Marcel E. Zughaib

Recurrent ischemia in the canine heart causes recurrent bursts of free radical production that have a cumulative effect on contractile function. A pathophysiological basis for chronic myocardial "stunning".

Open-chest dogs (total number used, 117) underwent 10 5-min coronary occlusions (O) interspersed with 10 min of reperfusion (R). When systolic thickening fraction was measured 9 min after each R, the first O-R cycle was found to cause the largest decrement, with only a slight additional loss during the next four cycles and no further loss during the last five cycles (group IV), suggesting that the first few episodes of ischemia preconditioned the myocardium against the stunning induced by the last five episodes. However, different results were obtained when the total deficit of wall thickening during the final 4-h R interval was measured. The total deficit was similar after one and three 5-min O (groups V and VI, respectively), indicating that the first ischemic episode did precondition against the next two episodes; however, it was approximately 2.5-fold greater after 10 O (group IV) than after 3, indicating that the first 3 episodes failed to precondition against the next 7. Thus, at some point between the 4th and 10th O, the preconditioning effect was lost and recurrent ischemic episodes started to have a cumulative effect. Measurements of free radicals with alpha-phenyl N-tert-butyl nitrone (PBN) demonstrated a burst of free radical generation immediately after the 1st, 5th, and 10th R (group VIII). The total cumulative release of PBN adducts during the initial 5 min of reflow was 58% less after the 5th R than after the 1st (P < 0.05) but did not differ significantly between the 1st and 10th R. When administered throughout the 10 O-R cycles, the .OH scavenger mercaptopropionyl glycine significantly enhanced the recovery of function (group I) and markedly suppressed the formation of free radicals (group VII). However, the beneficial effects of mercaptopropionyl glycine were completely, or largely, lost if the drug was discontinued after the first five (group II) or eight (group III) O-R cycles, respectively, implying that (a) the oxidative stress associated with the last five, or even two, cycles was sufficient to cause severe postischemic dysfunction, and (b) the cumulative injury caused by repetitive ischemic episodes is mediated by recurrent oxidative stress. This study provides direct in vivo evidence that oxygen radicals play an important role in the pathogenesis of myocardial stunning after repetitive ischemia, and implicates .OH as a primary culprit. Taken together, the data indicate that recurrent brief ischemic episodes result in recurrent bouts of oxyradical-mediated injury that have a cumulative effect on contractility, a situation that could lead to protracted or even chronic myocardial stunning.

Augmentation of endogenous adenosine attenuates myocardial 'stunning' independently of coronary flow or hemodynamic effects.

BackgroundMounting evidence suggests a protective effect of exogenous adenosine in myocardial ischemia and reperfusion. We tested the hypothesis that augmentation of endogenous adenosine levels, achieved by inhibiting adenosine catabolism and washout, is beneficial in postischemic myocardial dysfunction (“stunning”). Methods and ResultsIn phase I of the study, open-chest dogs undergoing a 15-minute coronary artery occlusion and 4 hours of reperfusion received an intracoronary infusion of either saline (controls, n=23) or 6-(4-nitrobenzyl)-mercapto: purine ribonucleoside (NBMPR, a selective nucleoside transport inhibitor) combined with erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA, a potent adenosine deaminase inhibitor) (EHNA+NBMPR, n=15) starting 15 minutes before coronary occlusion and ending 15 minutes after the initiation of reflow. Regional myocardial function (assessed as systolic wall thickening) was similar in control and treated groups at baseline and during ischemia. After reperfusion, however, the dogs treated with EHNA+NBMPR exhibited a significant improvement in the recovery of function, which was evident as early as 30 minutes after restoration of flow and was sustained throughout the rest of the reperfusion phase. The enhanced recovery effected by EHNA+NBMPR could not be attributed to nonspecific factors such as differences in collateral flow during occlusion, coronary flow after reperfusion, arterial pressure, heart rate, or other hemodynamic variables. In phase II of the study, the myocardial content of adenine nucleotides and nucleosides was measured by high performance liquid chromatography in myocardial biopsies obtained serially from open-chest dogs undergoing the same protocol used in phase I. There were no significant differences between control (n=8) and treated (n=9) dogs with respect to myocardial levels of adenosine triphosphate (ATP) at 30 and 60 minutes after reperfusion, indicating that the beneficial effects of EHNA+NBMPR cannot be ascribed to repletion of ATP stores. Compared with controls, dogs treated with EHNA+NBMPR exhibited a much larger increase in myocardial adenosine (6.07±1.47 vs 1.03±0.16 nmol/mg protein, P<.05) and a much smaller increase in inosine (0.52±0.27 vs 3.04±0.54 nmol/mg protein, P<.05) at the end of ischemia, such that the inosine-to-adenosine ratio noted in controls was completely reversed (=6:1 vs =1:6, respectively). In the treated group, adenosine levels remained markedly increased compared with controls up to 1 hour after reperfusion. ConclusionsThis study demonstrates that (1) administration of an adenosine deaminase inhibitor plus a nucleoside transport blocker is remarkably effective in augmenting myocardial adenosine levels during regional ischemia and subsequent reperfusion in vivo, (2) this augmentation of adenosine results in a significant and sustained attenuation of myocardial stunning, and (3) the attenuation of stunning is not due to ATP repletion or to nonspecific actions on hemodynamic variables or coronary flow. These findings suggest that endogenous adenosine production during ischemia serves as an important pathophysiological mechanism that protects against myocardial stunning. The results also suggest that augmentation of endogenous adenosine (without exogenous adenosine administration) represents an effective therapeutic approach to the alleviation of reversible postischemic dysfunction.

Effect of Adenosine on Myocardial ‘Stunning’ in the Dog

Recent evidence suggests a cardioprotective effect of adenosine in myocardial ischemia and reperfusion. The present study was undertaken to determine (1) whether adenosine attenuates myocardial stunning, (2) if so, whether the beneficial effect of adenosine takes place during ischemia or after reperfusion, and (3) whether adenosine preconditions against myocardial stunning. A total of 93 dogs were used. In phase A of the study, open-chest dogs undergoing a 15-minute occlusion of the left anterior descending coronary artery followed by 4 hours of reperfusion received an intracoronary infusion of either saline (group I [control], n = 14), 2 mg/min adenosine from 30 minutes before occlusion until 1 hour after reperfusion (group II, n = 10), or 2 mg/min adenosine from 2 minutes before reperfusion until 1 hour after reperfusion (group III, n = 11). Regional myocardial function (assessed as systolic wall thickening) was similar in the three groups at baseline and during ischemia. After reperfusion, dogs treated with adenosine before, during, and after ischemia (group II) demonstrated a significant improvement in the recovery of function that persisted throughout the 4 hours of reperfusion. In contrast, in dogs treated only during the reperfusion period (group III), the recovery of function was not statistically different from that in control dogs. The enhanced recovery effected by adenosine in group II could not be ascribed to differences in ischemic zone size, collateral flow during occlusion, coronary flow after reperfusion, arterial pressure, heart rate, or other hemodynamic variables. In phase B of the study, dogs received an intracoronary infusion of either saline (group IV [control], n = 6) or adenosine (4 mg/min from 40 to 10 minutes before occlusion [group V, n = 6]). Despite pretreatment with adenosine, the recovery of function in group V was indistinguishable from that in the control group. This study demonstrates that (1) continuous administration of adenosine before, during, and after ischemia results in a significant and sustained attenuation of myocardial stunning; (2) this improved recovery of function cannot be attributed to nonspecific variables, such as collateral flow during coronary occlusion, coronary flow after reperfusion, or other hemodynamic factors, and therefore reflects a direct cardioprotective action of adenosine; (3) the protection against stunning is lost or markedly diminished if adenosine is given only at reperfusion; and (4) administration of adenosine before ischemia does not precondition the myocardium against the stunning induced by a 15-minute occlusion.(ABSTRACT TRUNCATED AT 400 WORDS)

Myocardial Reperfusion Injury: Fact or Myth? A 1993 Appraisal of a Seemingly Endless Controversy a

Early reperfusion of ischemic myocardium is now widely accepted as a cornerstone of therapy for acute coronary syndromes. However, experimental studies have suggested that this approach is not without risk, due to the occurrence of so-called reperfusion-induced injury. The seemingly paradoxical concept that reperfusion can be associated with undesirable events dates back to 1935, when Tennant and Wiggers reported the occurrence of ventricular fibrillation upon reperfusion of dog hearts. I In 1960, Jennings e t a1.2 described adverse structural and electrophysiological changes associated with reperfusion of canine hearts, and in the 1970s the term “oxygen paradox” was coined by Hearse and coworkers to indicate massive cardiac enzyme leakage and ultrastructural injury resulting from reoxygenation of rat heart^.^ Numerous subsequent studies have provided additional evidence that, although early restoration of blood flow is crucial for the prevention of cell death, it may also be associated with a component of injury consisting ofcharacteristic metabolic, electrophysiological, morphological, and functional derangements.4.5 Among these derangements, three have been postulated to be induced by reperfusion itself and to have pathophysiological importance: ventricular arrhythmias (especially ventricular fibrillation); transient mechanical dysfunction, also termed “myocardial stunning”; and myocardial cell death (infirction). The purpose of this essay is to review the experimental evidence for the existence of “reperfusion injury” with a focus on the three derangements that are of potential clinical significance, namely, arrhythmias, stunning, and infirction.

Moderate ischemic injury and myocardial stunning

Reperfusion of acutely ischemic myocardium is associated with a constellation of characteristic structural and functional derangements, which range widely in severity [1]. At one end of the spectrum are transient, completely reversible abnormalities such as reperfusion arrhythmias and postischemic myocardial dysfunction or “myocardial stunning” [2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14]. At the other end are severe, irreversible abnormalities such as cell death (infarction). Thus, myocardial stunning should be considered as a mild, sublethal sequela of ischemia/reperfusion injury.

Oxidative Stress in the Pathogenesis of Postischemic Ventricular Dysfunction (Myocardial “Stunning”)

Since its first description in 1982 by Braunwald and Kloner (1982), extensive research has focused on the phenomenon of myocardial “stunning” or postischemic dysfunction, and on the elucidation of its mechanisms. Only a handful of other areas of cardiology in the 1980s have generated so much interest and experimental work in such a short time span. As is often the case with newly described pathophysiological entities, several pathogenetic hypotheses were initially advanced (for review, see Bolli, 1990). At the time of this writing, the “oxyradical” and the “calcium” hypotheses appear to be the most plausible explanations for stunning (for review, see Bolli, 1990).

Wirkung der ACE-Hemmer auf das myokardiale Ischämie-/Reperfusionstrauma: Eine Übersicht

Es gibt mehrere Mechanismen, uber die ACE-Hemmer wahrend einer myokardialen Ischamie und Reperfusion vorteilhaft sein konnten: dazu gehoren 1. eine reduzierte Bildung von Angiotensin II, 2. ein verminderter Bradykinin-Stoffwechsel, 3. eine antioxidative Aktivitat und 4. moglicherweise andere, noch unbekannte Mechanismen. Eine reduzierte Bildung von Angiotensin II sollte gunstig sein, da dieses Peptid einige Wirkungen ausubt, die fur das ischamische/reperfundierte Myokard moglicherweise schadlich sind; dazu zahlen eine Vasokonstriktion, eine vermehrte Freisetzung von Norepinephrin, die Stimulation von Phospholipase C und/oder A2 und eine erhohte Nachlast mit einer damit verbundenen Zunahme des Sauerstoffbedarfs. Ein reduzierter Bradykininstoffwechsel konnte gunstig sein, indem er die myokardiale Glukose-Aufnahme erhoht, indem er eine Vasodilatation verursacht und indem er die Bildung von Endothelium-derived relaxing factor und von Prostazyklin stimuliert. Obwohl fruhere Studien vermuten liesen, das sulfhydrylhaltige ACE-Hemmer Superoxidanionen „einfangen“, haben neuere Daten gezeigt, das diese Medikamente Hydroxylradikale und unterchlorige Saure „einfangen“, ohne eine Wirkung auf das Superoxidanion. Studien an isolierten Herzen haben ergeben, das ACE-Hemmer die metabolischen, arrhythmischen und kontraktilen Storungen abmildern, die mit der Ischamie und Reperfusion einhergehen, und sie liesen vermuten, das diese gunstigen Wirkungen durch eine Potenzierung von Bradykinin und/oder eine vermehrte Prostazyklinsynthese vermittelt werden. Studien an Modellen eines myokardialen „Stunning“ nach einer kurzen (15minutigen) Ischamie in vivo (narkotisierte Hunde) weisen darauf hin, das ACE-Hemmer die Erholung der kontraktilen Funktion nach einer einzelnen kurzen ischamischen Episode verbessern. Daten uber die Wirkung dieser Medikamente auf das myokardiale „Stunning“ nach einer prolongierten, teilweise reversiblen Episode, nach mehreren aufeinanderfolgenden kurzen ischamischen Episoden und nach einer globalen Ischamie stehen nicht zur Verfugung. Der Mechanismus, auf dem die heilsamen Wirkungen von ACE-Hemmern beim „Stunning“ beruhen, bleibt ein Ratsel. Eine antioxidative Wirkung kann (im Fall thiolhaltiger Molekule) eine Rolle spielen, oder eine Potenzierung von Prostaglandinen (im Fall von Molekulen, die kein Thiol enthalten). Fest steht soviel: die verbesserte Erholung der Funktion, die durch diese Medikamente bewirkt wird, ist nicht auf hamodynamische Effekte zuruckzufuhren oder auf die Hemmung des Converting enzyme per se und auch nicht auf eine „antiischamische“ Wirkung (da die Medikamente wirkten, wenn sie zum Zeitpunkt der Reperfusion verabreicht wurden). Die Wirkungen der ACE-Hemmer auf die myokardiale Infarktgrose bleiben umstritten.

Postischemic Myocardial Dysfunction (Myocardial “Stunning”): Role of Oxidative Stress

It is now recognized that spontaneous reperfusion after coronary spasm or thrombosis is a common occurrence in patients with coronary artery disease. In addition, coronary reperfusion by means of thrombolytic therapy, percutaneous transluminal angioplasty or bypass surgery is rapidly emerging as the fundamental strategy in the management of acute ischemic syndromes. The recent appreciation of the role of reperfusion in the natural history of coronary artery disease, coupled with the explosive growth of interventional recanalization, has provided the impetus to investigate the consequences of restoring blood flow to the ischemic myocardium. Experimental studies have demonstrated that, although early reperfusion limits or even prevents necrosis, this beneficial effect does not lead to immediate functional improvement; rather, the return of contractility in tissue salvaged by reperfusion is delayed for hours, days or even weeks [1–9], a phenomenon that has been termed “stunned myocardium” [10].