Cardiac protective effects of remote ischaemic preconditioning in children undergoing tetralogy of fallot repair surgery: a randomized controlled trial

Abstract

Aims: Remote ischaemic preconditioning (RIPC) by inducing brief ischaemia in distant tissues protects the heart against myocardial ischaemia-reperfusion injury (IRI) in children undergoing open-heart surgery, although its effectiveness in adults with comorbidities is controversial. The effectiveness and mechanism of RIPC with respect to myocardial IRI in children with tetralogy of Fallot (ToF), a severe cyanotic congenital cardiac disease, undergoing open heart surgery are unclear. We hypothesized that RIPC can confer cardioprotection in children undergoing ToF repair surgery.

Methods and results: Overall, 112 ToF children undergoing radical open cardiac surgery using cardiopulmonary bypass (CPB) were randomized to either a RIPC group (n = 55) or a control group (n = 57). The RIPC protocol consisted of three cycles of 5-min lower limb occlusion and 5-min reperfusion using a cuff-inflator. Serum inflammatory cytokines and cardiac injury markers were measured before surgery and after CPB. Right ventricle outflow tract (RVOT) tissues were collected during the surgery to assess hypoxia-inducible factor (Hif)-1α and other signalling proteins. Cardiac mitochondrial injury was assessed by electron microscopy. The primary results showed that the length of stay in the intensive care unit (ICU) was longer in the control group than in the RIPC group (52.30 ± 13.43 h vs. 47.55 ± 10.34 h, respectively, P = 0.039). Patients in the control group needed longer post-operative ventilation time compared to the RIPC group (35.02 ± 6.56 h vs. 31.96 ± 6.60 h, respectively, P = 0.016). The levels of post-operative serum troponin-T at 12 and 18 h, CK-MB at 24 h, as well as the serum h-FABP levels at 6 h, after CPB were significantly lower, which was coincident with significantly higher protein expression of cardiac Hif-1α, p-Akt, p-STAT3, p-STAT5, and p-eNOS and less vacuolization of mitochondria in the RIPC group compared to the control group.

Conclusion: In ToF children undergoing open heart surgery, RIPC attenuates myocardial IRI and improves the short-term prognosis.

Figure 1

Trial flow diagram.

Figure 2

Ventilation time curve (A) and ICU stay time curve (B). N = 57 in the control group and N = 55 in the RIPC group. *P < 0.05 vs. control group.

Figure 3

Protein expression of RVOT myocardium. (A): Hif-1α expression in the RIPC group is higher than that in the control group (P = 0.0008). (B–E): RIPC group ratio of phosphorylated Akt (P = 0.0096), STAT3 (P = 0.0144), STAT5 (P = 0.0156), and eNOS (P = 0.0279) to total protein are higher than that in the control group. (F): Phosphorylated PTEN shows no difference between the groups. n = 20 in the control and n = 19 in the RIPC group. *P < 0.05 vs. control group.

Figure 4

Ultrastructure of RVOT myocardium. (A): All the mitochondria exhibit swelling, with one also showing vacuolization; (B): Mitochondria exhibit marked swelling; (C): A ruptured mitochondrion; (D): Distinct abnormal contraction of myofibrils; (E): Due to abnormal contraction, the myofibrils snapped; (F): The structure of the myofibrils were disrupted, with lysis at the centre. The typical ultrastructural changes of the myocardium are indicated by the arrow.

Figure 5

Schematic of proposed signalling involved in remote ischaemic preconditioning cardioprotection (RIPC) in ToF children undergoing elective radical ToF repair surgery. RIPC reduces the postoperative cardiac ischaemic injury through activating the PI3K/Akt and JAK/STAT3/5 signalling pathways, which is associated with nuclear accumulation of Hif-1a and STAT3/5 and subsequent induction of myocardial eNOS activation and mitochondrial protection.