Remote Ischemic Conditioning: From Bench to Bedside

Remote ischemic conditioning (RIC) is a therapeutic strategy for protecting organs or tissue against the detrimental effects of acute ischemia-reperfusion injury (IRI). It describes an endogenous phenomenon in which the application of one or more brief cycles of non-lethal ischemia and reperfusion to an organ or tissue protects a remote organ or tissue from a sustained episode of lethal IRI. Although RIC protection was first demonstrated to protect the heart against acute myocardial infarction, its beneficial effects are also seen in other organs (lung, liver, kidney, intestine, brain) and tissues (skeletal muscle) subjected to acute IRI. The recent discovery that RIC can be induced non-invasively by simply inflating and deflating a standard blood pressure cuff placed on the upper arm or leg, has facilitated its translation into the clinical setting, where it has been reported to be beneficial in a variety of cardiac scenarios. In this review article we provide an overview of RIC, the potential underlying mechanisms, and its potential as a novel therapeutic strategy for protecting the heart and other organs from acute IRI

Neutrophil gelatinase-associated lipocalin prior to cardiac surgery predicts acute kidney injury and mortality.

OBJECTIVE: We aimed to investigate whether preoperative serum neutrophil gelatinase-associated lipocalin (sNGALpre-op) predicted postoperative acute kidney injury (AKI) during hospitalisation and 1-year cardiovascular and all-cause mortality following adult cardiac surgery. METHODS: This study was a post hoc analysis of the Effect of Remote Ischemic Preconditioning on Clinical Outcomes in Patient Undergoing Coronary Artery Bypass Graft Surgery trial involving adult patients undergoing coronary artery bypass graft. Postoperative AKI within 72 hours was defined using the International Kidney Disease: Improving Global Outcomes classification. RESULTS: 1371 out of 1612 patients had data on sNGALpre-op. The overall 1-year cardiovascular and all-cause mortality was 5.2% (71/1371) and 7.7% (105/1371), respectively. There was an observed increase in the incidence of AKI from the first to the third tertile of sNGALpre-op (30.5%, 41.5% and 45.9%, respectively, p220 ng/L) had an estimated twofold increase risk of cardiovascular and all-cause mortality at 1 year. CLINICAL TRIAL REGISTRATION: NCT101247545; Post-results

Effect of Remote Ischaemic preconditioning on Clinical outcomes in patients undergoing Coronary Artery bypass graft surgery (ERICCA study): a multicentre double-blind randomised controlled clinical trial

BackgroundNovel cardioprotective strategies are required to improve clinical outcomes in higher-risk patients undergoing coronary artery bypass graft (CABG) with or without valve surgery. Remote ischaemic preconditioning (RIPC) in which brief episodes of non-lethal ischaemia and reperfusion are applied to the arm or leg has been demonstrated to reduce perioperative myocardial injury (PMI) following CABG with or without valve surgery.ObjectiveTo investigate whether or not RIPC can improve clinical outcomes in this setting in the Effect of Remote Ischaemic preconditioning on Clinical outcomes in patients undergoing Coronary Artery bypass graft surgery (ERICCA) study in patients undergoing CABG surgery.DesignMulticentre, double-blind, randomised sham controlled trial.SettingThe study was conducted across 30 cardiothoracic centres in the UK between March 2010 and March 2015.ParticipantsEligible patients were higher-risk adult patients (aged &gt; 18 years of age; additive European System for Cardiac Operative Risk of ≥ 5) undergoing on-pump CABG with or without valve surgery with blood cardioplegia.InterventionsPatients were randomised to receive either RIPC (four 5-minute inflations/deflations of a standard blood pressure cuff placed on the upper arm) or the sham control procedure (simulated RIPC protocol) following anaesthetic induction and prior to surgical incision. Anaesthetic management and perioperative care were not standardised.Main outcome measuresThe combined primary end point was the rate of major adverse cardiac and cerebral events comprising cardiovascular death, myocardial infarction, coronary revascularisation and stroke within 12 months of randomisation. Secondary end points included perioperative myocardial and acute kidney injury (AKI), intensive care unit and hospital stay, inotrope score, left ventricular ejection fraction, changes in quality of life and exercise tolerance.ResultsIn total, 1612 patients (sham control group,n = 811; RIPC group,n = 801) were randomised in 30 cardiac surgery centres in the UK. There was no difference in the primary end point at 12 months between the RIPC group and the sham control group (26.5% vs. 27.7%; hazard ratio 0.95, 95% confidence interval 0.79 to 1.15;p = 0.58). Furthermore, there was no evidence for any differences in either adverse events or the secondary end points of PMI (72-hour area under the curve for serum high-sensitivity troponin T), inotrope score, AKI, intensive therapy unit and hospital stay, 6-minute walk test and quality of life.ConclusionsIn patients undergoing elective on-pump CABG with or without valve surgery, without standardisation of the anaesthetic regimen, RIPC using transient arm ischaemia–reperfusion did not improve clinical outcomes. It is important that studies continue to investigate the potential mechanisms underlying RIPC, as this may facilitate the translation of this simple, non-invasive, low-cost intervention into patient benefit. The limitations of the study include the lack of standardised pre-/perioperative anaesthesia and medication, the level of missing and incomplete data for some of the secondary end points and the incompleteness of the data for the echocardiography substudy.Trial registrationClinicalTrials.gov NCT01247545.FundingThis project was funded by the Efficacy and Mechanism Evaluation programme, a MRC and NIHR partnership, and the British Heart Foundation.</jats:sec

Remote Ischemic Preconditioning and Outcomes of Cardiac Surgery.

BACKGROUND: Whether remote ischemic preconditioning (transient ischemia and reperfusion of the arm) can improve clinical outcomes in patients undergoing coronary-artery bypass graft (CABG) surgery is not known. We investigated this question in a randomized trial. METHODS: We conducted a multicenter, sham-controlled trial involving adults at increased surgical risk who were undergoing on-pump CABG (with or without valve surgery) with blood cardioplegia. After anesthesia induction and before surgical incision, patients were randomly assigned to remote ischemic preconditioning (four 5-minute inflations and deflations of a standard blood-pressure cuff on the upper arm) or sham conditioning (control group). Anesthetic management and perioperative care were not standardized. The combined primary end point was death from cardiovascular causes, nonfatal myocardial infarction, coronary revascularization, or stroke, assessed 12 months after randomization. RESULTS: We enrolled a total of 1612 patients (811 in the control group and 801 in the ischemic-preconditioning group) at 30 cardiac surgery centers in the United Kingdom. There was no significant difference in the cumulative incidence of the primary end point at 12 months between the patients in the remote ischemic preconditioning group and those in the control group (212 patients [26.5%] and 225 patients [27.7%], respectively; hazard ratio with ischemic preconditioning, 0.95; 95% confidence interval, 0.79 to 1.15; P=0.58). Furthermore, there were no significant between-group differences in either adverse events or the secondary end points of perioperative myocardial injury (assessed on the basis of the area under the curve for the high-sensitivity assay of serum troponin T at 72 hours), inotrope score (calculated from the maximum dose of the individual inotropic agents administered in the first 3 days after surgery), acute kidney injury, duration of stay in the intensive care unit and hospital, distance on the 6-minute walk test, and quality of life. CONCLUSIONS: Remote ischemic preconditioning did not improve clinical outcomes in patients undergoing elective on-pump CABG with or without valve surgery. (Funded by the Efficacy and Mechanism Evaluation Program [a Medical Research Council and National Institute of Health Research partnership] and the British Heart Foundation; ERICCA ClinicalTrials.gov number, NCT01247545.)

Multi-Modality Imaging of Atheromatous Plaques in Peripheral Arterial Disease: Integrating Molecular and Imaging Markers

Peripheral artery disease (PAD) is a common and debilitating condition characterized by the narrowing of the limb arteries, primarily due to atherosclerosis. Non-invasive multi-modality imaging approaches using computed tomography (CT), magnetic resonance imaging (MRI), and nuclear imaging have emerged as valuable tools for assessing PAD atheromatous plaques and vessel walls. This review provides an overview of these different imaging techniques, their advantages, limitations, and recent advancements. In addition, this review highlights the importance of molecular markers, including those related to inflammation, endothelial dysfunction, and oxidative stress, in PAD pathophysiology. The potential of integrating molecular and imaging markers for an improved understanding of PAD is also discussed. Despite the promise of this integrative approach, there remain several challenges, including technical limitations in imaging modalities and the need for novel molecular marker discovery and validation. Addressing these challenges and embracing future directions in the field will be essential for maximizing the potential of molecular and imaging markers for improving PAD patient outcomes

Clinical practice guidelines of remote ischemic conditioning for the management of cerebrovascular diseases

Remote ischemic conditioning (RIC) using transient limb ischemia and reperfusion has been shown in small clinical studies to reduce myocardial injury and infarction in cardiac patients, although larger clinical outcome studies have been neutral. Experimental and emerging clinical studies have also reported beneficial effects of limb RIC in a number of different settings of cerebrovascular disease including stroke (ischemic and hemorrhagic), carotid artery stenosis, intracranial artery stenosis, aneurysms, small vessel disease, and vascular cognitive impairment. Although limb RIC has many advantages, in that it is non-invasive, easy to administer, relatively innocuous, cost-effective, has few or no contraindications, and may be deployed under various circumstances (e.g., home, ambulance, and hospital), several questions remain regarding its clinical application for cerebrovascular disease. Therefore, in this document, we aim to provide practicing clinicians with a coherent synthesis of the latest scientific evidence, and we propose several recommendations to help facilitate the clinical application of limb RIC for the management of cerebrovascular disease

A Systematic Quality Scoring Analysis to Assess Automated Cardiovascular Magnetic Resonance Segmentation Algorithms

BACKGROUND: The quantitative measures used to assess the performance of automated methods often do not reflect the clinical acceptability of contouring. A quality-based assessment of automated cardiac magnetic resonance (CMR) segmentation more relevant to clinical practice is therefore needed. OBJECTIVE: We propose a new method for assessing the quality of machine learning (ML) outputs. We evaluate the clinical utility of the proposed method as it is employed to systematically analyse the quality of an automated contouring algorithm. METHODS: A dataset of short-axis (SAX) cine CMR images from a clinically heterogeneous population (n = 217) were manually contoured by a team of experienced investigators. On the same images we derived automated contours using a ML algorithm. A contour quality scoring application randomly presented manual and automated contours to four blinded clinicians, who were asked to assign a quality score from a predefined rubric. Firstly, we analyzed the distribution of quality scores between the two contouring methods across all clinicians. Secondly, we analyzed the interobserver reliability between the raters. Finally, we examined whether there was a variation in scores based on the type of contour, SAX slice level, and underlying disease. RESULTS: The overall distribution of scores between the two methods was significantly different, with automated contours scoring better than the manual (OR (95% CI) = 1.17 (1.07–1.28), p = 0.001; n = 9401). There was substantial scoring agreement between raters for each contouring method independently, albeit it was significantly better for automated segmentation (automated: AC2 = 0.940, 95% CI, 0.937–0.943 vs manual: AC2 = 0.934, 95% CI, 0.931–0.937; p = 0.006). Next, the analysis of quality scores based on different factors was performed. Our approach helped identify trends patterns of lower segmentation quality as observed for left ventricle epicardial and basal contours with both methods. Similarly, significant differences in quality between the two methods were also found in dilated cardiomyopathy and hypertension. CONCLUSIONS: Our results confirm the ability of our systematic scoring analysis to determine the clinical acceptability of automated contours. This approach focused on the contours' clinical utility could ultimately improve clinicians' confidence in artificial intelligence and its acceptability in the clinical workflo

The 10th Biennial Hatter Cardiovascular Institute workshop: cellular protection—evaluating new directions in the setting of myocardial infarction, ischaemic stroke, and cardio-oncology

Due to its poor capacity for regeneration, the heart is particularly sensitive to the loss of contractile cardiomyocytes. The onslaught of damage caused by ischaemia and reperfusion, occurring during an acute myocardial infarction and the subsequent reperfusion therapy, can wipe out upwards of a billion cardiomyocytes. A similar program of cell death can cause the irreversible loss of neurons in ischaemic stroke. Similar pathways of lethal cell injury can contribute to other pathologies such as left ventricular dysfunction and heart failure caused by cancer therapy. Consequently, strategies designed to protect the heart from lethal cell injury have the potential to be applicable across all three pathologies. The investigators meeting at the 10th Hatter Cardiovascular Institute workshop examined the parallels between ST-segment elevation myocardial infarction (STEMI), ischaemic stroke, and other pathologies that cause the loss of cardiomyocytes including cancer therapeutic cardiotoxicity. They examined the prospects for protection by remote ischaemic conditioning (RIC) in each scenario, and evaluated impasses and novel opportunities for cellular protection, with the future landscape for RIC in the clinical setting to be determined by the outcome of the large ERIC-PPCI/CONDI2 study. It was agreed that the way forward must include measures to improve experimental methodologies, such that they better reflect the clinical scenario and to judiciously select combinations of therapies targeting specific pathways of cellular death and injury

Effect of remote ischaemic conditioning on infarct size and remodelling in ST-segment elevation myocardial infarction patients: the CONDI-2/ERIC-PPCI CMR substudy.

The effect of limb remote ischaemic conditioning (RIC) on myocardial infarct (MI) size and left ventricular ejection fraction (LVEF) was investigated in a pre-planned cardiovascular magnetic resonance (CMR) substudy of the CONDI-2/ERIC-PPCI trial. This single-blind multi-centre trial (7 sites in UK and Denmark) included 169 ST-segment elevation myocardial infarction (STEMI) patients who were already randomised to either control (n = 89) or limb RIC (n = 80) (4 × 5 min cycles of arm cuff inflations/deflations) prior to primary percutaneous coronary intervention. CMR was performed acutely and at 6 months. The primary endpoint was MI size on the 6 month CMR scan, expressed as median and interquartile range. In 110 patients with 6-month CMR data, limb RIC did not reduce MI size [RIC: 13.0 (5.1-17.1)% of LV mass; control: 11.1 (7.0-17.8)% of LV mass, P = 0.39], or LVEF, when compared to control. In 162 patients with acute CMR data, limb RIC had no effect on acute MI size, microvascular obstruction and LVEF when compared to control. In a subgroup of anterior STEMI patients, RIC was associated with lower incidence of microvascular obstruction and higher LVEF on the acute scan when compared with control, but this was not associated with an improvement in LVEF at 6 months. In summary, in this pre-planned CMR substudy of the CONDI-2/ERIC-PPCI trial, there was no evidence that limb RIC reduced MI size or improved LVEF at 6 months by CMR, findings which are consistent with the neutral effects of limb RIC on clinical outcomes reported in the main CONDI-2/ERIC-PPCI trial