摘要:

AbstractAfter prolonged ischemia, reperfusion of the myocardium with oxygenated blood results in high levels of superoxide anions. Several mechanisms for superoxide anion generation have been proposed, including increased xanthine oxidase activity, neutrophil activation, and arachidonate cascade activation. Superoxide anion accumulation may cause enzyme inactivation and lipid peroxidation in the sarcolemma with resultant intracellular calcium accumulation and excitation‐contraction uncoupling. A review of a number of animal studies has shown that free radical scavengers such as superoxide dismutase and catalase can preserve myocardial function and metabolism during transplantation. In addition, other data indicate a role for inhibitors of free radical generation (i.e., allopurinol or oxypurinol), iron chelators (i.e., deferoxamine), or metabolic substrates such as L‐glutamate in the inhibition of free radical myocardial injury. In addition, glutathione has been demonstrated to produce faster recovery of ventricular function in hypothermia preserved and reperfused rat hearts, presumably by inhibiting free radical production. Confirmatory data for human cardiac transplantation is not yet availa

ISSN:0886-0440    

DOI:10.1111/j.1540-8191.1993.tb01317.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

AbstractInduction of ventricular fibrillation (VF) is an important part of the process of inserting implantable cardioverter defibrillators (ICDs), allowing the measurement of defibrillation thresholds. However, animal studies have revealed that repeated cycles of VF and defibrillation result in depressed left ventricular (LV) function and reduced cardiac output. Short intervals of VF do not affect myocardial contractility but longer periods produce heart failure. Induced VF was used in a canine model to study profound myocardial stunning leading to heart failure, as well as the therapeutic potential of the phosphodiesterase inhibitor, amrinone (combined with epinephrine and norepinephrine). Amrinone was found to significantly (p<0.05) increase contractility when added to a stable preparation supported by epinephrine and norepinephrine infusion; amrinone or catecholamines alone had no effect. In the clinical setting, the following factors may affect LV contractility during ICD surgery: catecholamines released as a result of hypotension; negative VF; ischemia; antiarrhythmic drugs; anesthetics; and bradycardia after device testing. Patients (n = 125) have tolerated ICD insertion well. Early data reveals no significant changes in ejection fraction. Though rare, death due to myocardial stunning and LV power failure can occur during ICD insertion. It may be possible to use arterial pressure monitoring to predict this event in vulnerable patients.

ISSN:0886-0440    

DOI:10.1111/j.1540-8191.1993.tb01318.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

AbstractMechanisms of myocardial stunning include myocardial adenosine triphosphate (ATP) depletion, catecholamine release, and oxygen free radical formation. Although the latter is the most widely supported mechanism, levels of 5′‐nucleotidase (directs AMP dephosphorylation) are inversely related to functional recovery following ischemia and may also have a role in ischemic injury. Previous studies reveal that 5′‐nucleotidase levels increase with age and also vary with species. An inhibitor of this enzyme (alpha, beta methylene adenosine 5′‐diphosphate) was effective in maintaining AMP levels in vitro but was ineffective in dogs due to limited permeability. Observed species‐specific differences in recovery from myocardial stunning may be related to differences in AMP accumulation and subsequent metabolism. Species showing improved recovery from stunning may accumulate AMP as a result of feedback inhibition of 5′‐nucleotidase. Using a model of extreme experimentally‐induced ischemia, we found that adenosine treatment allowed full recovery of ventricular function within 30 minutes, probably by entrapping ATP catabolites. Similarly, enhancement of adenosine production by N‐diarylalkylpeprazine derivatives has also been shown to be cardioprotective in the setting of global normothermic ischemia. Novel strategies for pharmacological intervention in the ATP catabolic pathway should use animal models involving species that are tolerant t

ISSN:0886-0440    

DOI:10.1111/j.1540-8191.1993.tb01319.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

AbstractIn order to study the metabolic consequences of myocardial stunning, repeated coronary occlusions were performed in dogs. The production of CO2, adenosine triphosphate (ATP), phosphocreatine (PCr), and inorganic phosphate (Pi) by myocardial cells was assessed, along with extracellular and intracellular pH. Our results indicate that regional coronary artery occlusion reduces the ability of the myocardium to produce H+and CO2and to replenish ATP post ischemia. These alterations, then, represent the hallmark of metabolic viability during periods of ischemic insult. Decreases in PCr and Piwere completely eliminated during reperfusion and, therefore, are not reflective of myocardial stunning. When normothermic cardiopulmonary bypass (CPB) is instituted and the coronary artery is occluded three times with reperfusion between each occlusion, alterations in myocardial H+and high energy phosphates are identical to those observed using only repetitive coronary occlusion. Systemic hypothermia during CPB does not protect against myocardial stunning; however, it is anticipated that interventions that prevent the reduction in H+and ATP levels may overcome the effects of myocardial stunning that occur during cardiac surgery.

ISSN:0886-0440    

DOI:10.1111/j.1540-8191.1993.tb01320.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

AbstractMyocardial stunning, or reversible postischemic ventricular dysfunction, occurs clinically much more frequently than was originally assumed when this phenomenon was first described in experimental studies. Despite the fact that stunned myocardium may appear histologically normal and have a normal metabolic profile, ventricular contractility is severely impaired. In a number of studies using both global and regional stunning models, we have demonstrated impaired oxygen extraction and abnormal patterns of oxygen consumption. In addition, impaired calcium transport or uptake by the sarcoplasmic reticulum occurs and there is sarcolemmal disruption during stunning despite reversibility of the ischemic injury. Although oxygen free radical production is thought to occur only early during postischemic reflow, the use of oxygen radical scavengers in a model of regional stunning was shown to attenuate the ventricular dysfunction.

ISSN:0886-0440    

DOI:10.1111/j.1540-8191.1993.tb01321.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

AbstractThe effect of myocardial stunning on mitochondrial function was examined in rabbit hearts. After global normothermic ischemia followed by reperfusion, we previously found that mitochondrial high energy phosphate content was not significantly diminished. To determine whether myocardial stunning results from altered excitation‐contraction coupling, we examined function and calcium uptake by sarcoplasmic reticulum (SR). Hearts were subjected to global ischemia under normothermic conditions. Ischemic hearts had significantly lower velocity of Ca2+ uptake by the SR (Vmax36.3 ± 1.94 nmol/min per mg vs 49.3 ± 2.54 nmol/min per mg control) but velocity was restored by reperfusion. Similarly, myocardial ATP content was decreased during ischemia (4.5 ± 1.23 μmol/g dry weight vs 13.6 ± 0.98 μmol/g control) but returned to normal during reperfusion. Incubation of homogenates with 610 μM ryanodine did not alter the difference in Vmaxbetween control, ischemic, or reperfused hearts, suggesting that ischemia affects SR Ca2+ pumping without affecting Ca2+ release. Recovery of calcium uptake during reperfusion also indicates that SR Ca2+ ATPase function is not the major cause of myocardial stunning. Potentiated contractions were studied in a Langendorff heart model, revealing that postrest potentiation (PRP) and peak paired‐pulse potentiation (PPP) increase as a result of ischemia. On reperfusion, PPP also increased, but there was a decrease in PRP of left ventricular pressure (LVP) and LV dP/dt (PRP LV dP/dt = 127% preischemia vs 112% at 2 min postischemia), indicating than an impairment of an SR function other than Ca2+ ATPase occurs during myocardia

ISSN:0886-0440    

DOI:10.1111/j.1540-8191.1993.tb01322.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

AbstractPharmacological modulation of ATP sensitive potassium channels (K+ATPchannels) in vivo may influence ischemia and reperfusion injury of myocardium. The purpose of this investigation was to ascertain the actions of multiple K+ATPchannel openers and interactions with a K+ATPchannel antagonist in a model of stunned myocardium in anesthetized and conscious dogs. The results indicate that the K+ATPchannel openers, aprikalim and nicorandil, enhance recovery of regional contractile function of stunned myocardium. This action was blocked by the selective K+ATPantagonist, glyburide. The beneficial effects of K+ATPchannel openers were not related to changes in systemic hemodynamics or coronary collateral perfusion, but instead may be a manifestation of direct cardioprotective actions of these compounds.

ISSN:0886-0440    

DOI:10.1111/j.1540-8191.1993.tb01323.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

AbstractPossible mechanisms of myocardial stunning at the cellular level include oxygen free radical production, neutrophil‐induced damage, accelerated degradation of adenosine triphosphate (ATP), ischemia‐induced myofibrillar damage, and calcium overload due to abnormal sodium/calcium exchange. Although the role of free radicals is generally accepted, their source(s) and clinical importance remain controversial. Similarly, an association of a declining ATP pool with myocardial stunning is well established but may not have clinical relevance as treatments that result in functional recovery do not always increase ATP levels. Little evidence exists for a strong link between myofibril damage and myocardial stunning. In contrast to these mechanisms, altered calcium homeostasis is an attractive hypothesis because: normal hearts perfused with high levels of calcium develop contractile dysfunctions similar to stunning; stunned hearts perfused with low calcium have increased function; calcium overload inhibition attenuates stunning; and reduced calcium ATPase activities have been found in sarcoplasmic reticulum from stunned hearts. Future research efforts should strive to simultaneously evaluate flow, function, and metabolic changes that occur in the stunned heart. Changes in the latter may eventually be studied using the techniques of molecular biology, integrating knowledge at the molecular level with clinical ne

ISSN:0886-0440    

DOI:10.1111/j.1540-8191.1993.tb01324.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

AbstractThe use of animal models is a valuable approach to the elucidation of the pathophysiology of myocardial stunning. Coronary occlusion followed by reperfusion produces stunning experimentally, mimicking a myocardial infarction followed by thrombolysis, angioplasty, or coronary bypass. Timing of occlusion and duration to avoid necrosis is critically dependent on the animal species used. For example, 10 minutes of occlusion is required in pigs, 20 minutes in canine models, and sheep or rabbits may require ischemic times somewhere in between. Alternatively, two to six cycles of occlusion followed by reperfusion (repetitive occlusion) may be used. In addition, global ischemia with the heart vented and on cardiopulmonary bypass may simulate myocardial stunning. In this case, 30 minutes produces 50% reductions in myocardial contractility in dogs while 10 minutes is needed in pigs. Animal models have also included the study of a stunned heart in an in vitro apparatus. In these models, discontinuation of perfusion for 10 to 15 minutes is needed to produce stunning in rats, 20 minutes in rabbits, and probably longer periods in dogs and pigs. Myocyte cell cultures may also be valuable for studying responses to ischemia and reperfusion at the cellular level. It is generally agreed that cardioplegic protection, antioxidants, metabolic enhancements, and blockade of calcium overload are some of the strategies that can minimize or eliminate myocardial stunning.

ISSN:0886-0440    

DOI:10.1111/j.1540-8191.1993.tb01325.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

AbstractFew studies have examined how load affects the contraction of the myocardium following ischemia. We have therefore developed a canine model in which preload (left atrial pressure) and afterload (mean arterial pressure) are independently varied and heart rate is kept constant. Systolic contraction was found to increase in proportion to preload under preischemic conditions. However, postischemic systolic contractions were reduced and the response to preload was also markedly diminished. Response of systolic thickening to preload was significant in controls (p = 0.003, N = 8) but nonsignificant after 10 minutes of ischemia and 1 hour of reperfusion. Effects of inotropic stimulation were also examined. Dobutamine restored systolic thickening and myocardial contraction to baseline levels following ischemia. However, contraction following dobutamine treatment remained lower than that observed under preischemic conditions. The ideal treatment of the postischemic myocardium should provide low afterload, high heart rate, and high contractility.

ISSN:0886-0440    

DOI:10.1111/j.1540-8191.1993.tb01326.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY