Confounders of Cardioprotection by Remote Ischemic Preconditioning in Patients Undergoing Coronary Artery Bypass Grafting

Abstract

Objectives: Remote ischemic conditioning (RIC) by repetitive blood pressure cuff inflation/deflation around a limb provides cardioprotection in patients undergoing coronary artery bypass grafting (CABG). Cardioprotection is confounded by risk factors, comorbidities and comedications. We aimed to identify confounders that possibly attenuate the protection provided by RIC. Methods: In a retrospective analysis of our single-center, randomized, double-blind trial of patients undergoing elective CABG with/without RIC prior to ischemic cardioplegic arrest, we analyzed demographics, medications and intraoperative variables. The primary end point was myocardial injury, as reflected by the area under the curve for serum troponin I (TnI) from baseline to 72 h after surgery. Results: In models with 2 independent variables and in the multivariate analysis, age and aortic cross-clamp time impacted on TnI release. Subgroup analyses confirmed RIC-induced protection in all age tertiles. There was no protection with an aortic cross-clamp time ≤56 min (RIC/control = 1.026 not significant), but there was protection with 57-75 min (RIC/control = 0.757; p = 0.0348) and ≥76 min (RIC/control = 0.735; p = 0.0277). Gender, β-blockers, statins, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and intraoperative nitroglycerine did not impact on TnI release. Conclusion: Age, gender, β-blockers, statins, ACE inhibitors, ARBs and intraoperative nitroglycerine have no significant impact on RIC-induced cardioprotection during CABG. However, greater myocardial ischemia/reperfusion injury at longer cross-clamp time facilitates the detection of protection by RIC.

Mitochondrial and Contractile Function of Human Right Atrial Tissue in Response to Remote Ischemic Conditioning

“…When analyzing this cohort separately for males and females, there was a significant troponin reduction by RIPC only in males. Lack of apparent protection by RIPC in females may also relate to the small sample size, given that in larger cohorts there was no interaction of sex with protection by RIPC in a meta‐analysis of trials in patients with elective percutaneous coronary intervention,35 in a retrospective analysis of the CONDI (Effect of RIC on Clinical Outcomes in STEMI Patients Undergoing pPCI) trial in patients with primary percutaneous coronary intervention,36 and in a retrospective analysis of our previous study in patients undergoing elective bypass surgery 37. Cardioprotection was associated with improved function of mitochondria, confirming the notion that mitochondria are a target of RIPC's protection.…”

Time to Give Up on Cardioprotection?

“…175 Aging per se attenuates cardioprotective signaling, [176][177][178] although in 2 retrospective analyses for confounders, protection by remote ischemic preconditioning was seen in all age cohorts of patients undergoing surgical coronary revascularization 179 and protection by remote ischemic perconditioning was seen n.s. P P P P P P P P P P P P P P P P P in all age cohorts of patients with acute STEMI undergoing primary PCI.…”

“…19,230,231 On the contrary, with a short duration of ischemia, all ischemic myocardium may be rescued by reperfusion per se, and an additional cardioprotection may be difficult to demonstrate. 20,179,231 Also, with a short duration of ischemia, ischemic postconditioning may even add to myocardial injury.…”

“…Because conditioning interventions protect only from ischemia/reperfusion injury but not from trauma, the traumatic component of injury dilutes the cardioprotective effects of conditioning. Protection by remote ischemic preconditioning 179 and also protection by cyclosporine A 237 become only apparent by reduced troponin release after CABG when cardiopulmonary bypass times are longer. Although further studies on protection of patients at high risk for ischemic events when undergoing cardiovascular surgery are certainly warranted, the setting of cardiovascular surgery is not well suited to resolve the fundamental question whether conditioning procedures can provide clinical benefit for patients with AMI.…”

Remote Ischemic Conditioning and the Long Road to Clinical Translation

“…In addition to the possible confounding effect of diabetes mellitus and other comorbidities, 14 there is evidence that the magnitude of cardioprotection achieved with RIC is proportional to the ischemic burden. 6,15,16 Specifically, in patients undergoing CABG, recent retrospective analysis revealed that RIC evoked significant reductions in troponin I release with cross-clamp times >57 minutes, but had no effect with ischemic durations ≤56 minutes. 16 Accordingly, in cohorts undergoing elective cardiac surgeries, with crossclamp times as short as 18 minutes in the ERICCA trial, 8 and in which myocardial ischemia-reperfusion injury may have already been blunted by cardioplegia, hypothermia and, in subsets of patients, volatile anesthetics and opioids, the scope for improvement with RIC may have been modest at best.…”