Thyroid hormone and the cardiovascular system

Thyroid hormone has profound effects on the heart and cardiovascular system. This article describes the cellular mechanisms by which thyroid hormone acts at the level of the cardiac myocyte and the vascular smooth muscle cell to alter phenotype and physiology. Because it is well established that thyroid hormone, specifically T(3), acts on almost every cell and organ in the body, studies on the regulation of thyroid hormone transport into cardiac and vascular tissue have added clinical significance. The characteristic changes in cardiovascular hemodynamics and metabolism that accompany thyroid disease states can then be best understood at the cellular level.     

甲状腺激素与心血管疾病

甲状腺激素在心血管系统中作用广泛。甲状腺功能亢进或减退均可引起相关的心血管功能紊乱,而亚临床甲状腺疾病也与心血管疾病风险和病死率增加密切相关。     

Thyroid hormones and the cardiovascular system: Pathophysiology and interventions

Thyroid dysfunction, however mild, can significantly affect the cardiovascular (CV) system. The effects of thyroid hormones may be viewed as genomic and non-genomic, with the former occurring over a longer time scale and both affecting structural and functional proteins in CV tissue. As the interplay between thyroid function and the CV system becomes elucidated, particularly in the context of a system biology approach, the heart failure phenotype is better understood. Symptomatology is related to disturbance in inotropic and chronotropic function. Moreover, biochemical changes reflected by thyroid function testing with the non-thyroidal illness syndrome can prognosticate and guide therapy in heart failure. In addition, empiric treatment with thyroid hormone analogues or T3 represent emergent and highly controversial interventions.     

Thyroid hormone is required for hypothalamic neurons regulating cardiovascular functions

Thyroid hormone is well known for its profound direct effects on cardiovascular function and metabolism. Recent evidence, however, suggests that the hormone also regulates these systems indirectly through the central nervous system. While some of the molecular mechanisms underlying the hormone’s central control of metabolism have been identified, its actions in the central cardiovascular control have remained enigmatic. Here, we describe a previously unknown population of parvalbuminergic neurons in the anterior hypothalamus that requires thyroid hormone receptor signaling for proper development. Specific stereotaxic ablation of these cells in the mouse resulted in hypertension and temperature-dependent tachycardia, indicating a role in the central autonomic control of blood pressure and heart rate. Moreover, the neurons exhibited intrinsic temperature sensitivity in patch-clamping experiments, providing a new connection between cardiovascular function and core temperature. Thus, the data identify what we believe to be a novel hypothalamic cell population potentially important for understanding hypertension and indicate developmental hypothyroidism as an epigenetic risk factor for cardiovascular disorders. Furthermore, the findings may be beneficial for treatment of the recently identified patients that have a mutation in thyroid hormone receptor α1.     

Thyroid hormone resistance

General resistance to the action of thyroid hormones is characterized by increased levels of thyroid hormones and normal thyroid hormone binding proteins but clinical euthyroidism. There is a wide clinical spectrum ranging from patients with congenital goitre and signs of subclinical hypothyroidism to subjects with no physical abnormality. In the most affected patients special physical features have been described. Serum thyrotrophin (TSH) and the response to thyrotrophin releasing hormone (TRH) is mostly normal but may fluctuate being at times elevated and even markedly increased values may be encountered. Studies on lymphocytes and fibroblasts indicate that a decreased affinity of thyroid hormones for nuclear receptors, a decreased binding capacity of the receptors or some post-receptor mechanism may be responsible for these changes. Hitherto, six families, comprising 24 patients and seven single cases, have been described. The pedigrees are compatible with dominant inheritance. Selective refractoriness of the pituitary thyrotrophs to thyroid hormones has been described in five patients with hyperthyroidism. Excessive secretion of TSH is the cause of hyperthyroidism. In four of the cases reported TRH caused an exaggerated TSH response and TSH was partially suppressible by additional exogenous thyroid hormone. The response of TSH and the behaviour of the alpha- and beta-subunits of TSH distinguish this syndrome from TSH-induced hyperthyroidism due to pituitary tumours. The underlying mechanisms are unknown.     

Thyroid hormone pattern and aggressiveness

Summary The aggressiveness induced by the forced isolation of animals may be mediated by endocrine changes. The present study focuses on the possible mediation of the pituitary-thyroid axis in the mouse (Mus musculus). The blood levels of the hormone fractions examined (T4, T3 and rT3) in isolated animals showed a significant increase in comparison with the individuals which were classified from an ethological point of view as submissive, whereas in comparison with the individuals which were classified as dominant, no difference was found for T4 and rT3, but a significant increase of T3 occurred. The choice of the categories of comparison (dominant and submissive as opposed to isolated mice) derives from the hypothesis, which has already been confirmed experimentally on an ethological level, that in this species the isolated individuals are homologous to socially dominant animals as far as aggressiveness is concerned. The endocrinological results obtained in this study support this hypothesis. Thus it is concluded that, in the species under study, isolation induces pituitary-thyroid axis activation which is similar to that found in dominant individuals and at least partially responsible for the isolation aggressiveness. The mediation of the action of TRH on the central nervous system in this phenomenon is suggested as an interesting hypothesis. Research supported by a grant from theMinistero della Pubblica Istruzione, Roma, Italy.     

Thyroid hormone action in the absence of thyroid hormone receptor DNA-binding in vivo

Thyroid hormone action is mediated by thyroid hormone receptors (TRs), which are members of the nuclear hormone receptor superfamily. DNA-binding is presumed to be essential for all nuclear actions of thyroid hormone. To test this hypothesis in vivo, the DNA-binding domain of TR-beta was mutated within its P-box (GS mutant) using gene targeting techniques. This mutation in vitro completely abolishes TR-beta DNA-binding, while preserving ligand (T3) and cofactor interactions with the receptor. Homozygous mutant (TR-betaGS/GS) mice displayed abnormal T3 regulation of the hypothalamic-pituitary-thyroid axis and retina identical to abnormalities previously observed in TR-beta KO (TR-beta-/-) mice. However, TR-betaGS/GS mutant mice maintained normal hearing at certain frequencies and did not display significant outer hair cell loss, in contrast to TR-beta-/- mice. DNA-binding, therefore, is essential for many functions of the TR, including retinal development and negative feedback regulation by thyroid hormone of the hypothalamic-pituitary-thyroid axis. Inner ear development, although not completely normal, can occur in the absence of TR DNA-binding, suggesting that an alternative and perhaps novel thyroid hormone-signaling pathway may mediate these effects.     

Breathing and the cardiovascular system

The close coupling between the systems of breathing and circulation provide potential hazards to physiological function because breathing is subject to conscious control. Emotional input to the respiratory system is often at odds with degree of muscle activity, thereby disrupting the matching of breathing to actual metabolic needs. Hyperventilation is the most common example. Research on the consequences of this mismatch are described in connection with occurrence of coronary vasospasms and angina, effort syndrome, respiratory sinus arrhythmia, cardiac rehabilitation and functional cardiac symptoms. Principles and techniques for training relaxation through breathing awareness and self-regulation are described.     

Thyroid hormone resistance and increased metabolic rate in the RXR-gamma-deficient mouse

Vitamin A and retinoids affect pituitary-thyroid function through suppression of serum thyroid-stimulating hormone (TSH) levels and TSH-beta subunit gene expression. We have previously shown that retinoid X receptor-selective (RXR-selective) ligands can suppress serum TSH levels in vivo and TSH-beta promoter activity in vitro. The RXR-gamma isotype has limited tissue distribution that includes the thyrotrope cells of the anterior pituitary gland. In this study, we have performed a detailed analysis of the pituitary-thyroid function of mice lacking the gene for the RXR-gamma isotype. These mice had significantly higher serum T4 levels and TSH levels than did wild-type (WT) controls. Treatment of RXR-gamma-deficient and WT mice with T3 suppressed serum TSH and T4 levels in both groups, but RXR-gamma-deficient mice were relatively resistant to exogenous T3. RXR-gamma-deficient mice had significantly higher metabolic rates than did WT controls, suggesting that these animals have a pattern of central resistance to thyroid hormone. RXR-gamma, which is also expressed in skeletal muscle and the hypothalamus, may have a direct effect on muscle metabolism, regulation of food intake, or thyrotropin-releasing hormone levels in the hypothalamus. In conclusion, the RXR-gamma isotype appears to contribute to the regulation of serum TSH and T4 levels and to affect peripheral metabolism through regulation of the hypothalamic-pituitary-thyroid axis or through direct effects on skeletal muscle.     

Thyroid hormone replacement: an iatrogenic problem

Thyroid hormone replacement is one of the very few medical treatments devised in the 19th century that still survive. It is safe, very effective and hailed as a major success by patients and clinicians. Currently, it is arguably the most contentious issue in clinical endocrinology. The current controversy and patient disquiet began in the early 1970s, when on theoretical grounds and without proper assessment, the serum thyrotropin (TSH) concentration was adopted as the means of assessing the adequacy of thyroxine replacement. The published literature shows that the serum TSH concentration is a poor indicator of clinical status in patients on thyroxine. The adequacy of thyroxine replacement should be assessed clinically with the serum T3 being measured, when required, to detect over‐replacement.