Postconditioning protects human atrial muscle through the activation of the RISK pathway

Ischemic postconditioning (IPost) has been demonstrated to reduce myocardial injury in patients undergoing primary coronary angioplasty for an acute myocardial infarction.Pre-clinical animal studies suggest that pro-survival protein kinases of the Reperfusion Injury Salvage Kinase (RISK) pathway such as Akt and Erk1/2 mediate the cardioprotective effect of IPost.Whether IPost can protect human myocardial tissue ex vivo and whether it recruits the RISK pathway in human myocardium are both not known. To investigate this, atrial appendages were harvested from patients undergoing cardiac surgery. From these samples atrial trabeculae were isolated and mounted on a superperfusion apparatus and subjected to 90 min of hypoxia followed by 120 min of reoxygenation at the end of which function expressed as a percentage of the recovery of baseline contractile function was determined.Atrial trabeculae were randomized to control, hypoxic preconditioning (HPre), hypoxic postconditioning comprising either four 30-s (HPost-30) or 60-s (HPost-60) episodes of alternating hypoxia and reoxygenation, and HPost in the presence or absence of UO126 (a MEK1/2 inhibitor) or LY294002 (a PI3K inhibitor).HPre and HPost-60 improved the recovery of baseline contractile function (45.4 +/- 3.2% with HPre and 45.2 +/- 2.2% with HPost-60 vs 26.7 +/- 2.1 % in control: N >= 6/group: P < 0.05), whereas HPost-30 failed to cardioprotect (28.3 +/- 3.4% with HPost-30 vs 26.7 +/- 2.1 % in control: N >= 6/group: P > 0.05). The cardioprotective effect of HPost-60 was abolished in the presence of either LY (28.1 +/- 2.5% with HPost-60+LY vs 45.2 +/- 2.2% with HPost-60: N >= 6/group: P < 0.05) or UO (32.7 +/- 1.8% with HPost-60+UO vs 45.2 +/- 2.2% with HPost-60:N=7/group: P < 0.05). The kinase inhibitors alone had no effect on functional recovery (28.2 +/- 3.6% with LY and 30.1 +/- 4.8% with UO vs 26.7 +/- 2.1 % in control: N >= 5/group: P > 0.05). In conclusion, we demonstrate for the first time that postconditioning protects human myocardium ex vivo and that this effect is dependent on the activation of the RISK pathway.