Reentrant Pathway Research Articles

Activation mapping of reentry around an anatomic barrier in the canine atrium. Observations during entrainment and termination.

We determined total right atrial activation sequences during entrainment and termination of flutter induced in dogs with a surgically induced atrial lesion. This type of atrial flutter is due to circus movement of an impulse around the tricuspid valve orifice. We recorded simultaneously from 96 bipolar intracavity electrodes in the right atrium of the isolated, perfused heart. By constructing isochronal maps, we demonstrated the pattern of atrial activation during atrial pacing protocols that either entrained or entrained and then terminated the reentrant rhythm. We show that during pacing the antidromic wavefront from the paced impulse (An) collides with the orthodromic wavefront from the previous paced impulse (On-1). During entrainment, the site of collision of the orthodromic and antidromic wavefronts was constant during pacing at a fixed rate but shifted in the antidromic direction as the pacing rate increased. Furthermore, the last paced beat was entrained only up to the site of collision of the previous paced beat. During one period of entrainment, termination of the reentrant arrhythmia occurred because On-1 blocked in the reentrant pathway due to refractory tissue left by On-2. However, subsequent An did not collide directly with On as was expected, but rather On blocked by an interaction with tissue left refractory by An. Because On was blocked, no reentry occurred when pacing ended.

Oral amiodarone loading therapy. I. The effect on serial signal-averaged electrocardiographic recordings and the QT c in patients with ventricular tachyarrhythmias

The effect of amiodarone loading (1400 mg/day for 7 days) and maintenance therapy (400 mg/day) on the signal-averaged electrocardiogram (SAECG) and the QT c were evaluated in 14 patients. Daily recordings were taken for the first 7 days of loading and on the ninth, twelfth, fourteenth, and twenty-first day of maintenance therapy. All patients had inducible sustained ventricular tachycardia (VT), 10 of them had late potential (LP) positive recording, and four were LP negative during control measurements. Amiodarone loading significantly changed all SAECG indices and prolonged the QT c. Changes induced by amiodarone were present within 24 hours of administration. The time to reach peak effect varied from 6 to 9 days. The maximum increase in late potential duration (LPD) was threefold greater than the increase in filtered ORS duration or QT c (61% vs 18% vs 14%, respectively), suggesting a more pronounced effect on the reentrant pathway than on the remaining myocardium. Of the four LP negative patients, three became LP positive while receiving amiodarone. In conclusion, amiodarone affects all SAECG indices. However, the magnitude of the changes varies, being most pronounced on the LPD. Amiodarone affects the SAECG and the QT c within the first 24 hours. The time of onset of the peak effect varies from 6 to 9 days. LP negative patients with inducible VT frequently became LP positive during amiodarone therapy.

Mechanism of ventricular vulnerability to single premature stimuli in open-chest dogs.

To determine the mechanism of ventricular vulnerability to electrical stimulation, we simultaneously recorded from 120 transmural electrodes in a 35 X 20 X 5-mm portion of right ventricular infundibulum in seven dogs. Baseline pacing (S1) was performed from outside the mapped region followed by single premature stimulation (S2) of increasing strength at the center of the mapped region. In five of six episodes of ventricular fibrillation and 26 of 30 episodes of repetitive responses, complete reentrant pathways were observed. Earliest activation following S2 was not at the site of S2 stimulation but was at a point between the S1 and S2 sites of stimulation. Activation spread away from the early site toward the opposite side of the mapped region around the sides of an arc of block near the S2 site to form a "figure-of-eight." The activation fronts coalesced to activate the region around the S2 site last and, if the difference in times between activation at the early site and near the S2 site was large, reentered the tissue toward the S1 site. Ventricular refractory periods were determined in four dogs following S1 pacing; the regions with the greatest nonuniformity in the dispersion of refractoriness were not the regions of unidirectional block after S2 stimulation. Thus, 1) ventricular fibrillation and repetitive responses induced electrically with S1 and S2 stimuli at different ventricular sites arise by figure-of-eight reentry, 2) this reentry is caused by the ability of S2 stimulation both to prolong refractoriness near the S2 site and to initiate a propagated response in the region between the S1 and S2 sites, and 3) a nonuniform dispersion of refractoriness is not crucial for the electrical induction of reentry leading to ventricular fibrillation or repetitive responses when S1 and S2 stimuli are given at different locations on the right ventricular outflow tract.

Histopathological analysis of surgically resected myocardium in patients with sustained ventricular tachycardia.

Surgical resection of the endocardium and subendocardium often abolishes sustained ventricular tachycardia (VT) in patients with old myocarcial infarct (OMI), unknown myocardial disease, and arrhythmogenic right ventricular dysplasia (ARVD), presumably by interrupting the reentrant pathway. In order to define the morphologic characteristics of histologic components in the reentrant pathway, we carried out histopathological analysis of surgically resected specimens from 17 patients who underwent this procedure. Bundles of apparently viable and hydropic myocardial fibers embedded in dense fibrous and adipose tissues were identified throughout the specimens obtained from OMI, ARVD and idiopathic VT cases. In 3 patients with idiopathic VT, most of the resected areas were composed of ventricular muscle, the components of which appeared histologically similar to Purkinje fibres. In all patients, the abnormal muscle cells were characterized by a loss of contractile elements, hydropic cytoplasm and an elliptic shape. Such an abnormal structure and arrangement of surviving cardiac fibers following tissue injury might play an important role in creating abnormalities of transmembrane potential, leading to the micro-reentrant circuits that give rise to ventricular tachycardias.

Sinus Rhythm Mapping in a Canine Model of Ventricular Tachycardia

The relationship between electrograms recorded during sinus rhythm and the activation sequence during ventricular tachycardia induced by programmed stimulation was investigated in a canine model of myocardial infarction. Thirteen dogs were studied 3 days (n = 10) or 14 days (n = 3) after coronary occlusion. Sixty-three unipolar electrograms were simultaneously recorded with a sock electrode array connected to a digital recording system, and analyzed by computer. Bipolar electrograms were recorded sequentially from the same sites with an analog recorder. Categories of unipolar electrograms were defined with reference to the QRS complex during sinus rhythm as follows: Class A included electrograms with an intrinsic deflection inscribed within the QRS complex, class B included those which did not exhibit any intrinsic rs deflection, and class C included those with an intrinsic deflection inscribed later than QRS. The epicardial distribution of each class of electrograms was significantly different between the preparations with, and those without inducible tachycardia (72% versus 63% of electrograms being in class A, 20% versus 35% in class B, and 8% versus 2% in class C; p less than 0.005). When tachycardia was inducible, class C epicardial electrograms were located in an area extending across the region of infarction, which corresponded to the common reentrant pathway of figure-of-eight patterns mapped during tachycardia. When ventricular tachycardia was not inducible, class B electrograms were recorded all over this region. The morphology of bipolar electrograms had no predictive value in identifying the common reentrant pathway. These results support the view that the inducibility of reentrant tachycardia is dependent upon critically located delayed activity detected during sinus rhythm by unipolar recordings.

Reentry as a cause of ventricular tachycardia in patients with chronic ischemic heart disease: electrophysiologic and anatomic correlation.

In this report we describe electrophysiologic and histologic findings in hearts and endocardially resected preparations from patients with sustained ventricular tachycardias in the chronic phase of myocardial infarction. We recorded simultaneously from 64 endocardial sites during tachycardia in 72 patients that were operated on for medically intractable ventricular tachycardias. Two other patients underwent heart transplantation, and mapping was performed on the explanted isolated heart connected to a Langendorff perfusion set-up. During operation 139 tachycardias with different morphologies could be induced. Although the majority of evidence supports the concept of a reentrant mechanism for these tachycardias, we found that 105 tachycardias appeared to arise at a focal area of less than 1.4 cm2. In only three cases macroreentry around the infarction scar could be detected. Of 21 tachycardias in which the "origin" appeared to be focal, earliest subendocardial activation was preceded by discrete electrograms of low amplitude (presystolic activity). In three tachycardias presystolic activity was detected at several sites, permitting reconstruction of its route. Histology of the endocardial resected preparation in one of these cases revealed separate zones of viable myocardial fibers in areas in which presystolic activity was recorded. These zones were located intramurally and subendocardially, supporting the concept that reentry occurred via isolated bundles of surviving myocytes at the border of the infarct and the larger subendocardial muscle mass. Conduction velocity through the isolated tracts was on the order of 25 cm/sec. Similar reentrant pathways were found in the two isolated hearts. Extracellular and intracellular recordings were made from 20 endocardial preparations that were excised from areas in which tachycardia originated. Preparations were superfused in a tissue bath. These experiments showed that action potentials were usually close to normal, but occasionally action potentials with reduced amplitude and slow upstrokes were found. In addition, there were cells that exhibited both fast and slow upstrokes, depending on the direction of the wavefront. Histology of seven resected preparations and the isolated hearts showed subendocardially as well as intramurally located zones of viable myocardium. Fractionation of extracellular electrograms and slow conduction were found in areas where surviving muscle fibers and strands of fibrous tissue were interwoven, and in zones where muscle fibers were oriented in parallel but isolated by strands of connective tissue.(ABSTRACT TRUNCATED AT 400 WORDS)

Type A Alternating Wenckebach Periodicity in the Reentrant Pathway of Interpolated Ventricular Extrasystoles

A 67-year-old man with interpolated ventricular extrasystoles is reported in whom alternate sinus QRS complexes were followed by interpolated ventricular extrasystoles with progressively lengthening coupling intervals until one of these alternate sinus complexes failed to be followed by an extrasystole. This is the first report to suggest the presence of type A alternating Wenckebach periodicity in the reentrant pathway of interpolated ventricular extrasystoles. It is suggested that 2:1 block occurred at a proximal level in the reentrant pathway, while Wenckebach block occurred at a distal level in the pathway.

Observations on rapid ventricular pacing during reentrant ventricular tachycardia in canine myocardial infarction--the use of epicardial mapping in demonstrating the modes of resetting, concealed perpetuation and termination of reentry.

The changes in activation sequences in and around the epicardial reentrant circuit were analyzed during rapid pacing against ventricular tachycardia by using a canine infarction model. In 13 episodes of sustained ventricular tachycardia induced by a premature stimulation technique in eight dogs, reentry circuits were located in the superficial subepicardial myocardium in eight. Pacing stimuli were clearly demonstrated to enter the reentrant circuit in two directions: one wavefront collided with the orthodromic reentrant wavefront and the other entered prematurely into the reentrant circuit to reset the tachycardia (resetting phenomenon). With a faster pacing rate, stimuli failed to reset the tachycardia due to slower entry into the circuit despite the fact that most epicardial recording sites were activated by pacing wavefronts (concealed perpetuation). Termination of tachycardia was achieved by a local conduction block in the center of the reentrant circuit. A pacing impulse which encountered the local block was also shown to reinitiate the tachycardia using a different reentrant pathway. These different phenomena could be observed in consecutive pacing beats. These epicardial mapping data provided a direct electrophysiological basis for the mechanisms of reentrant ventricular tachycardia and the mode of its termination.

Reentrant and nonreentrant mechanisms contribute to arrhythmogenesis during early myocardial ischemia: results using three-dimensional mapping.

The present study assessed the mechanisms responsible for the initiation and maintenance of premature ventricular complexes (PVCs) and ventricular tachycardia (VT) during early ischemia using a unique computerized mapping system capable of recording simultaneously from 232 individual intramural sites. In the chloralose-anesthetized cat, during normal sinus rhythm prior to ischemia, ventricular activation was rapid with a total activation time of 25 +/- 2 msec. Five minutes after occlusion of the left anterior descending (LAD) coronary artery, activation was delayed during sinus rhythm (64 +/- 6 msec) (p less than 0.001 vs. control) and was characterized by slow conduction in the same plane and block in both the same plane and in the endocardial-to-epicardial direction. In 76% of cases (16 of 21), initiation of single PVCs and the first beat of VT occurred through intramural reentry. In all but one case, initiation occurred in the subendocardium, adjacent to the site of delayed subendocardial and midmyocardial activation of the preceding sinus beat. The activation time of the sinus beat preceding the PVC or VT was significantly prolonged (149 +/- 7 msec, p less than 0.001 vs. sinus beats during ischemia not followed by a PVC or VT) with most of the delayed activity occurring in the subendocardium and midmyocardium, a finding that would not have been apparent by epicardial mapping alone. The length of the reentrant pathway ranged from 1.8-3.0 cm. Marked delay was a necessary, but not a sufficient, condition for reentry to occur since, in some cases, delays as large as 220 msec was found without initiation of reentry or the occurrence of nonreentrant PVCs or VT. Maintenance of VT by intramural reentry arose in either the subendocardium or the subepicardium and was primarily dependent on the continued presence of marked transmural delay (159 +/- 8 msec). In contrast, in 24% of cases (5 of 21), initiation of the first beat of VT arose in either the subendocardium or subepicardium by a mechanism other than reentry as evidenced by the lack of intervening electrical activity between the end of the preceding sinus beat and the initiation of the ectopic beat. The preceding sinus beat was characterized by delay (129 +/- 12 msec) comparable to that of sinus beats preceding reentrant ectopic beats (p = NS), but the marked delay was distant from the site of nonreentrant initiation. Ventricular tachycardia could be initiated by one mechanism (reentrant or nonreentrant) and maintained or terminated by another mechanism.(ABSTRACT TRUNCATED AT 400 WORDS)

Surgical therapy for supraventricular tachycardia, a potentially curable disorder

One hundred fifty-six patients underwent investigation and operation for supraventricular tachycardia: 145 had attempts at curative operations and 11 had His bundle section. Operative mortality was 0.68% and there were no late deaths among patients having curative operations. One patient died suddenly 1 year after His bundle section. All patients underwent electrophysiologic study before discharge and 6 months postoperatively. A satisfactory result, without supraventricular tachycardia and without medication, was achieved in 96.5% of all patients. Ninety-three percent have no supraventricular tachycardia and no demonstrable reentrant pathway at electrophysiologic study. All free wall accessory atrioventricular connections were divided and 97.7% of the patients were cured. Ninety percent of patients with posterior septal accessory atrioventricular connections had a satisfactory result, with cure demonstrated at late electrophysiologic study in 84%. Fifteen patients with atrioventricular junctional reentrant tachycardia were all cured, with preservation of normal atrioventricular conduction. Eight (88%) of nine patients with right atrial tachycardia were cured, and two patients with nodoventricular fibers and one patient with incessant atrioventricular junctional tachycardia had satisfactory results. Supraventricular tachycardia is now a potentially curable disorder when managed by low risk surgical procedures that offer a high cure rate.

Reentrant Ventricular Arrhythmias in the Late Myocardial Infarction Period: 14. Mechanisms of Resetting, Entrainment, Acceleration, or Termination of Reentrant Tachycardia by Programmed Electrical Stimulation

The mechanisms of resetting, entrainment, acceleration, or termination of reentrant ventricular tachycardia by programmed electrical stimulation were studied in the canine post-infarction model. In this model, reentrant circuits were localized in the epicardial layer overlying the infarction and were accessible to detailed mapping by multiplexer techniques. The reentrant circuit has a characteristic figure-eight configuration in the form of two circulating wavefronts around arcs of functional conduction block that coalesce into a slow common reentrant wavefront. Termination of reentrant tachycardia occurred when a stimulated wavefront arrived earlier to a strategically located area in the proximal portion of the zone of slow conduction, before refractoriness expired distally, resulting in conduction block. The three factors that determined if the stimulated wavefront could reach this zone in time for conduction block were: the cycle length of stimulation; the number of stimulated beats; and the site of stimulation. The most optimal situation for stimulated termination of reentry was a critically coupled single stimulus applied to the ischemic zone close to the proximal side of the zone of slow conduction that captured locally and conducted prematurely to the strategic zone for conduction block. When a single stimulated wavefront failed to terminate reentry, one or more subsequent wavefronts succeeded. However, the stimulated train had to be terminated following the beat that interrupted reentry. Otherwise, a subsequent stimulated beat could reinitiate the same reentrant circuit or induce a different circuit. The new circuit could have a shorter revolution time, resulting in tachycardia acceleration, and occasionally degeneration into ventricular fibrillation. Overdrive termination of reentry required both a critical cycle length of stimulation and a critical number of beats in a stimulated train. Otherwise, the stimulated train could establish a new balance of refractoriness and conduction velocity in the reentrant pathway. This could perpetuate the reentrant process at the shorter cycle length of the stimulated train and spontaneous reentry would resume on termination of the train (entrainment). The study provides better understanding of the mechanisms of action of programmed electrical stimulation on reentrant ventricular tachycardia.

A Review of Early Intervention Studies with Beta Blockers in Patients with Myocardial Infarction

Transmembrane potentials and local extracellular electrograms were recorded from isolated Langendorff perfused canine and porcine hearts. Experiments were also performed on hearts in open-chested anaesthetized animals. Following occlusion of a major coronary artery, resting membrane potential decreased, resulting in depression of the TQ segment. Action potential amplitude and upstroke velocity decreased, leading to ST elevation and delayed activation. At resting membrane potentials around -60 mV, ischaemic cells became inexcitable. Arguments are presented that action potentials during the first 10 min of ischaemia, when malignant ventricular arrhythmias frequently occur, are not 'slow responses' but are instead 'depressed fast responses' where inward current is carried by Na+ ions through partially inactivated fast channels. Mapping experiments, in which 60 to 98 electrograms were simultaneously recorded during spontaneous ventricular arrhythmias demonstrated that ventricular tachycardia is due to macro-re-entry with the re-entrant pathway having a wavelength of the order of 6 cm. No evidence was found for macro-re-entry being the cause of ventricular premature depolarizations. A hypothesis is put forward, whereby the experimental findings of a 'focal' origin are explained on the basis of electrotonic transmission through a small inexcitable zone close to the ischaemic border.

Atrial reentry around an anatomic barrier with a partially refractory excitable gap. A canine model of atrial flutter.

We have characterized, in dogs, a model of inducible regular atrial tachycardia that resembles atrial flutter. The model involves creating a Y-shaped lesion comprised of an intercaval incision and a connected incision across the right atrium. It is suitable for serial studies of the effects of pacing or antiarrhythmic drugs in chronically instrumented animals studied in the awake state for at least several months. The postoperative cycle length of the induced tachycardia varies from 143 to 188 msec, depending on the size of the dog. The tachycardia cycle length was consistent for each dog, and the rhythm--once induced--was very stable until terminated by pacing. The mechanism of the tachycardia was reentry due to circus movement based on the ability to induce and terminate it by premature impulses or overdrive, the ability to reset the tachycardia by single premature stimuli, the pattern of entrainment during overdrive stimulation, and the ability to terminate the tachycardia by interrupting the conduction pathway. The window of reset determined by the range of coupling intervals of premature stimuli that were able to enter and reset the tachycardia ranged from 56 to 82 msec. There appears to be incomplete recovery of excitability by the end of the excitable gap as evidenced by the fact that even late premature impulses that enter the reentrant circuit conduct more slowly than the tachycardia impulse, and because stimulation of muscarinic receptors that shortens the duration of the action potential and refractoriness also reduces the cycle length of the tachycardia. Epicardial and endocardial activation mapping during tachycardia showed the reentrant pathway does not merely encircle the lesion, particularly over the left atrial epicardium near the intercaval lesion. Rather, the impulse appears to travel around the atrial tissue just above the tricuspid ring, including a portion that travels through the right side of the lower intraatrial septum. Thus, the model involves circus movement around an anatomic barrier through normal tissue that contains no depressed segments. During the circus movement, there is a relatively long excitable gap during which there is incomplete recovery of excitability. This model should be useful for studies of the mechanism of antiarrhythmic drug action and the responses to premature stimulation in this particular subclass of reentrant rhythms, and for comparison with the behavior and responses of other forms of reentry.

Mechanisms of concealed ventricular bigeminy: The concept of concealed conduction in the reentrant pathway

To clarify the presence of concealed conduction in the reentrant pathway of extrasystoles, 20 patients with ventricular extrasystoles were studied in whom two forms of interectopic periods were found in the same recording. One form is the XS1S2X period, in which two sinus QRS complexes (S1 and S2) intervene between an interpolated extrasystole (the first X) and the next extrasystole (the second X). The other is the XS2X or XS1X period, in which one sinus QRS complex intervenes between two extrasystoles. In all patients except one, the XX interval in the XS1S2X period was longer than that in the XS2X or XS1X period though shorter than twice the latter XX interval. This strongly suggests the presence of two-level block in the reentrant pathway of the extrasystoles. It appears that the sinus impulse S1 in the XS1S2X period invaded a large portion of the reentrant pathway and then was blocked at a distal site of the pathway; namely, that concealed conduction of the impulse S1 occurred in the pathway. It is suggested that such concealed conduction prolonged the conduction time of the following sinus impulse, S2, in the reentrant pathway, resulting in lengthening of the XX interval. The presence of three- or four-level block is also suggested. By the use of such multilevel block, mechanisms of concealed ventricular bigeminy are explained.

Electrophysiological and pharmacological studies on the mechanisms of ventricular tachycardia.

Employing electrophysiological and pharmacological methods, the mechanisms of recurrent ventricular tachycardia were studied in 31 patients, 18 with old myocardial infarction and 13 with idiopathic ventricular tachycardia. In the cases of ventricular tachycardia with old myocardial infraction, the initiation and termination of the tachycardia could be achieved by programmed electrical stimulation in 13 out of 18 patients. Endocardial mapping showed that the earliest excitation site during tachycardia was at the border zone of infarction, where the diastolic fragmented activity was detected. Programmed electrical stimulation sometimes provoked more than two kinds of QRS morphology of tachycardia in the same patient. Class IA antiarrhythmic agents were effective in terminating tachycardia. These data suggest that there are multiple reentrant pathways consisting of partially depressed fast fibers at the border zone of infarction. In the cases with idiopathic ventricular tachycardia, the induction and termination of tachycardia was effected by electrical stimulation in 8 out of 13 patients. For the termination of tachycardia, long overdrive pacing was sometimes necessary. The diastolic fragmented activity could not be detected by endocardial mapping. A class IV drug such as verapamil was more effective for the termination of tachycardia than class I drugs, and there were repetitive short runs of ventricular extrasystole observed until the final termination. These data support the reentrant pathways containing slow with enhanced automaticity as the circuit of idiopathic ventricular tachycardia.

Reentrant ventricular arrhythmias in the late myocardial infarction period. 12. Spontaneous versus induced reentry and intramural versus epicardial circuits

One to 5 days after one-stage ligation of the left anterior descending coronary artery in dogs, reentrant excitation can be induced by programmed premature stimulation in the surviving electrophysiologically abnormal, thin epicardial layer overlying the infarct. In experiments in four dogs, reentrant excitation occurred "spontaneously" during a regular sinus or atrial rhythm. A tachycardia-dependent Wenckebach conduction sequence in a potentially reentrant pathway was the initiating mechanism for spontaneous reentrant tachycardias and was the basis for both manifest and concealed reentrant extrasystolic rhythms. In all dogs showing spontaneous reentry, reentrant excitation could also be induced by premature stimulation at cycle lengths much shorter than those associated with spontaneous reentry, and induced reentrant circuits were always different from those during spontaneous reentry. In two dogs, the reentrant circuit was located intramurally in close proximity to a patchy septal infarction. The study illustrates that irrespective of the anatomic localization of reentrant circuits (epicardial or intramural), their dimension (large or small) or their mechanism of initiation (programmed premature stimulation or "spontaneous"), reentrant excitation always occurred in a figure 8 configuration (or a modification thereof). The figure 8 model, rather than the ring model or the leading circle model, may be the common model of reentry in the mammalian heart.

Ventricular fibrillation during coronary angiography: An analysis of mechanisms

To investigate the mechanisms of ventricular fibrillation (VF) during coronary angiography, we assessed ventricular automaticity, local QT intervals, local conduction characteristics, and the ability to induce arrhythmias with premature ventricular stimulation in 30 dogs after intracoronary injections of 4 to 6 cc of Renografin 76 (RG 76). Ventricular automaticity was measured in six dogs as the idioventricular escape rate following intense vagal stimulation and was unchanged (51 ± 6 vs 52 ± 6 bpm, p > 0.05) with 6 cc of RG 76. In addition, 8 of 10 injections of 6 cc of RG 76 produced VF at a heart rate of 200 bpm compared to only 2 of 10 injections at a heart rate of 80 bpm ( p < 0.05). Composite and bipolar plunge electrodes were placed in the region perfused by the left anterior descending coronary artery (LAD) and circumflex coronary artery to assess QT intervals and conduction characteristics. RG 76, 4cc, produced a 116 ± 18 msec increase in the QT intervals recorded from the region perfused by the LAD, resulting in a marked dispersion in repolarization. Both local bipolar and composite electrograms showed minimal conduction delay, which rarely extended beyond the QRS of a lead II ECG during atrial paced rhythm. As premature beats (spontaneous or induced) conducted through the region of QT prolongation, marked conduction delay was recorded from bipolar electrograms, while composite electrograms recorded continuous fractionated electrical activity spanning the diastolic interval at the onset of VF. An early cycle premature impulse applied after every fourth atrial paced beat in the circumflex region produced VF in 23 of 25 injections of 4 cc of RG 76. The addition of CaCl 2 (40 mEq/L) to RG 76 markedly attenuated the QT prolongation, local fractionation, and conduction delay and totally prevented VF in response to premature stimulation. We conclude that the regional QT prolongation produced by RG 76 renders the myocardium vulnerable to VF by increasing the temporal dispersion of repolarization. VF appears to result from slow conduction of premature beats through incompletely repolarized myocardium leading to the formation of multiple reentrant pathways. However, the mechanism of the first premature beat in spontaneous VF remains unknown.

Effects of hypoxia and ischaemia on coronary vascular resistance, A-V node conduction and S-A node excitation.

Hypoxia and ischaemia produce relaxation of the vascular smooth muscle of the resistance vessels in the myocardium. A low pH may contribute to the arteriolar dilatation but cannot account for the major response. In all likelihood the reduced pO2 acts indirectly by release of a vasodilator mediator rather than by a direct effect on the vascular muscle. Potassium release may account for a transient component of the vasodilation, but it appears that a major factor is the release of adenosine from the ischaemic tissue. Adenosine also appears to be responsible for slowing of the sinus rate and impaired A-V conduction in myocardial ischaemia. These observations are of clinical significance because hypoxia-induced A-V block, such as may occur in inferior myocardial infarction, can be abolished by an adenosine antagonist such as aminophylline. In contrast, adenosine is also useful in the treatment of some cardiac arrhythmias. Supraventricular tachycardia, in which the A-V node is involved in the re-entrant pathway, is readily abolished in humans by the intravenous administration of small doses of adenosine.

Bretylium tosylate in patients with acute myocardial infarction

Experience with bretylium tosylate accumulated during a period of over 10 years, during which time > 1,500 patients with acute myocardial infarction were treated, is summarized. On the diagnosis of acute infarction, the agent was given by continuous intravenous drip at a rate of 10 mg/kg/24 hours for 5 to 7 days for prophylaxis of ventricular fibrillation. Bretylium administration prevented primary ventricular fibrillation in about 99% of these patients. No undesirable side effects were observed with this protocol, which lessens the initial sympathomimetic effect of the drug while allowing sufficient time for the adrenergic neuronal blocking effect to develop. The beneficial effects of the drug are believed to be due, in part, to a direct electrophysiologic effect on both normal and ischemic myocardium. This effect equalizes the duration of both the effective refractory periods and the ventricular action potentials, and it creates conditions capable of blocking reentrant pathways. Bretylium stabilizes the duration of electrical systole in patients with acute myocardial infarction. Hemodynamic studies during bretylium treatment further confirm the effectiveness of this drug and have prompted additional studies to evaluate its potential as an agent capable of decreasing impedance in acute myocardial infarction.

Actions of disopyramide on potential reentrant pathways and ventricular tachyarrhythmias in conscious dogs during the late post-myocardial infarction phase

The effect of intravenous disopyramide (plasma level 3.7 ± 1.6 μg/ml, mean ± standard deviation) on reentrant ventricular tachyarrhythmias was studied by programmed ventricular stimulation in 11 conscious dogs 3 to 8 days after experimental myocardial infarction. Sustained ventricular tachycardia (VT) was induced in 4 dogs (mean cycle length 173 ± 14 ms) and nonsustained VT in 7 (8 ± 4 beats, mean cycle length 136 ± 18 ms). Disopyramide prevented induction of VT in 1 of 4 dogs with sustained VT and 3 of 7 with nonsustained VT, and increased VT cycle length by more than 30 % in 2 dogs with sustained VT and 2 of 7 with nonsustained VT. Disopyramide prolonged refractoriness in the infarct zone, measured by analysis of electrograms from an implanted “composite” electrode, by 38 to 53%, depending on the mode of pacing. These values were significantly greater than the increase produced by disopyramide in ventricular effective refractory period (13 ± 12%), QRS duration and QT interval. Disopyramide has a selective effect on potential reentry circuits in ischemic myocardium, and prolongs refractoriness in abnormal myocardium to a greater extent than its effect on the normal ventricle.