Abstract
Pre-clinical animal studies have shown that triiodothyronine (T3) replacement therapy improves cardiac contractile function after myocardial infarction (MI). We hypothesized that T3 treatment could prevent adverse post-infarction cardiomyocyte remodeling by maintaining transverse-tubule (TT) structures, thus improving calcium dynamics and contractility.MethodsMyocardial infarction (MI) or sham surgeries were performed on female Sprague-Dawley rats (aged 12 wks), followed by treatment with T3 (5μg/kg/d) or vehicle in drinking water for 16 wks (n = 10–11/group). After in vivo echocardiographic and hemodynamic analyses, left ventricular myocytes were isolated by collagenase digestion and simultaneous calcium and contractile transients in single cardiomyocytes were recorded using IonOptix imaging. Live cardiomyocytes were stained with AlexaFluor-488 conjugated wheat germ agglutinin (WGA-488) or di-8-ANEPPS, and multiple z-stack images per cell were captured by confocal microscopy for analysis of TT organization. RTqPCR and immunoblot approaches determined expression of TT proteins.ResultsEchocardiography and in vivo hemodynamic measurements showed significant improvements in systolic and diastolic function in T3- vs vehicle-treated MI rats. Isolated cardiomyocyte analysis showed significant dysfunction in measurements of myocyte relengthening in MI hearts, and improvements with T3 treatment: max relengthening velocity (Vmax, um/s), 2.984 ± 1.410 vs 1.593 ± 0.325, p < 0.05 and time to Vmax (sec), 0.233 ± 0.037 vs 0.314 ± 0.019, p < 0.001; MI + T3 vs MI + Veh, respectively. Time to peak contraction was shortened by T3 treatment (0.161 ± 0.021 vs 0.197 ± 0.011 s., p < 0.01; MI + T3 vs MI + Veh, respectively). Analysis of TT periodicity of WGA- or ANEPPS-stained cardiomyocytes indicated significant TT disorganization in MI myocytes and improvement with T3 treatment (transverse-oriented tubules (TE%): 9.07 ± 0.39 sham, 6.94 ± 0.67 MI + Veh and 8.99 ± 0.38 MI + T3; sham vs MI + Veh, p < 0.001; MI + Veh vs MI + T3, p < 0.01). Quantitative RT-PCR showed that reduced expression of BIN1 (Bridging integrator-1), Jph2 (junctophilin-2), RyR2 (ryanodine receptor) and Cav1.2 (L-type calcium channel) in the failing myocardium were increased by T3 and immunoblot analysis further supporting a potential T3 effect on the TT-associated proteins, BIN1 and Jph2.In conclusion, low dose T3 treatment initiated immediately after myocardial infarction attenuated adverse TT remodeling, improved calcium dynamics and contractility, thus supporting the potential therapeutic utility of T3 treatment in heart failure.
Highlights
Anterior wall thickness was decreased in myocardial infarction (MI) compared to sham animals, but wall thickness in systole was significantly greater in MI + T3 compared to MI + Veh suggesting improved ventricular remodeling with T3 treatment
The impaired left ventricular (LV) function with increased filling pressures in MI + Veh animals resulted in a 40% increase in left atrial diameter that was decreased by T3 treatment to an atrial chamber size not different from sham animals (Table 1)
Using quantitative RT-PCR, we showed that bridging integrator-1 (BIN1) (p < 0.01) and Jph2 mRNAs were significantly decreased in MI compared to sham hearts, and that expression of these genes were increased toward sham levels with T3 treatment (Fig. 5a)
Summary
Patients with heart failure (HF) resulting from coronary artery disease or other causes that lead to systolic or diastolic dysfunction often present with thyroid abnormalities with low circulating thyroid hormones (subclinical hypothyroidism or low T3 syndrome), occurring with increasing frequency with increased disease severity (Ascheim and Hryniewicz 2002; Ertugrul et al 2011; Pingitore et al 2005; Rothberger et al 2017; Hayashi et al 2016; Iervasi et al 2003; Hamilton et al 1990; Kannan et al 2018). Jph gene therapy in mice with HF was shown to normalize RyR2-induced calcium release, while β-adrenergic receptor blocker treatment improved TT integrity and Jph expression in mice after myocardial infarction (Reynolds et al 2016; Fu et al 2016; Lyon et al 2012; Chen et al 2012)
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