Abstract
BackgroundA large body of evidence suggests that thyroid hormones (THs) are beneficial for the treatment of cardiovascular disorders. We have shown that 3 days of triiodo-L-thyronine (T3) treatment in myocardial infarction (MI) rats increased left ventricular (LV) contractility and decreased myocyte apoptosis. However, no clinically translatable protocol is established for T3 treatment of ischemic heart disease. We hypothesized that low-dose oral T3 will offer safe therapeutic benefits in MI.Methods and ResultsAdult female rats underwent left coronary artery ligation or sham surgeries. T3 (~6 μg/kg/day) was available in drinking water ad libitum immediately following MI and continuing for 2 month(s) (mo). Compared to vehicle-treated MI, the oral T3-treated MI group at 2 mo had markedly improved anesthetized Magnetic Resonance Imaging-based LV ejection fraction and volumes without significant negative changes in heart rate, serum TH levels or heart weight, indicating safe therapy. Remarkably, T3 decreased the incidence of inducible atrial tachyarrhythmias by 88% and improved remodeling. These were accompanied by restoration of gene expression involving several key pathways including thyroid, ion channels, fibrosis, sympathetic, mitochondria and autophagy.ConclusionsLow-dose oral T3 dramatically improved post-MI cardiac performance, decreased atrial arrhythmias and cardiac remodeling, and reversed many adverse changes in gene expression with no observable negative effects. This study also provides a safe and effective treatment/monitoring protocol that should readily translate to humans.
Highlights
Thyroid hormones (THs) serve as a master regulator in the control of diverse molecular, physiological and pathophysiological remodeling processes in the heart and vascular system [1, 2]
T3 decreased the incidence of inducible atrial tachyarrhythmias by 88% and improved remodeling
These were accompanied by restoration of gene expression involving several key pathways including thyroid, ion channels, fibrosis, sympathetic, mitochondria and autophagy
Summary
Thyroid hormones (THs) serve as a master regulator in the control of diverse molecular, physiological and pathophysiological remodeling processes in the heart and vascular system [1, 2]. Studies have repeatedly shown increased morbidity and mortality in heart failure (HF) patients with low serum TH levels [3, 4]. We have successfully demonstrated prevention/attenuation of left ventricular (LV) dysfunction/remodeling without significantly altering thyroid homeostasis using low dose oral triiodo-L-thyronine (T3) treatment in models of diabetic cardiomyopathy and hypertensive heart failure [5, 14]. The major goal of this study was to explore a safe therapeutic window for oral T3 treatment of myocardial infarction (MI) in rats and verify efficacy of a selected dose within that window. The ongoing THiRST (Thyroid Hormone Replacement Therapy in ST Elevation MI) trial investigating oral T3 treatment of STEMI patients served as a major catalyst for this animal study We hypothesized that low-dose oral T3 will offer safe therapeutic benefits in MI
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