Cardioprotective effect of combination therapy by mild hypothermia and local or remote ischemic preconditioning in isolated rat hearts

Abstract

A multitargeted strategy to treat the consequences of ischemia and reperfusion (IR) injury in acute myocardial infarction may add cardioprotection beyond reperfusion therapy alone. We investigated the cardioprotective effect of mild hypothermia combined with local ischemic preconditioning (IPC) or remote ischemic conditioning (RIC) on IR injury in isolated rat hearts. Moreover, we aimed to define the optimum timing of initiating hypothermia and evaluate underlying cardioprotective mechanisms. Compared to infarct size in normothermic controls (56 ± 4%), mild hypothermia during the entire or final 20 min of the ischemic period reduced infarct size (34 ± 2%, p < 0.01; 35 ± 5%, p < 0.01, respectively), while no reduction was seen when hypothermia was initiated at reperfusion (51 ± 4%, p = 0.90). In all groups with effect of mild hypothermia, IPC further reduced infarct size. In contrast, we found no additive effect on infarct size between hypothermic controls (20 ± 3%) and the combination of mild hypothermia and RIC (33 ± 4%, p = 0.09). Differences in temporal lactate dehydrogenase release patterns suggested an anti-ischemic effect by mild hypothermia, while IPC and RIC preferentially targeted reperfusion injury. In conclusion, additive underlying mechanisms seem to provide an additive effect of mild hypothermia and IPC, whereas the more clinically applicable RIC does not add cardioprotection beyond mild hypothermia.

Intra‐ischemic hypothermia cardioprotection involves modulation of PTEN/Akt/ERK signaling and fatty acid oxidation

“…Taken together, these results demonstrate that rapid application of mild-to-moderate intra-ischemic TH leads to enhanced functional recovery in the non-paced, isolated rat heart. This is supported by other studies in which TH initiated during ischemia or immediately after reperfusion led to significantly decreased LV infarct size following global ischemia in the isolated rat heart (Hjortbak et al, 2021;Mochizuki et al, 2012).…”