Electrophysiologic effects of bretylium on canine ventricular muscle during acute ischemia and reperfusion

Electrophysiologic effects of bretylium were assessed on a recently developed animal model for analysis of conduction of premature impulses and excitation threshold. Bretylium was administered intravenously 10 mg/kg over 10 minutes followed by 2 mg/min of infusion immediately after coronary ligation. Conduction of the premature impulse was recorded in the epicardial and endocardial sites both in the base-to-apex and apex-to-base directions, in the normal, in the center, and across the border of ischemic myocardium. Compared to the control group of animals, bretylium did not cause any significant change in the conduction characteristics in the ischemic myocardium; however, it delayed the conduction of premature impulses in the normal myocardium. Thus the disparity in conduction times between the normal and the ischemic myocardium was lessened by bretylium. Further, conduction of impulses from normal tissue across the border of ischemia was also delayed. Bretylium also decreased the excitability threshold in the ischemic myocardium, although the normal myocardial excitation threshold was unaffected. These unique effects of bretylium on conduction and excitability in the normal, in the center, and across the border of ischemic myocardium, when a therapeutic dosage of the drug is used, further validate its antiarrhythmic potential and offer an insight into its mechanism of action in the setting of acute myocardial ischemia.     

Characteristics of conduction of premature impulses during acute myocardial ischemia and reperfusion: A comparison between anterograde and retrograde activation

Unidirectional delay in conduction has been postulated to be a necessary prerequisite for reentry, but it has not been demonstrated in vivo in the acutely ischemic or reperfused myocardium. To assess changes in conduction velocity as a function of the direction of impulse transmission, cardiac conduction was studied in normal, ischemic and reperfused segments of myocardium and across the border of these segments.In eight dogs, conduction times between multiple needle electrodes were estimated. During atrial pacing, premature impulses at 50 percent prematurity were delivered to the middle of the myocardium at each needle site in series. The radial spread of the premature impulse from any needle site to the bipolar electrodes in the remaining needles situated in the epicardium and in the endocardium was measured. Conduction time was defined as the interval in milliseconds between pacing artifact and the first high frequency deflection in the epicardial and endocardial electrograms. Conduction times were measured in both the anterograde (base to apex, anterograde conduction time) and the retrograde (apex to base, retrograde conduction time) direction. Results showed that retrograde conduction time was slower than anterograde conduction time in normal myocardium. This disparity was accentuated in ischemic myocardium and, on reperfusion, retrograde and anterograde conduction times tended to return toward preischemic levels.Across the border of the ischemic segment, exit of an impulse from the ischemic area retrograde to the normal area was considerably slower than in the reverse direction. Both anterograde and retrograde conduction times within the ischemic area were affected adversely by the creation of an adjacent ischemic area, presumably because of cut-off of collateral supply. The differential effect of ischemia and reperfusion on anterograde and retrograde conduction times was also different in the epicardium and endocardium.These findings suggest that the effects of ischemia on conduction are complex and that conduction times depend significantly on direction of the impulse. In addition, disparity between anterograde and retrograde conduction times differs significantly in the epicardium and endocardium. These findings have relevance for assessment of drug effects on conduction in the normal, ischemic and reperfused myocardium and in studies on the relation between unidirectional delay and induction of reentrant tachyarrhythmias.     

Ventricular late potentials in acute myocardial infarct

Ventricular late potentials are regarded as an expression of delayed impulse conduction in an area of myocardial ischemia and, accordingly, indicative of a preformed reentry circuit. Late potentials can be detected in chronic, stable coronary artery disease and their presence correlates closely with impairment of ventricular function and with the probability of future occurrence of tachyarrhythmic events or sudden cardiac death. While repetitive ventricular arrhythmias in the chronic stage of coronary artery disease result almost invariably from circling intraventricular wavefronts, tachyarrhythmias associated with acute myocardial infarction appear attributable to differing pathomechanisms. According to experimental studies, in acute myocardial infarction, three phases of arrhythmogenesis can be differentiated: phase 1 encompasses the first hours after vessel occlusion which generally corresponds with the prehospital phase. Due to the difference in potential of up to 25 mV between ischemic and nonischemic cardiac muscle areas, an injury current is called into existence which leads to depolarization of normal cardiac muscle tissue. The ectopic impulses so precipitated, the conduction of which is supported by the functional inhomogeneity of the infarcted region, are capable of initiating reentry tachycardia. During phase 2, a few hours to days after the ischemic event, only the subendocardial Purkinje fibers in the infarcted region exhibit focal arrhythmogenicity. In contrast to the working myocardial cells, the latter survive due to their immediate proximity to the cardiac chamber and show, ischemia-induced, a propensity to high-frequency impulse formation in terms of abnormal automaticity. Similar to the experimental findings, the cause of the frequently-observed ventricular arrhythmias in the early hospital phase appears predominantly attributable to a focal arrhythmia mechanism. During phase 3, several days to weeks after the acute myocardial ischemic event, reentry mechanisms again are in the foreground in which the electrophysiologic changes in the Purkinje fibers, in terms of increasing desynchronization, together with conduction barriers arising through the infarct scar, pave the way for reentry phenomenon. After abrupt restoration of patency of a previously occluded vessel the very frequent "reperfusion arrhythmias" are also attributable primarily to reentry mechanisms due to inhomogeneous improvement of the conduction properties in the region of the reperfused myocardium. Ventricular late potentials can be registered both invasively by means of epi- or endocardial leads as well as noninvasively from the body surface.(ABSTRACT TRUNCATED AT 400 WORDS)     

Early phase acute myocardial infarct size quantification: validation of the triphenyl tetrazolium chloride tissue enzyme staining technique

Gross histochemical delineation of myocardium which has lost dehydrogenase enzyme activity has been shown to facilitate macroscopic recognition of necrotic myocardium. The present study was undertaken to assess the accuracy of the triphenyl tetrazolium chloride (TTC) technique for quantitating myocardial infarct size very early after coronary occlusion. In 16 closed-chest dogs the left anterior descending coronary artery was occluded with an intra-arterial balloon. Twelve dogs were killed 6 hours after occlusion, their hearts excised, cut from apex to base into 1 cm thick slices, and incubated in TTC. Whole-mount histologic sections of each slice were prepared. Myocardial infarct size was measured by planimetry of photographs of each gross slice and histologic section using classical criteria of necrosis. Myocardial infarct size determined in 54 slices by the TTC technique and histologically was similar (25 +/- 16% vs 27 +/- 16% of the left ventricular mass, mean +/- SD) with close correlation between the two methods (r = 0.91). Four dogs were killed 3 hours after occlusion and TTC stained and unstained myocardium was studied by electron microscopy. When the TTC technique identified necrosis so did electron microscopy. Areas identified by the TTC technique as non-necrotic were either normal or only ischemic by electron microscopy. Thus, using TTC, necrosis can be quantitated reliably 6, and even 3 hours after coronary occlusion, before histologic changes are clearly diagnostic. This technique represents a reliable, practical means for quantitation of recent infarction and for studying the evolution of ischemic injury in its early phase.     

Effects of verapamil on ventricular rhythm during acute coronary occlusion

The effects of verapamil on electrophysiologic parameters of the ventricle were studied during acute coronary occlusion in anesthetized open-chest dogs. Those parameters measured in the study were idioventricular automaticity, ventricular conduction, and fibrillation threshold. The incidence of rapidly repetitive beats and fibrillation induced by two successive premature beats was also studied. Verapamil significantly decreased idioventricular automaticity (in five dogs), improved conduction through the ischemic area (in six dogs), and increased fibrillation threshold of the ischemic ventricular (in eight dogs). The drug was effective in abolishing rapidly repetitive beats and fibrillation induced by closely coupled premature beats during acute coronary occlusion. Rapidly repetitive beats occurred in nine out of 15 dogs and these repetitive beats were degenerated into fibrillation in seven dogs before verapamil. Following pretreatment with the drug, rapidly repetitive beats and fibrillation occurred in none of the 15 dogs. The results indicate that verapamil can be very effective against ventricular arrhythmias occurring in association with myocardial infarction.     

Electrophysiologic observations on ventricular tachyarrhythmias following reperfusion

The threat of reperfusion ventricular fibrillation could potentially deter attempts of reperfusion in patients with acute myocardial infarction. Delineation of the mechanisms of this arrhythmia could pave the way to newer interventions designed as prevention or definitive treatment. Therefore the purpose of the present study was to investigate the features of initiation of reperfusion-induced ventricular fibrillation, and further to distinguish between episodic and sustained ventricular arrhythmias following reperfusion. Nine instances of reperfusion ventricular fibrillation and five instances of episodic tachyarrhythmia were analyzed in the study utilizing endocardial bipolar electrograms from normal, ischemic, reperfused, and the border of these myocardial segments. In 11 of 14 instances, the site of initiation of the tachyarrhythmias was in the reperfused myocardium; however, maintenance of the arrhythmia defined as diastolic and or continuous electrical activity suggestive of reentry was not seen in the reperfused myocardium in any of these instances. Diastolic electrical activity was observed in 8 of 14 instances, and was seen either in the center or border of ischemic myocardium. Neither heart rate or mean aortic pressure was different between episodic and sustained arrhythmia groups; however, the initial beat of the fatal arrhythmia was significantly more premature than that of episodic arrhythmia. In addition, shorter cycle length, greater variations in the cycle length, and greater disparity in local activation during the tachyarrhythmia were seen in the sustained arrhythmia group compared to the episodic group; cycle length increased and the disparity in local activation improved gradually prior to the termination of the arrhythmia. There was no particular difference in conduction delay immediately prior to reperfusion between control and reperfusion ventricular fibrillation groups. We conclude that different mechanisms exist for the initiation and maintenance of reperfusion-induced arrhythmias. Further, several features seem to distinguish episodic from fatal arrhythmias following reperfusion.     

Angina pectoris, myocardial infarction and sudden cardiac death with normal coronary arteries: a clinicopathologic study of 9 patients with progressive systemic sclerosis

The syndrome of angina pectoris or acute myocardial infarction without obstructive coronary artery disease has been the subject of much interest. We studied nine autopsied patients with progressive systemic sclerosis and evidence of ischemic heart disease but morphologically normal coronary arteries. Three patients had angina pectoris and three others chest pains of unknown etiology, six had ventricular arrhythmias, four had clinically suspected acute myocardial infarction, and eight had sudden cardiac death. At autopsy extensive focal myocardial necrosis was present in seven patients and myocardial scarring in all nine, but all patients had widely patent intramural and extramural coronary arteries. The finding of contraction band myocardial necrosis in seven of the eight patients who experienced sudden death suggests that the myocardial damage was a consequence of reperfusion of focally nonperfused myocardium, and thus due to a myocardial Raynaud's phenomenon. Patients with PSS may provide a model of spasm of intramyocardial vessels causing angina pectoris or myocardial infarction with morphologically normal coronary arteries.     

Regional myocardial blood flow and ventricular arrhythmias following one-stage and two-stage coronary artery occlusion in anesthetized dogs

Experiments were performed in 29 anesthetized dogs to compare effects of one-stage and two-stage coronary artery occlusion on ventricular arrhythmias and regional myocardial blood flow (MBF). Two periods of arrhythmias were observed and both were associated with evidence suggesting reentry; i.e., activity in ischemic zone electrograms which bridged the diastolic intervals preceding ventricular ectopic beats. Early ventricular arrhythmias followed progressive deterioration of conduction in the ischemic zone, whereas later arrhythmias occurred unexpectedly with the sudden appearance of bridging activity. One-stage occlusion produced a higher incidence of ventricular arrhythmias and ventricular fibrillation than two-stage occlusion. However, there was no difference in central ischemic zone blood flow, indicating that the protective effect of two-stage occlusion was not due to greater blood flow in this region. These results suggest that factors other than the degree of MBF reduction are important determinants of the incidence and severity of ventricular arrhythmias following coronary artery occlusion.     

Tritiated digoxin. XX. Tissue distribution in experimental myocardial infarction

The role and potential hazards of digitalis glycoside administration in acute myocardial infarction remain controversial. We investigated the concentration of tritiated digoxin in normal, ischemic, and infarcted left ventricular myocardium of the dog after ligation of the anterior interventricular coronary artery. The normal homogeneous distribution of tritiated digoxin in the normal canine left ventricle was altered following acute myocardial infarction. The ischemic and infarcted zones exhibited a marked diminution in digoxin concentration. Oxidative phosphorylation determinations confirmed tissue hypoxia in the infarcted zone. The gradient of digoxin concentration between normal, ischemic, and infarcted zones of myocardium may potentiate the development of an arrhythmia in the electrically unstable infarcted myocardium.     

Effects of diltiazem on conduction of premature impulses during acute myocardial ischemia and reperfusion

The effect of diltiazem on conduction of cardiac impulses was studied using premature impulses. Conduction times were measured in the epicardium and endocardium in both anterograde and retrograde directions during ischemia and reperfusion of the left ventricular anterior wall. In 16 dogs (8 control and 8 treated with diltiazem), the left anterior descending artery was occluded initially below the second diagonal branch and 30 minutes later below the first diagonal branch. Infusion of diltiazem (0.02 mg/kg per min) was begun at the time of the first ligation in the treated dogs. Conduction delay in normal, ischemic and reperfused myocardium and at the border of ischemia or reperfusion was compared in the two groups. In addition, treated and nontreated ischemic zones were analyzed in the diltiazem-treated group. Results showed significantly less ischemia-induced conduction delay in the diltiazem-treated group in both ischemic myocardium and at the border of ischemia. This beneficial effect was seen in the ischemic segment in the treated dogs whether or not the medication was given before or after coronary ligation. Further, the effect of the drug on epicardial and endocardial conduction did not differ significantly. These data suggest that diltiazem may have potential value in the treatment of ventricular reentrant arrhythmias associated with acute ischemia over and above the well recognized hemodynamic and metabolic effects of calcium channel blocking agents.     

Adrenergic effects on reentrant ventricular rhythms in subacute myocardial infarction.

BACKGROUND. Reentry has been shown to be a mechanism of ventricular arrhythmias elicited by programmed premature stimulation in the subacute ischemic period of dogs subjected to myocardial infarction. The spatial distribution of refractoriness in these hearts has been shown to play an important part in the formation of functional arcs of conduction block during programmed ventricular stimulation. Because the adrenergic nervous system influences cardiac arrhythmias and myocardial infarction can directly affect sympathetic innervation in the heart, we investigated the role of the sympathetic nervous system on reentry in the canine heart 4 days after infarction. METHODS AND RESULTS. The influences of adrenergic stimuli on the initiation of reentrant ventricular excitation were studied using a 128-channel computerized recording system in the canine heart 4 days after ligation of the left anterior descending coronary artery. Bilateral stimulation of the ansae subclavia preferentially improved conduction of premature beats in the normal zones. This corresponded to an improvement in excitability, as measured by a decrease in stimulus strength at the same premature coupling interval as control. Consequently, the effective refractory period was preferentially shortened at normal sites but not at ischemic sites. Both of these changes contributed to a shift of the arc of functional conduction block toward more normal tissue. As a result, sites proximal to the arc of functional conduction block had more time to recover excitability and thereby were available to be reexcited by the distal activation wave front. Conversely, intravenous infusion of norepinephrine preferentially shortened the effective refractory period of sites in the ischemic zone, thereby indicating that denervation hypersensitivity had occurred at these sites. The spatial dispersion of refractoriness and the arc of functional conduction block were significantly reduced in size. As a consequence, previously inducible reentrant rhythms were no longer inducible. CONCLUSIONS. Sympathetic stimulation can be considered an arrhythmogenic intervention, whereas norepinephrine infusion may be considered antiarrhythmic in this experimental model.     

Electrophysiologic studies on reentrant ventricular arrhythmia in the late myocardial infarction period

The mechanisms of reentrant ventricular tachycardia were studied in canine post-infarction model. In 15 dogs that weighed 10-20 kg, the anterior descending coronary artery was ligated. 3 to 7 days after coronary artery occlusion, the dogs were reoperated to set up a composite electrode or a patch electrode with 32 bipolar electrodes. The composite electrode was utilized to record ventricular late potentials (VLPs) from the epicardial surface of the infarction zone (IZ) and adjacent normal zone (NZ). The bipolar electrodes were used to record the epicardial isochronal maps. 16 bipolar electrodes were placed over the area of infarction and its bordering zone and the other 16 bipolar electrodes were distributed over the remaining surface of the ventricle. Reentrant ventricular tachycardias were induced by programmed electrical stimulation. The VLPs and epicardial isochronal activation were recorded by SC-16 oscillograph and computerized mapping system during sinus rhythm and programmed stimulation. The experiments showed; 1) VLPs were demonstrated in 11 of the 15 dogs (73.3%) during programmed stimulation. 2) The reentrant circuit has a characteristic figure-8 configuration in the form of two circulating wave-fronts around arcs of functional conduction block that coalesce into a slow commun reentrant wave-front. One of the two synchronous circuits traveled clockwise and the other counter-clockwise. 3) VLPs represent a delayed depolarization at the ischemic myocardium, where the impulse conducts slowly in the reentrant circuit. It is clear that the present study may increase the understanding of the mechanism of ventricular arrhythmias in the late myocardial infarction period.     

Prognosis after myocardial infarction

A substantial number of patients die in the first year after myocardial infarction. The major determinants of risk during this period appear to be the extent of either damaged or potentially ischemic myocardium and the degree of electrical instability. Anterior infarction, early left ventricular failure, late significant arrhythmias, and markedly reduced radionuclide left ventricular ejection fraction are the major clinical markers of risk.     

Electrocardiographic antecedents of primary ventricular fibrillation. Value of the R-on-T phenomenon in myocardial infarction.

Primary ventricular fibrillation was seen in 20 of 450 consecutive patients (4-4%) admitted within 24 hours after the onset of acute myocardial infarction. Compared with patients without primary ventricular fibrillation they showed a lower mean age group and a higher incidence of anterior infarction. Warning ventricular arrhythmias preceded primary ventricular fibrillation in 58% of cases. However, warning arrhythmias were also present in 55% of patients without primary ventricular fibrillation. The following mechanisms of initiation of primary ventricular fibrillation were seen. 1) In one patient, it was initiated by supraventricular premature beats showing aberrant intraventricular conduction. 2) In 2 patients, ventricular tachycardia degenerated into primary ventricular fibrillation. 3) In 17 patients, it was initiated by a ventricular premature beat; in 10 of these, the premature beat showed early coupling (RR/QT less than 1--the R-on-T phenomenon). However, ventricular premature beats showing the R-on-T phenomenon were also observed in 49% of patients without primary ventricular fibrillation. In 7, primary ventricular fibrillation was initiated by a late-coupled ventricular premature beat (RR/QT greater than 1); in 2, the very late coupling resulted in a ventricular fusion beat. The study suggests that warning arrhythmias and the R-on-T phenomenon are poor predictors of primary ventricular fibrillation in acute myocardial infarction. The observation that 41% of primary ventricular fibrillation was initiated by a late-coupled ventricular premature beat suggests that ventricular vulnerability during acute myocardial infarction may extend throughout most of the cardiac cycle and is not necessarily confined to the QT interval.     

Electrocardiographic antecedents of primary ventricular fibrillation. Value of the R-on-T phenomenon in myocardial infarction.

Primary ventricular fibrillation was seen in 20 of 450 consecutive patients (4-4%) admitted within 24 hours after the onset of acute myocardial infarction. Compared with patients without primary ventricular fibrillation they showed a lower mean age group and a higher incidence of anterior infarction. Warning ventricular arrhythmias preceded primary ventricular fibrillation in 58% of cases. However, warning arrhythmias were also present in 55% of patients without primary ventricular fibrillation. The following mechanisms of initiation of primary ventricular fibrillation were seen. 1) In one patient, it was initiated by supraventricular premature beats showing aberrant intraventricular conduction. 2) In 2 patients, ventricular tachycardia degenerated into primary ventricular fibrillation. 3) In 17 patients, it was initiated by a ventricular premature beat; in 10 of these, the premature beat showed early coupling (RR/QT less than 1--the R-on-T phenomenon). However, ventricular premature beats showing the R-on-T phenomenon were also observed in 49% of patients without primary ventricular fibrillation. In 7, primary ventricular fibrillation was initiated by a late-coupled ventricular premature beat (RR/QT greater than 1); in 2, the very late coupling resulted in a ventricular fusion beat. The study suggests that warning arrhythmias and the R-on-T phenomenon are poor predictors of primary ventricular fibrillation in acute myocardial infarction. The observation that 41% of primary ventricular fibrillation was initiated by a late-coupled ventricular premature beat suggests that ventricular vulnerability during acute myocardial infarction may extend throughout most of the cardiac cycle and is not necessarily confined to the QT interval.     

Unreliability of conventional electrocardiographic monitoring for arrhythmia detection in coronary care units

To evaluate the reliability of conventional coronary care unit electrocardiographic monitoring, a study was made of 31 consecutive patients with uncomplicated verified acute myocardial infarction. All patients were monitored routinely with conventional equipment, and at the same time the electrocardiogram for each patient was recorded continuously on electromagnetic tape and stored for later analysis by an automated arrhythmia detection system. All patients studied were within 24 hours of the onset of chest pain and on entry into study all were free of shock, heart block, bundle branch block, severe heart failure or an existing arrhythmia. By conventional monitoring, premature ventricular contractions were recognized in 64.5 percent of patients compared with 100 percent using the automated detection system (P <0.01). The corresponding percentages for recognition of premature atrial contractions were 45.2 vs. 96.8 percent (P < 0.001); serious ventricular arrhythmias, 16.1 vs. 93.5 percent (P <0.001); multifocal premature ventricular contractions, 6.5 vs. 87.1 percent (P < 0.001); and consecutive premature ventricular contractions, 13.0 vs. 77.5 percent (P < 0.001), respectively. The delay from the time of first occurrence as detected by the automated system to recognition by the conventional monitoring system averaged 18 hours for premature ventricular contractions, 10 hours for serious ventricular arrhythmias and 23 hours for premature atrial contractions. The on-line use of an automated arrhythmia detection system in the coronary care unit is suggested if further improvement in the elimination of arrhythmias as a primary cause of death after myocardial infarction is to be achieved. The presence of serious ventricular arrhythmias in virtually all patients after myocardial infarction suggests that prophylactic antiarrhythmic agents be used in this setting; however, none of the presently available antiarrhythmic agents have been shown to reduce mortality when given prophylactically following myocardial infarction.     

Relation of ventricular arrhythmias in the late hospital phase of acute myocardial infarction to sudden death after hospital discharge.

To determine the prognostic significance of ventricular arrhythmias persisting during the hospital ambulatory phase of acute myocardial infarction, 64 patients with acute myocardial infarction underwent continuous 10-hour Holter monitoring an average of 11 days after discharge from the coronary care unit (CCU). Patients were categorized according to the results of ambulatory monitoring: 27 patients had ventricular extrasystoles, which were complicated (multifocal, R on T, paired, more than 5/min), or ventricular tachycardia; 22 had uncomplicated premature ventricular contractions; and 15 exhibited no ventricular arrhythmias. The 64 patients were followed prospectively for an average course of 25.8 months; 12 died suddenly; 8 died of other causes, and 44 survived. In all patients who died suddenly, ventricular ectopy was recorded on Holter monitoring before their discharge from the hospital (complicated premature ventricular contractions, eight patients; uncomplicated premature ventricular contractions, four patients); there were no sudden deaths in the patients without ventricular arrhythmias. Patients who died suddenly and those survived were similar in respect to age (60, 62 years), sex, location of infarction, presence of coronary risk factors, severity of acute myocardial infarction (Q waves, cardiac enzymes), serum cholesterol levels, evidence of cardiomegaly on roentgenograms, presence of ventricular gallop and drug therapy received. The occurrence of acute arrhythmias in the CCU did not separate patients who died suddenly from those who survived; there were no differences in ventricular tachycardia or ventricular fibrillation (3 or 12 patients who died suddenly, 6 of 44 patients who survived) or complicated premature ventricular contractions (4 or 12 patients who died suddenly, 18 of 44 patients who survived). Electrocardiograms obtained late in the hospital course revealed no differences in the extent of Q or T wave changes between these two groups. However, the extent of S-T segment abnormality was greater in patients who died suddenly than in patients who survived (5.6 compared to 1.8 leads/standard tracing, p smaller than 0.02) suggesting that the arrhythmias in the former were related to persistent ischemia or segmental ventricular dyssynergy. Thus, in this relatively small number of patients, ventricular arrhythmias persisting late in the hospital course of patients admitted for acute myocardial infarction are shown to predispose to subsequent sudden death.     

Subendocardial origin of ventricular arrhythmias in 24-hour-old experimental myocardial infarction.

In 12 anesthetized open-chest dogs, ventricular epicardial activation maps were constructed and electrograms were recorded from the bundle of His, left bundle branch, and subendocardial Purkinje fibers 24 hours following Harris 2-stage ligation of the left anterior descending coronary artery. All animals developed ectopic ventricular depolarizations and/or ventricular tachycardia. The earliest area of epicardial activation was located along the border of the infarct in the left ventricle in all animals. Bipolar recording from various levels of the conduction system and ventricular myocardium revealed that the earliest recorded electrical activity originated in subendocardial Purkinje fibers which had survived the acute myocardial infarction. The origin of these arrhythmias was further studied by pacing through the electrode which had recorded the early Purkinje activity and comparing the surface ECG and activation sequence with that of the spontaneous rhythm. These data tend to support the hypothesis that ventricular arrhythmias occurring 24-72 hours following acute myocardial infarction have their origin in the subendocardial Purkinje network which has survived the infarction.     

The effect of atropine on cardiac arrhythmias and conduction. Part 2

The effects of atropine on various components of the specialized conduction system of the heart and the myocardium itself are reviewed. These actions are sometimes unpredictable or paradoxical, depending on the component showing the dominant effect and the health of the entire system. Atropine is best known for its chronotropic effect. Improved sinoatrial conduction has been demonstrated but the effect on the refractoriness of atrial muscle is unsettled. Atropine stimulates the atrioventricular (A-V) junctional pacemaker and facilitates conduction through the A-V node. The response of the subjunctional portion of the specialized conduction system to the drug is unpredictable and controversial in some respects.Atropine is useful in the diagnosis of sinus node dysfunction, in the evaluation of coronary artery disease during atrial pacing, and in attempting to produce normal conduction in patients with the Wolff-Parkinson-White Syndrome. Its principal therapeutic application is in correcting the hypotension-bradycardia syndrome occurring during acute myocardial infarction. It also has a role in the temporary management of sinus node dysfunction. Atropine may also cause arrhythmias, including atrial fibrillation, A-V dissociation, ventricular tachycardia, and ventricular fibrillation. The clinical settings in which atropine may be arrhythmogenic are discussed.     

Antiarrhythmic actions of tocainide in canine models of previous myocardial infarction.

The antiarrhythmic and antifibrillatory efficacies of the class IB antiarrhythmic agent tocainide were characterized in conscious dogs in the early subacute phase of anterior myocardial infarction (48 hours after infarction) and in anesthetized dogs with ventricular tachyarrhythmias that were inducible by programmed stimulation more chronically (10.8 +/- 1.0 days) after anterior myocardial infarction. The frequency of spontaneous premature ventricular complexes in the early subacute postinfarction phase was reduced significantly from 48.4% +/- 10.5% to 8.2% +/- 5.0% of total complexes (p less than 0.01) by the cumulative intravenous administration of 10 mg/kg tocainide. In the late postinfarction setting, the intravenous administration of tocainide (6 mg/kg intravenous loading dose + 100 micrograms/kg/min intravenous maintenance infusion) suppressed the initiation of ventricular tachyarrhythmias by programmed stimulation in 5 of 12 animals that were tested and slowed the rate of tachycardia in 3 additional animals. However, the incidence of ventricular fibrillation and of the total number of arrhythmia-related deaths that resulted from the occurrence of a secondary ischemic insult in the presence of previous infarction did not differ significantly between tocainide (75% [9 of 12] incidence of both ventricular fibrillation and of total number of arrhythmia-related deaths) and saline-vehicle control groups (80% [12 of 15] incidence of ventricular fibrillation; 93.3% [14 of 15] incidence of total number of arrhythmia-related deaths). These findings suggest that although class I agents such as tocainide may be efficacious in the suppression of spontaneous premature ventricular complexes and ventricular arrhythmias immediately after myocardial infarction, they may be of limited value in the prevention of malignant ischemic arrhythmias that occur later after myocardial infarction.