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.

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.

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 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.

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.

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 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.

Association of serum triiodothyronine with B-type natriuretic peptide and severe left ventricular diastolic dysfunction in heart failure with preserved ejection fraction.

There are well-documented changes in thyroid hormone metabolism that accompany heart failure (HF). However, the frequency of thyroid hormone abnormalities in HF with preserved ejection fraction (HFpEF) is unknown, and no studies have investigated the association between triiodothyronine (T(3)) and markers of HF severity (B-type natriuretic peptide [BNP] and diastolic dysfunction [DD]) in HFpEF. In this study, 89 consecutive patients with HFpEF, defined as symptomatic HF with a left ventricular ejection fraction >50% and a left ventricular end-diastolic volume index <97 ml/m(2), were prospectively studied. Patients were dichotomized into 2 groups on the basis of median T(3) levels, and clinical, laboratory, and echocardiographic data were compared between groups. Univariate and multivariate linear regression analyses were performed to determine whether BNP and DD were independently associated with T(3) level. We found that 22% of patients with HFpEF had reduced T(3). Patients with lower T(3) levels were older, were more symptomatic, more frequently had hyperlipidemia and diabetes, and had higher BNP levels. Severe (grade 3) DD, higher mitral E velocity, shorter deceleration time, and higher pulse pressure/stroke volume ratio were all associated with lower T(3) levels. T(3) was inversely associated with log BNP (p = 0.004) and the severity of DD (p = 0.039). On multivariate analysis, T(3) was independently associated with log BNP (ß = -4.7 ng/dl, 95% confidence interval -9.0 to -0.41 ng/dl, p = 0.032) and severe DD (ß = -16.3 ng/dl, 95% confidence interval -30.1 to -2.5 ng/dl, p = 0.022). In conclusion, T(3) is inversely associated with markers of HFpEF severity (BNP and DD). Whether reduced T(3) contributes to or is a consequence of increased severity of HFpEF remains to be determined.

Thyroid hormone and the cardiovascular system.

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.

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.

Effects of amiodarone therapy on thyroid function.

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.

Physiological replacement of T3 improves left ventricular function in an animal model of myocardial infarction-induced congestive heart failure.

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

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.

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.

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.

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.