Effects of remote ischemic conditioning on microcirculatory alterations in patients with sepsis: a single-arm clinical trial

Abstract Background Remote ischemic conditioning (RIC) is a promising technique that may protect organs and tissues from the effects of additional ischemic episodes. However, the therapeutic efficacy of RIC in humans with sepsis remains unknown. We hypothesized that RIC might improve sublingual microcirculation in patients with sepsis. Methods This prospective single-arm trial was performed in a mixed ICU at a tertiary teaching hospital. We included patients with sepsis or septic shock within 24 h of ICU admission. The RIC procedure comprised 3 cycles of brachial cuff inflation to 200 mmHg for 5 min followed by deflation to 0 mmHg for another 5 min. The procedure took 30 min. RIC was performed at the time of study inclusion and repeated after 12 and 24 h. Sublingual microcirculatory measurements were obtained before and after each RIC procedure using a Cytocam®-incident dark-field (IDF) device (Braedius Medical, Huizen, The Netherlands). The microcirculatory data were compared with a historical control. Data are reported as the medians along with the 25th and 75th percentiles. Results Twenty-six septic patients with a median age of 65 (57–81) years were enrolled in this study. The median Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) scores at admission were 20 (13–23) and 10 (9–12), respectively. All patients were receiving vasopressors. After the 1st RIC procedure, the microvascular flow index (MFI) and the proportion of perfused vessels (PPV) among small vessels were significantly higher than before the procedure, with pre- and post-treatment values of 2.17 (1.81–2.69) and 2.59 (2.21–2.83), respectively, for MFI (p = 0.003) and 87.9 (82.4–93.8) and 92.5 (87.9–96.1) %, respectively, for PPV (p = 0.026). This result was confirmed by comparison with a historical control group. We found no change in microcirculatory flow or density parameters during repeated RIC after 12 h and 24 h. Conclusion In patients with sepsis, the first remote ischemic conditioning procedure improved microcirculatory flow, whereas later procedures did not affect sublingual microcirculation. Trial registration NCT04644926, http://www.clinicaltrials.gov. Date of registration: 25 November 2020. Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04644926.

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

Stroke ◽

10.1161/str.48.suppl_1.tp407 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Yuan Wang ◽

Haiqing Song ◽

Kai Dong ◽

Ran Meng ◽

Shuying Wang ◽

...

Keyword(s):

Risk Factors ◽

Flow Velocity ◽

Small Vessel Disease ◽

Cerebral Small Vessel Disease ◽

Vascular Risk Factors ◽

Control Group ◽

Vascular Risk ◽

Remote Ischemic Conditioning ◽

Ischemic Conditioning ◽

Vessel Disease

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.

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Remote ischemic conditioning for acute moderate ischemic stroke (RICAMIS): Rationale and design

International Journal of Stroke ◽

10.1177/1747493019879651 ◽

2019 ◽

Vol 15 (4) ◽

pp. 454-460

Author(s):

Xiao-Qiu Li ◽

Lin Tao ◽

Zhong-He Zhou ◽

Yu Cui ◽

Hui-Sheng Chen ◽

...

Keyword(s):

Ischemic Stroke ◽

Clinical Studies ◽

Ischemia Reperfusion Injury ◽

Neuroprotective Effect ◽

Ischemia Reperfusion ◽

Control Group ◽

Open Label ◽

Remote Ischemic Conditioning ◽

Ischemic Conditioning ◽

Experimental Group

Rationale A large number of basic and clinical studies have proved that remote ischemic conditioning has neuroprotective effect. For example, remote ischemic conditioning showed a neuroprotective role in cerebral ischemia-reperfusion injury model. Recent clinical studies suggested that remote ischemic conditioning may improve neurological function and reduce the risk of recurrence in ischemic stroke patients. However, there is a lack of convincing evidence for the neuroprotective effect of remote ischemic conditioning on ischemic stroke, which deserves further study. Aim To explore the efficacy and safety of remote ischemic conditioning for acute moderate ischemic stroke. Sample size estimates A maximum of 1800 subjects are required to test the superiority hypothesis with 80% power according to a one-sided 0.025 level of significance, stratified by gender, age, time from onset to treatment, National Institutes of Health Stroke Scale (6–10 vs. 11–16), degree of responsible vessel stenosis, location of stenosis, and stroke etiology. Methods and design Remote Ischemic Conditioning for Acute Moderate Ischemic Stroke is a prospective, random, open label, blinded endpoint and multi-center study. The subjects are divided into experimental group and control group randomly. The experimental group was treated with remote ischemic conditioning twice daily with 200 mmHg pressure for 10–14 days besides guideline-based therapy. The control group was treated according to the guidelines. Study outcome The primary efficacy endpoint is favorable functional outcome, defined as modified Rankin Scale 0–1 at 90 days post-randomization.

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Effects of chronic remote ischemic conditioning on atrial fibrillation burden in patients with permanent pacemakers

10.21203/rs.3.rs-57419/v1 ◽

2020 ◽

Author(s):

Long Chen ◽

Yaowu Liu ◽

Didi Zhu ◽

Jinbo Yu ◽

Chunlei Yu ◽

...

Keyword(s):

Atrial Fibrillation ◽

High Rate ◽

Control Group ◽

Clinical Trial Registration ◽

Daily Lives ◽

Remote Ischemic Conditioning ◽

Ischemic Conditioning ◽

Pressure Cuff ◽

Registration Number ◽

Atrial Fibrillation Burden

Abstract Background: The burden of atrial fibrillation (AF) has been attractive recently and may be associated with stroke risk and mortality. Remote ischemic conditioning could reduce the incidence, inducibility and sustainability of AF. But the effects of chronic remote ischemic conditioning (CRIC) on atrial fibrillation burden in patients with pacemaker implanted are still unknown.Design: This was a single‑center, prospective, randomized, open-labeled clinical study.Methods: Sixty-six patients with permanent pacemakers were randomly divided into CRIC group and control group after 4 weeks screening. CRIC treatment was performed twice a day for 12 weeks. A remote ischemic conditioning protocol consisted of 4 × 5 min inflation/deflation of the blood pressure cuff applied in the upper arm to create intermittent arm ischemia. Pacemaker programming was performed for four times: before screening (-4-week), after screening and before randomization (0-week, baseline), 4-week and 12-week follow-up. Data including AF burden, longest duration of AF and cumulative numbers of atrial high-rate episodes (AHREs) were collected.Results: Sixty-one patients (31 patients in CRIC group and 30 patients in control group) completed the study. CRIC was well-tolerated by patients after 12 weeks treatment. The burden of AF in CRIC group was decreased significantly at 4-week compared with that at 0-week (14.7%±18.5% vs 17.0%±20.7%, p < 0.001), which further decreased at 12-week compared with that at 0-week (8.6%±10.2% vs 17.0%±20.7%, p < 0.001) and that at 4-week (8.6%±10.2% vs 14.7%±18.5%, p < 0.001), which was not observed in the control group. AF burden also reduced significantly after 12-week CRIC compared with that in control group (8.6%±10.2% vs 17.6%±19.5%, p = 0.013). Repeated measurement ANOVA showed that the changes of AF burden was associated with CRIC instead of time (p < 0.01). In addition, there were trends that longest duration of AF and cumulative numbers of AHREs were reduced after 12-week CRIC.Conclusions: This study suggests that a 12-week course of CRIC treatment could reduce AF burden in patients with permanent pacemakers, supporting widespread use of CRIC in the daily lives of these patients, which need to be verified in the future.Clinical Trial RegistrationRegistration name: Effects of remote ischemic conditioning on atrial fibrillation burden in patients with paroxysmal atrial fibrillationRegistration number: ChiCTR-IOR-17012666Registered 14 September 2017; URL: www.chictr.org.cn/showproj.aspx?proj=21591

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Abstract 2628: Remote Ischemic Conditioning Reduces Brain Edema in Experimental Ischemia/Reperfusion Injury

Stroke ◽

10.1161/str.43.suppl_1.a2628 ◽

2012 ◽

Vol 43 (suppl_1) ◽

Author(s):

Changhong Ren ◽

Mingqing Gao ◽

Ning Li ◽

Jinqiang Cao ◽

Yuchuan Ding ◽

...

Keyword(s):

Tight Junction ◽

Brain Edema ◽

Treated Group ◽

Tight Junction Protein ◽

Control Group ◽

Remote Ischemic Conditioning ◽

Ischemic Conditioning ◽

Mca Occlusion ◽

Junction Protein ◽

And Control

Background and Purpose _Remote ischemic conditioning (RIC) has been shown to provide neuroprotective effects, but the precise mechanisms underlying the therapeutic effects still remain unclear. In this study, we investigate changes in blood-brain barrier (BBB) permeability and edema formation, in association with expression of matrix metalloproteinases (MMP), tight junction proteins and aquaporins (AQP) in RIC treated rats following unilateral middle cerebral artery (MCA) occlusion and reperfusion. Methods _Ischemic stroke model was generated by occlusion of the right MCA for 1.5 hours in male Sprague-Dawley rats. Remote ischemic conditioning was conducted immediately after MCA occlusion in the bilateral lower limb by occluding and releasing the femoral artery for three cycles; each occlusion and release lasted for 10 minutes. Edema levels and BBB integrity were studied by quantification of brain water content and extravasations of Evans blue at 48 hours after reperfusion, respectively. Protein expression of occludin, claudin-5, ZO-1, MMP-2, MMP-9, as well as AQP-4 and AQP-9, were determined by Western blot analysis at 48 hours after reperfusion. The activity of MMP-2 and MMP-9 were determined by gelatin zymography at the same time points. Results _Treatment with RIC significantly ( P <0.05) reduced brain edema ( P <0.01) and BBB dysfunction when compared to the control ischemic groups. IPC treatment resulted in a significant ( P <0.05) increase in the expression of tight junction protein occludin in comparison to the control non-treatment group. The expressions of claudin-5 and ZO-1were not different between RIC-treated group and control group. RIC treatment diminished ischemia-induced MMP-9 ( P <0.01) but not MMP-2. The expressions of AQP-4 and AQP-9 were not different between RIC-treated group and control group. Conclusions _RIC ameliorates brain edema and BBB disruption after stroke, in association with a reduction of MMP-9 and increase in the expression of tight junction protein occludin. These results provide clues to neuroprotective properties of RIC.

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Experience of Sublingual Microcirculation Evaluation in Adults Patients with Severe Dengue

Open Forum Infectious Diseases ◽

10.1093/ofid/ofx163.875 ◽

2017 ◽

Vol 4 (suppl_1) ◽

pp. S360-S360

Author(s):

Fernando Rosso ◽

Gustavo Ospina ◽

Edgardo Quiñones ◽

Ana Maria Sanz

Keyword(s):

Fluid Challenge ◽

Significant Negative Correlation ◽

Dark Field ◽

Severe Dengue ◽

Flow Index ◽

Vascular Density ◽

Positive Serology ◽

Volume Depletion ◽

Sidestream Dark Field ◽

Sublingual Microcirculation

Abstract Background Severe microcirculatory changes are involved in the pathophysiological mechanisms that lead to irreversible final stages of dengue shock. We report our experience of the evaluation of sublingual microcirculation in adult patients with severe dengue Methods Adults patients with severe dengue (by WHO 2009 criteria) were included. Dengue diagnostics was made by positive serology for IgM / IgG, antigen NS1 or PCR. Sublingual Microcirculation (SM) was evaluated by Sidestream Dark Field imaging. Microvascular flow index (MFI), proportion of small-perfused vessels (%SVP), heterogeneity index (HI) and Total Vascular Density were calculated. All patients received Fluids Challenge (FC) at hospital admission. Results SM was assessed in 10 patients. The median age was 65 years [IQR: 34–70], 60% were male. Eight patients were admitted to the ICU, of which 63% required invasive ventilatory and vasoactive support. One patient died. After the fluid challenge, the median of the %SVP was 94 [IR: 97 – 77], the median of the MFI was 2.82 [IR: 2, 85 – 2, 14]. There were not significant differences in %SVP and MFI among the patients who survived. In the deceased patient, the %SVP with continuous flow was 59, 18% and the MFI was 1, 45; these values were significantly decreased compared with patients who survived. A significant negative correlation between hematocrit and %SVP, and MFI was found. Conclusion Initial fluid challenge, that identifies and treats volume depletion, could correct microcirculation abnormalities evaluated by SDF imaging. However, in the patient who did not respond to this challenge, significant alterations of the MFI and the %SVP were evidenced. There is a need for more studies to improve our understanding of the role of microcirculation evaluation in these patients. Disclosures All authors: No reported disclosures.

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Characteristics and Clinical Significance of Microcirculation in Populations Residing at Different Altitudes

10.21203/rs.3.rs-30900/v1 ◽

2020 ◽

Author(s):

Siqing Ma ◽

Zong-Zhao He ◽

Jun-Ming Luo ◽

Kang Song ◽

Jing-Yuan Xu ◽

...

Keyword(s):

Field Method ◽

Dark Field ◽

Vessel Density ◽

Physiological Adaptation ◽

Flow Index ◽

Sidestream Dark Field ◽

Blood Oxygen Saturation ◽

Cell Parameters ◽

Sublingual Microcirculation ◽

Different Altitudes

Abstract Background: This study aimed to evaluate changes in microcirculation, physiological characteristics, and the pathomechanism of and potential treatment alternatives for severe septic shock among healthy individuals residing at different altitudes.Methods: Seventy individuals, 35 from Xining and 35 from Nanjing, were recruited, and their body temperature, pulse, respiration, mean arterial pressure, peripheral blood oxygen saturation, and blood cell parameters were determined. Microcirculation indices of sublingual microcirculation were monitored using the sidestream dark field method.Results: Erythrocyte counts and hemoglobin levels were significantly higher among individuals from Xining than among those from Nanjing (P < 0.05); however, platelet counts were significantly lower among those from Xining (P < 0.05). Microcirculation indices of total vessel density, perfused vessel density, and the proportion of perfused vessels were significantly higher among individuals from Xining than among those from Nanjing; however, the microvascular flow index was lower among those from Xining. Microvascular density was significantly higher among individuals from Xining than among those from Nanjing.Conclusion: Microvascular densit may be a physiological adaptation among populations at moderate-to-high altitudes.

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Remote Ischemic Conditioning Improves Cognition in Patients with Subcortical Ischemic Vascular Dementia

10.21203/rs.2.10140/v1 ◽

2019 ◽

Author(s):

Zhangyuan Liao ◽

Yali Bu ◽

Meijie Li ◽

Ranran Han ◽

Nan Zhang ◽

...

Keyword(s):

White Matter ◽

Vascular Dementia ◽

Upper Limb ◽

Verbal Learning ◽

Control Group ◽

Lesion Volume ◽

Remote Ischemic Conditioning ◽

Ischemic Conditioning ◽

Hs Crp

Abstract Background ： Subcortical ischemic vascular dementia (SIVD) is very common among the older people, but has no approved treatment. Preclinical trials show that remote ischemic conditioning (RIC) reduces recurrence of ischemic stroke. We hypothesize that RIC may also be an effective therapy for patients with SIVD. Methods ： Thirty-seven consecutive SIVD cases were enrolled in this randomized control study. Eighteen RIC patients underwent five brief cycles of conditioning (bilateral upper limb compression at 200 mmHg) followed by reperfusion twice daily over 6 consecutive months. Nineteen control patients underwent the same process, but at a pressure of 60 mmHg which caused no restriction on the blood flow of the upper limb. The primary outcome measures were changes in neuropsychological assessments. The secondary outcomes included the changes in high-sensitive C-reactive protein (hs-CRP) concentration, white matter lesion volume (WMLV), diffusion tension imaging (DTI) metrics of white matter. All data were collected at baseline and follow-up. Results ： A significant treatment difference favoring RIC at 6 months was observed on performance of Hopkins Verbal Learning Test-Revised (HVLT-R), Controlled Oral Word Association Test(COWAT), Trail Making Test A and B (TMT-A & TMT-B), and Judgment of Line Orientation (JLO) (p<0.05). The control group did not show much improvement after the treatment, and only with a slight change in HVLT-R and TMT-R(p<0.05). Covariance analysis of efficacy between the two groups suggested that RIC patients performed better on JLO than control patients at the 6-month follow-up (RIC 23.10 vs. control 18.56; p=0.013). Although DTI metrics were comparable, Hs-CRP levels and WMLV in RIC patients showed a declining trend. Conclusions： Over the 6-month treatment period, we found that RIC was safe and effective for improving cognitive function in SIVD patients.

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Abstract P416: Remote Ischemic Conditioning Reduces Perihematomal Edema After Intracerebral Hemorrhage: First Proof-Of-Concept Randomized Controlled Trial

Stroke ◽

10.1161/str.52.suppl_1.p416 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Zhao Wenbo ◽

Fang Jiang ◽

Sijie Li ◽

Yuchuan Ding ◽

Xunming Ji

Keyword(s):

Intracerebral Hemorrhage ◽

Controlled Trial ◽

Neurological Deterioration ◽

Hematoma Expansion ◽

Control Group ◽

Hematoma Volume ◽

Remote Ischemic Conditioning ◽

Ischemic Conditioning ◽

Significant Difference ◽

Perihematomal Edema

Introduction: The prognosis of intracerebral hemorrhage (ICH) is poor because of the mass effect arising from the hematoma and the associated perihematomal edema (PHE). Remote ischemic conditioning (RIC) has been shown to promote hematoma clearance and reduce PHE in animal models, however it remains unknown whether RIC is safe and effective in reducing PHE in ICH patients. Objective: To evaluate the safety and efficacy of RIC in reducing PHE after ICH. Methods: In this open-label, rater-blind, randomized control trial, 40 subjects with supratentorial ICH (hematoma volume:10-30 ml) diagnosed between 24 to 48 hours of onset were assigned to the RIC group or control group. All subjects received standard background medical therapy. Subjects in the RIC group underwent repeated daily RIC (4 cycles of 5 minutes inflation [200 mmHg] /deflation [0 mmHg] of cuff on one arm) for 7 consecutive days. The primary efficacy outcome was PHE volume at 7 days, and both absolute PHE volume and relative PHE volume (defined as absolute PHE volume divided by hematoma volume) were measured. Safety outcome included death, neurological deterioration, hematoma expansion, and any other severe adverse events. Results: All 40 subjects completed this study. Mean age was 59.3±11.7 years, and 57.5% were male. At baseline, the median National Institutes of Health Stroke Scale score was 9.5 (range 1-28), median Glasgow Come Score was 15 (range 10-15), and mean ICH volume was 13.9±4.5 ml. The mean relative PHE volume was 1.11±0.26 in the control group and 1.05±0.23 in the RIC group at baseline; and 1.49±0.30 vs. 1.33 ±0.32 at Day 3 (p>0.05 each) respectively. After 7 days of treatment, RIC significantly reduced the relative PHE volume as compared to the control (1.77±0.39 vs. 2.02±0.27, p=0.02). The absolute PHE volume and hematoma volume at Day 3 and Day 7 had no significant difference between groups (p>0.05 each). No subject died or suffered from neurological deterioration or hematoma expansion and no adverse event was associated with RIC. Conclusion: RIC seemed to be safe in patients with ICH and induced a significant reduction in the relative PHE volume after 7 day of treatment. These results warrant a further study with large sample to examine the effect of RIC on functional outcome after ICH.

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Inhaled Nitric Oxide with Intravenous Hydrocortisone Does Not Improve Microvascular Perfusion in Septic Pigs.

10.21203/rs.3.rs-586452/v1 ◽

2021 ◽

Author(s):

Malgorzata Grotowska ◽

Waldemar Gozdzik ◽

Piotr Harbut ◽

Claes Frostell

Keyword(s):

Nitric Oxide ◽

Organ Dysfunction ◽

Capillary Flow ◽

Dark Field ◽

Inhaled Nitric Oxide ◽

Colon Perforation ◽

Flow Index ◽

Control Group ◽

Sidestream Dark Field ◽

Microvascular Flow

Abstract BackgroundCapillary flow restoration in sepsis may prevent organ dysfunction caused by a prolonged impairment of microvascular flow. The main aim of the study was to investigate the microcirculatory effect of inhaled nitric oxide (iNO) combined with intravenous hydrocortisone in a porcine model of sepsis. The second aim was to evaluate the influence of hemodynamic resuscitation with noradrenaline and crystalloids on capillary flow.Materials and MethodsIn the study, 11 piglets of Polish breed were generally anaesthetized and underwent surgical colon perforation. The animals were randomly allocated to one of three treatment groups. Group 1 received iNO and hydrocortisone, whereas Group 2 was a control group. Both groups were resuscitated with crystalloids and noradrenaline if hypotensive. Group 3 received no treatment at all.In a 30-hour period of observation, we assessed microcirculation using sidestream dark field imaging (SDF) and monitored hemodynamics with a pulmonary artery catheter.Results We found no effect of iNO with hydrocortisone on microcirculation in septic piglets. Fluid and vasopressor treatment postponed microvascular flow impairment and led to a higher microcirculatory flow index, greater proportion of perfused vessels, and perfused vessel density.ConclusionCrystalloid and vasopressor treatment postpones microvascular flow derangement and organ dysfunction in septic piglets.

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Remote ischemic conditioning fails to protect against ischemia-reperfusion injury in patients with untreated familial hypercholesterolemia

European Heart Journal ◽

10.1093/eurheartj/ehab724.1205 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

Author(s):

O Kovamees ◽

A Mahdi ◽

T Wodaje ◽

D Verouhis ◽

J Brinck ◽

...

Keyword(s):

Endothelial Dysfunction ◽

Familial Hypercholesterolemia ◽

Animal Studies ◽

Ldl Cholesterol ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Control Group ◽

Remote Ischemic Conditioning ◽

Ischemic Conditioning ◽

Clinical Endpoints

Abstract Background/Introduction Remote ischemic conditioning (RIC) is the action of brief periods of ischemia to a remote tissue and has been suggested to protect against myocardial ischemia-reperfusion (IR) injury. The outcomes of clinical trials in terms of clinical endpoints and infarct size reduction have been variable, which may be related to influence of comorbidities on the effect of RIC. Animal studies suggest that hypercholesterolemia attenuates the cardioprotective effect of RIC, but no data from study on patients are available. Hence, our aim was to investigate the response of RIC on IR-induced endothelial dysfunction in patients with familial hypercholesterolemia (FH). Purpose To investigate if RIC protects against endothelial dysfunction induced by IR in patients with FH with high (≥5.5 mmol/L) and low (≤2.5 mmol/L) LDL-cholesterol levels. Methods All subjects with FH (n=12) with LDL ≥5.5 mmol/L, FH with LDL <2.5 mmol/L (n=12), and age-matched healthy control subjects (n=12) participated in two protocols separated by at least one week. In both protocols, endothelium-dependent vasodilatation was assessed by determination of flow-mediated vasodilatation (FMD) of the brachial artery at baseline and again after 20 minutes of forearm ischemia and 20 minutes of reperfusion. Forearm ischemia was induced by inflating a blood pressure cuff on the upper arm to 200 mmHg. An additional inflatable cuff was placed around the left thigh. In one protocol (IR+sham), this cuff was left uninflated. In the second protocol (IR+RIC), it was inflated to 200 mmHg in four cycles of 5 minutes inflation and 5 min deflation with the first cycle starting at the onset of forearm ischemia. Results Plasma mean LDL-cholesterol was significantly higher in the FH group with high LDL (6.6±1.4 mmol/L) compared to the control group (2.4±0.7 mmol/L; p<0.01) and the low LDL FH group (2.0±0.6 mmol/L; p<0.001). FMD was markedly reduced (p<0.05) in all subjects following IR+sham, indicating IR-induced endothelial dysfunction in all three groups. As expected, RIC prevented the reduction in FMD after IR in the control group (Fig 1). By contrast, in the FH group with high LDL, RIC failed to protect from IR-induced endothelial dysfunction. Thus, in this group the decrease in FMD was similar after IR+RIC and IR+ sham (Fig 1). In the FH group with LDL <2.5 mmol/L, the decrease in FMD induced by IR was attenuated by RIC (p=0.05). Conclusion These observations suggest that RIC, which protects from IR-induced endothelial dysfunction in healthy controls, fails to protect from IR-induced endothelial dysfunction in patients with FH and LDL-cholesterol >5.5 mmol/L. The protective effect of RIC is restored after treatment of hypercholesterolemia. This finding may have bearings on the clinical efficacy of RIC in patients with ST-elevation myocardial infarction. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Heart-lung foundation

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