Developing Oral LT3 Therapy for Heart Failure - PROJECT SUMMARY
Heart failure is the most common reason for adult hospitalization in the developed world. Therapies that target
reversible causes of myocardial and peripheral organ dysfunction are likely to provide added benefit in heart
failure with reduced ejection fraction (HFrEF). In addition, there are no proven effective pharmacologic
therapies for heart failure with preserved ejection fraction (HFpEF), which accounts for ≥50% of the heart
failure burden. Triiodothyronine (T3), an endogenous thyroid hormone, exerts multiple effects on the
cardiovascular system, mediated through T3 receptors in the myocardium and vasculature and directly on ion
channels and mitochondria. Overarching effects of T3 include an increase in myocardial contractility and a
decrease in systemic vascular resistance. Despite the high prevalence (~20-30%) of low T3 syndrome in heart
failure, the exogenous administration of liothyronine (LT3), the synthetic form of T3, remains an underexplored
therapeutic option. Low T3 syndrome has been associated with increased mortality in patients with HFrEF and
disease severity in HFpEF, but whether it is a marker of poor health or a mediator of clinically relevant
abnormalities in heart failure is unknown. Our overall goal is to determine the safety, feasibility, and preliminary
efficacy of oral LT3 therapy in patients with HF and low T3. Proof of concept clinical studies using short-term
intravenous LT3 infusions have demonstrated beneficial effects on biomarkers and safety in patients with
ischemic HFrEF. However, knowledge gaps remain regarding the safety of oral LT3 therapy in HFrEF.
Furthermore, no studies have examined LT3 safety in HFpEF. We intend to fill those gaps through two parallel,
randomized, double-blind, placebo-controlled studies of LT3 administration in patients with low T3 syndrome:
one in patients with HFrEF and the other in patients with HFpEF. Our safety outcomes will be T3 levels and
rhythm monitoring. Our preliminary efficacy outcomes will be peak rate of oxygen consumption (VO2), quality
of life, cardiac biomarkers, home activity via actigraphy, and noninvasive assessments of LV function, vascular
function, and ventricular-arterial coupling. The proposed studies will assess the safety and preliminary efficacy
of administering oral LT3 therapy in two independent study populations. Our team includes a thyroidologist
clinical investigator working closely with seasoned HFrEF and HFpEF investigators with extensive early phase
trial experience. Strengths of the proposed trials include the controlled design, selection of patients most likely
to benefit (those with low T3 levels), careful titration of LT3, and use of clinically relevant outcomes. Conduct of
both studies in parallel will enable efficiencies in recruitment and comparisons of safety. The results of these
studies will provide essential data to determine if larger scale clinical trials of T3 therapy should be pursued in
patients with each condition.
