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. 2018 Aug 16;10(8):1825-1855.
doi: 10.18632/aging.101527.

Remote ischemic conditioning: a promising therapeutic intervention for multi-organ protection

Da Zhou #  1   2   3   4 , Jiayue Ding #  1   2   3   4 , Jingyuan Ya  1   2   3   4 , Liqun Pan  1   2   3   4 , Yuan Wang  1   2   3   4 , Xunming Ji  5   2   3   4 , Ran Meng  1   2   3   4
Affiliations

Remote ischemic conditioning: a promising therapeutic intervention for multi-organ protection

Da Zhou et al. Aging (Albany NY). .

Abstract

Despite decades of formidable exploration, multi-organ ischemia-reperfusion injury (IRI) encountered, particularly amongst elderly patients with clinical scenarios, such as age-related arteriosclerotic vascular disease, heart surgery and organ transplantation, is still an unsettled conundrum that besets clinicians. Remote ischemic conditioning (RIC), delivered via transient, repetitive noninvasive IR interventions to distant organs or tissues, is regarded as an innovative approach against IRI. Based on the available evidence, RIC holds the potential of affording protection to multiple organs or tissues, which include not only the heart and brain, but also others that are likely susceptible to IRI, such as the kidney, lung, liver and skin. Neuronal and humoral signaling pathways appear to play requisite roles in the mechanisms of RIC-related beneficial effects, and these pathways also display inseparable interactions with each other. So far, several hurdles lying ahead of clinical translation that remain to be settled, such as establishment of biomarkers, modification of RIC regimen, and deep understanding of underlying minutiae through which RIC exerts its powerful function. As this approach has garnered an increasing interest, herein, we aim to encapsulate an overview of the basic concept and postulated protective mechanisms of RIC, highlight the main findings from proof-of-concept clinical studies in various clinical scenarios, and also to discuss potential obstacles that remain to be conquered. More well designed and comprehensive experimental work or clinical trials are warranted in future research to confirm whether RIC could be utilized as a non-invasive, inexpensive and efficient adjunct therapeutic intervention method for multi-organ protection.

Keywords: age-related arteriosclerotic vascular disease; clinical translation; ischemia-reperfusion injury; multi-organ protection; remote ischemic conditioning.

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Conflict of interest statement

CONFLICTS OF INTEREST: All authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Schematic diagram showing the main points pertaining to the study. Abbreviations: AIS, acute ischemic stroke; CCI, Chronic cerebral ischemia; SAH, subarachnoid hemorrhage; CEA, carotid endarterectomy; CAS, carotid angioplasty and stenting; CSVD, cerebral small vessel disease; TBI, traumatic brain injury; CABG, coronary artery bypass graft surgery; SPCI, selective percutaneous coronary intervention; PPCI, primary percutaneous coronary intervention; CHF, chronic heart failure; ARD, acute renal dysfunction.
Figure 2
Figure 2
General illustration of remote ischemic conditioning (RIC). Remote ischemic conditioning, in which transient sublethal episodes of ischemia and reperfusion are applied to a limb (upper arm or thigh) or limbs, can be delivered before (remote ischemic preconditioning), during (remote ischemic perconditioning) or after (remote ischemic postconditioning) a subsequent and potentially lethal ischemic attack. Neuronal, humoral as well as immunological mediators are postulated to exert critical roles in the transduction of protective signals generated from limbs and surrounding structures to the targeted organs or tissues. The application of RIC has been extended from initially reducing cardiac infarct sizes resulting from acute myocardial infarction to providing protection for a diversity of organs or tissues (other than the heart), which are likely susceptible to ischemia-reperfusion injury, such as the brain, kidney, lung, liver and skin.
Figure 3
Figure 3
Simplified overview of the protective pathways of Remote Ischemic Conditioning (RIC). eNOS/PKG pathway is presented in gray, RISK pathway in yellow and green, and SAFE pathway in purple. Abbreviations: RISK, reperfusion injury salvage kinase; SAFE, survivor activating factor enhancement; SDF-1α, stromal cell derived factor-1α; IGF-1, insulin like growth factor-1; FGF-2: fibroblast growth factor-2; ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; TNF-α, tumor necrosis factor-α; IL-6, interleukin-6; IL-10, interleukin-10; CXCR4, chemokine 4 receptor; GFR, growth factor receptor; A1R, A3R, adenosine receptor A1, A3; δ/κ, δ- and κ- opioid receptor; B2R, bradykinin receptor B2; M3R, muscarinic receptor M3; NPR, natriuretic peptide receptor; TNFR, tumor necrosis factor receptor; gp130, glycoprotein 130; KATP, ATP-dependent potassium channel; Cx 43, connexin43; MEK1/2, also known as mitogen-activated protein kinase kinase 1/2; Erk1/2, extracellular-regulated kinases 1/2; PI3K, phosphatidylinositol-4, 5-bisphosphate3-kinase; PIP3, phos-phatidylinositol-3, 4, 5-biphosphate; PDK, phosphatidylinositol kinase; Akt, also known as protein kinase B; P70s6K, p70 ribosomal protein s6 kinase; GSK3β, glycogen synthase kinase 3β; HIF-1α, hypoxia inducible factor-1α; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; eNOS, endothelial nitric oxide synthase; NO, nitric oxide; sGC, soluble guanylate cyclase; cGMP, cyclic guanine monophosphate; PKG, protein kinase G; PKC, protein kinase C; MPTP, mitochondrial permeability transition pore; JKA, Janus kinase; STAT1, STAT3, STAT5, signal transducer and activator of transcription 1, 3, 5; ROS, reactive oxygen species; miRNA, microRNA.
Figure 4
Figure 4
Specific circulating markers for different organ scenarios. Abbreviations: AIS, acute ischemic stroke; ASH, acute subarachnoid hemorrhage; sIAS, symptomatic intracranial arterial stenosis; CEA, carotid endarterectomy; CAS, carotid angioplasty and stenting; CVSD, cerebral small vessel disease; CABG, coronary artery bypass graft surgery; SPCI, selective percutaneous coronary intervention; PPCI, primary percutaneous coronary intervention; CHF, chronic heart failure; NSE, neuronal specific enolase; S-100B, S100 calcium binding protein B; GFAP, glial fibrillary acidic protein; AQP-4, aquaporin-4; Ngb, Neuroglobin; cTnI, cardiac troponin I; cTnT, cardiac troponin T; CK-MB, creatine kinase-myocardial band; Mb, myoglobin; BNP, brain natriuretic protein; TIMP-2, tissue inhibitor of metalloproteinases-2; IGFBP-7, insulin like growth factor-binding protein-7; HMGB-1, high-mobility group box protein-1; sCr, serum creatinine; NGAL, neutrophil gelatinase-associated lipocalin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; PaO2/FiO2, partial pressure of oxygen/fraction of inspired oxygen.
Figure 5
Figure 5
Clinical trials of remote ischemic conditioning (RIC) on multi-organ protection. (A) Studies of RIC effects on the brain, (B) studies of RIC effects on the kidney, (C) and (D) studies of RIC effects on the heart. Abbreviations: CSVD, cerebral small vessel disease; TBI, traumatic brain injury; CEA, carotid endarterectomy; CAS, carotid angioplasty and stenting; sIAS, symptomatic intracranial arterial stenosis; SAH, subarachnoid hemorrhage; AIS, acute ischemic stroke; MFV, mean flow velocity; MCA, middle cerebral artery; DHI, dizziness handicap inventory; WMLs, white matter lesions; NSE, neuron-specific enolase; S-100B, S100 calcium binding protein B; mRS, modified Rankin scale; CBF, cerebral blood flow; GW exp. and methy. change, genome-wide expression and methylation change; ICP, intracranial pressure; SPCI, selective percutaneous coronary intervention; CABG, coronary artery bypass graft surgery; HD, hemodialysis; DDR, deceased donor renal; DCDR, donation after cardiac death renal; LDR, living-donor renal; ARD, acute renal dysfunction; CIN, contrast-induced nephropathy; tCr50, the estimated time to a 50% decrease in baseline plasma creatinine; NGAL, neutrophil gelatinase-associated lipocalin; eGFR, estimated glomerular filtration rate; PPCI, primary percutaneous coronary intervention; HHF, hospitalization for heart failure; MS, myocardial salvage; MI, myocardial infarction; hs-cTnT, high sensitive-cardiac troponin T; hs-cTnI, high sensitive-cardiac troponin I; MACCE, major adverse cardiac and cerebral event; CK, creatine kinase; CK-MB, creatine kinase-myocardial band; RF, renal failure.
Figure 6
Figure 6
Forest plot with 95% confidence interval for primary or secondary outcomes. (A) Heart: the incidence of complication MI in recipients who underwent CABG or PCI in RIC group compared with controls; the post-treatment mRS in cerebral infarction treated with RIC compared with controls; (B) Heart: the mortality of recipients who underwent CABG or PCI in RIC group compared with controls; (C) Heart: the incidence of complication-stroke in recipients who underwent CABG or PCI in RIC group compared with controls; (D) Kidney and Brain: the eGFR in recipients who underwent renal transplantation and the post-treatment mRS in cerebral infarction, in RIC group compared with controls. Abbreviations: MI, myocardial infarction; CABG, coronary artery bypass graft surgery; PCI, percutaneous coronary intervention; RIC, remote ischemic conditioning; eGFR, estimated glomerular filtration rate; mRs, modified Rankin scale.
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