Cardioprotection by Ischemic and Nonischemic Myocardial Stress and Ischemia in Remote Organs Implications for the Concept of Ischemic Preconditioning (original) (raw)
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Myocardial protection with postconditioning is not enhanced by ischemic preconditioning
The Annals of Thoracic Surgery, 2004
preconditioning Myocardial protection with postconditioning is not enhanced by ischemic http://ats.ctsnetjournals.org/cgi/content/full/78/3/961 located on the World Wide Web at: The online version of this article, along with updated information and services, is Print ISSN: 0003-4975; eISSN: 1552-6259. Southern Thoracic Surgical Association.
Journal of Molecular and Cellular Cardiology, 2001
L. M. S, L. S, R. B. J K. A. R. Duration and Reinstatement of Myocardial Protection Against Infarction by Ischemic Preconditioning in Open Chest Dogs. Journal of Molecular and Cellular Cardiology (2001) 33, 1561-1570. These studies were undertaken to determine the duration of protection against myocardial infarction provided by ischemic preconditioning in the canine heart, and to learn if cardioprotection can be restored by another preconditioning stimulus when the initial effect is lost. Control and four preconditioning groups of anesthetized, open-chest dogs were compared. All underwent a test 60 min episode of ischemia, induced by occlusion of the anterior descending (LAD) artery, followed by 3 h of reperfusion. Preconditioning was induced by one 10 min LAD occlusion, followed by either 10 min, 2, 3, or 5 h of reperfusion. In order to test whether preconditioning could be reinstated, another group of dogs with preconditioning plus 3 h reperfusion underwent a second 10 min preconditioning stimulus with 10 min reperfusion before the 60 min test-occlusion. Infarct size (as percent of area-at-risk) was analyzed (using analysis of covariance) with respect to coronary collateral blood flow measured with radioactive microspheres. Infarct size was limited markedly by preconditioning (23±6 v 6±2%, P<0.05) but the protective effect was dissipated partially after 2 h reperfusion and was dissipated completely after 3 h reperfusion (20±4%, non-significant v Control and significant P<0.05 v preconditioning). Protection was restored in three of six dogs with preconditioning +5 h reperfusion, suggesting that the second window of protection appears early in some canine hearts. When preconditioning was repeated after 3 h reperfusion, cardioprotection was reinstated fully (7±2%, P<0.05 v Control and NS v preconditioning). The results show that maximal preconditioning cardioprotection is present in the dog heart after 10 min of reperfusion and is dissipated totally following 3 h of reperfusion. However, a second preconditioning stimulus of 10 min of ischemia followed by 10 min of reperfusion to the dissipated preconditioned heart reinstates full preconditioning. Thus, this model provides a system to test for theoretical causes of the preconditioned state. Final mediators should be present when preconditioning is present and absent when preconditioning is dissipated. It is noteworthy that a second window of protection appeared in 50% of dogs when the period of reperfusion was extended to 5 h.
American journal of physiology. Heart and circulatory physiology, 2003
Ischemic preconditioning (Pre-con) is an adaptive response triggered by a brief ischemia applied before a prolonged coronary occlusion. We tested the hypothesis that repetitive ischemia applied during early reperfusion, i.e., postconditioning (Post-con), is cardio-protective by attenuating reperfusion injury. In anesthetized open-chest dogs, the left anterior descending artery (LAD) was occluded for 60 min and reperfused for 3 h. In controls (n = 10), there was no intervention. In Pre-con (n = 9), the LAD was occluded for 5 min and reperfused for 10 min before the prolonged occlusion. In Post-con (n = 10), at the start of reperfusion, three cycles of 30-s reperfusion and 30-s LAD reocclusion preceded the 3 h of reperfusion. Infarct size was significantly less in the Pre-con (15 +/- 2%, P < 0.05) and Post-con (14 +/- 2%, P < 0.05) groups compared with controls (25 +/- 3%). Tissue edema (% water content) in the area at risk was comparably reduced in Pre-con (78.3 +/- 1.2, P <...
Cardiac effects of postconditioning depend critically on the duration of index ischemia
AJP: Heart and Circulatory Physiology, 2006
Postconditioning is known as the phenomenon whereby brief intermittent ischemia applied at the onset of reperfusion following index ischemia limits myocardial infarct size. While there is evidence that the algorithm of the postconditioning stimulus is an important determinant of the protective efficacy, the importance of the duration of index ischemia on the outcome of the effects of postconditioning has received little attention. Pentobarbital-anesthetized Wistar rats were therefore subjected to index ischemia produced by coronary artery occlusions (CAO) of varying duration (15-120-min) followed by reperfusion, without or with postconditioning produced by 3 cycles of 30-s of reperfusion and reocclusion (3POC30). 3POC30 limited infarct size produced by 45-min CAO (CAO45) from 45±3% to 31±5%, and CAO60 from 60±3% to 47±6% (both P?0.05). In contrast, 3POC30 increased infarct size produced by CAO15 from 3±1% to 19±6% and CAO30 from 36±6 to 48±4% (both P?0.05). This deleterious effect of 3POC30 was not stimulus-sensitive as postconditioning with 3POC5 and 3POC15 after CAO30 also increased infarct size. The cardioprotection by 3POC30 after CAO60 was accompanied by an increased stimulation of Akt-phosphorylation after 7 min of reperfusion, and a 36% lower superoxide production, measured by dihydroethidium fluorescence after 2 hours of reperfusion.
Annals of the New York Academy of Sciences, 1996
Ischemic preconditioning is a form of myocardial adaptation through which the heart is protected, by short periods of ischemic stress, against the serious consequences of a subsequent prolonged period of i~chemia.l-~ This increased tolerance of the heart following subjection to brief periods of ischemic stress is manifested by a reduced area of myocardial necrosis,l by enhanced recovery of contractile function during reperfusion5 and by a reduced severity of the life-threatening ventricular arrhythmias that arise during a period of ischemia and reperfusion.6-8 There are good reasons for believing that the antiarrhythmic effect of ischemic preconditioning is an even more important manifestation of this protection than is the reduction in myocardial ischemic damage.8 This review summarizes the evidence that preconditioning reduces the severity of these ventricular arrhythmias, that this protection is both acute and delayed and that the mechanisms involve the release of mediators from endothelial cells.
Basic Research in Cardiology, 2002
Myocardial stretch induces several electrophysiological changes and arrhythmias, but little is known on its possible role in triggering ventricular fibrillation (VF) during acute coronary occlusion. In thiopental-anesthetized, open-chest pigs submitted to a 40-min ligation of the left anterior descending coronary artery, the association between the early increase in end-diastolic length (measured by means of ultrasonic crystals) in the ischemic region and subsequent VF was analyzed. Animals received no treatment (n = 35) or intravenous nitroglycerin (2.5 μg/kg/min for 20 min, starting 10 min after coronary occlusion, n = 8) or Gd3+ (80 μM/kg for 35 min, starting 5 min before occlusion, n = 15). Twenty-four animals (41 %) had VF, 16 to 39 min after coronary occlusion. The magnitude of ischemic dilation and the incidence of VF were similar among groups. End-diastolic length in the ischemic region 15 min after coronary occlusion was 115.7 ± 1.2 % of baseline in animals with VF and 111.4 ± 0.9 % in those without (P = 0.007), and was the strongest predictor of this arrhythmia (P = 0.003) after adjusting for treatment and other possible confounding variables. Thus, the dilation of the ischemic region is closely and independently associated with VF following coronary occlusion. Although the interventions tested in the present study failed to protect against this arrhythmia, the results strongly suggest an influence of ischemic dilation on VF.
Consequences of Brief Ischemia: Stunning, Preconditioning, and Their Clinical Implications: Part 2
Circulation, 2001
In experimental studies in the dog, total proximal coronary artery occlusions of up to 15 minutes result in reversible injury, meaning that the myocytes survive this insult. The 15 minutes of ischemia, however, induce numerous changes in the myocardium, including certain monuments to the brief episode of ischemia that may persist for days. One of these monuments is stunned myocardium, which represents "prolonged postischemic contractile dysfunction of myocardium salvaged by reperfusion." The mechanism of stunning involves generation of oxygen radicals as well as alteration in calcium homeostasis and possibly alteration in contractile protein structure. Stunning has been observed in several clinical scenarios, including after percutaneous transluminal coronary angioplasty, unstable angina, stressinduced ischemia, after thrombolysis, and after cardiopulmonary bypass. Oxygen radical scavengers and calcium channel blockers have been shown to enhance function of stunned myocardium in experimental studies, and in a few clinical studies, calcium channel blockers have been shown to ameliorate stunning. Although brief periods of ischemia can contribute to prolonged left ventricular dysfunction and even heart failure, they paradoxically play a cardioprotective role. Episodes of ischemia as short as 5 minutes, followed by reperfusion, protect the heart from a subsequent longer coronary artery occlusion by markedly reducing the amount of necrosis that results from the test episode of ischemia. This phenomenon, called ischemic preconditioning, has been observed in virtually every species in which it has been studied and is a powerful cardioprotective effect. The mechanism of ischemic preconditioning involves both triggers and mediators and involves complex second messenger pathways that appear to involve such components as adenosine, adenosine receptors, the epsilon isoform of protein kinase C, the ATP-dependent potassium channels, as well as others, including a paradoxical protective role of oxygen radicals. Both an early and a late phase of preconditioning have been described, and the mechanisms underlying their induction are under investigation. That preconditioning may occur in humans is suggested by the observations that repetitive balloon inflations in the coronary artery are associated with progressively less chest pain, ST-segment elevation, lactate production, the protective effects of preinfarction angina, the anginal "warm-up phenomenon," and studies performed on human cardiac biopsies that show metabolic properties suggesting preconditioning. Development of pharmacological agents that stimulate second messenger pathways thought to be involved in preconditioning, but without causing ischemia, could result in novel approaches to treating ischemia. Hence, on one hand, brief episodes of ischemia can have a negative effect on the heart: stunning; and on the other hand, they have a protective effect: preconditioning. The future challenge is how to minimize the stunning phenomenon and maximize the preconditioning phenomenon in clinical practice. (Circulation. 2001;104:2981-2989.)
Revista Española de Cardiología (English Edition), 2013
Distension of the ischemic region has been related to an increased incidence of spontaneous ventricular arrhythmias following coronary occlusion. This study analyzed whether regional ischemic distension predicts increased ventricular fibrillation inducibility after coronary occlusion in swine. In 18 anesthetized, open-chest pigs, the left anterior descending coronary artery was ligated for 60 min. Myocardial segment length in the ischemic region was monitored by means of ultrasonic crystals. Programmed stimulation was applied at baseline and then continuously between 10 and 60 min after coronary occlusion. Coronary occlusion induced a rapid increase in end-diastolic length in the ischemic region, which reached 109.4% (0.9%) of baseline values 10 min after occlusion (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;.001). On average, 6.6 (0.5) stimulation protocols were completed and 5.4 (0.6) ventricular fibrillation episodes induced between 10 and 60 min of coronary occlusion. Neither baseline serum potassium levels nor the size of the ischemic region were significantly related to ventricular fibrillation inducibility. In contrast, the increase in end-diastolic length 10 min after coronary occlusion was associated directly (r=0.67; P=.002) with the number of induced ventricular fibrillation episodes and inversely (r=-0.55; P=.018) with the number of extrastimuli needed for ventricular fibrillation induction. Regional ischemic expansion predicts increased ventricular fibrillation inducibility following coronary occlusion. These results highlight the potential influence of mechanical factors, acting not only on the triggers but also on the substrate, in the genesis of malignant ventricular arrhythmias during acute ischemia.