JACC Vol. 16, No. 6 November 1 5.1990:1475--80

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Tocainide and Mortality After Myocardial Infarction : A Prospective Study in Conscious Dogs EMILIO VANOLI, MD, STEPHEN S . HULL, JR ., PHD,* REX D . STITH, PHD,* PHILIP B . ADAMSON, MS,* ROBERT D . FOREMAN, PHD,* PETER 1 . SCHWARTZ, MD, FACC Oklahoma City, Oklahoma sad Milan, Italy

The production of an anterior myocardial infarction as part of an experimental animal model for sudden death was burdened by a persistently elevated mortality rule (30%) despite the use of traditional antiarrhythmic drugs . Moe. tality was reduced when tocainide 1600 mg three times daily) was empirically administered for 4 days before and 4 days after myocardial infarction. Retrospective analysis showed that mortality at 4 days after infarction was signif . icandy, lower in the tocainidedreated dogs than In the preceding large group of dogs that had not been so treated (5 19%] of 55, versus 64 132%] of 199, p < 0.01). This difference was still evident 30 days after myocardial infe-_tion (13 [24%] of 55 versus 03 (42%] of 199 ; p < 0.05). This observation led to the present prospective study in 106 dogs with a similar protocol but with a randomized sequence. At 4 days after myocardial infarction, the mortally, rate was 55% lower in the tocainide group than in the

Sudden cardiac death in patients with ischemic heart disease remains a baffling problem despite apparent progress in the understanding of cardiac electrophysiology and the availability of new and potent antiarrhythmic drugs. As the results of the Cardiac Arrhythmias Suppression Trial (I) indicate with finality, therapy with a drug that suppresses ventricular arrhythmias does not necessarily reduce the risk for sudden death . In fact, the question of antiarrhythmic versus antifibrillatory effects is as open as ever (2) . Therefore, a serendipitous experimental observation seemed worth pursuing further si5d has generated a prospective study that shows increased survival in the postinfarction

From the Units' di Studio delle Aritmie. Cenlro di Fisiologia Clinics ° Ipertensione . Isdtut. di Clinics Medics IL Utu,c . tn' degli Saudi di Milano, Milan, Italy, and 'Depanment

of Physiology

and Biophysie , University of

Oklahoma Health Sinn,, Cenreq Oklahoma City . Oklahoma. This study was supported in pan

by

Grant HL33727 from the Nations: Institutes of Health,

Bethesdo. Maryland. Address for oodals: Peter J . Schwanz,

Sago . Via F. Stones . 35. 20122 Milan . Italy . 01990 by the

American College of Cardiology

MD,

Clinics Medics 11-Pd .

control group (7 [12 .5%] of 56 versus 14120%] of 50; p < 0.05) . During the 10 day' after treatment withdrawal 9 (10"0) of 49 dogs in the tocainide group died compared with only 2 (5%) of 36 in the control group. This rebound in mortality produced similar survival figures in the two groups at 14 and at 30 day after infarction when mortality vas 30% (17 of 56) in the :acalnide group and 34% (17 of 50) in the control group. The forelock, plasma levels were 7 .4 ± 4 pglmt the day before infarction and 7 .2 ± 3 Jag/ml 3 days after infarction. This study indicates that mortality in the first few days after myocardial infarction can be reduced by tocainide . The results may be of potential interest for the out of hospital management of patients with a recent myocardial infarction. (J Am Coll Cordial 1990;16:1475-80)

period after treatment with tocainide, a class IB antiarrhythmic drug (3). A high mortality rue in the early days after myocardial infarction was the rain problem encountered in the preparation of our experimental animal model for the study of sudden cardiac death (4,5) . Within 4 days after the production of a myocardia. infarction by ligation of the left anterior descending coronary artery, almost 30^io of dogs were regularly lost because of sudden death . This early postinfarction mortality rate had renamed constant over the years and had not been obviously affected by the use of either quinidine or prucainamide. An at :empt was then made with the use of tocainide. To our ssrprise, a marked reduction in the postinfarction mortality rate became evident and administration of tocainide became routine in our laboratory . The striking reduction in mortality after treatment with tocainide and the potential clinical relevance of this finding led us to design a randomized prospective study to assess if tocainide could effectively reduce mortality in the first few days after infarction . 0735-1097,90153 .50



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VANOLI ET AL . TOCAINIDE AND MORTALITY AFTER MYOCARDIAL INFARCTION

Methods Mongrel dogs (15 to 20 kg) conditioned for chronic study were purchased from a United States Department of Agriculture registered animal dealer. Surgical preparation and coronary artery seclusion. The procedure describing the surgically created myocardial infarction has been presented in detail elsewhere (4,5) . In brief, anesthesia was induced by thiamylal sodium (25 mg/kg body weight) and maintained by respirator-assisted inhalation of anesthetic (halothzne, 0 .5% to 1 .5%) in an oxygennitrous oxide mixture. A thoracotomy was performed with aseptic procedure in the fourth intercostal space . Through this opening a tygon catheter was inserted in the aortic arch and the pericardium was opened and suspended in a cradle . The circumflex branch of the left coronary artery was dissected free from the surrounding tissue for 2 cm at its origin. A 20 MHz Doppler flow probe and a pneumatic occluder were positioned around the vessel . The instrumentation in the aortic arch and around the left circumflex coronary artery was part of the preparation of a long-term animal model for the study of sudden cardiac death (4,5) and was never used during the 30 days of follow-up . The anterior descending branch of the left coronary artery was dissected for a short distance immediately proximal to the first diagonal branch. The vessel was then occluded in two stages, as described by Harris (6). A stenosis was initially performed by tying together the vessel and a 21 gauge needle, which was then removed . After 20 min the vessel was completely ligated. The pericardium was loosely sewn and the chest was closed . The distal ends of the instrumentation were tunneled under the skin and exteriorized on the dorsal surface of the neck . Immediately after endotracheal extubation, every dog received a fast-acting analgesic, pentazocine lactate (Talwin), I mg/kg intramuscularly, followed 4 h later by a longer-acting analgesic, nalbuphine hydrochloride (Nubain), 0 .5 mg/kg intramuscularly . Appropriate antibiotic therapy was also administered . The same technical staff performed most of the surgical interventions. Duration of surgery rarely exceeded 3 h . The electrocardiogram was continuously monitored during surgery and during recovery from anesthesia. We adhered strictly to the guidelines for the appropriate care and use of research animals established by the National Institutes of Health, the American Physiological Society and the American Heart Association . Tocainide plasma level determination, Tocainide plasma levels were assessed by a modification of the method described by Shihabi et at. (7) . Blood samples were collected from the cephalic vein and centrifuged . Plasma samples were thawed and aliquots were filtered through Centrifree (Amicon) filter tubes to deproteinize the samples . Two hundred microliters of deproteinized plasma was mixed with an equal volume of acetonitrile and refiltered in microfuge tubes . The

JACC Vol . 16, No. 6 November 15, 19901475-50

high-pressure liquid chromatography instrumentation consisted of a BAS model 400 (Bioanalytical Systems) . The mobile phase was delivered at a rate of 1 .3 ml/min onto a Syneropak SCD-100 column (150 x 4 .6 mm, 5 pg particles) (Synchrom) . Samples were delivered into a 10 µl loop by a Precision auto sampler, model LC-2000 (Dynatech). The column eluent was detected with an ultraviolet detector with a 229 nm filter. The mobile phase consisted of 25 mM ammonium phosphate buffer in 24% acetonitrile, pH 7 .3 . Stock tocainide standard was 100 mg/liter in acetonitrile . Working standards were made from the stock standard by dilution in water. To obtain control plasma samples, known amounts of tocainide were added to plasma samples from control dogs . These samples, prepared in the same manner as others, were used to determine percent recovery . We found the assay to be linear (r = 0.99) between I and 20 mg/liter and the recovery to be 100% . The between-assay variability was 9 .5% . Experimental protocol. The study consisted of two parts : In the first part a retrospective analysis compared the mortality rate that occurred after myocardial infarction in 199 consecutive dogs with that of a second group of 55 dogs identically prepared but treated with tocainide . During the period in which these 55 dogs were studied, 12 additional dogs were prepared identically without treatment with tocainide to verify that the mortality rate had not changed over time . In the second part of the study 134 dogs were prospectively randomized to either myocardial infarction and treatment with tocainide or myocardial infarction alone . Tocainide (600 mg twice a day at 8 AM and 5 PM) was given orally beginning 4 days before the production of infarction and continuing for 4 days after. The time of surgery allowed the dog to receive one tablet in the morning just before surgery and one in the late afternoon after recovery from anesthesia. Dogs in the control group did not receive any antiarrhythmic drugs . Blood samples for the assay of rocainide plasma levels were taken in the afternoon the day before surgery and on the 3rd day after surgery (both before tocainide administration). Mortality that occurred in the very early phase of the myocardial infarction was calculated separately from mortality after recovery from anesthesia . Follow-up continued for 30 days after infarction . All dogs included in the study were considered to be in good condition by the technical and veterinary staff on the basis of daily inspection . A necropsy was performed in all dogs that died during follow-up . If the death was determined to be secondary to extracardiac conditions, that is, overwhelming infection or technical problems, the dog was excluded from the analysis. Only cardiac-related deaths were analyzed . Extracardiac mortality was approximately 3% .



JACC Vol . 16 . No . G November 15, 1990:1475-80

TOCAINIDE AND MART

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VANOLI ET AL. AFTER MYOCARDIAL INFARCTION

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1

2

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Control

1477

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Figure 1 . Cardiac mortality at 4 days after myocardial infarction in the retrospective study of 211 dogs that did not receive tocainidc (groups I and 3) and of 55 tccainide-treated dogs (group 2).

Figure 2. Cardiac mortality at 4 days after myocardial infarction in the prospective study in the control group (n = 50) and the tocainidc-heated group (n = 56) .

Statistical analysis . Curves of survival after myocardial infarction were calculated according to the method of Cutler and Ederer (8) . Differences in mortality rate at different times after coronary artery ligation were compared by chi-square test. A p < 0 .05 was considered significant for the differences tested .

in the second part cf the follow-up was 16% (8 of the 50 dogs that survived the first part of the follow-up), almost double the initial 9% . Thirty days after infarction the difference in mortality between the two groups, although less impressive, was still significant (83 142%) of 199 versus 13 124%) of 55 ; p < 0 .05).

Results

Retrospective Study A total of 266 dogs recovered from anesthesia and were used for this analysis . Within the total group of dogs, three subgroups were identified . Group I (n = 199) included the dogs which were operated on before locainide treatment started; group 2 dogs (n = 55) received tocainide and were operated on after group 1 ; group 3 dogs (n = 12) did not receive tocainide and were operated on during the same time frame as group 2 dogs . Mortality was calculated on the basis of the information on surgery, recovery phase and necropsy, as provided by the records . Early mortality . In group 1, 64 (32%) of the 199 dogs died during the first 4 days after myocardial infarction . In contrast, only 5 (9%) of the 55 dogs in group 2 died during the first 4 days after myocardial infarction . The difference in mortality rate between the two groups was highly significant (p < 0.01) . In group 3, 6 (50%) of the 12 dogs died within 4 days of infarction, thus confirming the elevated mortality rate as a consequence of the anterior infarction in nontreated dogs (group) (Fig. 1). Later mortality. In group 1, 19 of the 135 dogs that survived the first 4 days subsequently died . This resulted in a mortality rate (14%) markedly lower than the initial 32% . An opposite trend was observed in group 2, where mortality

Prospective Study A total of 134 dogs were used in the prospective study ; 71 were treated with tocainide and 62 served as a control group . Five dogs (two in the control group and three in the locainide-treated group) were excluded from the study because they died of technical issues. Early mortality. The incidence of ventricular fibrillation in the first 3 h after infarction was not different in the two groups of dogs, because it occurred in 11(18%) of 61 control dogs and in 12 (18%) of68 tocainide-treated dogs . Among the dogs that survived the first 3 h after myocardial infarction, mortality in the subsequent 4 days was reduced by 55% in the tocainide-treated group, as compared with the control group : 7 (12 .5%%) of 56 versus 14 (28%) of 50 ; p < 0.05 (Fig . 2) . Analysis of survival curves (Fig . 3) indicates that at 48 h after myocardial infarction mortality was already markedly reduced in the treated as compared with the control group . After tocainide therapy was discontinued on the 5th day after myocardial infarction, mortality in the tocainide group progressively increased, so that the two survival curves became very similar . Later mortality. During the 10 days after cessation of treatment with tocainide, the mortality rate in the surviving dogs was 18% (9 of 49) in !he group treated with tocainide, as



VANOLI ET AL. TOC .4INIDE AND MORTALITY AFTER MYOCARDIAL INFARCTION

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mr.reuon Figure 3 . Survival curves of the control and tocainide-treated groups in the prospective study . Mortality in the Isl day after myocardial infarction incorporates dogs that died during the perioperative phase, that is, the first 3 h after occlusion of the left anterior descending coronary artery. The cessation of treatment 4 days after infarction is indicated by the vertical dotted line. Survival in the tocainide-treated group is significantly higher during the first 4 days after infarction. After treatment is withdrawn, mortality increases in the tocainide group and the two curves become almost indistinguishable. opposed to 5% (2 of 36) in the control group . This resulted in a total mortality that was not different iii the two groups of dogs at 14 days after myocardial infarction : 16 (29%) of 56 in the tocainide group versus 16 (32%) of 50 in the control group . Only two dogs (one in each group) died during the remaining 15 days of observation and the mortality rate at 30 days after infarction was 30% (17 of 56) in the tocainide group and 34% (17 of 50) in the control group . Tocainide plasma levels . Tocainide plasma levels were measured in 22 dogs before and after the production of the anterior myocardial infarction . Mean plasma levels of tocainide were 7.4 ± 4 jug/ml (range 2 .7 to 15.7) before surgery and 7 .2 t 3 pest (range 4 to 16.8) after surgery . Discussion This study shows that oral administration of tocainide can effectively reduce mortality in conscious dogs during the first 4 days after a myocardial infarction . This protective effect

JACC Vol. 16. No .6 November 15, 1990:1475-e0

begins only after the very early phase of a coronary artery occlusion. Tocainlde plasma levels. The dosages used in the present study resulted in plasma levels of tocainide within ranges considered therapeutic in human studies (9-13) . These levels - 1-re lower than those attained in other experimental studies that reported an antiarrhythmic effect of tocainide . Specifically, in one study (14-16) tocainide was able to increase ventricular fibrillation threshold only when plasma levels were > l0 pg*ml . In an open chest preparation sympathetic activity and circulating cathecolamines are likely to be markedly increased and this increase may explain, at least in part, the high dosages of tocainide needed to observe a protective effect in this latter study. In another study (I5), however, tocainide concentration of 5 to 10 pg/ml in the perfusing solution suppressed arrhythmias due to enhanced automaticity induced by epinephrine in Purkinje fibers . In the present study in conscious dogs, we tested the efficacy of tocainide with dosages leading to plasma levels that can be attained clinically without significant side effects . Mortality In the acute phase of myocardial infarction. Tocainide did not reduce the incidence of ventricular fibrillation between the two stages of coronary artery occlusion or in the first 3 h after complete ligation of the artery . Arrhythmias that occur at this time are thought to depend on either reentry or abnormal automaticity (17,18) . Reflex sympathetic activation that occurs during the first few minutes of acute myocardial ischemia (19) plays an important role in the genesis of malignant arrhythmias (2023). As a consequence, drugs devoid of any antiadrenergic effect may be ineffective in preventing ventricular fibrillation and sudden death in the very early phase of acute myocardial ischemia . This concept is supported by data obtained in a feline preparation in which malignant arrhythmias can be consistently induced by the combination of transient coronary artery occlusion and brief stimulation of the left stellate ganglion (24) . This experimental model allows evaluation of antiarrhythmic drugs by internal control analysis . Although amiodarone and antiadrenergic and calcium channel blocking drugs provided effective protection in this model, class IB and IC antiarrhythmic drugs failed to prevent ventricular tachyarrhythmias (25-27) . The two class III agents tested were lidocaine and mexiletine, congeners of tocainide . A clinical counterpart of this observation is represented by the evidence that lidocaine is frequently ineffective when administered in the first few hours after the beginning of symptoms of acute myocardial ischemia (28). For these reasons the failure of tocainide to provide any protection during the very early phase of acute myocardial ischemia was not unexpected . Mortality In the subacute phase of myocardial infarction . The efficacy of tocainide in reducing mortality in the subacute phase after myocardial infarction represents novel information. Although arrhythmia monitoring was not per-



IACC Vol. 16, No. 6 November 15, 1990:1475-a0

VANOLI ET AL . 'rOCAINIDE AND MVttIALI'rV AFTER MYOCARDIAL INFARCTION

1479

. the dogs formed during the recovery phase after infarction cordial isthtrciioe is indicated by two different aspects f,were visited by the personnel three to four limes a day ; the data . the reduced mortality during the 4 days after myocardogs that died included in the study were considered in good dial infarction associated with treatment and the rather condition before they were found dead . Thus . it seems dramatic increase in mortality after tocainide withdrawal . legitimate to consider that most of the deaths that occurred Indeed, as demonstrated by the survival curves (Fig. 3), in our study were sudden . within a few days after cessation of treatment any distinction There is clinical and experimental evidence that indicates between the placebo- and tocainide-treated groups had disa powerful antiarrhythmic effect of tocainide but there are appeared . It is tempting to postulate that the dogs that died few studies relevant to the problem of sudden cardiac death after cessation of treatment with tocainide would have died that involve tocainide . In two previous experimental studies earlier if they had not been treated. Implications . This study indicates that mortality in the (16,29) locainide abolished ventricular tachyarrhythmias dependent on chronic ischemia induced by an ameroid confew days immediately after myocardial infarction can be strictor (16) and significantly reduced the inducibility of significantly reduced by treatment with tocainide . The study was not designed for and provides no data to suggest that ventricular tachycardias in conscious dogs that underwent an electrophysiologic study 7 to 30 days after a myocardial this beneficial effect would last beyond the subacute phase . infarction (29) . At that time different electrophysiologic mechanisms beIn clinical studies of postinfarction patients or of patients come involved in the genesis of lethal arrhythmias (including with coronary artery disease, a remarkable antiarrhythmic transient ischemic episodes, perturbations in autonomic effect of tocainide was also observed (9-I3) ; nevertheless . activity and abnormal mechanical stretch) that may no such an effect was not associated with a reduced mortality longer be preventable by a drug like tocainide . as are the arrhythmias of the very early phase. The possibility. not (13). Indeed, in the only prospective study conducted with tocainide in 56 tocainide-treated and 56 placebo-treated raised before, that tocainide may decrease the probability of patients (13), a similar mortality rate was noted during the 6 a lethal arrhythmia in a period up to 2 weeks after a months of follow-up . It is fair to say that of the four deaths myocardial infarction may be of clinical interest for patients in the tocainide-treated group, only one occurred in a patient managed in an out of hospital s. .ting. with tocainide plasma levels within the therapeutic range . Thus, there is no clear evidence that conclusively demonWe gratefully acknowledge the technical assislanceof Sandra S . Bryaut. Gary strates the effect of tocainide on the incidence of sudden N . Curio, Carlos M . Reynolds and to Chadene Smith for word processing and other assistance. death in patients recovering from a myocardial infarction . Mechanisms of tocainide protective effect . The strikingly protective effect of tocainide in the subacute phase of the myocardial infarction in our study was rather unexpected References based on current knowledge but it does not contradict the lack of effect on the tachyarrhythmias of the very early I . The Cardiac AnhythmiaSuppressiuuThat (CAM lnvestigators .Preliminary report: effect of encain de and Recainide on nonaity in u randomphase after coronary artery occlusion . Indeed, at this time ized trial of arrhythmia suppression aver myocardial infarction. N Engl J reflex sympathetic hyperactivity . which plays an important Med 1989 ;321 :406-12 . role in the genesis of these arrhythmias, has already suh2. Anderson IL . Antifibnltatory 7ersus xntiectopic menpy . Am 1 Cordial sided (30) and other electrophysiologic mechanisms have 1954 :54fsuppiAh7A-13A . became important (6,31) . The polymorphic ventricular (achy3. GraBner C . Conmdson TB, Hafvendahl S . Rvded L . Tocainide kinetics cardias usually observed in dogs during the first days after after intravenous and oral administration in healthy subjects and in patients with .,ate myocardial infarction . Clin PhannnrotThct 1950 ;17 : myocardial infarction depend mostly on abnormal automa6a-n . ticity and on triggered activity (32,33) . 4 . Schwanz PJ, Hillman GE, StoneHL . Autonomic mechaaismsin venuic Relevant to this is the finding that tocainide suppresses aloe fibrillation induced by myocardial ischemic during csercise in dogs arrhythmias due to enhanced automaticity of Purkinje fibers with healed myocardial infarction : an experimemat model for sudden cardiac death. Circulation 1984;69 :790-8W . (15). This electrophysiologic effect probably depends on the fact that class III antiarrhythmic drugs reduce transmem5 . Schwanz PJ . Vanoli E, Stramba-Badiale M, De Ferrari GM, Billman GE, Foreman RD . Autonomic mechanisms and sudden dead, new insights brane inward Na' currents and lead to a reduction of from anal ysis oflu oreceptorreheaesinconsciousdonswithandwithout intracellular sodium; as a consequence, intracellular Ca" a myocardial infarction. Circulation 1988 ;78:969-79 . concentration decreases (34) . High levels of intracellular 6. Harris AS . Delayed development ofventricularectopierhythms following Cat' can enhance triggered activity (35) . Long-term treatexperimental coronary occlusion. Circulation 1950 ;1 :!318-28 . ment with class IB drugs may reduce and should reduce the 7. Shihabi ZK . Sam 1. Dyer RD . Tocainide determination by high . incidence of rapid ventricular tachycardias dependent on performance liquid chmmatogmphy . J Liq Chromatogr 1988;11:2391-7 . triggered activity. 8. Cutler SJ. Ederer F . Maximum utilization of the life table method in of analyzing survival. J Chronic Dis 1958 ;8 :699-712. The efficacy of tocainide in the subacate phase ntyo-



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comnary death. Ann NY Acad Sci 1982 :162-80. 22 . Corn PB, Yamada KA, Witkowsky FX. Mechanisms cemroling cardiac autonomic function and their relation 1 . arrhythmngenesis . In: Faaard MA, Haber E, Jennings RD . Katz AM . Martian HE, eds . The Head and CaNievascalar System . New York: Raven, 1986 :1341-403. 23 . Schwartz PJ, Priori SO . Sympathetic nervous system and sudden death .

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acfmity: nTat of nifrdipine. Are Heart J 1989;11607-45. 29 . AdB yAAJ, WebbSW.Thetreatment ofventdculararrhylhmiasinarole myocardial infarction. Br 1 Hoop Mod 1979 ;21 :356-63, 29 . Uprichard ACG . Allen ID, Harron DWG . Effects of tocainide enanliomIre an experimental atrhythmias produced by programmed electrical slimuktioa . J Cardiovasc Pharmaco119880 1 :235-41 . 3D . Lombordi F, Verner RL . Lown B . Relation between sympathetic neural activity, commry dynamics and vulrenbility, to ventricular fibrillation dunrtg myocardial ischemia and repernision . Am Heart J 1983;105:95965 . 31 . Scherlag 03, Katel G. Buchmann J, Harrison L, Luoaara R. Mechanisms of spontaneous and induced ventricular atrhythmias in the 24lruur Wavered dog heart- Am 1 Cannot 198351 :207-13. 32 . Le None H. Dangrame KH. Danilo P Jr, Ross . MR. An evaimlion of autasnaticity and triggered aclivily in the canine heart one to four days after aryourdal infarction . Circulation 1985 ;71 :1224-36 . 33 . DaaimurKH,I7resdnerXPJr,ZaireS .Automatic andtdggendimpulse initiation in canine suhepicardial ventricular muscle cells from border zones of 24-hour Intramural infants: new mechanisms for malignant cardiac arthyefsmies? Circulation 1989 ;78:1020-30. 34. Eisler DA. Lederor WJ, Shen S-S. The role of intracellular sodium nclivity in the anti-arrhythmic action of local anaesthetics in sheep P000tde hares. J Physiol 1983;340 :329-57, 35. Wil AL, Ruses MR . ABerdepolarizatians and triggered activity . In: Ref 22:1949-90.

Tocainide and mortality after myocardial infarction: a prospective study in conscious dogs.

The production of an anterior myocardial infarction as part of an experimental animal model for sudden death was burdened by a persistently elevated m...
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