Safety and Hemodynamic Effects of Intravenous Triiodothyronine in Advanced Congestive Heart Failure

Hamilton, Michèle A.; Stevenson, Lynne Warner; Fonarow, Gregg C.; Steimle, Anthony; Goldhaber, Joshua I.; Child, John S.; Chopra, Inder J.; Moriguchi, J.; Hage, A.

doi:10.1016/s0002-9149(97)00950-8

Cited by 197 publications

(123 citation statements)

References 22 publications

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“…Additionally, abnormal TH signaling͞metabolism is reported in both heart disease and after cardiopulmonary bypass surgery (5, 7). Thus, TH therapy has been advocated for treating cardiac disease (12,13), although clear benefit has been difficult to demonstrate, particularly with chronic use, possibly because of adverse extracardiac effects of TH (5,27). The response of our D2-overexpressing mice to AB supports the conclusion that cardiac-restricted T3 production by D2 protects against deterioration of heart function induced by pressure overload.…”

Section: Effects Of D2 Expression On Cardiac Function and Ca 2؉ Cyclingsupporting

confidence: 57%

Cardiac-specific elevations in thyroid hormone enhance contractility and prevent pressure overload-induced cardiac dysfunction

Trivieri

Oudit

Sah

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Thyroid hormone (TH) is critical for cardiac development and heart function. In heart disease, TH metabolism is abnormal, and many biochemical and functional alterations mirror hypothyroidism. Although TH therapy has been advocated for treating heart disease, a clear benefit of TH has yet to be established, possibly because of peripheral actions of TH. To assess the potential efficacy of TH in treating heart disease, type 2 deiodinase (D2), which converts the prohormone thyroxine to active triiodothyronine (T3), was expressed transiently in mouse hearts by using the tetracycline transactivator system. Increased cardiac D2 activity led to elevated cardiac T3 levels and to enhanced myocardial contractility, accompanied by increased Ca 2؉ transients and sarcoplasmic reticulum (SR) Ca 2؉ uptake. These phenotypic changes were associated with up-regulation of sarco(endo)plasmic reticulum calcium ATPase (SERCA) 2a expression as well as decreased Na ؉ ͞Ca 2؉ exchanger, ␤-myosin heavy chain, and sarcolipin (SLN) expression. In pressure overload, targeted increases in D2 activity could not block hypertrophy but could completely prevent impaired contractility and SR Ca 2؉ cycling as well as altered expression patterns of SERCA2a, SLN, and other markers of pathological hypertrophy. Our results establish that elevated D2 activity in the heart increases T3 levels and enhances cardiac contractile function while preventing deterioration of cardiac function and altered gene expression after pressure overload.calcium ͉ cardiac hypertrophy ͉ sarcoplasmic reticulum ͉ deiodinase ͉ transgenic mice T hyroid hormone (TH) is essential for normal development in vertebrates (1), with TH levels rising postnatally and peaking in the third week of life (2). This surge is critical for fetal-to-adult switch in the cardiac gene program and is responsible for changes in Ca 2ϩ homeostasis, myosin isozyme content [␣-myosin heavy chain (MHC)-to-␤-MHC switch], and action potential profile (3, 4). Intriguingly, the genetic and functional changes associated with heart failure, such as reduced Ca 2ϩ transients and ␣-MHC-to-␤-MHC shifts, which recapitulate the fetal gene program, are also observed in hypothyroidism (5, 6). In addition, TH metabolism and signaling are abnormal in heart failure (5, 7, 8). For example, circulating and cardiac triiodothyronine (T3) levels (i.e., active TH) are reduced in advanced heart disease, after acute myocardial infarction, and in patients with cardiopulmonary bypass. These T3 changes occur in association with decreased peripheral conversion of thyroxine (T4) into T3 (5, 8) and elevated cardiac deiodinase type 3 (D3) activity (9). TH receptor expression is also altered in pathological hypertrophy (10), and myocardial contractility is impaired in mice lacking TH receptors (11). Not surprisingly, TH and its analogue 3,5-diiodothyropropionic acid (DITPA) have been advocated for treating heart failure (12, 13) and for reversing cardiac dysfunction in patients with hypothyroidism (5), although TH use has been limited by car...

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Section: Effects Of D2 Expression On Cardiac Function and Ca 2؉ Cyclingsupporting

confidence: 57%

Cardiac-specific elevations in thyroid hormone enhance contractility and prevent pressure overload-induced cardiac dysfunction

Trivieri

Oudit

Sah

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…Cardiac failure was shown to be associated with both a decline in circulating TH levels (11,17) and altered cardiac TH signaling, as evidenced by changes in myocardial expression of TH nuclear receptor isoforms (15,16). The observation that short-term TH administration improves cardiac performance, both in animal models (2, 23) of cardiac dysfunction and in patients (11,17,22) suffering from cardiac failure, agrees with this notion. At this time, our understanding of the temporal adaptive response to TH supplementation in heart disease is very limited.…”

mentioning

confidence: 64%

Treatment of subclinical hypothyroidism reverses ischemia and prevents myocyte loss and progressive LV dysfunction in hamsters with dilated cardiomyopathy

Khalife

Tang

Kuzman

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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. Treatment of subclinical hypothyroidism reverses ischemia and prevents myocyte loss and progressive LV dysfunction in hamsters with dilated cardiomyopathy. Am J Physiol Heart Circ Physiol 289: H2409 -H2415, 2005. First published July 15, 2005; doi:10.1152/ajpheart.00483.2005.-Growing evidence suggests that thyroid dysfunction may contribute to progression of cardiac disease to heart failure. We investigated the effects of a therapeutic dose of thyroid hormones (TH) on cardiomyopathic (CM) hamsters from 4 to 6 mo of age. CM hamsters had subclinical hypothyroidism (normal thyroxine, elevated TSH). Left ventricular (LV) function was determined by echocardiography and hemodynamics. Whole tissue pathology and isolated myocyte size and number were assessed. TH treatment prevented the decline in heart rate and rate of LV pressure increase and improved LV ejection fraction. The percentage of fibrosis/necrosis in untreated 4-mo-old CM (4CM; 15.5 Ϯ 2.2%) and 6-mo-old CM (6CM; 21.5 Ϯ 2.4%) hamsters was pronounced and was reversed in treated CM (TCM; 11.9 Ϯ 0.9%) hamsters. Total ventricular myocyte number was the same between 4-and 6-mo-old controls but was reduced by 30% in 4CM and 43% in 6CM hamsters. TH treatment completely prevented further loss of myocytes in TCM hamsters. Compared with agematched controls, resting and maximum coronary blood flow was impaired in 4CM and 6CM hamsters. Blood flow was completely normalized by TH treatment. We conclude that TH treatment of CM hamsters with subclinical hypothyroidism normalized impaired coronary blood flow, which prevented the decline in LV function and loss of myocytes. thyroid hormones; remodeling; fibrosis; blood flow THE EFFECTS OF THYROID HORMONES (TH) on the cardiovascular system have been well studied. It is clear that both hypothyroidism and hyperthyroidism can lead to deleterious changes in cardiovascular function. Decreased TH levels have been reported in a variety of nonthyroidal illnesses (18), including congestive heart failure (12) and myocardial infarction (6). The decrease in TH levels also appears to be related to the severity of heart failure (12). This is not a minor point, because low 3,5,3'-triiodothyronine (T 3 ) concentrations are a strong, independent predictive marker of poor prognosis in cardiac patients and might represent a determining factor directly implicated in the evolution and prognosis of these conditions (14). Growing evidence also suggests that subclinical thyroid dysfunction might play an important role in heart failure (10, 21). This is highly relevant from a clinical standpoint because this patient group does not typically receive TH treatment.Development of heart failure is accompanied by a variety of neuroendocrine changes. Cardiac failure was shown to be associated with both a decline in circulating TH levels (11,17) and altered cardiac TH signaling, as evidenced by changes in myocardial expression of TH nuclear receptor isoforms (15,16). The observation that short-term TH administration improves cardiac performance, both in anim...

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“…Furthermore, it provides an explanation for the observed increased mortality in patients with cardiac dysfunction and low circulating TH (30) and for the beneficial effect of TH treatment in heart failure (31,32). It should be noted that low serum T 3 with unchanged T 4 , known as non-thyroidal illness (NTI), occurs during various disease states and particularly in myocardial infarction and heart failure (33).…”

Section: Discussionmentioning

confidence: 99%

Time-dependent changes in the expression of thyroid hormone receptor α1 in the myocardium after acute myocardial infarction: possible implications in cardiac remodelling

et al. 2007

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The present study investigated whether changes in thyroid hormone (TH) signalling can occur after acute myocardial infarction (AMI) with possible physiological consequences on myocardial performance. TH may regulate several genes encoding important structural and regulatory proteins particularly through the TRa1 receptor which is predominant in the myocardium. AMI was induced in rats by ligating the left coronary artery while sham-operated animals served as controls. This resulted in impaired cardiac function in AMI animals after 2 and 13 weeks accompanied by a shift in myosin isoforms expression towards a fetal phenotype in the non-infarcted area. Cardiac hypertrophy was evident in AMI hearts after 13 weeks but not at 2 weeks. This response was associated with a differential pattern of TH changes at 2 and 13 weeks; T 3 and T 4 levels in plasma were not changed at 2 weeks but T 3 was significantly lower and T 4 remained unchanged at 13 weeks. A twofold increase in TRa1 expression was observed after 13 weeks in the non-infarcted area, P!0.05 versus sham operated, while TRa1 expression remained unchanged at 2 weeks. A 2.2-fold decrease in TRb1 expression was found in the non-infarcted area at 13 weeks, P!0.05, while no change in TRb1 expression was seen at 2 weeks. Parallel studies with neonatal cardiomyocytes showed that phenylephrine (PE) administration resulted in 4.5-fold increase in the expression of TRa1 and 1.6-fold decrease in TRb1 expression versus untreated, P!0.05. In conclusion, cardiac dysfunction which occurs at late stages after AMI is associated with increased expression of TRa1 receptor and lower circulating tri-iodothyronine levels. Thus, apo-TRa1 receptor state may prevail contributing to cardiac fetal phenotype. Furthermore, down-regulation of TRb1 also contributes to fetal phenotypic changes. a1-adrenergic signalling is, at least in part, involved in this response. 156 415-424 European Journal of Endocrinology

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Safety and Hemodynamic Effects of Intravenous Triiodothyronine in Advanced Congestive Heart Failure

Cited by 197 publications

References 22 publications

Cardiac-specific elevations in thyroid hormone enhance contractility and prevent pressure overload-induced cardiac dysfunction

Cardiac-specific elevations in thyroid hormone enhance contractility and prevent pressure overload-induced cardiac dysfunction

Treatment of subclinical hypothyroidism reverses ischemia and prevents myocyte loss and progressive LV dysfunction in hamsters with dilated cardiomyopathy

Time-dependent changes in the expression of thyroid hormone receptor α1 in the myocardium after acute myocardial infarction: possible implications in cardiac remodelling

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