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Division of Endocrinology North Shore University Hospital NYU School of Medicine Manhasset, New York 11030
Address all correspondence and requests for reprints to: Irwin Klein, M.D., Chief, Division of Endocrinology, North Shore University Hospital, NYU School of Medicine, 300 Community Drive, Manhasset, New York 11030. E-mail: Iklein{at}NSHS.edu
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Introduction |
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 Top Introduction References |
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and ß, sarcoplasmic
reticulum calcium activated ATPase (SERCA2), phospholamban, the
ß-adrenergic receptor, adenylyl cyclase V and VI, and various
membrane ion channels (3). This list continues to
grow.
Predictable increases in heart rate, cardiac contractility, and cardiac
mass (hypertrophy) result from chronic thyroid hormone treatment
(3). While the effect of thyroid hormone on gene
transcription is mediated by T3 binding to
discrete nuclear receptors (6), the effect on cardiac mass
is indirectly mediated by an increase in cardiac workload
(7). Two T3-binding nuclear receptors, TR1
and TRß1, are present in the cardiac myocyte. Studies of transgenic
animals lacking TR1 serve to link this receptor isoform with
T3-mediated changes in heart rate (8).
Studies of cardiac contractility using a variety of in vivo and in vitro measures have shown that the hyperthyroid heart is hypercontractile compared with the euthyroid myocardium, and that the hypothyroid heart has impaired systolic and diastolic performance (3). Functionally and phenotypically, the failing mammalian heart resembles the hypothyroid heart (9) and has the potential to respond to thyroid hormone treatment with a restoration of the normal profile of gene expression (10).
Extending the observation that T3 exerts positive inotropic effects on the heart, various reports have addressed whether thyroid hormone could be used to improve the performance of the failing myocardium (11, 12). While initial results have been promising, the concern for unwanted effects of T3 to increase total body or cardiac oxygen consumption (BMR) has limited the enthusiasm for this approach. However, the recent observation indicating that the hypothyroid heart is energetically inefficient, has promoted renewed interest in harnessing the inotropic and lusitropic effects of T3 as novel therapy targeting the heart (3, 10, 13).
In this issue of Endocrinology, Pachucki and colleagues
(14) have developed a transgenic mouse with cardiac
selective expression of the type 2 iodothyronine deiodinase (D2) with
the goal of producing cardiac specific thyrotoxicosis. This ingenious
application of transgenic methodology draws from the ability of the
MHC- promoter to selectively drive expression of D2 in cardiac
myocytes, and thereby isolate the effects of T3
on the heart (15). Their findings are informative but
somewhat unexpected.
The success of the model is confirmed by finding increased mRNA for D2
in heart (and pulmonary myocardium) accompanied by increased D2
enzymatic activity (15). Because D2 is normally not
expressed in rodent hearts (myocytes) but is expressed in human heart,
this in some ways reproduces the human condition (16).
Surprisingly the authors did not achieve the measurable increase in
myocardial T3 levels resulting from the increase
in D2 activity. This lack of increase in intracellular
T3 may explain the lack of change in MHC- and
SERCA2 mRNAs, which are well-characterized T3
responsive genes (3, 4). However, the authors did report
an increase in heart rate in the transgenic mice, a sensitive measure
of thyroid hormone action, and suggest that the increase in mRNA
expression of the hyperpolarization activated cyclic nucleotide-gated
ion channel 2 (HCN2) in the ventricle may explain this effect
(17). The precise mechanism for the positive chronotropic
effects of T3 are not understood. Experimental evidence
supports a potential role for TR1 in the T3-mediated
regulation of the HCN2, KV1.5, KV4.2, and KV4.3 genes that may alter
pacemaker current (18, 19). Because
T3 effects on cardiac genes have been shown to be
chamber specific, this relationship would be more compelling if the
changes in thyroid hormone-sensitive membrane ion channels were
observed in the atria (20).
Does this approach allow us to selectively target the heart for the potential therapeutic inotropic effects of T3? In a recent study, Everts and colleagues (21) have demonstrated an energy-dependent carrier mediated mechanism for thyroid hormone uptake in rodent myocytes that is selective for T3. In those studies 125-T4 uptake was much lower and not competed by unlabeled hormone, raising the question of whether T4 is taken up in any significant amount by cardiac cells. Failure of T4 to accumulate in the myocyte could explain the inability of Pachucki et al. (14) to observe significant increases in T3 concentrations in the D2 transgenic hearts.
These and other studies clearly demonstrate that the heart is one of
the most thyroid hormone-responsive tissues (organ) in the body and
that cardiac functional parameters are excellent measures of the
cellular action of T3 (3).
Measurable and opposite changes of cardiac contractility have been
demonstrated in both subclinical hyperthyroidism and subclinical
hypothyroidism (22). At the present time, it remains
unresolved whether the low serum T3 levels that
accompany many nonthyroidal illnesses reflect a decrease in hormone
action at the cellular level (23). In a chronic animal
model of the low T3 state, cardiac gene
expression and left ventricular function were shown to be impaired,
similar to that seen with hypothyroidism (24). The
phenotypic changes including MHC- and SERCA2 expression and left
ventricular contractile function that occurred in this model of low
T3 state were restored to the euthyroid condition
by chronic T3 (but not T4) infusion
in amounts calculated to return serum T3 levels
to normal (24).
There are a growing number of human cardiac disease states in which thyroid hormone metabolism is altered leading to a fall in serum T3. Within 48 h after acute myocardial infarction (25) or within 6–24 h after cardiac surgery requiring cardiopulmonary bypass in adults and children (26, 27), serum T3 levels decline. In children, the fall in T3 was more pronounced and prolonged in patients with a more complex surgical procedures (27). Replacement T3 therapy to restore serum T3 levels to normal improved the postoperative outcome and cardiac function in newborn children without untoward effects (28, 29). In patients with congestive heart failure, it has been observed that as many as 30% have low T3 levels that correlate with the severity of the clinical assessment of heart failure (3, 11). Chronic administration of amiodarone, a drug commonly used in this setting to prevent ventricular arrhythmias is also known to lower serum T3 (3). Initial attempts to improve cardiac function by thyroid hormone treatment of patients with the most severe degrees of heart failure have been promising (11, 12).
Taken together, these observations suggest that the fall in
T3 with nonthyroidal illness in humans may
adversely effect cardiac function (24), and similar to
that of hypothyroidism (2, 3, 22) benefit from hormone
replacement. The inability of patients with nonthyroidal illness to
convert T4 to T3, perhaps
as a result of an increase in interleukin-6 and a fall in hepatic type
1 deiodinase activity (23), suggest that the treatment by
necessity would be T3 given at replacement doses
to normalize serum levels (24, 28). Various noninvasive
measures of cardiac contractility would then serve to confirm the
therapeutic utility of this approach. Is it possible to target the
heart for selective thyroid hormone action? A thyromimetic with
selective TR1 binding activity that would
target the cardiac myocyte (30), might result in such an
effect and allow for chronic T3 treatment without
unwanted effects on oxygen metabolism. Alternative strategies such as
selective overexpression of D2 in the human heart using a
methodological approach similar to that reported in this issue of
Endocrinology might also accomplish such a goal.
Received October 24, 2000.
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TopIntroductionReferences |
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1. EMBO J 17:455–461
This article has been cited by other articles:
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  M. A. Sussman When the Thyroid Speaks, the Heart Listens Circ. Res., September 28, 2001; 89(7): 557 - 559. [Full Text] [PDF]
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