Remote ischemic preconditioning in elective percutaneous coronary intervention does not protect myocardium nor mobilize endothelial progenitor cells

Protecting myocardium or reducing the extent of reperfusion injury in the setting of percutaneous coronary intervention (PCI) has been a long-sought holy grail whether achieved by drug, device, or technique. Since the seminal finding of Murry et al. [1] that brief repeated sublethal episodes of ischemia/reperfusion can paradoxically protect cardiomyocytes from subsequent ischemic injury, many investigators have tried to exploit the phenomenon of ischemic preconditioning (IPC) in humans. Ischemic postconditioning, which is intermittent interruptions of blood flow to the heart muscle following recent sustained ischemia, has also been shown to reduce myocardial damage in animal models [2] as well as humans following primary PCI (PPCI) for ST-segment elevation myocardial infarction (MI). Related to, but distinct from cardiac IPC and ischemic postconditioning, is remote ischemic preconditioning (RIPC). This is the protective effect of repetitive ischemic reperfusion cycles in accessible organs, such as skeletal muscle, on remote organs, such as the heart and kidney. To date, no pharmacological therapies have been successfully developed to protect the myocardium following ischemic injury despite promising animal studies and our advanced understanding of the molecular mechanisms involved. IPC could potentially confer different forms of cardioprotection including reducing infarct size, lethal arrhythmias, and cardiac dysfunction following ischemic injury. Animal models have demonstrated that IPC reduces cell apoptosis through autacoids and their receptors (e.g., adenosine, bradykinin, and opioids), kinase signaling pathways, and mitochondrial modulations. Another pathway for the protective effects of IPC involves the release of cytokines such as vascular endothelial growth factor leading to the mobilization of endothelial progenitor cells (EPCs) to the blood stream. EPCs preserve the microcirculation through aiding in the repair of endothelial cells and the release of nitric oxide and other mediators. Hence, EPCs are an important surrogate of vascular health and outcomes in patients with cardiovascular disease [3]. The mechanisms behind the protective effect of RIPC are less well understood but involve the activation of the kinase signaling pathways in cardiomyocytes through neuronal or humoral pathways. While animal models have shown promising results, human studies have demonstrated mixed and inconsistent effects of RIPC on myocardial necrosis and clinical outcomes [4]. Despite set-backs, the concept of ischemic conditioning remains a high-interest protective strategy following ischemic cardiac injury. Randomized trials have observed potential beneficial effects of RIPC regarding peak troponin levels, ST-segment deviation, and myocardial salvage index (as a percentage of the left ventricle mass) among patients undergoing PPCI [5]. The salubrious effects of RIPC on surrogate endpoints extend to elective PCI for stable coronary artery disease and coronary artery bypass surgery in some observations. In contrast, other studies have not demonstrated benefit, but rather potentially harmful effects of RIPC in patients with chronic ischemic heart disease undergoing elective PCI, with reported increased inflammation and peri-procedural MI in the RIPC-treated group [4]. Furthermore, none of the RIPC human studies have proved a protective role regarding renal function or hard clinical endpoints. In a metaanalysis combining 23 clinical RIPC trials (N1⁄4 1,878),