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Thyroid Hormone and Cardioprotection

Anthony Martin Gerdes, Kaie Ojamaa

10.1002/cphy.c150012

Source: Volume 6, Issue 3, July 2016

Published online: June 2016

Full Article on Wiley Online Library



ABSTRACT

The heart is a major target of thyroid hormones, with maintenance of euthyroid hormone balance critical for proper function. In particular, chronic low thyroid function can eventually lead to dilated heart failure with impaired coronary blood flow. New evidence also suggests that heart diseases trigger a reduction in cardiac tissue thyroid hormone levels, a condition that may not be detectible using serum hormone assays. Many animal and clinical studies have demonstrated a high prevalence of low thyroid function in heart diseases with worse outcomes from this condition. Animal and human studies have also demonstrated many benefits from thyroid hormone treatment of heart diseases, particularly heart failure. Nonetheless, this potential treatment has not yet translated to patients due to a number of important concerns. The most serious concern involves the potential of accidental overdose leading to increased arrhythmias and sudden death. Several important clinical studies, which actually used excessive doses of thyroid hormone analogs, have played a major role in convincing the medical community that thyroid hormones are simply too dangerous to be considered for treatment in cardiac patients. Nonetheless, this issue has not gone away due primarily to overwhelmingly positive evidence for treatment benefits and a new understanding of the cellular and molecular mechanisms underlying those benefits. This review will first discuss the clinical evidence for the use of thyroid hormones as a cardioprotective agent and then provide an overview of the cellular and molecular mechanisms underlying beneficial changes from thyroid hormone treatment of heart diseases. © 2016 American Physiological Society. Compr Physiol 6:1199‐1219, 2016.

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Figure 1. Figure 1. Summary of cardioprotective effects of thyroid hormones. Rajagopalan V, Gerdes AM. Role of thyroid hormones in ventricular remodeling. Curr Heart Fail Rep 12: 141‐149, 2015. With permission from Springer.
Figure 2. Figure 2. Actions of TH initiated at sites at the plasma membrane or cytosol and within the nucleus of myocytes, vascular smooth muscle, or endothelial cells or fibroblasts. Intracellular signaling cascades are activated by T3 or T4 binding to integrins or TRs localized to lipid‐enriched membrane microdomains or unknown intracellular sites. T3‐regulated genes are indicated showing effects that enhance cardiomyocyte contractility and calcium transients, decreased fibrosis, increased fuel efficiency, and mitochondrial biogenesis. Non‐nuclear responses of T3 result in activation of survival pathways, physiologic hypertrophy, decreased oxidative stress, and changes in plasma membrane ion currents.
Figure 3. Figure 3. Schematic representation of TR isoforms and their functional properties. Two genes encoding TR isoforms, THRA and THRB. The highly homologous DNA‐binding domains, TH‐binding domains, and activation domains are indicated. Numbers indicate amino acid position. M indicates methionine for translation initiation. tts is transcriptional start site. Regions of variable amino acid sequences are indicated by different patterned areas. NLS is nuclear localization signal. Reported molecular weights of proteins, DNA‐ and T3‐binding properties and transactivation (+) or repression (−) indicated.


Figure 1. Summary of cardioprotective effects of thyroid hormones. Rajagopalan V, Gerdes AM. Role of thyroid hormones in ventricular remodeling. Curr Heart Fail Rep 12: 141‐149, 2015. With permission from Springer.


Figure 2. Actions of TH initiated at sites at the plasma membrane or cytosol and within the nucleus of myocytes, vascular smooth muscle, or endothelial cells or fibroblasts. Intracellular signaling cascades are activated by T3 or T4 binding to integrins or TRs localized to lipid‐enriched membrane microdomains or unknown intracellular sites. T3‐regulated genes are indicated showing effects that enhance cardiomyocyte contractility and calcium transients, decreased fibrosis, increased fuel efficiency, and mitochondrial biogenesis. Non‐nuclear responses of T3 result in activation of survival pathways, physiologic hypertrophy, decreased oxidative stress, and changes in plasma membrane ion currents.


Figure 3. Schematic representation of TR isoforms and their functional properties. Two genes encoding TR isoforms, THRA and THRB. The highly homologous DNA‐binding domains, TH‐binding domains, and activation domains are indicated. Numbers indicate amino acid position. M indicates methionine for translation initiation. tts is transcriptional start site. Regions of variable amino acid sequences are indicated by different patterned areas. NLS is nuclear localization signal. Reported molecular weights of proteins, DNA‐ and T3‐binding properties and transactivation (+) or repression (−) indicated.
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Article Title: Thyroid Hormone and Cardioprotection
 

How to Cite

Anthony Martin Gerdes, Kaie Ojamaa. Thyroid Hormone and Cardioprotection. Compr Physiol 2016, 6: 1199-1219. doi: 10.1002/cphy.c150012