L S Gettes

Effect of serial brief ischemic episodes on extracellular K+, pH, and activation in the pig.

This study was performed to determine the reproducibility of the ionic and electrical changes associated with serial ischemic episodes. We used ion-selective and bipolar plunge electrodes to determine the changes in left ventricular extracellular potassium ([K+]e), extracellular pH (pHe), and local activation during sequential 10 min occlusions of the left anterior descending coronary artery separated by 50 min of reperfusion in open-chest anesthetized pigs. We found that uniformly during the initial occlusion, and in approximately 50% of animals during the second occlusion, [K+]e rose more rapidly but to a lower level than in subsequent occlusions. By the third occlusion the changes in [K+]e were reproducible. Extracellular acidosis was greatest in the first occlusion and decreased progressively with each subsequent occlusion. Local activation was characterized by a decrease in spontaneous improvement and increase in block with each successive occlusion. The occurrence of ventricular fibrillation could not be directly attributed to the magnitude of the change in [K+]e or pHe. Moreover, the occurrence of ventricular fibrillation in one occlusion did not necessarily predict its occurrence thereafter. Our results indicate that serial episodes of ischemia are associated with different but predictable changes in ionic and electrical events that may be clinically relevant and that must be appreciated before the results from similar protocols with serial ischemic episodes can be interpreted meaningfully.

Effect of graded coronary flow reduction on ionic, electrical, and mechanical indexes of ischemia in the pig.

This study was performed to determine the relative sensitivities of ionic, electrical, and mechanical indexes of myocardial ischemia. We used ion-selective and bipolar plunge electrodes, epicardial unipolar electrodes, a suction electrode, and ultrasonic crystals to determine the changes in intramyocardial extracellular potassium ([K+]e) and extracellular pH (pHe), local activation, epicardial TQ-ST segment, monophasic action potential duration (MAPD), and regional contractility during graded coronary flow reduction in open-chest pigs. A carotid-to-coronary shunt was created to perfuse the left anterior descending coronary artery via a roller pump. The shunted coronary flow was reduced in a stepwise fashion at 5-min intervals. In 25 pigs, the approximate myocardial blood flow associated with the initial changes in each variable was as follows: midmyocardial [K+]e, pHe, and TQ-ST segment, 0.7 to 0.8 ml/min/g; subepicardial [K+]e and TQ-ST segment, 0.6 to 0.7 ml/min/g; segmental shortening, 0.5 to 0.6 ml/min/g; local activation and epicardial TQ-ST segment, 0.3 to 0.4 ml/min/g; epicardial MAPD, 0.15 to 0.2 ml/min/g. Our results indicate that changes in [K+]e, pHe, and TQ-ST segment provide the most sensitive means of detecting myocardial ischemia and of determining the effect of interventions capable of influencing the ischemic process.

Effects of verapamil on ischemia-induced changes in extracellular K+, pH, and local activation in the pig.

In experimental animals, the calcium channel-blocking agents lessen the arrhythmogenic, ionic, metabolic, and electrical changes that occur during acute myocardial ischemia. To date, these effects have been studied separately, and the effects of these agents on local activation have not been correlated with ionic or metabolic effects. In open-chest, anesthetized swine, we used bipolar and ion-selective plunge electrodes to simultaneously measure ischemia-induced changes in left ventricular local activation, extracellular K+ ([K+]e), and extracellular pH (pHe). The effects of verapamil (0.2 mg/kg) on these variables were studied during a series of 10 min occlusions of the left anterior descending coronary artery. Compared with control occlusions, verapamil (1) slowed the rise in [K+]e at the center of the ischemic zone and at its lateral margin and decreased the peak [K+]e by 0.9 mM at the center (p less than .05) and by 0.1 mM at the margin (p = .10); (2) slowed the development of acidosis and decreased the peak level of acidosis beyond that expected solely as a result of serial occlusions by 0.19 pH units at the center (p less than .05) and by 0.07 pH units at the margin (p = .10); and (3) slowed the development of local activation delay and often prevented the local activation block that was observed during control occlusions. Effects on local activation became less marked at [K+]e levels greater than 9.0 mM, and the effects of verapamil on local activation were not explained solely by its effects on the local rise in [K+]e or fall in pHe. A possible mechanism for this additional effect on local activation is suggested by preliminary results showing a diminution by verapamil of ionic inhomogeneity.

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

BackgroundConduction 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 ResultsIn 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). ConclusionsCompared 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.

Effects of verapamil and propranolol on changes in extracellular K+, pH, and local activation during graded coronary flow in the pig.

The beta-adrenergic and calcium channel blocking agents are known to reduce heart rate and alter myocardial contractility. More recent evidence suggests that both agents affect the metabolic consequences of ischemia, independent of their effects on heart rate and contractility. We used a low-flow model of ischemia in swine with heart rate held constant by atrial pacing. Blood was shunted from the carotid artery to the left anterior descending coronary artery through a controlled-flow roller pump to assess the threshold flow for the rise in extracellular potassium ([K+]e) and fall in extracellular pH (pHe) associated with ischemia during control situations and after the administration of either propranolol or verapamil. We also measured the changes in activation delay and contractility associated with graded flow reductions in the presence and absence of these drugs. We found that when heart rate is held constant, 1) verapamil shifts the threshold flow for [K+]e and pHe to lower levels, but propranolol does not; 2) verapamil lessens activation delay, while propranolol aggravates the delay; and 3) verapamil reduces afterload and selectively depresses contractility in the reperfused ischemic zone. We conclude that the calcium channel blockers and the beta-adrenergic-blocking agents have different effects and possibly different modes of action and should not be considered interchangeable when evaluating therapeutic options for patients with ischemic heart disease.

Enhancement of procainamide-induced rate-dependent conduction slowing by elevated myocardial extracellular potassium concentration in vivo.

Procainamide, a type 1A antiarrhythmic drug, blocks sodium channels and reduces the maximum rate of rise of the cardiac action potential (Vmax) in a rate-dependent fashion. In vitro, the magnitude of this rate-dependent reduction in Vmax is greater in tissue that is partially depolarized at rest than in tissue with a normal resting potential. Reductions in Vmax produced by drugs that block sodium channels are also directly related to the reductions in longitudinal conduction velocity of action potential propagation in papillary muscle preparations. We therefore sought to determine whether the rate-dependent conduction slowing induced by procainamide in the intact canine heart is enhanced in myocardial tissue abnormally depolarized by an elevated myocardial extracellular potassium concentration, [K+]o. QRS duration and epicardial activation times were measured as indexes of myocardial conduction. QRS duration and epicardial activation times were measured at control (4.0 mM) and at intermediate (6.5 mM) and high (9.2 mM) myocardial [K+]o in the presence or absence of a clinically relevant procainamide concentration (12.2 +/- 2.6 g/ml) at the longest obtainable interstimulus interval of 440 msec and at 330, 280, and 250 msec. Intermediate and high myocardial [K+]o alone induced rate-dependent conduction slowing as the frequency of stimulation increased (cycle length 440 msec to 330, 280, and 250 msec). In the presence of procainamide, rate-dependent conduction slowing was observed at all levels of myocardial [K+]o, and the amount of rate-dependent change in conduction time increased as the myocardial [K+]o was increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Failure of Impulse Propagation in a Mathematically Simulated Ischemic Border Zone: Influence of Direction of Propagation and Cell‐to‐Cell Electrical Coupling

Propagation in a Modeled Ischemic Border Zone. 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.

Metabolic protection by verapamil during graded coronary flow reduction independent of effect on baseline systolic function. Separation of mechanical and ionic markers of ischemia.

Pretreatment with the calcium channel-blocking agent verapamil lowers the coronary flow associated with the first rise in myocardial extracellular potassium [( K+]e). The mechanisms underlying this effect are unclear. It is not known whether this effect is a manifestation of verapamil-induced reduction in baseline cardiac work before the reduction in coronary flow, is dependent on a selective depression of contractility within the low-flow region, or is independent of an effect on myocardial work. This study was performed to determine the relations between changes in regional contractility and [K+]e before and after verapamil (0.2 mg/kg followed by 6.5 micrograms/kg/min) when left anterior descending (LAD) coronary flow is progressively reduced and when verapamil-induced alterations in baseline myocardial work are prevented by atrial pacing and by dobutamine (4.3 +/- 2.2 micrograms/kg/min) to maintain systemic arterial blood pressure and contractility. Before verapamil-dobutamine, myocardial [K+]e rose and regional contractility fell when LAD coronary flow was reduced to 87.7 +/- 9.6% and 83.4 +/- 7.4%, respectively, of the unrestricted control value (p = NS). After verapamil-dobutamine, the threshold flow for rise in [K+]e decreased to 56.4 +/- 13.5% of the unrestricted control flow (p = 0.003), but the threshold flow for regional contractility fall was unchanged (84.8 +/- 11.3%). Our results indicate that the protective effect of verapamil on preventing ischemia-induced [K+]e release is not dependent on a reduction in baseline myocardial work. In this setting, calcium channel blockade by verapamil results in a dissociation between the ionic and mechanical events that occur when coronary flow is reduced.

Ionic Changes Associated with Acute Ischemia

Harris et al. [1] were the first to appreciate that occlusion of a coronary artery is followed by an increase of potassium in the extracellular space of the area deprived of its circulation. They then performed a series of experiments, which led them to conclude that the increase in extracellular potassium was a major factor, perhaps the major factor in the pathogenesis of the acute ventricular arrhythmias, including ventricular fibrillation, which accompany coronary occlusion [1, 2]. Later, it was shown that acute coronary occlusion leads to a fall in extracellular pH [3] and a rise in extracellular pCO2 [4] within the ischemic zone. Within the last decade, a variety of new techniques, including ion selective electrodes, nuclear magnetic resonance, and voltage and ion sensitive dyes, have permitted the more precise characterization of the intracellular and extracellular ionic changes that occur when the coronary circulation is abruptly or progressively interrupted and a more accurate correlation of these ionic changes to the associated metabolic, electrical, and mechanical changes. As is usually the case, each new observation has served to bring into sharp focus the limits of our understanding and has spawned a series of new questions. In this presentation, we will briefly review the characteristics, causes, and effects of the potassium and pH changes that occur when coronary flow is interrupted and some of the factors that modify these changes.