Remote Ischemic Conditioning Treatment Research Articles

Age affects the association of red blood cell indices with efficacy of remote ischemic conditioning in patients with acute moderate ischemic stroke

We conducted a post hoc analysis of Remote Ischemic Conditioning for Acute Moderate Ischemic Stroke (RICAMIS) to investigate whether red blood cell (RBC) indices are associated with efficacy of remote ischemic conditioning (RIC), and whether the association is affected by age. In this post hoc analysis, patients with RBC indices at admission were enrolled. RBC indices including RBC count, hematocrit (HCT), mean corpuscular volume (MCV), hemoglobin (HB), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) were analyzed. According to the median of these RBC indices, eligible patients were divided into high and low groups, which were further subdivided into RIC and control subgroups. Primary endpoint was excellent functional outcome defined as a modified Rankin Scale score of 0–1 at 90 days, which was used to evaluate RIC efficacy. RIC efficacy as well as effect of age on RIC efficacy were analyzed across the high and low groups of different RBC indices, and the interaction effects of RBC indices on RIC efficacy were evaluated. A total of 1640 patients were enrolled in the final analysis. In overall patients, no significant interaction effects of RIC intervention by all RBC indices were found, although there was a trend in interaction effect of RIC intervention by MCH (p = 0.116). However, we found an effect of age on the association of MCH with RIC efficacy. In patients over 60 years old, MCH significantly affected RIC efficacy (p = 0.006) and RIC significantly produced a higher proportion of primary outcome in high MCH (72.6% vs. 59.1%, P < 0.001) vs. low MCH group (61.2% vs. 62%, P = 0.829), which was not identified in patients under 60 years old. Furthermore, RIC efficacy decreased with increasing age in patients with low MCH with significant interaction effect (p = 0.012), while RIC efficacy increased with increasing age in patients with high MCH although no significant interaction (p = 0.126). No significant interaction effects of RIC intervention by RBC count, HCT, MCV, HB, and MCHC were found regardless of age. This secondary analysis of RICAMIS suggested that RIC exhibited more obvious benefit in AIS patients over 60 years old with high MCH compared with those with low MCH group, but RBC count, HCT, MCV, HB, and MCHC were not associated with the efficacy of RIC treatment regardless of age.

Remote ischemic conditioning slows blood-retinal barrier damage in type 1 diabetic rats

Diabetic retinopathy (DR) is one of the major complications of diabetes and can cause severe visual impairment. Blood-retina barrier (BRB) destruction resulted from chronic hyperglycemia underlines its major pathological process. However, current treatments have limited efficacy and may even cause serious complications. Remote ischemic conditioning (RIC), through repeated transient mechanical occlusion of limb blood vessels, has been confirmed to promote blood–brain barrier integrity after stroke, but its role in BRB disruption has not been elucidated. This study aimed to investigate the protective effects of RIC on the BRB in diabetic rats and its potential mechanisms. 48 Sprague-Dawley rats were randomly assigned to the Sham group, Sham + RIC group, diabetes mellitus (DM) group and DM+RIC group. The diabetic model was successfully induced by intraperitoneal injection of streptozotocin (STZ). RIC treatment was administered daily and lasted for 9 weeks. In functional analysis, RIC improved the retinal function based on electroretinogram data and reduced the leakage of BRB in diabetic rats. In proteomic analysis, tight junction pathway was enriched after RIC treatment, in which Patj gene was significantly increased. We also found that RIC increased mRNA levels of Patj, claudin-1 and zonula occludens (ZO)-1, protein expression of claudin-1 when compared with diabetic models. In conclusion, RIC slowed BRB damage in diabetic rats which may be related to the preservation of tight junction proteins. RIC may be a promising protective strategy for the treatment of DR.

Remote Ischemic Conditioning Improves Cardiovascular Function in Heart Failure Patients.

Recently, it has been shown that remote ischemic conditioning (RIC) can be used as a healthy regimen to reverse disease and aging. With this in mind, we are studying the consequences of RIC on cardiovascular function in heart failure patients. Forty patients with stable heart failure were prospectively enlisted and randomly divided into RIC (n = 20) and control (n = 20) groups. The RIC protocol consists of a 3-min inflation and then deflation of the blood pressure cuff attached to the upper arm to produce transient ischemia of the arm. RIC treatment was performed once daily for 1 year. NYHA class, left ventricular ejection fraction (LVEF), left atrial and ventricular dimensions were all assessed in two groups. RIC was well tolerated. After 1 year of treatment, New York Heart Association (NYHA) class improved and LVEF showed a significant increase from 37.11% to 52.44% (P < 0.0001). Additionally, the dimensions of the left atrium (from 50.55 to 43.25 mm) and ventricle (from 53.04 to 50.15 mm) were significantly reduced in the RIC group. This study suggests that 1 year of RIC treatment as a health strategy could improve cardiovascular function in heart failure patients, leading to its widespread use in these patients.

Association of systolic blood pressure variability with remote ischemic conditioning in acute ischemic stroke

Systolic blood pressure variability (SBPV) is associated with outcome in acute ischemic stroke. Remote ischemic conditioning (RIC) has been demonstrated to be effective in stroke and may affect blood pressure. Relationship between SBPV and RIC treatment after stroke warrants investigation. A total of 1707 patients from per-protocol analysis set of RICAMIS study were included. The SBPV was calculated based on blood pressure measured at admission, Day 7, and Day 12. (I) To investigate the effect of SBPV on efficacy of RIC in stroke, patients were divided into High and Low categories in each SBPV parameter. Primary outcome was excellent functional outcome at 90 days. Compared with Control, efficacy of RIC in each category and interaction between categories were investigated. (II) To investigate the effect of RIC treatment on SBPV, SBPV parameters were compared between RIC and Control groups. Compared with Control, a higher likelihood of primary outcome in RIC was found in high category (max–min: adjusted risk difference [RD] = 7.2, 95% CI 1.2–13.1, P = 0.02; standard deviation: adjusted RD = 11.5, 95% CI 1.6–21.4, P = 0.02; coefficient of variation: adjusted RD = 11.2, 95% CI 1.4–21.0, P = 0.03). Significant interaction of RIC on outcomes were found between High and Low standard deviations (adjusted P < 0.05). No significant difference in SBPV parameters were found between treatment groups. This is the first report that Chinese patients with acute moderate ischemic stroke and presenting with higher SBPV, who were non-cardioemoblic stroke and not candidates for intravenous thrombolysis or endovascular therapy, would benefit more from RIC with respect to functional outcomes at 90 days, but 2-week RIC treatment has no effect on SBPV during hospital.

Remote ischemic conditioning prevents ischemic cerebrovascular events in children with moyamoya disease: a randomized controlled trial.

Moyamoya disease (MMD) is a significant cause of childhood stroke and transient ischemic attacks (TIAs). This study aimed to assess the safety and efficacy of remote ischemic conditioning (RIC) in children with MMD. In a single-center pilot study, 46 MMD patients aged 4 to 14years, with no history of reconstructive surgery, were randomly assigned to receive either RIC or sham RIC treatment twice daily for a year. The primary outcome measured was the cumulative incidence of major adverse cerebrovascular events (MACEs). Secondary outcomes included ischemic stroke, recurrent TIA, hemorrhagic stroke, revascularization rates, and clinical improvement assessed using the patient global impression of change (PGIC) scale during follow-up. RIC-related adverse events were also recorded, and cerebral hemodynamics were evaluated using transcranial Doppler. All 46 patients completed the final follow-up (23 each in the RIC and sham RIC groups). No severe adverse events associated with RIC were observed. Kaplan-Meier analysis indicated a significant reduction in MACEs frequency after RIC treatment [log-rank test (Mantel-Cox), P = 0.021]. At 3-year follow-up, two (4.35%) patients had an ischemic stroke, four (8.70%) experienced TIAs, and two (4.35%) underwent revascularization as the qualifying MACEs. The clinical improvement rate in the RIC group was higher than the sham RIC group on the PGIC scale (65.2% vs. 26.1%, P < 0.01). No statistical difference in cerebral hemodynamics post-treatment was observed. RIC is a safe and effective adjunct therapy for asymptomatic children with MMD. This was largely due to the reduced incidence of ischemic cerebrovascular events.

Baseline systolic blood pressure, hypertension history, and efficacy of remote ischemic conditioning.

We performed a post hoc exploratory analysis of Remote Ischemic Conditioning for Acute Moderate Ischemic Stroke (RICAMIS) to determine whether hypertension history and baseline systolic blood pressure (SBP) affect the efficacy of remote ischemic conditioning (RIC). Based on the full analysis set of RICAMIS, patients were divided into hypertension versus non-hypertension group, or <140 mmHg versus ≥140 mmHg group. Each group was further subdivided into RIC and control subgroups. The primary outcome was modified Rankin Scale (mRS) 0-1 at 90 days. Efficacy of RIC was compared among patients with hypertension versus nonhypertension history and SBP of <140 mmHg versus ≥140 mmHg. Furthermore, the interaction effect of treatment with hypertension and SBP was assessed. Compared with control group, RIC produced a significantly higher proportion of patients with excellent functional outcome in the nonhypertension group (RIC vs. control: 65.7% vs. 57.0%, OR 1.45, 95% CI 1.06-1.98; p = 0.02), but no significant difference was observed in the hypertension group (RIC vs. control: 69.1% vs. 65.2%, p = 0.17). Similar results were observed in SBP ≥140 mmHg group (RIC vs. control: 68.0% vs. 61.2%, p = 0.009) and SBP <140 mmHg group (RIC vs. control: 65.6% vs. 64.7%, p = 0.77). No interaction effect of RIC on primary outcome was identified. Hypertension and baseline SBP did not affect the neuroprotective effect of RIC, but they were associated with higher probability of excellent functional outcome in patients with acute moderate ischemic stroke who received RIC treatment.

P.030 Remote ischemic conditioning in acute ischemic stroke and small vessel disease – a feasibility study

Background: We tested the hypothesis that delivering remote ischemic conditioning (RIC) with an adjunct tissue reflectance sensor (TRS) device may be feasible in patients with acute ischemic stroke (AIS) and cerebral small vessel disease (cSVD). Methods: AIS patients with neurological deficits within 7 days of symptom onset were screened for moderate to severe cSVD. Eligible patients were randomized 2:1 to receive intervention RIC or sham RIC (7 days). The primary outcome measure was intervention feasibility. It was assessed as an intervention-related comfort by a 5-point Likert scale during each session (1-very uncomfortable, 5-very comfortable). The secondary outcome measure was assessment of TRS derived dermal blood concentration and blood oxygenation changes during RIC. Results: Forty-seven (32 intervention, 15 sham) patients were enrolled at a median (IQR) 39.7 (25-64) hours after symptom onset, with mean±SD age of 75±12 years, 22 (46.8%) were females and median baseline NIHSS of 5(3-7). The Likert scale was 3.5 (3-4) in the intervention group and 4 (4-5) in the sham group. The TRS derived blood concentration and blood oxygenation changes were proportionate in the intervention arm and absent in the sham arm. Conclusions: RIC treatment with TRS is feasible in patients with AIS+cSVD. The efficacy of RIC needs further assessment.

Abstract 61: The Effect of Remote Ischemic Conditioning in Stroke Subtypes: A Subgroup Analysis From the RESIST Trial

Introduction: Remote ischemic conditioning (RIC) is a simple and non-invasive procedure that has proved safe and feasible in numerous smaller clinical trials. Still, mixed results have been found in recent large randomized controlled trials. Here we present a predefined subgroup analysis of the RESIST trial on the effect of RIC in subgroups of acute ischemic stroke (AIS) and whether this effect is modified by adherence to RIC. Methods: The subgroups were defined as large artery atherosclerotic disease (LAA), small vessel disease (SVD), cardioembolic, and unknown/other/multiple/rare, and were based on ICD-10 discharge diagnoses assigned by the treating physician to define stroke etiology. Acceptable treatment adherence was defined as at least 80% received out of planned cycles. The outcome analysis used the entire range (‘shift analysis’) of the 90-day modified Rankin Scale score (ordinal logistic regression). ClinicalTrials.gov:NCT03481777. Results: A total of 902 patients were included in the target population group, 466 in the sham group, and 436 in the RIC group. RIC did not significantly improve functional outcome in adherent patients with LAA, cardioembolic or multiple/unknown etiologies. In SVD patients (n=94), with good treatment adherence, RIC treatment was associated with a significantly improved 90-day functional outcome, unadjusted OR (95% CI): 2.47 (1.01-6.02), p= 0.047. In patients with SVD, 4 patients (8%) in the RIC group compared to 0 patients in the sham group had atrial fibrillation (AF), p=0.050. The association remained significant after adjusting for AF, adjusted OR (95% CI): 2.64 (1.07-6.54), p= 0.035. Conclusions: In patients with AIS due to SVD, who had good treatment adherence, RIC treatment was associated with improved functional outcome at 90 days. These results are encouraging but should only be hypothesis-generating for future studies.

Effect of Remote Ischemic Conditioning in Ischemic Stroke Subtypes: A Post Hoc Subgroup Analysis From the RESIST Trial.

Remote ischemic conditioning (RIC) is a simple and noninvasive procedure that has proved to be safe and feasible in numerous smaller clinical trials. Mixed results have been found in recent large randomized controlled trials. This is a post hoc subgroup analysis of the RESIST trial (Remote Ischemic Conditioning in Patients With Acute Stroke), investigating the effect of RIC in different acute ischemic stroke etiologies, and whether an effect was modified by treatment adherence. Eligible patients were adults (aged ≥18 years), independent in activities of daily living, who had prehospital stroke symptoms with a duration of less than 4 hours. They were randomized to RIC or sham. The RIC treatment protocol consisted of 5 cycles with 5 minutes of cuff inflation alternating with 5 minutes with a deflated cuff. Acceptable treatment adherence was defined as when at least 80% of planned RIC cycles were received. The analysis was performed using the entire range (shift analysis) of the modified Rankin Scale (ordinal logistic regression). A total of 698 had acute ischemic stroke, 253 (36%) were women, and the median (interquartile range) age was 73 (63-80) years. Median (interquartile range) overall adherence to RIC/sham was 91% (68%-100%). In patients with a stroke due to cerebral small vessel disease, who were adherent to treatment, RIC was associated with improved functional outcome, and the odds ratio for a shift to a lower score on the modified Rankin Scale was 2.54 (1.03-6.25); P=0.042. The association remained significant after adjusting for potential confounders. No significant associations were found with other stroke etiologies, and the overall test for interaction was not statistically significant (χ2, 4.33, P=0.23). In patients with acute ischemic stroke due to cerebral small vessel disease, who maintained good treatment adherence, RIC was associated with improved functional outcomes at 90 days. These results should only serve as a hypothesis-generating for future trials. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03481777.

Dyslipidemia and Efficacy of Remote Ischemic Conditioning in Acute Moderate Ischemic Stroke: A Post Hoc Analysis of the RICAMIS Study.

Ischemic conditioning-induced cardioprotection was attenuated by dyslipidemia in some animal and clinical studies, which is not investigated in patients with stroke. We conducted a post hoc analysis of the RICAMIS (Remote Ischemic Conditioning for Acute Moderate Ischemic Stroke) trial to investigate the association of dyslipidemia on admission with the efficacy of remote ischemic conditioning (RIC). In this analysis, eligible patients were divided into dyslipidemia and normal-lipid groups according to the levels of 4 blood lipid profiles (total cholesterol, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol), which were further subdivided into RIC and control subgroups. We analyzed the differences in functional outcome between RIC and control subgroups in dyslipidemia and normal-lipid patients, respectively, and the interaction effects of RIC treatment with blood lipid levels were evaluated. Among 1776 patients from intention-to-treat analysis, 1419 patients with data of blood lipid profiles were included in the final analysis. A significantly higher proportion of modified Rankin Scale score 0 to 1 was identified in the RIC versus control subgroup across the normal-total cholesterol group (69.9% versus 63.5%; P=0.04), normal-triglycerides group (68.1% versus 60.5%; P=0.016), high-low-density lipoprotein cholesterol group (65.7% versus 57.7%; P=0.025), and normal-high-density lipoprotein cholesterol group (68.3% versus 60.5%; P=0.005). Similar statistical trends were found in the high-total cholesterol group (62.8% versus 55.5%; P=0.059), high-triglycerides group (67.8% versus 60.1%; P=0.099), normal-low-density lipoprotein cholesterol group (69.8% versus 63.7%; P=0.105), but no statistical significance was found in the low-high-density lipoprotein cholesterol group (63.4% versus 61%; P=0.705). Furthermore, no significant interaction effect of RIC intervention by blood lipid profiles was found. Similar results were obtained for lipids as continuous variables. Blood lipids on admission was not associated with the neuroprotective effect of RIC.

Remote Ischemic Conditioning for Acute Stroke

Despite some promising preclinical and clinical data, it remains uncertain whether remote ischemic conditioning (RIC) with transient cycles of limb ischemia and reperfusion is an effective treatment for acute stroke. To evaluate the effect of RIC when initiated in the prehospital setting and continued in the hospital on functional outcome in patients with acute stroke. This was a randomized clinical trial conducted at 4 stroke centers in Denmark that included 1500 patients with prehospital stroke symptoms for less than 4 hours (enrolled March 16, 2018, to November 11, 2022; final follow-up, February 3, 2023). The intervention was delivered using an inflatable cuff on 1 upper extremity (RIC cuff pressure, ≤200 mm Hg [n = 749] and sham cuff pressure, 20 mm Hg [n = 751]). Each treatment application consisted of 5 cycles of 5 minutes of cuff inflation followed by 5 minutes of cuff deflation. Treatment was started in the ambulance and repeated at least once in the hospital and then twice daily for 7 days among a subset of participants. The primary end point was improvement in functional outcome measured as a shift across the modified Rankin Scale (mRS) score (range, 0 [no symptoms] to 6 [death]) at 90 days in the target population with a final diagnosis of ischemic or hemorrhagic stroke. Among 1500 patients who were randomized (median age, 71 years; 591 women [41%]), 1433 (96%) completed the trial. Of these, 149 patients (10%) were diagnosed with transient ischemic attack and 382 (27%) with a stroke mimic. In the remaining 902 patients with a target diagnosis of stroke (737 [82%] with ischemic stroke and 165 [18%] with intracerebral hemorrhage), 436 underwent RIC and 466 sham treatment. The median mRS score at 90 days was 2 (IQR, 1-3) in the RIC group and 1 (IQR, 1-3) in the sham group. RIC treatment was not significantly associated with improved functional outcome at 90 days (odds ratio [OR], 0.95; 95% CI, 0.75 to 1.20, P = .67; absolute difference in median mRS score, -1; -1.7 to -0.25). In all randomized patients, there were no significant differences in the number of serious adverse events: 169 patients (23.7%) in the RIC group with 1 or more serious adverse events vs 175 patients (24.3%) in the sham group (OR, 0.97; 95% CI, 0.85 to 1.11; P = .68). Upper extremity pain during treatment and/or skin petechia occurred in 54 (7.2%) in the RIC group and 11 (1.5%) in the sham group. RIC initiated in the prehospital setting and continued in the hospital did not significantly improve functional outcome at 90 days in patients with acute stroke. ClinicalTrials.gov Identifier: NCT03481777.

Remote ischemic conditioning in the treatment of acute cerebral infarction: A case control study

ObjectiveThis paired case-control study aimed to evaluate the efficacy and safety of remote ischemic conditioning (RIC) in patients with acute cerebral infarction (CI) and explore potential serological markers of RIC. MethodsPatients with acute CI (<72 h) were matched 1:1 according to age, sex, and CI conditions and were divided into the RIC group and the control group. The RIC group received RIC intervention for 7 days on top of routine treatment, while the control group received a sham RIC. The curative effects and adverse reactions were observed. ResultA total of 66 patients (mean age 60.00 ± 11.37 years; mean time of acute CI onset 32.91 ± 17.94 h) completed the study. The National Institute of Health stroke scale score on day 7, modified Rankin Scale scores on day 7 and day 90 were significantly lower than the baseline in the RIC group (P < 0.001, P = 0.003, P = 0.004, respectively) but not in the control group (P = 0.056, P = 0.169, P = 0.058, respectively). RIC was well-tolerated, and no adverse events were reported. Both plasma hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor increased in the RIC group from day 0 to day 7, while they decreased in the control group. The changes in plasma HIF-1α in the RIC group were statistically different from those in the control group (P = 0.006). ConclusionEarly and short-term RIC treatment was well-tolerated and effective in improving the prognosis in acute CI. HIF-1α can be recognized as a biomarker for evaluating the efficacy of RIC treatment.

Time from Onset to Remote Ischemic Conditioning and Clinical Outcome After Acute Moderate Ischemic Stroke.

We conducted a post hoc exploratory analysis of Remote Ischemic Conditioning for Acute Moderate Ischemic Stroke (RICAMIS) to determine whether early remote ischemic conditioning (RIC) initiation after stroke onset was associated with clinical outcome in patients with acute moderate ischemic stroke. In RICAMIS, patients receiving RIC treatment in the intention-to-treat analysis were divided into 2 groups based on onset-to-treatment time (OTT): early RIC group (OTT ≤ 24 hours) and late RIC group (OTT 24-48 hours). Patients receiving usual care without RIC treatment from intention-to-treat analysis were assigned as the control group. The primary outcome was excellent functional outcome at 90 days. Among 1,776 patients from intention-to-treat analysis, 387 were in the early RIC group, 476 in the late RIC group, and 913 in the control group. In the post hoc exploratory analysis, a higher proportion of excellent functional outcome was found in the early RIC versus control group (adjusted absolute difference = 8.1%, 95% confidence interval [CI] = 2.5%-13.8%, p = 0.005), but no difference in outcomes was detected in the late RIC versus control group (adjusted absolute difference = 3.3%, 95% CI = -2.1% to 8.6%, p = 0.23), or in the early RIC versus late RIC group (adjusted absolute difference = 5.0%, 95% CI = -1.3% to 11.2%, p = 0.12). Similar results were found in the per-protocol analysis. Among patients with acute moderate ischemic stroke who are not candidates for intravenous thrombolysis or endovascular therapy, early RIC initiation within 24 hours of onset may be associated with higher likelihood of excellent clinical outcome. ANN NEUROL 2023.

Effects of remote ischemic conditioning on sleep complaints in Parkinson's disease-rationale, design, and protocol for a randomized controlled study.

ObjectiveSleep disturbances are common non-motor symptoms of Parkinson's disease. The symptoms affect the quality of patients' life by impeding normal sleep cycles and causing excessive daytime sleepiness. Remote Ischemic Conditioning (RIC) is a therapy often used for ischemic stroke patients to minimize infarct size and maximize post-stroke neurological function. Animal experiments have shown that RIC plays a protective role for retinal ganglion cells and other critical areas of the brain of Parkinson's disease. However, whether RIC improves excessive daytime sleepiness (EDS) for patients with Parkinson's disease remains to be determined.MethodsThis is a single-center, double-blind, and randomized controlled trial, which includes patients with Parkinson's disease with EDS. All recruited patients will be randomly assigned either to the RIC or the control group (i.e., sham-RIC) with 20 patients in each group. Both groups receive RIC or sham-RIC treatment once a day for 28 days within 24 h of enrollment. Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), Parkinson Disease Sleep Scale-2 (PDSS-2), Parkinson's Disease Questionnaire39 (PDQ39) score scales, and adverse events, such as inability to tolerate the treatment leading to suspension of the study or objective signs of tissue or neurovascular injury caused by RIC and/or sham-RIC are evaluated at 7, 14, 28, and 90 days after enrollment.ResultsThe primary goal of this study is to assess the feasibility of the treatments in patients with Parkinson's disease by measuring serious RIC-related adverse events and any reduced incidence of adverse events during the trial and to study potential efficacy, improvement of patients' excessive daytime sleepiness, quality of life-based on ESS, PSQI, PDSS-2, and PDQ39 scores. The secondary goal is to confirm the safety of the treatments.ConclusionThis study is a prospective randomized controlled trial to determine the safety, feasibility, and potential efficacy of RIC for patients with Parkinson's disease associated with EDS.

Factors That Influence Compliance to Long-Term Remote Ischemic Conditioning Treatment in Patients With Ischemic Stroke.

Objectives: To investigate the treatment compliance of patients with ischemic stroke to remote ischemic conditioning (RIC) and to determine the factors that influence compliance.Methods: We conducted a retrospective study of patients with ischemic stroke who were treated with RIC. Treatment compliance was determined and analyzed in patients who had received 1 year of RIC training. Factors that influenced patient compliance were also determined using univariate and multivariate regression analyses.Results: Between March 2017 and February 2018, 91 patients were recruited into this study. The mean (±SD) age was 57.98 ± 10.76 years, and 78 (85.7%) patients were male. The baseline Kolcaba comfort scale of patients with good compliance scores were higher than those with poor compliance. The scores of the four dimensions in the scale and the total score are as follows: physiological dimensions, 15.0 (12.0,17.0) vs 17.0 (13.0,19.0); psychological dimensions, 30.0 (25.0,34.0) vs 31.0 (27.0,35.0); sociological dimensions, 20.0 (18.0,24.0) vs 21.0 (18.0,23.0); environmental dimensions, 19.0 (12.0,24.0) vs 20.0 (17.0,22.0); and total points, 82.0 (69.0,94.0) vs 91.0 (78.0,98.0). the differences between the groups were significant (p < 0.05), except for the sociological dimensions. A history of hypertension, number of follow-ups, and the physiological, psychological, and environmental dimensions of the comfort scale were related to patient compliance, out of which the number of follow-ups (Adjusted OR = 2.498, 95% confidence interval (CI) 1.257–4.964) and the physiological discomfort (Adjusted OR = 1.128, 95% CI 1.029–1.236) independently influenced compliance (p < 0.05).Conclusion: In patients with ischemic cerebrovascular disease who were treated with RIC, the number of follow-up visits and physiological discomfort associated with RIC treatment independently influenced patient compliance. Further studies are needed to investigate the RIC protocols and their corresponding nursing models.

Quantitative Proteomic Analysis of Plasma after Remote Ischemic Conditioning in a Rhesus Monkey Ischemic Stroke Model.

Background: Animal and clinical studies have shown that remote ischemic conditioning (RIC) has protective effects for cerebral vascular diseases, with induced humoral factor changes in the peripheral blood. However, many findings are heterogeneous, perhaps due to differences in the RIC intervention schemes, enrolled populations, and sample times. This study aimed to examine the RIC-induced changes in the plasma proteome using rhesus monkey models of strokes. Methods: Two adult rhesus monkeys with autologous blood clot-induced middle cerebral artery (MCA) occlusion underwent RIC interventions twice a week for five consecutive weeks. Each RIC treatment included five cycles of five minutes of ischemia alternating with five minutes of reperfusion of the forearm. The blood samples were taken from the median cubital vein of the monkeys at baseline and immediately after each week’s RIC stimulus. The plasma samples were isolated for a proteomic analysis using mass spectrometry (MS). Results: Several proteins related to lipid metabolism (Apolipoprotein A-II and Apolipoprotein C-II), coagulation (Fibrinogen alpha chain and serpin), immunoinflammatory responses (complement C3 and C1), and endovascular hemostasis (basement membrane-specific heparan sulfate proteoglycan) were significantly modulated after the RIC intervention. Many of these induced changes, such as in the lipid metabolism regulation and anticoagulation responses, starting as early as two weeks following the RIC intervention. The complementary activation and protection of the endovascular cells occurred more than three weeks postintervention. Conclusions: Multiple protective effects were induced by RIC and involved lipid metabolism regulation (anti-atherogenesis), anticoagulation (antithrombosis), complement activation, and endovascular homeostasis (anti-inflammation). In conclusion, this study indicates that RIC results in significant modulations of the plasma proteome. It also provides ideas for future research and screening targets.

Translational challenges of remote ischemic conditioning in ischemic stroke - a systematic review.

Remote ischemic conditioning (RIC) has well‐established cardioprotective effects in preclinical studies and promising results in preclinical stroke research. Effective translation from preclinical studies to clinical trials has yet to be accomplished, perhaps because of the use of multiple applications of RIC (e.g., pre‐, per‐, or post‐conditioning) in preclinical studies by both invasive and non‐invasive protocols, some of which not clinically applicable. Our systematic review conformed to PRISMA guidelines and addressed differences in clinically relevant RIC applications and outcomes between preclinical and clinical studies. We retrieved a total of 30 studies (8 human; 22 animal) that met the inclusion criteria of testing clinically relevant procedures; namely, non‐invasive and per‐ or post‐conditioning protocols. Per‐conditioning was applied in 6 animal and 3 human studies, post‐conditioning was applied in 16 animal and 5 human studies, and both conditioning methods were applied in 2 animal studies. Application of RIC varied between human and animal studies regarding initiation, duration, repetition, and number of limbs included. Study designs did not systematically apply blinding, randomization, or placebo controls. On only a few occasions did preclinical studies include animals with clinically relevant comorbidities. Clinical trials were challenged by not completing the intended number of RIC cycles or addressing this deficit in the data analysis. Consistency and transferability of methods used for positive animal studies and subsequent human studies are essential for the optimal translation of results. Consensus on preclinical and clinical RIC procedures should be reached for a full understanding of the possible beneficial effects of RIC treatment in stroke.

Fibrinolysis and Remote Ischemic Conditioning: Mechanisms and Treatment Perspectives in Stroke.

Stroke is a leading cause of death and disability. Intravenous thrombolysis and mechanical thrombectomy have greatly improved outcomes in acute ischemic stroke (AIS). However, only a minority of patients receive reperfusion therapies, highlighting the need for novel neuroprotective therapies. Remote ischemic conditioning (RIC), consisting of brief, intermittent extremity occlusion and reperfusion induced with an inflatable cuff, is a potential neuroprotective therapy in acute stroke. The objective of this narrative review is to describe the effect of RIC on endogenous fibrinolysis and, from this perspective, investigate the potential of RIC in the prevention and treatment of stroke. A systematic literature search was performed in PubMed, and human studies in English were included. Seven studies had investigated the effect of RIC on fibrinolysis in humans. Long-term daily administration of RIC increased endogenous fibrinolysis, whereas a single RIC treatment did not acutely influence endogenous fibrinolysis. Fifteen studies had investigated the effect of RIC as a neuroprotective therapy in the prevention and treatment of stroke. Long-term RIC administration proved effective in reducing new cerebral vascular lesions in patients with established cerebrovascular disease. In patients with acute stroke, RIC was safe and feasible, though its clinical efficacy as a neuroprotectant is yet unproven. In conclusion, a single RIC treatment does not affect fibrinolysis in the acute phase, whereas long-term RIC administration may increase endogenous fibrinolysis. Increased endogenous fibrinolysis is unlikely to be the mediator of the acute neuroprotective effect of RIC in stroke patients, whereas it may partly explain the reduced stroke recurrence associated with long-term RIC treatment.

Exosomes isolated from the plasma of remote ischemic conditioning rats improved cardiac function and angiogenesis after myocardial infarction through targeting Hsp70.

Remote ischemic conditioning (RIC) is a promising therapeutic strategy to protect heart against ischemic-reperfusion injury. Exosomes have been proved to be an important regulator in many pathological processes. Whether the exosomes derived from RIC could improve cardiac remodeling and function after myocardial infarction (MI) has not been reported. MI animal model was established by ligating the left coronary artery. The bilateral hindlimbs of rats were subjected to RIC treatment using tourniquets. Exosomes were isolated from the plasma of RIC rats and identified by transmission electron microscope. The proliferation, migration, and apoptosis of endothelial cells were measured by CCK8, traswell, and flow cytometry. Western blotting, and qRT-PCR were applied to measure the expression of angiogenesis-related molecules, and immunohistochemistry staining was used to observe the expression of vWF. RIC and RIC exosomes remarkably facilitated cardiac function, cardiac cell remodeling, and angiogenesis. RIC exosomes markedly increased the cell ratio in the G1 phase, cell migration, cell proliferation, tube formation, and inhibited cell apoptosis through Hsp70. The expression of eNOS, iNOS, HIF-1α, Ang-1, and VEGF was markedly increased by RIC exosomes. RIC exosomes significantly improved cardiac function, cardiac remodeling, and angiogenesis after MI, and they accelerated angiogenesis through increasing the levels of angiogenesis-related molecules.

Remote Ischemic Conditioning Improves Attention Network Function and Blood Oxygen Levels in Unacclimatized Adults Exposed to High Altitude.

Remote ischemic conditioning (RIC) confers protection on major organs from hypoxic/ischemic injuries; however, its impacts on attention network function and blood oxygen levels in unacclimatized adults exposed to high altitudes have yet to be elucidated. In this study, we recruited 120 healthy male volunteers, of which one was exposed to high altitude and the other was exposed to low altitude. The two cohorts were further divided into RIC and sham control groups. The attentional network test (ANT) was performed to evaluate cognitive function before and after RIC treatment. Other outcomes such as heart rate, blood pressure, blood oxygen saturation, cerebral tissue oxygenation index (CTOI), and cerebrovascular hemodynamic indices were also evaluated. Prior to RIC treatment, there were no significant differences in orienting or executive function between the treatment and control arms of either cohort. Alerting function was significantly lower in the high-altitude cohort than in the low-altitude cohort. There were significant reductions in both blood oxygen and CTOI in the high-altitude cohort relative to the low-altitude cohort, while the pulse index (PI) of the former cohort was significantly increased. After RIC treatment, there was a significant difference in alerting function between the high-altitude RIC group and its associated control. The CTOI of the treatment group increased from 60.39±3.40% to 62.78±4.40%, and blood oxygenation also improved. Furthermore, this group showed a significant reduction in its PI. Exposure to high-altitude environments had a significant impact on alerting function, blood oxygen, CTOI, and PI. RIC ameliorated changes in attentional function, as well as blood oxygen and CTOI, suggesting that it potentially alters cerebrovascular compliance upon exposure to high altitude.