Abstract P128: Type II Deiodinase Upregulation in Patients with End-Stage Dilated Cardiomyopathy

Abstract

Background: Dilated cardiomyopathy (DCM) is the most common form of heart disease, with a 50% survival rate 5yrs after diagnosis. Low thyroid hormone levels are an independent risk factor for heart failure progression. Recent studies in animal models with heart failure have shown re-expression of a fetal enzyme, type III deiodinase (D3) that functions to reduce thyroid hormone concentrations. Alternatively, an increase in β-adrenergic stimulation during heart failure may increase expression of type II deiodinase (D2) that would function to increase thyroid hormone concentration. We hypothesized that human hearts in end-stage dilated heart failure would have increased D3/D2 expression and lower myocardial and serum thyroid hormone concentrations. Methods and Results: Serum and left ventricular (LV) tissue from patients with dilated heart failure undergoing heart transplantation, and organ donors not meeting the criteria for heart donation were obtained with full consent and Institutional Review Board approval. Deiodinase expression was measures with real time rtPCR and thyroid hormone concentrations measured with radioimmunoassay. Interestingly, D3 expression and protein levels were not elevated in DCM patients vs. “non-failing” heart samples. On the other hand, D2 expression and protein levels were increased in DCM hearts and tended to have greater myocardial thyroid hormone concentrations (P =0.10). In spite of the increase in D2 expression in DCM patients, serum thyroid hormone concentrations were significantly lower than serum obtained from healthy volunteers, (P<0.05). Changes in thyroid hormone receptors and thyroid hormone dependent downstream signaling changes for Akt, mTOR, and ERK are currently being investigated. Conclusions: Contrary to our hypothesis, patients with end-stage DCM have a reduced D3/D2 expression ratio and tend to have elevated myocardial thyroid hormone concentrations. Compensatory increases in D2 expression may enhance myocardial T3 production in DCM patients; however changes in thyroid hormone receptors and downstream signaling may negate this effect. Importantly, serum T3 concentrations were significantly reduced which likely contributed to patients progression toward end stage heart failure.