Heart failure (HF) with reduced ejection fraction (HFrEF) remains a major public health burden, affecting over 6 million adults in the United States. Despite advances in HF guideline-directed medical therapy (GDMT), HFrEF continues to carry high rates of morbidity and mortality. This excess burden of poor outcomes underscores the need for novel therapies targeting HFrEF disease progression.
Preclinical investigations have identified triiodothyronine (T3) as a promising target for cardiac regeneration. Murine modeling of ischemic cardiomyopathy has demonstrated cardiomyocyte remuscularization following transient T3 administration with β1-selective receptor blockade, induced by dual-specificity phosphatase-5 (DUSP5) expression, a nuclear phosphatase associated with cellular proliferation and differentiation. , In humans, low T3 is common among patients with advanced HFrEF and independently predicts poor outcomes. Small trials in patients with HFrEF and low T3 have shown that T3 supplementation is well-tolerated and may improve LV function and quality of life. ,,, However, concern remains regarding arrhythmic risk, especially in euthyroid patients. Thus, we conducted a phase I clinical trial to evaluate the safety, tolerability, and preliminary effects of short-term oral T3 therapy in euthyroid patients with ischemic HFrEF treated with β1-adrenergic antagonists.
We recruited patients with ischemic cardiomyopathy, left ventricular ejection fraction (LVEF) ≤40%, and an implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy defibrillator. Five participants were sequentially allocated to treatment with T3 and 5 to usual care; all with 6 months of planned follow-up. The trial was approved by the IRB of Emory University (Atlanta, GA), registered (NCT05384847), and overseen by a Data and Safety Monitoring Board. Euthyroid adults aged 18-80 years with ischemic HFrEF, New York Heart Association (NYHA) Class II-III symptoms, and on stable GDMT were eligible. All participants transitioned to metoprolol succinate ≥3 weeks before enrollment to ensure β1-selective blockade. Key exclusion criteria included nonischemic HFrEF, recent history of acute coronary syndrome, known thyroid disease, or advanced HF therapies.
The first 2 T3-treated participants received 5 µg oral T3 twice daily for 2 days, followed by 10 µg twice daily for 3 days. T3 levels in this subgroup increased from 114.5 (111.8,117.3) to 155.5 (151.3,160.0) ng/dl. After demonstration of safety, the next 3 participants received 10 µg T3 twice daily for 2 days, followed by 20 µg T3 twice daily for 3 days. T3 levels in this subgroup increased from 133.0 (119.0,147.0) to 180.5 (169.3,191.8) ng/dl. During T3 administration, participants were monitored with continuous telemetry, thyroid function laboratory testing, adverse event monitoring, ICD interrogation, high-sensitivity troponin I (hsTnI), and brain natriuretic peptide (BNP) levels. In addition, transthoracic echocardiography (TTE), 6-minute walk test (6MWT) and Kansas City Cardiomyopathy Questionnaire (KCCQ) testing were completed at baseline, 3-month and 6-months. The primary safety endpoints were occurrence of clinical arrhythmias, angina, or adverse cardiovascular events. Secondary endpoints included changes in vital signs and thyroid laboratory assessments. Exploratory endpoints included changes in TTE indices and functional assessments (6MWT and KCCQ).
In the 10 enrolled participants, (mean age 67.3 years, 20% women, 30% Black, and mean LVEF 36%), baseline thyroid parameters were similar between groups. No clinical arrhythmias, angina, or adverse cardiovascular events occurred. One participant developed asymptomatic sinus tachycardia, and 1 participant experienced recurrence of known nonsustained ventricular tachycardia. BNP decreased during hospitalization.
At 3 months, T3-treated participants demonstrated improved 6MWT distance compared to usual care, which persisted at 6 months. KCCQ scores were similar between groups. LVEF remained stable over 6 months in both groups, and LV volumes were stable in T3-treated patients but increased numerically in the usual care group. BNP levels increased in usual care group but not in the T3 group during follow-up, while hsTnI remained unchanged in both arms ( Table 1 ).
Table 1
Characteristics of study cohort
| Variables (median [IQR]) | Usual care | T3-treated |
|---|---|---|
| N = 5 | N = 5 | |
| KCCQ-OS | ||
| Baseline | 88.8 (83.9, 89.1) | 81.2 (77.1, 85.9) |
| 6 mo | 90.6 (88.0, 91.7) | 88.8 (87.5, 92.2) |
| 6-Minute walk test (feet) | ||
| Baseline | 1,211 (1,147, 1,306) | 1,123 (1,112, 1,362) |
| 6 mo | 1,151 (1,027, 1,295) | 1,263 (1,175, 1,319) |
| hsTnI (pg/ml) | ||
| Baseline | 6.0 (5.0, 10.0) | 11.0 (9.0, 13.0) |
| Post-T3 | NA | 12.0 (5.0, 13.0) |
| 6 mo | 7.0 (5.0, 7.0) | 10.0 (7.5, 12.5) |
| BNP (pg/ml) | ||
| Baseline | 96.0 (71.0, 144.0) | 33.0 (31.0, 807.0) |
| Post-T3 | NA | 24.0 (20.0, 216.0) |
| 6 mo | 166.0 (59.0, 175.0) | 29.0 (24.3, 76.0) |
| TTE parameters | ||
| Baseline | ||
| LVEF, Biplane (%) | 36.0 (32.0, 38.0) | 38.0 (35.0, 42.0) |
| LVEDV (ml) | 132.0 (121.0, 222.0) | 162.0 (141.0, 197.0) |
| LVESV (ml) | 87.0 (73.2, 141.0) | 124.0 (77.0, 126.0) |
| 6 mo | ||
| LVEF, Biplane (%) | 35.0 (33.0, 44.0) | 37.5 (30.0, 43.8) |
| LVEDV (ml) | 207.0 (143.0, 235.0) | 163.0 (102.78, 226.5) |
| LVESV (ml) | 118.0 (79.4, 168.0) | 114.5 (58.3, 171.0) |
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