Effects of remote ischaemic preconditioning on peri-operative myocardial injury and clinical outcomes in patients undergoing elective cardiac bypass surgery

Ischaemic heart disease (IHD) is a major cause of morbidity and mortality in the world. Coronary artery bypass graft (CABG) surgery is the revascularisation strategy of choice in a significant number of patients, particularly those with diabetes mellitus and complex coronary disease. During cardiac surgery, the myocardium is subjected to peri-operative myocardial injury (PMI), which has been associated with worse short and long-term clinical outcomes. Higher-risks patients are currently being operated on with subsequent higher risk of PMI and worse prognosis: therefore new strategies are required to potentiate the innate mechanisms of cardioprotection. In this regard, remote ischaemic preconditioning (RIPC) is a promising non-invasive intervention able to reduce PMI in these patients: however, not all the studies have shown significant cardioprotection with RIPC for a number of factors, amongst which the intensity of the preconditioning stimulus may play a significant role. We therefore investigated whether an enhanced RIPC stimulus, given with transient simultaneous multi-limb ischaemia/reperfusion, was able to reduce PMI and improve short-term clinical outcomes in patients undergoing elective cardiac surgery: we demonstrated that our preconditioning stimulus can significantly reduce PMI, length of intensive care unit (ICU) stay and incidence of atrial fibrillation (AF) in these patients. In addition, further retrospective analyses showed improved myocardial protection in preconditioned diabetic patients undergoing CABG surgery and in control CABG subjects receiving combined antegrade and retrograde cardioplegia compared to control CABG patients having antegrade cardioplegia or intermittent cross-clamp-fibrillation. We also conducted a multi-centre, double-blinded randomised control clinical trial, in which we investigated the effects of RIPC on clinical outcomes at 1 year in high-risk patients undergoing elective CABG surgery with or without valve surgery (the ERICCA trial). The results of this study are due to be presented in March 2015 and have the potential to significantly impact on clinical practice in cardiac surgery

Is there a role for ischaemic conditioning in cardiac surgery?

Coronary artery disease (CAD) is a major cause of morbidity and mortality worldwide. Coronary artery bypass graft (CABG) surgery is the revascularisation strategy of choice in patients with diabetes mellitus and complex CAD. Owing to a number of factors, including the ageing population, the increased complexity of CAD being treated, concomitant valve and aortic surgery, and multiple comorbidities, higher-risk patients are being operated on, the result of which is an increased risk of sustaining perioperative myocardial injury (PMI) and poorer clinical outcomes. As such, new treatment strategies are required to protect the heart against PMI and improve clinical outcomes following cardiac surgery. In this regard, the heart can be endogenously protected from PMI by subjecting the myocardium to one or more brief cycles of ischaemia and reperfusion, a strategy called "ischaemic conditioning". However, this requires an intervention applied directly to the heart, which may be challenging to apply in the clinical setting. In this regard, the strategy of remote ischaemic conditioning (RIC) may be more attractive, as it allows the endogenous cardioprotective strategy to be applied away from the heart to the arm or leg by simply inflating and deflating a cuff on the upper arm or thigh to induce one or more brief cycles of ischaemia and reperfusion (termed "limb RIC"). Although a number of small clinical studies have demonstrated less PMI with limb RIC following cardiac surgery, three recently published large multicentre randomised clinical trials found no beneficial effects on short-term or long-term clinical outcomes, questioning the role of limb RIC in the setting of cardiac surgery. In this article, we review ischaemic conditioning as a therapeutic strategy for endogenous cardioprotection in patients undergoing cardiac surgery and discuss the potential reasons for the failure of limb RIC to improve clinical outcomes in this setting. Crucially, limb RIC still has the therapeutic potential to protect the heart in other clinical settings, such as acute myocardial infarction, and it may also protect other organs against acute ischaemia/reperfusion injury (such as the brain, kidney, and liver)

Protection of organs other than the heart by remote ischemic conditioning

Organ or tissue dysfunction due to acute ischemia–reperfusion injury (IRI) is the leading cause of death and disability worldwide. Acute IRI induces cell injury and death in a wide variety of organs and tissues in a large number of different clinical settings. One novel therapeutic noninvasive intervention, capable of conferring multiorgan protection against acute IRI, is ‘remote ischemic conditioning’ (RIC). This describes an endogenous protective response to acute IRI, which is triggered by the application of one or more brief cycles of nonlethal ischemia and reperfusion to one particular organ or tissue. Originally discovered as a therapeutic strategy for protecting the myocardium against acute IRI, it has been subsequently demonstrated that RIC may confer protection against acute IRI in a number of different noncardiac organs and tissues including the kidneys, lungs, liver, skin flaps, ovaries, intestine, stomach and pancreas. The discovery that RIC can be induced noninvasively by applying the RIC stimulus to the skeletal tissue of the upper or lower limb has facilitated its application to a number of clinical settings in which organs and tissues are at high risk of acute IRI. In this article, we review the experimental studies that have investigated RIC in organs and tissues other than the heart, and we explore the therapeutic potential of RIC in preventing organ and tissue dysfunction induced by acute IRI

SARS-CoV-2 and Pre-existing Vascular Diseases: Guilt by Association?

Severe Acute Respiratory Syndrome coronavirus-2 has rapidly spread and emerged as a pandemic. Although evidence on its pathophysiology is growing, there are still issues that should be taken into consideration, including its effects on pre-existing peripheral vascular disease. The aim of this review is to describe the thrombotic and endothelial dysfunctions caused by SARS-CoV-2, assess if cardiovascular comorbidities render an individual susceptible to the infection and determine the course of pre-existing vascular diseases in infected individuals. A search through MEDLINE, PubMed and EMBASE was conducted and more than 260 articles were identified and 97 of them were reviewed; the rest were excluded because they were not related to the aim of this study. Hypertension, cardiovascular disease, diabetes mellitus and cerebrovascular diseases comprised 24.30% ± 16.23%, 13.29% ± 12.88%, 14.82% ± 7.57% and 10.82% ± 11.64% of the cohorts reviewed, respectively. Arterial and venous thrombotic complications rocketed up to 31% in severely infected individuals in some studies. We suggest that hypertension, cardiovascular diseases, diabetes and cerebrovascular diseases may render an individual susceptible to severe COVID-19 infection. Pre-existing vascular diseases are expected to deteriorate with SARS-CoV-2 infection as a consequence of its increased thrombotic burden and the development of endothelial dysfunction. COVID-19 has emerged only a few months ago and it is premature to predict the long-term effects to the vascular system. Its disturbances of the coagulation mechanisms and effects on vascular endothelium will likely provoke a surge of vascular complications in the coming months

Remote Ischemic Preconditioning: Would You Give Your Right Arm to Protect Your Kidneys?

Commentary on Zarbock A, Schmidt C, Van Aken H, et al. Effect of remote ischemic preconditioning on kidney injury among high-risk patients undergoing cardiac surgery: a randomized clinical trial. JAMA. 2015;313(21):2133-2141

Stratigraphic context and paleoenvironmental significance of minor taxa (Pisces, Reptilia, Aves, Rodentia) from the late Early Pleistocene palaeoanthropological site of Buia (Eritrea)

none13noneL. Rook; M. Ghinassi; G. Carnevale; M. Delfino; M. Pavia; L. Bondioli ; F. Candilio; A. Coppa; B. Martínez-Navarro; T. Medin; M. Papini; C. Zanolli; Y. LibsekalL., Rook; Ghinassi, Massimiliano; G., Carnevale; M., Delfino; M., Pavia; L., Bondioli; F., Candilio; A., Coppa; B., Martínez Navarro; T., Medin; M., Papini; C., Zanolli; Y., Libseka

One session of remote ischemic preconditioning does not improve vascular function in acute normobaric and chronic hypobaric hypoxia

Application of repeated short duration bouts of ischemia to the limbs, termed remote ischemic preconditioning (RIPC), is a novel technique that may have protective effects on vascular function during hypoxic exposures. In separate parallel-design studies, at sea-level (SL; n=16), and after 8-12 days at high-altitude (HA; n=12; White Mountain, 3800m), participants underwent either a sham protocol or one session of 4x5 minutes of dual-thigh cuff occlusion with 5-minutes recovery. Brachial artery flow-mediated dilation (FMD; ultrasound), pulmonary artery systolic pressure (PASP; echocardiography), and internal carotid artery flow (ICA; ultrasound) were measured at SL in normoxia and isocapnic hypoxia [end-tidal PO (PETO ) maintained to 50mmHg], and during normal breathing at HA. The hypoxic ventilatory response (HVR) was measured at each location. All measures at SL and HA were obtained at baseline (BL), 1 hour, 24 hours, and 48 hours post-RIPC or sham. At SL, RIPC produced no changes in FMD, PASP, ICA flow, end-tidal gases or HVR in normoxia or hypoxia. At HA, although HVR increased 24 hours post RIPC compared to BL (2.05{plus minus}1.4 vs. 3.21{plus minus}1.2 L•min-1•%SaO2-1, p<0.01), there were no significant differences in FMD, PASP, ICA flow, resting end-tidal gases. Accordingly, a single session of RIPC is insufficient to evoke changes in peripheral, pulmonary, and cerebral vascular function in healthy adults. Although chemosensitivity may increase following RIPC at HA, this did not confer any vascular changes. The utility of a single RIPC session seems unremarkable during acute and chronic hypoxia

Remote ischemic conditioning: from experimental observation to clinical application: report from the 8th Biennial Hatter Cardiovascular Institute Workshop

In 1993, Przyklenk and colleagues made the intriguing experimental observation that 'brief ischemia in one vascular bed also protects remote, virgin myocardium from subsequent sustained coronary artery occlusion' and that this effect '.... may be mediated by factor(s) activated, produced, or transported throughout the heart during brief ischemia/reperfusion'. This seminal study laid the foundation for the discovery of 'remote ischemic conditioning' (RIC), a phenomenon in which the heart is protected from the detrimental effects of acute ischemia/reperfusion injury (IRI), by applying cycles of brief ischemia and reperfusion to an organ or tissue remote from the heart. The concept of RIC quickly evolved to extend beyond the heart, encompassing inter-organ protection against acute IRI. The crucial discovery that the protective RIC stimulus could be applied non-invasively, by simply inflating and deflating a blood pressure cuff placed on the upper arm to induce cycles of brief ischemia and reperfusion, has facilitated the translation of RIC into the clinical setting. Despite intensive investigation over the last 20 years, the underlying mechanisms continue to elude researchers. In the 8th Biennial Hatter Cardiovascular Institute Workshop, recent developments in the field of RIC were discussed with a focus on new insights into the underlying mechanisms, the diversity of non-cardiac protection, new clinical applications, and large outcome studies. The scientific advances made in this field of research highlight the journey that RIC has made from being an intriguing experimental observation to a clinical application with patient benefit