Reperfusion-induced arrhythmias are critically dependent upon occluded zone size: relevance to the mechanism of arrhythmogenesis

The relationship between reperfusion-induced arrhythmias and the size of the occluded zone was examined. The isolated perfuse rat heart was used because its negligible collateral flow maximizes susceptibility to arrhythmias and reduces variability. Ischemia lasting 10 min was followed by 10 min of reperfusion. A constant-pressure perfusion system (which precludes coronary steal) permitted measurement of the rapidity of restoration of coronary flow. Mean occluded zone sizes of 0, 7.2 +/- 1.1, 19.5 +/- 1.5, 45.8 +/- 1.7, 30.1 +/- 4, and 100% of the total ventricular weight were obtained by sham ligation, distal, medial and proximal ligation of the left main coronary artery, right arterial ligation and the induction of global ischemia, respectively. Occluded zone size correlated positively (r = 0.86, P less than 0.001) with a linearly-additive arrhythmia score irrespective of the site of ischemia (left versus right ventricle). In globally ischemic hearts, ventricular fibrillation (VF) depended upon ventricular beating rate during ischemia, occurring only if the rate exceeded 150 beats/min. If this factor were taken into consideration, VF incidence exhibited a sigmoidal relationship with occluded zone size. During the first min of reperfusion, the rapidity of restoration of coronary flow was inversely related to occluded zone size (P less than 0.001) and had a small but significant effect on the severity of arrhythmias; slow recovery of flow increased susceptibility. We conclude that when reperfusion is elicited at the moment of peak susceptibility to arrhythmias, VF incidence is determined principally by occluded zone size. Heart rate during ischemia becomes relevant at rates less than 150 beats/min, when a protective effect is seen. Since VF incidence was 100% in hearts reperfused after global ischemia, an interface between non-ischemic tissue and reperfused tissue is therefore unnecessary for arrhythmogenesis during reperfusion, and flow of injury current between non-ischemic and reperfused tissue can be ruled out as a mechanism of arrhythmogenesis. The initiation of reperfusion-induced arrhythmias must therefore take place within the reperfused tissue.     

Potentiation of reperfusion-associated ventricular fibrillation by left ventricular hypertrophy

Important electrophysiological alterations that may predispose hearts to arrhythmias have been described for hypertrophied myocytes, and hypertrophy coupled with ischemia has been associated with an increased incidence of sudden death; however, an influence of hypertrophy on reperfusion arrhythmias has not been previously described. We hypothesized that reperfusion-associated arrhythmias would be potentiated by left ventricular hypertrophy. After induction of renovascular hypertension, 37 awake, unsedated dogs (17 with left ventricular hypertrophy and 20 without hypertrophy) underwent 15 minutes of coronary artery occlusion and reperfusion. All dogs were pretreated with lidocaine bolus injections and with lidocaine by continuous infusion during coronary occlusion and reperfusion. Reperfusion-associated ventricular fibrillation occurred in seven of 17 dogs with left ventricular hypertrophy versus one of 18 dogs without hypertrophy (p less than or equal to 0.05). The presence of hypertension was not significantly associated with an increased incidence of reflow ventricular arrhythmias. Neither QT interval nor area-at-risk was different between the dogs with and without reperfusion ventricular fibrillation; however, increased heart rate just before reperfusion did correlate with an increased incidence of ventricular fibrillation at reperfusion. Thus, 1) left ventricular hypertrophy was associated with a significantly increased incidence of reperfusion-induced ventricular fibrillation after 15 minutes of ischemia, 2) this increased incidence was independent of the presence of hypertension, and 3) lidocaine protected control and hypertrophied hearts against ventricular fibrillation during ischemia but was ineffective in protecting hypertrophied hearts against reperfusion-induced ventricular fibrillation.     

Reperfusion-induced arrhythmias in the isolated rabbit heart: characterization of the influence of the duration of regional ischemia and the extracellular potassium concentration

The systematic investigation of the genesis and control of arrhythmias during ischemia and reperfusion requires a reproducible preparation in which arrhythmias can be induced with relative ease. The requirements for appropriate statistical analysis often requires that large numbers of animals be studied and hence cost becomes an important factor. The rat offers many advantages but is often criticized on the basis of its atypical action potential and a need exists for an alternative small animal model. The guinea-pig, because of its highly collateralized coronary circulation, cannot be used for the induction of regional ischemia and the rabbit is often dismissed on the grounds that it has a low incidence of arrhythmias. In the present study we have shown that if the perfusion conditions (duration of ischemia and extracellular potassium concentrations) are appropriately selected then the rabbit heart exhibits a high and reproducible susceptibility to reperfusion-induced arrhythmias. Hearts (n = 10 in each group) were subjected to 20 min of regional ischemia induced by coronary artery ligation, the potassium concentration of the perfusate being 2.50, 2.75, 3.00, 3.25, 3.50 or 4.38 mM. A bell-shaped relationship was demonstrated with an optimum susceptibility at 3.00 mM where 60% of the hearts exhibited reperfusion-induced ventricular fibrillation and 80% of the hearts exhibited ventricular tachycardia. With concentration of potassium above 3.00 mM there was a progressive decline in susceptibility (only one out of ten hearts fibrillated when potassium was 4.38 mM). With concentrations of potassium below 3.00 mM there was also a reduction in susceptibility to fibrillation. Using an optimally arrhythmogenic concentration of 3.00 mM potassium, hearts (n = 10 in each group) were subjected to 10, 15, 20, 25, 30 or 40 min of regional ischemia followed by 5 min reperfusion. A bell-shaped time-susceptibility curve was obtained such that with increasing durations of ischemia from 20 to 30 min there was an increasing incidence of reperfusion-induced arrhythmias. Beyond this optimum (at which 60% exhibited reperfusion-induced ventricular fibrillation) there was a decline in the susceptibility of the hearts to fibrillation. Heart rate and coronary flow exhibited no consistent significant relationship with either potassium concentration or duration of regional ischemia. Studies of the time of onset and duration of reperfusion-induced arrhythmias showed that 90% of arrhythmias were initiated within the first 60 s of reperfusion but that the duration was highly variable.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of glibenclamide on ventricular arrhythmias and cardiac function in ischaemia and reperfusion in isolated rat heart.

OBJECTIVE: The aim was to investigate the effects of glibenclamide, a specific blocker of the ATP sensitive potassium channel, on the incidence of ventricular arrhythmias and the functional changes occurring during myocardial ischaemia and reperfusion. METHODS: Hearts (n = 10 per group) were obtained from male Wistar rats, weight 250-300 g. The study was performed in isolated Langendorff perfused rat hearts subjected to ligation of the left coronary artery and reperfusion. Because of the occurrence of arrhythmias, cardiac function was not evaluated during reperfusion. Glibenclamide (1 or 10 microM) was added to the perfusion solution before the coronary artery occlusion, during ischaemia or after reperfusion. In some experiments the incidence of various durations of ischaemia (5, 10, 15, and 30 min) was evaluated. RESULTS: During the preischaemic period, glibenclamide induced a marked reduction in coronary flow, with a slight decrease in heart rate and left ventricular pressure. The ischaemia induced decrease in left ventricular pressure was markedly attenuated when glibenclamide was given before ischaemia. Thus the isovolumetric left ventricular pressure measured after 15 min ischaemia, which represents 59(SEM 6)% of the preischaemic value in the control group, was increased to 82(9) and 94(8)% in presence of glibenclamide (1 and 10 microM, p < 0.05 respectively). The effect was less pronounced when glibenclamide was added to the perfusion fluid during the ischaemic period. None of the hearts showed ventricular fibrillation during the ischaemic period. Glibenclamide (1 and 10 microM) did not reduce the incidence of reperfusion induced ventricular fibrillation. However, a defibrillatory action was observed since glibenclamide reduced the duration of ventricular fibrillation during reperfusion. CONCLUSIONS: Glibenclamide may increase the probability of spontaneous termination of ventricular fibrillation and facilitate the restoration of the myocardial function during regional ischaemia.     

Prevention of ischemic and reperfusion arrhythmias using the calmodulin blocker trifluoperazine

Models of ischemic and reperfusion arrhythmias were reproduced in isolated rat hearts by means of the ligation and subsequent reocclusion of the left descending coronary artery. The introduction of trifluoperazine (TFP, 10(-6) M) and verapamil (2.5 X 10(-8) M) into the perfusion medium produced a 20% depression of contractility in aerobic conditions; an additional depression of contractility at 20 min of ischemia and 10 min of reperfusion was 40 and 50%, respectively, for TFP and about the same for verapamil, as compared to the control. Antiarrhythmic effect of TFP was much higher, as compared to that of verapamil. The calmodulin blocker reduced fivefold total duration of arrhythmias, whereas the calcium-incorporation blocker only reduced it by 2.5 times. The antiarrhythmic effect of TFP was even more marked, as compared to verapamil, at reperfusion: TFP reduced total duration of ventricular tachycardias and ventricular fibrillations by 2 and 35 times, respectively, while verapamil had no effect on those types of arrhythmia. A possible mechanism of antiarrhythmic action of the calmodulin blocker TFP is discussed.     

Free radicals and reperfusion-induced arrhythmias: protection by spin trap agent PBN in the rat heart

Using the isolated perfused rat heart with transient (10-minute) regional ischemia induced by coronary artery ligation, we have shown that PBN (N-tert-butyl-alpha-phenylnitrone), an organic spin trap agent designed specifically to form "stable" adducts with free radicals in electron spin resonance studies, can dramatically reduce the vulnerability of the myocardium to reperfusion-induced ventricular fibrillation. Studied in the concentration range of 5-1,000 microM/L, PBN added to the perfusate 5 minutes prior to ischemia exerted a dose-dependent protective effect. At the optimum concentration of 30 microM/L PBN reduced the incidence of ventricular fibrillation to 50% (6 of 12) from its control value of 100% (12 of 12). The antiarrhythmic effect was achieved without any substantial effect on coronary flow or heart rate. Investigating whether this was a direct antiarrhythmic effect, operating during reperfusion, or an indirect effect arising from the action of PBN on the heart during ischemia, PBN (30 microM/L) was added to the perfusion fluid 2 minutes before reperfusion. In the control group, 100% of the hearts fibrillated whereas only 50% fibrillated in the PBN group. Additional studies were designed to ascertain whether the drug caused an absolute reduction in vulnerability to reperfusion-induced arrhythmias (irrespective of the duration of ischemia) or whether it only shifted the ischemic time-reperfusion vulnerability curve to the right (i.e., delayed the onset of vulnerability). Thus, studies were undertaken to define the relation between the duration of ischemia and the incidence of reperfusion-induced arrhythmias in control hearts and hearts treated with PBN.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of beta-adrenoreceptor antagonism in the prevention of reperfusion ventricular arrhythmias: effects of acebutolol, atenolol, and d-propranolol on isolated working rat hearts subject to myocardial ischemia and reperfusion

The role of catecholamines in the genesis of ventricular arrhythmias during the reperfusion period following coronary occlusion remains incompletely understood. An isolated rat heart preparation, free from the influence of autonomic innervation or of circulating catecholamines, was used to assess the effects of beta-adrenoceptor blockade. The hearts were prelabeled with tritiated norepinephrine ( NE3H ), and the total radioactivity and that in NE3H were measured in the effluent coronary flow. The left main coronary artery was ligated for 10 minutes after which reperfusion followed. The liberation of NE3H and the development of ventricular tachycardia and fibrillation were monitored throughout. The cardioselective beta-antagonist agent, acebutolol, in a high concentration (1.1 X 10(-4)M), had good beta-antagonist effect in response to the added isoproterenol (10(-6)M); this concentration of acebutolol also suppressed sustained reperfusion ventricular arrhythmias but unexpectedly increased the release of NE3H . Atenolol, another cardioselective agent, did not prevent reperfusion ventricular arrhythmias even in a high concentration of 40 mg/L (1.5 X 10(-4)M). The d-isomer of propranolol, with poorer beta-antagonist properties than the l-isomer, prevented such ventricular arrhythmias in a concentration of 1.3 X 10(-5)M, which was low when compared to that of atenolol. It is proposed that the beta-antagonist activity of the compounds tested could not explain the inhibition of reperfusion ventricular arrhythmias and that another quality such as membrane-stabilizing activity may be involved.     

Increased R-wave amplitude induced by acute myocardial ischemia in the dog: A predictor of malignant ventricular arrhythmias

The ability of an increase of 25 % or greater in the sum of R-wave amplitudes in leads X, Y, Z, L₂, and V₅ to predict the occurrence of malignant ventricular arrhythmias (10 or more ventricular premature beats/min, ventricular tachycardia [5 or more consecutive premature beats], and/or fibrillation) was evaluated in 17 dogs during experimental acute myocardial ischemia. Each dog underwent a 15 minute ligation of the left anterior descending coronary artery followed by reperfusion and after recovery, 2 hours later, a 15 minute ligation of the circumflex coronary artery. During ligation of the left anterior descending coronary artery, 12 of 17 dogs (71%) showed no R-wave increase and no arrhythmias (true-negative response). In 5 (29%) of 17 dogs malignant ventricular arrhythmias developed: 2 of 5 (40%) dogs with arrhythmias had a concomitant R-wave increase (true-positive response), and 3 of 5 (60%) with arrhythmias had a less than 25% increase in R-wave amplitude (false-negative results). During circumflex coronary artery ligation, 13 of 17 (76%) dogs showed both R-wave increases and arrhythmias (true-positive response). Four (24%) of 17 dogs had no arrhythmias: 3 of 4 (75%) with no arrhythmias also had a less than 25% increase in R-wave amplitude (true-negative response), whereas 1 of 4 (25%) dogs with no arrhythmias had an increase in R-wave amplitude (false-positive response). In dogs with both arrhythmias and R-wave increases, R-wave changes preceded the onset of arrhythmias by a mean (± standard deviation) of 1 minute 27 seconds (± 43 seconds). Overall, R-wave increases were highly sensitive (83%), specific (94%), and predictive (94%) for the occurrence of malignant ventricular arrhythmias during experimental acute myocardial ischemia.     

Effect of BN 50739, a new platelet activating factor antagonist, on ischaemia induced ventricular arrhythmias in isolated working rat hearts.

STUDY OBJECTIVE--The aim was to investigate the role of platelet activating factor (PAF) in myocardial ischaemia by using BN 50739, a new specific PAF receptor antagonist with a hetrazepine framework. DESIGN--Isolated working rat hearts were subjected to regional ischaemia, induced by ligation of the left main coronary artery for 30 min, followed by reperfusion. BN 50739 was applied at concentrations of 10(-7), 10(-6), 10(-5) and 5 X 10(-5) M, and its effects on the incidence of ischaemia induced and reperfusion induced ventricular tachycardia and ventricular fibrillation and heart functions, such as heart rate, coronary flow, aortic flow, left ventricular developed pressure (LVDP), its first derivative (LVdP/dtmax), and left ventricular end diastolic pressure (LVEDP), were determined. EXPERIMENTAL MATERIAL--Studies were performed on isolated working hearts of male Sprague-Dawley rats weighing 300-360 g. Hearts were perfused with BN 50739 dissolved in dimethylsulphoxide. Control hearts were perfused with the vehicle. MEASUREMENTS AND MAIN RESULTS--Regional ischaemia triggered ventricular arrhythmias showing high incidence between 12 and 20 min with peak appearance at 16 min. BN 50739 induced dose dependent protection against ventricular tachycardia and fibrillation: incidences declined from their respective control values of 91% and 75% to 33% (p less than 0.05) and 8% (p less than 0.05) after exposure to 10(-5) M, and to 25% (p less than 0.05) and 8% (p less than 0.05) after exposure to 5 X 10(-5) M concentrations. Reperfusion of the ischaemic myocardium resulted in an immediate appearance of ventricular tachycardia and fibrillation, but these were not suppressed by the PAF antagonist. Regional ischaemia slightly reduced heart rate, markedly decreased coronary flow, aortic flow, LVDP and LVdP/dtmax, and increased LVEDP. With the exception of LVEDP, these variables were not influenced by the drug. BN 50739, applied at a concentration of 5 X 10(-5) M, reduced LVEDP significantly during the whole ischaemic period. CONCLUSIONS--Under in vitro conditions PAF is likely to be involved in the genesis of ischaemia induced ventricular arrhythmias since BN 50739, a specific PAF receptor antagonist, exerts a protective effect against these rhythm disturbances. This suggests that PAF antagonists may have benefit in the clinical management of acute myocardial ischaemia.     

Attenuation of reperfusion-induced ventricular fibrillation in the rat isolated hypertrophied heart by preischemic diltiazem treatment

Summary The ability of the calcium antagonist diltiazem to protect against reperfusion-induced arrhythmias in hypertrophied myocardium was studied. Hearts from normotensive and DOCA-salt hypertensive rats were Langendorff perfused and subjected to 10 minutes of stabilization, 10 minutes of left coronary artery occlusion, and 5 minutes of reperfusion. The incidence and duration of ventricular tachycardia (VT) and ventricular fibrillation (VF) during reperfusion were determined and the effects of diltiazem or vehicle (given as a single bolus 3 minutes before coronary artery occlusion) were assessed in hypertrophied and normal hearts. In vehicle-treated (control) hypertrophied hearts, VF incidence was 91% compared with 67% in normal hearts, and the median duration of VF was 272 seconds (mean 207.4±32.3) compared with 27 seconds (mean 110.6±36.6; p<0.05), respectively, suggesting that reperfusion VF is more severe in hypertrophied hearts. In normal hearts, diltiazem 18 µg reduced VT incidence from 92% to 55%, reduced VF from 67% to 27%, and sustained VF from 42% to 9%. In hypertrophied hearts, 18 µg diltiazem reduced the VT incidence from 100% to 58%, reduced VF from 91% to 25% (p<0.01), and sustained VF from 82% to 8% (p<0.01). Median VF duration in this group was reduced to 0 seconds (p<0.05; mean 24.7±22.6). Diltiazem did not significantly affect heart rate or coronary flow rate decreases during ischemia. However, developed tension, at the onset of ischemia, was lower in diltiazem-treated groups than in the control groups. We suggest that the attenuation by diltiazem of reperfusion-induced arrhythmias observed in this model was related to an energy-sparing effect during ischemia. This study shows that diltiazem administered acutely before the onset of ischemia attenuates reperfusion-induced arrhythmias in the hypertrophied myocardium, despite its greater susceptibility to reperfusion-induced arrhythmias.     

Pacing and reperfusion induced arrhythmias: protection by slow heart rate in the rat heart

Using the isolated perfused rat heart with transient (10 min) regional ischaemia induced by coronary artery ligation, we have shown that slow heart rate can dramatically reduce the vulnerability of the myocardium to reperfusion induced ventricular fibrillation and ventricular tachycardia. In the heart rate range of 200-400 beats.min-1, slower heart rates exerted a frequency dependent protective effect against reperfusion induced arrhythmias. At the optimal rate of 200 beats.min-1, the incidence of total ventricular fibrillation (irreversible plus reversible) and ventricular tachycardia fell to 33% and 50% of their control values (100%). The anti-arrhythmic effect was achieved with only a minor (less than 20%) effect on coronary flow. To ascertain whether or not slow heart rate achieved an absolute reduction in vulnerability to arrhythmias irrespective of the duration of ischaemia, hearts were also subjected to 5, 10, 20, 30 or 40 min of ischaemia followed by 30 min of reperfusion with and without pacing at 200 beats.min-1. A bellshaped time-response profile was obtained in both groups. In unpaced controls (n = 12) this gave a maximal vulnerability to arrhythmias after 10 min of ischaemia. In the paced hearts (n = 12) the curve was shifted to the right, with a peak vulnerability at 20 min. These results show that the action of pacing is to exert a delaying effect which extends the duration of ischaemia that can be tolerated before the heart becomes vulnerable to reperfusion induced arrhythmias. Heart rate can have a substantial effect on reperfusion induced arrhythmias and should be considered when making therapeutic interventions and risk assessments in this setting.     

Effect of some free radical scavengers on reperfusion induced arrhythmias in the isolated rat heart

The possible role of oxygen free radicals in the development of reperfusion arrhythmias was investigated using a 10-min period of coronary ligation followed by reperfusion in the isolated rat heart. Superoxide dismutase (5 to 20 u/ml) glutathione (10(-5) to 10(3)M) and ascorbic acid (10(-4) to 5 X 10(-4) M) when given before coronary ligation attenuated the development of reperfusion arrhythmias. Mannitol (2 X 10(-2)M) and catalase (100 and 300 u/ml) did not have any significant effect on reperfusion arrhythmias when given alone but they did potentiate the antiarrhythmic effect of superoxide dismutase. Glutathione, and a combination of superoxide dismutase, catalase and mannitol also reduced the incidence of reperfusion induced ventricular fibrillation when given just before reperfusion. By perfusing hearts with ferricytochrome C it was possible to show an increased reduction of ferricytochrome C during the first minute of reperfusion which could be prevented by the addition of superoxide dismutase. These results provide evidence that oxygen free radicals are produced and may be important in the genesis of reperfusion induced arrhythmias in the isolated rat heart.     

苯那普利对大鼠心肌缺血再灌注心律失常的保护作用

目的　观察苯那普利对大鼠心肌缺血 /再灌注 ( I/ R)心律失常的影响。方法　选用雄性 SD大鼠 3 2只随机等分为二组 :苯那普利组 (苯那普利 10 mg· kg-1 .d-1 )和对照组 (生理盐水 2 ml/ d) ,二周后制作大鼠心肌 I/ R模型 ,观察缺血 10 min再灌注 2 0 min心律失常发生率和持续时间 ,左心室心肌超氧化物歧化酶 ( SOD)、一氧化氮 ( NO)及血压变化。结果　与对照组比苯那普利组大鼠缺血心室颤动 ( VF)发生率、再灌注室性心动过速 ( VT)、VF发生率及死亡率明显降低 ( P<0 .0 1) ;缩短缺血 /再灌注 VT持续时间 ( P<0 .0 1)。苯那普利对血压无明显影响 ( P>0 .0 5 )但可增加左心室心肌 SOD和 NO含量 ( P<0 .0 1)。结论　苯那普利具有抗大鼠 I/ R心律失常作用。     

Effects of Na+/H+ exchange inhibitors in cardiac ischemia.

To investigate a possible protective role of Na+/H+ exchange inhibition under ischemic conditions isolated rat hearts were subjected to regional ischemia and reperfusion. In these experiments all 6 untreated hearts suffered ventricular fibrillation on reperfusion. Addition of 1 x 10(-5) mol/l amiloride or 3 x 10(-7) mol/l 5-(N-ethyl-N-isopropyl)amiloride (EIPA) markedly decreased the incidence and duration of ventricular fibrillation or even suppressed fibrillation completely as in the case of 1 x 10(-6) mol/l EIPA. Both compounds diminished the activities of lactate dehydrogenase and creatine kinase in the venous effluent of the hearts during ischemia. At the end of the experiments tissue contents of glycogen, ATP and creatine phosphate were increased in the treated hearts as compared to control hearts. In an additional experiment the beneficial effects of Na+/H+ exchange inhibition during ischemia was confirmed in vivo with anaesthetized rats undergoing coronary artery ligation. In these animals amiloride or EIPA pretreatment caused a marked reduction of ventricular premature beats and ventricular tachycardia as well as a complete suppression of ventricular fibrillation. The concentration dependent inhibition of Na+ influx via Na+/H+ exchange by amiloride and EIPA was investigated in erythrocytes from hypercholesterolemic rabbits with Na+/H+ exchange activated by exposure to hyperosmotic medium. Furthermore the inhibition of Na+ influx by EIPA after intracellular acidification was studied in cardiac myocytes of neonatal rats. Both agents were effective in the same order of potency in the ischemic isolated working rat heart as in the erythrocyte model in which they inhibited Na+/H+ exchange.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mannitol and reperfusion-induced arrhythmias: possible mechanisms of action in the isolated rat heart

Mannitol has been shown to exert a dose-dependent, antiarrhythmic effect in the rat heart during reperfusion following a brief period of regional myocardial ischemia. Isolated perfused rat hearts were used to determine whether this protective effect is direct (ie, operative during reperfusion) or indirect (ie, due to an action during ischemia). Hearts (12 in each group) were subjected to 5, 10, 20, 30 or 40 mins of regional ischemia which was induced by ligation of the left anterior descending coronary artery. Upon reperfusion 25%, 100%, 83%, 33% and 17%, respectively, of the hearts fibrillated and 8%, 92%, 58%, 17% and 17% remained in irreversible fibrillation for the duration of the reperfusion period. Addition of mannitol (50 mM, the optimal antiarrhythmic dose) to the perfusion fluid throughout the experiment (early administration) caused a shift of this 'bell-shaped' time-vulnerability curve to the right such that the highest incidence of arrhythmias occurred after 20 mins rather than 10 mins of ischemia. Similar shifts were seen in other indices of electrical instability. Regional ischemia caused a 40 to 45% reduction in coronary flow in all groups of hearts, with no significant difference between the control and the mannitol-treated series. Heart rate fell by a mean of 10 to 15% in all control hearts and by a similar extent in mannitol-treated hearts. In additional studies, mannitol (50 mM) was administered 2 mins before reperfusion and throughout the reperfusion period (late administration studies). In the mannitol-free control group 100% of the hearts exhibited fibrillation and 92% remained in fibrillation for the duration of the reperfusion period.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reperfusion arrhythmias in the murine heart: their characteristics and alteration after ischemic preconditioning

In this study, we examined the features of reperfusion arrhythmias and the effect of preconditioning (PC) in the mouse for future application of genetically engineered mice to study mechanisms of this type of arrhythmia. Under pentobarbital anesthesia, reperfusion arrhythmias were induced by temporary occlusion of the left anterior descending coronary artery was occluded for periods ranging from 2 to 15 min and then reperfused. In the second protocol, hearts were preconditioned with 2- or 3-min ischemia and 5-min reperfusion prior to the 5 min of coronary occlusion. An electrocardiogram was recorded throughout the experiment, and arrhythmias were diagnosed according to the Lambeth Convention criteria. The incidences of reperfusion-induced ventricular tachycardia (VT) in hearts that received 2, 3, 5, 10 and 15-min ischemia (n = 10∼14) were 0, 9, 73, 55 and 30%, respectively. Ventricular fibrillation (VF) was not observed upon reperfusion regardless of the ischemia duration. PC with 2-min ischemia and with 3-min ischemia (n = 10 for each PC) reduced the incidences of reperfusion VT after 5-min ischemia to 40% and 10%, respectively. However, in mice that developed reperfusion VT, the VT duration was similar to that in non-preconditioned controls, ranging from 1 to 16 s. These results suggest that the relationship between ischemia duration and incidence of VT upon subsequent reperfusion is “bell shaped ” and that PC has anti-arrhythmic effects in the mouse, as it does in anesthetized rat hearts. However, there appear to be differences in the incidence of reperfusion-induced VF and the duration of reperfusion VT between these species. Thus, the present murine preparation, appears to be a useful model for studying the mechanism of reperfusion VT and PC, though it does not share all of the features of reperfusion arrhythmias with the anesthetized rat preparation. Received: 11 February 1999, Returned for revision: 9 March 1999, Revision received: 17 May 1999, Accepted: 8 June 1999     

Susceptibility of hypertrophied rat hearts to ventricular fibrillation during acute ischemia

This study compared arrhythmias induced by acute ischemia in Langendorff preparations of normal and hypertrophied rat hearts. Left ventricular pressure overload was induced by partial ligation of the abdominal aorta 6 to 8 weeks prior to study. The ratio of left ventricular weight to body weight (LVW/BW) and systolic blood pressure (SBP) were significantly higher in two groups of rats with hypertrophied hearts (moderate hypertrophy: 2.68 +/- 0.06 mg/g, 182 +/- 3 mmHg; severe hypertrophy: 3.31 +/- 0.03 mg/g, 238 +/- 5 mmHg) than in normal hearts (2.18 +/- 0.03 mg/g, 125 +/- 3 mmHg), while there were no differences in body weights. During 30 min of ischemia produced by left coronary artery occlusion in the Langendorff preparations, ventricular fibrillation occurred in six of 20 (30%) normal, six of nine (67%) moderately hypertrophied, and 14 of 14 (100%) severely hypertrophied preparations (P less than 0.001 normal vs severely hypertrophied). Tachyarrhythmias occurred in 15 of 20 (75%) normal, eight of nine (89%) moderately hypertrophied, and 14 of 14 (100%) severely hypertrophied hearts. Heart rate and coronary efflux before and during the ischemic period did not differ between normal and hypertrophied hearts. The ratio of non-perfused to perfused areas of the left ventricle, measured by Evans blue dye staining and with computerized planimetry, also was not different for normal (57.6 +/- 2.3%) and hypertrophied hearts (moderate hypertrophy 62.5 +/- 3.3%, and severe hypertrophy 59.1 +/- 2.0%). Additional control studies using larger hearts from older rats also indicate that myocardial mass was not an important determinant of ischemic arrhythmias in hypertrophy. Prolongation of endocardial and epicardial conduction time during 30 min of ischemia was not different between normal and hypertrophied hearts. Action potential duration and refractory periods were significantly longer in ventricular cells of hypertrophied hearts than in normals, and superfusion with hypoxia/zero glucose solution shortened these parameters to a greater extent in hypertrophied cells. These results lead us to conclude that hypertrophied hearts have a greater susceptibility to ventricular fibrillation during acute ischemia, and that dispersion of refractoriness may play a role in this phenomenon.     

Effect of preconditioning ischemia on reperfusion arrhythmias after coronary artery occlusion and reperfusion in the rat

Severe arrhythmias occur predictably on reperfusion after 5 minutes of coronary occlusion in the rat. There is little data available on whether ischemic preconditioning (PC) of hearts can reduce the incidence of such arrhythmias. The effect of PC (three cycles of 2 minutes of coronary occlusion and 5 minutes of reperfusion) on development of arrhythmias after a subsequent 5-minute coronary artery occlusion and reperfusion was studied. Rats (n = 16 each group) underwent 5-minute occlusion and reperfusion alone or preceded by PC; arrhythmias were monitored during ischemia and for 10 minutes of reperfusion, and biopsies were taken for creatine phosphate and adenosine triphosphate in ischemic and nonischemic zones of the left ventricle. PC reduced the incidence of ventricular tachycardia (VT) during occlusion (81% control versus 13% PC, p less than 0.001). On subsequent reperfusion, ventricular fibrillation (VF) developed in zero PC animals versus 13 (81%) of controls (p less than 0.001), and irreversible VF in zero of PC versus seven (44%) of controls (p = 0.007). VT occurred in four (25%) of PC versus all (100%) of controls (p less than 0.001). PC reduced mean duration of VT plus VF from 320 +/- 54 to 5 +/- 1 seconds (p less than 0.001) and delayed arrhythmia onset from 8 +/- 2 to 85 +/- 35 seconds after reperfusion. There was no difference in creatine phosphate levels in the ischemic zone at the end of reperfusion in PC animals compared with controls without irreversible VF (16.2 +/- 4.1 versus 15.5 +/- 3.9 nmol/mg protein, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)     

Exercise training after experimental myocardial infarction increases the ventricular fibrillation threshold before and after the onset of reinfarction in the isolated rat heart

Previous work has shown that exercise training increases the ventricular fibrillation threshold of the isolated perfused rat heart. The aim of our study was to determine whether exercise training that begins after myocardial infarction can similarly increase the ventricular fibrillation threshold. Rats that had suffered an experimental myocardial infarction were subject to a running training program. Thereafter, the ventricular fibrillation threshold was measured before and after the onset of acute reinfarction induced by a second coronary artery ligation. Ventricular fibrillation thresholds were significantly elevated in trained rats during normoxia (13.7 +/- 2.2 vs. 4.7 +/- 0.8 mA, p less than 0.01) and during acute ischemia (6.8 +/- 1.6 vs. 3.0 +/- 0.7 mA, p less than 0.02). The myocardial cyclic AMP level was lower in the nonischemic zone of the trained hearts (0.21 +/- 0.01 vs. 0.28 +/- 0.01 nmol/g, p less than 0.05), which also had lower cyclic AMP levels after epinephrine challenge (0.50 +/- 0.05 vs. 0.73 +/- 0.09 nmol/g, p less than 0.01; 1.41 +/- 0.11 vs. 1.85 +/- 0.09 nmol/g, p less than 0.02 after epinephrine 10(-7) M and 5 x 10(-6) M injection, trained vs. untrained). Both propranolol 10(-6) M and epinephrine 5 x 10(-7) M attenuated the difference in ventricular fibrillation thresholds before and after second coronary artery ligation and eliminated any difference in cyclic AMP content of both the nonischemic and ischemic myocardial tissue.(ABSTRACT TRUNCATED AT 250 WORDS)     

Spontaneous and electrically induced ventricular arrhythmias during acute ischemia superimposed on 2 week old canine myocardial infarction

The arrhythmogenic effect of acute reversible myocardial ischemia before and 2 weeks after experimental myocardial infarction was investigated in 37 dogs that underwent reversible 10 min occlusion of the first major marginal branch of the left circumflex coronary artery. Subsequently, 24 of the dogs underwent experimental myocardial infarction with permanent left anterior descending coronary ligation, and 13 dogs served as sham-operated controls. Two weeks later, an open chest programmed electrical stimulation was performed in the 13 sham-operated and 24 postinfarction dogs to determine its accuracy in predicting the ventricular arrhythmias that develop during a subsequent episode of acute reversible ischemia. After programmed electrical stimulation, the left circumflex marginal branch was reversibly occluded for 10 min at the same site. The incidence of spontaneous ventricular fibrillation during reversible left circumflex marginal coronary occlusion did not differ from the first to the second study in sham-operated dogs, whereas in the postinfarction dogs, it increased from 13% before infarction to 54% after infarction (p = 0.005). The outcome of programmed electrical stimulation predicted spontaneous ventricular arrhythmias during coronary occlusion in only 21% of the postinfarction dogs. The accuracy of programmed electrical stimulation was 42% and its predictive value was 47% in detecting the dogs with spontaneous ventricular fibrillation. Regional myocardial blood flow measurements by microsphere technique identified the severity of reversible ischemia in the infarct border and periinfarction zones as a correlate of spontaneous ventricular fibrillation during coronary occlusion. In contrast, total infarct size correlated with electrically induced but not with spontaneous ventricular arrhythmias.