Abstract 4147079: Effects of Oral LT3 in Participants with Isolated Low T3 levels and Heart Failure: A Randomized, Placebo-controlled, Crossover Trial

Introduction: Observational studies in heart failure (HF) patients have shown that low levels of the thyroid hormone triiodothyronine (T3) with otherwise normal thyroid testing (‘low T3 syndrome’) is a risk factor for adverse clinical outcomes. Preclinical studies have shown beneficial effects from T3 therapy on myocardial contractility, myocardial relaxation, and vascular resistance, but human studies are lacking. Research Question: In patients with HF and low T3 syndrome, is oral liothyronine (LT3) safe, and does it impact cardiovascular clinical and physiologic phenotypes? Aims: Primary aim: To evaluate the safety of oral LT3 therapy in HFrEF and HFpEF. Secondary aim: To evaluate the feasibility and preliminary efficacy of oral LT3 therapy in HFrEF and HFpEF. Methods: A total of 28 participants with HFrEF and 28 with HFpEF aged 18+ years enrolled in a single-center, randomized, double-blind, placebo-controlled, crossover trial and were prescribed LT3 or placebo for 8 weeks with a 2-week washout period. Primary outcomes were safety as assessed by T3 level; arrhythmic events by EKG, 14-day adhesive patch monitoring, and ICD (HFrEF only); and adverse events. Secondary efficacy outcomes included Kansas City Cardiomyopathy Questionnaire, NT-proBNP level, peak O2 consumption during a cardiopulmonary exercise test, and actigraphy. Secondary mechanistic outcomes included non-invasive assessments of cardiac and arterial function measured via echocardiography and arterial tonometry. Results: Low T3 syndrome was present in 20% of screened participants. After LT3 treatment, T3 levels markedly increased compared with placebo. Heart rate was higher on LT3 (mean difference 2.4 beats per minute, p <0.05), but otherwise, primary safety and secondary efficacy endpoints were not different between LT3 and placebo. In HFrEF participants, secondary mechanistic endpoints indicated an increase in LV ejection fraction and the intensity of forward compression and backward suction waves generated by the LV (p <0.05), despite GDMT and beta-blockade. Conclusion: In participants with HF and low T3 syndrome, oral LT3 titrated to T3 levels in the upper reference range was safe. LT3 increased heart rate, and, among HFrEF participants, increased LV ejection fraction and other parameters of LV inotropic and lusitropic function. A larger clinical trial of LT3 in HFrEF patients with low T3 syndrome is required to determine if these efficacy signals translate into clinical benefit.