Cardioprotection by post-conditioning with exogenous triiodothyronine in isolated perfused rat hearts and isolated adult rat cardiomyocytes

Abstract

Ischemic post-conditioning (iPoCo) by coronary re-occlusion/reperfusion during immediate reperfusion after prolonged myocardial ischemia reduces infarct size. Mechanical manipulation of culprit lesions, however, carries the risk of coronary microembolization which may obscure iPoCo’s cardioprotection. Pharmacological post-conditioning with exogenous triiodothyronine (T3) could serve as an alternative conditioning strategy. Similar to iPoCo, T3 may activate cardioprotective prosurvival pathways. We aimed to study T3’s impact on infarct size and its underlying signal transduction. Hearts were isolated from male Lewis rats (200–380 g), buffer-perfused and subjected to 30 min/120 min global zero-flow ischemia/reperfusion (I/R). In additional hearts, either iPoCo (2 × 30 s/30 s I/R) was performed or T3 (100–500 µg/L) infused at reperfusion. Infarct size was demarcated with triphenyl tetrazolium chloride staining and calculated as percent of ventricular mass. Infarct size was reduced with iPoCo to 16 ± 7% vs. 36 ± 4% with I/R only. The maximum infarct size reduction was observed with 300 µg/L T3 (14 ± 2%). T3 increased the phosphorylation of protein kinase B and mitogen extracellular-regulated-kinase 1/2, both key enzymes of the reperfusion injury salvage kinase (RISK) pathway. Pharmacological RISK blockade (RISK-BL) during reperfusion abrogated T3’s cardioprotection (35 ± 10%). Adult ventricular cardiomyocytes were isolated from buffer-perfused rat hearts and exposed to 30 min/5 min hypoxia/reoxygenation (H/R); reoxygenation was initiated without or with T3, respectively, and without or with RISK-BL, respectively. Maximal preservation of viability was observed with 500 µg/L T3 after H/R (27 ± 4% of all cells vs. 5 ± 3% in time-matched controls). Again, RISK-BL abrogated protection (11 ± 3%). Mitochondria were isolated at early reperfusion from buffer-perfused rat hearts without or with iPoCo or 300 µg/L T3, respectively, at reperfusion. T3 improved mitochondrial function (i.e.: increased respiration, adenosine triphosphate production, calcium retention capacity, and decreased reactive oxygen species formation) to a similar extent as iPoCo. T3 at reperfusion reduces infarct size by activation of the RISK pathway. T3’s protection is a cardiomyocyte phenomenon and targets mitochondria.

The Potential of Thyroid Hormone Therapy in Severe COVID-19: Rationale and Preliminary Evidence

“…In contrast, the same dose of T3 in normal isolated perfused hearts did not have any effect on myocardial function. In accordance with this, a recent study has also shown that high-dose T3 administration at reperfusion can reduce infarct size and improve mitochondrial function [43]. Furthermore, high-dose T3 increased contractile recovery in human right atrial trabeculae subjected to hypoxia and reoxygenation [44].…”

Effect of sleeve gastrectomy, Roux-en-Y gastric bypass, and ileal transposition on myocardial ischaemia–reperfusion injury in non-obese non-diabetic rats

“…BS also improves responsiveness to endogenous thyroid hormones and decreases the levels of thyroid-stimulating hormone in obese patients 76 , 77 . These observations are important in the context of BS-mediated cardiac protection since it is known that thyroid hormones may increase myocardial tolerance to ischemia–reperfusion 78 , 79 .…”

Free triiodothyronine serves as a potential predictor of long-term heart failure following acute myocardial infarction

“…Can exogenous FT3 supplementation improve prognosis in AMI patients? Previous animal studies had preliminary con rmed that administration of exogenous T3 after AMI had a myocardial protective effect [20], which similar to betablockers [21]. Pingitore et al further conducted a clinical trial involving 37 AMI patients with low T3 syndrome to observe the e cacy and safety of long-term oral synthetic T3.…”