Cardioprotective effect of remote ischemic preconditioning with postconditioning on donor hearts in patients undergoing heart transplantation: a single-center, double-blind, randomized controlled trial.

BACKGROUND: The cardioprotective effect of remote ischemic preconditioning (RIPC) in cardiovascular surgery is controversial. This study investigated whether RIPC combined with remote ischemic postconditioning (RIPostC) reduces myocardial injury to donor hearts in patients undergoing heart transplantation. METHODS: One hundred and twenty patients scheduled for orthotopic heart transplantation were enrolled and randomly assigned to an RIPC+RIPostC group (n = 60) or a control (n = 60) group. In the RIPC+RIPostC group, after anesthesia induction, four cycles of 5-min of ischemia and 5-min of reperfusion were applied to the right upper limb by a cuff inflated to 200 mmHg (RIPC) and 20 min after aortic declamping (RIPostC). Serum cardiac troponin I (cTnI) levels were determined preoperatively and at 3, 6, 12, and 24 h after aortic declamping. Postoperative clinical outcomes were recorded. The primary endpoint was a comparison of serum cTnI levels at 6 h after aortic declamping. RESULTS: Compared with the preoperative baseline, in both groups, serum cTnI levels peaked at 6 h after aortic declamping. Compared with the control group, RIPC+RIPostC significantly reduced serum cTnI levels at 6 h after aortic declamping (38.87 ± 31.81 vs 69.30 ± 34.13 ng/ml, P = 0.02). There were no significant differences in in-hospital morbidity and mortality between the two groups. CONCLUSION: In patients undergoing orthotopic heart transplantation, RIPC combined with RIPostC reduced myocardial injury at 6 h after aortic declamping, while we found no evidence of this function provided by RIPC+RIPostC could improve clinical outcomes. TRIAL REGISTRATION: Trial Registration Number: chictr.org.cn . no. ChiCTR-INR-16010234 (prospectively registered). The initial registration date was 9/1/2017.

Cardioprotective signalling: Past, present and future.

A few decades ago, cardiac muscle was discovered to possess signalling pathways that, when activated, protect the myocardium against the damage induced by ischaemia-reperfusion. The ability of cardiac muscle to protect itself against injury has been termed 'cardioprotection'. Many compounds and procedures can trigger cardioprotection including conditionings (exposure to brief episodes of ischaemia-reperfusion to protect against sustained ischaemia-reperfusion), hypoxia, adenosine, acetylcholine, adrenomedullin, angiotensin, bradykinin, catecholamines, endothelin, estrogens, phenylephrine, opioids, testosterone, and many more. These triggers activate many intracellular signalling factors including protein kinases, different enzymes, transcription factors and defined signalling pathways to target structures in mitochondria, sarcoplasmic reticulum, nucleus and sarcolemma to mediate cardioprotection. Although a lot of information about cardioprotection has been acquired, there are still two major outstanding issues to be addressed in the future 1) better understanding of spatio-temporal relationships between signalling elements, and; 2) devising therapeutic strategies against myocardial diseases based on cardioprotective signalling. Further research is required to paint integral picture of cardioprotective signalling and more clinical studies are required to properly test clinical efficacy and safety of potential cardioprotective strategies. Therapies against cardiac diseases based on cardioprotective strategies would be a perfect adjunct to current therapeutic strategies based on restitution of coronary blood flow and regulation of myocardial metabolic demands.

The EUROpean and Chinese cardiac and renal Remote Ischemic Preconditioning Study (EURO-CRIPS CardioGroup I): A randomized controlled trial.

BACKGROUND: The potential protective effects of remote ischemic preconditioning (RIPC) on contrast-induced nephropathy (CIN) after percutaneous coronary intervention (PCI) remain to be defined. METHODS AND RESULTS: A double blind, randomized, placebo controlled multicenter study was performed. Patients younger than 85years old, with a renal clearance of 30-60ml/min/1.73m2, who were candidates for PCI for all clinical indications except for primary PCI, were allocated 1:1 to RIPC or to standard therapy. The primary endpoint was incidence of CIN. The secondary endpoint was incidence of peri-procedural myocardial infarction (PMI). From February 2013 to April 2014, 3108 patients who were scheduled for coronary angiography were screened for the study. 442 fulfilled the inclusion criteria and 223 received PCI. These patients were randomized to sham RIPC (n=107) or treatment group (n=116). The only pre-specified subgroup of diabetic patients included 85 (38%) cases. RIPC significantly reduced CIN incidence in the overall population (12.1% vs. 26.1%, p=0.01, with a NNT=9) and in non-diabetic patients (9.2% vs. 25.0%, p=0.02), but showed no benefit in diabetics (16.7% vs. 28.2%, p=0.21). A trend for lower PMI was seen in the intervention arm (creatine kinase - muscle brain >5 URL; 8.4% vs. 16.4%, p=0.07; troponin T >5 URL; 27% vs. 38%, p=0.21). CONCLUSIONS: Remote ischemic preconditioning significantly reduces the incidence of acute kidney injury in non-diabetic patients undergoing PCI. Larger sample size is presumably needed to assess the effect of RIPC for patients with diabetes mellitus. Clinical Trial number:NCT02195726https://www.clinicaltrial.gov/.

Impact of remote ischaemic preconditioning on major clinical outcomes in patients undergoing cardiovascular surgery: A meta-analysis with trial sequential analysis of 32 randomised controlled trials.

BACKGROUND: The impact of remote ischaemic preconditioning (RIPC) on major clinical outcomes in patients undergoing cardiovascular surgery remains controversial. We systematically reviewed the available evidence to evaluate the potential benefits of RIPC in such patients. METHODS: PubMed, Embase, and Cochrane Library databases were searched for relevant randomised controlled trials (RCTs) conducted between January 2006 and March 2016. The pooled population of patients who underwent cardiovascular surgery was divided into the RIPC and control groups. Trial sequential analysis was applied to judge data reliability. The pooled relative risks (RRs) with 95% confidence intervals (CIs) between the groups were calculated for all-cause mortality, major adverse cardiovascular and cerebral events (MACCEs), myocardial infarction (MI), and renal failure. RESULTS: RIPC was not associated with improvement in all-cause mortality (RR, 1.04; 95%CI, 0.82-1.31; I2=26%; P>0.05) or MACCE incidence (RR, 0.90; 95%CI, 0.71-1.14; I2=40%; P>0.05) after cardiovascular surgery, and both results were assessed by trial sequential analysis as sufficient and conclusive. Nevertheless, RIPC was associated with a significantly lower incidence of MI (RR, 0.87; 95%CI, 0.76-1.00; I2=13%; P≤0.05). However, after excluding a study that had a high contribution to heterogeneity, RIPC was associated with increased rates of renal failure (RR, 1.53; 95%CI, 1.12-2.10; I2=5%; P≤0.05). CONCLUSIONS: In patients undergoing cardiovascular surgery, RIPC reduced the risk for postoperative MI, but not that for MACCEs or all-cause mortality, a discrepancy likely related to the higher rate of renal failure associated with RIPC.

Renoprotection by remote ischemic conditioning during elective coronary revascularization: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Remote ischemic conditioning (RIC) has been recognized an emerging non-invasive approach for preventing acute kidney injury (AKI) in patients undergoing either elective coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention (PCI). On the other hand, accumulating evidence has indicated the involving role of pre-CABG contrast usage for coronary angiography in post-surgery AKI risk. Along with the shortening time delay of CABG after coronary angiography, and the prevalent hybrid coronary revascularization (HCR), the AKI prevention by RIC has faced challenges following coronary revascuralization. METHODS: Randomized controlled trials (RCTs) were searched from Pubmed, EMBase, and Cochrane library (until May 2016). The primary outcome was postoperative AKI. The second outcomes were included the requirement for renal replacement therapy (RRT), and in-hospital or 30-day mortality. RESULTS: Twenty eligible RCTs (CABG, 3357 patients; PCI, 1501 patients) were selected. RIC significantly halved the incidence of AKI following PCI when compared with controls [n=1501; odds ratio (OR)=0.51; 95% CI, 0.32 to 0.82; P=0.006; I(2)=29.6%]. However, RIC did not affect the incidence of AKI following CABG (n=1850; OR=0.94; 95% CI, 0.73 to 1.19; P=0.586; I(2)=12.4%). The requirement for RRT and in-hospital mortality was not affected by RIC in CABG (n=2049, OR=1.04, P=0.87; n=1920, OR=0.89, P=0.7; respectively). CONCLUSIONS: Our meta-analysis suggests that RIC for preventing AKI following CABG has faced with challenges in terms of AKI, the requirement for RRT, and mortality. However, RIC shows a renoprotective benefit for PCI. Hence, our findings may infer the preserved renal effects of RIC in CABG with preconditioning before the coronary angiography, or in HCR.

Time to Give Up on Cardioprotection? A Critical Appraisal of Clinical Studies on Ischemic Pre-, Post-, and Remote Conditioning.

The mortality from acute myocardial infarction (AMI) remains significant, and the prevalence of post-myocardial infarction heart failure is increasing. Therefore, cardioprotection beyond timely reperfusion is needed. Conditioning procedures are the most powerful cardioprotective interventions in animal experiments. However, ischemic preconditioning cannot be used to reduce infarct size in patients with AMI because its occurrence is not predictable; several studies in patients undergoing surgical coronary revascularization report reduced release of creatine kinase and troponin. Ischemic postconditioning reduces infarct size in most, but not all, studies in patients undergoing interventional reperfusion of AMI, but may require direct stenting and exclusion of patients with >6 hours of symptom onset to protect. Remote ischemic conditioning reduces infarct size in patients undergoing interventional reperfusion of AMI, elective percutaneous or surgical coronary revascularization, and other cardiovascular surgery in many, but not in all, studies. Adequate dose-finding phase II studies do not exist. There are only 2 phase III trials, both on remote ischemic conditioning in patients undergoing cardiovascular surgery, both with neutral results in terms of infarct size and clinical outcome, but also both with major problems in trial design. We discuss the difficulties in translation of cardioprotection from animal experiments and proof-of-concept trials to clinical practice. Given that most studies on ischemic postconditioning and all studies on remote ischemic preconditioning in patients with AMI reported reduced infarct size, it would be premature to give up on cardioprotection.

9th Hatter Biannual Meeting: position document on ischaemia/reperfusion injury, conditioning and the ten commandments of cardioprotection.

In the 30 years since the original description of ischaemic preconditioning, understanding of the pathophysiology of ischaemia/reperfusion injury and concepts of cardioprotection have been revolutionised. In the same period of time, management of patients with coronary artery disease has also been transformed: coronary artery and valve surgery are now deemed routine with generally excellent outcomes, and the management of acute coronary syndromes has seen decade on decade reductions in cardiovascular mortality. Nonetheless, despite these improvements, cardiovascular disease and ischaemic heart disease in particular, remain the leading cause of death and a significant cause of long-term morbidity (with a concomitant increase in the incidence of heart failure) worldwide. The need for effective cardioprotective strategies has never been so pressing. However, despite unequivocal evidence of the existence of ischaemia/reperfusion in animal models providing a robust rationale for study in man, recent phase 3 clinical trials studying a variety of cardioprotective strategies in cardiac surgery and acute ST-elevation myocardial infarction have provided mixed results. The investigators meeting at the Hatter Cardiovascular Institute workshop describe the challenge of translating strong pre-clinical data into effective clinical intervention strategies in patients in whom effective medical therapy is already altering the pathophysiology of ischaemia/reperfusion injury-and lay out a clearly defined framework for future basic and clinical research to improve the chances of successful translation of strong pre-clinical interventions in man.

Remote ischemic preconditioning does not affect the incidence of acute kidney injury after elective abdominal aortic aneurysm repair.

OBJECTIVE: Open abdominal aortic aneurysm (AAA) repair is associated with a high risk of renal injury with few known strategies demonstrating a reduction in this risk. Remote ischemic preconditioning (RIPC) has been identified as having the potential to minimize organ injury following major vascular surgery. This trial investigated the potential for RIPC to attenuate renal and myocardial injury in patients undergoing elective open AAA repair. DESIGN: Prospective, randomized double-blinded control trial. SETTING: Tertiary referral hospital. PARTICIPANTS: Sixty-two patients undergoing elective open AAA repair. INTERVENTION: RIPC was achieved via three 5-minute cycles of upper limb ischemia using a blood pressure cuff or control (sham cuff). MEASUREMENTS: Primary outcome was the occurrence of renal injury, as measured by an increase in creatinine during the first 4 postoperative days. Secondary outcomes included urinary neutrophil-gelatinase-associated lipocalin (NGAL), occurrence of acute kidney injury (AKI), occurrence of myocardial injury as defined by troponin rise, incidence of postoperative complications, and mortality. There was no difference in postoperative creatinine levels, NGAL levels, or the occurrence of AKI between the groups at any postoperative time point. Similarly, there was no difference in the occurrence of myocardial injury or mortality. Of note, 6 patients in the RIPC group, while no patient in the control group, experienced postoperative complications that required repeat surgical laparotomy, potentially masking any renoprotective effects of RIPC. CONCLUSION: RIPC did not reduce the risk of postoperative renal failure or myocardial injury in patients undergoing open AAA repair. The authors' results do not support the introduction of this technique to routine clinical practice.

Future perspective of cardioplegic protection in cardiac surgery.

"Depolarized arrest", induced by hyperkalemic (moderately increased extracellular potassium) cardioplegia is the gold standard to achieve elective temporary cardiac arrest in cardiac surgery. Hyperkalemic cardioplegic solutions provide good myocardial protection, which is relatively safe and easily and rapidly reversible. However, this technique has detrimental effects associated with ionic imbalance involving sodium and calcium overload of the cardiac cell induced by depolarization of the cell membrane. Hence, the development of an improved cardioplegic solution that enhances myocardial protection would be expected as an alternative to hyperkalemic cardioplegia. In this review, we assess the potential disadvantages of "depolarized arrest" and the suitability and clinical potential of "non-depolarized arrest". "Magnesium cardioplegia" and "esmolol cardioplegia" has been shown to exert superior protection with comparable safety profiles to that of hyperkalemic cardioplegia. These alternative techniques require further examination and investigation to challenge the traditional view that hyperkalemic arrest is best. Endogenous cardioprotective strategies, termed "ischemic preconditioning" and "ischemic postconditioning", may have a role in cardiac surgery to provide additional protection. The elective nature of cardiac surgery, with the known onset of ischemia and reperfusion, lends it to the potential of these strategies. However, the benefit of preconditioning and postconditioning during cardiac surgery is controversial, particularly in the context of cardioplegia. The clinical application of these strategies is unlikely to become routine during cardiac surgery because of the necessity for repeated aortic crossclamping with consequent potential for embolic events, but offers considerable potential especially if "pharmacological" preconditioning and postconditioning could be established.

[Cardioprotective effect of remote postconditioning: mechanisms and possibility of clinical application].

Experimental data indicate that postconditioning at distance is an effective method of cardiac protection against reperfusion injury. Remote postconditioning prevents reperfusion necrosis and apoptosis of cardiomyocytes, decreases probability of postinfarction remodeling of the heart. Cardioprotective effect of remote postconditioning is depended on release from tissues after transient ischemia of humoral factor(s) increasing cardiac tolerance to long-term ischemia-reperfusion. Clinical studies show that postconditioning at distance is an effective method of prevention of reperfusion injury of the heart during coronary artery bypass surgery.

Myocardial conditioning: opportunities for clinical translation.

Myocardial conditioning is an endogenous cardioprotective phenomenon that profoundly limits infarct size in experimental models. The current challenge is to translate this paradigm from the laboratory to the clinic. Accordingly, our goal in this review is to provide a critical summary of the progress toward, opportunities for, and caveats to, the successful clinical translation of postconditioning and remote conditioning, the 2 conditioning strategies considered to have the broadest applicability for real-world patient care. In the majority of phase II studies published to date, postconditioning evoked a ≈35% reduction of infarct size in ST-segment-elevation myocardial infarction patients. Essential criteria for the successful implementation of postconditioning include the appropriate choice of patients (ie, those with large risk regions and negligible collateral flow), timely application of the postconditioning stimulus (immediately on reperfusion), together with proper choice of end points (infarct size, with concomitant assessment of risk region). Remote conditioning has been applied in planned ischemic events (including cardiac surgery and elective percutaneous coronary intervention) and in ST-segment-elevation myocardial infarction patients during hospital transport. Controversies with regard to efficacy have emerged, particularly among surgical trials. These disparate outcomes in all likelihood reflect the remarkable heterogeneity within and among studies, together with a deficit in our understanding of the impact of these variations on the infarct-sparing effect of remote conditioning. Ongoing phase III trials will provide critical insight into the future role of postconditioning and remote conditioning as clinically relevant cardioprotective strategies.

Extracardiac approaches to protecting the heart.

Myocardial adaptation to ischemia in the form of ischemic preconditioning is clinically attractive, but not easily usable in cardiac surgery until molecular mimics are discovered. The various forms of pre- and postconditioning, including remote preconditioning, indicate that a 'universal' protection is evoked. A growing body of evidence indicates that events underlying myocardial adaptation to ischemia may either involve, or be parallel to, signaling of the innate immune response. The heart can be protected through giving cytokines or fragments of bacterial walls. A possible role for cytokines, Toll-like receptors, and nuclear factor kappa B for evoking ischemic preconditioning are discussed. Through stimulating innate immunity, there is potential to bring preconditioning into the clinics in a reasonable time frame. Other approaches to myocardial protection, using cell transfer, gene therapy, and microRNA, are briefly commented on.

Cardioprotection by volatile anesthetics.

Preconditioning describes a very powerful endogenous mechanism by which the heart may be protected against ischemia and reperfusion injury. Transient administration of a volatile anesthetic before a prolonged ischemic episode reduces myocardial infarct size to a degree comparable to that observed during ischemic preconditioning. Many components of the signal transduction pathways responsible for cardioprotection are shared by anesthetic and ischemic preconditioning. Exposure to volatile anesthetics generates small "triggering" quantities of reactive oxygen species (ROS) by directly interacting with the mitochondrial electron transport chain or indirectly through a signaling cascade in which G-protein-coupled receptors, protein kinases, and mitochondrial ATP-sensitive potassium (K(ATP)) channels play important roles. Several clinical studies also suggest that preconditioning by volatile anesthetics exerts beneficial effects in patients undergoing cardiac surgery. This review summarizes some of the recent major developments in the understanding of cardioprotection by volatile anesthetics.

Coordinated induction of iNOS-VEGF-KDR-eNOS after resveratrol consumption: a potential mechanism for resveratrol preconditioning of the heart.

Existing evidence indicates that resveratrol, a red wine and grape-derived polyphenolic antioxidant, can pharmacologically precondition the heart in a nitric oxide (NO)-dependent manner. To further explore the role of NO in resveratrol-mediated cardioprotection, the induction for the expression of the potential molecular targets of NO including VEGF and KDR as well as iNOS and eNOS were examined by Western blot analysis and immunohistochemistry. Two groups of rats were studied, one group of animals was fed resveratrol for 7 days while the other group was given water only. After 1, 3, 5 and 7 days, the rats were sacrificed and the expression of the proteins was examined by Western blot analysis. Western blot detected an overexpression of iNOS and VEGF within 24 h of resveratrol treatment while the induction of KDR was not increased until after 3 days and eNOS expression after 5 days of resveratrol treatment. These expressions were further increased after 7 days of resveratrol treatment, when the rats were sacrificed for the isolated working heart preparation. Resveratrol provided cardioprotection as evidenced by superior post-ischemic ventricular recovery, reduced myocardial infarct size and decreased number of apoptotic cardiomyocytes. Immunohistochemistry was performed in the hearts at baseline, and at the end of 30-min ischemia/2-h reperfusion. The hearts obtained from resveratrol-treated rats revealed enhanced expression for iNOS, eNOS and VEGF and KDR compared to control hearts at the end of reperfusion. The results of this study demonstrate that resveratrol leads to a coordinated upregulation of iNOS-VEGF-KDR-eNOS, which is likely to play a role in resveratrol-mediated cardioprotection.

Síndrome de precondicionamiento cardíaco / Syndrome of heart preconditioning

El precondicionamiento cardíaco es incluído actualmente entre los nuevos síndromes isquémicos y considerado un importante mecanismo endógeno que protege al corazón del daño isquémico prolongado. Por otro lado, se incrementa la mortalidad cardiovascular de pacientes diabéticos tratados con hipoglucemiantes orales, por lo que se hace necesario conocer las drogas que bloquean esta forma endógena de protección para alcanzar finalmente el modelado molecular de nuevos fármacos y el precondicionamiento farmacológico