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(Circulation. 2001;103:1089.)
© 2001 American Heart Association, Inc.

Clinical Investigation and Reports

Signaling Pathways Responsible for Fetal Gene Induction in the Failing Human Heart

Evidence for Altered Thyroid Hormone Receptor Gene Expression

Presented in part at the 72nd Scientific Sessions of the American Heart Association, Atlanta, Ga, November 7–10, 1999, and published in abstract form (Circulation. 1999;100[suppl I]:I-507).

Koichiro Kinugawa, MD, PhD; Wayne A. Minobe, BS; William M. Wood, PhD; E. Chester Ridgway, MD; John D. Baxter, MD; Ralff C. J. Ribeiro, MD, PhD; Magdy F. Tawadrous, MD; Brian A. Lowes, MD; Carlin S. Long, MD; Michael R. Bristow, MD, PhD

From the Division of Cardiology (K.K., W.A.M., M.F.T., B.A.L., M.R.B.) and Division of Endocrinology, Metabolism, and Diabetes (W.M.W., E.C.R.), University of Colorado Health Sciences Center, and the Cardiology Section, Denver Health Medical Center (C.S.L.), Denver, Colo; and the Metabolic Research Unit, University of California, San Francisco (J.D.B., R.C.J.R.).

Correspondence to Michael R. Bristow, MD, PhD, Head, Division of Cardiology, University of Colorado Health Sciences Center, 4200 E Ninth Ave, Campus Box B139, Denver, CO 80262. E-mail michael.bristow{at}uchsc.edu

Background—We have previously demonstrated that changes in myosin heavy chain (MHC) isoforms that occur in failing human hearts resemble the pattern produced in rodent myocardium in response to hypothyroidism. Because thyroid hormone status is usually within normal limits in these patients, we hypothesized that failing/hypertrophied human myocardium might have a defect in thyroid hormone signaling due to alterations in expression of thyroid hormone receptors (TRs).

Methods and Results—To examine this hypothesis, we used RNase protection assay to measure mRNA levels of TRs in failing left ventricles that exhibited a fetal pattern of gene expression, ie, decreased expression of -MHC with increased ß-MHC expression compared with left ventricles from age-matched controls. We detected expression of TR-₁, -₂, and -ß₁ isoforms in human left ventricles. In failing left ventricles, TR-₁ was downregulated, whereas TR-₂, a splice variant that does not bind thyroid hormone but inhibits responses to liganded TRs, was increased. Expression levels of TR-ß₁ did not differ significantly between the 2 groups. According to linear regression analysis, expression levels of TR-₁ and -₂ were positively and negatively correlated with those of -MHC, respectively.

Conclusions—We conclude that decreases in TR-₁ and increases in TR-₂ may lead to local attenuation of thyroid hormone signaling in the failing human heart and that the resulting tissue-specific hypothyroidism is a candidate for the molecular mechanism that induces fetal gene expression in the failing human ventricle.

Key Words: thyroid • hormones • receptors • myosin • heart failure

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