The remote ischemic preconditioning algorithm: effect of number of cycles, cycle duration and effector organ mass on efficacy of protection

Abstract

Remote ischemic preconditioning (rIPC), induced by cycles of transient limb ischemia and reperfusion (IR), is cardioprotective. The optimal rIPC-algorithm is not established. We investigated the effect of cycle numbers and ischemia duration within each rIPC-cycle and the influence of effector organ mass on the efficacy of cardioprotection. Furthermore, the duration of the early phase of protection by rIPC was investigated. Using a tourniquet tightened at the inguinal level, we subjected C57Bl/6NTac mice to intermittent hind-limb ischemia and reperfusion. The rIPC-protocols consisted of (I) two, four, six or eight cycles, (II) 2, 5 or 10 min of ischemia in each cycle, (III) single or two hind-limb occlusions and (IV) 0.5, 1.5, 2.0 or 2.5 h intervals from rIPC to index cardiac ischemia. All rIPC algorithms were followed by 5 min of reperfusion. The hearts were subsequently exposed to 25 min of global ischemia and 60 min of reperfusion in an ex vivo Langendorff model. Cardioprotection was evaluated by infarct size and post-ischemic hemodynamic recovery. Four to six rIPC cycles yielded significant cardioprotection with no further protection by eight cycles. Ischemic cycles lasting 2 min offered the same protection as cycles of 5 min ischemia, whereas prolonged cycles lasting 10 min abrogated protection. One and two hind-limb preconditioning were equally protective. In our mouse model, the duration of protection by rIPC was 1.5 h. These findings indicate that the number and duration of cycles rather than the tissue mass exposed to rIPC determines the efficacy of rIPC.

Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection

“…The number and duration of the conditioning cycles must be kept constant and accurately reported. In pigs, three or four cycles of 3–5 min local or remote ischemia/reperfusion induce efficient and reproducible cardioprotection in most [158, 228, 252, 385, 393], but not all studies [29]. In a recent study in pigs, remote ischemic perconditioning attenuated ischemic injury even before reperfusion, as assessed by attenuated ST-segment elevation during ongoing ischemia [252].…”

“…While animal studies allow the establishment of an optimal algorithm of cardioprotective treatments by studying the influence of number and duration of cycles, influence of effector organ mass and timing of remote ischemic preconditioning on infarct size [228, 393] and such studies are also feasible in larger animals, they are more challenging in the clinical setting, because dose–response studies using infarct size or myocardial salvage require acute settings and a large number of patients, regardless of whether the endpoint is determined from a biochemical injury marker or an imaging modality.…”

Time to Give Up on Cardioprotection?

“…The optimal stimulus may depend on the patient cohort under study, that is, a stronger stimulus may be necessary to induce protection in, for example, diabetics. 238 On the contray, a stimulus can be too strong and protection be lost [239][240][241] or even a state of hyperconditioning be induced with increased myocardial injury.…”

Remote Ischemic Conditioning and the Long Road to Clinical Translation

“…With regard to the first issue, recent dose-response studies conducted using young adult male mice demonstrated that the standard RIC stimulus (four 5-minute periods of limb ischemia, interspersed with 5 minutes of reperfusion) yielded a significant infarctsparing effect, with no added benefit provided by increasing the number of ischemia-reperfusion cycles. 13 However, there is no evidence to establish that this algorithm is effective (and optimal) for all patients and all applications. Is the standard stimulus equally appropriate for CABG (as implied by the outcome of the majority of phase II studies), the ≈50% of patients in ERICCA who underwent CABG combined with valve surgery, and the ≈50% of patients in RIPHeart who underwent valve repair/reconstruction or other surgical procedures?…”