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Translational potential of thyroid hormone and its analogs
Journal of Molecular and Cellular Cardiology 51 (2011) 506–511
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Journal of Molecular and Cellular Cardiology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / y j m c c
Review article
Translational potential of thyroid hormone and its analogs Reza Arsanjani a,b, Madeline McCarren c, Joseph J. Bahl a,b, Steven Goldman a,b,⁎ a b c
Southern Arizona VA Health Care System, Section of Cardiology, Department of Medicine, 1-111C, 3601 S. 6th Avenue, Tucson, AZ 85723, USA Sarver Heart Center, University of Arizona, 1501 N. Campbell Avenue, Tucson, AZ 85724, USA Hines VA, Pharmacy Benefits Management, 5000 S. 5th Avenue, M/S 119D, Hines IL 60141, USA
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Article history: Received 3 September 2010 Received in revised form 4 November 2010 Accepted 21 December 2010 Available online 5 January 2011 Keywords: Thyroid hormone Thyroid hormone analogs Heart failure Hypercholesterolemia Review
a b s t r a c t Thyroid hormone has unique properties affecting the heart, and the vasculature and cholesterol metabolism. There is interest in using thyromimetic agents as possible treatment options for heart failure based on data demonstrating the ability of these agents to improve systolic and diastolic left ventricular function as well as their vasodilatory action. The inverse relationship between heart failure severity and serum triiodothyronine (T3) levels has also been interpreted by some as an indication that thyroid hormone therapy might be useful. In the 1950s, investigators began developing thyroid hormone analogs that could lower cholesterol, that selectively bind to β1-type nuclear thyroid hormone receptors (TR), which are responsible for cholesterol-lowering activity, without activating α1-type receptors in the heart. The identification of 3,5-diiodothyropropionic acid (DITPA) that binds to both α- and β-type TRs with relatively low affinity was unique in that this analog improves left ventricular function in heart failure as well as lowers cholesterol. The aim of this review is to summarize information known about the interactions between thyroid hormones and the cardiovascular system, and the potential therapeutic effects of thyroid analogs in chronic heart disease. This article is part of a special issue entitled “Key Signaling Molecules in Hypertrophy and Heart Failure.” Published by Elsevier Ltd.
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mechanisms of thyroid hormone actions on the cardiovascular system. 2.1. Nuclear receptors . . . . . . . . . . . . . . . . . . . . . . 2.2. Intracellular calcium and potassium . . . . . . . . . . . . . . 2.3. Contractile proteins . . . . . . . . . . . . . . . . . . . . . 2.4. Catecholamines . . . . . . . . . . . . . . . . . . . . . . . 2.5. Alterations in cardiovascular function . . . . . . . . . . . . . 2.6. Lipid metabolism . . . . . . . . . . . . . . . . . . . . . . 3. Studies of thyromimetic agents for heart failure . . . . . . . . . . . 4. Development of thyroid hormone analog DITPA to treat heart failure . . . 5. Lipid-lowering activity of T3 and its analogs . . . . . . . . . . . . . 6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . Disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction More than 5 million Americans have heart failure with an estimated 550,000 new cases occurring each year, making it the leading cause of hospitalization in the United States [1]. Significant ⁎ Corresponding author. Sarver Heart Center, University of Arizona, 1501 N. Campbell Avenue, Tucson, AZ 85724, USA. Tel.: +1 520 792 1450x5081; fax: +1 520 629 4636. E-mail address: [email protected] (S. Goldman). 0022-2828/$ – see front matter. Published by Elsevier Ltd. doi:10.1016/j.yjmcc.2010.12.012
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strides have been made in understanding the pathophysiology of acute and chronic heart failure, but despite these advances and improved overall survival of heart failure patients [2], the condition remains a leading cause of morbidity and mortality, especially with a progressively aging population. Therefore, identification of novel therapeutic approaches for heart failure remains very important. Interest in thyromimetic agents as a possible treatment option stems from previous studies demonstrating the ability of these agents to improve both systolic and diastolic left ventricular function as well as
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hormone regulation of cardiac growth via the TRα1 receptor that define cardiomyocyte phenotype alterations that ultimately could change cardiac function. Understanding these mechanisms allows investigators to explore cellular targets for developing unique thyroid hormone analogs. 2.2. Intracellular calcium and potassium
Fig. 1. Schematic representation of binding of TR to the basic hexameric consensus sequence AGGT/ACA separated by a 4 bp spacer in a T3-sensitive gene. The TR is shown binding as a heterodimer with RXR, the 9-cis retinoic acid receptor, with an orientation such that the TR occupies the 3′ half site. TR and RXR have multiple transcription coactivators and corepressors (Morkin et al. JMCC 2004;37:1137-46).
their vasodilatory action. The inverse relationship between heart failure severity and serum triiodothyronine (T3) levels has also been interpreted by some as an indication that thyroid hormone therapy might be useful [3]. The aim of this review is to summarize information known about the interactions between thyroid hormones and the cardiovascular system, and the potential therapeutic effects of thyroid analogs in chronic heart disease. 2. Mechanisms of thyroid hormone actions on the cardiovascular system 2.1. Nuclear receptors Thyroid hormone exerts its effects on the cellular level by binding to thyroid hormone nuclear receptors which in turn bind to the regulatory region of genes (thyroid hormone response elements) and modify their expression (Fig. 1) [4]. Two separate genes code for four separate thyroid hormone receptor (TR) isoforms, TRα1, TRα2, TRβ1 and TRβ2 [5]. TRα1 is the principal isoform in the heart, accounting for 70% of cardiac TR mRNA [6]. Thyroid hormone binds to TR resulting in induction of several genes by binding to thyroid hormone receptor elements (TRE), as homodimers or heterodimers [7]. Active transcriptions ensue, and large quantities of mRNA are produced which are then translated in specific proteins. Other genes are negatively regulated by T3 and are induced in the absence of T3 [8]. Cardiac genes positively regulated by thyroid hormones include those coding for sarcoplasmic reticulum calcium adenosine triphosphatase (ATPase), α-myosin heavy chain, β1-adrenergic receptors, sodium/ potassium, voltage-gated potassium channels, and atrial natriuretic hormone [3,9]. Cardiac enzymes negatively regulated by thyroid hormones include β-myosin heavy chains, phospholamban, sodium/ calcium exchanger, TR α1, and adenylyl cyclase types V and VI [3,9]. The mechanism of thyroid hormone and TR regulation of protein synthesis and cardiac hypertrophy via the TRα1 receptor has been extensively studied in isolated cardiomyocytes by Kenessay and Ojamaa [10–12]. Initially these investigators examined transcription of T3 responsive genes and found T3 induced proteosome-mediated degradation of TRα1 [11]. They also showed T3 mediated increases in protein synthesis through activation of phosphatidylinositol 3-kinase (PI3K) and the Akt-mTOR-S6K signaling pathway. Using transduced rat ventricular myocytes, these same investigators showed that PKCα was a regulator of TR function suggesting that nuclear localization of PKCα may control transcription of the TRα gene [11]. Taken together as a body of work, these data explore the mechanisms of thyroid
Thyroid hormone affects systolic contractile function and diastolic relaxation by influencing the rate of release and reuptake of calcium into the sarcoplasmic reticulum [13]. Thyroid hormone induces expression of the sarcoplasmic reticulum calcium ATPase gene (SERCa2) resulting in an increased calcium release from sarcoplasmic reticulum and accounting for an increased contractile activity [14,15]. Phospholamban is a membrane protein regulated by thyroid hormone that decreases the rate of muscle relaxation and contractility by inhibiting the sarcoplasmic reticulum calcium pump, thereby decreasing heart rate and stroke volume, respectively [15]. Phosphorylation of phospholamban leads to a loss of its ability to inhibit the sarcoplasmic reticulum calcium pump. Phospholamban expression and its level of phosphorylation, as well as upregulation of SERCa2, may account for an increased systolic contractile function and a decreased diastolic relaxation time noted in patients with hyperthyroidism. In addition, thyroid hormone negatively regulates sodium/ calcium exchanger and upregulates sodium/potassium ATPase and voltage-gated potassium channels. The resulting changes in intracellular calcium and potassium lead to increased inotropy and heart rate [16]. Recent work shows that SERCAa2 levels are induced by T3 interacting with TRβ1 and not with TRα1 [17]. The TRα1 binds to the highly conserved consensus sequence of the phospholamban promoter leading to decreases in histone acetylation and lysine 4 methylation, and two modifications of phospholamban DNA that would normally be associated with increased gene expression and by being removed are associated with a mechanism responsible for gene silencing [17]. 2.3. Contractile proteins Thyroid hormone also influences the systolic contractile function by altering cardiac contractile proteins. Myosins are a large family of motor proteins responsible for actin-based motility, with the myosin heavy chains (MHC) functioning as the molecular motor for driving muscle contractions. Each hexameric myosin molecule is composed of two MHC and four myosin light chains [18]. Cardiomyocytes express two MHC isoforms, α and β, each exhibiting different ATPase activity. Three separate myosin isoforms have been isolated from mammal hearts, V1–V3 [18], each differing from each other only in their MHC composition. V1 has the highest ATPase activity and is composed of two α-MHC, V2 has one α-MHC and one β-MHC, while V3 has the lowest ATPase activity and is composed of two β-MHC [18]. T3 stimulates transcription of the α-MHC gene and inhibits β-MHC mRNA production in vivo and in cultured heart cells, although the responsiveness of the gene to T3 varies among different mammals [18]. These changes in MHC isoforms are correlated with alterations in myosin ATPase activity and actinomycin cross bridge cycle rate and consequently increase in the speed of muscle contraction [19,20]. In addition, thyroid hormone also increases the levels of actin thin filament and troponin-I isoforms [21]. 2.4. Catecholamines Tachycardia and increased contractility noted in the hyperthyroid state is similar to the effect seen by sympathomimetic agents. In addition, sympatholytic agent administration is associated with clinical amelioration of symptoms of hyperthyroidism [9,22], leading to the hypothesis that some of the effects of thyroid hormone seen are
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due to an increased catecholamine state or an increased responsiveness to catecholamine stimulation. However, plasma and urine levels of catecholamines are normal in the hyperthyroid state [23], leading to the hypothesis that an elevated thyroid state leads to increased responsiveness to catecholamine stimulation. Cardiac tissues contain both β1 and β2-adrenergic receptors; with β1 accounting for 70% of all β-adenoreceptors, as well as accounting for the majority of β-adenoreceptors in the sinoatrial node [24]. Several studies have demonstrated, in response to thyroid hormone, an increased number of β-adrenergic receptors and increased sensitivity to sympathomimetic stimulation [25,26], with β-1 adenoreceptor mRNA increasing significantly [27]. Thyroid hormone transcriptionally regulates the pacemaker-related genes and hyperpolarization-activated cyclic nucleotide-gated channels 2 and 4 [28], as well as controlling other components of β-adrenergic system such as guanine nucleotide regulatory proteins and adenylate cyclase [25]. These changes lead to increased heart rate and improved diastolic performance. 2.5. Alterations in cardiovascular function The effects of thyroid hormone on the heart are well known and will not be reviewed here but appropriate references are provided that specifically address thyroid hormone induced changes that potentially could affect the use of thyroid hormone analogs to treat cardiovascular disease such as changes in vascular tone, blood volume and the induction of cardiac arrhythmias [29–49]. An in depth review of cardiac hypertrophy and thyroid hormone signaling has recently been published [50]. 2.6. Lipid metabolism Hypothyroidism obviously has effects on lipid metabolism resulting in elevations of serum total and low-density-lipoprotein (LDL) cholesterol concentrations and apolipoprotein B that are reversible with thyroid replacement therapy [51,52]. This reversal of lipid levels with thyroid hormone administration has been the stimulus to develop analogs of thyroid hormone to treat hypercholesterolemia. One interesting clinical point is that post-menopausal women with thyroid levels at the low end of normal were at high risk for increased mortality because of cardiovascular disease, presumably due to high triglyceride and cholesterol levels without estrogen to counteract the risk. This suggests that it may be time to revise the range of “normal” for thyroid hormone, with respect to the lower end of the normal range [53], similar to the change in thinking about cholesterol levels (as risk became associated with the higher end of that “normal” range). The development of thyroid hormone analogs to treat hypercholesterolemia is discussed later in this review. 3. Studies of thyromimetic agents for heart failure A low T3 state is common, occurring in up to a third of patients with dilated cardiomyopathy [54]. As previously mentioned, studies have shown that the decline in serum T3 is proportional to the severity of heart failure, based on the New York Heart Association functional classification [3]. Studies have shown that low-T3 syndrome is a strong predictor of death in cardiac patients and might be directly implicated in the poor prognosis of cardiac patients [55]. Patients with ischemic and non-ischemic heart failure had total T3, brain natriuretic peptide, and ejection fraction that were each independent predictors of cardiac and total death [56]. Reduction in T3 appears to represent a continuum and likely represents a marker of progressive cardiac dysfunction seen in patients with heart failure [57,58]. In addition, subclinical hypothyroidism, defined as a belownormal thyroid stimulating hormone in association with a normal total and free T4 and T3, has been associated with increased mortality in patients with ischemic and non-ischemic heart disease [59].
Therefore, restoration of thyroid hormone to normal levels should, in theory, reverse the negative effects of altered thyroid metabolism. Investigators studied the safety and efficacy of administering single intravenous dose of T3 to patients with advanced heart failure. Treatment with T3 resulted in an increase in cardiac output and a decrease in systemic vascular resistance two hours after administration, without any evidence of myocardial ischemia, arrhythmias, or other significant side effects [60]. Oral daily levothyroxine to patients with chronic heart failure for 12 weeks resulted in improved exercise tolerance, increased cardiac index, and decreased systemic vascular resistance [61]. T3 was previously found to reduce surgical death in patients at high risk of death during open heart surgery [62]. Although the above studies show that thyroid replacement therapy may be beneficial for treatment of heart failure, there are no randomized trials comparing T4 versus T3. However, studies have shown that constant infusion of T4 was unable to normalize T3 levels in tissue, including in myocardium [63], which may be related to the impaired peripheral conversion of T4 to T3. In addition, high dose thyroid infusion over prolonged periods results in detrimental effects following an initial improvement in cardiac performance [64]. Furthermore, the beneficial effects of thyroid hormone in heart disease need to be balanced against the differential organ response to systemic thyroid hormone therapy. Lastly, doses need to be adjusted to keep T3 levels constant and within physiological range, which is currently not possible with pills. 4. Development of thyroid hormone analog DITPA to treat heart failure Based on the limitations of using the native thyroid hormone to treat heart failure, there has been enthusiasm for the development of thyroid hormone analogs which are organ-selective without the undesirable side effects. In developing thyroid hormone analogs to treat heart failure, our laboratory initially screened a series of analogs by defining their abilities to induce increases in mRNA for alpha MHC in neonatal cardiomyocytes in culture [65]. Based on this information we focused on separating the inotropic and chronotropic effects of potential candidate analogs by defining dose response data for heart rate versus LV dP/dt. Our idea was to find an analog that would provide the largest increase in LV dP/dt for the smallest increase in heart rate [66]. Ultimately, as a precursor to performing a clinical trial, we examined potential analogs in animal models of heart failure including the rat and rabbit coronary artery ligation models [67,68]. Doing the work in live animals helped us understand the integrated effects of the analogs on the heart and the peripheral circulation, something that would need to be addressed clinically and could not be evaluated in-vitro [49]. At this point in time, we had to decide between pursuing clinical studies or more animal studies such as a mortality study in rats. We decided to initiate the clinical work because no matter what the animal data showed, we would have to pursue this in patients. For our clinical studies we selected 3,5-diiodothyropropionic acid (DITPA), a thyroid analog of T2 with weak T3 activity that improves LV function without increasing the heart rate in animal models of heart failure [66–68]. This analog, DITPA, also stimulates coronary vascular growth [69], which might further lead to a decline in systemic vascular resistance. In a pilot clinical study, DITPA was dosed at 180 mg/day for two weeks, followed by 360 mg/day for two additional weeks. This regimen of DITPA was well tolerated in patients with NYHA functional class II–III heart failure, with significant improvement in cardiac function as well as reduction in systemic vascular resistance [70]. Treatment with DITPA resulted in the reduction of total serum cholesterol and triglycerides [70]. In a follow-up larger multicenter Phase II randomized controlled trial supported by the Department of Veterans Affairs Cooperative Studies Program, treatment was planned for six months, titrating to a dose
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that would just suppress TSH to below 0.02 mU/L, or a maximum of 360 mg/day. The choice of dosing regimen was based on the concept of using the maximum tolerated dose to provide the best opportunity to detect a beneficial effect; the available funds did not permit a doseranging study. Unfortunately, with longer use and a larger sample size, it became clear that this regimen exceeded the maximum tolerated. There were a variety of non-specific adverse effects sufficient to prompt a reduction or cessation of therapy. Further complicating interpretation was our inclusion of a patient-reported global assessment of well-being that was not specific for heart failure symptoms in our primary composite outcome. It is not surprising, in retrospect, that the primary outcome did not indicate global patient benefit with DITPA even though DITPA improved some hemodynamic and metabolic parameters [71]. A trial with a much more modest dose (perhaps 90 mg/day) would be of great interest, although the narrow therapeutic window is also indicative of the need to continue the search for analogs. 5. Lipid-lowering activity of T3 and its analogs We have previously published an in-depth review of the actions of thyroid hormone analogs on hypercholesterolemia, including an outline of all the previous work done in this area [53]. In brief, the fact that thyroid hormone can lower the total serum cholesterol through an accelerated LDL-cholesterol clearance rate has been known for years [72–74]. The mechanism is thought to be related to the fact that T3 increases levels of the hepatic LDL receptor and its mRNA [75,76], as well as increasing the activity of lipoprotein lipase [77]. In the 1950s, attempts were made to prevent/treat coronary artery disease with large doses of desiccated thyroid, but because of side effects these studies were discontinued [78,79]. The complications seen with cholesterollowering dosages of thyroid hormone led to a search for analogs that were equally effective in lowering cholesterol but were less calorigenic. Most of these analogs reduced the serum cholesterol without elevating metabolic rate. An attempt to address the question of whether a thyroid analog could prevent coronary heart disease was made in The Coronary Drug Project [80]. The analog used was dextro-thyroxine (D-T4), the racemate of levo-thyroxine (L-T4), which was expected to have less calorigenic potential than L-T4. The D-T4 arm was discontinued because of a higher proportion of death. These findings were used as the reason not to use thyroid hormone and its analogs in patients with coronary artery disease. What was not appreciated until much later was the fact that the D-T4 may have been contaminated with as much as 0.5% L-T4 (equivalent to 30 μg/day), which may have been its only active component producing the adverse events [81]. The interest in using thyroid hormone analogs to treat hypercholesterolemia has increased because of the development of analogs that either have selective effects on liver versus heart or bind selectively to TRβ1 [53]. Although a complete review of all T3 analogs is beyond the scope of this review, a possible approach is to capitalize on the fact that thyroid hormone actions on the heart are mainly mediated through TRα1, a selective TRβ1 agonist, and in principle, might mediate lipid-lowering actions of the hormone without unwanted cardiac side effects [82]. Patient populations that could potentially benefit from such an agent are those patients who have side effects to statins (such as myalgias) and those individuals who still have aggressive progression of their coronary disease despite being on statins. Some of the older analogs have modest selectivity for binding to TRb1. For example, Triac has an affinity for TRβ1 that is two- or three-times greater than T3 [83]. An example of later work is the selective analog, 3,5-dichloro-4[(4-hydroxy-3-isopropylphenoxy) phenyl] acetic acid (KB-141), that binds with 14 times greater affinity to TRβ1 than TRα1 and has been reported to have a 10-fold difference between doses producing heart rate increase and doses with cholesterol-lowering activity [84,85]. Another potential beneficial effect of thyroid hormone and its analogs is the ability to increase
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plasma levels of apolipoprotein A-1, which is the predominant lipoprotein in HDL cholesterol [86]. The interest in developing T3 analogs as an adjunctive agent to treat hypercholesterolemia has resulted in recent publications showing that these analogs effectively lower lipid levels in patients on statins. The use of DITPA to treat heart failure resulted in important metabolic alterations such as lowering serum cholesterol, LDL and triglycerides with no change in HDL [71,87]. The other important metabolic effect of DITPA was a significant reduction in body weight. Another analog, KB2115 (or eprotirome) was also shown to reduce serum cholesterol in patients already receiving a statin [88]. 6. Conclusions Thyroid hormone has significant cardiovascular effects, and based on previous studies, low thyroid hormone levels are a strong predictor of death in cardiac patients. Limited data currently available indicates thyroid replacement therapy could improve clinical outcomes, although there are no large randomized trials showing improved outcomes. There are hemodynamic improvements with thyroid analog therapy, but the only large-scale multicenter trial showed that the analog DITPA was poorly tolerated at the doses chosen. There is current enthusiasm to develop thyroid hormone analogs to treat hypercholesterolemia. The future of thyroid hormone therapy for the cardiovascular system involves further development of tissue-specific thyroid analogs, possible gene therapy, and possible alterations in thyroid hormone signaling pathways. Disclosures US Patent No: 6,534,676 B2 UA #03-075 Method to treat chronic heart failure and/or elevated cholesterol with thyroid analog (DITPA) issued 3/18/03. AU Patent No: 2002243801 Method to Treat Chronic Heart Failure and/or Elevated Cholesterol Levels using 3,5-Diiodothyropropionic Acid and Method to Prepare Same. US Patent No: 7,504,435. Method for Stimulating Weight Loss and/ or for Lowering Triglycerides in Patients issued 3/17/09, expiration date 4/13/2025. Acknowledgments This review is dedicated to our friend and colleague, Eugene Morkin, MD who passed away in 2009. Without his insight and stimulation, much of this work would not have been done. This work is supported in part by grants from the Department of Veterans Affairs, Cooperative Studies Program and Merit Review Program. References [1] Rosamond W, Flegal K, Friday G, Furie K, Go A, Greenlund K, et al. American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007;115:e69–e171. [2] Roger VL, Weston SA, Redfield MM, Hellermann-Homan JP, Killian J, Yawn BP, et al. Trends in heart failure incidence and survival in a community-based population. J Am Med Assoc 2004;292:344–50. [3] Klein I, Danzi S. Thyroid disease and the heart. Circulation 2007;9(116):1725–35. [4] Brent GA, Moore DD, Larsen PR. Thyroid hormone regulation of gene expression. Annu Rev Physiol 1991;53:17–35. [5] Lazar MA. Thyroid hormone receptors: multiple forms, multiple possibilities. Endocr Rev 1993;14:184–93. [6] Gloss B, Trost S, Bluhm W, Swanson E, Clark R, Winkfein R, et al. Cardiac ion channel expression and contractile function in mice with deletion of thyroid hormone receptor alpha or beta. Endocrinology 2001;142:544–50. [7] Lazar MA, Chin WW. Nuclear thyroid hormone receptors. J Clin Invest 1990;86: 1777–82. [8] Wu Y, Koenig RJ. Gene regulation by thyroid hormone. Trends Endocrinol Metab 2000;11:207–11.
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Sick euthyroid syndrome in patients with moderate-to-severe chronic heart failure. Eur Heart J 1996;17:1860–6. [55] Iervasi G, Pingitore A, Landi P, Raciti M, Ripoli A, Scarlattini M, et al. Low-T3 syndrome: a strong prognostic predictor of death in patients with heart disease. Circulation 2003;107:708–13. [56] Passino C, Pingitore A, Landi P, Fontana M, Zyw L, Clerico A, et al. Prognostic value of combined measurement of brain natriuretic peptide and triiodothyronine in heart failure. J Card Fail 2009;15:35–40. [57] Pingitore A, Landi P, Taddei MC, Ripoli A, L'Abbate A, Iervasi G. Triiodothyronine levels for risk stratification of patients with chronic heart failure. Am J Med 2005;118:132–6. [58] Hamilton MA, Stevenson LW, Luu M, Walden JA. Altered thyroid hormone metabolism in advanced heart failure. J Am Coll Cardiol 1990;16:91–5. [59] Iervasi G, Molinaro S, Landi P, Taddei MC, Galli E, Mariani F, et al. Association between increased mortality and mild thyroid dysfunction in cardiac patients. Arch Intern Med 2007;167:1526–32. [60] Hamilton MA, Stevenson LW, Fonarow GC, Steimle A, Goldhaber JI, et al. Safety and hemodynamic effects of intravenous triiodothyronine in advanced congestive heart failure. Am J Cardiol 1998;81:443–7. [61] Moruzzi P, Doria E, Agostoni PG, Capacchione V, Sganzerla P. Usefulness of L-thyroxine to improve cardiac and exercise performance in idiopathic dilated cardiomyopathy. Am J Cardiol 1994;73:374–8. [62] Novitzky D, Fontanet H, Snyder M, Coblio N, Smith D, Parsonnet V. Impact of triiodothyronine on the survival of high-risk patients undergoing open heart surgery. Cardiology 1996;87:509–15. [63] Escobar-Morreale HF, del Rey FE, Obregón MJ, de Escobar GM. Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat. Endocrinology 1996;137:2490–502. 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Ventricular performance and remodeling in rabbits after myocardial infarction: effects of a thyroid hormone analogue. Circulation 1995;91:794–802. [69] Wang X, Zheng W, Christensen LP, Tomanek RJ. DITPA stimulates bFGF, VEGF, angiopoietin, and Tie-2 and facilitates coronary arteriolar growth. Am J Physiol Heart Circ Physiol 2003;284:H613–8. [70] Morkin E, Pennock G, Spooner PH, Bahl JJ. Underhill Fox K, Goldman S. Pilot studies on the use of 3, 5-diiodothyropropionic acid, a thyroid hormone analog, in the treatment of congestive heart failure. Cardiology 2002;97:218–25. [71] Goldman S, McCarren M, Morkin E, Ladenson PW, Edson R, Warren S, et al. DITPA (3, 5-Diiodothyropropionic Acid), a thyroid hormone analog to treat heart failure: phase II trial veterans affairs cooperative study. Circulation 2009;119:3039–100. [72] Walton KW, Campbell DA, Tonks EL. The significance of alterations in serum lipids in thyroid dysfunction. I. 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Contents lists available at ScienceDirect
Journal of Molecular and Cellular Cardiology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / y j m c c
Review article
Translational potential of thyroid hormone and its analogs Reza Arsanjani a,b, Madeline McCarren c, Joseph J. Bahl a,b, Steven Goldman a,b,⁎ a b c
Southern Arizona VA Health Care System, Section of Cardiology, Department of Medicine, 1-111C, 3601 S. 6th Avenue, Tucson, AZ 85723, USA Sarver Heart Center, University of Arizona, 1501 N. Campbell Avenue, Tucson, AZ 85724, USA Hines VA, Pharmacy Benefits Management, 5000 S. 5th Avenue, M/S 119D, Hines IL 60141, USA
a r t i c l e
i n f o
Article history: Received 3 September 2010 Received in revised form 4 November 2010 Accepted 21 December 2010 Available online 5 January 2011 Keywords: Thyroid hormone Thyroid hormone analogs Heart failure Hypercholesterolemia Review
a b s t r a c t Thyroid hormone has unique properties affecting the heart, and the vasculature and cholesterol metabolism. There is interest in using thyromimetic agents as possible treatment options for heart failure based on data demonstrating the ability of these agents to improve systolic and diastolic left ventricular function as well as their vasodilatory action. The inverse relationship between heart failure severity and serum triiodothyronine (T3) levels has also been interpreted by some as an indication that thyroid hormone therapy might be useful. In the 1950s, investigators began developing thyroid hormone analogs that could lower cholesterol, that selectively bind to β1-type nuclear thyroid hormone receptors (TR), which are responsible for cholesterol-lowering activity, without activating α1-type receptors in the heart. The identification of 3,5-diiodothyropropionic acid (DITPA) that binds to both α- and β-type TRs with relatively low affinity was unique in that this analog improves left ventricular function in heart failure as well as lowers cholesterol. The aim of this review is to summarize information known about the interactions between thyroid hormones and the cardiovascular system, and the potential therapeutic effects of thyroid analogs in chronic heart disease. This article is part of a special issue entitled “Key Signaling Molecules in Hypertrophy and Heart Failure.” Published by Elsevier Ltd.
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mechanisms of thyroid hormone actions on the cardiovascular system. 2.1. Nuclear receptors . . . . . . . . . . . . . . . . . . . . . . 2.2. Intracellular calcium and potassium . . . . . . . . . . . . . . 2.3. Contractile proteins . . . . . . . . . . . . . . . . . . . . . 2.4. Catecholamines . . . . . . . . . . . . . . . . . . . . . . . 2.5. Alterations in cardiovascular function . . . . . . . . . . . . . 2.6. Lipid metabolism . . . . . . . . . . . . . . . . . . . . . . 3. Studies of thyromimetic agents for heart failure . . . . . . . . . . . 4. Development of thyroid hormone analog DITPA to treat heart failure . . . 5. Lipid-lowering activity of T3 and its analogs . . . . . . . . . . . . . 6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . Disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction More than 5 million Americans have heart failure with an estimated 550,000 new cases occurring each year, making it the leading cause of hospitalization in the United States [1]. Significant ⁎ Corresponding author. Sarver Heart Center, University of Arizona, 1501 N. Campbell Avenue, Tucson, AZ 85724, USA. Tel.: +1 520 792 1450x5081; fax: +1 520 629 4636. E-mail address: [email protected] (S. Goldman). 0022-2828/$ – see front matter. Published by Elsevier Ltd. doi:10.1016/j.yjmcc.2010.12.012
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strides have been made in understanding the pathophysiology of acute and chronic heart failure, but despite these advances and improved overall survival of heart failure patients [2], the condition remains a leading cause of morbidity and mortality, especially with a progressively aging population. Therefore, identification of novel therapeutic approaches for heart failure remains very important. Interest in thyromimetic agents as a possible treatment option stems from previous studies demonstrating the ability of these agents to improve both systolic and diastolic left ventricular function as well as
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hormone regulation of cardiac growth via the TRα1 receptor that define cardiomyocyte phenotype alterations that ultimately could change cardiac function. Understanding these mechanisms allows investigators to explore cellular targets for developing unique thyroid hormone analogs. 2.2. Intracellular calcium and potassium
Fig. 1. Schematic representation of binding of TR to the basic hexameric consensus sequence AGGT/ACA separated by a 4 bp spacer in a T3-sensitive gene. The TR is shown binding as a heterodimer with RXR, the 9-cis retinoic acid receptor, with an orientation such that the TR occupies the 3′ half site. TR and RXR have multiple transcription coactivators and corepressors (Morkin et al. JMCC 2004;37:1137-46).
their vasodilatory action. The inverse relationship between heart failure severity and serum triiodothyronine (T3) levels has also been interpreted by some as an indication that thyroid hormone therapy might be useful [3]. The aim of this review is to summarize information known about the interactions between thyroid hormones and the cardiovascular system, and the potential therapeutic effects of thyroid analogs in chronic heart disease. 2. Mechanisms of thyroid hormone actions on the cardiovascular system 2.1. Nuclear receptors Thyroid hormone exerts its effects on the cellular level by binding to thyroid hormone nuclear receptors which in turn bind to the regulatory region of genes (thyroid hormone response elements) and modify their expression (Fig. 1) [4]. Two separate genes code for four separate thyroid hormone receptor (TR) isoforms, TRα1, TRα2, TRβ1 and TRβ2 [5]. TRα1 is the principal isoform in the heart, accounting for 70% of cardiac TR mRNA [6]. Thyroid hormone binds to TR resulting in induction of several genes by binding to thyroid hormone receptor elements (TRE), as homodimers or heterodimers [7]. Active transcriptions ensue, and large quantities of mRNA are produced which are then translated in specific proteins. Other genes are negatively regulated by T3 and are induced in the absence of T3 [8]. Cardiac genes positively regulated by thyroid hormones include those coding for sarcoplasmic reticulum calcium adenosine triphosphatase (ATPase), α-myosin heavy chain, β1-adrenergic receptors, sodium/ potassium, voltage-gated potassium channels, and atrial natriuretic hormone [3,9]. Cardiac enzymes negatively regulated by thyroid hormones include β-myosin heavy chains, phospholamban, sodium/ calcium exchanger, TR α1, and adenylyl cyclase types V and VI [3,9]. The mechanism of thyroid hormone and TR regulation of protein synthesis and cardiac hypertrophy via the TRα1 receptor has been extensively studied in isolated cardiomyocytes by Kenessay and Ojamaa [10–12]. Initially these investigators examined transcription of T3 responsive genes and found T3 induced proteosome-mediated degradation of TRα1 [11]. They also showed T3 mediated increases in protein synthesis through activation of phosphatidylinositol 3-kinase (PI3K) and the Akt-mTOR-S6K signaling pathway. Using transduced rat ventricular myocytes, these same investigators showed that PKCα was a regulator of TR function suggesting that nuclear localization of PKCα may control transcription of the TRα gene [11]. Taken together as a body of work, these data explore the mechanisms of thyroid
Thyroid hormone affects systolic contractile function and diastolic relaxation by influencing the rate of release and reuptake of calcium into the sarcoplasmic reticulum [13]. Thyroid hormone induces expression of the sarcoplasmic reticulum calcium ATPase gene (SERCa2) resulting in an increased calcium release from sarcoplasmic reticulum and accounting for an increased contractile activity [14,15]. Phospholamban is a membrane protein regulated by thyroid hormone that decreases the rate of muscle relaxation and contractility by inhibiting the sarcoplasmic reticulum calcium pump, thereby decreasing heart rate and stroke volume, respectively [15]. Phosphorylation of phospholamban leads to a loss of its ability to inhibit the sarcoplasmic reticulum calcium pump. Phospholamban expression and its level of phosphorylation, as well as upregulation of SERCa2, may account for an increased systolic contractile function and a decreased diastolic relaxation time noted in patients with hyperthyroidism. In addition, thyroid hormone negatively regulates sodium/ calcium exchanger and upregulates sodium/potassium ATPase and voltage-gated potassium channels. The resulting changes in intracellular calcium and potassium lead to increased inotropy and heart rate [16]. Recent work shows that SERCAa2 levels are induced by T3 interacting with TRβ1 and not with TRα1 [17]. The TRα1 binds to the highly conserved consensus sequence of the phospholamban promoter leading to decreases in histone acetylation and lysine 4 methylation, and two modifications of phospholamban DNA that would normally be associated with increased gene expression and by being removed are associated with a mechanism responsible for gene silencing [17]. 2.3. Contractile proteins Thyroid hormone also influences the systolic contractile function by altering cardiac contractile proteins. Myosins are a large family of motor proteins responsible for actin-based motility, with the myosin heavy chains (MHC) functioning as the molecular motor for driving muscle contractions. Each hexameric myosin molecule is composed of two MHC and four myosin light chains [18]. Cardiomyocytes express two MHC isoforms, α and β, each exhibiting different ATPase activity. Three separate myosin isoforms have been isolated from mammal hearts, V1–V3 [18], each differing from each other only in their MHC composition. V1 has the highest ATPase activity and is composed of two α-MHC, V2 has one α-MHC and one β-MHC, while V3 has the lowest ATPase activity and is composed of two β-MHC [18]. T3 stimulates transcription of the α-MHC gene and inhibits β-MHC mRNA production in vivo and in cultured heart cells, although the responsiveness of the gene to T3 varies among different mammals [18]. These changes in MHC isoforms are correlated with alterations in myosin ATPase activity and actinomycin cross bridge cycle rate and consequently increase in the speed of muscle contraction [19,20]. In addition, thyroid hormone also increases the levels of actin thin filament and troponin-I isoforms [21]. 2.4. Catecholamines Tachycardia and increased contractility noted in the hyperthyroid state is similar to the effect seen by sympathomimetic agents. In addition, sympatholytic agent administration is associated with clinical amelioration of symptoms of hyperthyroidism [9,22], leading to the hypothesis that some of the effects of thyroid hormone seen are
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due to an increased catecholamine state or an increased responsiveness to catecholamine stimulation. However, plasma and urine levels of catecholamines are normal in the hyperthyroid state [23], leading to the hypothesis that an elevated thyroid state leads to increased responsiveness to catecholamine stimulation. Cardiac tissues contain both β1 and β2-adrenergic receptors; with β1 accounting for 70% of all β-adenoreceptors, as well as accounting for the majority of β-adenoreceptors in the sinoatrial node [24]. Several studies have demonstrated, in response to thyroid hormone, an increased number of β-adrenergic receptors and increased sensitivity to sympathomimetic stimulation [25,26], with β-1 adenoreceptor mRNA increasing significantly [27]. Thyroid hormone transcriptionally regulates the pacemaker-related genes and hyperpolarization-activated cyclic nucleotide-gated channels 2 and 4 [28], as well as controlling other components of β-adrenergic system such as guanine nucleotide regulatory proteins and adenylate cyclase [25]. These changes lead to increased heart rate and improved diastolic performance. 2.5. Alterations in cardiovascular function The effects of thyroid hormone on the heart are well known and will not be reviewed here but appropriate references are provided that specifically address thyroid hormone induced changes that potentially could affect the use of thyroid hormone analogs to treat cardiovascular disease such as changes in vascular tone, blood volume and the induction of cardiac arrhythmias [29–49]. An in depth review of cardiac hypertrophy and thyroid hormone signaling has recently been published [50]. 2.6. Lipid metabolism Hypothyroidism obviously has effects on lipid metabolism resulting in elevations of serum total and low-density-lipoprotein (LDL) cholesterol concentrations and apolipoprotein B that are reversible with thyroid replacement therapy [51,52]. This reversal of lipid levels with thyroid hormone administration has been the stimulus to develop analogs of thyroid hormone to treat hypercholesterolemia. One interesting clinical point is that post-menopausal women with thyroid levels at the low end of normal were at high risk for increased mortality because of cardiovascular disease, presumably due to high triglyceride and cholesterol levels without estrogen to counteract the risk. This suggests that it may be time to revise the range of “normal” for thyroid hormone, with respect to the lower end of the normal range [53], similar to the change in thinking about cholesterol levels (as risk became associated with the higher end of that “normal” range). The development of thyroid hormone analogs to treat hypercholesterolemia is discussed later in this review. 3. Studies of thyromimetic agents for heart failure A low T3 state is common, occurring in up to a third of patients with dilated cardiomyopathy [54]. As previously mentioned, studies have shown that the decline in serum T3 is proportional to the severity of heart failure, based on the New York Heart Association functional classification [3]. Studies have shown that low-T3 syndrome is a strong predictor of death in cardiac patients and might be directly implicated in the poor prognosis of cardiac patients [55]. Patients with ischemic and non-ischemic heart failure had total T3, brain natriuretic peptide, and ejection fraction that were each independent predictors of cardiac and total death [56]. Reduction in T3 appears to represent a continuum and likely represents a marker of progressive cardiac dysfunction seen in patients with heart failure [57,58]. In addition, subclinical hypothyroidism, defined as a belownormal thyroid stimulating hormone in association with a normal total and free T4 and T3, has been associated with increased mortality in patients with ischemic and non-ischemic heart disease [59].
Therefore, restoration of thyroid hormone to normal levels should, in theory, reverse the negative effects of altered thyroid metabolism. Investigators studied the safety and efficacy of administering single intravenous dose of T3 to patients with advanced heart failure. Treatment with T3 resulted in an increase in cardiac output and a decrease in systemic vascular resistance two hours after administration, without any evidence of myocardial ischemia, arrhythmias, or other significant side effects [60]. Oral daily levothyroxine to patients with chronic heart failure for 12 weeks resulted in improved exercise tolerance, increased cardiac index, and decreased systemic vascular resistance [61]. T3 was previously found to reduce surgical death in patients at high risk of death during open heart surgery [62]. Although the above studies show that thyroid replacement therapy may be beneficial for treatment of heart failure, there are no randomized trials comparing T4 versus T3. However, studies have shown that constant infusion of T4 was unable to normalize T3 levels in tissue, including in myocardium [63], which may be related to the impaired peripheral conversion of T4 to T3. In addition, high dose thyroid infusion over prolonged periods results in detrimental effects following an initial improvement in cardiac performance [64]. Furthermore, the beneficial effects of thyroid hormone in heart disease need to be balanced against the differential organ response to systemic thyroid hormone therapy. Lastly, doses need to be adjusted to keep T3 levels constant and within physiological range, which is currently not possible with pills. 4. Development of thyroid hormone analog DITPA to treat heart failure Based on the limitations of using the native thyroid hormone to treat heart failure, there has been enthusiasm for the development of thyroid hormone analogs which are organ-selective without the undesirable side effects. In developing thyroid hormone analogs to treat heart failure, our laboratory initially screened a series of analogs by defining their abilities to induce increases in mRNA for alpha MHC in neonatal cardiomyocytes in culture [65]. Based on this information we focused on separating the inotropic and chronotropic effects of potential candidate analogs by defining dose response data for heart rate versus LV dP/dt. Our idea was to find an analog that would provide the largest increase in LV dP/dt for the smallest increase in heart rate [66]. Ultimately, as a precursor to performing a clinical trial, we examined potential analogs in animal models of heart failure including the rat and rabbit coronary artery ligation models [67,68]. Doing the work in live animals helped us understand the integrated effects of the analogs on the heart and the peripheral circulation, something that would need to be addressed clinically and could not be evaluated in-vitro [49]. At this point in time, we had to decide between pursuing clinical studies or more animal studies such as a mortality study in rats. We decided to initiate the clinical work because no matter what the animal data showed, we would have to pursue this in patients. For our clinical studies we selected 3,5-diiodothyropropionic acid (DITPA), a thyroid analog of T2 with weak T3 activity that improves LV function without increasing the heart rate in animal models of heart failure [66–68]. This analog, DITPA, also stimulates coronary vascular growth [69], which might further lead to a decline in systemic vascular resistance. In a pilot clinical study, DITPA was dosed at 180 mg/day for two weeks, followed by 360 mg/day for two additional weeks. This regimen of DITPA was well tolerated in patients with NYHA functional class II–III heart failure, with significant improvement in cardiac function as well as reduction in systemic vascular resistance [70]. Treatment with DITPA resulted in the reduction of total serum cholesterol and triglycerides [70]. In a follow-up larger multicenter Phase II randomized controlled trial supported by the Department of Veterans Affairs Cooperative Studies Program, treatment was planned for six months, titrating to a dose
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that would just suppress TSH to below 0.02 mU/L, or a maximum of 360 mg/day. The choice of dosing regimen was based on the concept of using the maximum tolerated dose to provide the best opportunity to detect a beneficial effect; the available funds did not permit a doseranging study. Unfortunately, with longer use and a larger sample size, it became clear that this regimen exceeded the maximum tolerated. There were a variety of non-specific adverse effects sufficient to prompt a reduction or cessation of therapy. Further complicating interpretation was our inclusion of a patient-reported global assessment of well-being that was not specific for heart failure symptoms in our primary composite outcome. It is not surprising, in retrospect, that the primary outcome did not indicate global patient benefit with DITPA even though DITPA improved some hemodynamic and metabolic parameters [71]. A trial with a much more modest dose (perhaps 90 mg/day) would be of great interest, although the narrow therapeutic window is also indicative of the need to continue the search for analogs. 5. Lipid-lowering activity of T3 and its analogs We have previously published an in-depth review of the actions of thyroid hormone analogs on hypercholesterolemia, including an outline of all the previous work done in this area [53]. In brief, the fact that thyroid hormone can lower the total serum cholesterol through an accelerated LDL-cholesterol clearance rate has been known for years [72–74]. The mechanism is thought to be related to the fact that T3 increases levels of the hepatic LDL receptor and its mRNA [75,76], as well as increasing the activity of lipoprotein lipase [77]. In the 1950s, attempts were made to prevent/treat coronary artery disease with large doses of desiccated thyroid, but because of side effects these studies were discontinued [78,79]. The complications seen with cholesterollowering dosages of thyroid hormone led to a search for analogs that were equally effective in lowering cholesterol but were less calorigenic. Most of these analogs reduced the serum cholesterol without elevating metabolic rate. An attempt to address the question of whether a thyroid analog could prevent coronary heart disease was made in The Coronary Drug Project [80]. The analog used was dextro-thyroxine (D-T4), the racemate of levo-thyroxine (L-T4), which was expected to have less calorigenic potential than L-T4. The D-T4 arm was discontinued because of a higher proportion of death. These findings were used as the reason not to use thyroid hormone and its analogs in patients with coronary artery disease. What was not appreciated until much later was the fact that the D-T4 may have been contaminated with as much as 0.5% L-T4 (equivalent to 30 μg/day), which may have been its only active component producing the adverse events [81]. The interest in using thyroid hormone analogs to treat hypercholesterolemia has increased because of the development of analogs that either have selective effects on liver versus heart or bind selectively to TRβ1 [53]. Although a complete review of all T3 analogs is beyond the scope of this review, a possible approach is to capitalize on the fact that thyroid hormone actions on the heart are mainly mediated through TRα1, a selective TRβ1 agonist, and in principle, might mediate lipid-lowering actions of the hormone without unwanted cardiac side effects [82]. Patient populations that could potentially benefit from such an agent are those patients who have side effects to statins (such as myalgias) and those individuals who still have aggressive progression of their coronary disease despite being on statins. Some of the older analogs have modest selectivity for binding to TRb1. For example, Triac has an affinity for TRβ1 that is two- or three-times greater than T3 [83]. An example of later work is the selective analog, 3,5-dichloro-4[(4-hydroxy-3-isopropylphenoxy) phenyl] acetic acid (KB-141), that binds with 14 times greater affinity to TRβ1 than TRα1 and has been reported to have a 10-fold difference between doses producing heart rate increase and doses with cholesterol-lowering activity [84,85]. Another potential beneficial effect of thyroid hormone and its analogs is the ability to increase
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plasma levels of apolipoprotein A-1, which is the predominant lipoprotein in HDL cholesterol [86]. The interest in developing T3 analogs as an adjunctive agent to treat hypercholesterolemia has resulted in recent publications showing that these analogs effectively lower lipid levels in patients on statins. The use of DITPA to treat heart failure resulted in important metabolic alterations such as lowering serum cholesterol, LDL and triglycerides with no change in HDL [71,87]. The other important metabolic effect of DITPA was a significant reduction in body weight. Another analog, KB2115 (or eprotirome) was also shown to reduce serum cholesterol in patients already receiving a statin [88]. 6. Conclusions Thyroid hormone has significant cardiovascular effects, and based on previous studies, low thyroid hormone levels are a strong predictor of death in cardiac patients. Limited data currently available indicates thyroid replacement therapy could improve clinical outcomes, although there are no large randomized trials showing improved outcomes. There are hemodynamic improvements with thyroid analog therapy, but the only large-scale multicenter trial showed that the analog DITPA was poorly tolerated at the doses chosen. There is current enthusiasm to develop thyroid hormone analogs to treat hypercholesterolemia. The future of thyroid hormone therapy for the cardiovascular system involves further development of tissue-specific thyroid analogs, possible gene therapy, and possible alterations in thyroid hormone signaling pathways. Disclosures US Patent No: 6,534,676 B2 UA #03-075 Method to treat chronic heart failure and/or elevated cholesterol with thyroid analog (DITPA) issued 3/18/03. AU Patent No: 2002243801 Method to Treat Chronic Heart Failure and/or Elevated Cholesterol Levels using 3,5-Diiodothyropropionic Acid and Method to Prepare Same. US Patent No: 7,504,435. Method for Stimulating Weight Loss and/ or for Lowering Triglycerides in Patients issued 3/17/09, expiration date 4/13/2025. Acknowledgments This review is dedicated to our friend and colleague, Eugene Morkin, MD who passed away in 2009. Without his insight and stimulation, much of this work would not have been done. This work is supported in part by grants from the Department of Veterans Affairs, Cooperative Studies Program and Merit Review Program. References [1] Rosamond W, Flegal K, Friday G, Furie K, Go A, Greenlund K, et al. American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007;115:e69–e171. [2] Roger VL, Weston SA, Redfield MM, Hellermann-Homan JP, Killian J, Yawn BP, et al. Trends in heart failure incidence and survival in a community-based population. J Am Med Assoc 2004;292:344–50. [3] Klein I, Danzi S. Thyroid disease and the heart. Circulation 2007;9(116):1725–35. [4] Brent GA, Moore DD, Larsen PR. Thyroid hormone regulation of gene expression. Annu Rev Physiol 1991;53:17–35. [5] Lazar MA. Thyroid hormone receptors: multiple forms, multiple possibilities. Endocr Rev 1993;14:184–93. [6] Gloss B, Trost S, Bluhm W, Swanson E, Clark R, Winkfein R, et al. Cardiac ion channel expression and contractile function in mice with deletion of thyroid hormone receptor alpha or beta. Endocrinology 2001;142:544–50. [7] Lazar MA, Chin WW. Nuclear thyroid hormone receptors. J Clin Invest 1990;86: 1777–82. [8] Wu Y, Koenig RJ. Gene regulation by thyroid hormone. Trends Endocrinol Metab 2000;11:207–11.
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