Sara Danzi

Thyroid Hormone and the Cardiovascular System

Thyroid hormone has profound effects on the heart and peripheral vascular system. This is best demonstrated by the characteristic changes in cardiovascular hemodynamics that accompany both hyper- and hypothyroidism. These effects can be explained by the ability of thyroid hormone to regulate expression of specific cardiac genes as well as to alter systemic vascular resistance. Treatment of the underlying disease process predictably reverses these changes and restores normal cardiovascular physiology. Recent observations suggest therapeutic benefit of thyroid hormone when administered short term to patients who have undergone cardiac surgery and also when given to patients with varying degrees of heart failure. The rapidity of these effects suggests nonnuclear sites of action that may involve membrane ion channel function causing altered myocyte contractility and excitability. This in turn could explain the varied effects of thyroid hormone on cardiac rhythm disturbances and on vascular tone. Thus, the clinical signs and symptoms of thyroid disease are the result of both nuclear and nonnuclear actions of thyroid hormone on the heart and systemic vasculature.

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 (T3) concentrations. In a rodent model of myocardial infarction-induced CHF and low serum T3, we hypothesized that replacing T3 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 T3 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 mm Hg/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). &agr;-myosin heavy chain expression was also significantly reduced by 77% (P<0.001), and &bgr;-myosin heavy chain expression was increased by 21%. Continuous T3 replacement was initiated 1 week post-myocardial infarction with osmotic mini-pumps (6 &mgr;g/kg/d), which returned serum T3 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 T3 replacement (6279±347 mm Hg/s; P<0.05) and a trend toward improved diastolic function (12.3±0.6 ms) was noted. T3 replacement in CHF animals also significantly increased &agr;- and reduced &bgr;-MHC expression, (P<0.05). Conclusions—These data indicate that T3 replacement to euthyroid levels improves systolic function and tends to improve diastolic function, potentially through changes in myocardial gene expression.

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.

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.

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.

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.

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 (β = -4.7 ng/dl, 95% confidence interval -9.0 to -0.41 ng/dl, p = 0.032) and severe DD (β = -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 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.

Differential Regulation of the Myosin Heavy Chain Genes α and β in Rat Atria and Ventricles: Role of Antisense RNA

BACKGROUNDnThe 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.nnnMETHODSnHypothyroid 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.nnnRESULTSnWe 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.nnnCONCLUSIONSnIn 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.

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 β 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 β (THR-β) 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-β 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-β 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.