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Key Points Currently, no treatment has been proven to be effective for preventing 'myocardial reperfusion injury' — the death of cardiomyocytes that paradoxically occurs when reperfusing ischaemic myocardium One or more brief cycles of ischaemia and reperfusion can protect the heart from acute myocardial infarction and myocardial reperfusion injury — a phenomenon termed 'ischaemic conditioning' Ischaemic conditioning can be applied either directly to the heart or from afar; that is, to a remote organ or tissue (such as an arm or a leg) Investigation of signalling pathways underlying ischaemic conditioning has identified molecular targets for pharmacological manipulation — a therapeutic strategy termed 'pharmacological cardioprotection' Proof-of-concept clinical studies have shown mixed results of ischaemic conditioning in cardiac surgery and percutaneous coronary intervention; more consistently positive results have been observed in acute myocardial infarction The results of large, multicentre, randomized, controlled clinical trials of ischaemic conditioning on clinical outcomes after cardiac surgery have highlighted the challenges in translating cardioprotection into clinical practice Ischaemic conditioning is an endogenous cardioprotective strategy that involves the application of brief cycles of ischaemia and reperfusion either directly to the heart, or to a remote organ or tissue, and which has been shown to reduce infarct size. In this Review, Hausenloy and Yellon summarize the various forms of ischaemic conditioning and pharmacological cardioprotection, and highlight the challenges of translating these methods into the clinical setting. The 30-year anniversary of the discovery of 'ischaemic preconditioning' is in 2016. This endogenous phenomenon can paradoxically protect the heart from acute myocardial infarction by subjecting it to one or more brief cycles of ischaemia and reperfusion. Apart from complete reperfusion, this method is the most powerful intervention known for reducing infarct size. The concept of ischaemic preconditioning has evolved into 'ischaemic conditioning', a term that encompasses a number of related endogenous cardioprotective strategies, applied either directly to the heart (ischaemic preconditioning or postconditioning) or from afar, for example a limb (remote ischaemic preconditioning, perconditioning, or postconditioning). Investigations of signalling pathways underlying ischaemic conditioning have identified a number of therapeutic targets for pharmacological manipulation. Over the past 3 decades, a number of ischaemic and pharmacological cardioprotection strategies, discovered in experimental studies, have been examined in the clinical setting of acute myocardial infarction and CABG surgery. The results from many of the studies have been disappointing, and no effective cardioprotective therapy is currently used in clinical practice. Several large, multicentre, randomized, controlled clinical trials on cardioprotection have highlighted the challenges of translating ischaemic conditioning and pharmacological cardioprotection strategies into patient benefit. However, a number of cardioprotective therapies have shown promising results in reducing infarct size and improving clinical outcomes in patients with ischaemic heart disease.

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.

BackgroundThe benefit of ischemic postconditioning (IPostC) might be the throttled inflow following cold ischemia. The current study investigated advantage and mechanisms of IPostC in healthy and fatty rat livers.MethodsMale SD rats received a high-fat diet to induce fatty livers. Isolated liver perfusion was performed after 24 h ischemia at 4 °C as well as in vivo experiments after 90 min warm ischemia. The so-called follow-up perfusions served to investigate the hypothesis that medium from IPostC experiments is less harmful. Lactate dehydrogenase (LDH), transaminases, different cytokines, and gene expressions, respectively, were measured.ResultsFatty livers showed histologically mild inflammation and moderate to severe fat storage. IPostC reduced LDH and TXB2 in healthy and fatty livers and increased bile flow. LDH, TNF-α, and IL-6 levels in serum decreased after warm ischemia + IPostC. The gene expressions of Tnf, IL-6, Ccl2, and Ripk3 were downregulated in vivo after IPostC.ConclusionsIPostC showed protective effects after ischemia in situ and in vivo in healthy and fatty livers. Restricted cyclic inflow was an important mechanism and further suggested involvement of necroptosis. IPostC represents a promising and easy intervention to improve outcomes after transplantation.

Previous studies indicate that remote ischemic conditioning performed before percutaneous coronary intervention (PCI) reduces infarct size in patients with ST-elevation myocardial infarction (STEMI). It remains unclear whether remote conditioning affords protection when performed in adjunct to primary PCI. We aimed to study whether remote ischemic per-postconditioning (RIperpostC) initiated after admission to the catheterization laboratory attenuates myocardial infarct size in patients with anterior STEMI. In this prospective multicenter trial 93 patients with anterior STEMI were randomized to RIperpostC or sham procedure as adjunct to primary PCI. RIperpostC was started on arrival in the catheterization laboratory by 5-minute cycles of inflation and deflation of a blood pressure cuff around the left thigh and continued throughout the PCI procedure. Infarct size and myocardium at risk were determined by cardiac magnetic resonance at day 4 to 7. The primary outcome was myocardial salvage index. There was no significant difference in myocardial salvage index between the RIperpostC and control group (median 48.5% and interquartile range 30.9%-60.8% vs 49.2% [42.1%-58.8%]). Neither did absolute infarct size in relation to left ventricular myocardial volume differ significantly (RIperpostC 20.6% [14.1%-31.7%] vs control 17.9% [13.4%-25.0%]). The RIperpostC group had larger myocardial area at risk than the control group (43.1% (35.4%-49.7%) vs 37.0% (30.8%-44.1%) of the left ventricle, P=.03). Peak value and area under the curve for troponin T did not differ significantly between the study groups. RIperpostC initiated after admission to the catheterization laboratory in patients with anterior STEMI did not confer protection against reperfusion injury. [Display omitted]

Local ischemic postconditioning (IPost) and remote ischemic perconditioning (RIPer) are promising cardioprotective therapies in ST-elevation myocardial infarction (STEMI). We aimed: (1) to investigate whether RIPer initiated at the catheterization laboratory would reduce infarct size, as measured using serum creatine kinase-MB isoenzyme (CK-MB) release as a surrogate marker; (2) to assess if the combination of RIPer and IPost would provide an additional reduction. Patients (n = 151) were randomly allocated to one of the following groups: (1) control group, percutaneous transluminal coronary angioplasty (PTCA) alone; (2) RIPer group, PTCA combined with RIPer, consisting of three cycles of 5-min inflation and 5-min deflation of an upper-arm blood-pressure cuff initiated before reperfusion; (3) RIPer+IPost group, PTCA combined with RIPer and IPost, consisting of four cycles of 1-min inflation and 1-min deflation of the angioplasty balloon. The CK-MB area under the curve (AUC) over 72 h was reduced in RIPer, and RIPer+IPost groups, by 31 and 29 %, respectively, compared to the Control group; however, CK-MB AUC differences between the three groups were not statistically significant (p = 0.06). Peak CK-MB, CK-MB AUC to area at risk (AAR) ratio, and peak CK-MB level to AAR ratio were all significantly reduced in the RIPer and RIPer+IPost groups, compared to the Control group. On the contrary, none of these parameters was significantly different between RIPer+IPost and RIPer groups. To conclude, starting RIPer therapy immediately prior to revascularization was shown to reduce infarct size in STEMI patients, yet combining this therapy with an IPost strategy did not lead to further decrease in infarct size.

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.

Background Acute ST-elevation myocardial infarction (STEMI) is associated with a high incidence of complications as well as a considerable hospitalization rate and economic burden. Preliminary evidence suggests that remote ischemic conditioning (RIC) is a promising non-invasive intervention that may effectively and safely reduce myocardial infarct size, subsequent cardiac events and complications, and mortality. However, RIC’s cardio-protective effect remains under debate, especially for single timepoint RIC programs. Adequately powered large-scale randomized controlled trials investigating clinical outcomes are thus needed to clarify the role of full disease cycle RIC programs. Methods The intelligent “Internet Plus”-based full disease cycle remote ischemic conditioning (i-RIC) trial is a pragmatic, multicenter, randomized controlled, parallel group, clinical trial. The term, intelligent “Internet Plus”-based full disease cycle, refers to smart devices aided automatic and real-time monitoring of remote ischemic pre-, per- or post-conditioning intervention for patients with STEMI undergoing percutaneous coronary intervention (PCI). Based on this perspective, 4700 STEMI patients from five hospitals in China will be randomized to a control and an intervention group. The control group will receive PCI and usual care, including pharmacotherapy, before and after PCI. The intervention group will receive pre-, per-, and post-operative RIC combined with long-term i-RIC over a one-month period in addition. A smartphone application, an automated cuff inflation/deflation device and “Internet Plus”-based administration will be used in the long-term phase. The primary outcome is the combined cardiac death or hospitalization for heart failure rate. Secondary outcomes include clinical and functional outcomes: major adverse cardiac and cerebrovascular events rate, all-cause mortality, myocardial reinfarction rate, readmission rate for heart failure and ischemic stroke rate, unplanned revascularization rate, plasma concentration of myocardial infarction-related key biomarkers, infarct size, cardiac function, cardiopulmonary endurance, health-related quality of life, total hospital length of stay, total medical cost, and compliance with treatment regime. Discussion The i-RIC trial is designed to test the hypothesis that clinical and functional outcomes can be improved with the i-RIC program in STEMI patients undergoing PCI. The concept of RIC is expected to be enhanced with this intelligent “Internet Plus”-based program focusing on the full disease cycle. If the i-RIC program results in superior improvement in primary and secondary outcomes, it will offer an innovative treatment option for STEMI patients and form the basis of future recommendations. Clinical Trial Registration Chinese Clinical Trial Registry ( http://www.chictr.org.cn ): ChiCTR2000031550, 04 April 2020.

After acute myocardial infarction, the presence of no-reflow (or microvascular obstruction: MVO) has been associated with adverse left ventricular (LV) remodeling and worse clinical outcome. This study examined the effects of mechanical ischemic postconditioning on early and late MVO size in acute ST-elevation myocardial infarction (STEMI) patients. Fifty patients undergoing primary coronary angioplasty for a first STEMI with TIMI grade flow 0–1 and no collaterals were randomized to ischemic postconditioning (PC) ( n  = 25) or control ( n  = 25) groups. Ischemic PC consisted in the application of four consecutive cycles of a 1-min balloon occlusion, each followed by a 1-min deflation at the onset of reperfusion. Early (3 min post-contrast) and late (10 min post-contrast) MVO size were assessed by contrast-enhanced cardiac-MRI within 96 h after reperfusion. PC was associated with smaller early and late MVO size (3.9 ± 4.8 in PC versus 7.8 ± 6.6 % of LV in controls for early MVO, P  = 0.02; and 1.8 ± 3.1 in PC versus 4.1 ± 3.9 % of LV in controls for late MVO; P  = 0.01). This significant reduction was persistent after adjustment for thrombus aspiration, which neither had any significant effect on infarct size, nor on early or late MVO ( P  = NS for all). Attenuation of MVO was associated to infarct size reduction. Mechanical postconditioning significantly reduces MVO in patients with acute STEMI treated with primary angioplasty.

Objective Determine whether remote ischaemic postconditioning (RIP) protects against percutaneous coronary intervention-related myocardial infarction (PCI-MI). Design Single-centre, randomised, blinded to the researchers, clinical trial. ClinicalTrials.gov (NCT 01113008). Setting Tertiary hospital centre. Patients 232 patients underwent elective PCI for stable or unstable angina. Interventions Patients were randomised to RIP (induction of three 5-min cycles of ischaemia in the arm after the PCI) versus placebo. Main outcome measures The primary outcome measure was the peak 24-h troponin I level. PCI-MI was defined by an elevation of troponin values >3 or >5 of the 99th percentile according to the classical or the new definition. The secondary outcome measure was hospital admission, PCI for stable angina or acute coronary syndrome and mortality after 1 year of follow-up. The use of RIP in diabetic patients was specifically studied. Results The mean age was 64.6 years, and 42% were diabetic. The peak troponin in the RIP patients was 0.476 vs 0.478 ng/mL (p=0.99). PCI-MI occurred in 36% of the RIP patients versus 30.8% in the placebo group (p=0.378). Diabetic RIP patients had more PCI-MI (new definition): OR 2.7; 95% CI 1.10 to 6.92; p=0.027. The secondary outcome measure was seen in 11.7% of the RIP patients versus 10.8% in the placebo group (p=0.907). Conclusions RIP did not reduce the damage associated with elective PCI or cardiovascular events during the follow-up. The diabetic population who underwent RIP had more PCI-MI.

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.