Abstract 9149: Mechanism of Thyroid-Hormone-Deficiency-Caused Cardiac Injury in a Rat Model: Effects of Left Ventricle and Myocyte Functional Performance, [Ca2+]i Transient Response and Beta-Adrenergic Modulation
Background. Thyroid hormone deficiency is associated in some patients with the development of congestive cardiomyopathy. However, the mechanism is unclear. Although hemodynamic abnormalities have been described, the cardiac pathophysiology is unclear. We assessed cardiac insufficiency in male SD rats with methimazole-induced hypothyroidism (Hypo). We tested the hypothesis that Hypo rats would demonstrate impaired left ventricular (LV) myocyte function and [Ca2+]i regulation with desensitization of cardiac β-adrenergic signaling.
Methods. We compared myocyte β1-adrenoceptor (AR) expression and assessed LV and myocyte basal systolic and diastolic function, peak [Ca2+]i transient ([Ca2+]iT) and response to β-adrenergic simulation in 10 normal control (C) and 6 Hypo rats induced by methimazole (∼30 mg/kg/day for 8 weeks in the drinking water).
Results. Compared to controls, total serum concentrations of T3 and T4 were significantly reduced in Hypo rats (T3: 21.5 vs 99.5 ng/dl and T4: 1.0 vs 4.8 μg/dl). Ejection fraction (33% vs 63%), LV contractility measured by EES (0.7 vs 1.2 mmHg/μl) and MSW (57.2 vs 88.9 mmHg) were significantly decreased. LV time constant of relaxation (τ) (16.8 vs 10.7 ms) was increased by 57%. Importantly, these abnormalities of LV in Hypo rats were paralleled by concomitant depressions in myocyte contraction and relaxation indicated by decreased dL/dtmax (57%, Hypo: 63.5±5.4 vs C: 147.8±5.6 μm/s) and dR/dtmax (52%, 59.4±7.4 vs 123.8±7.5 μm/s) with reduced [Ca2+]iT (-31%, 0.18 vs 0.26) and markedly slowed the decline of [Ca2+]i . β1-AR expression decreased about 36% in Hypo compared with controls (0.48 vs 0.75). This was accompanied by attenuated responses to β-adrenergic stimulation. Isoproterenol (10-8 M) produced significantly less increases in dL/dtmax (30.7% vs 92.9%), dR/dtmax (23.4% vs 66.9%), and [Ca2+]iT (17% vs 34%) in Hypo myocytes compared to normal.
Conclusions. Hypothyroidism produces LV and myocyte systolic and diastolic dysfunction, [Ca2+]iT reduction and decreased myocyte β1-AR expression with impaired β-adrenergic regulation. The defects in cardiomyocyte force-generating capacity and relaxation process with impaired [Ca2+]i regulation may be the primary cause of hypothyroid cardiomyopathy.
- © 2011 by American Heart Association, Inc.