Thyroid Abnormalities in Heart Failure.

The effects of hyperthyroidism and hypothyroidism on the heart and cardiovascular system are well documented. It has also been shown that various forms of heart disease including but not limited to congenital, hypertensive, ischemic, cardiac surgery, and heart transplantation cause an alteration in thyroid function tests including a decrease in serum liothyronine (T3). This article discusses the basic science and clinical data that support the hypothesis that these changes pose pathophysiologic and potential novel therapeutic challenges.

Amiodarone-induced thyroid dysfunction.

Amiodarone is an effective medication for the treatment of cardiac arrhythmias. Originally developed for the treatment of angina, it is now the most frequently prescribed antiarrhythmia drug despite the fact that its use is limited because of potential serious side effects including adverse effects on the thyroid gland and thyroid hormones. Although the mechanisms of action of amiodarone on the thyroid gland and thyroid hormone metabolism are poorly understood, the structural similarity of amiodarone to thyroid hormones, including the presence of iodine moieties on the inner benzene ring, may play a role in causing thyroid dysfunction. Amiodarone-induced thyroid dysfunction includes amiodarone-induced thyrotoxicosis (AIT) and amiodarone-induced hypothyroidism (AIH). The AIT develops more commonly in iodine-deficient areas and AIH in iodine-sufficient areas. The AIT type 1 usually occurs in patients with known or previously undiagnosed thyroid dysfunction or goiter. The AIT type 2 usually occurs in normal thyroid glands and results in destruction of thyroid tissue caused by thyroiditis. This is the result of an intrinsic drug effect from the amiodarone itself. Mixed types are not uncommon. Patients with cardiac disease receiving amiodarone treatment should be monitored for signs of thyroid dysfunction, which often manifest as a reappearance of the underlying cardiac disease state. When monitoring patients, initial tests should include the full battery of thyroid function tests, thyroid-stimulating hormone, thyroxine, triiodothyronine, and antithyroid antibodies. Mixed types of AIT can be challenging both to diagnose and treat and therapy differs depending on the type of AIT. Treatment can include thionamides and/or glucocorticoids. The AIH responds favorably to thyroid hormone replacement therapy. Amiodarone is lipophilic and has a long half-life in the body. Therefore, stopping the amiodarone therapy usually has little short-term benefit.

Thyroid Abnormalities in Heart Failure.

The effects of hyperthyroidism and hypothyroidism on the heart and cardiovascular system are well documented. It has also been shown that various forms of heart disease including but not limited to congenital, hypertensive, ischemic, cardiac surgery, and heart transplantation cause an alteration in thyroid function tests including a decrease in serum liothyronine (T3). This article discusses the basic science and clinical data that support the hypothesis that these changes pose pathophysiologic and potential novel therapeutic challenges.

Triiodothyronine Supplementation in Infants and Children Undergoing Cardiopulmonary Bypass (TRICC): a multicenter placebo-controlled randomized trial: age analysis.

BACKGROUND: 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. METHODS AND RESULTS: 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). CONCLUSIONS: 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.

Assessment of the Adequacy of Thyroid Hormone Replacement Therapy in Hypothyroidism.

Background: Recent studies identify a significant number of treated hypothyroid patients who express dissatisfaction with their therapy. At present there are sufficient measures of thyroid function to enable the clinician to establish a diagnosis of thyroid disease with a high degree of sensitivity and specificity. The purpose of this study was to quantitate the use of a new and novel assessment of clinically relevant hypothyroid symptoms in the management of patients with thyroid disease and to identify a tool that could help clinicians to assess adequacy of LT4 treatment. Methodology: Unselected outpatients of the Thyroid Clinic of the North Shore University Hospital at Manhasset completed a questionnaire asking them to rate their physical symptoms related to thyroid disease as part of their standard care. This questionnaire consisted of 10 signs and symptoms. The questionnaire was collected from 198 control subjects, 241 subjects with primary hypothyroidism (under treatment), 113 euthyroid subjects (benign nodular thyroid disease), 73 previously hyperthyroid subjects (previously treated), and 27 subjects with thyroid cancer. A repeat questionnaire was obtained from 48 subjects with primary hypothyroidism (20%), 19 euthyroid subjects (17%), and 17 subjects previously hyperthyroid (23%). Data Analysis: The mean score for the sum of the signs and symptoms in the primary hypothyroid group with no medication change was 9.62 ± 1.29 for the initial questionnaire, and 10.04 ± 1.32 for the follow up questionnaire (not significant). For the primary hypothyroid patients requiring a medication change, at the time of the initial questionnaire the mean serum TSH was 12.86 ± 2.75 mcU/ml. Concurrently with the normalization of TSH, a statistically significant improvement in the sum of signs and symptoms mean score for this group was noted (16.32 ± 1.93 initial vs. 10.32 ± 1.46 after treatment to normalize TSH). Conclusion: The proposed newly devised hypothyroid scale correctly identified subjects with TSH elevation and clinical/subclinical hypothyroidism based on their clinical signs and symptoms. In this particular subset of patients, the hypothyroid symptom scale showed a statistically significant improvement in the sum of the signs and symptoms with the normalization of the subjects' thyroid function.

Hypothyroid Symptoms in Levothyroxine-Treated Patients.

PURPOSE: Approximately 15% of patients with hypothyroidism are dissatisfied with their treatment due to persistence of residual symptoms associated with hypothyroidism. The purpose of this study was to compare thyroid symptoms using the hypothyroid symptom scale (HSS) in patients receiving stable thyroid therapy for 6 months to patients without hypothyroidism. The HSS was used to identify the percentage of levothyroxine-treated hypothyroid patients with residual or persistent hypothyroid symptoms. METHODS: Patients included in the study had hypothyroidism and were receiving a stable/maintenance dose of levothyroxine sodium therapy, unchanged for at least 6 months. A control group of patients were included if they did not have an active prescription for thyroid hormone therapy. The HSS was administered via phone or face-to-face interactions. Patients were asked to score 10 symptoms over the past month on a scale of 0 to 4 (e.g., 0, absence of, to 4, severe symptoms). Results were analyzed using descriptive and inferential statistics. T-tests and chi-squared analysis were used to assess differences in continuous and categorical variables. RESULTS: A total of 68% of the contacted patients responded to the survey. A total of 302 patients were in the intervention group and 273 were in the control group. The mean total HSS scores between groups were significantly higher in the treatment compared to the control group (13.92 ± 10.91 vs.10.07 ± 7.85; P < 0.001). CONCLUSION: Significantly more patients receiving thyroid hormone therapy experienced residual thyroid symptoms compared to control patients. Attempts should be made to offer alternatives for hypothyroid patients with persistent symptoms.

Thyroid disease and the heart.

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.

Recent considerations in the treatment of hypothyroidism.

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.

Differential regulation of the myosin heavy chain genes alpha and beta in rat atria and ventricles: role of antisense RNA.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Thyrotoxic cardiac disease.

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.

Thyroid Hormones and Cardiovascular Function and Diseases.

Thyroid hormone (TH) receptors are present in the myocardium and vascular tissue, and minor alterations in TH concentration can affect cardiovascular (CV) physiology. The potential mechanisms that link CV disease with thyroid dysfunction are endothelial dysfunction, changes in blood pressure, myocardial systolic and diastolic dysfunction, and dyslipidemia. In addition, cardiac disease itself may lead to alterations in TH concentrations (notably, low triiodothyronine syndrome) that are associated with higher morbidity and mortality. Experimental data and small clinical trials have suggested a beneficial role of TH in ameliorating CV disease. The aim of this review is to provide clinicians dealing with CV conditions with an overview of the current knowledge of TH perturbations in CV disease.

Potential therapeutic applications of thyroid hormone analogs.

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.

Thyroid Disease and the Heart.

Thyroid hormones have an intimate relationship with cardiac function. Some of the most significant clinical signs and symptoms of thyroid disease are the cardiac manifestations. In both hypothyroidism and hyperthyroidism, the characteristic physiological effects of thyroid hormone can be understood from the actions at the molecular and cellular level. Here we explore topics from the metabolism and cellular effects of thyroid hormone to special considerations related to statin and amiodarone therapy for the alterations in thyroid hormone metabolism that accompany heart disease.

Effect of triiodothyronine on gene transcription during cardiopulmonary bypass in infants with ventricular septal defect.

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.

Potential uses of T3 in the treatment of human disease.

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.

Thyroid hormone-regulated cardiac gene expression and cardiovascular disease.

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.

Evaluation of the therapeutic efficacy of different levothyroxine preparations in the treatment of human thyroid disease.

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 disease and the cardiovascular system.

Thyroid hormones, specifically triiodothyronine (T3), have significant effects on the heart and cardiovascular system. Hypothyroidism, hyperthyroidism, subclinical thyroid disease, and low T3 syndrome each cause cardiac and cardiovascular abnormalities through both genomic and nongenomic effects on cardiac myocytes and vascular smooth muscle cells. In compromised health, such as occurs in heart disease, alterations in thyroid hormone metabolism may further impair cardiac and cardiovascular function. Diagnosis and treatment of cardiac disease may benefit from including analysis of thyroid hormone status, including serum total T3 levels.

Discovery of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carbonitrile (MGL-3196), a Highly Selective Thyroid Hormone Receptor ß agonist in clinical trials for the treatment of dyslipidemia.

The beneficial effects of thyroid hormone (TH) on lipid levels are primarily due to its action at the thyroid hormone receptor ß (THR-ß) in the liver, while adverse effects, including cardiac effects, are mediated by thyroid hormone receptor α (THR-α). A pyridazinone series has been identified that is significantly more THR-ß selective than earlier analogues. Optimization of this series by the addition of a cyanoazauracil substituent improved both the potency and selectivity and led to MGL-3196 (53), which is 28-fold selective for THR-ß over THR-α in a functional assay. Compound 53 showed outstanding safety in a rat heart model and was efficacious in a preclinical model at doses that showed no impact on the central thyroid axis. In reported studies in healthy volunteers, 53 exhibited an excellent safety profile and decreased LDL cholesterol (LDL-C) and triglycerides (TG) at once daily oral doses of 50 mg or higher given for 2 weeks.