Cardioprotection by Ischemic and Nonischemic Myocardial Stress and Ischemia in Remote Organs Implications for the Concept of Ischemic Preconditioninga

Abstract

Ischemic preconditioning studies employ one or more brief total coronary artery occlusions separated by complete reperfusion to limit infarct size during a subsequent prolonged coronary artery occlusion. We now present evidence that in anesthetized pigs a partial coronary artery occlusion without intervening reperfusion between the partial and prolonged total occlusions can also precondition the myocardium provided that the reduction in coronary blood flow is sufficiently severe. Thus infarct size was reduced after a 60 min total coronary artery occlusion when the total occlusion was preceded by a partial coronary occlusion that reduced coronary blood flow by 70% but not when the flow reduction was only 30%. In this two-stage coronary occlusion model the degree of protection appears greater in the epicardial than in the endocardial half. In view of evidence that brief occlusions of a coronary artery also protect myocardium outside its perfusion territory, we subsequently investigated whether ischemia in remote organs can protect myocardium. Because of reports that development of infarct size may be temperature dependent, we also investigated whether the cardioprotection by remote organ ischemia was temperature dependent. In anesthetized rats a 15 min coronary artery occlusion was more effective in reducing infarct size produced by a subsequent 60 min total coronary artery occlusion when the experiments were performed at a body core temperature of 30-31 degrees C than at 36-37 degrees C, while infarct size of animals which were subjected to only the 60 min total coronary artery occlusion was the same for the two body core temperatures. In rats with a body core temperature of 36-37 degrees C a 15 min mesenteric artery occlusion, but not a 15 min renal artery occlusion, reduced infarct size produced by a subsequent 60 min coronary artery occlusion. When the experiments were performed at 30-31 degrees C both the mesenteric and renal artery occlusions were protective. These observations indicate the local myocardial ischemia is not required to protect the myocardium during a prolonged coronary occlusion. We further investigated whether myocardium could also be protected by a cardiac stimulus which does not produce ischemia at all. For this purpose we electrically paced the left ventricle of anesthetized pigs to produce heart rates of 200 bpm (which did not lead to ischemia as assessed by a number of functional and biochemical variables) and found that 30 min of ventricular pacing reduced myocardial infarct size produced by a subsequent 60 min coronary artery occlusion. The protection by ventricular pacing involved activation of K+ATP channels as pretreatment with glibenclamide abolished the protection by ventricular pacing. We conclude that a number of distinctly different stimuli can protect the myocardium suggesting that ischemic myocardial preconditioning could be just one feature of a more general protection phenomenon.

Functional Protection by Acute Phase Proteins α 1 -Acid Glycoprotein and α 1 -Antitrypsin Against Ischemia/Reperfusion Injury by Preventing Apoptosis and Inflammation

“…This so-called ischemic preconditioning has been attributed to local protective mechanisms, including induction of heatshock proteins 29 and adenosine formation. 30 However, brief ischemia in remote organs 31,32 or endotoxin pretreatment 4 -6 has been shown to confer similar protection, suggesting involvement of other than local mechanisms. Indeed, the observed I/R-induced SAP and AGP increase and elevated hepatic acute phase protein mRNA content show that renal I/R induces an APR.…”

Chronic skeletal muscle ischemia preserves coronary flow in the ischemic rat heart

“…In the experimental setting, a further approach of myocardial protection has been observed after short ischemic episodes of peripheral tissues, a process termed remote ischemic preconditioning (2,14). Cytoprotection in the heart has been demonstrated after ischemia in a variety of peripheral tissues, such as the mesenterium, kidney, and skeletal muscle (12,32). Of these, skeletal muscles have attracted considerable scientific interest because they are easily accessible and can be manipulated without major risk in the clinical setting, should this method prove of therapeutic value.…”

Remote ischemic preconditioning of flaps: A review

“…Verdouw et al were the first to report a real remote IP of the heart by mesenteric artery occlusion in a rat model. 42 The protective influence of limb ischemia on myocardial infarction was reported by Birnbaum et al 43 and Oxman et al 44 A study from our laboratory on remote IP of flaps showed, in a rat adipocutaneous flap model, that acute IP and enhancement of flap survival can be achieved not only by preclamping of the flap pedicle, but also by induction of an ischemia/reperfusion event in a body area distant from the flap prior to elevation. 45 An invasive procedure clamping the femoral artery was as effective to precondition the flap as a noninvasive tourniquet application to a rat hindlimb followed by 30 min of limb reperfusion (Figs.…”