Best Therapeutic Strategy for Triiodo‐L‐thyronine Treatment of Ischemic Heart Disease
Authors: Rajagopalan Viswanathan , Zhang Youhua , Pol Christiana , Seitter Samantha , Costello Clifford , Chen Yue‐feng , Li Ying , Gerdes Anthony M 
Published: November 2023

BackgroundA large body of evidence suggests that the alarmingly high incidence of hypothyroidism (low thyroid function, overt/subclinical) and low Triiodo‐L‐thyronine (T3) syndrome in patients with cardiovascular diseases (CVD) has significant negative outcomes. Recent rodent studies show that CVD, including experimental myocardial infarction, diabetic cardiomyopathy (DCM) and hypertensive (HTN) heart failure contribute to low myocardial T3 levels. We previously showed that low‐dose oral T3 therapy (3–4 ug/kg/day) resulted in significant cardioprotective benefits in both DCM and HTN without adverse effects. However, the best T3 treatment strategy for ischemic heart disease is not clear. We hypothesized that T3 supplementation initiated upon ischemic injury would offer optimum therapeutic benefits.Methods and ResultsAdult female rats underwent left coronary artery ligation (permanent [MI] or 60 min ischemia followed by reperfusion [IR]) or sham surgeries (n=7–11/group). T3 or vehicle (V) was available in drinking water ad libitum immediately following surgery and continuing for 2 months.We first investigated the extent to which IR contributed to salvaged myocardium than MI. Compared to untreated MI, untreated IR resulted in improved LV dP/dtmin (28%; p<0.05), decreased inducible atrial tachyarrhythmias (65%, p<0.05), reduced infarct fibrotic area by trichrome staining (38%, p<0.01) and increased non‐infarct length (24%, p<0.05). Low‐dose oral T3 treatment (5–8 μg/kg/day) further improved left ventricular (LV) dP/dtmax following both MI (12.3%, p<0.05) and IR (27.4%, p<0.01) and reduced infarct area.Our observations showed that it takes rats ~6 hours post‐surgery to begin drinking water. Therefore, we investigated whether continuous T3 supplementation initiated upon reperfusion confers better improvement than oral‐only treatment. Accordingly, we injected an intraperitoneal bolus of T3 (12 μg/kg/day) upon reperfusion along with ad libitum low‐dose oral T3 (5 μg/kg/day) in drinking water. We found that continuous T3 treatment (bolus+oral) resulted in additional improvements in LV dP/dtmax (mmHg/sec; IR+V:6330±198; IR+oral T3:7680±335, p<0.01 vs. IR+V; IR+bolus/oral T3:8938±606, p<0.001 vs. IR+V, p<0.05 vs. IR+oral T3), dP/dtmin and reduced LV end‐diastolic pressure (mmHg; IR+V:6.4±0.7; IR+oral T3:7.6±1.5; IR+bolus/oral T3:4.8±0.42) compared to oral T3 alone. Importantly, all these were accomplished without significant increases in heart rate, LV weight/body weight ratio and mean arterial pressure, compared to vehicle treatment (p=ns).ConclusionsLow‐dose oral T3 therapy supplemented with bolus treatment initiated upon reperfusion is safe and more efficacious than other approaches. Taken together, we have now established a safe therapeutic window (3–8 ug/kg/day) and clinically translatable protocols for low‐dose oral T3 treatment of diverse forms of CVD, viz., myocardial ischemic injury, DCM and HTN.Support or Funding InformationNIH Grant R01HL103671 for Dr. Anthony Martin Gerdes