 ± 8 beats/min compared with control, 300 ± 1 beats/min (Table 1) (23).

Effects of T3 treatment on cardiac mass and LV function after acute MI. Neither treatment dose of T3 had an effect on LV or RV mass beyond that caused by compensated hypertrophy after infarction (Table 1). LV EF measured by M-mode echocardiography averaged ~80% in sham-operated and control animals and was decreased by ~50% in the MI group throughout the period of study (Fig. 1). Administration of replacement dose of T3 by continuous infusion for 2 wk enhanced systolic function to 52 ± 2%EF, which was significantly higher than that of the untreated MI animals (42 ± 3%EF, P < 0.05; Fig. 1). Treatment of the MI animals for an additional 1 wk at a higher dose of T3 (20 µg/day) further increased %EF to ~73% of the control/sham EF (59 ± 2 vs. 82 ± 3%EF, MI + T3 vs. sham, respectively; Fig. 1). This higher-dose T3 treatment regimen of infarcted rats significantly improved LV function compared with the untreated MI group with EF of 46 ± 4% (Fig. 1).

Alterations in cardiac gene expression in response to MI and T3 treatment. Specific cardiac gene expression was determined in left ventricular tissue 3 and 4 wk after acute myocardial infarction and compared with MI animals treated with T3 during the same period with either a replacement (low, L) or a higher dose (high, H) of hormone. Figure 2 shows a representative Northern blot of the specific cardiac genes studied, and Table 3 summarizes the mRNA concentrations normalized for 18S ribosomal RNA. alpha -MHC mRNA in the MI animals decreased by ~65% of control values (P < 0.001), and this was accompanied by a three- and eightfold increase in beta -MHC mRNA content after 3 and 4 wk after acute MI, respectively (P < 0.01). Similarly, ventricular SERCA2 mRNA content was significantly decreased by 40 and 65% at 3 and 4 wk after acute MI, whereas PLB mRNA increased by 40% (P < 0.01) 4 wk after MI. The ratio of SERCA2 to PLB mRNA was decreased by 76% (P < 0.01) after MI compared with control animals. We also examined the expression of a voltage-gated K+ channel, Kv1.5, known to be rapidly T3 responsive (36). Using QRT-PCR methodology, Kv1.5 mRNA was decreased significantly by 66% after acute MI (Table 3).


View larger version (57K):
[in this window]
[in a new window]
 
Fig. 2.   Autoradiogram showing Northern blots containing total RNA (5 µg) isolated from left ventricles (LV) of control (C), MI, and MI + T3 (low, L, and high, H, treatment dose) animals and hybridized with specific probes to identify mRNAs encoding the alpha - and beta -myosin heavy chain (MHC) isoforms, sarcoplasmic reticulum Ca2+-activated ATPase (SERCA2), phospholamban (PLB), and 18S ribosomal RNA.


                              
View this table:
[in this window]
[in a new window]
 
Table 3.   Alterations in cardiac gene expression (mRNA) in response to MI and T3 treatment

Thyroid hormone treatment was initiated to determine whether T3 could reverse the changes in cardiac gene expression after acute MI. The major finding was the selective responsiveness of specific genes to T3 treatment in this model of cardiac dysfunction. T3 normalized the expression of Kv1.5 mRNA content in the MI animals treated at both doses. In contrast, treatment of the MI rats with replacement doses of T3 did not increase alpha -MHC mRNA to control levels, whereas expression of the beta -MHC mRNA was normalized (Table 3). However, treatment of the MI animals with a higher dose of T3 normalized alpha -MHC mRNA expression and further decreased beta -MHC mRNA content to levels below control level (0.06 ± 0.01 vs. 0.31 ± 0.10, P < 0.05). T3 treatment of the MI rats at either dose regimen significantly decreased expression of PLB compared with both MI and control animals. In contrast, T3 treatment did not alter expression of SERCA2 in the MI hearts, which remained ~50% (P < 0.01) lower than control. However, the summation of these effects of T3 at either dose was to increase the ratio of SERCA2 to PLB mRNA in the MI animals to control levels (Table 3).

Measurements of MHC and SERCA2 mRNA content in the RV of MI and T3-treated animals showed similar responses to what was observed in the LV. Specifically, beta -MHC expression increased fivefold, whereas alpha -MHC mRNA decreased ~40% after MI, and only the beta -MHC mRNA levels were normalized with T3 treatment. Similarly, SERCA2 mRNA in the RV of the MI animals was significantly decreased and remained unchanged by T3 treatment.

To control for a potential hemodynamic effect of thyroid hormone in this setting (34, 40), expression of a cardiac gene not responsive to T3, beta -tropomyosin, was measured. beta -Tropomyosin was increased significantly after acute MI compared with control animals (0.96 ± 0.04 vs. 0.70 ± 0.06, respectively, P < 0.05), and T3 treatment had no additional effect on expression of this gene (0.77 ± 0.9).


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Numerous reports document altered thyroid hormone metabolism with low serum T3 levels in patients with congestive heart failure, those undergoing coronary artery bypass graft surgery, and after acute MI (8, 13, 15, 25). Increased severity of cardiac disease (NY Heart Association class II-IV congestive heart disease) has been shown to correlate inversely with serum total T3 levels (13). The cause for the decrease in serum T3 (total and free T3) is multifactorial and can be attributed to 1) decreased hepatic conversion of T4 to T3, especially with advanced heart failure, as a result of a decrease in activity of the 5' monodeiodinase, 2) a decrease in binding to serum proteins, 3) an expanded volume of distribution, and 4) a shortened half-life (3, 12, 30). Serum interleukin 6 (IL-6), which has been shown to be increased in the low T3 syndrome, appears to inhibit the hepatic 5' monodeiodinase activity (3). Cardiac myocytes in the border zone of reperfused viable myocardium, as well as monocytes and macrophages in this area, produce IL-6, which may in part mediate the changes in serum T3 level after an acute MI (12). Although the low T3 syndrome was previously thought to represent a euthyroid condition not requiring thyroid hormone treatment, recent investigations have questioned this conclusion (6, 13, 21, 25).

In the present model of acute MI, LV mass increased significantly within 3 wk, reflecting hypertrophy and remodeling (41). Serial echocardiography measurements of EF and fractional shortening showed a 50% reduction by 1 wk post-MI that remained unchanged for up to 4 wk. Coronary artery ligation has been used to produce LV dysfunction in a variety of animal species, and the decrease in contractility reflects the magnitude of the infarct and the extent of LV remodeling (29). The present results are similar to those results described by Yue et al. (45), in which the decline in function in the postinfarcted myocardium was accompanied by changes in expression of alpha - and beta -MHC and SERCA2, known thyroid hormone-responsive genes, resulting in alterations in excitation-contraction coupling similar to those seen in hypothyroidism and heart failure (17, 43, 44).

In the present study, we were able to produce the low T3 syndrome after acute MI, which had not been previously documented in this animal model. Serum T3 levels fell by 50%, whereas serum T4 was maintained at control levels. Accompanying this decline in T3 were changes in expression of known thyroid hormone-responsive genes, including the MHCs, SERCA2, and PLB, as well as a potassium channel gene, Kv1.5, similar to that of hypothyroidism (14, 22, 34, 36). To test whether these phenotypic changes were at least in part the result of altered thyroid metabolism, animals were treated with a constant infusion of T3 to restore serum T3 levels to normal. The T3 replacement dose did not completely restore expression of these genes, contrary to our previous report in another model of the low T3 syndrome (21) or as would be expected when hypothyroid animals are rendered euthyroid (2). alpha -MHC and SERCA2 genes, both containing well-delineated thyroid-responsive DNA elements (7), were unresponsive to T3 replacement, and only at higher treatment doses of T3 was alpha -MHC mRNA returned to control levels, whereas SERCA2 mRNA remained relatively unaffected. In contrast, the negatively regulated beta -MHC and PLB genes responded as predicted to replacement T3 treatment, with expression falling to or below control levels (32, 34). Thus, in contrast to the coordinated phenotypic expression well documented in thyroid disease states (18), the hypertrophic remodeled myocardium showed varied and gene-specific T3 responsiveness. The mechanisms underlying these observations could include changes in thyroid hormone receptor expression (42) or transcriptional activity, as reported for pressure overload, hypertrophic growth (18), cardiac unloading and atrophy (35), and with mutant thyroid hormone receptors (38).

Previous studies by Gay and colleagues (9, 10) have tested whether T4 treatment could improve LV function when administered to rats after acute MI. Short-term (1-2 days) T4 treatment improved LV function (10); however, similar to the present study, restoration of normal MHC isoform distribution required higher doses of T4 than the dose required in the hypothyroid rat. In a rat model of heart failure due to pressure overload, Chang et al. (4) showed that T4 treatment increased LV systolic and diastolic functions and improved calcium handling consistent with changes in thyroid hormone-responsive genes. In that model and in the present study, the improvement in LV function in response to thyroid hormone treatment occurred despite the persistence of ventricular hypertrophy. It is interesting to speculate that thyroid hormone can reverse the pathological phenotype in both hypertensive and ischemic hypertrophic heart disease and thereby improve myocardial contractility. In chronic congestive heart failure in humans, studies have shown that T4 treatment for 3 mo increased the LV EF, lowered systemic vascular resistance, and improved the patient's functional status (31).

We have reported that, in hypothyroidism, cardiac PLB content, an inhibitor of SERCA2, was significantly increased (32). T3 treatment of hypothyroidism decreased PLB content and promoted phosphorylation of PLB, thereby decreasing its inhibitory action on sarcoplasmic reticulum calcium uptake and improving LV function (32). Therefore, it is plausible that, as a result of the low serum T3 after acute MI, cardiac PLB was similarly altered and that T3 replacement improved myocyte contractility through this pathway.

In conclusion, we observed that acute myocardial infarction in the rat produced by coronary artery ligation was associated with a fall in serum T3 levels, development of significant left ventricular dysfunction, and alterations in specific thyroid hormone-responsive genes. Thyroid hormone treatment at doses sufficient to normalize serum T3 significantly improved cardiac function and reversed some but not all of the changes in gene expression. We propose that T3 treatment in the setting of cardiac disease and altered thyroid hormone metabolism may have potential beneficial effects (25). The effect of long-term treatment on survival in congestive heart disease remains to be determined (26).


    ACKNOWLEDGEMENTS

This work was supported by National Heart, Lung, and Blood Institute Grants HL-03775 and HL-56804 (to K. Ojamaa) and HL-58849 (to I. Klein) and by the Hutzler Fund.


    FOOTNOTES

Address for reprint requests and other correspondence: K. Ojamaa, North Shore Univ. Hospital/NYU School of Medicine, 300 Community Dr., Manhasset, NY 11030 (E-mail: kojamaa{at}nshs.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.

Received 28 April 2000; accepted in final form 7 August 2000.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

1.   Arai, M, Matsui H, and Perisamy M. Sarcoplasmic reticulum gene expression in cardiac hypertrophy and heart failure. Circ Res 74: 555-564, 1994[ISI][Medline].

2.   Balkman, C, Ojamaa K, and Klein I. Time course of the in vivo effects of thyroid hormone on cardiac gene expression. Endocrinology 130: 1002-1006, 1992.

3.   Boelen, A, Platvoet-Ter Schiphorst MC, and Wiersinga WM. Association between serum interleukin-6 and serum 3,5,3'-triiodothyronine in nonthyroidal illness. J Clin Endocrinol Metab 77: 1695-1699, 1993[Abstract].

4.   Chang, KC, Figueredo VM, Schreur JHM, Kariya K, Weiner MW, Simpson P, and Camacho SA. Thyroid hormone improves function and Ca2+ handling in pressure overload hypertrophy. J Clin Invest 100: 1742-1749, 1997[Abstract/Free Full Text].

5.   Chopra, IJ. Euthyroid sick syndrome: is it a misnomer? J Clin Endocrinol Metab 82: 329-334, 1997[Free Full Text].

6.   DeGroot, LJ. Dangerous dogmas in medicine: the illness syndrome. J Clin Endocrinol Metab 84: 151-164, 1999[Free Full Text].

7.   Dillmann, WH. Biochemical basis of thyroid hormone action in the heart. Am J Med 88: 626-639, 1990[ISI][Medline].

8.   Franklyn, JA, Gammage MD, Raymsden DB, and Sheppard MC. Thyroid status in patients after acute myocardial infarction. Clin Sci (Colch) 67: 585-590, 1984[ISI][Medline].

9.   Gay, RG, Graham S, Aguirre M, Goldman S, and Morkin E. Effects of 10- to 12-day treatment with L-thyroxine in rats with myocardial infarction. Am J Physiol Heart Circ Physiol 255: H801-H806, 1988[Abstract/Free Full Text].

10.   Gay, R, Gustafson TA, Goldman S, and Morkin E. Effects of L-thyroxine in rats with chronic heart failure after myocardial infarction. Am J Physiol Heart Circ Physiol 253: H341-H346, 1987[Abstract/Free Full Text].

11.   Gheorghiade, M, and Bonow RO. Chronic heart failure in the United States: a manifestation of coronary artery disease. Circulation 97: 282-289, 1998[Free Full Text].

12.   Gwechenberger, M, Mendoza LH, Youker KA, Frangogiannis NG, Smith CW, Michael LH, and Entman ML. Cardiac myocytes produce interleukin-6 in culture and in viable border zone of reperfused infarction. Circulation 99: 546-551, 1999[Abstract/Free Full Text].

13.   Hamilton, MA, Stevenson LW, Luu M, and Walden JA. Altered thyroid hormone metabolism in advanced heart failure. J Am Coll Cardiol 16: 91-95, 1990[ISI][Medline].

14.   He, H, Giordano FJ, Hilal-Dandan R, Choi DJ, Rockman HA, McDonough PM, Bluhm WF, Meyer M, Sayen MR, Swanson E, and Dillmann WH. Overexpression of the rat sarcoplasmic reticulum Ca2+ ATPase gene in the heart of transgenic mice accelerates calcium transients and cardiac relaxation. J Clin Invest 100: 380-389, 1997[Abstract/Free Full Text].

15.   Holland, FW, Brown PS, Weintraub BD, and Clark RE. Cardiopulmonary bypass and thyroid function: a "euthyroid sick syndrome". Ann Thorac Surg 52: 46-50, 1991[Abstract].

16.   Holt, E, Sjaastad I, Lunde PK, Christensen G, and Sejersted OM. Thyroid hormone control of contraction and the Ca2+-ATPase/phospholamban complex in adult rat ventricular myocytes. J Mol Cell Cardiol 31: 645-656, 1999[ISI][Medline].

17.   Holt, E, Tonnessen T, Lunde PK, Semb SO, Wasserstrom JA, Sejersted OM, and Christensen G. Mechanisms of cardiomyocyte dysfunction in heart failure following myocardial infarction in rats. J Mol Cell Cardiol 30: 1581-1593, 1998[ISI][Medline].

18.   Izumo, S, Lompre A, Koren G, Schwartz K, Nadal-Ginard B, and Mahdavi V. Myosin heavy chain mRNA and protein isoforms during hypertrophy. J Clin Invest 79: 970-977, 1987[ISI][Medline].

19.   Kaasik, A, Paju K, Vetter R, and Seppet EK. Thyroid hormone increases the contractility but suppresses the effects of beta-adrenergic agonist by decreasing phospholamban expression in rat atria. Cardiovasc Res 35: 106-112, 1997[ISI][Medline].

20.   Kadambi, VJ, Ponniah S, Harrer JM, Hoit BD, Dorn GW, II, Walsh RA, and Kranias EG. Cardiac-specific overexpression of phospholamban alters calcium kinetics and resultant cardiomyocyte mechanics in transgenic mice. J Clin Invest 97: 533-539, 1996[Abstract/Free Full Text].

21.   Katzeff, H, Powell SR, and Ojamaa K. Alterations in cardiac contractility and gene expression during the low T3 syndrome. Am J Physiol Endocrinol Metab 273: E951-E956, 1997[Abstract/Free Full Text].

22.   Kiss, E, Jakab G, Kranias EG, and Edes I. Thyroid hormone-induced alterations in phospholamban protein expression. Regulatory effects on sarcoplasmic reticulum Ca2+ transport and myocardial relaxation. Circ Res 75: 245-251, 1994[Abstract].

23.   Klein, I. Thyroxine-induced cardiac hypertrophy: time course of development and inhibition by propranolol. Endocrinology 123: 203-210, 1988[Abstract].

24.   Klein, I, and Ojamaa K. Thyroid hormone and blood pressure regulation. In: Hypertension: Pathophysiology, Diagnosis, and Management (2nd ed.), edited by Laragh JH, and Brenner BM. New York: Raven, 1995, p. 2247-2262.

25.   Klemperer, JD, Klein I, Gomez M, Helm RE, Ojamaa K, Thomas SJ, Isom OW, and Krieger K. Effects of thyroid hormone supplementation in cardiac surgery. N Engl J Med 333: 1522-1527, 1995[Abstract/Free Full Text].

26.   Limbird, LE, and Vaughan DE. Commentary: augmenting beta-receptors in the heart: short-term gains offset by long-term pains? Circulation 97: 282-289, 1999[Free Full Text].

27.   Litwin, SE, Katz SE, Morgan JP, and Douglas PS. Serial echocardiographic assesment of left ventricular geometry and function after large myocardial infarction in the rat. Circulation 89: 345-354, 1994[Abstract].

28.   Lowes, BD, Minube W, Abraham WT, Groves BM, Gilbert EM, and Bristow M. Changes in gene expression in the intact human heart. Down regulation of alpha myosin heavy chain in failing myocardium. J Clin Invest 100: 2315-2324, 1997[Abstract/Free Full Text].

29.   Mahaffey, KW, Raia TE, Pennock G, Morkin E, and Goldman S. Left ventricular performance and remodeling in rabbits after myocardial interaction. Circulation 91: 794-802, 1995[Abstract/Free Full Text].

30.   Mainwaring, RD, Capparelli E, Schell K, Acosta M, and Nelson JC. Pharmacokinetic evaluation of triiodothyronine supplementation in children after modified Fontan procedure. Circulation 101: 1423-1429, 2000[Abstract/Free Full Text].

31.   Moruzzi, P, Doria E, and Agostoni PG. Medium-term effectiveness of L-thyroxine treatment in idiopathic dilated cardiomyopathy. Am J Med 101: 461-467, 1996[ISI][Medline].

32.   Ojamaa, K, Kenessey A, and Klein I. Thyroid hormone regulation of phospholamban phosphorylation in the rat heart. Endocrinology 141: 2139-2144, 2000[Abstract/Free Full Text].

33.   Ojamaa, K, and Klein I. In vivo regulation of recombinant cardiac myosin heavy chain gene expression by thyroid hormone. Endocrinology 132: 1002-1006, 1993[Abstract].

34.   Ojamaa, K, Klemperer JD, MacGilvray SS, Klein I, and Samarel A. Thyroid hormone and hemodynamic regulation of beta -myosin heavy chain promoter in the heart. Endocrinology 137: 802-808, 1996[Abstract].

35.   Ojamaa, K, Petrie JF, Balkman C, Hong C, and Klein I. Posttranscriptional modification of myosin heavy-chain gene expression in the hypertrophied rat myocardium. Proc Natl Acad Sci USA 91: 3468-3472, 1994[Abstract].

36.   Ojamaa, K, Sabet A, Kenessey A, Shenoy R, and Klein I. Regulation of rat cardiac Kv1.5 expression by thyroid hormone is rapid and chamber specific. Endocrinology 140: 3170-3176, 1999[Abstract/Free Full Text].

37.   Ojamaa, K, Samarel AM, Kupfer JM, Hong C, and Klein I. Thyroid hormone effects on cardiac gene expression independent of cardiac growth and protein synthesis. Am J Physiol Endocrinol Metab 263: E534-E540, 1992[Abstract/Free Full Text].

38.   Pazos-Moura, C, Abel ED, Boers ME, Moura E, Hampton TG, Wang J, Morgan JP, and Wondisford FE. Cardiac dysfunction caused by myocardium-specific expression of a mutant thyroid hormone receptor. Circ Res 86: 700-706, 2000[Abstract/Free Full Text].

39.   Polikar, R, Burger AG, and Scherer U. The thyroid and the heart. Circulation 87: 1435-1441, 1993[Abstract].

40.   Qi, M, Ojamaa K, Eleftheriades EG, Klein I, and Samarel AM. Regulation of rat ventricular myosin heavy-chain expression by serum and contractile activity. Am J Physiol Cell Physiol 267: C520-C528, 1994[Abstract/Free Full Text].

41.   Solomon, S, Greaves SC, Raxan M, Finn P, Pfeffer M, and Pfeffer JM. Temporal dissociation of left ventricular function and remodeling following experimental myocardial infarction in rats. J Card Fail 5: 213-223, 1999[Medline].

42.   Sylven, C, Jansson E, Sotonyi P, Waagstein F, Barkhem T, and Bronnegard M. Cardiac nuclear hormone receptor mRNA in heart failure in man. Life Sci 59: 1917-1922, 1996[ISI][Medline].

43.   Wolska, BM, Averyhart-Fullard V, Omachi A, Stojanovic MO, Kallen RG, and Solaro RJ. Changes in thyroid state affect pHi and Nai+ homeostasis in rat ventricular myocytes. J Mol Cell Cardiol 29: 2653-2663, 1997[ISI][Medline].

44.   Yamaguchi, F, Sanbe A, and Takeo S. Cardiac sarcoplasmic reticular function in rats with chronic heart failure following myocardial infarction. J Mol Cell Cardiol 29: 753-763, 1997[ISI][Medline].

45.   Yue, P, Long CS, Austin R, Chang KC, Simpson PC, and Massie BM. Post-infarction heart failure in the rat is associated with distinct alterations in cardiac myocyte molecular phenotype. J Mol Cell Cardiol 30: 1615-1630, 1998[ISI][Medline].


Am J Physiol Endocrinol Metab 279(6):E1319-E1324
0193-1849/00 $5.00 Copyright © 2000 the American Physiological Society