Effects of remote ischemic postconditioning on the pro-inflammatory neutrophils of peripheral blood in acute cerebral infarction.

BACKGROUND: Neutrophils play crucial roles in the inflammatory response after acute cerebral infarction (ACI). Previous studies revealed neutrophils are non-homogeneous and can be divided into at least two subtypes, pro-inflammatory and anti-inflammatory, correlated with patients' prognosis. OBJECTIVE: We aimed to explore the correlation between disease severity and peripheral blood neutrophils in patients with ACI and determine whether remote ischemic postconditioning (RIPostC) exerts neuroprotective effects by regulating neutrophils. METHODS: Patients (n = 38) with acute anterior circulation cerebral infarction were assigned to conventional treatment (n = 24; included aspirin, statins, neuro nutrition drugs, and circulation improvement drugs) or RIPostC (n = 14; 7-day ischemia adaptation [complete ischemia of both upper extremities for 5 minutes followed by remission for 5 minutes, 5 repeated cycles, twice a day, started from the morning of the second day of admission] based on conventional treatment) groups, based on their preference. General clinical data and peripheral blood samples were taken three times, in the morning before and 3 and 7 days after treatment. Fifteen adults with non-acute cerebral infarction matched for sex, age, and risk factors were recruited as controls; peripheral blood samples were only collected on the recruitment day. We used flow cytometry to detect the percentage of neutrophils and Real-Time PCR to detect the gene expression of interleukin (IL)-1ß in the peripheral blood samples. RESULTS: The percentage of neutrophils, pro-inflammatory neutrophils (IL-1ß high expression in flow cytometry), and IL-1ß mRNA expression increased after ACI (P = 0.01, P = 0.001, P < 0.001). The National Institutes of Health Stroke Scale (NIHSS) score of patients with ACI within one day of onset was positively correlated with the percentage of pro-inflammatory neutrophils (R = 0.618, P = 0.043). Pro-inflammatory neutrophils in the RIPostC group decreased compared with those in the conventional treatment group, with the most significant difference observed on Day 7 (P = 0.01). However, the percentage of neutrophils was not statistically different. IL-1ß mRNA expression decreased, with the most significant difference on Day 3 (P = 0.004). The NIHSS and Modified Rankin Scale scores for RIPostC decreased more significantly than for conventional treatment (P = 0.002, P = 0.019). CONCLUSION: More severe cerebral infarction was associated with a higher percentage of pro-inflammatory neutrophils. The neuroprotective effect of RIPostC may partly be exerted through gene regulation to reduce pro-inflammatory neutrophils.

Remote limb ischemic postconditioning attenuates myocardial dysfunction induced by testicular torsion/detorsion in rats.

Torsion of the spermatic cord is a urological emergency that must be treated immediately with surgery, yet detorsion of the testis can cause testicular tissue damage because of ischemia-reperfusion (I/R) injury. I/R injury is a complex pathophysiological process that may affect the functions of distant organs. Here, we examined whether testicular torsion/detorsion (TT) causes myocardial dysfunction. We next investigated the potential beneficial effect and underlying mechanisms of remote ischemic postconditioning (RIPost) on cardiac function after testicular torsion/detorsion. Male Sprague-Dawley rats were assigned to three different sets of experimental groups. Testicular I/R was induced by rotating the right testis to 1080° clockwise for 3 h followed by 3 h of detorsion. RIPost was induced at the onset of testicular detorsion by four cycles of 5-min bilateral femoral artery occlusion with 5-min reperfusion. Cardiac function was determined postdetorsion, and the cardioprotective effect of RIPost was examined. Testicular torsion/detorsion-treated rats had reduced serum testosterone levels, impaired systemic hemodynamics, elevated systemic inflammatory responses, and increased serum levels of lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), α-hydroxybutyrate dehydrogenase (α-HBDH), and cardiac troponin I (cTnI). However, RIPost attenuated remote heart dysfunction induced by testicular torsion/detorsion. Furthermore, RIPost enhanced the phosphorylation of ventricular signal transducer and activator of transcription (STAT)-3, which is a key component of the survivor activating factor enhancement (SAFE) signaling pathways. Inhibition of STAT-3 with Ag490 abolished the RIPost-induced cardioprotection and STAT-3 phosphorylation. Testicular torsion followed by detorsion may cause impaired cardiac function in rats. RIPost effectively attenuates this remote cardiac dysfunction. RIPost-induced protective effects may be mediated by the STAT-3 signaling pathway.

The effect of repeated remote ischemic postconditioning after an ischemic stroke (REPOST): A randomized controlled trial.

BACKGROUND AND AIMS: A potential strategy to treat ischemic stroke may be the application of repeated remote ischemic postconditioning (rIPostC). This consists of several cycles of brief periods of limb ischemia followed by reperfusion, which can be applied by inflating a simple blood pressure cuff and subsequently could result in neuroprotection after stroke. METHODS: Adult patients admitted with an ischemic stroke in the past 24 h were randomized 1:1 to repeated rIPostC or sham-conditioning. Repeated rIPostC was performed by inflating a blood pressure cuff around the upper arm (4 × 5 min at 200 mm Hg), which was repeated twice daily during hospitalization with a maximum of 4 days. Primary outcome was infarct size after 4 days or at discharge. Secondary outcomes included the modified Rankin Scale (mRS)-score after 12 weeks and the National Institutes of Health Stroke Scale (NIHSS) at discharge. RESULTS: The trial was preliminarily stopped after we included 88 of the scheduled 180 patients (average age: 70 years, 68% male) into rIPostC (n = 40) and sham-conditioning (n = 48). Median infarct volume was 2.19 mL in rIPostC group and 5.90 mL in sham-conditioning, which was not significantly different between the two groups (median difference: 3.71; 95% CI: -0.56 to 6.09; p = 0.31). We found no significant shift in the mRS score distribution between groups. The adjusted common odds ratio was 2.09 (95% CI: 0.88-5.00). We found no significant difference in the NIHSS score between groups (median difference: 1.00; 95% CI: -0.99 to 1.40; p = 0.51). CONCLUSION: This study found no significant improvement in infarct size or clinical outcome in patients with an acute ischemic stroke who were treated with repeated remote ischemic postconditioning. However, due to a lower-than-expected inclusion rate, no definitive conclusions about the effectiveness of rIPostC can be drawn.

Direct Ischemic Postconditioning After Carotid Endarterectomy in the Prevention of Postoperative Cerebral Ischemic Complications-Observational Case-Control Study.

INTRODUCTION: Ischemic postconditioning (IPCT) represents one of the several therapeutic strategies to attenuate ischemic reperfusion injury (IR) after carotid endarterectomy (CEA). We here present the first in-human study of IPCT in carotid surgery. METHODS: The study represents an observational case-control study, with the data collected in our Institution carotid database. From December 2015 to December 2020, a total of 300 patients were included in our study; IPCT group consisted of 148 patients in whom ischemic postconditioning was performed while control group consisted of 152 patients in whom IPCT was not performed. Indications for IPCT technique were: severe unilateral internal carotid artery (ICA) stenosis (>90%), severe bilateral ICA stenosis (>80%), severe ICA stenosis (>80%) with contralateral ICA occlusion and ICA subocclusion. IPCT was performed by applying 6 cycles of 30 sec reperfusion (declamping of ICA)/30 sec ischemia (clamping of ICA) after finishing the procedure and initial declamping. Two groups of patients were compared in terms of occurrence of intrahospital and early postoperative stroke, TIA (transient ischemic attack) and neurologic morbidity. RESULTS: Cumulative incidence of intrahospital postoperative stroke or TIA was significantly higher in the control group (5.3% vs 0.7%, P = .036). According to carotid plaque characteristics, patients in the IPCT group had significantly more frequent presence of heterogenous plaque, as well as ulcerated plaque, which was associated with the absence of postoperative stroke and significantly lower cumulative rate of TIA/stroke when compared to the control group (43.9% vs 8% and 47.3% vs 1.5%). During the follow-up period of 1 month after the surgery, there were no cases of stroke, TIA and deaths due to neurological causes in both groups of patients. CONCLUSION: Our results showed that IPCT significantly reduced the incidence of postoperative cerebral ischemic complications after CEA in high-risk patients for IR injury when compared to the control group.

Comparison of Effect of Ischemic Postconditioning on Cardiovascular Mortality in Patients With ST-Segment Elevation Myocardial Infarction Treated With Primary Percutaneous Coronary Intervention With Versus Without Thrombectomy.

In patients with ST-segment elevation myocardial infarction (STEMI), ischemic postconditioning (iPOST) have shown ambiguous results in minimizing reperfusion injury. Previous findings show beneficial effects of iPOST in patients with STEMI treated without thrombectomy. However, it remains unknown whether the cardioprotective effect of iPOST in these patients persist on long term. In the current study, all patients were identified through the DANAMI-3-iPOST database. Patients were randomized to conventional primary percutaneous coronary intervention (PCI) or iPOST in addition to PCI. Cumulative incidence rates were calculated, and multivariable analyses stratified according to thrombectomy use were performed. The primary end point was a combination of cardiovascular mortality and hospitalization for heart failure. From 2011 to 2014, 1,234 patients with STEMI were included with a median follow-up of 4.8 years. In patients treated without thrombectomy (n = 520), the primary end point occurred in 15% (48/326) in the iPOST group and in 22% (42/194) in the conventional group (unadjusted hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.41 to 0.94, p = 0.023). In adjusted Cox analysis, iPOST remained associated with reduced long-term risk of cardiovascular mortality (HR 0.53, 95% CI 0.29 to 0.97, p = 0.039). In patients treated with thrombectomy (n = 714), there was no significant difference between iPOST (17%, 49/291) and conventional treatment (17%, 72/423) on the primary end point (unadjusted HR 1.01, 95% CI 0.70 to 1.45, p = 0.95). During a follow-up of nearly 5 years, iPOST reduced long-term occurrence of cardiovascular mortality and hospitalization for heart failure in patients with STEMI treated with PCI but without thrombectomy.

Vascular conditioning prevents adverse left ventricular remodelling after acute myocardial infarction: a randomised remote conditioning study.

AIMS: Remote ischemic conditioning (RIC) alleviates ischemia-reperfusion injury via several pathways, including micro-RNAs (miRs) expression and oxidative stress modulation. We investigated the effects of RIC on endothelial glycocalyx, arterial stiffness, LV remodelling, and the underlying mediators within the vasculature as a target for protection. METHODS AND RESULTS: We block-randomised 270 patients within 48 h of STEMI post-PCI to either one or two cycles of bilateral brachial cuff inflation, and a control group without RIC. We measured: (a) the perfusion boundary region (PBR) of the sublingual arterial microvessels to assess glycocalyx integrity; (b) the carotid-femoral pulse wave velocity (PWV); (c) miR-144,-150,-21,-208, nitrate-nitrite (NOx) and malondialdehyde (MDA) plasma levels at baseline (T0) and 40 min after RIC onset (T3); and (d) LV volumes at baseline and after one year. Compared to baseline, there was a greater PBR and PWV decrease, miR-144 and NOx levels increase (p < 0.05) at T3 following single- than double-cycle inflation (PBR:ΔT0-T3 = 0.249 ± 0.033 vs 0.126 ± 0.034 µm, p = 0.03 and PWV:0.4 ± 0.21 vs -1.02 ± 0.24 m/s, p = 0.03). Increased miR-150,-21,-208 (p < 0.05) and reduced MDA was observed after both protocols. Increased miR-144 was related to PWV reduction (r = 0.763, p < 0.001) after the first-cycle inflation in both protocols. After one year, single-cycle RIC was associated with LV end-systolic volume reduction (LVESV) > 15% (odds-ratio of 3.75, p = 0.029). MiR-144 and PWV changes post-RIC were interrelated and associated with LVESV reduction at follow-up (r = 0.40 and 0.37, p < 0.05), in the single-cycle RIC. CONCLUSION: RIC evokes "vascular conditioning" likely by upregulation of cardio-protective microRNAs, NOx production, and oxidative stress reduction, facilitating reverse LV remodelling. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov . Unique identifier: NCT03984123.

Remote Ischemic Post-Conditioning may Improve Post-Stroke Cognitive Impairment: A Pilot Single Center Randomized Controlled Trial.

BACKGROUND AND PURPOSE: We aimed to demonstrate the tolerability and feasibility and the effect of remote ischemic post-conditioning on cognitive functioning in patients with post-stroke cognitive impairment. METHODS: This was a single-center, randomized, outcome-blinded, placebo-controlled trial, randomized 1:1 to receive 4 cycles of remote ischemic post-conditioning or a sham procedure for 7 days. The primary outcome measure was tolerability and feasibility of remote ischemic post-conditioning. Secondary outcomes to measure the neurological function with national institute of health stroke scale and the cognitive impairment with Montreal Cognitive Assessment scale and Alzheimer's disease assessment scale-cognitive (at baseline, 90 days, 180 days). RESULTS: 48 patients (24 RIPC and 24 Control) were recruited. remote ischemic post-conditioning was well tolerated with 90 out of 96 cycles completed in full. 4 patients experienced vascular events in the control group: 3 cerebrovascular and 1 cardiovascular event versus only 2 cerebrovascular events in the RIPC group. We showed the similar result in the neurological function with national institute of health stroke scale score with no statistically significant differences between RIPC and control group at baseline (P = 0.796) and 90 days (P = 0.401) and 180 days (P = 0.695). But compare with baseline, it was significantly difference in the control and RIPC group at 90 days (P < 0.05) and 180 days (P < 0.05). The comparison of Montreal Cognitive Assessment scale between two groups both showed that P > 0.05 at baseline which was no statistical difference, but P < 0.05 at 90 days and 180 days which were significant statistical difference. The comparison of Alzheimer's disease assessment scale-cognitive between two groups showed that P > 0.05 at baseline (P = 0.955) and 90 days (P = 0.138) was no statistical difference, but P = 0.005<0.05 at 180 days was significant statistical difference. CONCLUSIONS: The remote ischemic post-conditioning for post-stroke cognitive impairment was well tolerated, safe and feasible. The remote ischemic post-conditioning may improve neurological and cognitive outcomes in patients with post-stroke cognitive impairment. A larger trial is warranted. (Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: ChiCTR1800015231.).

The Future of Cardioprotection-Pointing Toward Patients at Elevated Risk as the Target Populations.

Translation of the cardioprotective effect by pharmacological and mechanical conditioning therapies into improvement of clinical outcome for the patients has been disappointing. Confounding factors like comorbidity and comedications may explain some of the loss in translation. However, the substantial improvement of outcome in disease states involving ischemia-reperfusion injury, that is, planned cardiac surgery, elective percutaneous coronary intervention, and even primary percutaneous coronary intervention for ST-segment myocardial infarction (STEMI), is the most plausible explanation for the missed demonstration of a clinical benefit. Remote ischemic conditioning has demonstrated consistent cardioprotective effect in experimental and in clinical proof-of-concept studies. As an adjunctive cardioprotective treatment beyond reperfusion, remote ischemic conditioning should address target populations at risk of extensive tissue damage, including patients who experience complications, which may induce profound myocardial ischemia in relation to cardiac surgery or elective percutaneous coronary intervention. Moreover, patients with STEMI and predictable impaired clinical outcome due to delayed hospital admission, high Killip class, cardiogenic shock, and cardiac arrest remain target groups. For high-risk patients, daily remote ischemic conditioning or the corollary of blood flow-restricted exercise may be alternative cardioprotective options during postoperative and post-myocardial infarct rehabilitation.

Remote ischemic conditioning combined with intravenous thrombolysis for acute ischemic stroke.

OBJECTIVE: The objective of this study was to investigate the safety and efficacy of remote ischemic conditioning (RIC) combined with intravenous thrombolysis (IVT) in the treatment of acute ischemic stroke (AIS). METHODS: Patients with AIS who underwent IVT were enrolled and 1:1 randomized to the RIC group and sham-RIC group in this study. RIC (or sham-RIC) was performed twice within 6-24 h of IVT. The subjects in the two groups were followed up for 90 days. The safety outcome included the ratio of hemorrhagic transformation (HT), adverse events during the follow-up, blood pressure within the first 24 h after IVT, and laboratory tests 24 h after IVT. The efficacy outcome included the modified Rankin Scale (mRS) score, National Institute of Health Stroke Scale (NIHSS) score during the follow-up, and level of high-sensitivity C-reactive protein (hs-CRP) tested 24 h after IVT. RESULTS: Forty-nine patients (24 in the RIC group and 25 in the sham-RIC group) were recruited. No significant difference was observed in the ratio of HT, adverse events, blood pressure, coagulation function or liver function between groups. In addition, there was no significant difference in mRS score and NIHSS score during the follow-up between groups. However, patients in the RIC group exhibited a significant lower level of hs-CRP compared with the control group (P = 0.048). INTERPRETATION: RIC combined with IVT is safe in the treatment of AIS. The neuroprotective and anti-inflammatory effects of this therapy warrant further study on a larger scale.

Interaction of ischaemic postconditioning and thrombectomy in patients with ST-elevation myocardial infarction.

OBJECTIVE: The Third Danish Study of Optimal Acute Treatment of Patients with ST-segment Elevation Myocardial Infarction - Ischaemic Postconditioning (DANAMI-3-iPOST) did not show improved clinical outcome in patients with ST-segment elevation myocardial infarction (STEMI) treated with ischaemic postconditioning. However, the use of thrombectomy was frequent and thrombectomy may in itself diminish the effect of ischaemic postconditioning. We evaluated the effect of ischaemic postconditioning in patients included in DANAMI-3-iPOST stratified by the use of thrombectomy. METHODS: Patients with STEMI were randomised to conventional primary percutaneous coronary intervention (PCI) or ischaemic postconditioning plus primary PCI. The primary endpoint was a combination of all-cause mortality and hospitalisation for heart failure. RESULTS: From March 2011 until February 2014, 1234 patients were included with a median follow-up period of 35 (interquartile range 28 to 42) months. There was a significant interaction between ischaemic postconditioning and thrombectomy on the primary endpoint (p=0.004). In patients not treated with thrombectomy (n=520), the primary endpoint occurred in 33 patients (10%) who underwent ischaemic postconditioning (n=326) and in 35 patients (18%) who underwent conventional treatment (n=194) (adjusted hazard ratio (HR) 0.55 (95%confidence interval (CI) 0.34 to 0.89), p=0.016). In patients treated with thrombectomy (n=714), there was no significant difference between patients treated with ischaemic postconditioning (n=291) and conventional PCI (n=423) on the primary endpoint (adjusted HR 1.18 (95% CI 0.62 to 2.28), p=0.62). CONCLUSIONS: In this post-hoc study of DANAMI-3-iPOST, ischaemic postconditioning, in addition to primary PCI, was associated with reduced risk of all-cause mortality and hospitalisation for heart failure in patients with STEMI not treated with thrombectomy. TRIAL REGISTRATION NUMBER: NCT01435408.

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

RATIONALE: Remote ischemic conditioning (RIC) or ischemic postconditioning (PostC) may protect the myocardium from ischemia-reperfusion injury in patients with ST-segment-elevation myocardial infarction. OBJECTIVE: 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. METHODS AND RESULTS: 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). CONCLUSIONS: 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. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov . Unique identifier: NCT02158468.

The effect of repeated remote ischemic postconditioning on infarct size in patients with an ischemic stroke (REPOST): study protocol for a randomized clinical trial.

BACKGROUND: Remote ischemic postconditioning (rIPostC) refers to the observation that repeated, short periods of ischemia protect remote areas against tissue damage during and after prolonged ischemia. Based on previous observations of a potential neuroprotective effect of rIPostC, the aim of this study is to evaluate whether repeated rIPostC after an ischemic stroke can reduce infarct size, which could be translated to an improvement in clinical outcomes. METHODS/DESIGN: We will enroll 200 ischemic stroke patients to daily rIPostC or sham conditioning during hospitalization into a randomized single-blind placebo-controlled trial. The intervention consists of twice daily exposure to four cycles of 5-min cuff inflation around the upper arm to > 20 mmHg above systolic blood pressure (i.e., rIPostC) or 50 mmHg (i.e., control), followed by 5 minutes of deflation. The primary outcome is infarct size, measured using an MRI diffusion-weighted image at the end of hospitalization. Secondary outcomes include the Modified Rankin Scale, National Institutes of Health Stroke Scale, quality of life, and cardiovascular and cerebrovascular morbidity and mortality. To explore possible underlying mechanisms of rIPostC, venous blood will be sampled to assess biomarkers of inflammation and vascular health. DISCUSSION: Previous studies in animals and humans, using a single bout of remote ischemic conditioning, report a potential effect of rIPostC in attenuating neural damage. Although repeated rIPostC has been investigated for cardiovascular disease patients and preclinical stroke models, no previous study has explored the potential physiological and clinical effects of repeatedly applying rIPostC during the hospitalization phase after a stroke. TRIAL REGISTRATION: Netherlands Trial Register, NTR6880 . Registered on 8 December 2017.

NHLBI-Sponsored Randomized Trial of Postconditioning During Primary Percutaneous Coronary Intervention for ST-Elevation Myocardial Infarction.

RATIONALE: Postconditioning at the time of primary percutaneous coronary intervention (PCI) for ST-segment-elevation myocardial infarction may reduce infarct size and improve myocardial salvage. However, clinical trials have shown inconsistent benefit. OBJECTIVE: We performed the first National Heart, Lung, and Blood Institute-sponsored trial of postconditioning in the United States using strict enrollment criteria to optimize the early benefits of postconditioning and assess its long-term effects on left ventricular (LV) function. METHODS AND RESULTS: We randomized 122 ST-segment-elevation myocardial infarction patients to postconditioning (4, 30 seconds PTCA [percutaneous transluminal coronary angioplasty] inflations/deflations)+PCI (n=65) versus routine PCI (n=57). All subjects had an occluded major epicardial artery (thrombolysis in myocardial infarction=0) with ischemic times between 1 and 6 hours with no evidence of preinfarction angina or collateral blood flow. Cardiac magnetic resonance imaging measured at 2 days post-PCI showed no difference between the postconditioning group and control in regards to infarct size (22.5±14.5 versus 24.0±18.5 g), myocardial salvage index (30.3±15.6% versus 31.5±23.6%), or mean LV ejection fraction. Magnetic resonance imaging at 12 months showed a significant recovery of LV ejection fraction in both groups (61.0±11.4% and 61.4±9.1%; P<0.01). Subjects randomized to postconditioning experienced more favorable remodeling over 1 year (LV end-diastolic volume =157±34 to 150±38 mL) compared with the control group (157±40 to 165±45 mL; P<0.03) and reduced microvascular obstruction ( P=0.05) on baseline magnetic resonance imaging and significantly less adverse LV remodeling compared with control subjects with microvascular obstruction ( P<0.05). No significant adverse events were associated with the postconditioning protocol and all patients but one (hemorrhagic stroke) survived through 1 year of follow-up. CONCLUSIONS: We found no early benefit of postconditioning on infarct size, myocardial salvage index, and LV function compared with routine PCI. However, postconditioning was associated with improved LV remodeling at 1 year of follow-up, especially in subjects with microvascular obstruction. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01324453.

Is there an effect of ischemic conditioning on myocardial contractile function following acute myocardial ischemia/reperfusion injury?

Ischemic conditioning induces cardioprotection; the final infarct size following a myocardial ischemic event is reduced. However, whether ischemic conditioning has long-term beneficial effects on myocardial contractile function following such an ischemic event needs further elucidation. To date, ex vivo studies have shown that ischemic conditioning improves the contractile recovery of isolated ventricular papillary muscle or atrial trabeculae following simulated ischemia. However, in vivo animal studies and studies in patients undergoing elective cardiac surgery show conflicting results. At the subcellular level, it is known that ischemic conditioning improved energy metabolism, preserved mitochondrial respiration, ATP production, and Ca2+ homeostasis in isolated mitochondria from the myocardium. Ischemic conditioning also presents with post-translational modifications of proteins in the contractile machinery of the myocardium. The beneficial effects on myocardial contractile function need further elucidation. This article is part of a Special Issue entitled: The power of metabolism: Linking energy supply and demand to contractile function edited by Torsten Doenst, Michael Schwarzer and Christine Des Rosiers.

The clinical impact of sex differences on ischemic postconditioning during primary percutaneous coronary intervention: a POST (the effects of postconditioning on myocardial reperfusion in patients with ST-segment elevation myocardial infarction) substudy.

The POST (the effects of postconditioning on myocardial reperfusion in patients with ST-Segment elevation myocardial infarction) study showed that ischemic postconditioning did not improve myocardial reperfusion in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). However, it has not been determined whether postconditioning is effective in women. This study sought to evaluate the impact of sex differences on ischemic postconditioning during the primary PCI. We analyzed clinical outcomes at 1 year in the 537 men and 163 women with STEMI, who were randomized to the postconditioning or to the conventional PCI group. Women were older, had higher rates of hypertension, were less likely to be current smokers, and had longer symptom-to-reperfusion time. The rate of major adverse cardiac events (MACE: a composite of death, myocardial infarction, severe heart failure, stent thrombosis, or target vessel revascularization) at 1 year was higher in women compared to men (9.8% vs. 5.4%, p = 0.044). MACE was significantly higher in women compared to men in the postconditioning group (12.2% vs. 5.4%, p = 0.042), but not in the conventional PCI group (7.9% vs. 5.4%, p = 0.391). However, women was not an independent predictor after adjusting baseline risk factors, angiographic and procedural parameters (HR 2.67, 95% CI 0.68-10.5, p = 0.158). Despite women having more adverse clinical characteristics, their prognosis was similar to men in the conventional group. Although women showed a higher rate of the MACE compared to men, women were not an independent predictor in the postconditioning group.

Upper Limb Ischemic Postconditioning as Adjunct Therapy in Acute Stroke Patients: A Randomized Pilot.

OBJECTIVE: This study aims to observe the clinical effect of upper limb ischemic postconditioning (LIPostC) as an adjunct to treatment with acute stroke patients, possibly due to increased cerebral perfusion. METHODS: We perform a randomized blinded placebo controlled trial in nonthrombolysis patients with acute ischemic stroke, within 72hours of ictus, divided into the LIPostC group and control group. The LIPostC group is induced by 4 cycles of intermittent repeated limb ischemia: alternating 5 minutes inflation (20mm Hg above systolic blood pressure) and 5 minutes deflation performed manually using a standard upper arm blood pressure cuff in the nonparetic arm. The control group receives a sham procedure (cuff inflation to 30mm Hg). Patients underwent the intervention from the time of enrollment to Day 14. Comparison of National Institutes of Health Stroke Scale (NIHSS) score, cerebral infarction volume, relative Perfusion weighted imaging (PWI) parameters (regional relative cerebral blood flow, regional relative mean transit time; preintervention [day 0], day 14, day 90), modified Rankin Scale (mRS; the preintervention score [day 0], the curative ratio at day 90 [we define 0-1 score as close to recovery or full recovery]). RESULTS: Sixty eligible patients with acute stroke (29 LIPostC and 31 control) are recruited age 65years (SD 12.22), blood pressure 156/74mm Hg (SD 14/10), and NIHSS score 5.98 (SD 3.35), mRS score 2.25 (SD .79). Only 1 in the LIPostC group is intolerant the first cycle to give up. All patients tolerate the sham procedure. Two patients experience recurrent stroke versus none in the LIPostC group. Day 90, compared with the control group, there is a significant decrease the NIHSS score, regional relative mean transit time (P < .05) and increase the curative ratio of mRS, regional relative cerebral blood flow(P < .05) in the LIPostC group, which infarct volume decreased by 31.3% (P < .05). CONCLUSIONS: LIPostC after acute stroke is well tolerated and appears safe and feasible. LIPostC may improve neurological outcome, and protective mechanisms may be increased cerebral blood flow to improve cerebral perfusion. A larger trial is warranted.

Postconditioning effects of argon or xenon on early graft function in a porcine model of kidney autotransplantation.

BACKGROUND: Ischaemia-reperfusion injury is inevitable during renal transplantation and can lead to delayed graft function and primary non-function. Preconditioning, reconditioning and postconditioning with argon and xenon protects against renal ischaemia-reperfusion injury in rodent models. The hypothesis that postconditioning with argon or xenon inhalation would improve graft function in a porcine renal autotransplant model was tested. METHODS: Pigs (n = 6 per group) underwent left nephrectomy after 60 min of warm ischaemia (renal artery and vein clamping). The procured kidney was autotransplanted in a separate procedure after 18 h of cold storage, immediately after a right nephrectomy. Upon reperfusion, pigs were randomized to inhalation of control gas (70 per cent nitrogen and 30 per cent oxygen), argon (70 per cent and 30 per cent oxygen) or xenon (70 per cent and 30 per cent oxygen) for 2 h. The primary outcome parameter was peak plasma creatinine; secondary outcome parameters included further markers of graft function (creatinine course, urine output), graft injury (aspartate aminotransferase, heart-type fatty acid-binding protein, histology), apoptosis and autophagy (western blot, terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) staining), inflammatory mediators and markers of cell survival/growth (mRNA and tissue protein quantification), and animal survival. Results are presented as median (i.q.r.). ANOVA and Kruskal-Wallis tests were used where indicated. RESULTS: Peak plasma creatinine levels were similar between the groups: control 20·8 (16·4-23·1) mg/dl, argon 21·4 (17·1-24·9) mg/dl and xenon 19·4 (17·5-21·0) mg/dl (P = 0·607). Xenon was associated with an increase in autophagy and proapoptotic markers. Creatinine course, urine output, injury markers, histology, survival and inflammatory mediators were not affected by the intervention. CONCLUSION: Postconditioning with argon or xenon did not improve kidney graft function in this experimental model. Surgical relevance Ischaemia-reperfusion injury is inevitable during renal transplantation and can lead to delayed graft function and primary non-function. Based on mainly small animal experiments, noble gases (argon and xenon) have been proposed to minimize this ischaemia-reperfusion injury and improve outcomes after transplantation. The hypothesis that postconditioning with argon or xenon inhalation would improve graft function was tested in a porcine kidney autotransplantation model. The peak plasma creatinine concentration was similar in the control, argon and xenon groups. No other secondary outcome parameters, including animal survival, were affected by the intervention. Xenon was associated with an increase in autophagy and proapoptotic markers. Despite promising results in small animal models, postconditioning with argon or xenon in a translational model of kidney autotransplantation was not beneficial. Clinical trials would require better results.

Ischemic postconditioning during primary percutaneous coronary intervention.

BACKGROUND: Although some studies have shown potential benefit for ischemic postconditioning (IPoC) during primary percutaneous coronary intervention (PCI) in improving surrogate markers of reperfusion and infarction size, the benefit of this approach on clinical outcomes remains unknown. METHODS AND RESULTS: Electronic databases were searched for randomized clinical trials that compared IPoC versus conventional treatment during primary PCI. Random effects DerSimonian-Laird risk ratios (RR) were calculated for different clinical and surrogate outcomes. The main outcome of this analysis was all-cause mortality. A total of 25 trials involving 3,619 patients were included in the analysis. At a mean follow up of 14 months (95% confidence interval (CI) 8.6-19.4 months), the incidence of all-cause mortality was 4.9% [95% CI 3.8-6.0%] in the IPoC group versus 3.8% [95% CI 1.9-5.7%] in the control group (RR 0.92, 95% CI 0.68-1.24, P = 0.74). The risk of reinfarction (2.7% [95% CI 1.1-4.3%] vs. 2.3% [0.6-4.0%]; RR 1.29, 95% CI 0.62-2.68, P = 0.72), heart failure (3.6% [95% CI 2.0-5.1%] vs. 5.7% [95% CI 3.3-8.2%]; RR 0.77, 95% CI 0.58-1.06, P = 0.24), target vessel revascularization (3.2% [95% CI 1.7-4.7%] vs. 2.4% [95% CI 1.4-3.3%]; RR 1.40, 95% CI 0.90-2.20, P = 0.20), and stent thrombosis (2.4% [95% CI 1.1-3.8%] vs. 1.8% [95% CI 0.5-3.2%]); RR 1.50, 95% CI 0.60-3.70, P = 0.40) was similar in both groups. CONCLUSIONS: IPoC does not appear to reduce the risk of clinical adverse events in patients with ST-elevation myocardial infarction undergoing primary PCI. © 2017 Wiley Periodicals, Inc.

Effects of liraglutide and ischemic postconditioning on myocardial salvage after I/R injury in pigs.

OBJECTIVES: Acute STEMI is routinely treated by acute PCI. This treatment may itself damage the tissue (reperfusion injury). Conditioning with GLP-1 analogs has been shown to reduce reperfusion injury. Likewise, ischemic postconditioning provides cardioprotection following STEMI. We tested if combined conditioning with the GLP-1 analog liraglutide and ischemic postconditioning offered additive cardioprotective effect after reperfusion of 45 min coronary occlusion of left anterior descending artery (LAD). DESIGN: Fifty-eight non-diabetic female Danish Landrace pigs (60 ± 10kg) were randomly assigned to four groups. Myocardial infarction (MI) was induced by occluding the LAD for 45 min. Group 1 (n = 14) was treated with i.v. liraglutide after 15 min of ischemia. Group 2 (n = 17) received liraglutide treatment concomitant with ischemic postconditioning, after 45 min of ischemia. Group 3 (n = 15) recieved ischemic postconditioning and group 4 (n = 12) was kept as controls. RESULTS: No intergroup differences in relative infarct size were detected (overall mean 57 ± 3%; p = 0.68). Overall mortality was 34% (CI 25-41%) including 26% post-intervention, with no intergroup differences (p = 0.99). Occurrence of ventricular fibrillation (VF) was 59% (CI 25-80%) including 39% postintervention with no intergroup differences (p = 0.65). CONCLUSIONS: In our closed-chest pig-model, we were unable to detect any cardioprotective effect of liraglutide or ischemic postconditioning either alone or combined.

Understanding pacing postconditioning-mediated cardiac protection: a role of oxidative stress and a synergistic effect of adenosine.

We and others have demonstrated a protective role for pacing postconditioning (PPC) against ischemia/reperfusion (I/R) injury in the heart; however, the underlying mechanisms behind these protective effects are not completely understood. In this study, we wanted to further characterize PPC-mediated cardiac protection, specifically identify optimal pacing sites; examine the role of oxidative stress; and test the existence of a potential synergistic effect between PPC and adenosine. Isolated rat hearts were subjected to coronary occlusion followed by reperfusion. PPC involved three, 30 s, episodes of alternating left ventricular (LV) and right atrial (RA) pacing. Multiple pacing protocols with different pacing electrode locations were used. To test the involvement of oxidative stress, target-specific agonists or antagonists were infused at the beginning of reperfusion. Hemodynamic data were digitally recorded, and cardiac enzymes, oxidant, and antioxidant status were chemically measured. Pacing at the LV or RV but not at the heart apex or base significantly (P < 0.001) protected against ischemia-reperfusion injury. PPC-mediated protection was completely abrogated in the presence of reactive oxygen species (ROS) scavenger, ebselen; peroxynitrite (ONOO-) scavenger, uric acid; and nitric oxide synthase inhibitor, L-NAME. Nitric oxide (NO) donor, snap, however significantly (P < 0.05) protected the heart against I/R injury in the absence of PPC. The protective effects of PPC were significantly improved by adenosine. PPC-stimulated protection can be achieved by alternating LV and RA pacing applied at the beginning of reperfusion. NO, ROS, and the product of their interaction ONOO- play a significant role in PPC-induced cardiac protection. Finally, the protective effects of PPC can be synergized with adenosine.