Biomedical subjects
Publications and source records attributed to L S Dreifus.
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Adenosine exerts pronounced depressant effects on cardiac pacemakers. Previous studies in vitro have indicated that different pacemakers exhibit variable sensitivity to adenosine: ventricular greater than junctional greater than sinus node pacemakers. This study tested the hypothesis that ventricular pacemakers are more sensitive to adenosine than sinus node pacemakers in vivo in an experimental canine model and determined the mechanism involved in this phenomenon using specific pharmacological interventions. For this purpose, dogs with chronic atrioventricular block, stable ventricular escape rhythm, and bilateral stellectomy and cervical vagotomy were studied. Dose-response curves for negative chronotropic action of adenosine in the sinus node and ventricular pacemakers were obtained in group 1 under base-line conditions, during isoproterenol infusion, and after subsequent administration of propranolol; in group 2 before and after administration of quinidine; in group 3 before and after administration of aminophylline; and in group 4 before and after administration of 1,3-dipropyl-8-phenylxanthine amine congener (XAC). Adenosine exerted a dose-dependent negative chronotropic effect on sinus node and ventricular pacemakers. At all doses tested, this action was more pronounced in the ventricle. Isoproterenol accentuated the action of adenosine in the sinus node (by 60-138%; P less than 0.05) but suppressed it in the ventricle (-37 to 53%; P less than 0.05). These effects of isoproterenol were attenuated by propranolol. Quinidine suppressed the action of adenosine in the sinus node (-38 to -52%; P less than 0.05) but not in the ventricle.(ABSTRACT TRUNCATED AT 250 WORDS)
Specific mechanisms of supraventricular tachycardia include sinoatrial, intra-atrial, atrioventricular (AV) nodal as well as concealed and manifest bypass tract reentry. In dual pathway reentry, at least one of the pathways involves the AV node, usually the slow pathway and the other pathway, perinodal fibers within the atria. Localization of the perinodal fibers is critical for ablative procedures to eliminate AV nodal tachycardias. Other mechanisms of supraventricular tachycardia include chaotic atrial tachycardia and automatic atrial tachycardia with and without AV block. However, drug therapy includes intravenous adenosine 6 mg, as well as the older standbys of digoxin, calcium and beta-blocking agents, and type 1a and 1c antiarrhythmias. In resistance cases, amiodarone is usually effective. However, for incessant supraventricular mechanisms, catheter or surgical ablative techniques are recommended to eliminate long-term drug administration.
The mechanisms responsible for slowing cardiac impulse conduction through the atrioventricular (AV) node are not well understood but include anatomical architecture, presence of cells with diverse electrophysiological characteristics, and modulation by autonomic nervous system. The present study was designed to determine the site of vagally induced slowing of conduction through the AV node. We attempted to correlate the electrophysiological response of AV nodal cells to postganglionic vagal stimulation applied in different regions of the node with the morphological findings and patterns of acetylcholinesterase-positive staining of nodal tissue. This multifaceted approach revealed that vagal stimulation produced localized hyperpolarization of the cells from the N region of the AV node, which correlated with the strong acetylcholinesterase positive staining of the central nodal area. In contrast, the density of the acetylcholinesterase staining decreased toward both the AN and His bundle regions, whereas vagal stimulation had a negligible effect on the cells from these regions. These results suggest that vagal-induced depression of AV nodal conduction is produced by release of acetylcholine predominantly around the midnodal region and the depressive action of acetylcholine is concentrated on the cells occupying the same region (i.e., the N cells). Thus, there appears to be a close juxtaposition of nerve elements and effector cells in the midnodal region of the AV node. This unique combination of available neuromediator and responding cells with hyperpolarization and depressed action potential determines the midnodal region as the focus of vagal effect on AV nodal conduction.
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The relation between extracellular potassium ion activity [( K+]o) and ventricular tachyarrhythmias was studied in an open chest canine model with the use of two protocols. In Protocol I, potassium chloride was administered into the proximal left anterior descending coronary artery at a rate of 0.125 mEq/min for either 20 min or until [K+]o = 20 mEq/liter, whichever came first. In Protocol II, the proximal left anterior descending coronary artery was occluded in one step and was reperfused 20 min later. Fifteen dogs were subjected to Protocol I, nine of which were also subjected to Protocol II. In the latter group, a recovery period of greater than or equal to 1 h separated the two protocols. Local K+ and intramyocardial activities were recorded with use of bifunctional ion-sensitive plunge electrodes at multiple sites located in the region of the left ventricle perfused by the left anterior descending artery and at one site outside of this region. The following variables were recorded and analyzed: Lead II electrocardiogram, heart rate, systemic arterial blood pressure, local [K+]o and its time derivative (dK+/dt), local electrograms and ventricular arrhythmias. Maximal [K+]o and dK+/dt were 23 +/- 3 mEq/liter and 9 +/- 1 mEq/liter per min in Protocol I and 14 +/- 1 mEq/liter and 3 +/- 1 mEq/liter per min in Protocol II, respectively. In both protocols, the occurrence of ventricular arrhythmias correlated with [K+]o (p less than 0.02) as well as with dK+/dt (p less than 0.05). Ventricular arrhythmias were more frequent and more severe in Protocol II than in Protocol I (p less than 0.05). Therefore, whereas K+ dynamics were more pronounced in Protocol I, ventricular arrhythmias were more severe in Protocol II. This occurrence was apparently due, at least in part, to less heterogeneous changes in K+ gradients during constant K+ infusion. It was concluded that, in addition to the magnitude of [K+]o, the rate of change of this variable (that is, dK+/dt) apparently plays an important role in the genesis of ischemic ventricular arrhythmias.
The well-known paradoxic behavior of atrioventricular conduction, the so-called gap phenomenon, that occurs when impulses within a certain range of coupling intervals are blocked while impulses with shorter coupling intervals are conducted is attributed to differences in properties of refractoriness in neighboring regions of the conduction system. In contrast, in the present study a model was developed showing a similar phenomenon, dependent on different electrophysiologic mechanisms and localized within the atrioventricular node in an isolated rabbit heart tissue preparation (n = 11). The hearts were paced at cycle length of 400-500 msec, and atrioventricular nodal conduction times (A2H2) were measured versus atrial extrastimulus (A1A2) coupling intervals by standard extrastimulus techniques. Postganglionic vagal stimulation was applied in the atrioventricular node as short bursts of subthreshold (for myocardium) stimuli with duration of 50-150 msec, amplitude of 20-800 microA, and absolute phase (delay after A1) of 0-500 msec. Vagal bursts with appropriate parameters consistently produced bimodal conduction curves. Initially, gradual shortening of the A1A2 coupling interval was associated with an increasing A2H2, with an accentuated increase (or even atrioventricular block) within an intermediate A1A2 range. However, further shortening of the A1A2 coupling interval produced a decrease in A2H2, which subsequently was followed by a block at the effective refractory period. Microelectrode recordings indicated that this characteristic bimodal pattern of conduction curves, demonstrating a gap, reflected transient vagally induced hyperpolarization in the N region of the node. In those instances where conduction block occurred and gap was manifest, the most marked hyperpolarization coincided with the time of arrival of midcycle premature extrastimuli, whereas the conduction of extrastimuli with either more or less prematurity was under less-marked vagal influence. Thus, this study demonstrates a new electrophysiologic mechanism producing anomalous conduction curves and the gap phenomenon within the atrioventricular node based on vagal-induced nonuniform recovery of diastolic excitability.
Bifunctional intramyocardial potassium ion (K+)-sensitive and bipolar wire electrodes were used to evaluate extracellular K+ dynamics and electrophysiologic changes during acute myocardial ischemia in the border zone, ischemic zone (5 to 7 mm from the border), central ischemic zone (15 to 25 mm from the border) and normal myocardium in 11 open chest dogs during a 30 min ligation of the left anterior descending coronary artery. At the end of this period, the hearts were injected with rhodamine dye and quickly frozen. Ultraviolet NADH (nicotinamide adenine dinucleotide) rhodamine fluorescence photography was used to localize the border between normally perfused and ischemic tissue and determine the site of electrodes in relation to this border. Before coronary ligation, extracellular K+ ranged from 4.0 +/- 0.3 to 4.3 +/- 0.3 mM in these four zones. After ligation, extracellular K+ accumulated in the ischemic and central ischemic zones in a pattern characterized by an initial rapid increase for approximately 5 min, followed by a slowly rising plateau phase, reaching maximal levels of 9.8 +/- 2.0 and 14.4 +/- 4.4 mM, respectively. In contrast, K+ dynamics in the border zone showed a biphasic response, with an initial rapid increase to a maximal level of 7.5 +/- 2.4 mM at approximately 9 min after coronary ligation, followed by a gradual decrease to a level of 5.3 +/- 1.2 mM by the end of the 30 min ligation period. No significant changes in K+ occurred in the normal zone throughout the ischemic period. The correlation of K+ electrode, electrophysiologic and postmortem NADH-rhodamine fluorescence data indicated the existence of a well defined border zone.(ABSTRACT TRUNCATED AT 250 WORDS)
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The effective management of cardiac arrhythmias remains a major challenge in cardiovascular therapeutics. The management of arrhythmias encompasses a wide spectrum of supraventricular and ventricular tachyarrhythmias occurring in patients with various cardiac diagnoses and different degrees of myocardial dysfunction. A number of the newer antiarrhythmic drugs that have either recently been released or appear promising are reviewed in this article. Drugs are described with respect to their basic pharmacology, electrophysiologic actions, pharmacokinetics and metabolism, hemodynamics, antiarrhythmic effects, side effects, interactions, indications, and dosage.
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A 47-year-old extremely active, entirely asymptomatic trained jogger was found dead in bed. He was known to have had sinus bradycardia with first-degree atrioventricular block for eight years and a type 1 second-degree block five years prior to death. A permanent pacemaker had been inserted, and apparently the patient was then in good health and maintained his jogging program until he died suddenly. The conduction system revealed an atrioventricular node situated more to the left of the atrial septum than usual, which made tenuous connection with the surrounding atria due to marked fatty infiltration. The atrioventricular node as it joined the left-sided His bundle revealed fatty metamorphosis, fibrosis, disarray of myocardial fibers, and mononuclear cell infiltration. The right bundle branch was intramyocardial and fibrosed throughout. Increased aging changes of the left side of the septum with arteriolosclerosis and patchy fibrosis were present. This is the first case in which the atrioventricular node was more to the left side of the atrial septum with fatty separation of the node from the surrounding atrial musculature, with myocardial disarray of the nodal-His bundle junction. Although congenital abnormality of the conduction system may remain silent without symptoms for a long time, it should be kept in mind that sudden death may occur sooner or later in some susceptible individuals.
Adenosine and ATP exert pronounced electrophysiologic actions on the mammalian heart including a negative chronotropic action on cardiac pacemakers and a negative dromotropic action on atrioventricular conduction. These actions are modulated by complex interactions of the two compounds with the autonomic nervous system. Since both adenosine and ATP are released from myocardial cells under physiologic and pathophysiologic conditions, they could play an important modulating role in cardiac electrophysiology. Indeed, studies during the last decade have yielded strong evidence for the role of adenosine in the genesis of specific arrhythmias associated with myocardial ischemia. Further studies are required to fully elucidate the mechanisms of actions of adenosine and ATP in vivo. These will undoubtedly enhance the understanding of the potential arrhythmogenic, as well as the antiarrhythmic actions of endogenous and exogenous adenosine and ATP.
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