Distribution of extracellular potassium and its relation to electrophysiologic changes during acute myocardial ischemia in the isolated perfused porcine heart

An experimental approach is described to quantitate inhomogeneity in extracellular K concentration ([K+]out) in the presence of ischemia and to relate this inhomogeneity to the electrophysiologic changes. Extracellular potassium concentration and local direct-current electrograms from the same sites were measured in isolated perfused pig hearts with the use of multiple electrodes. Dispersion of [K+]out is described under three conditions: (1) during regional ischemia in the "central zone" and the "borderzone", (2) during global ischemia, and (3) during perfusion of the heart with a high-K perfusate. Inhomogeneity was greatest during regional ischemia, especially in the borderzone, where generally lower concentrations were measured. When during regional ischemia the normal zone was perfused with a high-K perfusate, dispersion in the ischemic borderzone diminished, and higher concentrations than in the central zone were measured. During global ischemia inhomogeneity was slightly larger than during high-K perfusion. Dispersion during the latter was considered due to experimental error. A decrease in [K+]out during regional ischemia after the initial increase was closely correlated with electrical recovery of the electrograms. This decrease occurred earlier in the borderzone than in the central zone. During ischemia [K+]out was not related to the occurrence of monophasic electrograms, which are indicative of the absence of local regenerative responses. For every single electrode position a linear relationship between TQ depression and [K+]out was found, the slope of which varied with the position of the electrode. When all sites were taken together, there was no correlation between TQ depression and [K+]out. We conclude that: (1) inhomogeneity of K+ is largest in the borderzone, (2) potassium flows from the ischemic zone into the normal zone, (3) transient electrical recovery is related to a decrease (after an initial increase) in [K+]out, which is at least partly due to a flow of K+ toward the normal zone, (4) monophasic ("block") electrograms can be recorded from intrinsically excitable tissue, (5) for every single site in the ischemic region there is a linear relationship between local [K+]out and local TQ segment depression, and (6) the degree of TQ depression at a particular site is not a reliable index of the degree of ischemic injury at that site.     

Coexistence of two types of ventricular fibrillation during acute regional ischemia in rabbit ventricle

INTRODUCTION: We previously reported that a normal ventricle can demonstrate two types of ventricular fibrillation (VF), depending on the underlying electrophysiologic characteristics at the time of VF induction. We hypothesize that the two types of VF can coexist in acutely ischemic ventricles. METHODS AND RESULTS: Optical mapping studies were performed with di-4ANEPPS in 15 Langendorff-perfused rabbit hearts. Coronary artery branches were ligated to create regional ischemia in 10 hearts. Action potential duration measured to 50% repolarization (APD50) during ischemia showed an area with uniformly shortened APD50 (zone 1), an area with normal or lengthened APD50 (zone 3), and an area in between with an APD50 gradient (zone 2). Ischemia flattened APD restitution (APDR) slope and reduced conduction velocity in zone 1, creating a condition for type II VF. APDR steepened and the conduction velocity changed little in the nonischemic zone (zone 3), creating a condition for type I VF. During induced VF, the dominant frequency in zones 2 and 3 progressively increased after ischemia onset. The dominant frequency in zone 1 (ischemic zone) first decreased and then slightly increased but typically remained less than the dominant frequency in zone 3. The number of wavebreaks increased with time in all three zones (baseline: 4.3 +/- 1.5; 30 min: 11.7 +/- 5.6; 60 min: 15.6 +/- 11 per frame; P < 0.01). CONCLUSION: Two types of VF can coexist during acute regional ischemia. Both ischemic and nonischemic regions develop proarrhythmic changes during regional ischemia, thus contributing to increased ventricular vulnerability to VF and sudden death during acute coronary occlusion.     

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.     

心肌缺血早期室性心律失常发生机制的探讨

同步描记缺血和非缺血边缘区单相动作电位及体表心电图，探讨心肌缺血早期室性心律失常发生的可能机制。结果显示，不仅心室肌激动传导时间差异性延迟和复极化离散与心肌缺血性心律失常的发生有关，而且早期后去极化和触发活动也可能是缺血性心律失常启动的重要因素，并与折返机制互相影响。     

Alterations in electrophysiological properties during canine myocardial ischemia--variation with location in the ischemic zone in vivo

We examined electrophysiological properties of the ischemic myocardium of the canine heart. Multiple bipolar electrodes for stimulation or for recording electrograms were placed on the epicardial surface and at the endocardium of the ventricle. The time course of changes in excitability threshold, in effective refractory period and in local conduction time during ischemia was estimated at the epicardial and endocardial sides of the central ischemic zone, at the epicardial side of the peripheral ischemic zone and at both sides of the normal zone. Soon after left anterior descending coronary artery occlusion, a rise of excitability threshold, a lengthening of effective refractory period and a prolongation of conduction time consistently occurred in all portions of the ischemic zone. The degree of changes, however, was not uniform: it was greater at the epicardial side of the central ischemic zone. In most experiments, the changes reached maximum within 10 min after occlusion. Then, altered electrophysiological properties recovered to some extent or stabilized. The results indicate that electrophysiological properties deteriorate momentarily after coronary occlusion but then recover or stabilize, and that their changes during acute ischemia are not uniform in the ischemic region but severer at the central zone and epicardial side.     

Electrophysiologic Changes and Ventricular Fibrillation in Acute Regional Ischemia in the Porcine Heart: The Concept of Wavelength

Early Electrophysiologic Changes in Acute Ischemia. Introduction: The purpose of this study was to match changes in conduction velocity, refractoriness, and wavelength during acute regional ischemia with initiation of ventricular fibrillation. Methods and Results: In 30 isolated, Langendorff-perfused pig hearts we measured refractory period duration and conduction velocity in ventricular myocardium during the first minutes of regional ischemia in an attempt to determine the minimal changes in these parameters related to the occurrence of ventricular fibrillation (VF). In addition, we wanted to evaluate whether wavelength, i.e., the product of conduction velocity and refractory period, was a useful parameter to predict the occurrence of arrhythmias, as has been shown to be the case for atrial arrhythmias.¹ The refractory period increased significantly after 1 minute of ischemia at basic cycle length and after one and two premature beats. Longitudinal and transverse conduction velocities varied with ischemic time. Compared to the preocclusion value, the longitudinal conduction velocity decreased significantly, but only after 2 minutes of ischemia and at basic cycle length. Wavelength was the least sensitive parameter for ischemia: neither in the longitudinal nor in the transverse direction did it change significantly even during 5 minutes of ischemia. VF was never induced by applying a single premature stimulus within the ischemic area. It occurred in 33% of the occlusions when three successive premature stimuli were delivered from within the ischemic zone, and in 100% when they were applied to the nonischemic myocardium. Whenever fibrillation was induced, it occurred within 3 minutes following coronary occlusions. Wavelength, neither before nor after coronary occlusion, could predict whether VF would occur. The only difference between hearts that fibrillated by stimulation of the ischemic myocardium and those that did not was that, in the first group, the refractory period at the site of stimulation prolonged significantly less than in the no-VF group. Since electrophysiologic changes within the ischemic zone are inhomogeneous,² an attempt was made to measure simultaneously at 52 sites the onset of inhomogeneity by determining the average interval between local depolarization during VF. This so-called VF interval is an index of local refractoriness.³ The coefficient of variation of the VF interval, taken as an index of spatial dispersion in refractoriness, increased significantly 1 minute after occlusion in the border zone and 2 minutes after occlusion in the central ischemic area. Conclusion: In conclusion, wavelength is not a useful parameter to predict the occurrence of VF in hearts with regional ischemia because of the inhomogeneity in refractoriness, which develops within 2 minutes of ischemia. VF occurs when hearts are stimulated from sites with relatively short refractory periods, either within or outside the ischemic zone. (J Cardiovasc Electrophysiol, Vol. 3, pp. 128–140, April 1992)     

Dietary fish oil reduces the occurrence of early afterdepolarizations in pig ventricular myocytes

Fish oil reduces sudden cardiac death in post myocardial infarction patients. Life-threatening arrhythmias in heart failure are associated with repolarization abnormalities leading to EAD(1) formation. We examined the effects of incorporated fish oil omega3-PUFAs(2) on EAD formation in pig myocytes. Pigs were fed a diet rich in fish oil or sunflower oil (control) for 8 weeks. Myocytes were isolated by enzymatic dissociation and patch-clamped. Susceptibility to EAD formation was tested using E4031 (5 microM), a blocker of I(Kr). The fish oil diet in pigs resulted in increased incorporation of omega3-PUFAs in the sarcolemma of the myocytes compared to the control diet and caused a reduced occurrence of E4031-induced EADs in pig myocytes. A shorter action potential, a reduced action potential prolongation in response to E-4031 and a reduced reactivation of I(Ca,L) by omega3-PUFAs may explain the observed reduction in EADs. A diet rich in fish oil protects against EAD formation.     

Injury current and gradients of diastolic stimulation threshold, TQ potential, and extracellular potassium concentration during acute regional ischemia in the isolated perfused pig heart

During acute regional myocardial ischemia, a "current of injury" flows between the ischemic and the normal tissue. Its direction and magnitude change during the cardiac cycle. During diastole, the injury current flows intracellularly from the ischemic cells toward the normal cells and tends to depolarize the latter. The gain insight into the possible role of the injury current in arrhythmogenesis, we simultaneously determined diastolic stimulation threshold, [K+]o and TQ potential at multiple sites closely spaced across the cyanotic border in Langendorff-perfused pig hearts during the first 10 minutes after occlusion of the left anterior descending coronary artery. The position of the electrodes relative to the border was validated by their response to 1) regional ischemia and 2) selective perfusion with a high-K+ perfusate of the left anterior descending coronary artery. A temporary decrease of diastolic stimulation threshold preceded a rapid increase in the central ischemic zone; a lasting reduction (by +/- 20%) without a concomitant increase of [K+]o was observed at seven sites (of 39 sites tested), five of which were less than 2 mm outside the electrophysiological border. Moreover, up to 4 mm inside the electrophysiological border, a similar lasting decrease of diastolic stimulation threshold was accompanied by a moderate increase of [K+]o. We conclude that 1) the injury current causes increased excitability in normal tissue close to the "ischemic" border and 2) increased excitability related to a moderately increased [K+]o may persist up to 10 minutes of ischemia at the ischemic side of the border. Both factors may facilitate the induction of life-threatening arrhythmias in acute myocardial ischemia.     

Dietary fish oil prevents ventricular fibrillation following coronary artery occlusion and reperfusion

Coronary artery occlusion and reperfusion in the anesthetized rat was used as a whole animal model of arrhythmia and sudden cardiac death to examine the influence of long-term dietary lipid modulation of myocardial membrane fatty acids on the development of cardiac arrhythmias. Feeding rats a diet supplemented with tuna fish oil significantly reduced the incidence and severity of arrhythmias, preventing ventricular fibrillation during both occlusion and reperfusion. Dietary sunflower seed oil reduced arrhythmias during occlusion but not in reperfusion. Dietary fat can modify the vulnerability of the myocardium to arrhythmic stimuli. The efficacy of tuna fish oil in reducing vulnerability to both ischemic and reperfusion arrhythmias suggests a potential beneficial effect of dietary n-3 fatty acids in addition to their influence on hemostasis, plasma lipids, and atherosclerosis that may contribute to their proposed role in lowering cardiovascular disease mortality and morbidity.     

Sympathetic denervation limited to a region of acutely ischemic canine myocardium increases excitability threshold and duration of bipolar electrograms

This study determines the direct effects of sympathetic denervation on excitability threshold and bipolar electrograms in acutely ischemic myocardium. Regional denervation was performed by application of phenol to the epicardium surrounding the ischemic zone in order to eliminate the possible hemodynamic effects that global cardiac denervation may exert on the ischemic zone. Data were obtained during serial occlusions (≤6 minutes in duration) of left anterior coronary artery in open-chest dogs with sympathetic denervation performed before the last occlusion. Late diastolic threshold was measured every 5 seconds by a constant voltage pacemaker which automatically registered threshold in stimulus duration. During ischemia, regional denervation (n = 9) increased peak excitability threshold from 240 ± 51 (standard error of the mean) to 552 ± 182 μs (p < 0.05) and prolonged electrographic duration in epicardium from 19 ± 3 to 25 ± 4 ms (p < 0.025) and in endocardium from 20 ± 3 to 25 ± 4 ms (p < 0.01). Phenol application did not alter aortic pressure, ischemic wall motion (sonomicrometer technique), or ischemic zone blood flow (microsphere technique). Thus, acute sympathetic denervation when limited to ischemic myocardium increases the peak excitability threshold and concomitantly prolongs duration of bipolar electrograms.     

Models of stretch-activated ventricular arrhythmias

One of the most important components of mechanoelectric coupling is stretch-activated channels, sarcolemmal channels that open upon mechanical stimuli. Uncovering the mechanisms by which stretch-activated channels contribute to ventricular arrhythmogenesis under a variety of pathologic conditions is hampered by the lack of experimental methodologies that can record the 3-dimensional electromechanical activity simultaneously at high spatiotemporal resolution. Computer modeling provides such an opportunity. The goal of this review is to illustrate the utility of sophisticated, physiologically realistic, whole heart computer simulations in determining the role of mechanoelectric coupling in ventricular arrhythmogenesis. We first present the various ways by which stretch-activated channels have been modeled and demonstrate how these channels affect cardiac electrophysiologic properties. Next, we use an electrophysiologic model of the rabbit ventricles to understand how so-called commotio cordis, the mechanical impact to the precordial region of the heart, can initiate ventricular tachycardia via the recruitment of stretch-activated channels. Using the same model, we also provide mechanistic insight into the termination of arrhythmias by precordial thump under normal and globally ischemic conditions. Lastly, we use a novel anatomically realistic dynamic 3-dimensional coupled electromechanical model of the rabbit ventricles to gain insight into the role of electromechanical dysfunction in arrhythmogenesis during acute regional ischemia.     

Dietary lipid modulation of ventricular fibrillation threshold in the marmoset monkey.

Programmed electrical stimulation was used to examine the ability of long-term dietary lipid modulation to influence myocardial vulnerability to the induction of ventricular fibrillation in adult marmoset monkeys (Callithrix jacchus). Marmosets fed diets supplemented (to a total of 28.5% of the energy as fat) with polyunsaturated fatty acid (PUFA)-rich tuna fish oil or sunflower seed oil had significantly elevated mean ventricular fibrillation threshold compared with those fed a saturated animal fat supplemented diet or a reference diet not supplemented with fat (11.2% of the energy as fat). Fibrillation threshold was reduced during acute myocardial ischemia induced by coronary artery occlusion but still remained higher in the PUFA-fed animals than either the control or the ischemic threshold in reference or saturated fat supplemented animals. Dietary tuna fish oil was associated with a low incidence of sustained fibrillation episodes and no fatalities. These results indicate that myocardial substrate vulnerability to arrhythmic stimuli is increased during ischemia in a nonhuman primate model but dietary PUFA can reduce vulnerability under both normal and ischemic conditions. Reduced dietary fat intake alone was without effect.     

Recent Insights Pertaining to Sarcolemmal Phospholipid Alterations Underlying Arrhythmogenesis in the Ischemic Heart

Sarcolemmal Phospholipid Alterations and Arrhythmogenesis. Myocardial ischemia in vivo is associated with dramatic electrophysiologic alterations that occur within minutes of cessation of coronary flow and are rapidly reversible with reperfusion. This suggests that subtle and reversible biochemical alterations within or near the sarcolemma may contribute to the electrophysiologic derangements. Our studies have concentrated on two amphipathic metabolites, long-chain acylcarnitines and lysophosphatidylcholine (LPC). which have been shown to increase rapidly in ischemic tissue in vivo and to elicit electrophysiologic derangements in normoxic tissue in vitro. Incorporation of these amphiphiles into the sarcolemma at concentrations of 1 to 2 mole %, elicits profound electrophysiologic derangements analogous to those observed in ischemic myocardium in vivo. The pathophysiological effects of the accumulation of these amphiphites are thought to be mediated by alterations in the biophysical properties of the Sarcolemmal membrane, although there is a possibility of a direct effect upon ion channels. Inhibition of carnitine acyltransferase I (CAT-I) in the ischemic cat heart was found to prevent the increase in long-chain acylcarnitines and LPC and to significantly reduce the incidence of malignant arrhythmias including ventricular tachycardia and fibrillation. This review focuses on the electrophysiologic derangements that are observed during early ischemia and presents data supporting the concept that accumulation of these amphiphiles within the sarcolemma contributes to these changes. The potential contribution of these amphiphiles to the increases in extracellular potassium and intracellular calcium are examined. Finally, recent data pertaining to the accumulation of long-chain acylcarnitines on cell-to-cell uncoupling are presented. In addition to the events reviewed here, there are many other alterations that occur during early myocardial ischemia, but the results from multiple studies over the past two decades indicate that the accumulation of these amphiphiles contributes importantly to arrhythmogenesis and that development of specific inhibitors of CAT-I or phospholipase A may be a promising therapeutic strategy to attenuate the incidence of lethal arrhythmias associated with ischemic heart disease in man.     

Ability of Activation Recovery Intervals to Assess Action Potential Duration During Acute No-Flow Ischemia in the In Situ Porcine Heart

Activation Recovery Intervals During No-Flow Ischemia . Introduction : The ability to assess transmural changes in action potential duration during acute no-flow ischemia is essential to an understanding of the tachyarrhythmias that occur in this setting. The purpose of this study was to determine if activation recovery intervals determined from unipolar electrograms would provide this information.
Methods and Results : We recorded simultaneously transmembrane action potentials and unipolar electrograms from sites located as closely together as possible in the center and at the lateral margin of the ischemic zone during acute no-flow ischemia and correlated the changes in activation recovery intervals obtained from the unipolar electrograms to the changes in action potential duration. We found that the activation recovery intervals provided an accurate measure of the changes in action potential duration during acute no-flow ischemia provided the electrograms had a well-defined, single negative component to the QRS complex with a maximum negative dV/dt > 10 V/sec and a single positive component to the T wave having a maximum positive dV/dt > 1.6 V/sec. Electrograms meeting these criteria comprised 90% of the electrograms recorded at the margin of the ischemic zone throughout 60 minutes of no-flow ischemia. In the center of the ischemic zone, 75% of the recorded electrograms met these criteria for the first 20 minutes of no-flow ischemia. Thereafter, the percentage declined and after 40 minutes of no-flow ischemia, none of the electrograms recorded in the center of the ischemic zone met these criteria.
Conclusion : Activation recovery intervals obtained from unipolar electrograms provide an accurate assessment of changes in action potential duration throughout the ischemic zone during acute no-flow ischemia, provided the characteristics of the electrograms meet specific predetermined criteria.     

Myocardial ischemia and ventricular fibrillation: pathophysiology and clinical implications

Ventricular fibrillation (VF) and myocardial ischemia are inseparable. The first clinical manifestation of myocardial ischemia or infarction may be sudden cardiac death in 20-25% of patients. The occurrence of potentially lethal arrhythmia is the end result of a cascade of pathophysiological abnormalities that result from complex interactions between coronary vascular events, myocardial injury, and changes in autonomic tone, metabolic conditions and ionic state of the myocardium. It is also related to the time from the onset of ischemia. Within the first few minutes there is abundant ventricular arrhythmogenesis usually lasting for 30 min. Triggers for ischemic VF occur at the border zone or regionally ischemic heart. The border zone of ischemia is the predominant site of fragmentation. Acute ischemia opens K(ATP) channels and causes acidosis and hypoxia of myocardial cells leading to a large dispersion in repolarization across the border zone. Abnormalities of intracellular Ca2+ handling also occur in the first few minutes of acute myocardial ischemia and may be an important cause of arrhythmias in human coronary artery disease. Substrate on the other hand transforms triggers into VF and serves to maintain it through fragmentation of waves in the ischemic zone. Thrombin levels, stretch, catecholamine, genetic predisposition, etc. are some of these factors. Reentry models described are spiral wave reentry, 3 dimensional rotors, reentry around 'M' cells and figure-of-eight reentry. Continuing efforts to better understand these arrhythmias will help identify patients of myocardial ischemia prone to arrhythmias.     

Ventricular arrhythmias and local electrograms after chronic regional denervation of the ischemic area in the pig heart

Cardiac denervation has been proved to reduce the incidence of coronary occlusion arrhythmias in digs, but the effect of limiting the extent of sympathectomy to the ischemic area, particularly in hearts with sparse coronary collateral circulation, as in the human heart, needs further investigation. Ventricular arrhythmias and changes in epicardial direct current electrograms induced during acute left anterior descending coronary artery occlusion were recorded in 14 pigs subjected to regional denervation of the ischemic area 2 weeks before; these were compared with findings in 14 sham-operated control pigs. Regional denervation was induced by pericoronary application of phenol above the occlusion site and it was confirmed by the loss of myocardial catecholamine histofluorescence. During 35 min of ischemia, significant differences in occurrence of ventricular premature beats, ventricular tachycardia, ST segment elevation, TQ segment depression and epicardial activation delays were observed between the two groups of experiments, with lower values of each variable in the denervated hearts. Ventricular fibrillation occurred 32 times in 11 control pigs and only 15 times in eight denervated hearts. In contrast, programmed ventricular extrastimuli delivered during 35 to 50 min of ischemia induced 39 fibrillatory episodes in 13 denervated hearts and only 14 episodes in seven control pigs. Thus, denervation limited to the ischemic area in hearts with a human-like coronary artery pattern was associated with a decrease in the magnitude of early ischemic arrhythmias and electrocardiographic alterations, but the procedure was unable to prevent early induction of ventricular fibrillation.     

Late ventricular arrhythmias during acute regional ischemia in the isolated blood perfused pig heart. Role of electrical cellular coupling

OBJECTIVE: Acute ischemia comes with two phases of life-threatening arrhythmias, early (within 10 minutes, 1A) and late (after about 15 minutes, 1B). The mechanism of the latter is unknown and in this paper, we test the hypothesis that a phase of intermediate coupling between surviving epicardium and inexcitable midmyocardium underlies 1B arrhythmias. METHODS: Pig hearts (n=26) were retrogradely perfused with a blood Tyrode's mixture. The left anterior descending artery was occluded. We investigated (1) inducibility of ventricular fibrillation (VF) with programmed stimulation, (2) tissue impedance (Rt) heterogeneity within the ischemic zone, (3) multiple subepicardial and midmyocardial electrograms, (4) subepicardial lactate dehydrogenase (LDH) and glycogen content. RESULTS: In nine of ten hearts, one--three premature stimuli caused VF between 14 and 53 min of ischemia. This typically happened when the Rt of the ischemic zone had increased up to 40% of its final value. More uncoupling terminated the period of VF inducibility. The excitability of the surviving subepicardial layer was depressed during the same period with partial uncoupling, but recovered when the uncoupling from the midmyocardium had progressed further. CONCLUSIONS: We show that 1B-VF can be induced within a distinct time window and coincides with a distinct range of Rt rise. Subepicardium is electrically depressed, presumably through coupling with midmyocardium, complete uncoupling causes subepicardial recovery and terminates the substrate for 1B-VF. Hence, we suggest that the substrate for 1B-VF consists of intermediate coupling of subepicardium and midmyocardium.     

Dietary fish oil reduces the incidence of triggered arrhythmias in pig ventricular myocytes.

BACKGROUND: Fish oil reduces the incidence of sudden cardiac death in postmyocardial infarction patients. Triggered activity is the principal mechanism of arrhythmogenesis under these conditions. OBJECTIVE: The purpose of this study was to test whether dietary fish oil in pigs inhibits Ca2+ overload-induced triggered activity. METHODS: Pigs were fed a diet of fish oil or sunflower oil for 8 weeks. Ventricular myocytes (omega3: fish oil, n = 11; control: sunflower oil, n = 8) were isolated by enzymatic dissociation and used for patch clamp studies and intracellular Ca2+ recordings. Triggered activity was induced by rapid pacing in the presence of norepinephrine. RESULTS: Dietary fish oil reduced the incidence of triggered action potentials and delayed afterdepolarizations compared to control (9.1% in omega3 and 84.6% in control, P <.05), concomitant with a reduction in spontaneous Ca2+ release. Dietary fish oil prevented Ca2+ overload and reduced action potential prolongation in response to norepinephrine (DeltaAPD(90): 23.2 +/- 8.5 ms in omega3 and 107.4 +/- 15.9 in control, P <.05). omega3 myocytes displayed decreased sarcoplasmic reticulum Ca2+ content, reduced L-type Ca2+ current (I(Ca,L)), and less recruitment of the Na+/Ca2+ exchange current (I(NCX)) in response to norepinephrine compared to control. In the absence of norepinephrine, the slow component of the delayed rectifier current (I(Ks)) was larger in omega3 myocytes. In the presence of norepinephrine, I(Ks) increased to the same level in omega3 and control myocytes. CONCLUSION: Dietary fish oil reduces the incidence of triggered activity and prevents Ca2+ overload and AP prolongation in response to norepinephrine. Fish oil may prevent arrhythmias in patients with heart failure.     

Amlodipine, a long-acting calcium antagonist drug reduces ischemia-induced ventricular conduction delay in pig hearts

The effects of amlodipine, a novel, long-lasting calcium channel blocking agent, on ischemia-induced myocardial conduction delay was studied in anesthetized pigs paced at a constant heart rate. Acute coronary occlusion (3 minutes) significantly lengthened time to onset, time to peak and duration of bipolar electrograms recorded from both subendocardial and subepicardial left ventricular sites. After intravenous injection of amlodipine (0.3 mg/kg, n = 6), subsequent periods of ischemia greatly reduced (p less than 0.01) all indexes of subepicardial conduction delay. In the subendocardium, amlodipine decreased only time to onset (-25 +/- 4%, p less than 0.01) within the ischemic zone. Significant delays in all indexes were present during repeated ischemic periods in the placebo-treated control group (n = 5). Amlodipine also increased regional myocardial blood flow within the nonischemic myocardium by 25 +/- 10% and decreased mean aortic pressure by 7 +/- 2% without altering flow in the ischemic region. Left atrial pressure remained unchanged. Indexes of ischemia-induced conduction delay were more rapidly restored after reperfusion in amlodipine-pretreated than in control animals. In conclusion, amlodipine produced a beneficial blood flow-independent effect on ischemia-induced injury potentials. The effect may help to reduce the likelihood of development of lethal ventricular arrhythmias in the early stage of myocardial ischemia in the clinical setting.     

Acute coronary vascular and myocardial perfusion effects of conjugated equine estrogen in the anesthetized dog

Women generally exhibit angina rather than myocardial infarction as the first manifestation of heart disease. Postmenopausal use of hormone replacement therapy, specifically estrogens, is associated with reduced incidence of major cardiac events suggesting estrogen may protect the heart during ischemia. We recently showed that acute administration of conjugated equine estrogens prior to ischemia attenuated the ventricular arrhythmias of ischemia as well as those of reperfusion. This study looks at basal effects of estrogen on coronary blood flow and the effects of estrogen on regional blood flow during ischemia to determine if estrogen exerts its antiarrhythmic effects during ischemia by altering blood flow. Under conditions of natural blood flow, estrogen caused cyclic changes in blood flow. When coronary blood flow was controlled and limited, estrogen increased coronary perfusion pressure (118±8 mmHg vs. 85±10 mmHg in non-treated dogs, P<0.05) demonstrating an overall vasoconstrictor effect. Coronary blood flow and regional myocardial perfusion were determined before and during ischemia in anesthetized dogs with and without acutely-administered estrogen. Colored microspheres were injected at steady state prior to ischemia, and during steady state myocardial ischemia. Conjugated equine estrogen (10 μg/kg), administered about 6 min before ischemia, had no effect on regional perfusion under steady state conditions, nor in the non-ischemic zone during ischemia. Perfusion in the subepicardial and subendocardial ischemic zones in estrogen-treated dogs was significantly lower than in non-treated dogs [0.14±0.01 ml/min/g vs. 0.23±0.02 ml/min/g (P<0.05) in the epicardial ischemic zone; and, 0.15±0.02 ml/min/g vs. 0.22±0.03 ml/min/g (P<0.05) in the endocardial ischemic zone]. We conclude that the acute, systemic administration of estrogen in the anesthetized dog decreases regional perfusion in the ischemic myocardium and causes significant coronary vasoconstriction when flow is controlled and limited. Received: 3 March 1998, Returned for 1. revision: 28 April 1998, 1. Revision received: 29 May 1998, Accepted: 18 June 1998