Effects of Triiodothyronine (T3) in Ischemic Heart Failure

About six million adults in the United States have heart failure (HF). Myocardial ischemic injury is the most common trigger of HF and most deaths after a myocardial infarction (MI) are preceded by HF. Treatment for HF with reduced ejection fraction (HFrEF) consists of beta-adrenergic receptor antagonists, antagonists of the renin-angiotensin-aldosterone system (ACEI, ARB, angiotensin receptor neprilysin inhibition), aldosterone antagonists, and Sodium-glucose Cotransporter-2 (SGLT-2) antagonists. Despite these guideline-directed therapies, 1 in 2 HF patients dies within 5 years of diagnosis, a death rate similar to that of some cancers. Thus, the development of next-generation therapies to treat HF represents an important unmet clinical need.

The overarching goal of these preclinical and anticipated clinical studies is to develop translatable strategies, using transient triiodothyronine (thyroid hormone T3) administration in patients with HF receiving beta1-adrenergic receptor (AR) blocker therapy (metoprolol succinate) with other HF medications, to permanently improve left ventricular (LV) contractile function by regenerating cardiac muscle.

The most-cited basis of ineffective cardiac regeneration in mammals is the low proliferative capacity of adult cardiomyocytes. The investigators have sought to understand the most important aspects of these processes to develop therapies that can be used to build or rebuild heart muscle in diseased hearts.

In brief, the investigators' preclinical studies show that T3+metoprolol therapy regenerates heart muscle by increasing cardiomyocytes around the scar and increases the left ventricular ejection fraction (LVEF) thereby restoring LV wall contractility in the scar region. De novo cardiomyogenesis requires neovascularization along with cardiomyocyte proliferation so that the nutrient and oxygen demands of the expanding myocardium are met. Our preliminary studies also show that in chronic post-MI hearts, the mid-apical LV myocardium was repopulated with cardiomyocytes following T3+metoprolol therapy and, in this myocardium, cardiomyocytes were not hypertrophied (data not shown). Importantly, the researchers found no significant differences in mid-apical capillary-to-cardiomyocyte ratios between T3+metoprolol treated post-MI hearts and uninjured age-matched controls.

Together, these findings suggest lasting regenerative repair of hearts with severe preexisting ischemic injury after a brief period of T3+metoprolol combination therapy. Importantly, over the course of this 5-month follow up the research team did not observe any signs of arrhythmias or increase in mortality in mice treated with T3+metoprolol combination therapy. Low free T3 levels (<2.5pg/ml) are found in approximately 10% of patients with early HF and 58% of patients with late HF and are more frequently observed in patients with HF of NYHA class III-IV. This is likely secondary to the upregulation of type 3 iodothyronine deiodinase. Low T3 levels correlate with LVEF and BNP levels in HF. Importantly, a low T3 level in addition to BNP levels is an independent predictor of worse outcomes in patients with HF and after MI. The T3 production rate in normal humans is 16 ± 3 μg/m2 BSA/day. In patients with HF and low T3 levels, 20 μg/m2 BSA/d T3 increased T3 levels significantly to within the normal range. The rate of infusion on days 2 and 3 was then lowered to 13.4 μg/m2 BSA/day on average to maintain this level. There was a concomitant decrease in T4 (10.9 to 9.6 pg/ml) and thyroid-stimulating hormone (TSH) from 2.43 to 0.55 IU but they remained in the normal range.

Based on previous experience in patients with HF, researchers propose to employ a 5-day oral treatment with L-T3 in gradually increasing doses to rapidly establish higher T3 levels in patients with stable ischemic HF with an EF≤40%. The team anticipates that doses of T3 used in the proposed studies will not cause tachycardia or dysrhythmias. Even though the final L-T3 dose proposed here is twice that was previously used, the team believes that the possibility of inducing tachycardia is likely to be low because of the concomitant treatment with metoprolol succinate, a B1-selective (cardioselective) adrenergic receptor blocker therapy. Researchers do not anticipate the development of other hyperthyroid symptoms in these patients as L-T3 administration is only for a brief period of 5 days.

Inclusion criteria

• Aged 18-80 years, male or female;
• Confirmed diagnosis of ischemic HF with left ventricular ejection fraction (LVEF) ≤ 40% (measured by echocardiography within 1 month of Screening);
• Stable symptoms; NYHA class II-III without recent admission (1 month) for acute decompensation;
• Receiving guideline-based standard HF therapies at the maximum tolerated doses for >1 month. Patients on other beta-blockers will be switched to metoprolol succinate at equivalent doses for 3 weeks.
• Presence of ICD for >1 month or implantable cardiac resynchronization therapy defibrillator (CRT-D) for >3 months
• Understand and sign the informed consent form.

Exclusion criteria

• LVEF > 40%;
• Unremitting atrial fibrillation during the screening period or clinically significant ventricular tachycardia (on ICD interrogation);
• Non-ischemic HF including hypertrophic cardiomyopathy, peripartum or chemotherapy-induced cardiomyopathy, other non-ischemic cardiomyopathies, constrictive pericarditis, significant and uncorrected valvular heart disease (severe regurgitation or severe stenosis or valvular disease requiring surgery), congenital heart disease, primary pulmonary hypertension or secondary severe pulmonary hypertension (≥ 70 mmHg); large pericardial or pleural effusions; right heart failure due to lung disease;
• Recent admission (1 month) for acute decompensated HF;
• Angina pectoris, cerebrovascular accident, myocardial infarction, revascularization (PCI or other surgery), carotid artery or other large vessel surgery, or cardiac resynchronization therapy (CRT) implant within the past 3 months;
• Planned revascularization within 6 months;
• History of heart transplantation, use of ventricular assist device (VAD) or preparation for heart transplantation, VAD;
• Liver dysfunction (bilirubin or alkaline phosphatase > 2 times the upper limit of normal (ULN), aspartate aminotransferase or alanine aminotransferase > 3 times the upper limit of normal), estimated glomerular filtration rate (eGFR) calculated using the Modification of Diet in Renal Disease Study (MDRD) method < 30 ml/min/1.73 m2;
• Systolic blood pressure < 90 mmHg or > 160 mmHg;
• Blood K+ < 3.2 mmol/L or > 5.5 mmol/L;
• Women of childbearing age who are planning to become pregnant within 2 years, and pregnant or lactating women;
• Patients whose survival time is expected to be less than 6 months as judged by the investigator;
• Those who have participated in any drug clinical trial within the previous 3 months;
• Severe neurological disorders (Alzheimer's disease, progressive parkinsonism);
• The subjects with a history of cancer that limits life expectancy to <1 year;
• Endocrine disorders include thyroid disease, thyroid replacement therapy, pheochromocytoma, thyromegaly, etc.
• The subject, in the judgment of the Investigator, is unable to complete the study or to comply with the requirements of the study (for administrative or other reasons);
• Prisoners;
• Adults unable to consent;