Thyroid hormone signalling is altered in response to physical training in patients with end-stage heart failure and mechanical assist devices: potential physiological consequences?

Adamopoulos, S.; Gouziouta, Aggeliki; Mantzouratou, Polixeni; Laoutaris, Ioannis D.; Dritsas, Athanasios; Cokkinos, Dennis V.; Mourouzis, Iordanis; Sfyrakis, Petros; Iervasi, Giorgio; Pantos, Constantinos

doi:10.1093/icvts/ivt294

Cited by 39 publications

(20 citation statements)

References 14 publications

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“…Exercise is successful in reducing REM both in the animal and human, 61 and is beneficial in patients that have undergone left ventricular assist device (LVAD) placement. 62 Another emerging concept is post-MI continuous remote conditioning, which is successful in the animal. 63 Currently three large multicentre clinical trials are ongoing.…”

Section: Novel Drugs and Therapiesmentioning

confidence: 99%

Left Ventricular Remodelling: A Problem in Search of Solutions

Cokkinos

Belogianneas

2016

European Cardiology Review

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Cardiac remodelling (REM) is a generally unfavourable process that leads to left ventricular dilation in response to cardiac injury, predominantly acute myocardial infarction (AMI). REM occurs in around 30 % of anterior infarcts despite timely primary coronary intervention and the use of drugs, i.e. angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs), betablockers, aldosterone inhibitors and statins. In order to diagnose REM, many imaging modalities (echocardiography, cardiac magnetic resonance, scintigraphy) are employed together with an increasing number of serum biomarkers including microRNAs. The most widely used definition of REM is a >20 % increase in left ventricular end-diastolic volume (LVEDV). There is also evidence that regression of REM can occur, i.e. reverse REM. The latter is defined as a ≥10 % decrease in left ventricular end-systolic volume (LVESV) and confers a more favourable outcome. Many therapeutic agents may be used during primary intervention and over the long term; however, few have demonstrated significant benefits. Revascularisation, anti-REM surgery and, where indicated, cardiac resynchronisation therapy can be of benefit. Gene therapy by sarcoplasmic reticulum Ca2+ ATPase 2 (SERCA-2a) transfer has been investigated but data from the Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2) trial were disappointing. Progenitor cell therapy shows promise. In conclusion, therapy for REM remains inadequate.

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Section: Novel Drugs and Therapiesmentioning

confidence: 99%

Left Ventricular Remodelling: A Problem in Search of Solutions

Cokkinos

Belogianneas

2016

European Cardiology Review

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“…This may explain why T 3 is more effective than T 4 (Pantos et al 2009, 2011, Pantos & Mourouzis 2014. Thyroid hormone enhances the activation of Akt signaling, which is essential for mitochondrial function (Mourouzis et al 2012, Adamopoulos et al 2013. Furthermore, thyroid hormone increases basal expression and phosphorylation of heat shock protein-27, conferring protection of the myocardium against ischemia-reperfusion injury (Pantos et al 2003b).…”

Section: Thyroid Hormone Therapy: Potential Mechanismsmentioning

confidence: 99%

Thyroid hormone and the stunned myocardium

Novitzky¹,

Cooper²

2014

Journal of Endocrinology

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Acute critically ill patients experience a rapid decline in plasma free thyroid hormone levels (free triiodothyronine (FT 3 ) and free levothyroxine (FT 4 )), with a marked elevation of reverse T 3 , recognized as the euthyroid sick syndrome (ESS) or low-T 3 syndrome. The ESS is also often associated with depressed myocardial function, sometimes referred to as the 'stunned myocardium'. Its clinical effects may vary from minimal hemodynamic impairment to cardiogenic shock. Medical management may range from aspirin alone to placement of a left ventricular assist device. With adequate supportive therapy, recovery usually occurs within days or weeks. The effect of T 3 /T 4 therapy has been studied in three conditions in which the ESS and myocardial functional depression have been documented -i) transient regional myocardial ischemia and reperfusion, ii) transient global myocardial ischemia in patients undergoing cardiac surgery on cardiopulmonary bypass, and iii) transient inadequate global myocardial perfusion in brain-dead potential organ donors. Under all three conditions, myocardial ischemia leads to rapid loss of high-energy phosphates, accumulation of myocardial tissue lactate, and probably loss of homeostasis of cytosolic calcium, which may further increase cell injury. There is an inability to generate ATP through the Krebs cycle, which reduces the high-energy phosphate pool essential for all cell ATPases. Under all three conditions, following administration of T 3 /T 4 , the myocardial dysfunction was rapidly reversed. We, therefore, cautiously advocate the use of thyroid hormonal therapy to any patient with the ESS and/or a stunned myocardium.

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“…TH induces molecular changes that benefit the failing heart, including the stimulation of pro-survival pathways such as Akt and mTOR (Mourouzis et al 2012) that is accompanied by improved cardiac function, paralleling changes induced by exercise, mediated by IGF-1 (Ojamaa 2010), to drive increases in contractile proteins critical to cardiac function and performance (Periasamy et al 2008). Exercise has also been shown to increase myocardial TR expression and T3 levels in a small cohort of HF patients with ventricular assist devices (Adamopoulos et al 2013), underscoring the role for TH in promoting positive adaptive remodeling of the injured heart. Exogenous approaches to supplementing TH also hold promise as low-dose T3 replacement has been shown to restore cardiac T3 levels and ameliorate dysfunction in preclinical models of heart failure (Weltman et al 2014, Zhang et al 2014).…”

Section: Discussionmentioning

confidence: 99%

MuRF1 mono-ubiquitinates TRα to inhibit T3-induced cardiac hypertrophy in vivo

Wadosky

Berthiaume

Tang

et al. 2016

Journal of Molecular Endocrinology

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Thyroid hormone (TH) is recognized for its role in cellular metabolism and growth and participates in homeostasis of the heart. T3 activates pro-survival pathways including Akt and mTOR. Treatment with T3 after myocardial infarction is cardioprotective and promotes elements of physiological hypertrophic response after cardiac injury. Although T3 is known to benefit the heart, very little about its regulation at the molecular level has been described to date. The ubiquitin proteasome system (UPS) regulates nuclear hormone receptors such as estrogen, progesterone, androgen, and glucocorticoid receptors by both degradatory and non-degradatory mechanisms. However, how the UPS regulates T3-mediated activity is not well understood. In this study, we aim to determine the role of the muscle-specific ubiquitin ligase muscle ring finger-1 (MuRF1) in regulating T3-induced cardiomyocyte growth. An increase in MuRF1 expression inhibits T3-induced physiological cardiac hypertrophy, whereas a decrease in MuRF1 expression enhances T3’s activity both in vitro and in cardiomyocytes in vivo. MuRF1 interacts directly with TRα to inhibit its activity by posttranslational ubiquitination in a non-canonical manner. We then demonstrated that a nuclear localization apparatus that regulates/inhibits nuclear receptors by sequestering them within a subcompartment of the nucleus was necessary for MuRF1 to inhibit T3 activity. This work implicates a novel mechanism that enhances the beneficial T3 activity specifically within the heart, thereby offering a potential target to enhance cardiac T3 activity in an organ-specific manner.

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Thyroid hormone signalling is altered in response to physical training in patients with end-stage heart failure and mechanical assist devices: potential physiological consequences?

Abstract: The unloaded failing myocardium responded to physical training by enhancing thyroid hormone signalling. This response was associated with an up-regulation of Akt and suppression of JNK activation.

Cited by 39 publications

References 14 publications

Left Ventricular Remodelling: A Problem in Search of Solutions

Left Ventricular Remodelling: A Problem in Search of Solutions

Thyroid hormone and the stunned myocardium

MuRF1 mono-ubiquitinates TRα to inhibit T3-induced cardiac hypertrophy in vivo

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