Quantitative characterization of epicardial wave fronts during regional ischemia and elevated extracellular potassium ion concentration.

This study applied zero-delay wave number spectral estimation as a means of quantifying the changes in activation and recovery sequences of propagating plane waves on the epicardial surface of in situ porcine hearts during regional hyperkalemia and ischemia. Unipolar electrograms (104) were recorded from the left ventricular surface of nine hearts using a plaque electrode array with 1 mm spatial sampling intervals. The objectives were (1) to define a set of parameters capable of quantifying the spatial and temporal changes in measured extracellular potentials associated with localized ischemia prior to the onset of conduction block; (2) to elevate regional levels of extracellular potassium ion concentration and quantify potential changes due to this known physiologic manipulation; and (3) to use quantitative parameters to make statistical comparisons in order to distinguish wave fronts during normal, ischemic and hyperkalemic conditions. Results showed that the parameters of wave number and average temporal frequency and the associated power, as determined from the wave number spectrum, provided statistically significant (p<0.05) quantification of changes in wave front features during normal and ischemic or hyperkalemic conditions. The results were consistent with results obtained from conventional time-space domain methods like isochronal mapping and electrograms, with the advantage of a quantitative result enabling simple comparisons and trend analysis for large numbers of heart beats.

Ability of activation recovery intervals to assess action potential duration during acute no-flow ischemia in the in situ porcine heart. Experimental Cardiology Group, University of North Carolina at Chapel Hill.

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.

Comparison of the effects of regional ischemia and hyperkalemia on the membrane action potentials of the in situ pig heart. Experimental Cardiology Group, University of North Carolina at Chapel Hill.

INTRODUCTION: This study was designed to determine the role of increased extracellular potassium [K+]e on action potential duration (APD) in the in situ porcine heart during acute regional no-flow ischemia. METHODS AND RESULTS: In open chest, anesthetized swine, an arterial shunt from the carotid artery to the mid-left anterior descending coronary artery was created through which a solution of KCl was infused to raise [K+]e. Myocardial [K+]e was determined by potassium-sensitive electrodes, and transmembrane action potential was recorded by floating glass microelectrode. During the first 2 minutes of ischemia, APD at 90% repolarization (APD90) lengthened by 31.2 +/- 1.1 msec (P < 0.05). The comparable increase in [K+]e alone shortened APD90. During the next 6 minutes of ischemia, [K+]e rose to 11.3 +/- 0.3 mM and APD90 showed a decrease. However, the comparable increase in [K+]e by infusion of KCl caused further shortening of APD90 at similar levels of [K+]e. CONCLUSIONS: Acutely ischemic myocardium showed a brief increase in APD90 during the first 2 minutes of ischemia, followed by a fall in APD90 after 2 minutes of ischemia, but the shortening is less than anticipated by the rise in [K+]e. Thus, we hypothesize that other component(s) of ischemia may inhibit action potential repolarization.

Unanticipated lessening of the rise in extracellular potassium during ischemia by pinacidil.

BACKGROUND: The efflux of potassium (K) through the ATP-sensitive K channel is considered an important cause of the rise in extracellular K ([K+]e) during no-flow ischemia. We postulated that agents that enhance K conductance in this channel would enhance the rise in [K+]e. METHODS AND RESULTS: We studied the effects of 10 and 25 mumol/L pinacidil, and ATP-sensitive K channel opener that provides metabolic protection to the ischemic myocardium, on the rise in [K+]e recorded by K-sensitive electrodes, the change in action potential duration (APD) recorded by microelectrodes, and the changes in activation during ischemia in in situ pig hearts and Tyrode-perfused rabbit interventricular septa. Pinacidil 25 mumol/L unexpectedly lessened the rise in [K+]e and the activation delay in both preparations. Pinacidil 10 mumol/L had no effect in the rabbit and only a slight effect in the pig. Both concentrations significantly exaggerated the APD shortening induced by ischemia. By varying stimulation frequency, we demonstrated that the rise in [K+]e during ischemia, both before and after pinacidil, correlated with the time that the action potential was at its plateau voltage. CONCLUSIONS: Our results indicate that the rise in [K+]e during ischemia is due to multiple factors, including K conductance across membrane channels, K driving force as reflected by the time that the action potential is at its plateau voltage, and the metabolic effects of ischemia. The unanticipated lessening of the rise in [K+]e by pinacidil reflects the balance of its effects on these several parameters.

Correlation of ischemia-induced extracellular and intracellular ion changes to cell-to-cell electrical uncoupling in isolated blood-perfused rabbit hearts. Experimental Working Group.

BACKGROUND: The relationships between the metabolic, ionic, and electrical changes of acute ischemia have not been determined precisely because they have been studied under different experimental conditions. We used ion-selective electrodes, nuclear magnetic resonance spectroscopy, and the four-electrode method to perform four series of experiments in the isolated blood-perfused rabbit heart loaded with 5F-BAPTA during 30 to 35 minutes of no-flow ischemia. We sought to determine the relationship between changes in phosphocreatine (PCr), adenosine triphosphate (ATP), intracellular calcium ([CA2+]i), intracellular pH (pHi) extracellular potassium ([K+]e), extracellular pH (pHe), and whole-tissue resistance (rt). METHODS AND RESULTS: In the first 8 minutes of ischemia, [K+]e rose from 4.9 to 10.8 mmol/L, PCr fell by 90%, ATP decreased by 25%, and pHi and pHe decreased by 0.5 U, while [Ca2+]i and rt changed only slightly. Between 8 and 23 minutes, [K+]e changed only slightly; pHi, pHe, and ATP continued to fall, and [Ca2+]i rose. rt did not increase until >20 minutes of ischemia, when pHi was <6.0 and [Ca2+]i had increased more than three-fold. The increase in rt, indicating electrical uncoupling, coincided with the third phase of the [K+]e change. CONCLUSIONS: Our study suggests that cellular uncoupling occurs only after a significant rise in [Ca2+]i and fall in pHi and that these ionic and electrical changes can be identified by the change in [K+]e. Our study underscores the importance of using a common model while attempting to formulate an integrated picture of the ionic, metabolic, and electrical events that occur during acute ischemia.

Is a baseline electrophysiologic study mandatory for the management of patients with spontaneous, sustained, ventricular tachyarrhythmias?

Should the patient being treated for spontaneous, sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) routinely undergo a baseline, diagnostic, catheter electrophysiologic (EP) study? The potential patient advantages of such a policy include identification of the tachyarrhythmia-initiating episodes of presumed VT or VF, prediction of the subsequent risk of VT/VF recurrences, identification of VT mechanisms amenable to cure by catheter ablation, assessment of the response of a patient's VT to attempts at pace termination, evaluation of the patient's candidacy for some of the approaches to VT/VF therapy selection, and enhancement of our understanding of the mechanisms and therapeutics of VT/VF. Disadvantages of such a policy include patient discomfort, patient risks, and cost. Recognizing that the decision to perform a baseline catheter EP study in a patient with VT/VF must be based on an individualized, patient-based, risk-benefit analysis; this review details each of the advantages and disadvantages of doing so to identify patient populations for whom a baseline catheter EP study is or is not usually indicated.

Failure of impulse propagation in a mathematically simulated ischemic border zone: influence of direction of propagation and cell-to-cell electrical coupling.

INTRODUCTION: It is suggested that heterogeneous extracellular potassium concentration, cell-to-cell coupling, and geometric nonuniformities of the ischemic border zone contribute to the incidence of unidirectional block and subsequent development of lethal ventricular arrhythmias. METHOD AND RESULTS: A discrete electrical network was used to model a single cardiac fiber with a [K+]e gradient characteristic of an ischemic border zone. Directional differences in propagation were evaluated by creating discrete regions with increased gap junctional resistance within the [K+]e gradient. Furthermore, the effect of homogeneity/heterogeneity of call length on impulse propagation through the [K+]e gradient in the presence of increased gap junctional resistance was evaluated. The results indicate that failure of impulse propagation occurs at the junction between partially uncoupled and normally coupled cells. Furthermore, propagation failure was more likely to occur as the impulse propagated from a region of high [K+]e to low [K+]e. Heterogeneity in cell length contributes to the variability in the occurrence of unidirectional and bidirectional block. CONCLUSIONS: The onset of cellular uncoupling in an ischemic border zone may interact with the inherent [K+]e gradient leading to unidirectional conduction block. This mechanism may be important for the generation of reentrant arrhythmias at the ischemic border zone.

Electrophysiologic changes in ischemic ventricular myocardium: I. Influence of ionic, metabolic, and energetic changes.

Myocardial ischemia leads to significant changes in the intracellular and extracellular ionic milieu, high-energy phosphate compounds, and accumulation of metabolic by-products. Changes are measured in extracellular pH and K+, and intracellular pH, Ca2+, Na+, Mg2+, ATP, ADP, and inorganic phosphate. Alterations of membrane currents occur as a consequence of these ionic changes, adrenergic receptor stimulation, and accumulation of lactate, amphipathic compounds, and adenosine. Changes in the volume of the extracellular and intracellular spaces contribute further to the ultimate perturbations of active and passive membrane properties that underlie alterations in excitability, abnormal automaticity, refractoriness, and conduction. These characteristic changes of electrophysiologic properties culminate in loss of excitability and failure of impulse propagation and form the substrate for ventricular arrhythmias mediated through abnormal impulse formation and reentry. The ability to detail the changes in ions, metabolites, and high-energy phosphate compounds in both the extracellular and intracellular spaces and to correlate them directly with the simultaneously occurring electrophysiologic changes have greatly enhanced our understanding of the electrical events that characterize the ischemic process and hold promise for permitting studies aimed at developing interventions that may lessen the lethal consequences of ischemia.

Exaggerated atrial repolarization waves as a predictor of false positive exercise tests in an unselected population.

The authors previously postulated that a markedly downsloping PR-segment might be a marker for exaggerated atrial repolarization waves and demonstrated PR-segment appearance to be an independent predictor of a false positive exercise test. This study was conducted to determine the sensitivity, specificity, and predictive value of markedly downsloping PR-segments for predicting false positive exercise tests. The study group consisted of 82 consecutive patients with a positive exercise test (> or = 1.0 mm horizontal ST depression) and a normal resting electrocardiogram. Tests were predicted to be false positive based on previously defined criteria: (1) markedly downsloping PR-segments in two or more of leads II, III, and aVF and (2) exercise duration 4 minutes or longer. Patients were then classified according to available clinical information (coronary angiography and radionuclide stress testing) into true positive (due to myocardial ischemia, n = 62) and false positive (n = 20) groups. The sensitivity, specificity, and predictive value of the PR-segment/exercise duration criterion for predicting a false positive test were 70, 74, and 47%, respectively. Patients with false positive tests also had higher heart rates (158 +/- 16 vs 136 +/- 20 beats/min, P < .001) and less frequent chest pain (15 vs 46%, P = .017) during the exercise test. Patients with false positive exercise tests can be recognized by the achievement of a high peak exercise heart rate, the absence of exercise-induced chest pain, and the appearance of markedly downsloping PR-segments in the inferior leads.

Acute effects of amiodarone on membrane properties, refractoriness, and conduction in guinea pig papillary muscles.

Amiodarone has potent and complex antiarrhythmic effects associated with a rare incidence of proarrhythmia. For a comprehensive understanding of its antiarrhythmic mechanisms in the same preparations, amiodarone (50 microM) was employed as it would be in the clinical setting and applied to guinea pig papillary muscles impaled by microelectrodes, paced at different rates, and superfused with various concentrations of potassium ([K]e). Amiodarone exerted complex actions, as follows: (1) The maximum rate of rise (Vmax) of the fast action potential (i.e., [K]e = 5.4-9.0 mM) as well as that of the slow action potential (i.e., [K]e = 15.0 mM in the presence of 1.0 microM isoproterenol) was suppressed in a rate-dependent manner. (2) Amiodarone exhibited a rate- and [K]e-dependent increase in the ratio of effective refractory period vs action potential duration at 90% repolarization (ERP/APD90), disclosing post-repolarization refractoriness. (3) Amiodarone had no effect on passive cable factors, such as threshold current and tissue resistance, during propagation. These versatile electrophysiological effects of amiodarone may contribute to its unique antiarrhythmic effects, as well as the low incidence of proarrhythmia with this drug.

Marked activation delay caused by ischemia initiated after regional K+ elevation in in situ pig hearts.

BACKGROUND: Conduction mediated by the slow inward (Ca2+) current occurs in vitro under specific experimental conditions but has not been documented in ventricular muscle in vivo during regional myocardial ischemia, perhaps because certain constituents of ischemia (including hypoxia and acidosis) may inhibit the Ca2+ current in this setting. We hypothesized that slow conduction mediated by the Ca2+ current could occur during acute ischemia in situations in which the extracellular K+ rise was more marked relative to the degree of acidosis, as may occur at ischemic boundaries. METHODS AND RESULTS: In open-chest, anesthetized swine, an arterial shunt from the carotid artery to the mid-left anterior descending coronary artery was created through which a solution of KCl was infused to raise extracellular K+ ([K+]e) to approximately 9.4 mmol/L before the initiation of ischemia, which we termed "K(+)-modified ischemia." Ischemia initiated at a normal [K+]e ("unmodified ischemia") resulted in a mean activation delay in the center of the ischemic zone of 55 +/- 26 milliseconds after 5 minutes of ischemia and a decrease in epicardial longitudinal conduction velocity from 53 to 21 cm/s before the onset of conduction block. K(+)-modified ischemia resulted in a mean activation delay in the center of the ischemic zone of 181 +/- 8 milliseconds and a decrease in epicardial longitudinal conduction to less than 10 cm/s. K(+)-modified ischemia was associated with ventricular fibrillation in 85% of episodes compared with 28% of episodes of unmodified ischemia (P < .01). Verapamil prevented the occurrence of marked activation delay during K(+)-modified ischemia, producing local activation block following a maximum activation delay of 74 +/- 25 milliseconds. In two experiments, responses mediated by the slow inward current were produced by regional K+ elevation to 15 to 16 mmol/L, followed by concomitant regional administration of epinephrine (10(-7) mol/L). Regional [K+]e elevation alone to this level resulted in local activation block following a maximum activity delay of 70 to 80 milliseconds, whereas administration of epinephrine in combination with high [K+]e resulted in return of local activation with an activation delay of 160 to 180 milliseconds (ie, similar to that during K(+)-modified ischemia). CONCLUSIONS: Compared with unmodified ischemia, K(+)-modified ischemia resulted in marked activation delay and a high incidence of ventricular fibrillation. Based on measurements of longitudinal conduction velocity, the inhibitory effect of verapamil, and the results of experiments with high [K+]e plus epinephrine, we conclude that the marked activation delay during K(+)-modified ischemia represents conduction mediated by the slow inward current. Because the conditions produced by K(+)-modified ischemia (high [K+]e with minimal acidosis) are similar to conditions in and near ischemic border regions, we hypothesize that responses mediated by the slow inward current may occur in such regions during unmodified ischemia and may participate in the development of reentrant arrhythmias.

Effect of rate on changes in conduction velocity and extracellular potassium concentration during acute ischemia in the in situ pig heart.

INTRODUCTION: The purpose of our study was to determine if the slowing of longitudinal intraventricular conduction in the in situ porcine heart during acute regional no-flow ischemia was rate dependent. Further, we investigated whether any rate dependence could be correlated to a rate-dependent component of the ischemia-induced rise in extracellular potassium concentration, [K+]e. METHODS AND RESULTS: We studied in situ hearts in nine anesthetized open chest pigs in which acute no-flow ischemia was induced by occlusion of the left anterior descending coronary artery. To determine the effects of steady-state rate on the slowing of conduction and rise in [K+]e during ischemia, we varied the rate of stimulation during sequential occlusions from 90 to 150 beats/min. Longitudinal conduction velocity was determined by unipolar electrodes embedded in a plaque that was sutured to the epicardial surface in the center of the ischemic zone. Myocardial [K+]e was determined simultaneously by potassium-sensitive electrodes placed at or within 1 to 2 mm of the epicardium in close proximity to the activation recording electrodes. Conduction velocity decreased more rapidly at the more rapid rates of stimulation although the reduction in conduction velocity occurring prior to the onset of conduction block was similar at both rates. The potassium change was not rate dependent and rose at the same rate regardless of the rate of stimulation. CONCLUSION: Our study demonstrates that the steady-state rate-dependent component of the slowing of intraventricular conduction induced by acute ischemia in the in situ porcine heart occurs in the absence of a rate-dependent component in the rise of [K+]e. Between rates of 90 and 150 beats/min, the rate dependence of the conduction slowing may be attributed to one or more potassium-independent factors such as the rate-dependent changes in resting membrane potential, in Vmax of the action potential upstroke, and in cell-to-cell uncoupling, which have been observed in other models of acute ischemia.

Drug effects on the electrocardiogram. A review of their clinical importance.

It is clear that many patients are now being treated with multiple pharmacological agents which may alter membrane function and ionic fluxes across membranes. Therefore, these agents will frequently influence the electrical behavioural of all excitable tissues including the myocardial cell. The changes in the myocardial cell are often reflected by changes, some subtle, some obvious, on the body surface electrocardiogram. Thus, the electrocardiogram provides the physician with a reasonably simple and inexpensive tool for monitoring drug effects and for detecting changes that may be toxic and/or life-threatening. For this reason, an appreciation of these changes by the noncardiologist has become increasingly important.

Electrolyte abnormalities underlying lethal and ventricular arrhythmias.

It is well known that changes in serum potassium cause ventricular arrhythmias as a result of clearly documented changes in the electrophysiological characteristics of single fibers. Hypopotassemia induced by thiazide and loop diuretics may contribute to the incidence of sudden cardiac death in patients with hypertension and those with congestive heart failure. In addition, hypopotassemia appears to be an independent risk factor for lethal ventricular arrhythmias occurring in the setting of acute myocardial infarction and contributes significantly to arrhythmias associated with starvation and alcoholism. The increase in myocardial extracellular potassium that occurs in the ischemic zone after coronary occlusion is clearly a major factor in the genesis of lethal ventricular arrhythmias that occur in this setting. A decrease in serum magnesium is also believed to be arrhythmogenic, and magnesium depletion is thought to play a role in many of the arrhythmias associated with hypopotassemia. Moreover, the administration of magnesium salts may be effective in the management of life-threatening ventricular arrhythmias. However, definite evidence establishing a causal relation between ventricular arrhythmias and hypomagnesemia or intracellular magnesium depletion is lacking. Changes in intracellular calcium contribute to the arrhythmias associated with acute ischemia and with reperfusion and may be important in the genesis of ventricular tachycardia induced by exercise and by digitalis. Thus, electrolyte and metabolic abnormalities clearly underlie lethal ventricular arrhythmias in a wide variety of clinical situations and should be routinely considered as potential etiologic factors in patients with life-threatening ventricular arrhythmias, particularly those with hypertension and congestive heart failure who are receiving thiazide and loop diuretics.

Effects of ryanodine and BAY K 8644 on membrane properties and conduction during simulated ischemia.

We studied the effect of 1.0 microM ryanodine and 0.1 microM BAY K 8644 (putative modulators of intracellular calcium) on the changes in action potential characteristics, cellular coupling, and longitudinal conduction induced by simulated ischemia (9.0 mM K, 6.5 pH, 0 glucose, 20 mmHg PO2) in superfused guinea pig papillary muscles. Simulated ischemia (SI) depolarized the resting membrane by 5 mV and caused a 28% decrease in action potential upstroke (Vmax), a 65% decrease in action potential duration at 90% (APD90), a 40% increase in internal longitudinal resistance (ri), and a 17% decrease in conduction velocity as compared with the 9-K Tyrode control solution. These changes were reversible and reproducible. The decrease in Vmax induced by SI was greater than that associated with a K(+)-induced change in resting membrane potential (RMP). Ryanodine lessened the SI-induced APD90 shortening by 26%, the decrease in Vmax by 42%, the increase in ri by 33%, and the decrease in conduction velocity by 21%. BAY K 8644 did not alter SI-induced APD90 shortening but augmented the decrease in Vmax by 23%, the increase in ri by 67%, and the decrease in conduction velocity by 59%. Neither ryanodine nor BAY K 8644 altered the SI-induced changes in RMP. Our results suggest that changes in intracellular calcium during SI not only influence cellular coupling but also contribute to the apparent non-RMP-dependent component of the change in Vmax and to the change in APD90 induced by SI.