Low-dose T₃ replacement restores depressed cardiac T₃ levels, preserves coronary microvasculature and attenuates cardiac dysfunction in experimental diabetes mellitus.

Nathan Y Weltman,Evelyn H Schlenker,Christine J Pol,Yue-Feng Chen,Viswanathan Rajagopalan,Daria Colligiani,A Martin Gerdes,Alessandro Saba,Riccardo Zucchi,Kaie Ojamaa

doi:10.2119/molmed.2013.00040

Abstract

Thyroid dysfunction is common in individuals with diabetes mellitus (DM) and may contribute to the associated cardiac dysfunction. However, little is known about the extent and pathophysiological consequences of low thyroid conditions on the heart in DM. DM was induced in adult female Sprague Dawley (SD) rats by injection of nicotinamide (N; 200 mg/kg) followed by streptozotocin (STZ; 65 mg/kg). One month after STZ/N, rats were randomized to the following groups (N = 10/group): STZ/N or STZ/N + 0.03 μg/mL T3; age-matched vehicle-treated rats served as nondiabetic controls (C). After 2 months of T3 treatment (3 months post-DM induction), left ventricular (LV) function was assessed by echocardiography and LV pressure measurements. Despite normal serum thyroid hormone (TH) levels, STZ/N treatment resulted in reductions in myocardial tissue content of THs (T3 and T4: 39% and 17% reduction versus C, respectively). Tissue hypothyroidism in the DM hearts was associated with increased DIO3 deiodinase (which converts THs to inactive metabolites) altered TH transporter expression, reexpression of the fetal gene phenotype, reduced arteriolar resistance vessel density, and diminished cardiac function. Low-dose T3 replacement largely restored cardiac tissue TH levels (T3 and T4: 43% and 10% increase versus STZ/N, respectively), improved cardiac function, reversed fetal gene expression and preserved the arteriolar resistance vessel network without causing overt symptoms of hyperthyroidism. We conclude that cardiac dysfunction in chronic DM may be associated with tissue hypothyroidism despite normal serum TH levels. Low-dose T3 replacement appears to be a safe and effective adjunct therapy to attenuate and/or reverse cardiac remodeling and dysfunction induced by experimental DM.

Highlights

Cardiac complications are the leading cause of morbidity and mortality in individuals with diabetes mellitus (DM)
STZ/N was not associated with changes in serum T4, T3, FT3 or FT4 levels; TSH values were two-fold higher compared with control
This study evaluated the relationship between cardiac tissue hypothyroidism and cardiac dysfunction in the setting of DM

Summary

Introduction

Cardiac complications are the leading cause of morbidity and mortality in individuals with diabetes mellitus (DM). DM increases the risk of morbid events in individuals with coronary artery disease (CAD), hypertension (HTN), hypercholesterolemia, and postmyocardial infarction (MI) [1,2]. DM can lead to cardiac dysfunction, microvascular impairment, structural remodeling and eventually heart failure (HF) in the absence of a known underlying pathology (for example, CAD or HTN) [3,4]. THs influence myocardial contractility, total peripheral resistance and cardiac output [7,8]. Overt and subclinical hypothyroidism are associated with cardiovascular dysfunction including impaired contractility and decreased cardiac output, increased peripheral vascular resistance, impaired coronary blood flow and relaxation abnormalities, which results in an increased clinical risk for all-cause and cardiovascular mortality [9,10,11,12]

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