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.
Highlights
In patients with acute myocardial infarction, the only way to salvage myocardium at risk is early reperfusion
There is still an unmet need to protect myocardium at risk of infarction beyond the protection induced by early reperfusion [23]
T3 in doses which result in supraphysiological plasma T3 levels during reperfusion improved the recovery of coronary flow (CF) [4] and left ventricular (LV) contractile function [53] in isolated perfused rat hearts with global ischemia/ reperfusion (I/R)
Summary
In patients with acute myocardial infarction, the only way to salvage myocardium at risk is early reperfusion. Basic Research in Cardiology (2021) 116:27 of coronary re-occlusion/reperfusion at early reperfusion (ischemic post-conditioning; iPoCo) attenuate ischemia/ reperfusion (I/R) injury and reduce infarct size in preclinical and clinical studies [19, 51, 64]. The mechanical manipulation of culprit lesions carries the risk of coronary microembolization with subsequent injury [30], and iPoCo requires mechanical manipulation Such iatrogenic microembolization may obscure iPoCo’s cardioprotection [22]. In experimental models of myocardial infarction [12, 52], and in patients with acute ST-segment elevation myocardial infarction [57], exogenous triiodothyronine (T3) infusion during reperfusion restored the reduced endogenous T3 levels and improved left ventricular (LV) contractile function. T3 induces multiple genomic and non-genomic effects in the heart and vascular system [32, 56, 60], and the acute T3-induced effects must primarily rely on nongenomic effects
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