ABSTRACT
Background: The relationship between thyroid function and cardiac disease is complex. Both hypothyroidism and thyrotoxicosis can predispose to ventricular arrhythmia and other major adverse cardiovascular events (MACE), so that a U-shaped relationship between thyroid signaling and the incidence of MACE has been postulated. Moreover, recently published data suggest an association between thyroid hormone concentration and the risk of sudden cardiac death (SCD) even in euthyroid populations with high-normal FT4 levels. In this study, we investigated markers of repolarization in ECGs, as predictors of cardiovascular events, in patients with a spectrum of subclinical and overt thyroid dysfunction. Methods: Resting ECGs of 100 subjects, 90 patients (LV-EF > 45%) with thyroid disease (60 overt hyperthyroid, 11 overt hypothyroid and 19 L-T4-treated and biochemically euthyroid patients after thyroidectomy or with autoimmune thyroiditis) and 10 healthy volunteers were analyzed for Tp-e interval. The Tp-e interval was measured manually and was correlated to serum concentrations of thyroid stimulating hormone (TSH), free triiodothyronine (FT3) and thyroxine (FT4). Results: The Tp-e interval significantly correlated to log-transformed concentrations of TSH (Spearman's rho = 0.30, p < 0.01), FT4 (rho = -0.26, p < 0.05), and FT3 (rho = -0.23, p < 0.05) as well as log-transformed thyroid's secretory capacity (SPINA-GT, rho = -0.33, p < 0.01). Spearman's rho of correlations of JT interval to log-transformed TSH, FT4, FT3, and SPINA-GT were 0.51 (p < 1e-7), -0.45 (p < 1e-5), -0.55 (p < 1e-8), and -0.43 (p < 1e-4), respectively. In minimal multivariable regression models, markers of thyroid homeostasis correlated to heart rate, QT, Tp-e, and JT intervals. Group-wise evaluation in hypothyroid, euthyroid and hyperthyroid subjects revealed similar correlations in all three groups. Conclusion: We observed significant inverse correlations of Tp-e and JT intervals with FT4 and FT3 over the whole spectrum of thyroid function. Our data suggest a possible mechanism of SCD in hypothyroid state by prolongation of repolarization. We do not observe a U-shaped relationship, so that the mechanism of SCD in patients with high FT4 or hyperthyroidism seems not to be driven by abnormalities in repolarization.
ABSTRACT
Although technical problems of thyroid testing have largely been resolved by modern assay technology, biological variation remains a challenge. This applies to subclinical thyroid disease, non-thyroidal illness syndrome, and those 10% of hypothyroid patients, who report impaired quality of life, despite normal thyrotropin (TSH) concentrations under levothyroxine (L-T4) replacement. Among multiple explanations for this condition, inadequate treatment dosage and monotherapy with L-T4 in subjects with impaired deiodination have received major attention. Translation to clinical practice is difficult, however, since univariate reference ranges for TSH and thyroid hormones fail to deliver robust decision algorithms for therapeutic interventions in patients with more subtle thyroid dysfunctions. Advances in mathematical and simulative modeling of pituitary-thyroid feedback control have improved our understanding of physiological mechanisms governing the homeostatic behavior. From multiple cybernetic models developed since 1956, four examples have also been translated to applications in medical decision-making and clinical trials. Structure parameters representing fundamental properties of the processing structure include the calculated secretory capacity of the thyroid gland (SPINA-GT), sum activity of peripheral deiodinases (SPINA-GD) and Jostel's TSH index for assessment of thyrotropic pituitary function, supplemented by a recently published algorithm for reconstructing the personal set point of thyroid homeostasis. In addition, a family of integrated models (University of California-Los Angeles platform) provides advanced methods for bioequivalence studies. This perspective article delivers an overview of current clinical research on the basis of mathematical thyroid models. In addition to a summary of large clinical trials, it provides previously unpublished results of validation studies based on simulation and clinical samples.
