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Thyroid Disorders
Resistance to Thyroid Hormone and Cardiovascular Risk
Irene Campi, MD,
1
Deborah Mannavola, PhD
2
and Paolo Beck-Peccoz, MD
3
1. Clinical Fellow; 2. Research Assistant; 3. Full Professor of Endocrinology, and Director, School of Specialization in Endocrinology and Metabolic Diseases,
Fondazione Policlinico-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), University of Milan
Abstract
Resistance to thyroid hormone (RTH) is a dominantly inherited syndrome of impaired tissue responsiveness to thyroid hormones (TH) characterized
by high circulating TH in the presence of unsuppressed thyroid-stimulating hormone (TSH). TH achieve their action on the heart chiefly via thyroid
hormone receptor alpha 1 (TRα1), which is the TH receptor (TR) isoform predominantly expressed in such an organ. Data derived from animal models
suggest that in RTH the overstimulation of the TRα1 pathway by the high TH levels could explain the cardiovascular abnormalities seen in these
animals, although the discordant cardiac gene expression profile between wild-type (wt) and transgenic mice treated with triiodothyronine (T
3
) imply
that the effects of RTH on the heart are complex and not completely explicable by the heightened T
3
/TRα1 signaling. To date, only a few studies have
evaluated cardiovascular risk in RTH, with conflicting results, confirming the large variability of the RTH phenotype. In particular, some reports show
that several cardiovascular parameters seem to move toward hyperthyroidism, while others show a pattern that resembles thyroid hormone
deficiency. Finally, recent data suggest that in addition to reduced vascular compliance and echocardiographic abnormalities, RTH subjects may
exhibit some features of metabolic syndrome, suggesting an overall increased cardiometabolic risk in this disorder.
Keywords
Resistance to thyroid hormone (RTH), heart, cardiovascular risk, thyroid hormone receptors, animal model for RTH
Disclosure: The authors have no conflicts of interest to declare.
Received: June 18, 2009 Accepted: October 26, 2009
Correspondence: Paolo Beck-Peccoz, MD, University of Milan, Endocrinology and Diabetology Unit, Pad Granelli, Via F Sforza 35, 20122 Milan, Italy. E: paolo.beckpeccoz@unimi.it
Thyroid Hormones and the Heart Resistance to Thyroid Hormone
The heart represents an important target for thyroid hormones (TH).
1
Both Resistance to thyroid hormone (RTH) is a rare (probably one per 50,000)
transcriptional and non-transcriptional effects of TH may act to modulate dominantly inherited syndrome of impaired tissue responsiveness to
the function of the myocardium. In the short term, triiodothyronine (T
3
) TH.
12
A hallmark of this condition is the presence of high circulating TH
changes the performance of various sodium, potassium, and calcium in the presence of unsuppressed TSH. In the majority of RTH subjects
channels in the heart, possibly with an inotropic and chronotropic effect.
2,3
(about 85%), point mutations or small deletions in the thyroid hormone
Specific T
3
-response elements (TRE) has been demonstrated in different receptor beta (TRβ) gene are found. As a result, the mutant TR
genes, coding for proteins involved in the regulation of contractility and interferes with the function of normal TRs (dominant negative effect),
electrical activity of the heart.
4,5
A positive regulation has been which explains the dominant mode of inheritance of this syndrome (see
established for myosin heavy chain-α (MHCα)
6,7
, L-type and ryanodine Figure 1). However, about 15% of cases without mutation of the TRβ
calcium channel,
8,9
and other ions channels,
10
such as voltage-gated gene but with biochemical evidence of the syndrome have been
potassium channels;
2
while other genes, such as MHCβ and Na
+
/Ca
2+
reported.
13
Even if it has been supposed that a deficiency of a co-factor
exchanger, are downregulated by T
3
(see Table 1).
2,6,11
It has been could be present, to date the exact etiology of the resistance in these
suggested that T
3
actions on heart could be, to a certain extent, cases has not been understood.
13
mediated by increased activity of the sympathoadrenal system, given
the fact that cardiac symptoms of hyperthyroidism are relieved by The clinical presentation of RTH is highly variable. Classically, these
treatment with sympatholytic agents. Due to the fact that thyrotoxicosis subjects have been divided into two subgroups according to the absence
plasma and urine levels of catecholamines have been reported as or presence of symptoms of thyrotoxicosis, i.e. generalized thyroid
normal or decreased, increased sensitivity of the sympathetic system in hormone resistance (GRTH) and selective pituitary resistance (PRTH),
hyperthyroidism has been hypothesized. This effect may be mediated by respectively. Patients with GRTH usually display compensated
an increased number of β-adrenergic receptors. Moreover, increased hypothyroidism, while those with PRTH exhibit variable symptoms
levels of other components of the transmission system could be of hyperthyroidism.
14 –16
It is now generally accepted that such a distinction
involved, such as stimulatory guanine nucleotide-regulatory protein.
4
is clinically useful, although the TRβ mutations may be the same in both
© TOUCH BRIEFINGS 2009 117
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