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Thyroid: official journal of the American Thyroid Association 03/2012; 22(3):235-6. · 2.60 Impact Factor
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ABSTRACT: Thyroid hormone has profound effects on the heart and cardiovascular system. This article describes the cellular mechanisms by which thyroid hormone acts at the level of the cardiac myocyte and the vascular smooth muscle cell to alter phenotype and physiology. Because it is well established that thyroid hormone, specifically T(3), acts on almost every cell and organ in the body, studies on the regulation of thyroid hormone transport into cardiac and vascular tissue have added clinical significance. The characteristic changes in cardiovascular hemodynamics and metabolism that accompany thyroid disease states can then be best understood at the cellular level.
The Medical clinics of North America 03/2012; 96(2):257-68. · 2.18 Impact Factor
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Michael A Portman,
April Slee,
Aaron K Olson,
Gordon Cohen,
Tom Karl,
Elizabeth Tong,
Laura Hastings,
Hitendra Patel,
Olaf Reinhartz,
Antonio R Mott,
Richard Mainwaring,
Justin Linam, Sara Danzi
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ABSTRACT: Triiodothyronine levels decrease in infants and children after cardiopulmonary bypass. We tested the primary hypothesis that triiodothyronine (T3) repletion is safe in this population and produces improvements in postoperative clinical outcome.
The TRICC study was a prospective, multicenter, double-blind, randomized, placebo-controlled trial in children younger than 2 years old undergoing heart surgery with cardiopulmonary bypass. Enrollment was stratified by surgical diagnosis. Time to extubation (TTE) was the primary outcome. Patients received intravenous T3 as Triostat (n=98) or placebo (n=95), and data were analyzed using Cox proportional hazards. Overall, TTE was similar between groups. There were no differences in adverse event rates, including arrhythmia. Prespecified analyses showed a significant interaction between age and treatment (P=0.0012). For patients younger than 5 months, the hazard ratio (chance of extubation) for Triostat was 1.72. (P=0.0216). Placebo median TTE was 98 hours with 95% confidence interval (CI) of 71 to 142 compared to Triostat TTE at 55 hours with CI of 44 to 92. TTE shortening corresponded to a reduction in inotropic agent use and improvement in cardiac function. For children 5 months of age, or older, Triostat produced a significant delay in median TTE: 16 hours (CI, 7-22) for placebo and 20 hours (CI, 16-45) for Triostat and (hazard ratio, 0.60; P=0.0220).
T3 supplementation is safe. Analyses using age stratification indicate that T3 supplementation provides clinical advantages in patients younger than 5 months and no benefit for those older than 5 months. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00027417.
Circulation 09/2010; 122(11 Suppl):S224-33. · 14.74 Impact Factor
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ABSTRACT: Amiodarone is a benzofuran derivative approved for the treatment of cardiac arrhythmias. Traditionally classified as a class III antiarrhythmic agent, amiodarone possesses electrophysiologic properties of all four Vaughan-Williams classes. This drug, however, has high iodine content, and this feature plus the intrinsic effects on the body make amiodarone especially toxic to the thyroid gland. Treatment can result in a range of effects from mild derangements in thyroid function to overt hypothyroidism or thyrotoxicosis. The diagnosis and treatment of amiodarone-induced hypothyroidism is usually straightforward, whereas that of amiodarone-induced thyrotoxicosis and the ability to distinguish between the type 1 and type 2 forms of the disease are much more challenging. Dronedarone was approved in 2009 for the treatment of patients with atrial fibrillation. As amiodarone, dronedarone is a benzofuran derivative with similar electrophysiologic properties. In contrast to amiodarone, however, dronedarone is structurally devoid of iodine and has a notably shorter half-life. In studies reported before FDA approval, dronedarone proved to be associated with significantly fewer adverse effects than amiodarone, making it a more attractive choice for patients with atrial fibrillation or flutter, who are at risk of developing amiodarone-induced thyroid dysfunction.
Nature Reviews Endocrinology 11/2009; 6(1):34-41. · 9.97 Impact Factor
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ABSTRACT: Patients with congestive heart failure (CHF) often have low serum triiodothyronine (T(3)) concentrations. In a rodent model of myocardial infarction-induced CHF and low serum T(3), we hypothesized that replacing T(3) to euthyroid levels would improve left ventricular function without producing untoward signs of thyrotoxicosis.
Adult male Sprague-Dawley rats were subjected to left anterior descending coronary artery ligation (myocardial infarction). One week post-myocardial infarction, left ventricular fractional shortening was significantly reduced to 22+/-1% in CHF animals versus 38+/-1% for sham-operated controls (P<0.001). Serum T(3) concentration was also significantly reduced (80+/-3 versus 103+/-6 ng/dL; P<0.001), in CHF animals versus Shams. At 9 weeks post-myocardial infarction, systolic function (+dP/dt max) was significantly attenuated in CHF animals (4773+/-259 versus 6310+/-267 mmHg/s; P<0.001) as well as diastolic function measured by half time to relaxation (15.9+/-1.2 versus 11.1+/-0.3 ms; P<0.001). alpha-myosin heavy chain expression was also significantly reduced by 77% (P<0.001), and beta-myosin heavy chain expression was increased by 21%. Continuous T(3) replacement was initiated 1 week post-myocardial infarction with osmotic mini-pumps (6 microg/kg/d), which returned serum T(3) concentrations to levels similar to Sham controls while resting conscious heart rate, arterial blood pressure and the incidence of arrhythmias were not different. At 9 weeks, systolic function was significantly improved by T(3) replacement (6279+/-347 mmHg/s; P<0.05) and a trend toward improved diastolic function (12.3+/-0.6 ms) was noted. T(3) replacement in CHF animals also significantly increased alpha- and reduced beta-MHC expression, (P<0.05).
These data indicate that T(3) replacement to euthyroid levels improves systolic function and tends to improve diastolic function, potentially through changes in myocardial gene expression.
Circulation Heart Failure 05/2009; 2(3):243-52. · 6.29 Impact Factor
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ABSTRACT: The most recognizable features of hyperthyroidism are those that result from the effects of triiodothyronine (T3) on the heart and cardiovascular system: decreased systemic vascular resistance and increased resting heart rate, left ventricular contractility, blood volume, and cardiac output. Although these measures of cardiac performance are enhanced in hyperthyroidism, the finding of clinical cardiac failure can be somewhat paradoxical. About 6% of thyrotoxic individuals develop symptoms of heart failure, but less than 1% develop dilated -cardiomyopathy with impaired left ventricular systolic function. Heart failure resulting from thyrotoxicosis is due to a tachycardia-mediated mechanism leading to an increased level of cytosolic calcium during diastole with reduced ventricular contractility and diastolic dysfunction, often with tricuspid regurgitation. Pulmonary artery hypertension in thyrotoxicosis is gaining awareness as a cause of isolated right-sided heart failure. In both cases, older individuals are more likely to be affected. Treatment needs to be directed at management of the acute cardiovascular complications, control of the heart rate, and thyroid-specific therapy to restore a euthyroid state that will lead to resolution of the signs and symptoms of heart failure.
Current Heart Failure Reports 10/2008; 5(3):170-6.
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ABSTRACT: The myosin heavy chain (MHC) genes are regulated by triiodothyronine (T3) in a reciprocal and chamber-specific manner. To further our understanding of the potential mechanisms involved, we determined the T3 responsiveness of the MHC genes, alpha and beta, and the beta-MHC antisense (AS) gene in the rat ventricles and atria.
Hypothyroid rats were administered a single physiologic (1 microg) or pharmacologic (20 microg) dose of T3, and sequential measurements of beta-MHC hn- and AS RNA and alpha-MHC heterogeneous nuclear RNA from rat ventricular and atrial myocardium were performed with reverse transcription PCR.
We have demonstrated that T3 treatment increases the myocyte content of an AS beta-MHC RNA in atria and ventricles that includes sequences complementary to both the first 5' and last 3' introns of the beta-MHC sense transcript. In the hypothyroid rat ventricle, beta-MHC sense RNA expression is maximal, while in the euthyroid rat ventricle, beta-MHC AS RNA is maximal. beta-MHC AS expression increased by 52 +/- 9.8% at the peak, 24 hours after injection of a physiologic dose of T3 (1 microg/animal), while beta-MHC sense RNA decreased by 41 +/- 2.2% at 36 hours, the nadir. In hypothyroid atria, beta-MHC AS RNA was induced by threefold within 6 hours of administration of 1 microg T3, demonstrating that in the atria, beta-MHC AS expression is regulated by T3, while alpha-MHC expression is not.
In the hypothyroid rat heart ventricle, beta-MHC AS RNA expression increases in response to T3 similar to that of alpha-MHC. Simultaneous measures of beta-MHC sense RNA are decreased, suggesting a possible mechanism for AS to regulate sense expression. In atria, while alpha-MHC is not influenced by thyroid state, beta-MHC sense and AS RNA were simultaneously and inversely altered in response to T3. This confirms a close positive relationship between T3 and beta-MHC AS RNA in both the atria and ventricles, while demonstrating for the first time that alpha- and beta-MHC expression is not coupled in the atria.
Thyroid 07/2008; 18(7):761-8. · 4.79 Impact Factor
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ABSTRACT: Thyroid hormone deficiency has been recognized and treated with various forms of thyroid hormone replacement over the last century. Since the 1950s, synthetic L-thyroxine has been the therapy of choice. However, there is now recognition that the currently available regimens for the treatment of hypothyroidism may not adequately address the needs of all patients. This review summarizes recent considerations in the field of thyroidology to address the potential for improvement in the treatment of patients. The goal of these improvements should be to achieve both clinical and chemical euthyroidism.
Current opinion in investigational drugs (London, England: 2000) 05/2008; 9(4):357-62. · 3.31 Impact Factor
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Journal of Clinical Endocrinology & Metabolism 05/2008; 93(4):1172-4. · 6.50 Impact Factor
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ABSTRACT: The cardiovascular signs and symptoms of thyroid disease are some of the most profound and clinically relevant findings that accompany both hyperthyroidism and hypothyroidism. On the basis of the understanding of the cellular mechanisms of thyroid hormone action on the heart and cardiovascular system, it is possible to explain the changes in cardiac output, cardiac contractility, blood pressure, vascular resistance, and rhythm disturbances that result from thyroid dysfunction. The importance of the recognition of the effects of thyroid disease on the heart also derives from the observation that restoration of normal thyroid function most often reverses the abnormal cardiovascular hemodynamics. In the present review, we discuss the appropriate thyroid function tests to establish a suspected diagnosis as well as the treatment modalities necessary to restore patients to a euthyroid state. We also review the alterations in thyroid hormone metabolism that accompany chronic congestive heart failure and the approach to the management of patients with amiodarone-induced alterations in thyroid function tests.
Circulation 11/2007; 116(15):1725-35. · 14.74 Impact Factor
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ABSTRACT: Thyroid hormone (T3 and T4) has many beneficial effects including enhancing cardiac function, promoting weight loss and reducing serum cholesterol. Excess thyroid hormone is, however, associated with unwanted effects on the heart, bone and skeletal muscle. We therefore need analogs that harness the beneficial effects of thyroid hormone without the untoward effects. Such work is largely based on understanding the cellular mechanisms of thyroid hormone action, specifically the crystal structure of the nuclear receptor proteins. In clinical studies, use of naturally occurring thyroid hormone analogs can suppress TSH levels in patients with thyroid cancer without producing tachycardia. Many thyromimetic compounds have been tested in animal models and shown to increase total body oxygen consumption, and to lower weight and serum cholesterol and triglyceride levels while having minor effects on heart rate. Alternatively, analogs that specifically enhance both systolic and diastolic function are potentially useful in the treatment of chronic congestive heart failure. In addition to analogs that are thyroid hormone receptor agonists, several compounds that are thyroid hormone receptor antagonists have been identified and tested. This Review discusses the potential application of thyroid hormone analogs (both agonists and antagonists) in a variety of human disease states.
Nature Clinical Practice Endocrinology & Metabolism 10/2007; 3(9):632-40. · 7.55 Impact Factor
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ABSTRACT: Hypothyroidism is a common endocrine disease, which, in addition to its classic signs and symptoms, can present with primary complaints of myopathy. Myopathy can cause skeletal muscle weakness, tenderness, and pain and is often associated with elevated creatine kinase levels. There are many neuromuscular causes of myopathy, including inflammatory and infectious myopathies, metabolic and hereditary myopathies, and those caused by drugs or toxins. Hypothyroid patients with musculoskeletal symptoms can have elevated serum creatine kinase levels, which clinically resemble polymyositis. However, hypothyroid myopathies can be distinguished from polymyositis by coexisting signs and symptoms of hypothyroidism such as delayed relaxation phase of the deep tendon reflexes and the absence of inflammatory changes on muscle biopsy. The treatment of hypothyroidism with thyroid hormone replacement will alleviate symptoms of myopathy as well as lower the characteristic hyperlipidemia associated with hypothyroidism. Hypercholesterolemia, which can arise from different etiologies, is frequently treated with a class of HMG-CoA reductase inhibitors called statins. One of the most significant risks associated with the use of statins is the development of myopathy, a risk that may be compounded by the coexistence of hypothyroidism. The underlying metabolic mechanisms that account for muscle disease in these 2 settings show some common etiologies. The overlap of symptoms associated with hypothyroidism and statin-induced myopathy should prompt the physician to screen all patients presenting with myopathic symptoms with or without elevated creatine kinase levels and all hyperlipidemic patients before initiating statin therapy for hypothyroidism using a measurement of thyroid-stimulating hormone.
The Endocrinologist 08/2006; 16(5):279-285. · 0.09 Impact Factor
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ABSTRACT: Thyroid hormone regulates the transcription of several important cardiac genes. Although the thyroid gland produces predominantly thyroxine (T(4)), it is triiodothyronine (T(3)) that is transported across the sarcolemma and binds to nuclear thyroid hormone receptor proteins; yet various studies suggest that serum T(3) levels do not accurately reflect cellular T(3) action. To address this question, we studied the dose-response relationship of T(3) administered by constant infusion in hypothyroid animals with the simultaneous in vivo transcription rate of the cardiac-specific alpha-myosin heavy chain (MHC) gene, measured by quantitating alpha-MHC heteronuclear (hn)RNA content. Constant infusion of 4 mug T(3) x kg body wt(-1) x day(-1) for 3 days normalized serum T(3) and restored transcription to euthyroid levels; in contrast, daily injections of the same dose increased alpha-MHC transcription by only 55% of that obtained by infusion. Although infusion of T(3) at 1.25 microg T(3) x kg body wt(-1) x day(-1) was not sufficient to restore serum T(3) to normal, it was capable of restoring transcription to normal at 3 days, but when administered for 12 days, transcription of alpha-MHC was found to be 50% of euthyroid levels, demonstrating a decreased sensitivity to T(3) over time. Treatment with trichostatin A (TSA) to inhibit histone deacetylation increased levels of total nuclear acetylated histone H4 by almost 50% but was without effect on the real-time PCR measures of alpha-MHC hnRNA. TSA administered together with T(3) (10 mug T(3)/kg body wt) significantly increased transcription of alpha-MHC after 30 h, thus demonstrating a potential role for histones as cofactors in the T(3) regulation of cardiac alpha-MHC transcription.
AJP Heart and Circulatory Physiology 11/2005; 289(4):H1506-11. · 3.71 Impact Factor
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ABSTRACT: We tested the hypothesis that triiodothyronine (T3) supplementation alters gene transcription in the left ventricular myocardium of infants undergoing cardiopulmonary bypass for ventricular septal defect repair. To our knowledge, a novel heteronuclear assay demonstrated for the first time in human heart that rapid change in T3 levels altered the adenine nucleotide translocase-1 transcription rate during cardiopulmonary bypass.
The American Journal of Cardiology 04/2005; 95(6):787-9. · 3.37 Impact Factor
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ABSTRACT: Treatments for hypothyroidism have been available since the late 19th century, and have been continually improved by advancing our understanding of thyroid hormone pharmacology. Thyroxine (T4) monotherapy is currently the standard of care, but may leave some hypothyroid symptoms unaddressed. Triiodothyronine (T3), formed by the monodeiodination of T4, is the biologically active form of thyroid hormone based upon its ability to regulate gene expression at the nuclear level. A variety of human and animal studies have raised the question of whether T4 monotherapy is sufficient to restore tissue and organ intracellular T3 levels to normal. Furthermore, some evidence, albeit controversial, suggests that the addition of T3 (Cytomel) to T4 replacement therapy may improve patients' quality of life, psychometric performance and mood. Further developmental work is needed to refine T3 therapy in a way to enhance efficacy and lower the potential for unwanted effects.
Clinical Cornerstone 02/2005; 7 Suppl 2:S9-15.
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ABSTRACT: Triiodothyronine (T3) regulates cardiac contractility in part by regulating the expression of several important cardiac myocyte genes. In the rat, the T3-mediated induction of alpha-myosin heavy chain (MHC) transcription in hypothyroid hearts is rapid, exhibiting zero-order kinetics, whereas the repression of beta-MHC in these same hearts is much slower. To elucidate the mechanism for T3 transcriptional as well as posttranscriptional regulation of both MHC gene isoforms, we used an RT-PCR-based transcription assay and the RNA polymerase II inhibitor actinomycin D in an in vivo model to simultaneously measure specific alpha- and beta-MHC heterogeneous nuclear RNA (hnRNA), mRNA kinetics, and MHC antisense RNA. In vivo actinomycin D treatment blocked alpha-MHC transcription in euthyroid rats by >80% at 2 h and suggested a half-life of alpha-MHC hnRNA of approximately 1 h, whereas actinomycin D inhibited beta-MHC transcription in hypothyroid rats by >75% at 6 h, suggesting a significantly longer hnRNA half-life of approximately 4 h. The effect of actinomycin D on beta-MHC transcription was independent of T3. T3 treatment in hypothyroid animals caused beta-MHC mRNA to decline more rapidly than beta-MHC hnRNA, demonstrating, for the first time, a posttranscriptional mechanism(s). The measured change in beta-MHC mRNA half-life indicates a T3-mediated destabilization of beta-MHC mRNA. To understand the mechanism by which T3 destabilizes beta-MHC mRNA, we measured beta-MHC antisense RNA. beta-MHC antisense RNA is present in euthyroid myocytes, but levels are not significant in hypothyroid myocytes. This differential expression may explain some of the effects of T3 on MHC posttranscriptional regulation.
AJP Heart and Circulatory Physiology 02/2005; 288(2):H455-60. · 3.71 Impact Factor
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ABSTRACT: Thyroid hormone has well-recognized effects on the cardiovascular system and blood pressure regulation. Blood pressure is altered across the entire spectrum of thyroid disease. The effects of hyperthyroidism include increased cardiac output, contractility, tachycardia, widened pulse pressure, decreased systemic vascular resistance, and increased basal metabolic rate. The manifestations of hypothyroidism are in marked contrast to those of hyperthyroidism and include decreased cardiac output, narrow pulse pressure, increased systemic vascular resistance, and decreased metabolic rate. Although thyroid hormone affects almost all tissues of the body and mediates changes in homeostasis, adaptations of the cardiovascular system can result in changes in blood pressure to accommodate the new demands on the system. In this paper, we review the direct and indirect thyroid hormone-mediated effects on blood pressure.
Current Hypertension Reports 01/2004; 5(6):513-20. · 2.50 Impact Factor
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ABSTRACT: At the present time, optimal therapy for hypothyroidism requires replacement of the deficiency in thyroid hormone with synthetic levothyroxine. Precise titration of this narrow therapeutic index drug is necessary to return the patient to a chemically and clinically euthyroid state. Seven levothyroxine formulations are Food and Drug Administration (FDA)-approved and four are available to the physician. Proper dosage is established based on thyrotropin (TSH) testing and clinical evaluation. Each levothyroxine preparation must comply with FDA standards for bioavailability but may vary with respect to its dissolution and absorption properties and are not interchangeable. This equivalence testing is done on normal volunteers and requires a suprapharmacologic dose of levothyroxine in order to make the determination of bioavailability. In this review we discuss the various methods to evaluate therapeutic efficacy and bioequivalence of levothyroxine preparations in the treatment of thyroid disease. These are relevant to the physician and patient because small differences in the efficacy can produce unwanted effects of either underreplacement or overreplacement.
Thyroid 01/2004; 13(12):1127-32. · 4.79 Impact Factor
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ABSTRACT: We developed an RT-PCR assay to study both the time course and the mechanism for the triiodothyronine (T(3))-induced transcription of the alpha- and beta-myosin heavy chain (MHC) genes in vivo on the basis of the quantity of specific heterogeneous nuclear RNA (hnRNA). The temporal relationship of changes in transcriptional activity to the amount of alpha-MHC mRNA and the coordinated regulation of transcription of more than one gene in response to T(3) are demonstrated here for the first time. Quantitation of alpha-MHC hnRNA demonstrated that T(3) induced alpha-MHC transcription in hypothyroid rats within 30 min of a single injection of T(3) (0.5 microg/100 g body wt). Maximal transcription rates (135% +/- 15.8 of euthyroid values) occurred 6 h after injection and subsequently declined in parallel with serum T(3) levels. The transcription of beta-MHC was reduced to 86% of peak hypothyroid levels 6 h after a single T(3) injection and reached a nadir of 59% of hypothyroid levels at 36 h. Analysis of the time course of T(3)-mediated induction of alpha-MHC hnRNA and repression of beta-MHC hnRNA indicates that separate molecular mechanisms are involved in the coordinated regulation of these genes.
AJP Heart and Circulatory Physiology 07/2003; 284(6):H2255-62. · 3.71 Impact Factor
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ABSTRACT: The effects of hypothyroidism on the cardiovascular system have been the subject of much research over the last several decades. The hypothyroid cardiac phenotype includes impaired contractile function, decreased cardiac output, and alterations in myocyte gene expression. In the setting of cardiac disease, as in other acute illnesses, alterations in thyroid hormone metabolism occur that result in decreased serum triiodothyronine (T(3)) levels. This is referred to as low T(3) syndrome. Similarities between the heart failure phenotype and the hypothyroid cardiac phenotype are numerous including changes in the expression of thyroid hormone regulated myocyte specific genes. The heart responds in a very sensitive manner to reduced circulating levels of T(3) with decreased expression of positively regulated genes and increased expression of negatively regulated genes. In the present paper we review data on thyroid hormone mediated cardiac specific gene transcriptional regulation. T(3) replacement therapy for hypothyroidism restores normal expression of these T(3) regulated genes and recent experiments suggest that the diseased human heart in congestive failure would benefit from similar T(3) replacement therapy.
Thyroid 07/2002; 12(6):467-72. · 4.79 Impact Factor
