New mechanism of antiarrhythmic drug action: increasing L-type calcium current prevents reentrant ventricular tachycardia in the infarcted canine heart.

BACKGROUND: We studied whether increasing L-type calcium current has antiarrhythmic effects. METHODS AND RESULTS: Reentrant circuits in the epicardial border zone (EBZ) of healing canine infarcts were mapped during sustained ventricular tachycardia. The cardiac-specific L-type calcium current enhancer Bay Y5959 prevented initiation of sustained ventricular tachycardia in 7 of 14 experiments. Bay Y5959 caused slowing of conduction in areas of slow nonuniform conduction in reentrant circuits; block eventually occurred. Conduction was not affected in other regions of the circuits or in more normal areas of the EBZ, nor was the EBZ effective refractory period changed. Bay Y5959 also improved conduction of premature impulses so that lines of unidirectional block necessary for VT initiation were not formed, an effect not related to a change in the effective refractory period at the site of block. CONCLUSIONS: Block of conduction caused by enhanced L-type calcium current in reentrant circuits may result from a decreased gap junctional conductance consequent to an increase in intracellular calcium. An increase in L-type calcium current may improve conduction of premature impulses.

Static relationship of cycle length to reentrant circuit geometry.

BACKGROUND: Knowledge of the pathway common to both wave fronts in figure-8 reentrant circuits (ie, the isthmus) is of importance for catheter ablation to stop reentrant ventricular tachycardia. It was hypothesized that quantitative measures of reentry isthmus geometry were interrelated and could be correlated with tachycardia cycle length. METHODS AND RESULTS: A canine infarct model of reentrant ventricular tachycardia in the epicardial border zone with a figure-8 pattern of conduction was used for initial analysis (experiments in 20 canine hearts with monomorphic reentry). Sinus-rhythm and reentry activation maps were constructed, and quantitative (skeletonized) geometric parameters of the isthmus and border zone were measured from the maps. Regression equations were used to determine significant correlation relationships between skeletonized variables, which can be described as follows. Tachycardia cycle length, measured from the ECG R-R interval, increases with increasing isthmus length, width, narrowest width, angle with respect to muscle fibers, and circuit path length determined by use of sinus-rhythm measurements. After this procedure, in 5 test-set experiments, tachycardia cycle length measured from the R-R interval, in combination with regression coefficients calculated from initial experiments, correctly predicted isthmus geometry (mean estimated/actual isthmus overlap 70.5%). Also, the circuit path length determined with sinus-rhythm measurements correctly estimated the tachycardia cycle length (mean error 6.2+/-2.5 ms). CONCLUSIONS: Correlation relationships derived from measurements using reentry and sinus-rhythm activation maps are useful to assess isthmus geometry on the basis of tachycardia cycle length. Such estimates may improve catheter ablation site targeting during clinical electrophysiological study.

Mechanisms of resetting reentrant circuits in canine ventricular tachycardia.

BACKGROUND: Resetting has been used to characterize reentrant circuits causing clinical tachycardias. METHODS AND RESULTS: To determine the mechanisms of resetting, sustained ventricular tachycardia was induced in dogs with 4-day-old myocardial infarctions by programmed stimulation. Premature stimulation was accomplished from multiple regions within reentrant circuits; resetting curves were constructed and compared with activation maps. Monotonically increasing responses, or a "mixed" response (increasing portion preceded by a flat portion), occurred. All reentrant circuits had a fully excitable gap. Interval-dependent conduction delay and concealed retrograde penetration led to increased resetting response curves. CONCLUSIONS: Multiple mechanisms revealed by mapping cause resetting of reentrant circuits.

Conduction of the cardiac impulse. 3. Characteristics of very slow conduction.

The excitability of short segments (5-7 mm) of bundles of canine Purkinje fibers was depressed by exposure to 15-18 mM K(+), to 15-18 mM K(+) plus 5 x 10(-6) epinephrine or norepinephrine, to low K(+), and to low Na(+). The depressed segment was in the center chamber of a three-chamber bath; the ends of the bundle were exposed to normal Tyrode solution. Each method of depression resulted in slow and probably decremental conduction with an effective conduction velocity in the middle chamber of about 0.05 m/sec, or one-way block, or two-way block with summation of the graded responses in the depressed region. The action potential in the depressed segment (the slow response) differs from the normal action potential in its response to applied stimuli. A second active depolarization can be evoked by cathodal stimulation during much of the slow response. The response in the depressed segment is graded. The response of depressed fibers may depend on excitatory events similar to those responsible for the slow component of the cardiac action potential. It is suggested that the slow response can propagate, at least decrementally, in fibers in which the rapid, Na(+)-dependent upstroke is absent, and can cause reentrant excitation by so doing.

Mechanisms for spontaneous termination of monomorphic, sustained ventricular tachycardia: results of activation mapping of reentrant circuits in the epicardial border zone of subacute canine infarcts.

OBJECTIVES: The objective of this study was to determine why sustained ventricular tachycardias (VT) sometimes stop without outside intervention. BACKGROUND: Sustained, monomorphic VT in patients with ischemic heart disease is often caused by reentrant excitation. These tachycardias can degenerate into rapid polymorphic rhythms or occasionally terminate spontaneously. METHODS: Sustained VT was induced by programmed stimulation in dog hearts 4 to 5 days after ligation of the left anterior descending coronary artery. Activation in reentrant circuits in the epicardial border zone of the infarct was mapped using 192 to 312 bipolar electrodes. RESULTS: Spontaneous termination of sustained VT always occurred when the reentrant wave front blocked in the central common pathway in reentrant circuits with a figure-of-eight configuration. Two major patterns of termination were identified from activation maps of the circuits that were not distinguishable from each other on the surface electrocardiogram: 1) Abrupt termination was not preceded by any change in the pattern of activation or cycle length. It could occur at different locations within the central common pathway, was not related to the directions of the muscle fiber orientation and was not caused by a short excitable gap. 2) Termination caused by premature activation (after a short cycle) either resulted from shortening of the functional lines of block around which the reentrant impulse circulated or was caused by wave fronts originating outside the reentrant circuit. In only one episode were oscillations of cycle length associated with termination. CONCLUSIONS: The mechanisms for termination of reentry in functional circuits causing VT are different from those in anatomic circuits where oscillatory behavior precedes termination.

Role of alterations in refractoriness and conduction in the genesis of reentrant arrhythmias. Implications for antiarrhythmic effects of class III drugs.

Despite the fact that a number of different electrophysiologic mechanisms are capable of causing cardiac arrhythmias, reentrant excitation has emerged as the most important mechanism causing life-threatening arrhythmias that arise in the ventricles. Pharmacologic therapy of arrhythmias caused by reentry is aimed at preventing the conditions that either facilitate the initiation of the circulating reentrant excitation wave or the conditions that permit its persistence. This involves alterations in either refractoriness or conduction by the drugs. Both atrial and ventricular tachyarrhythmias may follow premature depolarizations that occur at a critical coupling interval to a previous excitation. One desirable property of antiarrhythmic drugs might be to prevent the initiation of reentrant excitation by the triggering premature impulse. Mechanisms are described to show how drugs that prolong the action potential duration (class III antiarrhythmic drugs) might have this effect. It is, however, emphasized that drug effects that have been documented in electrophysiologic studies on normal myocardium might not occur in an arrhythmogenic region that has pathologic alterations, because of changes in the properties of ion channels of the diseased myocardial cells. Antiarrhythmic drugs might also terminate ongoing reentrant excitation by causing block of conduction in the reentrant pathway, at least for one beat. Class III drugs are expected to stop the perpetuation of reentry by prolonging the action potential duration and the refractory period of myocardial fibers in the reentrant circuit to such an extent that the propagating reentrant impulse no longer finds excitable myocardium but blocks in refractory tissue. Therefore, the effectiveness of this drug class to terminate reentry should depend on at least 2 factors: the size of the excitable gap as the reentrant impulse moves around the circuit, which may be related to the mechanism that causes reentry, and the degree to which the drugs can prolong the action potential duration and refractory period at the rapid rates of tachycardia. Each of these factors is discussed with relation to the proposed mechanism of action of drugs that prolong repolarization.

Arrhythmogenic actions of antiarrhythmic drugs.

Cardiac arrhythmias may result from abnormalities of impulse propagation or abnormalities of impulse initiation. When arrhythmias are initiated by antiarrhythmic drugs, the most common mechanisms appear to be conduction block or reentry, and abnormal impulse initiation, which may be triggered by afterdepolarizations. The effects of drugs on conduction may result from their actions on the fast sodium channel, the slow calcium channel or their ability to prolong repolarization. The extent to which a drug that depresses fast sodium or slow calcium entry will exert its toxic effects depends in large part on its binding characteristics to its channel receptor site. Such toxicity represents a continuum for the therapeutic effects of these drugs. The factors that control drug access to binding sites, including lipid solubility, molecular size and extent of ionization, are reviewed, as are the contributions to conduction abnormalities of drug-induced changes in repolarization. The mechanisms whereby drugs induce abnormalities of impulse initiation are still a matter of conjecture. Apparently, drugs that increase inward plateau currents or decrease repolarizing potassium ion currents carry increased risk. Moreover, there is evidence for the role of early after depolarizations occurring secondary to prolonged repolarization as a possible cause of arrhythmias, including torsades de pointes. The mechanisms whereby antiarrhythmic drugs may contribute to this type of tachyarrhythmia are reviewed.

Method for evaluating the effects of antiarrhythmic drugs on ventricular tachycardias with different electrophysiologic characteristics and different mechanisms in the infarcted canine heart.

In a canine model of myocardial infarction caused by coronary occlusion and reperfusion, ventricular tachycardia occurs spontaneously at 24 hours and has many of the characteristics of an accelerated idioventricular rhythm. It cannot be induced by premature or rapid stimulation of the ventricles; overdrive pacing during this tachycardia usually causes some transient overdrive suppression but occasionally there is overdrive acceleration. We suggest that this arrhythmia is caused mainly by enhanced automaticity. Ventricular tachycardia also can be induced by premature or rapid ventricular pacing 3 to 5 days after infarction, but it does not occur spontaneously. It can be stopped by overdrive pacing, suggesting that it is caused by reentry. Electrocardiographic features are identical to chronic, recurrent sustained ventricular tachycardia in human patients. Because the arrhythmias occurring at different times probably result from different mechanisms this canine model is useful for comparing the actions of drugs on different kinds of arrhythmias. Lidocaine and procainamide generally abolished tachycardia 24 hours after infarction, but only procainamide abolished tachycardia 3 to 5 days after infarction. Isoproterenol accelerated tachycardia at both times. Verapamil did not abolish tachycardia 3 to 5 days after infarction.

Right atrial ultrastructure in congenital heart disease. I. Comparison of ventricular septal defect and endocardial cushion defect.

Ultrastructural studies were performed on portions of the operatively resected right atrium from six patients with a ventricular septal defect and six patients with an endocardial cushion defect. The six patients with a ventricular septal defect had normal right atrial mean pressure and no evidence of right atrial volume overload. Ultrastructurally, the atrial muscle cells in these patients appeared normal and measured 6 to 12 mu in diameter. The six patients with an endocardial cushion defect had elevated right atrial mean pressure and evidence of right atrial volume overload. Ultrastructurally, the atrial muscle cells in these patients were generally larger than 12 mu in diameter. The cells were irregular and had multiple and occasionally widened intercalated discs. In addition, there were degenerative changes in two patients with markedly increased atrial pressure. These changes included extensive loss of contractile elements, aggregation of small irregular mitochondria and proliferation of tubules of the sarcoplasmic reticulum. The structural changes suggest that hypertrophy of the right atrium may be secondary to volume overload of the atrium, whereas degenerative changes may be secondary to increased right atrial pressure.

Electrophysiologic mapping to determine the mechanism of experimental ventricular tachycardia initiated by premature impulses. Experimental approach and initial results demonstrating reentrant excitation.

Epicardial activation patterns were determined during repetitive responses and nonsustained and sustained ventricular tachycardias induced by premature impulses in infarcted canine hearts. A multiplexing system enabled recordings to be obtained from up to 192 electrodes simultaneously either from the entire epicardial surface with a sock electrode array or only from the sheet of epicardial muscle that survives over the infarcts, with a plaque electrode array. In hearts with an infarct caused by permanent occlusion of the left anterior descending coronary artery, the earliest epicardial excitation during nonsustained tachycardias occurred on the anterior left ventricle at the border of the infarcted region and in epicardial muscle surviving over the infarcted region. Circuitous conduction patterns leading to reentry occurred in the epicardial muscle over the infarct and probably caused the arrhythmias. During sustained tachycardia in hearts with an infarct caused either by permanent or temporary occlusion of the left anterior descending coronary artery, the earliest epicardial excitation also occurred at the border of the infarcted region, but there was no evidence of reentry in the surviving epicardial muscle.

Right atrial ultrastructure in congenital heart disease. II. Atrial septal defect: effects of volume overload.

Portions of operatively resected right atrium from 15 patients with atrial septal defect were studied ultrastructurally to determine whether the cell hypertrophy in the right atrium of patients with increased right atrial blood flow and increased right atrial pressure is caused by the increased blood flow. In 12 patients with normal right atrial mean pressure but increased right atrial blood flow the atrium was dilated but no atrial arrhythmias were noted clinically. Ultrastructurally, the atrial myocardial cells in these patients were normal, measuring 6 to 10 mu in diameter, and there was no evidence of cell hypertrophy or degeneration. The remaining three patients had elevated right atrial mean pressure and increased right atrial blood flow. Ultrastructurally, the atrial myocardial cells in all three patients were hypertrophied, and two patients had evidence of focal cell degeneration; the atrium was markedly dilated, but atrial arrhythmias were not noted. The lack of cell hypertrophy in the right atrium of the 12 patients with increased blood flow but normal mean pressure suggests that in congenital heart disease volume overload alone does not lead to cell hypertrophy of the right atrial myocardium.

Effects of left atrial enlargement on atrial transmembrane potentials and structure in dogs with mitral valve fibrosis.

The effects of left atrial enlargement on atrial cell electrophysiology and structure were studied in dogs with mitral valve fibrosis. Thirteen dogs (Groups I) had left atrial enlargement and intermittent atrial arrhythmias; 10 dogs (Group II) had left atrial enlargement and chronic atrial fibrillation. The resting and action potentials of cells in isolated preparations from the enlarged left atrium were found not to differ from those in the nonenlarged right atrium or in the atrium of control dogs. The resting and action potentials of cells in Group II atria did not differ significantly from those in Group I atria. Some cells (15 percent of the total studied) in the atria of dogs in Groups I and II were inexcitable, but either superfusion with acetylcholine or norepinephrine restored excitability. The structural studies showed that the left atrium of the dogs in Groups I and II had a reduced number of muscle cell layers spanning the wall with an unusually large amount of connective tissue between greatly hypertrophied cells. Very few degenerating cells were seen. Dramatic abnormalities of cell electrophysiology may not be involved in the genesis of arrhythmias in the enlarged canine atrium, and the altered morphologic features of the atrium in these dogs may be important in the genesis of persistent atrial arrhythmias.

Structural basis of ventricular arrhythmias in human myocardial infarction: a hypothesis.

The present study was undertaken using light and electron microscopic techniques to determine whether Purkinje fibers survive in the subendocardial region of anteroseptal infarcts in humans. Tissue was obtained for this purpose from 11 patients with 12 documented infarctions at the time of autopsy; six patients died within 72 hours of the infarction and five had healed infarcts. Seven of the 11 patients had ventricular arrhythmias. Light microscopic study indicated that intact cells with a normal appearance remained on the subendocardial surface, although the underlying ventricular muscle either was necrotic or was replaced by fibrous tissue. Electron microscopy demonstrated that these intact surviving cells over the surface of the infarct had few randomly oriented myofibrils, abundant glycogen, and other characteristics of Purkinje fibers. These cells could be readily distinguished from normal or infarcted ventricular muscle cells. Purkinje fibers, the most peripheral part of the conduction system, survive in extensive anteroseptal infarcts and may be the site of origin of ventricular arrhythmias.

Cellular electrophysiologic mechanisms of cardiac arrhythmias.

Cardiac arrhythmias result from abnormalities in the initiation of impulses or in the conduction of these impulses through the heart. Arrhythmias caused by impulse initiation may be caused by either automaticity or triggered activity. Arrhythmias caused by abnormalities in conduction are often the result of reentrant excitation. These arrhythmogenic mechanism arise because of alterations in the transmembrane potentials of cardiac cells that are often caused by disease. These cellular mechanisms causing arrhythmias are the subject of this article.

Cellular electrophysiologic mechanisms of cardiac arrhythmias.

Cardiac arrhythmias are caused by alterations in the electrophysiologic properties of the cardiac cells, which affect the characteristics of the transmembrane potentials. The electrophysiologic properties that cause arrhythmias are automaticity, triggered activity, and reentrant excitation. Each of these mechanisms is described in terms of the characteristics of the transmembrane potentials and how these influence the appearance of the arrhythmia on the electrocardiogram.