RIPC Remains a Promising Technique for Protection of the Myocardium during Open Cardiac Surgery: A Meta-Analysis and Systematic Review.

BACKGROUND: Remote ischemic preconditioning (RIPC) is the process of inducing brief ischemia in a tissue to prevent ischemic damage in another. This preconditioning can be induced simply by inflating a blood pressure cuff on a limb. Previous randomized controlled trials (RCT) have suggested that RIPC may infer myocardial protection during open cardiac surgery. One method of assessing the degree of myocardial damage incurred in these studies is to assay troponin concentration. Troponin is a cardiac enzyme released by damaged myocardiocytes. With the recent publication of several large RCTs in this area, a meta-analysis of the evidence was undertaken. METHODS: A systematic search of PubMed, EMBASE, and clinicaltrials.gov.uk was conducted using MeSH terms "ischaemic preconditioning" and "cardiac surgery." RCTs that examined post-surgery troponin concentrations were included in this review. The primary outcome investigated was troponin levels at six hours post-cardiac surgery. Secondary outcomes included six to eight hour and twenty-four hour troponin release. RESULTS: Thirteen RCTs, comprising 1398 participants, were identified for inclusion in this meta-analysis. Twelve hour postoperative troponin was significantly reduced by RIPC, standardized mean difference 1.29 (95% CI 0.34-2.24). Six to eight and twenty-four hour troponin were also significantly reduced, standardized mean differences 1.23 (95% CI 0.62-1.84) and 1.25 (95% CI 0.31-2.19) respectively. CONCLUSIONS: The reduction in troponin concentration suggests that RIPC reduces myocardial damage during open cardiac surgery, however, the degree of bias in the studies assessed may have had a significant impact on this result.

Remote ischaemic preconditioning in isolated aortic valve and coronary artery bypass surgery: a randomized trial†.

OBJECTIVES: This trial was designed and patients were recruited at a time when the benefits of remote ischaemic preconditioning during open-heart surgery were still controversial. We focused on a homogeneous patient population undergoing either isolated aortic valve replacement or coronary artery bypass grafting (CABG) surgery by investigating cardiac injury, metabolic stress and inflammatory response. METHODS: A 2-centre randomized controlled trial recruited a total of 124 patients between February 2013 and April 2015. Of them, 64 patients underwent CABG and 60 patients underwent aortic valve replacement. Patients were randomized to either sham or preconditioning. Remote ischaemic preconditioning was applied following anaesthesia and before sternotomy. Myocardial injury and inflammatory response were assessed by serially measuring cardiac troponin I, and interleukin-6, 8, 10 and the tumour necrosis factor (TNF-α). Biopsies from the left and the right ventricles were harvested after ischaemic reperfusion injury for nucleotides analysis. RESULTS: Application of remote ischaemic preconditioning did not alter the degree of troponin I release, levels of inflammatory markers and cardiac energetics in both the CABG and the aortic valve replacement groups. CONCLUSIONS: Preconditioning did not confer any additional cardioprotection in terms of reducing the levels of troponin I and inflammatory markers and preserving left and right ventricle energy metabolites in patients undergoing isolated CABG or aortic valve surgery. CLINICAL TRIAL REGISTRATION NUMBER: International Standard Randomized Controlled Trial Number (ISRCTN) registry ID 33084113 (doi: 10.1186/ISRCTN33084113) and UK controlled randomized trial number (UKCRN) registry ID 13672.

Preoperative Sildenafil administration in children undergoing cardiac surgery: a randomized controlled preconditioning study.

OBJECTIVES: Sildenafil has strong cardiac preconditioning properties in animal studies and has a safe side-effect profile in children. Therefore, we evaluated the application of Sildenafil preconditioning to reduce myocardial ischaemia/reperfusion injury in children undergoing surgical ventricular septal defect (VSD) closure. METHODS: This is a randomized, double-blind study. Children (1-17 years) undergoing VSD closure were randomized into three groups: placebo (Control group), preconditioning with 0.06 mg/kg (Sild-L group) and 0.6 mg/kg Sildenafil (Sild-H group). PRIMARY ENDPOINT: troponin release. CK-MB, Troponin I, inflammatory response (IL-6 and TNF-α), bypass and ventilation weaning times, inotropy score and echocardiographic function were assessed. Data expressed as median (range), and a value of P < 0.05 was considered significant. RESULTS: Thirty-nine patients were studied (13/group). Aortic cross-clamp time was similar [27 (18-85) and 27 (12-39) min] in the Control and Sild-L groups, respectively, but significantly longer [39 (20-96) min] in the Sild-H group when compared with the Control group. Area under the curve of CK-MB release was 1105 (620-1855) h ng/ml in the Control group, 1672 (564-2767) h ng/ml in the Sild-L group and was significantly higher in the Sild-H group [1695 (1252-3377) h ng/ml] when compared with the Control group. There were no significant differences in inflammatory response markers, cardiopulmonary bypass and ventilation weaning times, inotropy scores and echocardiographic function between the groups. CONCLUSIONS: In this small study, Sildenafil failed to reduce myocardial injury in children undergoing cardiac surgery, nor does it alter cardiac function, inotropic needs or postoperative course. A subclinical increase in cardiac enzyme release after Sildenafil preconditioning cannot be excluded. CLINICAL TRIALS REGISTRY: CTRI/2014/03/004468.

Frequency and clinical significance of ischemic preconditioning during percutaneous coronary intervention.

OBJECTIVES: We sought to examine the short- and long-term clinical consequences of ischemic preconditioning (IP) during percutaneous coronary intervention (PCI). BACKGROUND: Ischemic preconditioning has been demonstrated in animal models to significantly diminish the extent of myocardial necrosis consequent to coronary occlusion. Surrogate markers of ischemic injury (ST segment shift, lactate release, creatine kinase release) in humans have been shown to be similarly diminished with IP elicited during PCI. There are no studies of the frequency of inducibility of IP during PCI, nor are there longer-term data on the clinical relevance of IP. METHODS: A total of 382 patients underwent elective PCI employing a previously validated protocol to elicit IP. Procedural, in-hospital, and one-year outcomes were recorded. RESULTS: Ischemic preconditioning was elicited in 80% of patients and was associated with a significant reduction in the likelihood of in-hospital adverse cardiac events (IP group, 12.1%; non-IP group, 44.1%; p < 0.0001). Women and diabetic patients were less likely to exhibit IP. By one year, patients failing to manifest IP were at significantly greater risk of post-discharge death or non-fatal myocardial infarction (MI) (non-IP group, 25.9%; IP group, 11.1%; p < 0.002). Failure to manifest IP was significantly and independently associated with an increased risk of death or non-fatal MI by one year. CONCLUSIONS: Clinically relevant short- and long-term cardioprotection can be found in association with IP during PCI. In-hospital adverse ischemic events are significantly diminished in patients with IP, as are the risks of death or non-fatal MI at one year. Failure to elicit IP during PCI serves as an independent marker of increased risk of future ischemic events.

Bradykinin-induced preconditioning in patients undergoing coronary angioplasty.

OBJECTIVES: The purpose of this study was to determine whether administration of bradykinin reproduces the cardioprotective effects of ischemic preconditioning (PC) in patients undergoing percutaneous transluminal coronary angioplasty (PTCA). BACKGROUND: Experimental studies suggest that activation of the bradykinin B2 receptor is an important trigger of ischemic PC. However, it is unknown whether bradykinin can precondition human myocardium against ischemia in vivo. Multicenter clinical trials have demonstrated an anti-ischemic effect of angiotensin-converting enzyme inhibitors, which has been postulated to result from potentiation of bradykinin; however, direct evidence for an anti-ischemic action of bradykinin in patients is lacking. METHODS: Thirty patients were randomized to receive a 10-min intracoronary infusion of bradykinin (2.5 microg/min) or normal saline. Ten minutes later they underwent PTCA (three 2-min balloon inflations 5 min apart). RESULTS: In control patients, the ST-segment shift on the intracoronary and surface electrocardiogram was significantly greater during the first inflation than during the second and third inflations, consistent with ischemic PC. In bradykinin-treated patients, the ST-segment shift during the first inflation was significantly smaller than in the control group, and there were no appreciable differences in ST-segment shift during the three inflations. Measurements of chest pain score and regional wall motion during inflation (quantitative two-dimensional echocardiography) paralleled those of ST-segment shift. Infusion of bradykinin had no hemodynamic effects and no significant adverse effects. Thus, intracoronary infusion of bradykinin before PTCA rendered the myocardium relatively resistant to subsequent ischemia, and the degree of this cardioprotective effect was comparable to that afforded by the ischemia associated with the first balloon inflation in control subjects. In a separate cohort of seven patients given the same dose of bradykinin, coronary hyperemia resolved completely within 10 min after the end of the infusion, indicating that bradykinin-induced vasodilation cannot account for the protective effects observed during the first balloon inflation. CONCLUSIONS: Bradykinin preconditions human myocardium against ischemia in vivo in the absence of systemic hemodynamic changes. Pretreatment with bradykinin appears to be just as effective as ischemic PC and could be used prophylactically to attenuate ischemia in selected patients undergoing PTCA.

Diabetic inhibition of preconditioning- and postconditioning-mediated myocardial protection against ischemia/reperfusion injury.

Ischemic preconditioning (IPC) or postconditioning (Ipost) is proved to efficiently prevent ischemia/reperfusion injuries. Mortality of diabetic patients with acute myocardial infarction was found to be 2-6 folds higher than that of non-diabetic patients with same myocardial infarction, which may be in part due to diabetic inhibition of IPC- and Ipost-mediated protective mechanisms. Both IPC- and Ipost-mediated myocardial protection is predominantly mediated by stimulating PI3K/Akt and associated GSK-3ß pathway while diabetes-mediated pathogenic effects are found to be mediated by inhibiting PI3K/Akt and associated GSK-3ß pathway. Therefore, this review briefly introduced the general features of IPC- and Ipost-mediated myocardial protection and the general pathogenic effects of diabetes on the myocardium. We have collected experimental evidence that indicates the diabetic inhibition of IPC- and Ipost-mediated myocardial protection. Increasing evidence implies that diabetic inhibition of IPC- and Ipost-mediated myocardial protection may be mediated by inhibiting PI3K/Akt and associated GSK-3ß pathway. Therefore any strategy to activate PI3K/Akt and associated GSK-3ß pathway to release the diabetic inhibition of both IPC and Ipost-mediated myocardial protection may provide the protective effect against ischemia/reperfusion injuries.

[The prevention of reperfusion damages to the rat heart by preliminary short-term episodes of ischemia of different durations]. / Preduprezhdenie reperfuzionnykh povrezhdenii serdtsa krys s pomoshch'iu predvaritel'nykh kratkovremennykh épizodov ishemii razlichnoi dlitel'nosti.

Short ischemic episodes of 1 to 5 min duration in the rat isolated heart prevented the reperfusion-induced disturbances of the heart contractile function. 2-3-min ischemic episodes restricted development of arrhythmias and decreased electro-mechanical coupling processes.

Ischemic preconditioning during successive exercise testing.

It was suggested recently that ischemic preconditioning can occur in clinical practice. We investigated this hypothesis in 26 patients with old myocardial infarction (MI) or stable angina pectoris, subjected to two successive exercise testings at 1 hour interval. The ST depression was significantly lesser during the second exercise testing (1.83 +/- 0.12 mm, vs 1.02 +/- 0.14 mm p < 0.01) at the same double product (DP) (24.877 +/- 1206 vs 24.711 +/- 1152 p > 0.05) and peak effort (76.92 +/- 6.63 w vs 75.96 +/- 6.27 w p > 0.05). The improvement was attributed to ischemic preconditioning.

N-2-mercaptopropionylglycine, a scavanger of reactive oxygen species, does not modify the early antiarrhythmic effect of ischaemic preconditioning in anaesthetised dogs.

OBJECTIVE: The possible involvement of reactive oxygen species (ROS) in the protective effects of ischaemic preconditioning (PC) against arrhythmias was examined in anaesthetised dogs using the ROS scavenger N-2-mercaptopropionylglycine (MPG). METHODS: PC was induced in 20 chloralose-urethane anaesthetised dogs by two 5 min occlusions of the left anterior descending (LAD) coronary artery 20 min prior to the prolonged (25 min) ischaemia/reperfusion (I/R) insult. In 10 of these dogs MPG was infused locally into a small side branch of the LAD in a dose of 0.15 mg kg(-1) min(-1), starting 10 min prior to and continuing throughout the entire PC procedure. In another four dogs subjected to preconditioning in the absence and then 2h later in the presence of MPG free radical formation was evaluated by the chemiluminescence method. Eleven dogs, infused with saline and subjected to a 25 min I/R insult, served as controls. A further 9 dogs, which were not preconditioned, were given MPG over a period of 60 min prior to occlusion. RESULTS: Preconditioning markedly reduced the number of ventricular premature beats (VPBs; 86 +/- 34 v. 377 +/- 78; P < 0.05), the episodes of ventricular tachycardia (VT; 2.0 +/- 0.7 v. 13.6 +/- 4.5; P < 0.05) and the incidences of both VT (60% v. 91%) and ventricular fibrillation (0% v. 82%; P < 0.05) during the prolonged occlusion. Survival (from the combined ischaemia and reperfusion insult) was significantly increased (40% v. 0%; P < 0.05) by PC. MPG did not modify the protective effects of PC, although free radical (mostly superoxide) formation that occurred following PC was abrogated in the presence of MPG. Thus, the number of VPBs (111 +/- 39), VT episodes (1.2 +/- 0.9) and the incidences of VT (20%) and VF (0%) during occlusion were similar to the PC dogs. MPG itself did not significantly modify arrhythmia severity in non-PC dogs. CONCLUSIONS: We conclude that in our canine model of ischaemia/reperfusion the generation of ROS does not play a trigger role in the early PC-induced antiarrhythmic protection.