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Resistance to Thyroid Hormone and Cardiovascular Risk
regulation of cardiac energy substrate metabolism.
36
TRα
-/-
mice display was observed, namely mitral valve prolapse in RTH subjects. More recently,
a glucose/fatty acid oxidation balance comparable to wt. By contrast, Kahaly and collaborators
12
compared 54 RTH patients divided into three
TRβ KO exhibits a shift of metabolism toward glucose oxidation at the groups: healthy, hypothyroid, and hyperthyroid patients. In agreement with
expense of fatty-acid oxidation. In a pressure-overload-induced cardiac previous data, they observed that in RTH some parameters (cardiac output,
hypertrophy model, the current authors found an increase of glucose stroke volume, and isovolumic relaxation and deceleration times) were
oxidation. In these mice, TRβ expression in the heart is reduced by more moving toward hyperthyroidism, but others were not. Overall differences
than 70% compared with normal animals. Gene therapy with adenovirus in terms of cardiovascular changes were smaller between the RTH and
(AAV)-expressing TRβ tends to normalize the myocardial metabolism. control group than between the RTH and the hyperthyroid or hypothyroid
Interestingly, in this model hypertrophy is associated with a decreased patients, suggesting an incomplete response of the heart to TH.
contractile phenotype and an altered intracellular calcium transient,
37
Cardiovascular symptoms and signs were less frequent and severe in RTH
mainly due to a change in MHC isoform expression (from MHCα to compared with hyperthyroid subjects. RTH subjects showed a systolic
MHCβ) and a reduction in sarcoplasmic reticulum Ca
2+
-adenosine cardiac performance within the normal range; in particular, Doppler
triphosphate (ATPase) (SERCA), respectively. Treatment with AAV- velocities, heart rate, stroke volume, and cardiac output were significantly
expressing thyroid hormone receptor TRα1 or TRβ1 improves contractile lower with respect to hyperthyroid subjects. In comparison with controls,
function in hypertrophied hearts and increases SERCA levels, suggesting RTH patients exhibit an enhanced left ventricular (LV) contractile function
that receptor expression level, rather than isoforms, affects contractile and shorter diastolic parameters, while systolic and diastolic diameters of
function in cardiac hypertrophy.
37
the LV were not significantly different. Interestingly, in RTH subjects without
cardiac signs, median age, heart rate, and TH levels were higher and
Finally, TRβ KO mice and TRα/TRβ-double KO mice exhibited a significant diastolic relaxation time was shorter compared with those with
decrease in capillary density compared with wt mice, whereas there was palpitations and tachycardia. Nevertheless, all other cardiovascular
no change in capillary density in TRα KO mice. These data indicate that parameters showed no significant differences. Even if the heart rate was
TRβ expression in coronary endothelial cells plays an essential role in high, especially in subjects harboring the mutations Y321S, M334R, and
angiogenesis during cardiac development.
38
C446R, no significant correlation was found between cardiovascular
features and the type of mutation.
Resistance to Thyroid Hormone and
Cardiovascular Risk To a certain extent, some of these results were in contrast to the previous
The potential for cardiovascular derangements in RTH is complex, and to NIH paper.
39
Notably, in the Kahaly et al. paper a higher heart rate in RTH was
date only a few studies have evaluated the cardiovascular risk in these discovered. Moreover, the frequency of mitral valve prolapse was not
subjects.
12,39,40,42,44
It is well-known that either hyperthyroidism or increased in RTH compared with controls. Remarkably, a significantly higher
hypothyroidism causes alterations in the cardiovascular system and heart rate and a larger diameter of the left atrium (LA) and lower LV ejection
metabolism.
2,3
In overt and subclinical hypothyroidism, the increased fraction were found in affected children compared with controls of
serum levels of lipids and homocysteine together with diastolic comparable age, while in the Brucker-Davis paper adults but not children
hypertension and the increased systemic vascular resistance are exhibited improved of systolic cardiac performance. We have recently
potentially associated with an increased risk of atherosclerosis. Atrial published data that are apparently different from those of Kahaly and
fibrillation (AF) is a recognized complication of overt hyperthyroidism, and collaborators, although the different results could be explained by the
subclinical hyperthyroidism is also known to be a risk factor for different selection criteria of the RTH patients.
40
Our 16 RTH patients had
development of AF. Supraventricular dysrhythmias, particularly AF, in older no thyrotoxic cardiovascular signs and symptoms, were untreated with
hyperthyroid patients may account for some of the excess cardiovascular thyroid or cardiovascular drugs, and showed comparable heart rates to
and cerebrovascular mortality, especially due to embolic phenomena. the control group. They also displayed higher systolic, diastolic, and mean
arterial pressure than controls, but similar pulse pressure. The global LV
Data concerning the influence of RTH on the heart anatomy, investigated performance, as expressed by the stroke index, did not differ between the
chiefly by echocardiography,
13,39,40
are conflicting and confirm the extreme two groups. However, the level of global LV systolic function was lower in
variability and heterogeneity of clinical manifestations in RTH syndrome. RTH patients than in controls. Moreover, myocardial relaxation was
Similar to observations in hyperthyroid patients, Brucker-Davis et al.
35
deranged, similar to that observed in patients with overt and subclinical
discovered increased systolic cardiac performance in adults affected with thyroid hormone deficiency. Furthermore, the mean interventricular
RTH. This finding suggests that the heart is relatively less resistant than septum diastolic thickness and mean LV posterior wall diastolic thickness
other organs. Thus, the increase of contractility was less than expected were significantly lower in RTH patients. Consequently, the mean LV mass
given the level of thyroid hormone, implying the presence of some degree was reduced in RTH compared with unaffected individuals, suggesting the
of resistance in the ventricle. Moreover, given the fact that the increase of presence of reduced TH effects during heart development. Interestingly,
systolic cardiac performance was detected in adults only, the authors data from animal models could explain, to some extent, our
hypothesized that children with RTH could be more ‘resistant’ to thyroid observation,
19,41
as mutant TRβ prevented TH-induced cardiac hypertrophy,
hormone. A decrease in the mutant/normal receptor ratio with age was probably by interfering with the function of normal TR and inducing
assumed an explanation of these results. In contrast to previous reports, in hypothyroidism in the heart of the transgenic mice.
the National Institutes of Health (NIH) study the resting pulse was found to
be faster in RTH patients as a group, but not after adjustment for age. Finally, even if the pulse-pressure-to-stroke index ratio (a parameter of
Compared with normal controls, a higher frequency of valvular defects total arterial stiffness) was similar to controls, the systemic vascular
US ENDOCRINOLOGY 119
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