Modified Low-Dose Triiodo-L-thyronine Therapy Safely Improves Function Following Myocardial Ischemia-Reperfusion Injury

Abstract

Background: We have shown that thyroid hormones (THs) are cardioprotective and can be potentially used as safe therapeutic agents for diabetic cardiomyopathy and permanent infarction. However, no reliable, clinically translatable protocol exists for TH treatment of myocardial ischemia-reperfusion (IR) injury. We hypothesized that modified low-dose triiodo-L-thyronine (T3) therapy would confer safe therapeutic benefits against IR injury.Methods: Adult female rats underwent left coronary artery ligation for 60 min or sham surgeries. At 2 months following surgery and T3 treatment (described below), the rats were subjected to functional, morphological, and molecular examination.Results: Following surgery, the rats were treated with T3 (8 μg/kg/day) or vehicle in drinking water ad libitum following IR for 2 months. Oral T3 significantly improved left ventricular (LV) contractility, relaxation, and relaxation time constant, and decreased beta-myosin heavy chain gene expression. As it takes rats ~6 h post-surgery to begin drinking water, we then investigated whether modified T3 dosing initiated immediately upon reperfusion confers additional improvement. We injected an intraperitoneal bolus of T3 (12 μg/kg) upon reperfusion, along with low-dose oral T3 (4.5 μg/kg/day) in drinking water for 2 months. Continuous T3 therapy (bolus + low-dose oral) enhanced LV contractility compared with oral T3 alone. Relaxation parameters were also improved compared to vehicle. Importantly, these were accomplished without significant increases in hypertrophy, serum free T3 levels, or blood pressure.Conclusions: This is the first study to provide a safe cardiac therapeutic window and optimized, clinically translatable treatment-monitoring protocol for myocardial IR using commercially available and inexpensive T3. Low-dose oral T3 therapy supplemented with bolus treatment initiated upon reperfusion is safer and more efficacious.

Low T3 syndrome improves risk prediction of in-hospital cardiovascular death in patients with acute myocardial infarction

“…Supplementation of T3 has not been proven to be effective in improving outcomes among patients with noncardiac illnesses-induced LT3S [23]. However, the effect of T3 replacement in patients with AMI [9,24] remains to be further investigated.…”

Long non‑coding RNA H19 protects H9c2 cells against hypoxia‑induced injury by activating the PI3K/AKT and ERK/p38 pathways

“…The lncrna H19 (H19) is located on human chromosome 11 and expresses a 2.3 kb lncrna transcribed from the maternal inherited allele (13). increased expression of H19 was detected in rats following surgically induced myocardial i/r, suggesting that H19 may have a role in the protective mechanisms against i/r injury (14). Previous studies have also indicated that H19 exerts protective effects against hypoxia-induced injury in cardiomyocytes (15,16).…”

Comparison of Therapeutic Triiodothyronine Versus Metoprolol in the Treatment of Myocardial Infarction in Rats

“…Moreover, evidence is accumulating that TH administration post MI and HF improves cardiac contractility and myocardial remodeling, and improves cardiovascular risk factors, especially lipid profiles (12,13). It was recently demonstrated that T3 safely improved heart function and remodeling in experimental models of MI and ischemia-reperfusion injury (14,15). However, it has not been shown whether such a T3 treatment-monitoring protocol can serve as an efficient therapeutic strategy in comparison with existing standard therapies.…”