Remote Ischaemia Research Articles

NGAL in the Development of Acute Kidney Injury in a Murine Model of Remote Ischaemic Preconditioning and Liver Ischaemia Reperfusion.

Acute kidney injury (AKI) is common following liver transplantation and is associated with liver ischeamia reperfusion (IR) injury. The purpose of this study was to use a mouse model of liver IR injury and AKI to study the role of Neutrophil Gelatinase Associated Lipocalin (NGAL), a biomarker of AKI, in liver IR injury and AKI. We demonstrate an adapted, reproducible model of liver IR injury and AKI in which remote ischemic preconditioning (RIPC) by repeated episodes of hindleg ischemia prior to liver IR reduced the severity of the IR injury. In this model, serum NGAL at 2 h post reperfusion correlated with AKI development early following IR injury. This early rise in serum NGAL was associated with hepatic but not renal upregulation of NGAL mRNA, suggesting NGAL production in the liver but not the kidney in the early phase post liver IR injury.

Remote limb ischaemic conditioning produces cardioprotection in rats with testicular ischaemia-reperfusion injury.

What is the central question of this study? Can remote limb ischaemic conditioning produce cardioprotection in rats with testicular ischaemia-reperfusion injury? What is the main finding and its importance? Testicular ischaemia-reperfusion (TI/R)-injured rats were predisposed to myocardial reperfusion-induced atrioventricular block. Remote limb ischaemia preconditioning and postconditioning protected TI/R hearts against ischaemia-provoked ventricular arrhythmia and ultimately reduced the incidence of sudden cardiac death, with a possible role of c-Jun N-terminal kinase inhibition and connexin 43 activation. Remote ischaemic conditioning can protect hearts against arrhythmia. Testicularischaemia-reperfusion (TI/R) injury is associated with electrocardiographic abnormalities. We investigated the effect of remote limb ischaemia preconditioning (RIPre) and postconditioning (RIPost) on arrhythmogenesis in TI/R rats, and determined the potential role of c-Jun N-terminal kinase (JNK)/connexin 43 (Cx43) signalling. Rats were randomized to sham-operated, control, TI/R, RIPre and RIPost groups. TI/R rats were more predisposed to myocardial reperfusion-induced atrioventricular block (AVB). RIPre and RIPost reduced the incidence of sudden cardiac death (SCD) or AVB, and duration of ventricular tachyarrhythmias during myocardial reperfusion. RIPre and RIPost decreased myocardial I/R-induced phosphorylation level of JNK, while preserving myocardial Cx43 expression in TI/R rats. Taken together, TI/R rats were predisposed to myocardial reperfusion-induced AVB. RIPre and RIPost protected TI/R hearts against ischaemia-provoked ventricular arrhythmia and ultimately reduced the incidence of SCD by suppressing JNK activation and restoring Cx43 expression.

Not All Patients with Hemiplegia Need Alteplase: A Case of Hemiplegic Migraine.

Hemiplegic migraine (HM) is a rare type of migraine which presents with motor and sensory impairment like a cerebrovascular accident (CVA). We present a case of a 36-year-old female, with a prior CVA treated with alteplase, who presented to the emergency department with stroke-like symptoms with a duration of 1 hour. The NIH Stroke Scale score was 22 at presentation. The patient received alteplase under the supervision of a neurologist after head CT confirmed no bleed. Further work-up revealed no acute or remote ischaemia or infarction. This case demonstrates the importance of a thorough history, intercommunication between health systems and integrated Electronic Medical Records (EMR) for early diagnosis and management of HM.LEARNING POINTSHemiplegic migraine (HM) is difficult to diagnose and can mimic stroke, resulting in administration of dangerous medications such as thrombolytics/alteplase.A thorough history, intercommunication between health systems and integrated EMR are essential for early diagnosis and management of HM.

P3662The use of stress perfusion cardiovascular magnetic resonance imaging and fractional flow reserve in the assessment of remote artery ischaemia in patients with a chronic total occlusion

P3662The use of stress perfusion cardiovascular magnetic resonance imaging and fractional flow reserve in the assessment of remote artery ischaemia in patients with a chronic total occlusion

Remote vs. local ischaemic preconditioning in the rat heart: infarct limitation, suppression of ischaemic arrhythmia and the role of reactive oxygen species

The unmet clinical need for myocardial salvage during ischaemia-reperfusion injury requires the development of new techniques for myocardial protection. In this study the protective effect of different local ischaemic preconditioning (LIPC) and remote ischaemic preconditioning (RIPC) protocols was compared in the rat model of myocardial ischaemia-reperfusion, using infarct size and ischaemic tachyarrhythmias as end-points. In addition, the hypothesis that there is involvement of reactive oxygen species (ROS) in the protective signalling by RIPC was tested, again in comparison with LIPC. The animals were subjected to 30-min coronary occlusion and 90-min reperfusion. RIPC protocol included either transient infrarenal aortic occlusion (for 5, 15 and 30 min followed by 15-min reperfusion) or 15-min mesenteric artery occlusion with 15-min reperfusion. Ventricular tachyarrhythmias during test ischaemia were quantified according to Lambeth Conventions. It was found that the infarct-limiting effect of RIPC critically depends on the duration of a single episode of remote ischaemia, which fails to protect the heart from infarction when it is too short or, instead, too prolonged. It was also shown that RIPC is ineffective in reducing the incidence and severity of ischaemia-induced ventricular tachyarrhythmias. According to our data, the infarct-limiting effect of LIPC could be partially eliminated by the administration of ROS scavenger N-2-mercaptopropionylglycine (90 mg/kg), whereas the same effect of RIPC seems to be independent of ROS signalling.

Adaptive response to hypoxia and remote ischaemia pre-conditioning: a new hypoxia-inducible factors era in clinical medicine.

Transient ischaemia leads to tolerance to subsequent protracted ischaemia. This 'ischaemia pre-conditioning' results from the induction of numerous protective genes, involved in cell metabolism, proliferation and survival, in antioxidant capacity, angiogenesis, vascular tone and erythropoiesis. Hypoxia-inducible factors (HIF) play a pivotal role in this transcriptional adaptive response. HIF prolyl hydroxylases (PHDs), serving as oxygen sensors, control HIFα degradation. HIF-mediated ischaemic pre-conditioning can be achieved with the administration of PHD inhibitors, with the attenuation of organ injury under various hypoxic and toxic insults. Clinical trials are currently under way, evaluating PHD inhibitors as inducers of erythropoietin. Once their safety is established, their potential use might be further tested in clinical trials in various forms of acute ischaemic and toxic organ damage. Repeated transient limb ischaemia was also found to attenuate ischaemic injury in remote organs. This 'remote ischaemic pre-conditioning' phenomenon (RIP) has been extensively studied recently in small clinical trials, preceding, or in parallel with an abrupt insult, such as myocardial infarction, cardiac surgery or radiocontrast administration. Initial results are promising, suggesting organ protection. Large-scale multi-centre studies are currently under way, evaluating the protective potential of RIP in cardiac surgery, in the management of myocardial infarction and in organ transplantation. The mechanisms of organ protection provided by RIP are poorly understood, but HIF seemingly play a role as well. Thus, Inhibition of HIF degradation with PHD inhibitors, as well as RIP (in part through HIF), might develop into novel clinical interventions in organ protection in the near future.

Upper arm intermittent ischaemia reduces exercise-related increase of platelet reactivity in patients with obstructive coronary artery disease

ObjectiveTo assess whether upper arm ischaemia influences exercise-induced myocardial ischaemia and platelet activation in patients with coronary artery disease (CAD).DesignCrossover study.SettingUniversity hospital.PatientsTwenty patients (17 men) of mean±SD age 64±8 years...

118 High-resolution cardiac magnetic resonance perfusion imaging vs positron emission tomography for the detection and localisation of coronary artery disease

Background Non-invasive imaging has a key role in the detection of coronary artery disease (CAD). Its importance has been affirmed by recent National Institute of Clinical Excellence (NICE) guidelines. Localisation of ischaemia to a coronary territory is also important in patient management. Cardiac Magnetic Resonance (CMR) perfusion imaging is a well-established and radiation-free test for these purposes. However, there are few data comparing perfusion CMR with Positron Emission Tomography (PET), which is widely regarded as the non-invasive gold standard. Furthermore novel CMR methods, including those based on k-t acceleration techniques, allow myocardial perfusion imaging with unprecedented spatial resolution. Methods 31 patients with known or suspected CAD referred for diagnostic x-ray coronary angiography (XCA) underwent both CMR and PET examinations. Both PET and CMR protocols included adenosine stress and rest perfusion imaging. CMR perfusion imaging was performed at 1.5T with a k-t -accelerated steady-state free-precession sequence. PET imaging was performed with 13 N-Ammonia. The Abstract 118 figure 1 shows an example. Experts blinded to the clinical data analysed the imaging data and experts blinded to the imaging results visually analysed the XCA data. A significant coronary artery stenosis was defined as ≥70% reduction in diameter or a fractional flow reserve Results Patient characteristics are shown in the Abstract 118 table 1. Mean age ± SD was 64±9 years. One CMR examination was non-diagnostic. The interval between PET and CMR was 2±6 days (77% same day), between PET and XCA 22±28 days and between CMR and XCA 22±29 days. The prevalence of CAD was 81%. For the detection of CAD PET sensitivity was 80% (95% CI 59% to 92%) and specificity was 67% (24% to 94%). CMR sensitivity was 83% (95% CI 62 to 95%) and specificity was also 83% (36% to 99%). In patients with CAD ischaemia was localised to 63% of the territories supplied by stenotic arteries by PET and 76% by CMR. Remote ischaemia was detected in 24% of territories by PET and 16% by CMR. Conclusions CMR is at least as accurate as PET for the diagnosis of CAD and also for the localisation of ischaemia to coronary territories. Relatively low numbers mean that CIs are wide and further work is required. Using an anatomic test as the reference-standard for functional tests has well-described limitations. Remote ischaemia is likely to occur for several reasons including underestimation of disease severity at XCA, microvascular disease and also false positive results.

Combined morphine and limb remote ischaemia postconditioning may produce an enhanced cardioprotection

The limb remote ischaemia postconditioning (RIPOC), a newly conceived idea of applying brief limb ischaemic stimulus after onset of the myocardial ischaemia but prior to the reperfusion, can offer the possibility of applying this cardioprotective strategy to the patients with acute myocardial infraction. Although increasing numbers of circles and duration of limb ischaemia may augment the protective effect of the limb RIPOC, these ways are not feasible in a clinical setting. Morphine, a classic opioid drug, has been proven to enhance the cardioprotection obtained by the other interventions. Because both the RPIOC and opioid drugs produce the cardioprotection by multiple pathways, and there may be overlaps and cross talk in their mechanisms, we hypothesize that a combination of morphine and the limb RIPOC may produce an enhanced cardioprotection.

Effects of intermittent lower limb ischaemia on coronary blood flow and coronary resistance in pigs

Intermittent limb ischaemia prior to cardiac ischaemia is a cardioprotective stimulus. This study was to investigate whether this peripheral stimulus had any effects on basal coronary blood flow and resistance, and to explore its potential mechanisms by studying the effect of femoral nerve transection and Katp blockade by glibenclamide. Remote ischaemic preconditioning (rIPC) was induced by four 5-min cycles of lower limb ischaemia. Coronary resistance was measured using standard formulae and coronary blood flow in the left anterior descending artery (LAD) by a flow probe. In experiment 1, coronary ischaemia was induced by inflation of a cuff placed around the mid-LAD, and inflated until cessation of flow. Left ventricular (LV) function was assessed using dp/dt and Tau at 1 and 30 min of ischaemia. Experiment 1: 20 pigs were randomized to control (n = 6), rIPC (n = 7) or femoral nerve transection + rIPC (n = 7) groups. The femoral nerve was transected before the rIPC protocol. All data were collected at fixed heart rates of 120 bpm. Coronary resistance was decreased and flow was increased significantly by the rIPC stimulus (P = 0.003, P = 0.016, paired t-test), and these changes were preserved after femoral nerve transection. Experiment 2: 19 pigs were randomized to control (n = 5), rIPC (n = 8) or glibenclamide-treated rIPC (n = 6) groups. Data were collected at baseline, and during incremental pacing between 120 and 180 bpm. Experiment 1: Coronary resistance was decreased and flow was increased significantly by rIPC stimulus (P = 0.003, P = 0.016, paired t-test), and these changes were preserved after femoral nerve transaction. rIPC was associated with superior LV function (dp/dt(max)) at 30 min, compared with controls and the rIPC + femoral nerve transaction group. Experiment 2: Coronary resistance was significantly lower, and LAD flow was significantly higher in rIPC group (P < 0.0001, P = 0.0008, two-way anova). These effects were reversed in the glibenclamide group. The rIPC stimulus leads to reduced coronary resistance and increased flow. This effect, while modified by glibenclamide appears to be a generic effect of remote ischaemia rather than a direct preconditioning effect.

Remote ischaemic preconditioning of the hind limb reduces experimental liver warm ischaemia–reperfusion injury

Direct ischaemic preconditioning of the liver reduces ischaemia-reperfusion injury (IRI). Remote ischaemic preconditioning (RIPC) of a limb has been shown to reduce IRI to the heart. This study determined the effect of brief remote ischaemia to the limb in reducing early liver warm IRI. Twenty-eight male rabbits were allocated to four groups: sham operated, RIPC alone, IRI alone, and RIPC plus IRI. RIPC was induced in the leg with a tourniquet, before liver IRI, by three alternate cycles of 10 min ischaemia followed by 10 min reperfusion. Liver IRI was produced by total inflow occlusion for 25 min. Markers of liver injury and systemic and hepatic haemodynamics were measured for 2 h after reperfusion. At 2 h, IRI alone was associated with increased serum levels of aminotransferases, and reduced mean arterial blood pressure, hepatic blood flow and peripheral oxygen saturation. There was significant improvement in these variables in animals that had RIPC before liver IRI, and hepatic venous nitrate/nitrite levels were also significantly higher. In this experimental model RIPC appeared to reduce liver IRI.

DOES REMOTE ORGAN ISCHAEMIA TRIGGER CARDIAC PRECONDITIONING DURING CORONARY ARTERY SURGERY?

The aim of this study is to provide biochemical evidence of the occurrence of cardiac preconditioning via remote organ ischaemia on the patients undergoing coronary artery surgery. Eight male patients were randomly allocated into two groups. Blood samples were collected via coronary perfusion catheter immediately before cardiopulmonary bypass (point 0), prior to declamping aorta (point 1) and 5 min after declamping the aorta (point 2) to determine creatinine phosphokinase (CPK), CPK-MB and lactate dehydrogenase (LDH) levels in the control group. A tourniquet wrapped around the right upper extremity of the patient was inflated and deflated twice to perform 3 min of ischaemia separated with 2 min of reperfusion in the preconditioning group. Blood samples were withdrawn as described for the control group. Only LDH levels at point 2 were found to be significantly higher than the control group's. These data implied that preconditioning appeared to protect myocardium by enhancing anaerobic glycolysis.

Valor pronóstico de la ecocardiografía de esfuerzo postinfarto agudo de miocardio antes del alta hospitalaria

The aim of the present work was to ascertain the usefulness of exercise echocardiography performed prior to discharge following acute non-complicated myocardial infarction in the prognosis and detection of multi-vessel disease. Sixty-five consecutive patients with primary episode of acute non-complicated myocardial infarction, with normal or slightly depressed ventricular function, were studied. Submaximal exercise test including echocardiogram pre- and immediately post-exercise were performed 7 to 10 days after infarction. Mean follow-up was 15 +/- 8 months; 15 patients presented angina, 9 revascularization and 1 died. Electrocardiographic ischaemia had low sensitivity and negative predictive value regarding complications (44% and 73% respectively); however, its specificity and positive predictive values were high (97% and 92%). In contrast, echocardiography-detected ischaemia showed much better sensitivity and negative predictive values (72% and 83%), with a slight decrease in specificity and positive predictive values (87% and 78%). Both remote ischaemia and the increase in global score > 0.25 during exercise were of high prognostic value (p < 0.001). Remote echocardiographic ischaemia yielded the diagnosis of multi-vessel disease with greater sensitivity than electrocardiographic ischaemia (84% vs 41%). Exercise echocardiography is highly useful in the prognostic assessment of patients prior to discharge following acute non-complicated myocardial infarction. The ischaemia detected on sub-maximal exercise and assessed by echocardiography was much more sensitive than that detected by electrocardiography in the prediction of new coronary events and multi-vessel disease.

Early exercise testing after treatment with thrombolytic drugs for acute myocardial infarction: importance of reciprocal ST segment depression.

To investigate the clinical importance of reciprocal ST depression induced by exercise testing early after acute myocardial infarction in patients treated with thrombolysis. Prospective observational study. District general hospital in London. 202 patients (170 men) aged 33-69 with acute myocardial infarction treated with thrombolysis. All patients underwent exercise testing and coronary arteriography. ST depression induced by exercise was classified as either reciprocal (associated with ST elevation) or isolated (occurring on its own). The relation between reciprocal ST depression and the following end points was studied: characteristics of the infarct, left ventricular ejection fraction, extent of coronary artery disease on arteriography, and presence of angina induced by exercise. Reciprocal ST depression occurred almost exclusively in Q wave infarctions and was associated with a lower overall ejection fraction than isolated ST depression. It tended to be associated with persistent occlusion of the coronary artery related to the infarct and did not indicate remote ischaemia due to multivessel coronary disease. Unlike isolated ST depression, reciprocal ST depression was not associated with angina induced by exercise. Reciprocal ST depression induced by exercise is usually associated with extensive Q wave infarctions and persistent occlusion of the artery related to the infarct. It does not seem to indicate reversible ischaemia and should not be used as a non-invasive marker of multivessel disease in the assessment of requirements for further investigation soon after acute myocardial infarction.

Holter ST monitoring early after acute myocardial infarction: mechanisms of ischaemia in patients treated by thrombolysis.

To investigate the mechanisms of Holter ST shift in patients with acute myocardial infarction treated by thrombolysis. Prospective observational study. A London district general hospital. The study group consisted of 94 patients with acute myocardial infarction treated by thrombolysis. All underwent early 48 hour Holter ST monitoring and elective coronary arteriography. Relation of Holter ST shift to multivessel coronary disease, coronary patency, collateralisation, and morphology of the infarct related lesion. There was a trend towards an increased prevalence of Holter ST shift in patients with patency of the infarct related artery and those with multivessel disease. This was only significant in patients with three vessel disease, a significantly higher proportion of whom had > 3 episodes of ST shift (41% v 14%; p = 0.02) or a total duration of ST shift > 1 hour (35% v 13%; p = 0.04) than those with less extensive coronary disease. Holter ST shift occurred in a significantly higher proportion of patients with complex lesion morphology (Ambrose type 2 or 3) compared with those with lesions of Ambrose morphology type 1 or 2 (60% v 33%; p = 0.05). Holter ST shift detected early after thrombolysis is an ischaemic phenomenon with a complex pathophysiology. It reflects both remote ischaemia in patients with multivessel disease, and dynamic ischaemic processes related to complex lesion morphology in those with a patent infarct related artery.

Significance of reciprocal ST depression in acute myocardial infarction: a study of 258 patients treated by thrombolysis.

To investigate the clinical significance of reciprocal ST depression on the presenting electrocardiogram in patients with acute myocardial infarction treated by thrombolysis. A prospective cohort analytical study. A London district general hospital. Two hundred and fifty eight consecutive patients with acute myocardial infarction treated with thrombolysis. All patients underwent treadmill stress testing after a mean (SEM) of 10 (3) days; 200 patients (78%) were referred for coronary arteriography at 30 (16) days. Relation between reciprocal ST depression at presentation and several endpoints: time from start of chest pain to hospital presentation, electrocardiographic changes during early treadmill stress testing, presence of multivessel coronary disease, and clinical outcome in terms of recurrent ischaemic events (death, reinfarction, and unstable angina) during a 10 (range six to 12) month follow up. Presentation was generally early, but in this group of patients reciprocal ST depression was significantly related to the time from the start of symptoms, those with reciprocal change presenting on average one hour earlier than those without. Although reciprocal change on the presenting electrocardiogram was weakly associated with ST depression on treadmill stress testing, it was not indicative of remote ischaemia as a result of multivessel coronary disease or high grade collateralisation of the infarct related artery. There was no association between reciprocal change and the incidence of recurrent ischaemic events. Reciprocal ST depression on the presenting electrocardiogram seems to be a benign electrical phenomenon related to the time from the start of symptoms. It does not necessarily predict an adverse prognosis in patients treated by thrombolysis.

Effects of haemorrhage induced hypotension on coronary blood flow in an anaesthetised two vessel canine coronary stenosis-occlusion model

Previous experiments from our group have shown that left anterior descending coronary occlusion in the presence of hypotension caused by intravenous glyceryl trinitrate in an open chest canine model caused endocardial flow to fall in myocardium supplied by a stenosed circumflex coronary artery. The aim of the present study was to assess the effects of hypotension in a similar open chest model but without the vasodilating effect of glyceryl trinitrate on coronary vessels. Blood flow to and function of remote myocardium supplied by a stenosed circumflex coronary artery [gradient 27(SEM 3) mm Hg] was determined in anaesthetised dogs after haemorrhage induced hypotension [mean aortic pressure 70(3) mm Hg] and after left anterior descending coronary occlusion. Transmural blood flow was measured using microspheres and myocardial wall thickness with sonomicrometer crystals. 11 healthy mongrel dogs were used, weight 25 kg (range 19-33). Haemorrhage induced hypotension in the setting of a circumflex stenosis reduced endocardial blood flow to the posterior myocardial bed from 0.84 (0.14) to 0.57(0.07) ml.min-1.g-1 but did not alter percent myocardial thickening. When the left anterior descending coronary artery was occluded in the presence of the circumflex stenosis and haemorrhage induced hypotension, there was no further decrease in endocardial blood flow to or thickening of the posterior myocardial bed, despite a reduction in mean coronary artery pressure from 54(3) to 43(3) mm Hg. These findings are in contrast to our previous findings where hypotension was induced by glyceryl trinitrate. Remote myocardial ischaemia appears to be attenuated in this two vessel stenosis-occlusion model in which hypotension is produced by haemorrhage.

Mechanism of remote myocardial ischaemia after coronary occlusion in open chest dogs.

To determine whether or not the fall in coronary perfusion pressure after coronary occlusion is the cause of remote myocardial ischaemia, regional myocardial blood flow was measured using radiolabelled microspheres before and after left anterior descending (LAD) occlusion in the presence of a left circumflex artery stenosis in 22 anaesthetised dogs. Aortic pressure was maintained constant at the time of left anterior descending artery occlusion in 13 dogs (group 1) and proximal left circumflex artery pressure was held constant by a servocontrolled pump in nine dogs with a carotid artery-left circumflex artery shunt (group 2). Despite the maintenance of constant mean aortic pressure in group 1, remote posterior bed mean(SEM) endocardial flow fell from 0.69(0.05) to 0.43(0.07) ml.min-1.g-1 (p less than 0.05). In the dogs in which left atrial pressure rose to less than or equal to 9 mmHg after left anterior descending artery occlusion, remote bed endocardial flow did not fall significantly (0.66(0.07) to 0.56(0.11) ml.min-1.g-1; NS). In contrast, remote bed endocardial flow fell from 0.73(0.07) to 0.28(0.06) ml.min-1.g-1 (p less than 0.0001) after left anterior descending artery occlusion in the dogs in which left atrial pressure rose to greater than 9 mmHg. The fall in remote bed endocardial flow was prevented in group 2 dogs by maintaining proximal left circumflex artery pressure constant (0.95(0.08) to 0.86(0.09) ml.min-1.g-1; NS). An important mechanism for the development of remote myocardial ischaemia appears to be the fall in proximal coronary perfusion pressure at the time of coronary occlusion.