Direct evidence that hypoxia triggers the cardioprotective response of ischemic preconditioning in a dog double-circuit cardiopulmonary bypass model

Abstract Aims It has been widely accepted that ischemic preconditioning (IPC) exhibits a promising and reproducible cardioprotective effect against ischemia/reperfusion (I/R) injury. However, the actual trigger that amplifies the molecular signaling and protects I/R heart is still unclear. Main methods To separate the factors involved in IPC, we established a dog double-circuit cardiopulmonary bypass (CPB) model, which consists of a systemic circuit and a coronary circuit. Forty-two male adult beagle dogs were randomly allocated into 7 groups: sham, I/R, IPC, hypoxia preconditioning (HPC), accumulated metabolite preconditioning (MPC), oxygenated or deoxygenated erythrocytes preconditioning (OxyEPC and DeoxyEPC). After pretreatment, dogs were subjected to 2 h-cardiac arrest and 2 h-reperfusion. Key findings There were no differences in the cardiac function and hemodynamic parameters at baseline among groups. Like IPC, the hypoxia-related pretreatments HPC and DeoxyEPC improved post-arrest left ventricular systolic/diastolic performance and reduced pulmonary vascular resistance. The cardiac oxygen (O 2 ) utilization was also greatly elevated in these hypoxia-related pretreatment groups, as evidenced by increased cardiac O 2 consumption (VO 2 ) and O 2 extraction index (O 2 EI) and suppressed lactate level. Besides, we did not observe improvement of these parameters in the MPC and OxyEPC groups. Further study indicated that these hypoxia-related pretreatments were associated with the attenuation of pro-inflammatory cytokines release and the elevation of complex I-supported mitochondrial respiration. Significance With a dog double-circuit CPB model, we demonstrated that hypoxia is the actual trigger to initiate the cardioprotective effect of IPC in vivo, which was related to reduced cardiac inflammation and ameliorated complex-I supported mitochondrial function.