Cardiotrophin-1 protects the human myocardium from ischemic injury. Comparison with the first and second window of protection by ischemic preconditioning.

BACKGROUND: There are reports suggesting that cardiotrophin 1 (CT-1) is cytoprotective. We investigated the cardioprotective effects of CT-1 on the human myocardium and compared this benefit with the early and delayed protection afforded by ischemic preconditioning (PC).
METHODS: Right atrium specimens were prepared and incubated in buffer solution at 37 degrees C for 30 min stabilisation, before entering one of the three following studies. In study 1, muscles (n=6/group) were allocated to one of four groups: (i) aerobic control - incubated in oxygenated media for 210 min, (ii) ischemia alone - 90 min ischemia followed by 120 min reoxygenation, (iii) PC by 5 min ischemia-5 min reoxygenation before 90 min ischemia-120 min reoxygenation and (iv) CT-1 (1 nM) - 90 min ischemia-120 min reoxygenation with exposure to CT-1 throughout the protocol. In study 2, muscles (n=6/group) were allocated to one of four protocols as in study 1with the exception that were incubated for 24 h followed by 30 or 90 min ischemia-120 min reoxygenation on day 2. In study 3, the same groups were employed as in study 2 with the exception that only a 30-min period of ischemia was used and that CT-1 antibody (5 microg/ml) was added to all groups throughout the experimental protocol. Creatine kinase (CK, U/g wet wt.) leakage into the medium and MTT reduction (OD/mg wet wt.), an index of cell viability, were assessed at the end of the experiment.
RESULTS: In study 1, a first window of cardioprotection was observed with PC (CK=4.39+/-0.34; MTT=0.58+/-0.03 vs. CK=7.11+/-0.4;MTT=0.32+/-0.02 in the ischemic alone group; P<0.001) but not with CT-1(CK=6.65+/-0. 67; MTT=0.31+/-0.03, P=NS vs. ischemia alone). In study 2, PC applied on day 1 was protective against 30-min ischemia (CK=3.28+/-0. 43; MTT=0.68+/-0.046, P<0.001 vs. ischemia alone) but not against 90-min ischemia (CK=7.13+/-0.66; MTT=0.24+/-0.03, P=NS vs. ischemia alone) induced on day 2 (second window). However, when the tissue was exposed to CT-1 for 24 h, protection was similar to that of PC when subjected to 30 min of ischemia (CK=2.95+/-0.71; MTT=0.77+/-0. 05, P=NS vs. PC) and greater than PC when subjected to 90 min of ischemia (CK=4.56+/-0.51; MTT=0.39+/-0.03, P=0.002 vs. PC). In study 3, the CT-1 antibody did not affect the protection induced by PC (CK=3.36+/-0.6; MTT=0.69+/-0.06) but it abolished the protection obtained with CT-1(CK=5.15+/-0.81; MTT=0.42+/-0.06, P=NS vs. ischemia alone group).
CONCLUSIONS: CT-1 exhibits a significant protection of the human myocardium against ischemic injury when tissue is exposed to this factor for a long period (e.g. 24 h) but not when exposed for a short period (e.g. 2 h). In addition, the protection afforded by long exposure to CT-1 is as potent or even greater than the one obtained by the second window of PC. The protection induced by CT-1 but not that induced by PC can be abolished by CT-1 antibody suggesting that their beneficial action is attained by different mechanisms.

RCT Entities:   Population Interventions Outcomes