Remote Ischemic Conditioning Group Research Articles

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial

SummaryBackgroundRemote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months.MethodsWe did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed.FindingsBetween Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91–1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed.InterpretationRemote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI.FundingBritish Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden.

Combined Intrahospital Remote Ischemic Perconditioning and Postconditioning Improves Clinical Outcome in ST-Elevation Myocardial Infarction.

Remote ischemic conditioning (RIC) or ischemic postconditioning (PostC) may protect the myocardium from ischemia-reperfusion injury in patients with ST-segment-elevation myocardial infarction. To determine whether combined intrahospital RIC and PostC or PostC alone in addition to primary percutaneous coronary intervention (PCI) reduce long-term clinical events after ST-segment-elevation myocardial infarction. The present study is a post hoc analysis of a prospective trial which randomized 696 ST-segment-elevation myocardial infarction patients with symptoms <12 hours 1:1:1 to either combined RIC and PostC in addition to primary PCI, PostC alone in addition to primary PCI, or conventional PCI (control). Three cycles of RIC were performed by inflation of an upper arm blood pressure cuff for 5 minutes followed by deflation for 5 minutes. PostC was performed after primary PCI via 4 cycles of 30 seconds balloon occlusions followed by 30 seconds of reperfusion. Major adverse cardiac events consisting of cardiac death, reinfarction, and new congestive heart failure were assessed during long-term follow-up. Follow-up data were obtained in 97% of patients in median 3.6 years after the index event (interquartile range, 2.9-4.2 years). Major adverse cardiac events occurred in 10.2% of patients in the combined RIC and PostC group and in 16.9% in the control group (odds ratio, 0.56; 95% CI, 0.32-0.97; P=0.04). The difference was driven by a significantly reduced rate of new congestive heart failure in the RIC and PostC group (2.7% versus 7.8%; odds ratio, 0.32; 95% CI, 0.13-0.84; P=0.02). In contrast, PostC alone did not reduce major adverse cardiac events compared with controls (14.1% versus 16.9%; odds ratio, 0.81; 95% CI, 0.48-1.35; P=0.41), and the reduction of new congestive heart failure was not statistically significant (3.5% versus 7.8%; odds ratio, 0.43; 95% CI, 0.18-1.03; P=0.05). Cardioprotection by combined intrahospital RIC and PostC in addition to primary PCI significantly reduced the rate of major adverse cardiac events and new congestive heart failure after ST-segment-elevation myocardial infarction. URL: http://www.clinicaltrials.gov . Unique identifier: NCT02158468.

The Cardioprotective Effects of Remote Ischemic Conditioning in a Rat Model of Acute Myocardial Infarction.

BackgroundCardiac remote ischemic conditioning (RIC) is a noninvasive cardioprotective method in ischemia-reperfusion injury and acute myocardial infarction (AMI). The aims of this study were to investigate the effects of RIC in a rat model of AMI.Material/MethodsAdult male Sprague-Dawley rats included the AMI group that underwent ligation of the left anterior descending (LAD) coronary artery (n=24), the RIC group that consisted the AMI rat model treated with RIC once daily in the left hind limb until days 1, 7 and 14 (n=24), and the sham group (n=24). Myocardial infarct size was measured by routine histology with triphenyltetrazolium chloride (TTC) and Masson’s trichrome histochemical staining for myocardial necrosis and fibrosis, respectively. Serum levels of Bcl-2, Bax, caspase-3, and inducible nitric oxide synthase (iNOS) were measured by enzyme-linked immunosorbent assay (ELISA). The apoptosis index was detected using the TUNEL assay. Spectrophotometry of the myocardium was used to identify mitochondrial complexes and myocardial ATP.ResultsThe RIC group showed improved cardiac hemodynamics, reduced the size of the myocardial infarction, upregulated expression of Bcl-2, and down-regulation of the levels of Bax, caspase-3, and iNOS, and reduced cardiac myocyte apoptosis and inhibited the opening of the mitochondrial permeability transition pore (MPTP).ConclusionsIn a rat model of AMI, RIC improved the hemodynamic index, reduce the levels of apoptosis and myocardial injury, and improved mitochondrial function.

Influence of remote ischemic conditioning on radial artery occlusion.

This study aimed to explore the influence of remote ischemic conditioning (RIC) on radial artery occlusion (RAO) and distinguish the risk factors for RAO. A total of 640 consecutive patients who prospectively underwent transradial artery coronary angiography (TRACA) (322 patients received RIC before TRACA) were enrolled. RIC was not performed in 318 patients. RAO was estimated using Doppler ultrasonography after the procedure. Patients were divided into two groups according to the protocol of RIC: RIC and non-RIC. The rate of RAO was significantly lower in the RIC group than in the non-RIC group. Patients were divided into two groups according to the patency of radial artery: radial artery patency (RAP) and RAO. The radial artery diameter was significantly narrower in the RAO group (2.31 ± 0.53) than in the RAP group (2.59 ± 0.47). The rate of applying β-blocker was significantly higher in the RAP group (69%) than in the RAO group (41%). The rate of applying trimetazidine was significantly higher in the RAP group (49.1%) than in the RAO group (17.6%). The multiple logistic regression analysis using radial artery diameter, RIC, β-blocker, and trimetazidine treatments revealed that small radial artery diameter, lack of β-blockers, and RIC were independent predictors of RAO. RIC might help in improving the rate of RAO. The multiple logistic regression analysis showed that the lack of β-blockers, RIC, and small radial artery diameter were independent predictors of RAO.

Efficacy of remote ischemic conditioning on improving WMHs and cognition in very elderly patients with intracranial atherosclerotic stenosis.

Our previous study revealed that remote ischemic conditioning (RIC) reduced the incidence of stroke or TIA in octo- and nonagenarians with intracranial atherosclerotic stenosis (ICAS). Herein, we aimed to investigate whether RIC would influence the progression of white matter hyperintensities (WMHs) and cognitive impairment in the same group of patients. Fifty-eight patients with ICAS were randomly assigned in a 1:1 ratio to receive standard medical treatment with RIC (n=30) versus sham-RIC (n=28). The RIC protocol consisted of 5 cycles of alternating 5-min ischemia and 5-min reperfusion applied in the bilateral upper arms twice daily for 300 days. The efficacy outcomes included WMHs change on T2 FLAIR sequences, estimated by the Fazekas scale and Scheltens scale, cognitive change as assessed by the MMSE and MoCA, and some clinical symptoms within 300-day follow-up. Compared with the baseline, RIC treatment significantly reduced Fazekas and Scheltens scores at both 180-day (both p<0.05) and 300-day (both p<0.01) follow-ups, whereas no such reduction was observed in the control group. In the RIC group, Fazekas scores were significantly lower at 300-day follow-up (p<0.001) while Scheltens scores were significantly lower at both 180-day and 300-day follow-ups (both p<0.001), as compared with the control group. There were statistically significant between-group differences in the overall MMSE or MoCA scores, favoring RIC at 180-day and 300-day follow-ups (all p<0.05). RIC may serve as a promising adjunctive to standard medical therapy for preventing the progression of WMHs and ameliorating cognitive impairment in very elderly patients with ICAS.

Effects of different remote ischemic conditioning protocols in a rat model of arterialized orthotopic liver transplantation

Background: Ischemic-reperfusion (IR) injury still represents a major concern in clinical transplantation. In the present study we aimed to investigate the effects of remote ischemic conditioning (RIC) in a rat model of arterialized orthotopic liver transplantation. Methods: Male Lewis-rats were used (Σn=144; 240–340 g) and liver grafts were stored in 4 °C HTK-solution for 8h before implantation. Animals were randomly allocated into three experimental groups: RIC1, RIC2, Control. In RIC1, RIC2 groups conditioning was applied in recipients before liver exclusion or after reperfusion (4x5-5 min IR via aortic clamping), respectively. Animals were sacrificed at 1, 3, 24, 168h post-reperfusion (n=6 recipient/group/time point). Graft injury was evaluated using numerous methods. Results: RIC1 group showed significantly (p<0.05) improved portal venous flow and microcirculation (Microcirculation, mean ± SD, RIC1-1h vs. Control-1h, 105 ± 13 vs. 70 ± 17 AU). RIC has significantly reduced tissue injury according to the serum levels of ALT, AST, LDH and results of histology. Reduced TUNEL-staining and elevated pBAD/BAD protein ratio was detected in the RIC groups. Supporting findings were obtained from measurements of serum cytokine (IL-10, MCP-1) as well as tissue malondialdehyde and ATP levels. Hemoxygenase-1 mRNA-expression was significantly higher in RIC1 compared to Control. Conclusion: RIC in the recipient could protect liver grafts in our model against the detrimental effects of IR injury.

A12271 Which is better for patients treated with primary percutaneous coronary Intervention

Objectives: The aim of present study was to compare ischemic postconditioning (IPC) with remote ischemic conditioning (RIC) in STEMI patients treated with primary PCI, a network meta-analysis was performed using adjusted indirect treatment comparison (AITC) approach. Methods: A search was conducted using electronic database to identify RCTs reported either IPC or RIC in patients with STEMI during pPCI published in any language up to December 2017. Outcomes of interest were enzymatic infarct size, infarct size assessed by cardiac magnetic resonance (CMR), complete ST-segment resolution (cSTR) and cardiac events during follow-up. A network meta-analysis was performed using metan function in STATA version 12.0. Results: Thirty two studies including results of 3067 IPC and RIC patients were identified. Pooled results showed the RIC group was associated with lower enzymatic infarct size (IPC vs. RIC, SMD,0.992; 95%CI, 0.708 to 1.39). Compared with IPC,RIC significantly reduced infarct size evaluated by CMR. (IPC VS.RIC, SMD, 1.104; 95%CI, 0.665 to 1.883).There was a trend toward more cSTR in RIC patients than in IPC subjects (OR, 2.085; 95%CI, 0.76 to 5.768). There was no significant difference in all-cause mortality (OR, 0.32; 95%CI, 0.044to 2.332), reinfarction (OR, 0.631; 95%CI, 0.049 to 8.167) or Target vessel revascularization (TVR) (IPC VS.RIC: OR, 0.23; 95%CI, 0.023 to 2.431) with a mean follow up duration of 14 months among patients treated with RIC compared to IPC. Conclusion: In STEMI patients undergoing pPCI, available evidence from this network meta-analysis suggests RIC was associated with significant lower level of infarct size relative to IPC. However, no significantsuperiority of RIC vs. IPC was found in the present study on incidence of cSTR,all-cause mortality, reinfarct and TVR.

Remote ischaemic conditioning for prevention of acute kidney injury after valvular heart surgery: a randomised controlled trial

BackgroundRepeated remote ischaemic conditioning (RIC) during weaning from cardiopulmonary bypass and in the early postoperative period may confer protection against acute kidney injury (AKI). We evaluated the effect of repeated RIC on the incidence of AKI in patients undergoing valvular heart surgery. MethodsPatients were randomised into either the RIC (n=120) or control (n=124) group. A pneumatic tourniquet was placed on each patient's thigh. Upon removal of the aortic cross-clamp, three cycles of inflation for 5 min at 250 mm Hg (with 5 min intervals) were applied in the RIC group. Additionally, three cycles of RIC were repeated at postoperative 12 and 24 h. AKI was diagnosed based on the Kidney Disease: Improving Global Outcomes guideline. The incidences of renal replacement therapy, permanent stroke, sternal wound infection, newly developed atrial fibrillation, mechanical ventilation >24 h, and reoperation for bleeding during hospitalisation were recorded. ResultsThe incidences of AKI were not significantly different between the control (19.4%) and RIC (15.8%) groups (a difference of 3.5 percentage points; 95% confidence interval: –6.8%–13.9%; P=0.470). Perioperative serum creatinine concentrations were similar in the control and RIC groups (P=0.494). Fluid balance, urine output, blood loss, transfusion, and vasopressor/inotropic requirements were not significantly different between the groups (all P>0.05). The occurrences of a composite of morbidity and mortality endpoints were not significantly different between the control (46.0%) and RIC (39.2%) groups (a difference of 6.8 percentage points; 95% confidence interval: –6.4%–20.0%; P=0.283). ConclusionsThe results of our study do not support repeated RIC to decrease the incidence of AKI after valvular heart surgery. Clinical trial registrationNCT02720549.

Correction: Limited Clinical Utility of Remote Ischemic Conditioning in Renal Transplantation: A Meta-Analysis of Randomized Controlled Trials.

[This corrects the article DOI: 10.1371/journal.pone.0170729.].

Continuous remote ischemic conditioning attenuates cognitive and motor deficits from moderate traumatic brain injury.

While studies show that single-dose remote ischemic conditioning (RIC) improves outcomes, the effect of continuous (daily) RIC is unknown. Thus, we aimed to investigate the role of continuous RIC on cognitive and motor function following traumatic brain injury (TBI). We subjected 24 male C57BL mice to a cortical-controlled TBI. Two hours after TBI, the animals were randomly allocated to the RIC group (n = 12) or the sham group (n = 12). Remote ischemic conditioning was induced by noninvasive external compression of the hind limb using an occlusive band (six 4-minute cycles/24 hours) for six consecutive days. Before TBI, a baseline rotarod test and novel object recognition were performed. Post-TBI rotarod and novel object recognition tests were performed on Days 1 to 5, 7, 14, and 21. After the animals were sacrificed on Day 21, brain sections were analyzed using hematoxylin and eosin and glial fibrillary acidic protein staining to evaluate the hippocampal CA1 area for neuronal injury. Both the RIC and sham groups had lower latency to fall compared with the baseline post-TBI. The RIC animals had a higher latency to fall compared with the sham animals at all time points, statistically significant after Day 3, until Day 21 post-TBI. Both the RIC and sham groups had lower recognition index compared with the baseline post-TBI. The RIC animals had a significantly higher recognition index than the sham animals after Day 1, until Day 21 post-TBI. Hematoxylin and eosin and glial fibrillary acidic protein staining of the brain samples of the sham group revealed that more neurons in the hippocampal CA1 area appeared shrunken with eosinophilic cytoplasm and pyknotic nuclei compared with the brain samples of the RIC group. Postinjury continuous RIC resulted in improved cognitive functions and motor coordination in a mouse model of moderate TBI. Further studies are required to determine optimum dosage and frequency of this novel therapy to maximize its beneficial effects following TBI.

Limb remote ischemic conditioning of the recipient protects the liver in a rat model of arterialized orthotopic liver transplantation.

BackgroundIschemic-reperfusion (IR) injury still represents a major concern in clinical transplantation, especially in the era of extreme organ shortage and extended criteria donor organs. In the present study we aimed to investigate the hepatoprotective effects of remote ischemic conditioning (RIC) in a rat model of arterialized orthotopic liver transplantation (OLT).MethodsMale Lewis rats were used (n = 144 / 72 OLT cases; 240–340g) as donors and recipients. Livers were flushed and stored in 4°C HTK-solution for 8h before implantation. Recipients were randomly allocated into three experimental groups: RIC 1, RIC 2, Control. In RIC 1, RIC 2 groups, RIC was applied in the recipient before hepatectomy or after reperfusion (4x5-5min IR via clamping the infrarenal aorta), respectively. Animals were sacrificed at 1, 3, 24, 168h post-reperfusion (n = 6 recipient/group/time point). Hepatocellular injury, graft circulation, serum cytokines, tissue redox-stress and adenosine-triphosphate (ATP) levels have been assessed. Additional markers were analyzed, using Western blotting and reverse-transcription polymerase chain reaction.ResultsRIC 1 group showed significantly (p<0.05) improved portal venous and microcirculation flow as well as velocity. RIC has significantly reduced tissue injury according to the serum levels of transaminases and results of histopathological evaluation. Reduced TUNEL-staining (p<0.01 RIC 1–2 vs. Control) and elevated pBAD/BAD ratio was detected in the RIC groups (p<0.01 RIC 1 vs. Control). Supporting findings were obtained from measurements of serum IL-10 as well as tissue malondialdehyde and ATP levels. Hemoxygenase-1 (HO-1) mRNA-expression was significantly higher in RIC 1 compared to Control (p<0.05 RIC 1 vs. Control).ConclusionThese results suggest that RIC might confer potent protection against the detrimental effects of IR injury including tissue damage, apoptosis, graft circulation, inflammation, tissue energetic status in OLT. HO-1 overexpression might play an orchestrating role in RIC mediated organ protection. An earlier intervention (RIC 1 protocol) was more effective than remote conditioning after graft reperfusion.

Remote Ischemic Postconditioning Improves Myocardial Dysfunction Via the Risk and Safe Pathways in a Rat Model of Severe Hemorrhagic Shock.

Patients who have been resuscitated after severe hemorrhagic shock still have a high mortality rate. Previously published literature has suggested that remote ischemic postconditioning (RIPostC) has a cardioprotective effect, but few studies have focused on RIPostC performed after severe hemorrhagic shock. In this study, we aim to explore the effects and mechanism of RIPostC on myocardial ischemia and reperfusion injuries after hemorrhagic shock. Fifty male rats were randomized into four groups: sham, control, remote ischemic per-conditioning (RIPerC), and RIPostC. Hemorrhagic shock was induced by removing 45% of the estimated total blood volume. Remote ischemic conditioning (RIC) was induced by four cycles of limb ischemia for 5 min followed by 5 min of reperfusion, during and after resuscitation for the RIPerC and RIPostC groups, respectively. Myocardial function, survival rate, IL-6, IL-10, and SOD were detected. Myocardial damage was histopathologically analyzed, and proteins related to the reperfusion injury salvage kinase (RISK) pathway (Akt, MEK, ERK1/2) and the survival activating factor enhancement (SAFE) pathway (STAT-3 and STAT5) were measured. Compared with the control group, the ejection fraction and myocardial performance indexes were significantly better in both RIC groups 2 h after resuscitation. Myocardial damage was attenuated and survival time increased significantly in the RIC groups. IL-6 and cardiac troponin I (cTnI) levels were notably reduced in both RIC groups. Only RIPostC had significantly increased levels of SOD and IL-10. The SAFE and RISK pathways were activated by RIPostC, whereas the effect of RIPerC was not significant. RIPostC attenuated myocardial dysfunction and survival outcomes via the activation of the SAFE and RISK pathways in this rat model of hemorrhagic shock. RIPerC improves myocardial dysfunction, but might not do so via the SAFE and RISK pathways.

Remote ischemic conditioning preserves cognition and motor coordination in a mouse model of traumatic brain injury.

Management of traumatic brain injury (TBI) is focused on minimizing or preventing secondary brain injury. Remote ischemic conditioning (RIC) is an established treatment modality that has been shown to improve patient outcomes in different clinical settings by influencing inflammatory insults. In a clinical trial, RIC showed amelioration of SB100 and neuron-specific enolase. The aim of our study was to further elucidate the mechanisms and outcome when applying RIC in a mouse model of traumatic brain injury. We subjected 100 male C57BL mice to a closed-skull cortical-controlled impact injury. Two hours after the TBI, the animals were allocated to either the RIC group (n = 50) or the sham group (n = 50). By clamping the exposed femoral artery, we induced RIC by six 4-minute cycles of ischemia and reperfusion. Circulating levels of S100-B, neuron-specific enolase, and glial fibrillary acidic protein were measured at multiple time points. Animals were additionally observed daily for cognition and motor coordination via novel object recognition and rotarod. Brain sections were stained and evaluated for neuronal injury at post-TBI Day 5. The RIC animals had a significantly higher recognition index than did sham at 24, 48, and 72 hours after intervention. Rotarod latency was higher in the RIC animals compared to the sham animals at all-time points, and statistically significant at 120 hours after intervention. The RIC group demonstrated preserved cognitive function and motor coordination compared to the sham. On hematoxylin and eosin and immunohistochemical staining of brain sections, there was less area of neuronal degeneration and astrocytosis, respectively, in the RIC group compared to the sham group. There was no significant difference in systemic neuronal markers between the RIC and sham animals. Remote ischemic conditioning 2 hours after injury preserved cognitive functions and motor coordination in a mouse model of TBI. Remote ischemic conditioning can preserve viability of neurons and astrocytes after TBI and has potential as a clinically noninvasive and relatively easy method to improve outcome after TBI. Therapeutic studies, randomized controlled trial, level I.

Effects of Remote Ischaemic Conditioning on Heart Rate Variability and Cardiac Function in Patients With Mild Ischaemic Heart Failure

Cardioprotective effects of remote ischaemic conditioning (RIC) in the setting of ischaemic heart disease have been shown recently. But the effects of RIC on heart rate variability (HRV) and cardiac function in patients with stable ischaemic heart failure (IHF) are still unknown. Fifty patients with stable IHF were enrolled and randomly divided into RIC group and control group. Remote ischaemic conditioning treatment was performed twice a day for 6 weeks. A remote is chaemic conditioning protocol consisted of 4×5min inflation/deflation of the blood pressure cuff applied in the upper arm to create intermittent arm ischaemia. B-type natriuretic peptide (BNP), left ventricular ejection fraction (LVEF), 24-hour ambulatory electrocardiogram, and 6-minute walk distance (6MWD) were all assessed in two groups. Forty-seven patients completed the study. Remote ischaemic conditioning was well-tolerated by patients in the RIC group after 6 weeks treatment and LVEF showed a significant increase, from 39.2% to 43.4% (p<0.001), as well as decreased BNP, increased 6MWD and HRV, but this was not observed in the control group. In addition, the patients treated with RIC also showed improved NYHA class, LVEF, 6MWD, BNP level and HRV compared to control group. This study suggests that a 6-week course of RIC treatment could improve cardiac function and HRV in patients with mild and stable IHF, supporting widespread use of RIC in the daily lives of these patients.

Meta-analysis of remote ischemic conditioning in patients with acute myocardial infarction

Effects of remote ischemic conditioning (RIC) in acute myocardial infarction (AMI) patients remain conflicting. We performed this meta-analysis of randomized clinical trials (RCTs) to evaluate the benefits of the RIC in patients with AMI. Potentially relevant RCTs were identified by searching PubMed, Embase, Cochrane Library, VIP, CNKI, and Wanfang database until November 2016. RCTs evaluating RIC using intermittent limb ischemia-reperfusion in AMI patients were included. Thirteen RCTs were identified and analyzed. Meta-analysis showed that RIC significantly reduced the area under the curve (AUC) of creatine kinase-myocardial band (CK-MB) (standardized mean difference [SMD] −0.29; 95% confidence intervals [CI] −0.44 to −0.14; P = 0.0002) and AUC of troponin T (SMD −0.22; 95% CI −0.37 to −0.08; P = 0.003). Risk ratio (RR) for ≥70% ST-segment resolution favored RIC group than the control group (RR 1.39; 95% CI 1.03–1.86; P = 0.03). RIC also significantly reduced all-cause mortality (RR 0.33; 95%CI 0.17–0.64; P = 0.001). Subgroup analyses on the CK-MB AUC and ST-segment resolution ≥70% rate showed that the effects of RIC appeared to be affected by the limb used, duration of RIC, and clinical setting. RIC may offer cardioprotective effects by improving ST-segment resolution and reducing the infarct size in AMI patients.

The effects of remote ischemic conditioning in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention: a meta-analysis.

Timely and successful reperfusion is effective at improving outcome in patients presenting with ST elevation myocardial infarction (STEMI). However, abrupt restoration of blood flow may cause detrimental myocardial reperfusion injury. Remote ischemic conditioning (RIC) is a potent activator of innate protection against ischemia-reperfusion injury. This study assessed remote ischemic conditioning in patients presenting with STEMI treated with primary percutaneous coronary intervention (PCI). Relevant studies were identified through electronic literature search from PubMed, Medline, EMBASE, CNKI, WANFANG, and VIP. Studies published up to December 2015 were eligible for inclusion. RIC was performed by applying consecutive cycles of reocclusion/reperfusion through intermittent upper or lower limb ischemia before, during, or after reperfusion. The outcomes included creatine kinase-MB (CK-MB), ST resolution (STR), and left ventricular ejection fraction (LVEF). The 9 trials allocated 540 patients to perform RIC cycles before, during, or after reperfusion and 533 patients to usual PCI. Statistical analysis indicated that the peak of CK-MB and CK-MB AUC in RIC groups decrease significantly during the first 72 hours after PCI compared with controls (P=0.02 and P<0.01). The STR was significantly improved in RIC patients than in control subjects (P<0.001). LVEF is also improved 7 days after myocardial infarction (P=0.001). However, LVEF was not significantly different between study groups over 1 month (P=0.65). There may be a cardioprotective effect of RIC before, during, or after reperfusion, in the setting of acute STEMI.

Abstract WP295: Remote Limb Ischemic Conditioning in Murine Focal Cerebral Ischemia

Background &amp; Aims: Remote ischemic conditioning (RIC) could induce brain protection in cerebral ischemia. The conditioning can be divided into pre-, per- and post-conditioning. The aim of this study is to clarify which RIC is the most effective in murine focal ischemia. Methods: Adult male C57BL/6 mice were used in this study. Transient focal cerebral ischemia was produced with nylon-suture model by occluding middle cerebral artery (MCAO) for 45 minutes. Cortical cerebral blood flow (rCBF) was continuously measured during ischemia with laser Doppler flowmeter. Twenty-four hours after MCAO, the animals were sacrificed and their brains were removed. After cutting coronal 1-mm brain sections, infarct volume was measured after TTC staining. Fifty mice were divided into five groups (each n=10); sham RIC group, delayed preRIC group (RIC 24 hours before MCAO), early preRIC group (RIC 5 minutes before MCAO), perRIC group (RIC during MCAO), and postRIC group (RIC 5 minutes after MCAO). Hind limb ischemia was induced by making the snare as tight as possible using a hemostatic forceps for 5 minutes followed by loosening it for 5 minutes. Four cycles were performed as RIC. Results: Infarct volume were 58.8±10.1 mm 3 in sham RIC, 54.8±19.4 mm 3 in delayed preRIC, 69.3±10.8 mm 3 in early preRIC, 38.0±22.1 mm 3 in perRIC, and 64.5±13.5 mm 3 in postRIC groups. Infarct volume in perRIC was significantly smaller than that in sham RIC and other groups (P&lt;0.01). However, infarct volume of other RIC groups was not different with sham RIC group. After MCAO, rCBF reduced to 15.6% of baseline level in sham RIC, 11.2% in delayed preRIC, 11.9% in early preRIC, 13.4% in perRIC, and 10.8% in postRIC group. No difference was found in residual rCBF among all groups. At the end of MCAO, rCBF compared to rCBF immediate after occlusion was 102±21% in sham RIC, 112±25% in delayed preRIC, 98±22% in early preRIC, 131±33% in perRIC and 105±19% postRIC groups. Relative rCBF change at the end of MCAO in perRIC was significantly more than that in sham RIC group (P&lt;0.05). Conclusions: Among four RIC procedures, only perRIC showed clear brain protection against transient MCAO. Change during rCBF may suggest that enhancement of collateral circulation play a role in part on brain protective effect of perRIC.

Abstract TP407: Effects of Remote Ischemic Conditioning on Cerebral Small Vessel Disease Outcomes

Objective: To evaluate the preliminary efficacy of remote ischemic conditioning (RIC) on patients with cerebral small vessel disease (SVD). Methods: Thirty patients diagnosed with symptomatic SVD within 30 days of onset were enrolled in this prospectively randomized controlled study for 1 year. All patients received routine medical treatment including treating vascular risk factors according to the guideline. Patients in the experimental group (n=14) were administered 5 cycles consisting of ischemia followed by reperfusion for 5 minutes on bilateral upper limbs twice daily for 1 year. Those in the control group (n=16) underwent sham ischemia-reperfusion cycles. Primary outcome was the change of cognitive function measured by mini-mental state examination (MMSE) and montreal cognitive assessment scale (MoCA), and secondary outcomes were changes of plasma biomarkers, cerebral hemodynamic parameters measured by vascular ultrasound and brain lesions measured by MRI FLAIR both at baseline and at the end of 1 year visit. Results: Compared with patients in the control group, patients in the RIC group had higher flow velocity (FV), and lower pulsatility index (PI), but without statistical difference. Patients in the RIC group had improvement in visuospatial and executive abilities (3.86±1.03 vs. 4.43±0.85, p=0.026), reduced plasma triglyceride (1.60±0.74 vs. 1.25±0.38, p=0.019), low density lipoprotein (2.89±0.81 vs. 2.26±0.67, p=0.003) and homocysteine (15.66±10.11 vs. 13.66±9.80 p=0.017). Similarly in the RIC group, the diastolic flow velocity (DFV) of middle cerebral artery (MCA) (right: 33.93±7.67 vs. 36.93±6.12, p=0.032; left: 33.93±7.67 vs. 36.93± 6.12, p=0.032) and the mean flow velocity (MFV) of left MCA (35.00±5.04 vs. 39.50±5.59, p=0.003) increased, and the PI of MCA (right: 1.11±0.19 vs. 1.02±0.14 p=0.030; left: 1.10±0.22 vs. 0.99±0.14, p=0.037) decreased. Conclusion: RIC appears to be potentially effective for improving cognition, enhancing cerebral perfusion, and modifying vascular risk factors in SVD patients. Further studies focusing on long-term neurological outcomes and potential mechanisms underlying RIC on SVD patients are needed.

Abstract WP449: Short Term (1 month) Daily Remote Ischemic Conditioning (RIC) Induces Vascular Remodeling and Improves Long Term Outcomes (6 month) in a Mouse Model of Vascular Cognitive Impairment (VCI)

Background and Purpose: There is presently no specific therapy for the treatment of VCI. The bilateral carotid artery stenosis (BCAS) model is regarded as a valid model for VCI and vascular dementia. We reported that daily RIC is effective by improving cerebral blood flow (CBF), reducing white matter (WM) damage and improving cognition. The purpose of this study was to determine if 1MO RIC is as effective as 4MO RIC and if the treatment effects are durable out to 6MO. Methods: Microcoil induced BCAS model was used to induce chronic hypoperfusion. Adult C57BL/6J male mice (10-weeks) were randomly assigned to 4-different groups (N=10), and subjected to Sham-BCAS, BCAS-(+sham RIC), BCAS+RIC-1MO and BCAS+RIC-4MO. RIC was started 7d post-surgery daily for 1MO or 4MOs. Behavioral test and CBF was performed at 1, 4 and 6MO after BCAS surgery. Functional outcomes were assessed using novel object recognition (NOR) test for non-spatial working memory, and hanging wire test for motor impairment. Histopathology as well as immunohistochemistry for CD31 and myelin basic protein (MBP) were also performed on the of the brain tissue collected after the neurobehavioral tests. Statistical significance was determined at p &lt;0.05. Results: RIC-therapy for 1MO or 4MO significantly improved CBF in the BCAS+RIC groups. The RIC-1MO treatment was effective as the RIC-4MO treatment at improving CBF at 6MO. Mice from the BCAS group showed significant loss in the discrimination index as determined by the NOR test, and poor motor function in hanging wire test. RIC-therapy in BCAS+RIC (1MO &amp; 4MO) groups significantly improved functional outcomes as compared to the BCAS group whereas there was no difference between the RIC groups. Histopathological studies showed prevention of WM degeneration by RIC. Immunohistochemical analysis at 6 MOs showed increased CD31 staining (angiogenesis) and increased MBP staining (myelination) in the RIC groups compared to sham RIC. Conclusions: Both 1MO and 4MO RIC-therapy improve long term CBF and angiogenesis at 6 MO and reduce WM damage and improve functional outcomes. One month of daily RIC is as effective as 4MO of daily RIC at improving CBF and long term functional outcomes (6MO) in the BCAS model. This suggests that 1MO of RIC induces durable vascular remodeling.

Safety and efficacy of remote ischemic conditioning in pediatric moyamoya disease patients treated with revascularization therapy.

BACKGROUND:Revascularization surgery has been the standard treatment to prevent ischemic stroke in pediatric Moyamoya disease (MMD) patients with ischemic symptoms. However, perioperative complications, such as hyperperfusion syndrome, new infarct on imaging, or ischemic stroke, are inevitable. Remote ischemic conditioning (RIC) is a noninvasive and easy-to-use neuroprotective strategy, and it has potential effects on preventing hyperperfusion syndrome and ischemic infarction.AIMS:The aim of this study is to investigate the safety and efficacy of RIC in pediatric MMD patients undergoing revascularization surgery.METHOD:A total of 60 pediatric MMD patients with one or more ischemic symptoms will be recruited and allocated in 1:1 ratio to the RIC group and sham group, respectively. Both RIC and sham RIC will be performed twice daily for 7 consecutive days before revascularization surgery with different cuff pressures during the ischemia period (50 mmHg over-systolic blood pressure and 30 mmHg). Single photon emission computed tomography will be performed within 7 days preoperatively and 3 months postoperatively, respectively, to evaluate the cerebral perfusion status. Other outcomes, including safety, plasma biomarker, functional outcome, and the incidence of infarction and its size, will also be evaluated.CONCLUSION:This study will provide insights into the preliminary proof of principle, safety, and efficacy of RIC in pediatric MMD patients undergoing revascularization surgery therapy, and this data will provide parameters for future larger scale clinical trials if efficacious.