Short-term but not long-term triiodothyronine treatment improved cardiac function after myocardial infarction in male wild-type mice

ObjectivesThyroid hormone (TH), especially triiodothyronine (T3), plays an important role in cardiac physiology and in the remodeling process following myocardial infarction (MI). We investigated the effects of short-term (until day 5) and long-term (until day 56) post-MI T3 treatment on cardiac function, infarct size, hypertrophy, and gene expression in mice without and with deletion of TR, the main cardiac thyroid hormone receptor (wild-type (WT) and TRKO, respectively) MethodsWT and TRKO mice underwent permanent left anterior descending coronary artery (LAD) ligation or sham surgery followed by either short-term T3 for 5 days post-MI or long-term T3 until day 56, including a subgroup in which T3 treatment commenced 14 days post-MI; all groups were followed up for 4 weeks. T3 was delivered via drinking water at 500 ng/ml. Cardiac function was studied with echocardiography (ejection fraction, EF), infarct size by histology (Sirius red), heart weight normalized to tibia length, and transcriptomic profiling (RNA-seq) in WT hearts. ResultsShort-term T3 improved EF in WT but not in TRKO mice without induction of hypertrophy or changes in infarct size in either genotype. Long-term T3 induced cardiac hypertrophy in both WT and TRKO mice. However, long-term T3 did not improve EF or reduce infarct size. In TRKO mice, baseline EF post-MI was preserved without T3, but T3 treatment decreased EF. RNA-seq in long-term treated WT mice suggested modulation of Rho-GTPase signaling, mitochondrial biogenesis, and immune activation by T3. ConclusionsT3 therapy post-MI improved cardiac function only when applied acutely and for a short term. Long-term exposure led to cardiac hypertrophy without functional improvement and may even worsen cardiac function in TR-deficient settings. Timing, duration, and receptor status are highly relevant for TH-based interventions in MI.