Background-Ischemic preconditioning reduces local tissue injury caused by subsequent ischemia-reperfusion (IR), but may also have a salutary effect on IR injury of tissues remote from those undergoing preconditioning. We tested the hypothesis that limb ischemia induces remote preconditioning, reduces endothelial IR injury in humans, and reduces experimental myocardial infarct size. Methods and Results-Endothelial IR injury of the human forearm was induced by 20 minutes of upper limb ischemia (inflation of a blood pressure cuff to 200 mm Hg) followed by reperfusion. Remote preconditioning was induced by three 5-minute cycles of ischemia of the contralateral limb. Venous occlusion plethysmography was used to assess forearm blood flow in response to acetylcholine at baseline and 15 minutes after reperfusion. Experimental myocardial infarction was achieved by 40 minutes of balloon occlusion of the left anterior descending artery in 15-kg pigs. Remote preconditioning was induced by four 5-minute cycles of lower limb ischemia. Triphenyltetrazolium staining was used to assess the extent of myocardial infarction. In the human study, the response to acetylcholine was significantly attenuated in the control group after 15 minutes' reperfusion, but remote preconditioning prevented this reduction. Limb ischemia caused a significant reduction in the extent of myocardial infarction relative to the area at risk compared with control (26Ϯ9% versus 53Ϯ8%, PϽ0.05). Key Words: endothelium Ⅲ ischemia Ⅲ reperfusion Ⅲ ischemic preconditioning, remote I schemia-reperfusion (IR) complicates myocardial infarction and stroke and contributes to the associated tissue injury and mortality; reducing IR injury may improve the outcome of reperfusion therapy for these conditions. 1 One successful approach in the experimental setting is ischemic preconditioning (IPC), whereby prior sublethal ischemia induces a state of protection against subsequent prolonged IR. 2 Although animal studies have shown that protection occurs locally in the tissue being preconditioned, systemic effects of localized IPC have been observed. 3 This raises the possibility that regional ischemia of accessible nonvital tissues might protect remote vital organs undergoing IR, and some data support this in humans. 4 In the present study we tested the hypothesis that short periods of limb ischemia induce remote preconditioning and reduce IR injury in vivo. We used a human model of endothelial IR injury to test whether remote limb ischemia induces systemic preconditioning in humans. Furthermore, we studied an experimental model of myocardial infarction to characterize whether limb ischemia reduced myocardial IR injury. Conclusion-Remote Methods Study 1: Remote Preconditioning of Human Endothelium by Contralateral Limb Ischemia Subjects and Study DesignFourteen healthy volunteers, with a mean age of 33 (range, 26 to 52) years, gave informed signed consent and were randomized to remote preconditioning and control groups. Studies were approved by the local Research Ethics Committ...

Background-We have demonstrated that myocardial acceleration during isovolumic contraction (IVA) is a sensitive index of left ventricular contractile function. In this study, we assessed the utility of IVA to measure right ventricular (RV) contractile function. Methods and Results-We examined 8 pigs by using tissue Doppler imaging of the RV free wall and simultaneous measurements of intraventricular pressure, volume, maximal elastance (e max ), preload recruitable stroke work, and dP/dt max by conductance catheterization. Animals were paced in the right atrium at a rate of 130 beats per minute (bpm).IVA was compared with elastance during contractility modulation by esmolol and dobutamine and during preload reduction and afterload increase by transient balloon occlusion of the inferior vena cava and pulmonary artery, respectively. Data were also obtained during incremental atrial pacing from 110 to 210 bpm. Esmolol led to a decrease in IVA and dP/dt max . During dobutamine infusion, IVA, dP/dt max , preload recruitable stroke work, and e max all increased significantly. During preload reduction and afterload increase, IVA remained constant up to a reduction of RV volume by 54% and an RV systolic pressure increase of 58%. Pacing up to a rate of 190 bpm led to a stepwise increase in IVA and dP/dt max , with a subsequent fall at a pacing rate of 210 bpm. Conclusions-IVA is a measurement of RV contractile function that is unaffected by preload and afterload changes in a physiological range and is able to measure the force-frequency relation. This novel index may be ideally suited to the assessment of acute changes of RV function in clinical studies.

RK. Intermittent peripheral tissue ischemia during coronary ischemia reduces myocardial infarction through a K ATP-dependent mechanism: first demonstration of remote ischemic perconditioning. Am J Physiol Heart Circ Physiol 292: H1883-H1890, 2007. First published December 15, 2006; doi:10.1152/ajpheart.00617.2006.-Remote ischemic preconditioning reduces myocardial infarction (MI) in animal models. We tested the hypothesis that the systemic protection thus induced is effective when ischemic preconditioning is administered during ischemia (PerC) and before reperfusion and examined the role of the K ϩ -dependent ATP (K ATP) channel. Twenty 20-kg pigs were randomized (10 in each group) to 40 min of left anterior descending coronary artery occlusion with 120 min of reperfusion. PerC consisted of four 5-min cycles of lower limb ischemia by tourniquet during left anterior descending coronary artery occlusion. Left ventricular (LV) function was assessed by a conductance catheter and extent of infarction by tetrazolium staining. The extent of MI was significantly reduced by PerC (60.4 Ϯ 14.3 vs. 38.3 Ϯ 15.4%, P ϭ 0.004) and associated with improved functional indexes. The increase in the time constant of diastolic relaxation was significantly attenuated by PerC compared with control in ischemia and reperfusion (P ϭ 0.01 and 0.04, respectively). At 120 min of reperfusion, preload-recruitable stroke work declined 38 Ϯ 6% and 3 Ϯ 5% in control and PerC, respectively (P ϭ 0.001). The force-frequency relation was significantly depressed at 120 min of reperfusion in both groups, but optimal heart rate was significantly lower in the control group (P ϭ 0.04). There were fewer malignant arrhythmias with PerC during reperfusion (P ϭ 0.02). These protective effects of PerC were abolished by glibenclamide. Intermittent limb ischemia during myocardial ischemia reduces MI, preserves global systolic and diastolic function, and protects against arrhythmia during the reperfusion phase through a K ATP channeldependent mechanism. Understanding this process may have important therapeutic implications for a range of ischemia-reperfusion syndromes. remote preconditioning; cardioprotection REPERFUSION STRATEGIES are well established for the treatment of evolving clinical ischemia-reperfusion (I/R) syndromes. Recent approaches to further improve outcomes after myocardial infarction (MI) have focused on strategies to protect the myocardium during the ischemic and reperfusion phases, such as sodium-hydrogen pump inhibitors, glucose/insulin infusions, and anti-complement therapy, although these have shown no major additional benefits (15,16,26).One successful approach in the experimental setting is ischemic preconditioning, whereby prior sublethal I/R induces a state of protection against a subsequent prolonged ischemic episode (18). However, ischemic preconditioning has not translated into the clinical setting, not only because it is impossible to predict clinical acute coronary syndromes, but also, even in the setting of predictable I/R injury ...

Background-We have demonstrated that myocardial acceleration during isovolumic contraction (IVA) is a sensitive index of right ventricular contractile function. In this study, we assessed the usefulness of IVA to measure left ventricular (LV) contractile function and force-frequency relationships in an experimental preparation. Methods and Results-In study 1, we examined 6 pigs by use of tissue Doppler imaging of LV free wall and simultaneous measurements of intraventricular pressure, volume, maximal elastance (E max ), and dP/dt max by conductance catheterization. Animals were paced via the right atrium at a rate of 130 bpm. IVA was compared with elastance during contractility modulation by esmolol and dobutamine and assessed during preload reduction and afterload increase. In study 2, in 6 more pigs, force-frequency data were obtained during incremental atrial pacing from 120 to 180 bpm. Study 1: Esmolol led to a decrease in IVA and E max (PϽ0.03 and Ͻ0.02, respectively), both of which increased during dobutamine infusion (PϽ0.02 and Ͻ0.03, respectively). IVA was unaffected by significant (PϽ0.001) acute reduction of LV volume and a significantly increased LV afterload (systolic pressure increase, PϽ0.001). Study 2: There was a positive correlation between IVA and dP/dt max (r 2 ϭ0.92, PϽ0.05). As heart rate was increased from 120 to 160 bpm, there were significant increases in both IVA and dP/dt max (PϽ0. 0004 and Pϭ0.02, respectively). Over the same range of heart rates, there was no significant change in E max (Pϭ0.22). Conclusions-IVA is a measurement of LV contractile function that is unaffected by preload and afterload changes within a physiological range and can be used noninvasively to measure LV force-frequency relationships.

Aims/hypothesis.

Efficacy of ischemic preconditioning is decreased in animal models of type 2 diabetes mellitus while the responses in humans with diabetes are contradictory. It is unknown whether attenuation is related to decreased release of a mediating humoral cardioprotective factor or reduced ability to respond in the target tissue. The aim of the present study was to investigate the release and effect of a circulating cardioprotective factor in type 2 diabetes mellitus patients. Blood samples were drawn from nine non-diabetic subjects, eight diabetic patients without peripheral neuropathy, and eight diabetic patients with peripheral neuropathy before (control) and after a remote ischemic preconditioning (rIPC) stimulus. Blood samples were dialyzed against Krebs-Henseleit buffer and the cardioprotective effects of the dialysates were tested in rabbit hearts mounted on a Langendorff model and subjected to 30-min global ischemia and 120-min reperfusion. rIPC dialysate from non-diabetic and diabetic subjects without peripheral neuropathy reduced infarct size and improved hemodynamic recovery compared to control dialysate from non-diabetic and diabetic subjects. However, in the subgroup of diabetic patients with neuropathy the cardioprotective effect was attenuated. These findings indicate that the release mechanism involves neural pathways.

Remote ischemic preconditioning (rIPC), induced by cycles of transient limb ischemia and reperfusion (IR), is cardioprotective. The optimal rIPC-algorithm is not established. We investigated the effect of cycle numbers and ischemia duration within each rIPC-cycle and the influence of effector organ mass on the efficacy of cardioprotection. Furthermore, the duration of the early phase of protection by rIPC was investigated. Using a tourniquet tightened at the inguinal level, we subjected C57Bl/6NTac mice to intermittent hind-limb ischemia and reperfusion. The rIPC-protocols consisted of (I) two, four, six or eight cycles, (II) 2, 5 or 10 min of ischemia in each cycle, (III) single or two hind-limb occlusions and (IV) 0.5, 1.5, 2.0 or 2.5 h intervals from rIPC to index cardiac ischemia. All rIPC algorithms were followed by 5 min of reperfusion. The hearts were subsequently exposed to 25 min of global ischemia and 60 min of reperfusion in an ex vivo Langendorff model. Cardioprotection was evaluated by infarct size and post-ischemic hemodynamic recovery. Four to six rIPC cycles yielded significant cardioprotection with no further protection by eight cycles. Ischemic cycles lasting 2 min offered the same protection as cycles of 5 min ischemia, whereas prolonged cycles lasting 10 min abrogated protection. One and two hind-limb preconditioning were equally protective. In our mouse model, the duration of protection by rIPC was 1.5 h. These findings indicate that the number and duration of cycles rather than the tissue mass exposed to rIPC determines the efficacy of rIPC.

rIPC and diabetes mellitus per se influence myocardial O-GlcNAc levels through circulating humoral factors. O-GlcNAc signalling participates in mediating rIPC-induced cardioprotection and maintaining a state of inherent chronic activation of cardioprotection in diabetic myocardium, restricting it from further protection by rIPC.