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Remote ischaemic preconditioning has been associated with reduced risk of myocardial injury after coronary artery bypass graft (CABG) surgery. We investigated the safety and efficacy of this procedure. Eligible patients were those scheduled to undergo elective isolated first-time CABG surgery under cold crystalloid cardioplegia and cardiopulmonary bypass at the West-German Heart Centre, Essen, Germany, between April, 2008, and October, 2012. Patients were prospectively randomised to receive remote ischaemic preconditioning (three cycles of 5 min ischaemia and 5 min reperfusion in the left upper arm after induction of anaesthesia) or no ischaemic preconditioning (control). The primary endpoint was myocardial injury, as reflected by the geometric mean area under the curve (AUC) for perioperative concentrations of cardiac troponin I (cTnI) in serum in the first 72 h after CABG. Mortality was the main safety endpoint. Analysis was done in intention-to-treat and per-protocol populations. This trial is registered with ClinicalTrials.gov, number NCT01406678. 329 patients were enrolled. Baseline characteristics and perioperative data did not differ between groups. cTnI AUC was 266 ng/mL over 72 h (95% CI 237–298) in the remote ischaemic preconditioning group and 321 ng/mL (287–360) in the control group. In the intention-to-treat population, the ratio of remote ischaemic preconditioning to control for cTnI AUC was 0·83 (95% CI 0·70–0·97, p=0·022). cTnI release remained lower in the per-protocol analysis (0·79, 0·66–0·94, p=0·001). All-cause mortality was assessed over 1·54 (SD 1·22) years and was lower with remote ischaemic preconditioning than without (ratio 0·27, 95% CI 0·08–0·98, p=0·046). Remote ischaemic preconditioning provided perioperative myocardial protection and improved the prognosis of patients undergoing elective CABG surgery. German Research Foundation.

In this multicenter trial, higher-risk adults undergoing on-pump CABG (with or without valve surgery) were randomly assigned to preconditioning with transient arm ischemia and reperfusion or sham conditioning. Remote ischemic preconditioning did not improve clinical outcomes. Coronary heart disease is the leading cause of death and disability worldwide. For patients with multivessel coronary artery disease, the treatment of choice for many is revascularization by means of coronary-artery bypass grafting (CABG) surgery. As a result of the aging of the population, an increased prevalence of coexisting conditions (e.g., diabetes, obesity, and hypertension), and a growing need for concomitant valve surgery, higher-risk patients are undergoing CABG surgery (with or without valve surgery); the clinical outcomes in such patients have been worse than the outcomes in patients without so many problems. 1 , 2 Thus, novel cardioprotective interventions are indicated to . . .

IntroductionMyocardial injury after non-cardiac surgery (MINS) caused by an ischaemic mechanism is common and is associated with adverse short-term and long-term prognoses. However, MINS is a recent concept, and few studies have prospectively used it as a primary outcome. Remote ischaemic preconditioning (RIPC) is a non-invasive procedure that induces innate cardioprotection and may reduce MINS.Methods and analysisThis is a multicentre, randomised, sham-controlled, observer-blinded trial. Patients with a high clinical risk of cardiovascular events who are scheduled to undergo major abdominal surgery will be enrolled. A total of 766 participants will be randomised (1:1 ratio) to receive RIPC or control treatment before anaesthesia. RIPC will comprise four cycles of cuff inflation for 5 min to 200 mm Hg and deflation for 5 min. In the controls, an identical-looking cuff will be placed around the arm but will not be actually inflated. The primary outcome will be MINS, defined as at least one postoperative cardiac troponin (cTn) concentration above the 99th percentile upper reference limit of the cTn assay as a result of a presumed ischaemic mechanism. This trial will test the concentration of high-sensitivity cardiac troponin T (hs-cTnT). The secondary outcomes will be hs-cTnT levels reaching/above the prognostically important thresholds, peak hs-cTnT and total hs-cTnT release during the initial 3 days after surgery, length of hospital stay after surgery, length of stay in the intensive care unit, myocardial infarction, major adverse cardiovascular events, cardiac-related death, all-cause death within 30 days, 6 months, 1 year and 2 years after surgery, and postoperative complications and adverse events within 30 days after surgery.Ethics and disseminationThis study protocol (version 5.0 on 7 April 2023) was approved by the Ethics Committee of Sixth Affiliated Hospital of Sun Yat-sen University. The findings will be published in peer-reviewed journals.Trial registration number NCT05733208.

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.

Symptomatic intracranial arterial stenosis (SIAS) is very common in octo- and nonagenarians, especially in the Chinese population, and is likely the most common cause of stroke recurrence worldwide. Clinical trials demonstrate that endovascular treatment, such as stenting, may not be suitable for octogenarians with systemic diseases. Hence, less invasive methods for the octogenarian patients are urgently needed. Our previous study (unique identifier: NCT01321749) showed that repetitive bilateral arm ischemic preconditioning (BAIPC) reduced the incidence of stroke recurrence by improving cerebral perfusion (confirmed by single photon emission computed tomography and transcranial Doppler sonography) in patients younger than 80 years of age; however, the safety and effectiveness of BAIPC on stroke prevention in octo- and nonagenarians with SIAS are still unclear. The objective of this study was to evaluate the safety and effectiveness of BAIPC in reducing stroke recurrence in octo- and nonagenarian patients with SIAS. Fifty-eight patients with SIAS were enrolled in this randomized controlled prospective study for 180 consecutive days. All patients enrolled in the study received standard medical management. Patients in the BAIPC group (n = 30) underwent 5 cycles consisting of bilateral arm ischemia followed by reperfusion for 5 min each twice daily. Those in the control group (n = 28) underwent sham-BAIPC twice daily. Blood pressure, heart rate, local skin status, plasma myoglobin, and plasma levels of thrombotic and inflammatory markers were documented in both groups before beginning the study and for the first 30 days. Finally, the incidences of stroke recurrence and magnetic resonance imaging during the 180 days of treatment were compared. Compared with the control, BAIPC had no adverse effects on blood pressure, heart rate, local skin integrity, or plasma myoglobin, and did not induce cerebral hemorrhage in the studied cohort. BAIPC reduced plasma high sensitive C-reactive protein, interleukin-6, plasminogen activator inhibitor-1, leukocyte count, and platelet aggregation rate and elevated plasma tissue plasminogen activator (all p < 0.01). In 180 days, 2 infarctions and 7 transient ischemic attacks were observed in the BAIPC group compared with 8 infarctions and 11 transient ischemic attacks in the sham BAIPC group (p < 0.05). BAIPC may safely inhibit stroke recurrence, protect against brain ischemia, and ameliorate plasma biomarkers of inflammation and coagulation in octo- and nonagenarians with SIAS. A multicenter trial is ongoing. Clinical Trial Registration: www.clinicaltrials.gov, unique identifier: NCT01570231.

Remote ischemic preconditioning (RIPC) reduces ischemia-reperfusion injury in aortocoronary bypass surgery, potentially via extracellular vesicles (EVs) and their micro-RNA content. Clinical data implicate that propofol might inhibit the cardioprotective RIPC effect. This prospective, randomized study investigated the influence of different anesthetic regimes on RIPC efficacy and EV micro-RNA signatures. We also assessed the impact of propofol on cell protection after hypoxic conditioning and EV-mediated RIPC in vitro. H9c2 rat cardiomyoblasts were subjected to hypoxia, with or without propofol, and subsequent simulated ischemia-reperfusion injury. Apoptosis was measured by flow cytometry. Blood samples of 64 patients receiving anesthetic maintenance with propofol or isoflurane, along with RIPC or sham procedures, were analyzed, and EVs were enriched using a polymer-based method. Propofol administration corresponded with increased Troponin T levels (4669 ± 435.6 pg/mL), suggesting an inhibition of the cardioprotective RIPC effect. RIPC leads to a notable rise in miR-21 concentrations in the group receiving propofol anesthesia (fold change 7.22 ± 6.6). In vitro experiments showed that apoptosis reduction was compromised with propofol and only occurred in an EV-enriched preconditioning medium, not in an EV-depleted medium. Our study could clinically and experimentally confirm propofol inhibition of RIPC protection. Increased miR-21 expression could provide evidence for a possible inhibitory mechanism.

To test whether remote ischaemic conditioning (RIC) as adjuvant to standard of care (SOC) would prevent progression towards heart failure (HF) after ST-elevation myocardial infarction (STEMI). Single-centre parallel 1:1 randomized trial (computerized block-randomization, concealed allocation) to assess superiority of RIC (3 cycles of intermittent 5 min lower limb ischaemia) over SOC in consecutive STEMI patients (NCT02313961, clinical trials.gov). From 258 patients randomized to RIC or SOC, 9 and 4% were excluded because of unconfirmed diagnosis and previously unrecognized exclusion criteria, respectively. Combined primary outcome of cardiac mortality and hospitalization for HF was reduced in RIC compared with SOC (n = 231 and 217, respectively; HR = 0.35, 95% CI 0.15–0.78) as well as each outcome in isolation. No difference was found in serum troponin I levels between groups. Median and maximum follow-up time were 2.1 and 3.7 years, respectively. In-hospital HF (RR = 0.68, 95% CI 0.47–0.98), need for diuretics (RR = 0.68, 95% CI 0.48–0.97) and inotropes and/or intra-aortic balloon pump (RR = 0.17, 95% CI 0.04–0.76) were decreased in RIC. On planned 12 months follow-up echocardiography (n = 193 and 173 in RIC and SOC, respectively) ejection fraction (EF) recovery was enhanced in patients presenting with impaired left ventricular (LV) function (10% absolute difference in median EF compared with SOC; P < 0.001). In addition to previously reported improved myocardial salvage index and reduced infarct size RIC was shown beneficial in a combined hard clinical endpoint of cardiac mortality and hospitalization for HF. Improved EF recovery was also documented in patients with impaired LV function.

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

This multicenter, randomized, controlled trial involving adults undergoing elective cardiac surgery with cardiopulmonary bypass while under propofol anesthesia compared upper-limb remote ischemic preconditioning with a sham intervention. No relevant benefit was observed. Cardiac surgery is associated with a predictable risk of end-organ ischemic and reperfusion injury. Transient ischemia of nonvital tissue, known as remote ischemic preconditioning (RIPC), is reported to help remote vital organs withstand a subsequent prolonged ischemic event. 1 Although proof-of-concept trials suggested that RIPC provides protection against myocardial and kidney injury, as determined by serum cardiac and renal biomarkers, in patients undergoing cardiovascular surgery, 2 – 4 more recent studies failed to show significant differences between the RIPC and control groups with respect to troponin release, inotropic or vasoconstrictor support, renal dysfunction, and lung injury. 5 – 10 Only a few studies have included . . .

AimBlood flow restriction (BFR) exercise is a common alternative to traditional high-load resistance exercise used to increase muscle size and strength. Some populations utilizing BFR at a low load may wish to limit their cardiovascular response to exercise. Different contraction patterns may attenuate the cardiovascular response, but this has not been compared using BFR.PurposeTo compare the cardiovascular response to unilateral (UNI), bilateral (BIL), and alternating (ALT) BFR exercise contraction patterns.MethodsTwenty healthy participants performed four sets (30 s rest) of knee extensions to failure, using 30% one-repetition maximum, 40% arterial occlusion pressure, and each of the three contraction patterns (on different days, at the same time of day, separated by 2–10 days, randomized). Cardiovascular responses, presented as pre- to post-exercise mean changes (SD), were measured using pulse wave analysis and analyzed with Bayesian RMANOVA.ResultsALT caused greater changes in: aortic systolic [ΔmmHg: ALT = 21(8); UNI = 13(11); BIL = 15(8); BF10 = 29.599], diastolic [ΔmmHg: ALT = 13(8); UNI = 7(11); BIL = 8(8); BF10 = 5.175], and mean arterial [ΔmmHg: ALT = 19(8); UNI = 11(11); BIL = 13(7); BF10 = 48.637] blood pressures. Aortic [ΔmmHg bpm: ALT = 4945(2340); UNI = 3294(1408); BIL = 3428 (1461); BF10 = 113.659] and brachial [ΔmmHg bpm: ALT = 6134(2761); UNI = 4300(1709); BIL = 4487(1701); BF10 = 31.845] rate pressure products, as well as heart rate [Δbpm: ALT = 26(14); UNI = 19(8); BIL = 19(11); BF10 = 5.829] were greatest with ALT. Augmentation index [Δ%: UNI = -6(13); BIL = − 7(11); ALT = − 5(16); BF10 = 0.155] and wave reflection magnitude [Δ%: UNI = − 5(9); BIL = − 4(7); ALT = − 4(7); BF10 = 0.150] were not different.ConclusionThose at risk of a cardiovascular event may choose unilateral or bilateral BFR exercise over alternating until further work determines the degree to which it can be tolerated.