Ischemic Preconditioning as a Myocardial Protection Strategy in CABG: Evidence from a Prospective Clinical Study

Ischemic preconditioning (IPC) is commonly regarded as having a powerful internal protective effect on the organs. The mechanism of IPC is not clear yet, and the controversy over the benefits and protocol of IPC still continues. In this study, we used the sensitive and specific biochemical marker: cardiac troponin-I (CTnI) to evaluate whether IPC as an adjunct to intermittent cold blood cardioplegia (CBC) could reduce myocardial injury, as opposed to simple CBC during coronary artery bypass grafting (CABG). From May 2003 to December 2003, 40 patients with three vessel coronary artery disease (CAD) and stable angina, receiving first-time elective CABG, were randomly divided into two equal groups: IPC plus CBC (IPC + CBC group, n = 20); and CBC (CBC group, n = 20). The patients in IPC + CBC group received two cycles of ischemia (two min) and reperfusion (three min) before myocardial arrest induced by CBC. The patients in CBC group received 10-minute normothermic cardiopulmonary bypass (CPB) before CBC arrest. Clinical outcomes were observed during and after the operation. Serial venous blood samples were obtained before induction, after CPB, and postoperatively 6, 12, 24, and 72 hours. Hemodynamic indexes were obtained before and after the bypass by the radial catheter and Swan-Ganz catheter. In both groups, there were no differences regarding operative parameters. Compared to the baseline, the level of CTnI increased after CPB, peaked 6-12 hours (p < 0.01). Compared to IPC + CBC group, plasma concentrations of CTnI in CBC group were significantly higher at 6 and 12 hours (p < 0.05). CI recovery in IPC + CBC group was more significant than CBC group at 12 and 24 hours (p < 0.05). IPC + CBC also shortened the time of postoperative mechanical ventilation (p < 0.05) after surgery. Compared to the simple CBC in lower-risk CABG patients, IPC as an adjunct to CBC reduced CTnI release, improved heart function after surgery, and shortened the time of recovery in CAD patients.

Effect of Ischemic Preconditioning on Myocardial Protection in Coronary Artery Bypass Graft Patients: Can the Free Radicals Act as a Trigger for Ischemic Preconditioning?

Coronary artery bypass grafting (CABG) for unstable angina pectoris patients results in a higher incidence of arrhythmia and higher arrhythmic cardiac mortality. Ischemic preconditioning (IP) has proved effective in suppressing ischemia reperfusion arrhythmias in animals and in humans. The purpose of the present study was to investigate whether IP protects against postoperative arrhythmias in recent unstable angina patients undergoing urgent CABG. Forty-one patients with recent unstable angina and three-vessel coronary artery disease admitted for CABG were randomized into an IP group and a control group. The IP protocol involved twice occluding the ascending aorta with a cross-clamp for 2 minutes, followed by 3 minutes of reperfusion. Twenty-four-hour continuous electrocardiography (24-h ECG) was recorded from the preoperative day to the 2nd postoperative day. The incidences of supraventricular extrasystole (SVES), ventricular extrasystole (VES), supraventricular tachycardia (SVT), and ventricular tachycardia (VT) were 95.2%, 85.7%, 26.2%, and 26.2%, respectively, before surgery and 100.0%, 100.0%, 88.1%, and 76.2%, respectively, after surgery. IP significantly reduced the incidence of VT and the severity of SVES, VES, SVT, and VT after surgery. The period of mechanical ventilation and the length of stay in the intensive care unit were significantly shorter in the IP group. In summary, rhythm disturbances are common in CABG patients with recent unstable angina. IP significantly reduces rhythm disturbances, including SVES, VES, SVT, and VT after CABG. The findings indicate that IP could constitute an additional myocardial protective strategy in recently unstable angina patients undergoing CABG.

Protection of the human heart with ischemic preconditioning during cardiac surgery: role of cardiopulmonary bypass

Objective: Paraplegia is a serious complication of thoracic and thoracoabdominal aortic operations and is the result of ischemic spinal cord injury induced by low perfusion pressure during cross-clamping of the aorta. Ischemic preconditioning (IPC) of the heart or brain with reversible sublethal ischemic injury induces resistance to subsequent lethal ischemia. The aim of this study is to investigate whether ischemic tolerance can be induced by IPC of the spinal cord in a swine model. Study Design: The animals were randomly divided into three groups: the sham group (n = 3), control group (n = 6) and IPC group (n = 8). In the sham group, we performed a left thoracotomy without any ischemic injury. In the IPC group, the swine received a reversible ischemic spinal cord injury by aortic clamping for 20 min, whereas in the control group, no aortic cross-clamping was performed. Forty-eight hours later, the animals in both the IPC and control groups underwent aortic clamping for 30 min. Neurological examination was done 24 h later, and then the animals were euthanized for histopathology and a malonedialdehyde spectrophotometry assay of the spinal cord tissue. Results: A statistically significant difference in neurological outcome was observed between the control and IPC groups at 24 h after ischemic injury. The incidence of paraplegia and severe paresis was 100% in the control group and 62.5% in the IPC group (p =. 028). Between control and IPC groups, there was no statistically significant difference in histopathology and only a borderline statistical difference in the malonedialdehyde assay of the ischemic spinal cord (p =. 0745). Conclusion: In this study, IPC induced protection against a 30-min ischemic insult of the spinal cord, although complete recovery was not achieved (standing up or walking). We expect that combining this IPC with other existing protective methods might lead to a synergistic effect, which warrants further investigation.

Encouraging results on myocardial preconditioning in experimental models of infarction, stunning or prolonged ischemia raise the question whether preconditioning techniques may enhance conventional cardioplegic protection used for routine coronary surgery. A prospective clinical trial was conducted to investigate the effect of additional ischemic normothermic preconditioning prior to cardioplegic arrest applying cold blood cardioplegia in patients scheduled for routine coronary surgery (3 vessel disease, left ventricular ejection fraction > 50%). Two cross clamp periods of 5 min with the hearts beating in sinus rhythm were applied followed by 10 min of reperfusion, each (n = 7, group I). Inducing moderate hypothermia cold blood cardioplegia was delivered antegradely. In control groups, cold intermittent blood cardioplegia (n = 7, group II) was used alone. Coronary sinus effluents were analyzed for release of creatine kinase (CK), CK-MB, lactate, and troponin T at 1, 3, 6, 9, and 12 h. In addition, postoperative catecholamine requirements were monitored. The procedure was tolerated well, and no perioperative myocardial infarction in any of the groups studied occurred. Concentrations of lactate tended to be higher in group I, but this difference was not significant. In addition, no significant differences for concentrations of CK, CK-MB, and troponin T were found. Following ischemic preconditioning an increased dosage of dopamine was required within the first 12 h postoperatively (group I: 2.63 +/- 1.44 microg/kg/min, group II: 0.89 +/- 1.06 microg/kg/min). Combining ischemic preconditioning and cardioplegic protection with cold blood cardioplegia does not appear to ameliorate myocardial protection when compared to cardioplegic protection applying cold blood cardioplegia alone. Inversely, contractile function seemed to be impaired when applying this protocol of ischemic preconditioning.

Objective To evaluate the effect of ischemic preconditioning(IPC) on early postoperative pain in patients undergoing total knee arthroplasty. Methods A prospective randomized controlled trial of 40 patients undergoing elective total knee arthroplasty was performed in the First Affiliated Hospital of Anhui Medical University from October 2015 to April 2016.Patients (18-65 years old) with ASA grade Ⅰ-Ⅲ(American Society of Anesthesiologists), were randomly divided into control group and ischemic preconditioning(IPC) group, 20 patients in each group. In the IPC group, ischemic preconditioning was performed before the operation of completely blood block to the lower limbs of the operation side, the tourniquet was inflated for 5 min and deflated for 5 min, for a total of 2 cycles. In the control group, only the tourniquet was attached without inflation or deflation before the surgery completely blocked the lower limb blood supply. The basic information of the general clinical data, tourniquet block time and operation time of the two groups were recorded and compared. The mean arterial pressure (MAP), heart rate (HR) and oxygen saturation (SpO2) were measured before surgery, 30 minutes after the upper tourniquet, and at the end of the operation. Resting pain scores (VAS) were recorded at recovery time, 6 h after surgery, and 24 h after surgery. The number of pain remedies within 24 hours after surgery was recorded. Venous blood was collected 24 hours after surgery to detect the levels of creatine kinase(CK) and interleukin-6 (IL-6) in the blood. Results There were no significant differences in the general clinical data, tourniquet blockade time, and operation time between the two groups (P>0.05). There were no significant differences in MAP, HR and SpO2 between two groups at each time point (P>0.05). The VAS score (3.10±1.02) point in the IPC group was significantly lower than that in the control group (5.45±0.99) point (t=7.394, P 0.05). The number of pain remedies in the IPC group, was significantly lower than that in the control group at 24 hours after surgery (χ2=4.803, P 0.05). The serum IL-6 level was significantly lower in the IPC group(50.11±20.39) pg/mL than in the control group (70.80±34.82) pg/mL (t=6.628, P<0.05). Conclusions Ischemic preconditioning attenuates early postoperative pain and reduces the number of pain relief patients in total knee arthroplasty. The mechanism may be related to the reduction of inflammatory response by ischemic preconditioning. Key words: Reperfusion injury; Ischemic preconditioning; Interleukin-6; Arthroplasty, replacement, knee; Pain

Objectives — Pretreatment with diazoxide, a mitochondrial ATP-sensitive potassium channel (mito KATP) opener, was found to protect the rat heart against ischaemia-reperfusion (I/R) injury by mimicking ischaemic preconditioning (IPC). However, the protection mechanisms have not been fully clarified yet. We hypothesize that molecular regulation of mitochondrial energetics is integral to this cardioprotective programme. We explored the involvement of peroxisome proliferator-activated receptor g coactivator-1-1α (PGC-1α) in the effect of IPC and diazoxide preconditioning (DPC) with regard to its role in protection against I/R injury.Methods — 30 Wistar rats were used to establish the Langendorff isolated perfused heart model. Rats were randomly divided into 5 groups, 6 in each group: (1) the I/R group: after 30 min of equilibration perfusion, the heart was subjected to 30 min of ischaemia and 1h of reperfusion; (2) the IPC group: after 10 min of equilibration perfusion, the heart was subjected to two times 5 min ischaemia and 5 min of reperfusion, followed by 30 min of ischaemia and 1h of reperfusion; (3) the DPC group: after 10 min of equilibration perfusion, the heart was given two times a K-H perfusion solution containing diazoxide (100 mmol/l) for 5 min then a non-diazoxide K-H perfusion solution for 5 min, followed by 30 min of ischaemia and 1h of reperfusion; (4) a blank control group: an equal amount of saline was used instead of diazoxide. The perfusion procedure was the same as in the DPC group; (5) the dimethyl sulfoxide (DMSO) group: DMSO was applied instead of diazoxide, and the perfusion procedure was the same as in the DPC group. Cardiac apex muscle was cut for frozen section. Immunohistochemistry staining of PGC-1α was performed and average absorbance was calculated. An electron microscope was used for Flameng scoring of the myocardial mitochondria.Results — The average absorbance values of PGC-1α were: I/R group (3.88 ± 1.72), IPC group (10.94 ± 5.23), DPC group (8.40 ± 3.64), blank control group (3.55 ± 1.56) and DMSO group (4.16 ± 0.52), respectively. The expression of PGC-1α was significantly increased in the IPC and DPC groups and the differences were statistically significant compared to the I/R, blank control and DMSO groups, i.e., P < 0.01 for IPC group and P < 0.05 for DPC group. However, there was no significant difference between the IPC and DPC groups (P > 0.05). Flameng score: IPC group (0.44 ± 0.13), DPC group (0.47 ± 0.10), I/R group (1.78 ± 0.14), blank control group (1.70 ± 0.03) and DMSO group (1.68 ± 0.06). The Flameng score of the IPC and DPC groups was statistically significantly different as compared to the I/R group, blank control group and DMSO group (P < 0.01), but no significant difference was detected between the IPC and DPC groups (P > 0.05).Conclusion — IPC and DPC have a protective effect on myocardial mitochondria, and their mechanism of action may be related to activation and over-expression of PGC-1α.

Sudden cardiac death caused by arrhythmia remains a major unsolved problem after coronary artery bypass grafting (CABG). Ischemic preconditioning (IP) has proved effective in suppressing ischemia reperfusion arrhythmias in animals and humans. The purpose of the present study was to establish whether IP reduces postoperative arrhythmias in three-vessel coronary artery disease patients undergoing CABG. Forty-five patients with stable angina and three main coronary artery stenosis admitted for primary CABG surgery were randomized into an IP and a control group. The IP protocol entailed twice occluding the ascending aorta by cross-clamping for 2 min, followed by 3 min of reperfusion. Electrocardiography was continuously recorded from the day before surgery to the second postoperative day. During the recording, all patients developed SVES and VES after the operation. The incidences of SVT and ventricular tachycardia (VT) after surgery were 73.3 and 77.8%, respectively. IP significantly reduced VES events per hour during 2h after reperfusion. The SVT and VT incidence and events per hour were significantly lower in the IP group during 2h after reperfusion and 24h later. IP significantly reduced VES, SVT, and VT after surgery. The antiarrhythmic effect 24h after surgery indicates a delayed antiarrhythmic IP phenomenon in these patients. These findings would indicate that IP constitutes a potential additional myocardial protective strategy in multi-vessel diseased patients undergoing CABG.

Regional Ischemic Preconditioning Enhances Myocardial Performance in Off-Pump Coronary Artery Bypass Grafting

Off-pump coronary artery bypass grafting (CABG) has become a popular procedure. However, temporary occlusion of the target vessel is sometimes a threat to the patients. Although ischemic preconditioning (IP) has been proposed to reduce myocardial injury, its effects remain controversial. The coronary veins represent an alternate route for delivery of therapeutic agents and arterial blood to the acutely ischemic myocardium. The aim of this study was to investigate the protective effect against myocardial ischemia and reperfusion injury of combined IP and synchronized coronary venous retroperfusion (SCVR) in an off-pump CABG model. Twenty-one pigs were assigned to 3 groups of 7 animals. In the control group, the left anterior descending coronary artery (LAD) was occluded for 45 min followed by 2 h of reperfusion using a left intrathoracic artery (LITA) bypass circuit. In the IP group, LAD occlusion was done for 5 min with 15 min of reperfusion, followed by 45 min of LAD occlusion. In the SCVR group, pretreatment before LAD occlusion was the same as in the IP group. Then, SCVR was commenced just after the start of LAD occlusion for 45 min. The percent systolic shortening of ischemic myocardium (measured by sonomicrometry) after reperfusion via the LITA was significantly (p < 0.001) greater in the SCVR group (14.6 +/- 3.3%) than in the control group (-1.6 +/- 5.6%, 95%CI: -24.3 - -8.1) or the IP group (0.7 +/- 8.0%, 95%CI: -22.0 - -5.8) after 30 min of reperfusion, and this difference persisted throughout the reperfusion period. Infarct size (expressed as a percentage of the area at risk) was significantly (p < 0.001) smaller in the SCVR group (2.4 +/- 2.7%) than in the control group (83.0 +/- 2.3%, 95%CI: -99.0 - -62.4) or the IP group (42.0 +/- 23.0%, 95%CI: -58.0 - -21.3). Combined SCVR and IP had a potent myocardial protective effect in the present off-pump CABG model. This method may be clinically feasible and may be able to prolong a safe coronary occlusion.

The hypothesis that sarcolemmal Na+/H+ exchanger activity may contribute to myocardial injury during ischemia and reperfusion was first published in 1985,1 preceding by 1 year the first description of the ischemic preconditioning phenomenon.2 Initial pharmacological evidence in support of the Na+/H+ exchanger hypothesis was subsequently provided by Karmazyn,3 who showed that amiloride (an inhibitor of the exchanger) enhanced the postischemic recovery of contractile function and reduced creatine kinase leakage in rat hearts subjected to global ischemia and reperfusion. Since then, a number of Na+/H+ exchange inhibitors, including highly specific novel inhibitors such as HOE-694, HOE-642 (cariporide), and EMD-85131, have been shown to afford cardioprotective benefit in a variety of animal models of ischemia and reperfusion.4 Nevertheless, as an innovative approach to the protection of ischemic myocardium, Na+/H+ exchange inhibition has failed to capture the imagination of cardiologists (experimental and clinical alike) to quite the same extent as ischemic preconditioning. Indeed, a survey of articles published in Circulation and Circulation Research over the past decade reveals only 14 articles whose title or abstract contains the keywords “Na+/H+ exchange(r) and ischemia,” whereas 115 articles are identified when the combination “preconditioning and ischemia” is used. Is this a fair reflection of the relative cardioprotective efficacy, and perhaps the therapeutic potential, of these interventions? In this issue of Circulation , Gumina and colleagues5 report on a comparison of the efficacy of Na+/H+ exchange inhibition (achieved with BIIB-513, the latest addition to the family of novel Na+/H+ exchange inhibitors) versus ischemic preconditioning in limiting infarct size in dog hearts subjected to regional ischemia and reperfusion in vivo. This is the first such comparison in a large animal, and the …

This study investigated the cardioprotective effects of pharmacologic pretreatment with HOE642, a selective Na(+)/H(+ )exchanger (NHE) isoform-1 inhibitor, in immature rabbit hearts, as compared with ischemic preconditioning (IPC). For this study, 36 isolated immature New Zealand white rabbit hearts were equilibrated on the Langendorff apparatus. They were randomly divided into three groups: control group, IPC group, and HOE642 group. The hearts in each group were subjected to 60 min of ischemia plus 60 min of reperfusion (I/R). In the IPC group, the hearts were preconditioned by 5 min of ischemia followed by 10 min of reperfusion before I/R. In the HOE642 group, the hearts were pretreated with HOE642 (5 mumol/l) for 15 min before I/R. Left ventricular performance (LVDP, +dp/dt(max), -dp/dt(max)), coronory artery flow (CF), myocardial water content, adenosine triphosphate (ATP), cardiac-specific enzymes (creatine kinase [CK], CK fraction MB [CK-MB], and lacate dehydrogenase [LDH]), and intracellular calcium content were measured. Myocardial ultrastructure was observed under transmission electron microscopy. The recovery rates for left ventricular performance and CF in both the HOE642 and the IPC groups increased compared with those for the control subjects (p < 0.05). Moreover, the recovery rates for LVDP, +dp/dt(max), -dp/dt(max), and CF in the HOE642 group were markedly higher than in the IPC group at most time points of reperfusion (p < 0.05). Compared with the control group, CK, CK-MB, and LDH in the HOE642 group were decreased significantly (p < 0.05), whereas only LDH was reduced in the IPC group (p < 0.05). Water content was significantly reduced and ATP reserve was significantly increased in both the IPC and HOE642 groups (p < 0.05). However, compared with the IPC group, water content in the HOE642 group was significantly lower (81.26% +/- 1.26% vs 83.58% +/- 1.27%; p < 0.05) and ATP was significantly higher (21.46 +/- 2.40 vs 17.66 +/- 1.50 mug/g; p < 0.05). The HOE642 pretreatment exerted a better effect of reducing calcium overload than IPC (265.8 +/- 41.1 vs 408.5 +/- 56.8 mg/kg dry weight; p < 0.05). The blinded ultrastructural assessment under transmission electron microscopy showed that HOE642 brought about more myocyte salvage than IPC. This study demonstrated that HOE642 pretreatment is superior to IPC against ischemia and reperfusion injury in isolated immature rabbit myocardium.

Fibrillation in patients subjected to coronary artery bypass grafting

532 Postoperative atrial fibrillation increases long-term mortality in older patients undergoing CABG surgery