Remote ischemic preconditioning (RIPC) has emerged as an attractive strategy in clinical settings. Despite convincing evidence of the critical role played by circulating humoral mediators, their actual identities remain unknown. In this study, we aimed to identify RIPC-induced humoral mediators using a proteomic approach.
and Results Rats were exposed to 10-min limb ischemia followed by 5- (RIPC 5′) or 10-min (RIPC 10′) reperfusion prior to blood sampling. The control group only underwent blood sampling. Plasma samples were analyzed using surface-enhanced laser desorption and ionization - time of flight - mass spectrometry (SELDI-TOF-MS). Three protein peaks were selected for their significant increase in RIPC 10′. They were identified and confirmed as apolipoprotein A-I (ApoA-I). Additional rats were exposed to myocardial ischemia-reperfusion (I/R) and assigned to one of the following groups RIPC+myocardial infarction (MI) (10-min limb ischemia followed by 10-min reperfusion initiated 20 minutes prior to myocardial I/R), ApoA-I+MI (10 mg/kg ApoA-I injection 10 minutes before myocardial I/R), and MI (no further intervention). In comparison with untreated MI rats, RIPC reduced infarct size (52.2±3.7% in RIPC+MI vs. 64.9±2.6% in MI; p<0.05). Similarly, ApoA-I injection decreased infarct size (50.9±3.8%; p<0.05 vs. MI).
RIPC was associated with a plasmatic increase in ApoA-I. Furthermore, ApoA-I injection before myocardial I/R recapitulated the cardioprotection offered by RIPC in rats. This data suggests that ApoA-I may be a protective blood-borne factor involved in the RIPC mechanism.
Remote ischemic preconditioning (RIPC) is a phenomenon in which a short period of sub-lethal ischemia in one organ protects against subsequent bouts of ischemia in another organ. We hypothesized that RIPC in patients with intermittent claudication would increase muscle tissue resistance to ischemia, thereby resulting in an increased ability to walk.
In a claudication clinic, 52 ambulatory patients who presented with complaints of intermittent claudication in the lower limbs associated with an absent or reduced arterial pulse in the symptomatic limb and/or an ankle-brachial index <0.90 were recruited for this study. The patients were randomly divided into three groups (A, B and C). All of the patients underwent two tests on a treadmill according to the Gardener protocol. Group A was tested first without RIPC. Group A was subjected to RIPC prior to the second treadmill test. Group B was subjected to RIPC prior to the first treadmill test and then was subjected to a treadmill test without RIPC. In Group C (control group), both treadmill tests were performed without RIPC. The first and second tests were conducted seven days apart. Brazilian Clinical Trials: RBR-7TF6TM.
Group A showed a significant increase in the initial claudication distance in the second test compared to the first test.
RIPC increased the initial claudication distance in patients with intermittent claudication; however, RIPC did not affect the total walking distance of the patients.
Intermittent Claudication; Ischemic Preconditioning; Peripheral Arterial Disease
Novel treatment strategies are required to reduce the development of acute kidney injury (AKI) in patients undergoing cardiac surgery. In this respect, remote ischemic preconditioning (RIPC), a phenomenon in which transient nonlethal ischemia applied to an organ or tissue protects another organ or tissue from subsequent lethal ischemic injury, is a potential renoprotective strategy.
Secondary analysis of 2 randomized trials.
Setting & Participants
78 consenting selected nondiabetic patients in a university teaching hospital undergoing elective coronary artery bypass graft (CABG) surgery recruited to 2 previously reported randomized studies.
RIPC consisted of three 5-minute cycles of right forearm ischemia, induced by inflating a blood pressure cuff on the upper arm to 200 mm Hg, with an intervening 5 minutes of reperfusion, during which time the cuff was deflated. The control consisted of placing an uninflated cuff on the arm for 30 minutes.
AKI measured using Acute Kidney Injury Network (AKIN) criteria, duration of hospital stay, in-hospital and 30-day mortality.
Numbers of participants with AKI stages 1, 2, and 3 were 1 (3%), 3 (8%), and 0 in the intervention group compared with 10 (25%), 0, and 0 in the control group, respectively (P = 0.005). The decrease in AKI was independent of the effect of concomitant aortic valve replacement and cross-clamp times, which were distributed unevenly between the 2 groups.
Retrospective analysis of data. More patients in the RIPC group underwent concomitant aortic valve replacement with CABG; although we have corrected statistically for this imbalance, it remains an important confounding variable.
RIPC induced using transient forearm ischemia decreased the incidence of AKI in nondiabetic patients undergoing elective CABG surgery in this retrospective analysis. A large prospective clinical trial is required to study this effect and clinical outcomes in patients undergoing cardiac surgery.
Remote ischemic preconditioning; transient limb ischemia; coronary artery bypass graft surgery; acute kidney injury
Remote Ischemic Preconditioning (RIPC) induced by brief episodes of ischemia of the limb protects against multi-organ damage by ischemia-reperfusion (IR). Although it has been demonstrated that RIPC affects gene expression, the proteomic response to RIPC has not been determined. This study aimed to examine RIPC induced changes in the plasma proteome. Five healthy adult volunteers had 4 cycles of 5 min ischemia alternating with 5 min reperfusion of the forearm. Blood samples were taken from the ipsilateral arm prior to first ischaemia, immediately after each episode of ischemia as well as, at 15 min and 24 h after the last episode of ischemia. Plasma samples from five individuals were analysed using two complementary techniques. Individual samples were analysed using 2Dimensional Difference in gel electrophoresis (2D DIGE) and mass spectrometry (MS). Pooled samples for each of the time-points underwent trypsin digestion and peptides generated were analysed in triplicate using Liquid Chromatography and MS (LC-MS). Six proteins changed in response to RIPC using 2D DIGE analysis, while 48 proteins were found to be differentially regulated using LC-MS. The proteins of interest were involved in acute phase response signalling, and physiological molecular and cellular functions. The RIPC stimulus modifies the plasma protein content in blood taken from the ischemic arm in a cumulative fashion and evokes a proteomic response in peripheral blood.
Purpose of review
Ischemic preconditioning (IPC) is gaining attention as a novel neuroprotective therapy and could provide an improved mechanistic understanding of tolerance to cerebral ischemia. The purpose of this article is to review the recent work in the field of IPC and its applications to clinical scenarios.
The cellular signaling pathways that are activated following IPC are now better understood and have enabled investigators to identify several IPC mimetics. Most of these studies were performed in rodents, and efficacy of these mimetics remains to be evaluated in human patients. Additionally, remote ischemic preconditioning (RIPC) may have higher translational value than IPC. Repeated cycles of temporary ischemia in a remote organ can activate protective pathways in the target organ, including the heart and brain. Clinical trials are underway to test the efficacy of RIPC in protecting brain against subarachnoid hemorrhage.
IPC, RIPC, and IPC mimetics have the potential to be therapeutic in various clinical scenarios. Further understanding of IPC-induced neuroprotection pathways and utilization of clinically relevant animal models are necessary to increase the translational potential of IPC in the near future.
cerebral ischemia; neuroprotection; tolerance
Remote ischemic preconditioning (RIPC) induces a prolonged late phase of
multi-organ protection against ischemia-reperfusion (IR) injury. In the present
study, we tested the hypothesis that RIPC confers late protection against
myocardial IR injury by upregulating expression of interleukin (IL)-10. Mice
were exposed to lower limb RIPC or sham ischemia. After 24 h, mice with RIPC
demonstrated decreased myocardial infarct size and improved cardiac
contractility following 30-min ischemia and 120-min reperfusion (I-30/R-120).
These effects of RIPC were completely blocked by anti-IL-10 receptor antibodies.
In IL-10 knockout mice, RIPC cardioprotection was lost, but it was mimicked by
exogenous IL-10. Administration of IL-10 to isolated perfused hearts increased
phosphory-lation of the protein kinase Akt and limited infarct size after
I-30/R-120. In wild-type mice, RIPC increased plasma and cardiac IL-10 protein
levels and caused activation of Akt and endothelial nitric oxide synthase in the
heart at 24 h, which was also blocked by anti-IL-10 receptor antibodies. In the
gastrocnemius muscle, RIPC resulted in immediate inactivation of the phosphatase
PTEN and activation of Stat3, with increased IL-10 expression 24 h later.
Myocyte-specific PTEN inactivation led to increased Stat3 phosphorylation and
IL-10 protein expression in the gastrocnemius muscle. Taken together, these
results suggest that RIPC induces late protection against myocardial IR injury
by increasing expression of IL-10 in the remote muscle, followed by release of
IL-10 into the circulation, and activation of protective signaling pathways in
the heart. This study provides a scientific basis for the use of RIPC to confer
systemic protection against IR injury.
Remote ischemic preconditioning; Interleukin-10; Reperfusion injury; Phosphatase and tensin homologue deleted on chromosome ten; Stat3
Remote ischemic preconditioning (RIPC) can be induced by transient occlusion of blood flow to a limb with a blood pressure cuff and exerts multiorgan protection from ischemia/reperfusion injury. Ischemia/reperfusion injury in the intestinal tract leads to intestinal barrier dysfunction and can result in multiple organ failure. Here we used an intestinal cell line (CaCo-2) to evaluate the effects of RIPC-conditioned patient sera on hypoxia-induced cell damage in vitro and to identify serum factors that mediate RIPC effects. Patient sera (n = 10) derived before RIPC (T0), directly after RIPC (T1) and 1 h after RIPC (T2) were added to the culture medium at the onset of hypoxia until 48 h after hypoxia. Reverse transcription–polymerase chain reaction, lactate dehydrogenase (LDH) assays, caspase-3/7 assays, silver staining, gelatin zymography and Western blotting were performed. Hypoxia led to morphological signs of cell damage and increased the release of LDH in cultures containing sera T0 (P < 0.01) and T1 (P < 0.05), but not sera T2, which reduced the hypoxia-mediated LDH release compared with sera T0 (P < 0.05). Gelatin zymography revealed a significant reduction of activities of the matrixmetalloproteinase (MMP)-2 and MMP-9 in the protective sera T2 compared with the nonprotective sera T0 (MMP-2: P < 0.01; MMP-9: P < 0.05). Addition of human recombinant MMP-2 and MMP-9 to MMP-deficient culture media increased the sensitivity of CaCo-2 cells to hypoxia-induced cell damage (P < 0.05), but did not result in a reduced phosphorylation of prosurvival kinases p42/44 and protein kinase B (Akt) or increased activity of caspase-3/7. Our results suggest MMP-2 and MMP-9 as currently unknown humoral factors that may be involved in RIPC-mediated cytoprotection in the intestine.
AIM: To investigate the influence of remote ischemic preconditioning (RIPC) on anastomotic integrity.
METHODS: Sixty male Wistar rats were randomized to six groups. The control group (n = 10) had an end-to-end ileal anastomosis without RIPC. The preconditioned groups (n = 34) varied in time of ischemia and time of reperfusion. One group received the amino acid L-arginine before constructing the anastomosis (n = 9). On postoperative day 4, the rats were re-laparotomized, and bursting pressure, hydroxyproline concentration, intra-abdominal adhesions, and a histological score concerning the mucosal ischemic injury were collected. The data are given as median (range).
RESULTS: On postoperative day 4, median bursting pressure was 124 mmHg (60-146 mmHg) in the control group. The experimental groups did not show a statistically significant difference (P > 0.05). Regarding the hydroxyproline concentration, we did not find any significant variation in the experimental groups. We detected significantly less mucosal injury in the RIPC groups. Furthermore, we assessed more extensive intra-abdominal adhesions in the preconditioned groups than in the control group.
CONCLUSION: RIPC directly before performing small bowel anastomosis does not affect anastomotic stability in the early period, as seen in ischemic preconditioning.
Anastomotic healing; Hydroxyproline; Bursting pressure; Mucosal injury index; Wound healing; Remote ischemic preconditioning
A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether remote ischaemic preconditioning (RIPC) is of benefit to patients undergoing cardiac surgery. Altogether, more than 264 papers were found using the reported search, 16 of which represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. We conclude that RIPC is a safe protocol which could potentially be used in cardiac surgery to provide additional cardiac protection against ischaemia reperfusion injury, although it may not be appropriate for patients on K+ ATPase channel blockers (sulphonylureas) as they seem to eliminate the effect of RIPC. In our study, we found two meta-analyses of cardiac surgery with or without RIPC. Both unequivocally showed 0.81 and 0.74 standardized mean reduction in myocardial necrosis markers in patients receiving RIPC and cardiac or vascular surgery. No difference in perioperative myocardial infarction incidence or 30-day mortality were found. In adult cardiac surgery, we found 11 randomized control trials (RCTs) ranging in size from 45 to 162 patients. Two representative studies reported no difference in postoperative cardiac troponin I concentration in RIPC vs. controls. In one of the studies (CABG ± RIPC) no additional benefit could have been observed for RIPC regarding intra-aortic balloon pump usage (controls 8.5 vs. RIPC 7.5%), inotropic support (39 vs. 50%) or vasoconstrictor usage (66 vs. 64%). On the other hand, in the other study [CABG ± AVR (aortic valve replacement) ± RIPC] significant reduction of troponin I at 8 h postoperatively (controls, 2.90 µg/l vs. RIPC, 2.54 µg/l, P = 0.043) was shown. Marked reduction in cardiac necrosis markers was also found in several smaller RCTs concerning coronary artery bypass grafting (CABG) patients receiving RIPC preoperatively: with cold crystalloid cardioplegia (44.5% reduction), with cross-clamping and fibrillation (43% reduction) and with cold blood cardioplegia (42.4% reduction). The proof of concept trials summarized here give some early evidence that RIPC may potentially provide some reduction in myocardial injury. If confirmed, in future clinical studies this technique may one day lead to a method to reduce reperfusion injury in clinical practice.
Review; Myocardial protection; Remote ischaemic preconditioning
Protection of remote ischemic preconditioning on neurocognitive function caused by bilateral common carotid artery occlusion has been investigated in rats.
Thirty-six male Sprague-Dawley rats were divided into 3 groups – control group (Group C, n=12), bilateral carotid arteries occlusion group (Group B, n=12) and remote ischemic precondition group (Group P, n=12). In Group P, remote ischemic preconditioning (RIPC) was performed on the right femoral artery with 3 cycles (10 min) of occlusion/perfusion. After 3 cycles of preconditioning, bilateral carotid arteries were occluded immediately for 60 min. In Group B, ischemic insults were conducted without RIPC. Sham surgeries were performed in Group C. Evaluation of memory and learning capacity was performed on days 5–8 after surgery by Morris water maze testing of spatial learning capacity (n=6 for each group). Apoptosis of cells in the hippocampus region was determined by TUNEL tests and Bcl-2 at this region was determined by ELISA 24 h and 9 days after vessel occlusion (n=6 for each group).
Neurocognitive tests showed that latency time was significantly longer in Group B than in Group P on day 7 (p=0.016) and day 8 (p=0.036). Moreover, frequency of platform crossings was significant less in group B than in the other 2 groups on day 9. Bcl-2 level was significantly increased in the hippocampal region of rats in Group P on days 1 and 9 after vessel occlusion. TUNEL test showed that apoptosis could be observed at 24 h after occlusion in Group B, but not in Group P and Group C. No apoptosis was observed on day 9.
Our results suggest that RIPC can protect neurocognitive function of rats after bilateral carotid occlusions, and that Bcl-2 may play an important role in this protective effect.
remote ischemic preconditioning; neurocognition; water maze; Bcl-2
Remote ischaemic preconditioning (RIPC) gained attention as a possibility to reduce myocardial injury after a subsequent sustained episode of myocardial ischaemia. This prospective randomized study was carried out to assess whether RIPC reduces myocardial injury in coronary artery bypass grafting patients. Eighty patients were assigned to remote preconditioning or control treatment. Ischaemic preconditioning was induced by three 5-min cycles of upper limb ischaemia and reperfusion after anaesthesia induction. Haemodynamic and markers of myocardial damage were analysed preoperatively and over 48 h postoperatively. The cardiac index was higher immediately after remote preconditioning in the main group. There were no differences in other haemodynamic, troponin I and creatine kinase-MB concentrations at any time point between groups. Thus, short-term remote preconditioning improves haemodynamics and does not reduce myocardial injury after coronary artery bypass surgery. Further study of high-risk patients may be needed to fully evaluate the clinical effect of RIPC.
Remote ischaemic preconditioning; Myocardial protection; Troponin I; Coronary artery bypass grafting
Background: Hepatic ischemia and reperfusion injury (IRI) is a major complication in liver surgery, and hepatic steatosis is a primary factor aggravating cellular injury during IRI. Both pro-inflammatory cytokines and reactive oxygen species (ROS) are key mediators of hepatic IRI. Ischemic preconditioning (IpreC), remote ischemia preconditioning (RIPC) and ischemic postconditioning (IpostC) have offered protections on hepatic IRI, but all these methods have their own shortcomings. Grape seed proanthocyanidins (GSP) has a broad spectrum of pharmacological properties against oxidative stress. Thus, GSP has potential protective effects against hepatic IRI.
Methods: C57BL/6 mice suffering 30mins hepatic ischemia process were sacrificed after 1h reperfusion to build murine warm hepatic IRI model. The mice were injected GSP intraperitoneally 10, 20, 40mg/kg/day for 3 weeks as pharmacological preconditioning. Obese mice fed with high-fat diet for 24 weeks before used. Three pathways related to IRI, including ROS elimination, pro-inflammatory cytokines release and hypoxia responses were examined.
Results: Our data show that GSP could significantly reduce hepatic IRI by protecting hepatocyte function and increasing the activity of ROS scavengers, as well as decreasing cytokines levels. At the same time, GSP also enhance the hypoxia tolerance response. Combined GSP and postconditioning can provided synergistic protection. In the obese mice suffering hepatic IRI group, GSP was more effective than postconditioning on protecting liver against IRI, and the combined strategy was obviously superior to the solo treatment.
Conclusion: GSP could protect liver against IRI: particularly in high-fat diet induced obese mice. GSP used as pharmacological preconditioning and combined with other protocols have huge potential to be used in clinical.
Grape seed proanthocyanidins; postconditioning; preconditioning; ischemia; reperfusion injury.
Our previous randomized controlled trial demonstrated cardiorespiratory protection by remote ischemic preconditioning (RIPC) in children before cardiac surgery. However, the impact of RIPC on myocardial prosurvival intracellular signaling remains unknown in cyanosis. RIPC may augment phosphorylated protein signaling in myocardium and circulating leukocytes during tetralogy of Fallot (ToF) repair.
Methods and Results
Children (n=40) undergoing ToF repair were double‐blind randomized to RIPC (n=11 boys, 9 girls) or control (sham RIPC: n=9 boys, 11 girls). Blood samples were taken before, immediately after, and 24 hours after cardiopulmonary bypass. Resected right ventricular outflow tract muscle and leukocytes were processed for protein expression and mitochondrial respiration. There was no difference in age (7.1±3.4 versus 7.1±3.4 months), weight (7.7±1.8 versus 7.5±1.9 kg), or bypass or aortic cross‐clamp times between the groups (control versus RIPC, mean±SD). No differences were seen between the groups for an increase in the ratio of phosphorylated to total protein for protein kinase B, p38 mitogen activated protein kinase, signal transducer and activator of transcription 3, glycogen synthase kinase 3β, heat shock protein 27, Connexin43, or markers associated with promotion of necrosis (serum cardiac troponin I), apoptosis (Bax, Bcl‐2), and autophagy (Parkin, Beclin‐1, LC3B). A high proportion of total proteins were in phosphorylated form in control and RIPC myocardium. In leukocytes, mitochondrial respiration and assessed protein levels did not differ between groups.
In patients with cyanotic heart disease, a high proportion of proteins are in phosphorylated form. RIPC does not further enhance phosphorylated protein signaling in myocardium or circulating leukocytes in children undergoing ToF repair.
Clinical Trial Registration
URL: (http://www.anzctr.org.au/trial_view.aspx?id=335613. Unique identifier: Australian New Zealand Clinical Trials Registry number ACTRN12610000496011.
cyanosis; heart; mitochondria; pediatric surgery; remote ischemic preconditioning; tetralogy of Fallot
Background and Purpose
Making a limb transiently ischemic has been shown to induce ischemic tolerance in a distant organ. This phenomenon is known as remote ischemic limb preconditioning. We conducted a Phase IB study of remote ischemic limb preconditioning to determine the safety and feasibility of increasing durations of limb ischemia in patients with subarachnoid hemorrhage.
Patients with aneurysmal subarachnoid hemorrhage underwent limb preconditioning every 24 to 48 hours for 14 days. Limb preconditioning consisted of 3 5-minute inflations of a blood pressure cuff to 200 mm Hg around a limb followed by 5 minutes of reperfusion. In the lead-in phase, we preconditioned the upper extremities, but this proved impractical and we began preconditioning the leg in a similar manner. Ischemia times were then escalated to 7.5 and 10 minutes. After each session, a visual analog scale was obtained and the extremity examined for neurovascular complications.
A total of 33 patients completed the study. Mean age was 53±12 years and mean Hunt Hess score was 2.4±0.9. In the lead-in phase, an average of 7.7±2.4 preconditioning sessions was completed with mean visual analog scale 3.6±3.4. In the dose escalation phase, an average of 8.6±2.1 preconditioning sessions was done with mean visual analog scale 1.8±2.2 and 2.5±2.9 for the 7.5- and 10-minute cohorts, respectively. No session was prematurely terminated due to subject discomfort. No objective signs of neurovascular injury were observed.
We found limb preconditioning to be safe and well tolerated, even at ischemia times of 10 minutes, in critically ill patients with subarachnoid hemorrhage.
delayed cerebral ischemia; limb preconditioning; remote ischemic preconditioning
Remote ischemic preconditioning (RIPC) has been shown to enhance the tolerance of remote organs to cope with a subsequent ischemic event. We hypothesized that RIPC reduces postoperative neurocognitive dysfunction (POCD) in patients undergoing complex cardiac surgery.
We conducted a prospective, randomized, double-blind, controlled trial including 180 adult patients undergoing elective cardiac surgery with cardiopulmonary bypass. Patients were randomized either to RIPC or to control group. Primary endpoint was postoperative neurocognitive dysfunction 5–7 days after surgery assessed by a comprehensive test battery. Cognitive change was assumed if the preoperative to postoperative difference in 2 or more tasks assessing different cognitive domains exceeded more than one SD (1 SD criterion) or if the combined Z score was 1.96 or greater (Z score criterion).
According to 1 SD criterion, 52% of control and 46% of RIPC patients had cognitive deterioration 5–7 days after surgery (p = 0.753). The summarized Z score showed a trend to more cognitive decline in the control group (2.16±5.30) compared to the RIPC group (1.14±4.02; p = 0.228). Three months after surgery, incidence and severity of neurocognitive dysfunction did not differ between control and RIPC. RIPC tended to decrease postoperative troponin T release at both 12 hours [0.60 (0.19–1.94) µg/L vs. 0.48 (0.07–1.84) µg/L] and 24 hours after surgery [0.36 (0.14–1.89) µg/L vs. 0.26 (0.07–0.90) µg/L].
We failed to demonstrate efficacy of a RIPC protocol with respect to incidence and severity of POCD and secondary outcome variables in patients undergoing a wide range of cardiac surgery. Therefore, definitive large-scale multicenter trials are needed.
To investigate whether remote ischaemic preconditioning (RIPC) can attenuate the inflammatory response and enzyme leakage that can occur after uncomplicated routine percutaneous coronary intervention (PCI).
41 consecutive normotensive patients with stable angina and single‐vessel disease were assigned to be exposed to RIPC (n = 20) or not (control group; n = 21) before elective PCI with stent implantation. RIPC was induced by three cycles of 5‐min ischaemia–reperfusion of both upper limbs (inflation/deflation of blood pressure cuff). C reactive protein (CRP), creatine phosphokinase (CK), CK cardiac isoenzyme (CK‐MB) and troponin I (TNI) were serially measured for 48 h.
No difference in baseline values was observed between the groups. The CRP rose significantly (p<0.001) and at 48 h was similarly increased (>fourfold) in both groups (15.7 (2.6) v 14.0 (3.3) mg/l, RIPC v control; p = NS). However, sub‐group analysis on the basis of statin use showed that the highest rise was in the group of patients with RIPC not taking statins and was significantly greater than in patients with RIPC taking statins (23.8 (3.71) v 11.4 (3.0) mg/l, respectively, p<0.01). Both CK‐MB and TNI leakage were raised (slightly but significantly) after PCI in controls at 24 h compared with baseline values. However, this small rise was significantly worse after RIPC (CK‐MB, 1.33 (0.27) v 3.57 (0.97) ng/ml, p<0.01; TNI, 0.255 (0.059) v 0.804 (0.232) ng/ml, p<0.05, respectively at 24 h). The increase was more marked in the RIPC subgroup not taking statins.
RIPC does not reduce, but exacerbates, the enzyme and TNI release from the heart after single‐vessel angioplasty with stent. Furthermore, the increased circulating CRP remains raised. It seems that there is an enhanced inflammatory response after RIPC in the absence of statin treatment.
This study tests the hypothesis that local or remote ischemic preconditioning may protect the intestinal mucosa against ischemia and reperfusion injuries resulting from temporary supraceliac aortic clamping.
Twenty-eight Wistar rats were divided into four groups: the sham surgery group, the supraceliac aortic occlusion group, the local ischemic preconditioning prior to supraceliac aortic occlusion group, and the remote ischemic preconditioning prior to supraceliac aortic occlusion group. Tissue samples from the small bowel were used for quantitative morphometric analysis of mucosal injury, and blood samples were collected for laboratory analyses.
Supraceliac aortic occlusion decreased intestinal mucosal length by reducing villous height and elevated serum lactic dehydrogenase and lactate levels. Both local and remote ischemic preconditioning mitigated these histopathological and laboratory changes.
Both local and remote ischemic preconditioning protect intestinal mucosa against ischemia and reperfusion injury following supraceliac aortic clamping.
Aorta; Reperfusion; Ischemic Preconditioning; Intestinal Mucosa; Rats
To investigate the cardioprotective efficacy of remote ischaemic preconditioning (RIPC) in cardiac surgery.
We have performed a systematic search of MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials to identify randomized controlled trials involving RIPC.
Randomized controlled trials of RIPC in open cardiac surgery patients.
Main outcome measures
Meta-analysis was performed with the primary outcome the standardized mean difference between intervention and control groups in 12 hour postoperative troponin concentration. Heterogeneity was examined by fixed effects meta-regression.
Ten studies with a total of 693 participants were included in the meta-analysis. RIPC reduced troponin levels 12 hours after surgery compared with control. The fixed and random effects differences were 0.35 (95% CI 0.19 to 0.51) and 0.53 (95% CI 0.18-0.88) respectively. However, important heterogeneity was present. Fixed effects meta-regression partially accounted for heterogeneity based on whether studies had full blinding, comprising blinding of patients, surgeons, anaesthetists and investigators. Studies with incomplete or no blinding demonstrated a larger estimate of effect, 0.74 (95% CI 0.47 to 1.00) compared to those with full blinding, 0.13 (95% CI - 0.07 to 0.33).
Although our analysis suggests RIPC may result in cardiac protection during cardiac surgery, the effect was most marked in studies without full blinding, with a smaller and statistically non-significant effect in fully blinded studies. We propose that further double blind randomized controlled trials investigating the cardioprotective effects of RIPC in cardiac surgery are required to resolve the current clinical uncertainty.
The aim of our study was to investigate whether remote preconditioning (RPC) improves myocardial function after ischemia/reperfusion injury in both normal and hypertrophic isolated rat hearts. This is the first time in world literature that cardioprotection by RPC in hypertrophic myocardium is investigated.
Four groups of 7 male Wistar rats each, were used: Normal control, normal preconditioned, hypertrophic control and hypertrophic preconditioned groups. Moderate cardiac hypertrophy was induced by fludrocortisone acetate and salt administration for 30 days. Remote preconditioning of the rat heart was achieved by 20 minutes transient right hind limb ischemia and 10 minutes reperfusion of the anaesthetized animal. Isolated Langendorff-perfused animal hearts were then subjected to 30 minutes of global ischemia and reperfusion for 60 minutes. Contractile function and heart rhythm were monitored. Preconditioned groups were compared to control groups.
Left ventricular developed pressure (LVDP) and the product LVDP × heart rate (HR) were significantly higher in the hypertrophic preconditioned group than the hypertrophic control group while left ventricular end diastolic pressure (LVEDP) and severe arrhythmia episodes did not differ. Variances between the normal heart groups were not significantly different except for the values of the LVEDP in the beginning of reperfusion.
Remote preconditioning seems to protect myocardial contractile function in hypertrophic myocardium, while it has no beneficial effect in normal myocardium.
To test the hypothesis that remote ischaemic preconditioning (rIPC) reduces injury after cardiopulmonary bypass (CPB).
Randomised study with an experimental model of CPB (3 h CPB with 2 h of cardioplegic arrest). Twelve 15 kg pigs were randomly assigned to control or rIPC before CPB and followed up for 6 h.
rIPC was induced by four 5 min cycles of lower limb ischaemia before CPB.
Main outcome measures
Troponin I, glial protein S‐100B, lactate concentrations, load‐independent indices (conductance catheter) of systolic and diastolic function, and pulmonary resistance and compliance were measured before and for 6 h after CPB.
Troponin I increased after CPB in both groups but during reperfusion the rIPC group had lower concentrations than controls (mean area under the curve −57.3 (SEM 7.3) v 89.0 (11.6) ng·h/ml, p = 0.02). Lactate increased after CPB in both groups but during reperfusion the control group had significantly more prolonged hyperlactataemia (p = 0.04). S‐100B did not differ between groups. Indices of ventricular function did not differ. There was a tendency to improved lung compliance (p = 0.07), and pulmonary resistance changed less in the rIPC than in the control group during reperfusion (p = 0.02). Subsequently, peak inspiratory pressure was lower (p = 0.001).
rIPC significantly attenuated clinically relevant markers of myocardial and pulmonary injury after CPB. Transient limb ischaemia as an rIPC stimulus has potentially important clinical applications.
Ischemic preconditioning and some drugs can protect tissues from injury by preserving microcirculation. This study evaluated vascular permeability in a hamster cheek pouch preparation using either short ischemic periods or bradykinin as preconditioning stimuli followed by 30 min of ischemia/reperfusion.
Sixty-six male hamsters were divided into 11 groups: five combinations of different ischemic frequencies and durations (one, three or five shorts periods of ischemia, separated by one or five minutes) with 10 min intervals between the ischemic periods, followed by 30 min ischemia/reperfusion; three or five 1 min ischemic periods with 10 min intervals between them followed by the topical application of histamine (2 µM); bradykinin (400 nM) followed by 30 min of ischemia/reperfusion; and three control groups (30 min of ischemia/reperfusion or histamine or bradykinin by themselves). Macromolecular permeability was assessed by injection of fluorescein-labeled dextran (FITC-dextran, MW = 150 kDa; 250 mg/Kg body weight), and the number of leaks/cm2 was counted using an intravital microscope and fluorescent light in the cheek pouch.
Plasma leakage (number of leaks/cm2) was significantly reduced by preconditioning with three and five 1 min ischemic periods, one and three 5 min ischemic periods and by bradykinin. Histamine-induced macromolecular permeability was also reduced after three periods of 5 min of ischemia.
Short ischemic periods and bradykinin can function as preconditioning stimuli of the ischemia/reperfusion response in the hamster cheek pouch microcirculation. Short ischemic periods also reduced histamine-induced macromolecular permeability.
Ischemic Preconditioning; Bradykinin Preconditioning; Vascular Permeability; Microcirculation; Hamster Cheek Pouch
Although remote ischemic stimuli have been shown to elicit cardioprotection against ischemia/reperfusion injury, there is little known about the effects of nonischemic stimuli. We previously described a remote cardioprotective effect of nonischemic surgical trauma (abdominal incision) called remote preconditioning of trauma (RPCT). In the present study, we elucidate mechanisms underlying this phenomenon.
Methods and Results
We used a murine model of myocardial infarction to evaluate ischemia/reperfusion injury, and either abdominal surgical incision, or application of topical capsaicin, to elicit cardioprotection. We show that the cardioprotective effect of RPCT is initiated by skin nociception, and requires neurogenic signaling involving spinal nerves and activation of cardiac sensory and sympathetic nerves. Our results demonstrate bradykinin-dependent activation and repression, respectively, of PKCε and PKCδ in myocardium after RPCT, and we show involvement of the KATP channels in cardioprotection. Finally, we show that topical application of capsaicin, which selectively activates C sensory fibers in the skin, mimics the cardioprotective effect of RPCT against myocardial infarction.
Nontraumatic nociceptive preconditioning represents a novel therapeutic strategy for cardioprotection with great potential clinical utility.
apoptosis; capsaicin; infarction; nervous system; remote preconditioning; signal transduction; sympathetic
The present study was aimed to investigate the protective effects of different-time-ischemic preconditioning on the reperfusion injury in fatty livers in rats, and to elucidate the mechanisms underlying the protective effects and the optimal safe ischemic preconditioning time on the hepatic IR injury in steatotic livers.
A rat fatty liver model was established by high-fat diet feeding. We investigated the changes in the concentration of AST, ALT, LDH and NO in the serum, and of MDA, SOD, and MPO in the liver samples in response to different ischemic preconditioning times and ischemia-reperfusion injury. Histological analysis was performed to evaluate the results of the hepatic fatty infiltration. 1) At 24 h after 15 min ischemic preconditioning with 10 min reperfusion (15 min +10 min IP), the extent and area of the necrosis was markedly higher in the fatty liver samples with respect to IR, compared to the normal liver samples. 2) In response to the treatment of 5/8 min +10 min IP, the fatty liver group showed lower levels of serological indicators and liver MDA and MPO compared to the other groups, while the SOD activity of the fatty liver group was significantly higher than the other groups (p<0.05). Compared to the corresponding IR group, all IP groups showed a significantly higher serum NO concentration (p<0.05). Among the fatty liver groups, the 5/8 min+10 min IP group showed the highest NO concentration (p<0.05).
Fat infiltration could aggravate the ischemia-reperfusion injury in the rat liver. Furthermore, ischemic preconditioning could increase the tolerance of the fatty liver, which was induced by the high-fat diet, to hepatic ischemia-reperfusion injury in rats. The protocol of 5/8 min +10 min IP was the optimal regimen for the treatment of moderate and severe fatty livers.
Ischemia reperfusion injury is partly responsible for the high mortality associated with induced myocardial injury and the reduction in the full benefit of myocardial reperfusion. Remote ischemic preconditioning, perconditioning, and postconditioning have all been shown to be cardioprotective. However, it is still unknown which one is the most beneficial. To examine this issue, we used adult male Wistar rat ischemia reperfusion models to compare the cardioprotective effect of these three approaches applied on double-sided hind limbs.
The rats were randomly distributed to the following five groups: sham, ischemia reperfusion, remote preconditioning, remote perconditioning, and remote post-conditioning. The ischemia/reperfusion model was established by sternotomy followed by a 30-min ligation of the left coronary artery and a subsequent 3-h reperfusion. Remote conditioning was induced with three 5-min ischemia/5-min reperfusion cycles of the double-sided hind limbs using a tourniquet.
A lower early reperfusion arrhythmia score (1.50±0.97) was found in the rats treated with remote perconditioning compared to those in the ischemia reperfusion group (2.33±0.71). Meanwhile, reduced infarct size was also observed (15.27±5.19% in remote perconditioning, 14.53±3.45% in remote preconditioning, and 19.84±5.85% in remote post-conditioning vs. 34.47±7.13% in ischemia reperfusion, p<0.05), as well as higher expression levels of the apoptosis-relevant protein Bcl-2/Bax following global (ischemia/reperfusion) injury in in vivo rat heart models (1.255±0.053 in remote perconditioning, 1.463±0.290 in remote preconditioning, and 1.461±0.541 in remote post-conditioning vs. 1.003±0.159 in ischemia reperfusion, p<0.05).
Three remote conditioning strategies implemented with episodes of double-sided hind limb ischemia/reperfusion have similar therapeutic potential for cardiac ischemia/reperfusion injury, and remote perconditioning has a greater ability to prevent reperfusion arrhythmia.
Cardioprotective Property; Ischemia/Reperfusion Injury; Models
The present study has investigated the effectiveness of staged-preconditioning, in both remote and target organs. After IP the myocardial release of the biochemical markers including, creatine phosphokinase (CPK), cardiac creatine kinase (CK-MB), cardiac troponin T (cTnT) and lactate dehydrogenase (LDH) were evaluated in patients who underwent CABG, with and without staged-preconditioning. Sixty-one patients entered the study; there were 32 patients in the staged-preconditioning group and 29 patients in the control group. All patients underwent on-pump CABG using cardiopulmonary bypass (CPB) techniques. In the staged-preconditioning group, patients underwent two stages of IP on remote (upper limb) and target organs. Each stage of preconditioning was carried out by 3 cycles of ischemia and then reperfusion. Serum levels of biochemical markers were immediately measured postoperatively at 24, 48 and 72 h. Serum CK-MB, CPK and LDH levels were significantly lower in the staged-preconditioning group than in the control group. The CK-MB release in the staged-preconditioning patients reduced by 51% in comparison with controls over 72 h after CABG. These results suggest that myocardial injury was attenuated by the effect of three rounds of both remote and target organ IP.