Abstract 15920: Thyroid Hormones Maintain Functional T-Tubule Networks in Cardiomyocytes

In patients with pre-existing heart failure, subclinical hypothyroidism or low T3 syndrome are associated with poor outcomes, and several studies have reported improved prognosis with T3 treatment. In animal models of heart failure, we have shown that low dose T3 treatment improves contractile function by attenuating adverse remodeling of the T-tubule (TT) network, and here we studied T3 effects on TT organization and function in thyroid deficiency.Methods:Female Sprague Dawley rats (~220g) ingested 0.025% PTU in drinking water to induce thyroid deficiency. Control rats had access to untreated water. After 8 weeks, a subgroup of PTU treated rats received T3 (10ug/kg/d) in PTU-containing water for an additional 2 weeks. At week 10, echocardiography and LV pressures were recorded. Ventricular myocytes were isolated by collagenase digestion, and contractile and calcium transients were recorded in single myocytes by IonOptix imaging. Live cardiomyocytes were labeled with wheat germ agglutinin (WGA)-488 or di-8-ANNEPS, and images were captured by scanning confocal microscopy and analyzed for TT periodicity. Ventricular RNA was analyzed by RT-qPCR.Results:Echocardiography and hemodynamic measurements showed improved (p<0.0001) systolic and diastolic functions with T3 treatment vs PTU (+dP/dt = 7378?1441 vs 3253?343; -dP/dt = 6900?1280 vs 2901?348). Isolated cardiomyocyte contractile measurements were impaired in PTU and significantly improved with T3 treatment (Vmax contraction = 2.54?0.52 vs 1.67?0.38; time to peak contraction (s) = 0.20?0.03 vs 0.32?0.05; Vmax relengthening = 1.55?0.59 vs 1.00?0.34). Ca2+transients showed significant increases with T3 treatment vs PTU (Vmax Ca2+release = 16.28?2.21 vs 9.13?3.06; Vmax Ca2+reuptake = 1.07?0.24 vs 0.67?0.23). TT periodicity was significantly reduced in PTU myocytes and increased (p< 0.01) with T3 treatment (TTpower = 85?3 control, 73?3 PTU and 82?4 PTU+T3). Expression of bridging integrator 1 (Bin1), integral to TT formation, was decreased in thyroid deficiency and normalized by T3.Conclusions:T3 is a critical regulator of TT structures and further supports the role of thyroid hormones in maintaining cardiac function in chronic diseases with thyroid deficiency including heart failure.