Cellular Electrophysiological Changes Research Articles

Investigation of the Alterations in Cellular Electrophysiology Underlying Ventricular Arrhythmia in Dogs with the Multiple Organ Dysfunction Syndrome

Background: Multiple organ dysfunction syndrome (MODS)-specific cellular electrophysiological changes have so far not been reported and it seemed unlikely that they were related to arrhythmogenesis. Methods and Results: Twelve dogs, weight 12 ± 2 kg, were divided into a control group (n = 6) and an MODS group (n = 6). MODS lasting for 72 h was induced by the ‘two-hit’ method in 6 dogs. Ventricular myocytes were enzymatically isolated. Early afterdepolarizations (EADs), action potential duration (APD) and L-type calcium currents (ICa,L) were assessed. Sinus arrhythmias in all MODS dogs (100%; 6 of 6) and premature ventricular beats in 4 MODS dogs (66%; 4 of 6) were recorded, while no arrhythmias were found in the control animals. The prolongation of the APD was associated with a decreased ICa,L, and frequently provoked EADs were the typical electrophysiological alterations in the myocytes of MODS dogs. The action potential prolongation was shortened, the ICa,L blocked and EAD suppressed by using verapamil (100 μmol/l) in the myocytes of MODS dogs (66%; 4 of 6). Conclusion: The changes in cellular electrophysiology within 72 h in the heart of MODS dogs are APD prolongation, markedly decreased ICa,L as well as frequently provoked EAD, the most common types of arrhythmia being sinus arrhythmia and premature ventricular beats. This study suggests that verapamil appears to be an effective agent in reversing alterations in cellular electrophysiology at the early stage of MODS.

Atrial cellular electrophysiological changes in patients with ventricular dysfunction may predispose to AF

Left ventricular systolic dysfunction (LVSD) is a risk factor for atrial fibrillation (AF), but the atrial cellular electrophysiological mechanisms in humans are unclear. This study sought to investigate whether LVSD in patients who are in sinus rhythm (SR) is associated with atrial cellular electrophysiological changes that could predispose to AF. Right atrial myocytes were obtained from 214 consenting patients in SR who were undergoing cardiac surgery. Action potentials or ion currents were measured using the whole-cell-patch clamp technique. The presence of moderate or severe LVSD was associated with a shortened atrial cellular effective refractory period (ERP) (209 +/- 8 ms; 52 cells, 18 patients vs 233 +/- 7 ms; 134 cells, 49 patients; P <0.05); confirmed by multiple linear regression analysis. The left ventricular ejection fraction (LVEF) was markedly lower in patients with moderate or severe LVSD (36% +/- 4%, n = 15) than in those without LVSD (62% +/- 2%, n = 31; P <0.05). In cells from patients with LVEF <or= 45%, the ERP and action potential duration at 90% repolarization were shorter than in those from patients with LVEF > 45%, by 24% and 18%, respectively. The LVEF and ERP were positively correlated (r = 0.65, P <0.05). The L-type calcium ion current, inward rectifier potassium ion current, and sustained outward ion current were unaffected by LVSD. The transient outward potassium ion current was decreased by 34%, with a positive shift in its activation voltage, and no change in its decay kinetics. LVSD in patients in SR is independently associated with a shortening of the atrial cellular ERP, which may be expected to contribute to a predisposition to AF.

Phosphoinositide signalling and cardiac arrhythmias

Arrhythmias arise from a complex interaction between structural changes in the myocardium and changes in cellular electrophysiology. Electrophysiological balance requires precise control of sarcolemmal ion channels and exchangers, many of which are regulated by phospholipid, phosphatidylinositol(4,5)bisphosphate. Phosphatidylinositol(4,5)bisphosphate is the immediate precursor of inositol(1,4,5)trisphosphate, a regulator of intracellular Ca2+ signalling and, therefore, a potential contributor to arrhythmogenesis by altering Ca2+ homeostasis. The aim of the present review is to outline current evidence that this signalling pathway can be a player in the initiation or maintenance of arrhythmias.

Aldosterone-induced changes in the cardiac L-type Ca2+ current can be prevented by antioxidants in vitro and are absent in rats on low salt diet

Mineralocorticoid receptor (MR) activation modulates cardiac L-type Ca(2+) current (I (CaL)) and transient outward K(+) current (I (to)). The exact circumstances of MR activation, however, remain elusive. Here, we investigate the influence of corticosteroids on MR-mediated changes in cellular electrophysiology. In vitro incubation of adult rat ventricular myocytes with the MR agonist aldosterone (100 nM, 24 h) increased I (CaL) density by 34% (n = 16; p < 0.01). This effect was abrogated by co-incubation with the MR antagonist spironolactone (10 muM). To investigate whether an increase in serum aldosterone concentration is sufficient for an increase in I (CaL) in vivo, rats were subjected to low Na(+) diet (LSD, 0.013% Na(+)) for 28 days. This increased serum aldosterone concentration from 0.19 +/- 0.04 nM (n = 6) in control animals (0.3% Na(+), CSD) to 16.1 +/- 2.1 nM (n = 6; p < 0.0001). Strikingly, I (CaL) density was similar in both CSD and LSD rats (-12.9 +/- 0.9 pA pF(-1), n = 18 and -13.7 +/- 1.1 pA pF(-1), n = 16, respectively), as was I (to) density. In vitro, the glucocorticoid corticosterone (1 microM) also increased I (CaL) and this effect was blocked by spironolactone (10 microM). Co-incubation with corticosterone (1 microM, the normal serum concentration) and aldosterone (100 nM, mimicking low Na(+) intake) did not further increase I (CaL) compared to corticosterone alone. Moreover, co-incubation of myocytes with N-acetylcysteine (10 mM) prevented the aldosterone (100 nM) or corticosterone (1 microM)-induced increase in I (CaL). In conclusion, an increase in serum aldosterone concentration in response to LSD is not sufficient for an increase in I (CaL) density in cardiomyocytes in vivo. This is supported in vitro by the absence of an effect of aldosterone on I (CaL) in the presence of a physiological concentration of corticosterone. Moreover, the cellular redox state may modulate MR activation.

Regulation of ion channels and arrhythmias in the ischemic heart

Ventricular arrhythmias in the setting of ischemic heart disease is a leading cause of mortality in the United States. A better understanding of the complex changes associated with ischemic injury is likely to improve our ability to design better treatment strategies for patients who have coronary events. A major difficulty in treating those patients arises from the complexity of the electrophysiological changes that occur with varying time courses during the ischemic episode and the reperfusion phase. Here, we discuss some of the key cellular and network electrophysiological changes that are associated with ischemic injury and highlight the link between alterations in the energetic/metabolic substrate of the heart and electrical dysfunction.

Age-associated changes in electrophysiologic remodeling: a potential contributor to initiation of atrial fibrillation

Although the incidence of atrial fibrillation (AF) increases with age, the cellular electrophysiological changes that render the atria of aged individuals more susceptible to AF remain poorly understood. We hypothesized that dispersion of atrial repolarization increases with aging, creating a substrate for initiation of AF. Four groups of dogs were studied: adult and old dogs in normal sinus rhythm (SR) and adult and old dogs with chronic AF (CAF) induced by rapid atrial pacing. In each dog, action potentials (AP) were recorded with microelectrodes from isolated endocardial preparations of four regions of right atrium and three regions of left atrium. Two indices of AP duration (APD) heterogeneity were obtained in each dog by calculating standard deviation (SD) and the coefficient of variation (COV=[SD/mean] x 100%). In SR groups, APD averaged across all regions was significantly longer in old than in adult tissues. Both indices of APD heterogeneity were higher in old dogs in comparison to adult. At both ages, CAF was associated with significant APD shortening and a decrease in APD adaptation to rate. While CAF significantly increased both indices of APD heterogeneity in adult dogs, it significantly decreased them in old dogs. The increase of spatial variability in repolarization in old atria may contribute to the initiation of AF in the aged. CAF-induced APD shortening and a decrease in APD adaptation appear to be important for the maintenance of sustained AF in both adult and old atria. The CAF-induced increase in dispersion of repolarization may be important for AF stabilization in adults, while previously reported fibrosis and slowed conduction of premature beats may be important in the old for both AF initiation during SR and subsequent stabilization of AF.

Exercise-induced cardiac hypertrophy: a substrate for sudden death in athletes?

Cardiac hypertrophy is a general term signifying an increase in cardiac mass in response to applied stress. In mild, early hypertrophy, cardiac myocyte contractile performance may be normal or enhanced, whereas in severe hypertrophy associated with cardiac failure, myocyte contraction is reduced in amplitude and increased in duration. In contrast to the varied contractile response, the duration of electrical excitation shows similar changes in both mild and severe hypertrophy. Action potential duration in mid-myocardial and sub-epicardial layers is increased, which is associated with ventricular arrhythmias (in a similar manner to the long QT syndromes from other causes), based on afterdepolarizations and enhanced automaticity. Single-cell studies following exercise training in animal models show that exercise-induced cardiac hypertrophy displays features similar to mild, compensated hypertrophy from other causes. Developed shortening of unloaded single cells is increased or unchanged, and developed force in single myocytes is enhanced. Action potential duration is increased, apart from in the sub-endocardial layer. As with mild hypertrophy from other causes, this will be pro-arrhythmic because of altered dispersion of repolarization and enhanced automaticity. Major abnormalities of the ECG in man include frequent and complex ventricular ectopy, ST segment changes and prolongation of repolarization. In this review a case is presented for regarding exercise-induced cardiac hypertrophy as being no different from mild cardiac hypertrophy resulting from other, pathological causes. The cellular electrophysiological changes are sufficient to account for many of the abnormalities of the ECG, including high-grade ventricular ectopy. Sudden death in trained athletes who have no evidence of specific heart disease may be a direct consequence of cardiac hypertrophy and altered repolarization.

Chronic beta-adrenoceptor blockade and human atrial cell electrophysiology: evidence of pharmacological remodelling.

Chronic beta-adrenoceptor antagonist (beta-blocker) treatment reduces the incidence of reversion to AF in patients, possibly via an adaptive myocardial response. However, the underlying electrophysiological mechanisms are presently unclear. We aimed to investigate electrophysiological changes in human atrial cells associated with chronic treatment with beta-blockers and other cardiovascular-acting drugs. Myocytes were isolated enzymatically from the right atrial appendage of 40 consenting patients who were in sinus rhythm. The cellular action potential duration (APD), effective refractory period (ERP), L-type Ca(2+) current (I(CaL)), transient (I(TO)) and sustained (I(KSUS)) outward K(+) currents, and input resistance (R(i)) were recorded using the whole cell patch clamp. Drug treatments and clinical characteristics were compared with electrophysiological measurements using simple and multiple regression analyses. P<0.05 was taken as statistically significant. In atrial cells from patients treated chronically with beta-blockers, the APD(90) and ERP (75 beats/min stimulation) were significantly longer, at 213+/-11 and 233+/-11 ms, respectively (n=15 patients), than in cells from non-beta-blocked patients, at 176+/-12 and 184+/-12 ms (n=11). These cells also displayed a significantly reduced action potential phase 1 velocity (22+/-3 vs. 34+/-3 V/s). Chronic beta-blockade was also associated with a significant reduction in the heart rate (58+/-3 vs. 69+/-5 beats/min) and in the density of I(TO) (8.7+/-1.3 vs. 13.7+/-2.1 pA/pF), an increase in the R(i) (214+/-24 vs. 132+/-14 MOmega), but no significant change in I(CaL) or I(KSUS). The I(TO) blocker 4-aminopyridine largely mimicked the changes in phase 1 and ERP associated with chronic beta-blockade, in cells from non-beta-blocked patients. Chronic treatment of patients with calcium channel blockers or angiotensin converting enzyme inhibitors (n=11-13 patients) was not associated with any significant changes in atrial cell electrophysiology. The observed atrial cellular electrophysiological changes associated with chronic beta-blockade are consistent with a long-term adaptive response, a type of 'pharmacological remodelling', and provide mechanistic evidence supportive of the anti-arrhythmic actions of beta-blockade.

Electrophysiology of ventricular fibrillation and defibrillation.

The survival rate from ventricular fibrillation is very high for short-duration fibrillation (<30 secs) but decreases to approximately 3% to 30% in out-of-hospital conditions. During short-duration fibrillation, action potentials occur rapidly with no intervening period of electrical diastole; a shock defibrillates by interacting with the fibrillation action potential to produce a uniformly long postshock extension of refractoriness. In contrast, during long-duration fibrillation, ischemia-induced degradation of cellular electrophysiology occurs, which causes intervening periods of electrical diastole between fibrillation action potentials and, thus, slowing of fibrillation frequency. A successful defibrillation shock must now not only prolong refractoriness when delivered during the action potential but must also excite cells during the periods of depolarized diastole. Biphasic waveforms enhance both effects by causing premature membrane repolarization with the first pulse, thereby allowing sodium channel recovery from inactivation so that the second pulse produces better-formed responses both during the cellular action potential and during the depolarized diastole. Therefore, biphasic waveforms remain superior to monophasic waveforms for treatment of long-duration fibrillation. Improved understanding of the ischemia-induced changes in cellular electrophysiology will suggest further improvements in both defibrillator waveforms and resuscitation techniques.

Cellular electrophysiological changes in the hippocampus of freely behaving rats during local microdialysis with epileptogenic concentration of N-methyl-D-aspartate

N-methyl-D-aspartate (NMDA) receptor dysfunctions are thought to be involved in the pathophysiology of seizures of hippocampal origin. While the cellular effects of excessive NMDA receptor stimulation have been widely studied in vitro, no data are available on the sequence of cellular electrophysiological events that follow the overstimulation of hippocampal NMDA receptors in awake, behaving subjects. Therefore, the present study addressed this problem. Intrahippocampal microdialysis with 500 μM NMDA was performed in freely behaving rats, and the electrical activity of single neurons in the dialysis area were monitored. In all recorded neurons ( n = 9), regardless of their type, NMDA induced a long-lasting electrical silence preceded in most cells by a brief but robust firing rate increase. During these firing rate increases, place cells lost the spatial selectivity of their discharges, and a gradual reduction in the amplitude of the action potentials was also observed. Remarkably, electroencephalographic (EEG) seizures developed exclusively after the appearance of cellular electrical silence in the recording/dialysis site. The NMDA-induced electrophysiological changes were reversible. This study demonstrates that the combined single-cell recording–intracerebral microdialysis technique can be readily used for inducing focal epileptiform events in the hippocampus and monitoring the induced cellular electrophysiological events in behaving animals.

Sequential change in action potential of rabbit epicardium during and following radiofrequency ablation.

Although radiofrequency (RF) catheter ablation is used to treat certain cardiac arrhythmias, little is known regarding transient changes in cellular electrophysiology during and following RF delivery. Optical recordings of action potential (OAP) with voltage-sensitive dyes allow immunity from electrical noise during RF delivery. The purpose of this study was to clarify the possible synergistic effects of both the thermal and electrotonic components of RF ablation. In this study, OAPs were recorded on the epicardium of 16 isolated Langendorff-perfused rabbit hearts within or adjacent to lesions made by RF catheters. Hearts were perfused at room temperature with Tyrode's solution containing 2,3-butanedione monoxime and stained by the voltage-sensitive dye di-4-ANEPPS. OAPs were recorded before, during, and after RF pulses. Within the lesion, the action potential duration at 80% repolarization (APD80) of OAP decreased rapidly during the RF pulse, without recovery following the pulse. In the border zone surrounding the lesion, the RF energy resulted in a rapid decrease in APD80, which recovered promptly after the pulse (recovery time constant: 82 +/- 37 sec). APD80 was nonlinearly related to temperature during the RF ablation and responded faster to RF ablation than to purely thermal injury. The application of RF energy results in significant changes in myocardial cellular electrophysiologic properties. The RF energy has a combination of thermal and electrotonic effects on the myocardial tissue. The results of this in vitro study may illustrate the cellular basis for commonly observed phenomena in clinical practice.

High-resolution fluorescent labeling of living cerebellar slices

In the present study, we extend previous research on staining of living brain slices with fluorescent phospholids. This new procedure allows high-resolution staining of specific cell types, in particular, Purkinje cells, in the cerebellar slice while not affecting the intrinsic electrical activity of the tissue. Four different nitrobenzoxadiole (NBD)-phospholipids were incorporated into living cerebellar slices via loading from small unilamellar vesicles (SUVs), composed of a carrier and the fluorescent lipid. The labeled acidic phospholipid, NBD-phosphatidic acid (NBD-PA), produced the highest resolution images with exquisite labeling of the dendritic fields. The label was incorporated predominantly into the Purkinje cell body (excluding the nucleus), with more diffuse staining in other cell types, including stellate, basket and granule cells. The labeled lipid concentration and composition of the carrier lipid were significant in determining the specificity of labeling. Labeling, which was optimal after a 1 h incubation, was present throughout the depth of the slice. This procedure provides a promising approach to fluorescent labeling that will allow simultaneoss monitoring of changes in cellular morphology and electrophysiology of living brain slices.

High-resolution fluorescent labeling of living cerebellar slices

In the present study, we extend previous research on staining of living brain slices with fluorescent phospholids. This new procedure allows high-resolution staining of specific cell types, in particular, Purkinje cells, in the cerebellar slice while not affecting the intrinsic electrical activity of the tissue. Four different nitrobenzoxadiole (NBD)-phospholipids were incorporated into living cerebellar slices via loading from small unilamellar vesicles (SUVs), composed of a carrier and the fluorescent lipid. The labeled acidic phospholipid, NBD-phosphatidic acid (NBD-PA), produced the highest resolution images with exquisite labeling of the dendritic fields. The label was incorporated predominantly into the Purkinje cell body (excluding the nucleus), with more diffuse staining in other cell types, including stellate, basket and granule cells. The labeled lipid concentration and composition of the carrier lipid were significant in determining the specificity of labeling. Labeling, which was optimal after a 1 h incubation, was present throughout the depth of the slice. This procedure provides a promising approach to fluorescent labeling that will allow simultaneoss monitoring of changes in cellular morphology and electrophysiology of living brain slices.

Detrimental effects of electrical fields on cardiac muscle

The use of controlled electrical shock as a therapy to manage cardiac arrhythmia is a practice commonly used today. High intensity electrical fields are generated near the shock electrodes, and if the electrodes are placed directly on or inside the heart as is often the case, tissue injury and dysfunction may result if the shock intensity is too high. Many factors influence the degree of dysfunction, including the intensity of the shock poise, duration of the pulse, waveform shape, size and position of the electrodes, and physiological state of the heart. One of the most immediate indications of aberrant cardiac function is an abnormality in the electrocardiogram, which results from field-induced changes in cellular electrophysiology. This article reviews results obtained primarily from animal experiments which delineate the intensities of electrical field that produce electrical dysfunction at various structural levels of the heart. Possible mechanisms underlying the detrimental effects of electrical fields are presented with the main focus on electroporation of the cell membrane. Other mechanisms that are described include formation of oxygen-derived free radicals, conformational damage to ionic pumps/channels, barotrauma, and hyperthermia. Differences between cathodal and anodal shock effects, as well as factors which may ameliorate electrical field-induced cardiac dysfunction, are also discussed.

Cellular Electrophysiological Changes Induced In Vitro by Radiofrequency Current: Comparison with Electrical Ablation

The purpose of this study was to examine the cellular electrophysiological effects of radiofrequency energy delivery in an in vitro canine epicardial preparation and compare the effects of those of high energy electrical ablation in a similar preparation. Ten joules of direct current energy or 40 volts of radiofrequency energy were delivered by a 6 French 2-mm tip catheter to the epicardial surface of 2 x 3 cm epicardial strips superfused with Tyrode's solution. Direct current energy delivery produced a crater and central zone of necrosis surrounded by a border zone of viable but damaged tissue that extended up to 10-12 mm from the site of energy delivery. Cellular electrophysiological abnormalities that included a less negative resting membrane potential, decreased peak dV/dT, decreased action potential amplitude, and decreased action potential duration (APD) were approximately linearly related to the distance from the crater edge. In addition, viable and inexcitable cells were frequently interspersed. Between 2 and 5 mm from the crater edge, 36.4% of the cells were inexcitable whereas others displayed normal action potential characteristics. In contrast, radiofrequency current produced a central zone of necrosis surrounded by a smaller border zone. Cellular damage that was qualitatively similar to that produced by direct current energy extended only up to 6-8 mm from the edge of the crater. In addition, severe abnormalities were noted in intracellular potentials recorded within 2 mm of the ablation site, and only minor abnormalities further away. Lesions were relatively homogeneous. Between 2 and 5 mm from the ablation site only 2.6% of the cells were inexcitable (P < 0.05 vs direct current). In conclusion, radiofrequency current produces lesions that are smaller and more homogeneous than those produced by direct current ablation. Although the border zone is small, a region of partially depolarized but viable myocardium is present after radiofrequency current energy delivery. These findings provide a cellular basis for several clinical observations that have been made following radiofrequency current energy delivery.

In vivo electrophysiological detection of myocardial ischemia through monophasic action potential recording

D ETECTION OF myocardial ischemia by biochemical, mechanical, or electrocardiographic assessment is limited by the fact that one cannot determine the precise region that is affected by reduction of blood flow. This is especially true of the electrophysiological manifestations of ischemia since the initial changes that occur in a small area of myocardium are not indicated by the electrocardiogram (ECG). However, these changes are important because they are involved in the genesis of lethal cardiac arrhythmias. This article will review the evidence that monophasic action potential (MAP) recordings are sensitive to changes in the cellular electrophysiological properties of ischemic myocardium and that they can specifically localize the ischemic zone. The use of the MAP electrode clinically may permit the localization of changes in electrical activity resulting from disease. Additionally, the mechanisms underlying changes in MAP recordings during ischemia will be discussed. To understand the possible cellular mechanisms underlying ischemia-induced changes in MAPS requires a brief review of the cellular electrophysiological changes that are known to occur during ischemia.le3

Platelet-mediated alterations in cardiac cellular electrophysiology

Recent clinical and experimental evidence indicates that platelet activation contributes to the arrhythmogenic effects of myocardial ischaemia, but little is known about the electrophysiological effects produced by controlled platelet activation under conditions of normal perfusion and how these might relate to effects during ischaemia. To investigate this, we studied changes in cardiac cellular electrophysiology and arrhythmogenesis during infusion of platelets [10(8)/ml] in isolated, perfused guinea-pig hearts during normal perfusion and global myocardial ischaemia. Hearts were studied in four groups: group A (n = 4) receiving frozen/thawed (activated) platelets; group B (n = 4) receiving normal platelets in the presence of 10(-9) M platelet activating factor (PAF); group C (n = 9) receiving buffer only during normal perfusion and myocardial ischaemia; group D (n = 9) receiving platelets during normal perfusion and myocardial ischaemia. Infusion of platelets (group D) had no effects during normal perfusion, but activated platelets (group A) decreased action potential duration (APD) from 165 +/- 1 ms to 138 +/- 5 ms (mean +/- SE) at 15 min of normal perfusion (P less than 0.02) and produced ventricular fibrillation (VF) in 3/4 at 21 +/- 1 min. Infusion of platelets in the presence of PAF (group B) produced similar reductions of APD during normal perfusion and VF in 2/4. During ischaemia, platelets (group D) increased the incidence of VF (100% vs 56% group C, P less than 0.05) and enhanced the ischaemia-induced reductions in APD (107 +/- 3 ms vs 121 +/- 5 ms (group C) P less than 0.05 at 15 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Cellular electrophysiological changes during ischemia in isolated, coronary-perfused cat ventricle with healed myocardial infarction.

Cellular electrophysiological consequences of acute ischemia superimposed on healed myocardial infarction were studied in isolated, coronary-perfused cat left ventricles 2-4 months after ligation of multiple distal tributaries of the left anterior descending and circumflex coronary arteries. Oxygenated Tyrode's solution was perfused through the left anterior descending and circumflex coronary arteries, and the preparations were superfused with Tyrode's solution gassed with 95% N2-5% CO2. Transmembrane action potentials were recorded from the endocardial cells in normal and infarcted zones. There were no significant differences in measured action potential variables and refractory periods between cells in the normal and infarcted zones before acute ischemia. When coronary perfusion was discontinued ("ischemia"), resting potential, action potential amplitude, and action potential duration were reduced, and the refractory period was shortened progressively in cells of the normal zone. However, the action potential changes were less prominent, and the refractory period was unchanged in cells in the infarcted zone. As a result, there were significant differences in resting membrane potential, action potential amplitude, action potential duration, and refractory period between cells in the normal and infarcted zones at 10 minutes of ischemia. These differences became larger as the ischemic period was prolonged. Spontaneous rapid ventricular activity was observed during the last 20-30 minutes of ischemia in four of eight preparations with healed myocardial infarction, whereas no spontaneous rapid ventricular activity was recorded in any of six normal heart preparations. Our data suggest that superimposition of acute ischemia on healed myocardial infarction produces electrophysiological inhomogeneities that may enhance arrhythmogenesis.

Cellular electrophysiologic changes and “arrhythmias” during experimental ischemia and reperfusion in isolated cat ventricular myocardium

The cellular electrophysiologic consequences of both regional and global experimental ischemia and reperfusion were studied in the isolated cat myocardium, using conventional microelectrode techniques. Oxygenated Tyrode's solution was perfused through the left anterior descending and circumflex coronary arteries, while the preparation was superfused with Tyrode's solution gassed with 95% nitrogen and 5% carbon dioxide. Electrophysiologic characteristics of endocardial muscle cells were normal during coronary perfusion. When perfusion was discontinued for 30 minutes, resting membrane potential was decreased by 21.6 +/- 4.1%, action potential amplitude was decreased by 29.1 +/- 8.6% and action potential duration was decreased by 54.1 +/- 12.5% (p less than 0.001). Ectopic activity occurred after 5 to 10 minutes of ischemia and was more frequent in regional than in global ischemia (p less than 0.05). Rapid ventricular activity was observed in only 5 (17%) of 29 preparations during ischemia, whereas it occurred in 24 (83%) of 29 preparations during reperfusion. Rapid ventricular activity began 5 to 40 seconds (mean 19) after the start of reperfusion, stopped spontaneously after a mean of 113 +/- 211 seconds and occurred after both regional and global ischemia. The cellular electrophysiologic changes induced by ischemia returned to baseline values within the next 5 minutes. Repeated ischemia and reperfusion runs reproduced the same electrophysiologic changes and rapid ventricular activity. Coronary perfusion with procainamide (20 mg/liter) aggravated the ischemic depressions of action potential amplitude and action potential duration and increased conduction delay during ischemia, but it did not prevent rapid ventricular activity induced by reperfusion. In contrast, verapamil (1 mg/liter) perfusion did not affect the changes in action potential variables during ischemia but prevented reperfusion-induced rapid ventricular activity. Perfusion with calcium ion (Ca2+)-free Tyrode's solution just before ischemia and during reperfusion slowed or prevented reperfusion-induced rapid ventricular activity, without affecting the action potential changes during ischemia. It is concluded that, in these isolated perfused ventricular muscle preparations, different mechanisms may be operative in ischemic and reperfusion arrhythmias and Ca2+ may play an important role in the development of arrhythmias during the reperfusion phase of ischemia/reperfusion sequences.

The cellular electrophysiologic changes induced by high-energy electrical ablation in canine myocardium.

High-energy electrical ablation is a new experimental approach to control arrhythmias. In this study, the cellular electrophysiologic effects of high-energy shocks (5 to 40 J) delivered in vitro to 14 epicardial tissues from 11 dogs were studied in an attempt to understand the nature and extent of injury as well as potential arrhythmogenic mechanisms. In addition, this preparation was used to test the importance of cathode-anode configuration, current density, and fiber orientation in the induction of tissue injury in vitro. Electrophysiologic abnormalities were noted up to 10 mm from the electrode wall, and their extent was determined in part by current density and the cathode-anode orientation. A decrease in resting membrane potential, action potential amplitude, and dV/dT occurred in all tissues after high-energy shocks, which was worst nearest the cathode and of graded severity at increasing distances from the cathode. The most severe effects were noted with high current densities and in tissues located between the cathode and anode. In addition, impaired impulse conduction and abnormal repolarization were documented. Histologic study demonstrated contraction band necrosis immediately after delivery of high-energy shocks. The extent and distribution of the contraction bands was in part dependent on the energy delivered and the cathode-anode configuration. These findings suggest potential mechanisms for arrhythmogenesis and altered regional hemodynamic abnormalities that occur in vivo.