Increased R-wave amplitude induced by acute myocardial ischemia in the dog: A predictor of malignant ventricular arrhythmias

Increased R-Wave Amplitude Induced by Acute Myocardial Ischemia in the Dog : A Predictor of Malignant Ventricular Arrhythmias DANIEL DAVID, MD,* ERIC L . MICHELSON, MD,t MASAHITO NAITO, MD, MARK SCHAFFENBURG, and LEONARD S . DREIFUS, MD

The ability of an increase of 25 % or greater in the sum of R-wave amplitudes in leads X, Y, Z, L 2, and V 5 to predict the occurrence of malignant ventricular arrhythmias (10 or more ventricular premature beats/min, ventricular tachycardia [5 or more consecutive premature beats], and/or fibrillation) was evaluated in 17 dogs during experimental acute myocardial ischemia . Each dog underwent a 15 minute ligation of the left anterior descending coronary artery followed by reperfusion and after recovery, 2 hours later, a 15 minute ligation of the circumflex coronary artery . During ligation of the left anterior descending coronary artery, 12 of 17 dogs (71%) showed no R-wave increase and no arrhythmias (true-negative response) . In 5 (29 %) of 17 dogs malignant ventricular arrhythmias developed : 2 of 5 (40%) dogs with arrhythmias had a concomitant R-wave increase (true-positive response), and 3 of 5 (60 %) with arrhythmias had a

less than 25% increase in R-wave amplitude (false-negative results) . During circumflex coronary artery ligation, 13 of 17 (76%) dogs showed both R-wave increases and arrhythmias (true-positive response) . Four (24%) of 17 dogs had no arrhythmias : 3 of 4 (75 %) with no arrhythmias also had a less than 25% increase in R-wave amplitude (true-negative response), whereas 1 of 4 (25%) dogs with no arrhythmias had an increase In R-wave amplitude (false-positive response) . In dogs with both arrhythmias and R-wave increases, R-wave changes preceded the onset of arrhythmias by a mean (f standard deviation) of 1 minute 27 seconds (+43 seconds) . Overall, R-wave increases were highly sensitive (83%), specific (94%), and predictive (94%) for the occurrence of malignant ventricular arrhythmias during experimental acute myocardial ischemia.

R-wave amplitude increases have been observed in man during acute myocardial ischemia induced by both ex9 ercise and rapid atrial pacing .'- Alterations in R-wave amplitude were also recorded in dogs after acute ligation

perimental canine coronary artery occlusion, changes in intramyocardial conduction were a major determinant of alterations in R-wave amplitude 1 2 In other studies, 12-19 delays in intramyocardial conduction during the acute phase of myocardial ischernia were also closely associated with malignant ventricular arrhythmias . Conceivably, therefore, ischemia-induced alterations in R-wave amplitude might predict malignant ventricular arrhythmias . Thus, the present study was designed to determine the relation between R-wave amplitude alterations and the occurrence of malignant

of a major coronary artery' ° and may be seen as early as 10 seconds from the onset of ischemia ." After exFrom the Lankenau Medical Research Center and the Department of Medicine, Jefferson Medical College of the Thomas Jefferson University, Philadelphia, Pennsylvania . Manuscript received December 22, 1981 ; revised manuscript received May 17, 1982, accepted May 26, 1982 Supported in part by a Fellowship Award from the American Heart Association, Southeastern Pennsylvania Chapter, Philadelphia, Pennsylvania . I Recipient of Clinical Investigatorship Award 5 K08 HL00709-02 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland . Address for reprints : Eric L . Michelson, MD, The Lankenau Medical Research Center, Lancaster and City Line Avenues, Philadelphia, Pennsylvania 19151

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ventricular arrhythmias during the acute phase of experimental myocardial ischemia in a canine model .

Methods Seventeen healthy adult mongrel dogs (mean weight 16 .5 f 3 .4 kg) were studied under pentobarbital sodium anesthesia (30 mg/kg body weight initially, with subsequent I to 2 mg/kg

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TABLE I

BY

R WAVE CHANGES-DAVID ET AL

Correlation Between R-Wave Amplitude Changes and the Occurrence of Malignant Ventricular Arrhythmias During Acute Ischemia

Ox Ligation (n = 17)

LAD Ligation (n = 17)

No malignant ventricular arrhythmias Malignant ventricular arrhythmias

ER"

ERL2,v5t

0

0

ERI'

ERL2.VS1

ERt

ERL2 .V5'

ERj

ERLZVSl

12 12 1 1 3 3 (7 .2 t 2 .1) (6.3 ± 1 .8) (31 .0) (27 .31) (5 .9 + 1 .7) (6 .1 + 1 .7) 2 2 3 3 13 13 0 0 (29 .3 + 7 .9) (27.1 ± 8 .3) (15 .1 ± 4 .2) (13 7 + 4 3) (41 .3 ± 9 .1) (40 8 ± 10 2)

Numbers in parentheses indicate mean percentage change in R-wave amplitude from baseline ± standard deviation . Cx = circumflex coronary artery; LAD = left anterior descending coronary artery ; EAT = R-wave increase (25 % or greater) in leads X, Y, Z, V 2 , and V5 ; ERL2,v5t = R-wave increase (25% or greater) in leads L 2 and V 5 ; ERj= R-wave increase 25 % or less or R-wave decrease in leads X, Y, Z, L2 , and V5 ; ERLZV51 = R-wave increase 25 % or less or R-wave decrease in leads L 2 and V 5 .

bolus infusions as indicated to maintain effective anesthesia) . After intubation and ventilation with room air through a Harvard respirator, mid-sternotomy was performed, the pericardium opened, and the heart suspended in a pericardial cradle. The left anterior descending coronary artery was isolated approximately I to 3 cm beyond its origin from the left main stem, distal to the anterior septal artery and the first diagonal branch. Predictably, with our methods, occlusion at this site resulted in a relatively small area of ischemia in the canine myocardium . A snare ligature was placed around the artery for subsequent ligation . The left circumflex coronary artery was isolated approximately 1 to 2 cm from its origin and proximal to all branches, and a snare ligature was placed around the artery for subsequent ligation . Electrocardiographic leads 112 and V 5 and Frank orthogonal leads X, Y, and Z were recorded throughout the experiment . The animal's limbs were restrained and their position was kept constant throughout the experiment to avoid electrocardiographic distortion related to positional changes . 20 The electrocardiogram was recorded by means of an 8 channel recorder (Hewlett Packard model 4578A) with the recording frequency set between 0 .5 and 200 Hz . Data were also recorded continuously on an 8 channel FM tape recorder (Hewlett Packard model 3968A) for subsequent data reproduction and analysis . Experimental protocol : In each dog, a 1 stage temporary (15 minute) ligation of the left anterior descending coronary artery was performed ; release of the occlusion was followed by a 2 hour recovery period, after which a 1 stage temporary (15 minute) ligation of the left circumflex coronary artery was carried out, again followed by release of the occlusion . This sequence was chosen to enable us to perform both types of ligation in each dog . In preliminary studies the sequence of ligations was reversed (circumflex before left anterior descending coronary artery) in alternate animals . Although the results were similar, a large number of dogs were lost because of the high incidence of refractory ventricular fibrillation during circumflex coronary artery ligation, and therefore this protocol was abandoned . In those animals in which ventricular fibrillation occurred during ligation of the left anterior descending artery, the artery was immediately reperfused and defibrillation accomplished with I or 2 countershocks of 10 and 40 W-s, respectively . After a 2 hour recovery period, the circumflex ligation procedure was performed . Measurements and definitions : R-wave amplitude was measured from the P-R segment (zero level reference) to the peak of the R wave in leads L 2, V 5 , X, and Y and to the nadir of the Q wave in lead Z . These measurements were performed at 15 second intervals throughout the ligation period starting 5 minutes before ligation . Each data point represented a mean

of 10 consecutive beats to negate respiratory influences on R-wave amplitude . R-wave amplitudes were measured in all 5 recorded leads and summed arithmetically (ER) . All R-wave amplitude data in the text and tables represent summed data . To facilitate clinical correlations the sum of the R waves in leads L2 and V5 (ERt,2,V5) was calculated separately and correlated with the sum of R wave amplitudes in all 5 leads . An increase of 25% in R-wave amplitude was regarded as a positive response, a change that could be discriminated reproducibly without significant intra- or interobserver variability . On the basis of previous coronary occlusion studies in our laboratory, malignant ventricular arrhythmias were defined prospectively as the occurrence of I or more of the following : 10 or more ventricular premature beats/min, ventricular tachycardia (5 or more consecutive ventricular premature beats), and ventricular fibrillation . In analyzing our data, dogs classified as having "no malignant arrhythmias" had either no premature ventricular beats or only 1 to 2 premature heats/min . Statistical analysis : To evaluate the sensitivity, specificity, and predictive value of the observations made in this study the following formulas were used 21 : Sensitivity = true positives/(true positives + false negatives) X100 ; Specificity = true negatives/(true negatives + false positives) X100 ; Predictive value = true positives/(true positives + false positives) X100 . All data presented in the text with respect to the time course of ventricular arrhythmias represent a mean + standard deviation-Results

Left anterior descending coronary artery ligations : No malignant ventricular arrhythmias were observed in 12 (71%) of the 17 dogs during the 15 minutes after ligation of the left anterior descending coronary artery (Table I) . In each of these 12 animals (100%) the increases in both ER and ERL2,V5 were less than 25% above baseline (true negatives, Fig . 1) . In the remaining 5 of 17 dogs (29%) malignant ventricular arrhythmias (4 ventricular fibrillation, I ventricular tachycardia) occurred after ligation of the left anterior descending coronary artery . These arrhythmias occurred a mean of 6 minutes 17 seconds (f1 minute 37 seconds) after ligation . In 2 (40%) of these 5 dogs both ER as well as ERL2,V5 increased more than 25% above baseline (true positives) and preceded the onset of malignant ventricular arrhythmias in both cases by a mean of 1 minute 18 seconds (±38 seconds) . In 3 of 5 (60%) animals with

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TABLE II

Sensitivity, Specificity, and Predictive Value of R-Wave Amplitude Changes for the Occurrence of Malignant Ventricular Arrhythmias During Acute Ischemia Cx Ligation

LAD Ligation

Both Ligations

Sensitivity (%) 100 40 83 Specificity (%) 75 100 94 Predictive value(%) 93 100 94 Cx = circumflex coronary artery ; LAD = left anterior descending coronary artery .

arrhythmias no significant changes (less than 25%) in either XR or ZRL2,V5 were observed (false negatives) . Left circumflex coronary artery ligations : Malignant ventricular arrhythmias were observed in 13 (76%) of 17 dogs after ligation of the left circumflex coronary artery (10 ventricular fibrillation, 2 ventricular tachycardia, and I frequent premature ventricular beats) (Table I) . These arrhythmias occurred at a mean of 4 minutes 35 seconds (±2 minutes 15 seconds) after ligation. All 13 dogs (100%) with arrhythmias had an increase of 25% or greater in both ER and ZRL2,V5 (true positives) (Fig . 2) . Increases in ER and ERL2,v5 preceded the onset of malignant ventricular arrhythmias in each case, by a mean of 1 minute 37 seconds (±43 seconds) . In 4 of 17 dogs (24%) no malignant ventricular arrhythmias occurred, and 3 (75%) of these 4 had less than 25% increases in both ER and F+RL2,V5 (true negatives), whereas in I dog (25%) both ER and ERL2,VS increased 25% or greater (false positive) (Table I) . Overall, an increase of 25% or greater in ER during the period of acute myocardial ischemia after left anterior descending coronary artery ligation showed a

sensitivity of 40%, specificity of 100%, and a predictive value of 100% with respect to the occurrence of malignant ventricular arrhythmias (Table II) . In comparison, an increase of 25% or greater in ER during circumflex ligation showed a sensitivity of 100%, specificity of 75%, and a predictive value of 93% with respect to the occurrence of acute malignant ventricular arrhythmias . When the data for both ligation procedures were combined, ER amplitude increases showed an overall sensitivity of 83%, specificity of 94%, and a predictive value of 94% in predicting the occurrence of acute ischemiainduced malignant ventricular arrhythmias . Results for 2; RL2,V5 were identical to those for 2,R wave amplitude alterations with respect to sensitivity, specificity, and predictive value for malignant ventricular arrhythmias after both the left anterior descending and circumflex ligation procedures . In addition, ERhz,v,5 results were also concordant in each animal (Table 11) . Discussion R-wave amplitude increases have been observed in patients with acute myocardial ischemia induced by both exercise 18 and rapid atrial pacing . 9 R wave amplitude increases in the canine model of coronary artery occlusion have also been appreciated since the detailed observations of Rakita et al . 1 c In experimental canine preparations, R-wave amplitude changes during acute, extensive myocardial ischemia follow a typical pattern ." There is an initial (onset within 10 seconds) and transient (duration 30 to 60 seconds) decrease in R-wave amplitude followed by a secondary marked and persistent increase in R-wave amplitude It (Fig . 2) . In attempting to elucidate the pathophysiologic basis for this phenomenon, it was found that intramyocardial conduction changes rather than variations in intraven-

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Hlj~lA

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NI~1kN

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FIGURE 1 . Electrocardiographic trend recording during ligation (CAL) and reperfusion (REP) of the distal left anterior descending coronary artery . Frank orthogonal leads X, Y, and Z as well as scalar leads L2 and V5 are demonstrated . Representative ORS complexes are shown during the control period (C), at 30 seconds, at 5, 10, and 14 minutes after coronary artery ligation, and in the immediate postreperfusion period (PR). Note that R-wave amplitude does not change significantly from control in any of these leads either after the 15 minute ligation period or during reperfusion . Correspondingly, this dog had no malignant ventricular arrhythmia .



ARRHYTHMIA PREDICTION BY R WAVE CHANGES -DAVID ET AL .

tricular volume were the major factor determining Rwave amplitude changes during acute myocardial ischemia .r2 The initial decrease in R-wave amplitude was closely related to a transient shortening of intramyocardial conduction time (from endocardium to epicardium) observed during the first 30 to 60 seconds of acute myocardial ischemia, whereas the later and persistent increase in R-wave amplitude occurred in association with a marked delay in intramyocardial conduction . 12 It is well established that malignant ventricular arrhythmias occur commonly during acute experimental myocardial ischemia, although their frequency is highly variable (10 to 90%) . 21,22 The incidence of ventricular arrhythmias after coronary artery occlusion depends on many factors such as the vessel ligated, the method of occlusion (such as I stage versus 2 stage), and the site of occlusion (such as proximal versus distal) ; with the mass of tissue involved and the extent of preformed anastomosing collateral vessels as critical factors . 23 Previously, investigators have related the occurrence of malignant arrhythmias during acute ischemia to associated alterations and delays in local conduction . 13-19 Thus, on the basis of the association of both arrhythmias and R-wave amplitude changes with alterations in intramyocardial conduction it was of considerable interest to study the possible relation of arrhythmias and R-wave changes . Clinically, intramyocardial conduction changes cannot be measured directly . Therefore, the potential clinical importance of R-wave amplitude alterations as markers for subsequent malignant arrhythmias was considered . The results presented in this study clearly support this assumption. The combined data from both the left anterior descending and circumflex coronary artery legations show that R-wave amplitude increases are sensitive and specific predictors of malignant ventricular arrhythmias during the first 10 minutes of acute canine myocardial ischemia . Typically, R-wave amplitude changes preceded the occurrence of arrhythmias by a mean of approximately 1 minute 30 seconds . The circumflex coronary artery is the dominant coronary vessel in the dog . Its proximal ligation involves a large mass of myocardium, which presumably accounts in part for the high incidence of malignant ventricular arrhythmias. Intramyocardial conduction delay and fragmentation after circumflex ligation involves a large area of myocardium which may, in turn, account for the appearance of significant R-wave amplitude changes on the surface electrocardiogram . In contrast, ligation of the mid left anterior descending coronary artery involves a smaller mass of myocardial tissue in the dog and is therefore associated with a lower incidence of malignant ventricular arrhythmias . Because intramyocardial conduction abnormalities are confined to a relatively smaller region of myocardium, they are not as readily reflected as R-wave amplitude alterations on the scalar electrocardiogram . The fact that the results of both the circumflex and left anterior descending coronary artery ligations were analyzed in each dog

October

C

D

PR

P

' T/min

4 CAL

VT-VF

FIGURE 2. Electrocardiographic trend recording during ligation (CAL) and after reperfusion (PR) of the left circumflex coronary artery in the same dog shown in Figure 1 . Frank orthogonal leads X, Y, and Z as well as scalar leads L z and V5 are demonstrated . Representative QRS complexes are shown during the control period (C), 30 seconds after ligation (D), 4 minutes after ligation (P), and immediately after reperfusion and resuscitation from ventricular tachycardia (VT) followed closely by ventricular fibrillation (VF). Note that in each of the leads except Z, the R-wave amplitude shows an initial decrease at time D and subsequently a marked increase, evident at time P, immediately before the initiation of VT/VF . After reperfusion and resuscitation, R-wave amplitudes normalize, but marked S-T and T wave changes can still be detected . An increase in R-wave amplitude of 25% or greater from control is already evident more than t minute before the occurrence of VT-VF .

lends further support to these assumptions . These analyses are particularly relevant because differences exist in coronary artery distribution patterns between the dog and man, as already noted . Overall, R-wave amplitude changes were sensitive, specific, and predictive for the occurrence of arrhythmias when both the circumflex and left anterior descending coronary artery

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ARRHYTHMIA PREDICTION BY R WAVE CHANGES-DAVID ET AL

ligations were considered together in our model (Table 11) . Clinical implications: There is considerable interest in using noninvasive methods to identify patients at high risk for sudden cardiac death, particularly those susceptible to malignant ventricular arrhythmias . The present study suggests that increases in R-wave amplitude in association with acute ischemia may he a clinically useful marker of susceptibility to malignant arrhythmias . A recent case report 24 lends further clinical support to this hypothesis . This marker may be of major interest in patients who demonstrate marked R wave amplitude increases during exercise testing or ambulatory electrocardiographic monitoring, particularly those with critical coronary artery obstructive disease . Potentially, R-wave changes may provide a useful noninvasive means to select those patients in danger of sudden electrical death, who might then be candidates for further diagnostic and therapeutic procedures . Moreover, R-wave amplitude increases may herald the onset of malignant ventricular arrhythmias in patients with recurrent severe ischemic episodes hospitalized in the coronary care unit . To further facilitate the potential application of our findings to the human situation, we have reported the results of R-wave amplitude increases both in 5 monitored surface electrocardiographic leads (X, Y, Z, L2, and V 5 ) as well as in leads L 2 and V 5 , the leads most commonly used during exercise testing . Importantly, our results indicate that R-wave amplitude increases using leads L2 and V 5 are comparable in their predictive value to the sum of R wave amplitude increases using more elaborate monitoring systems (Table 1) . In summary, in this canine model of acute myocardial ischemia, R-wave amplitude increases were highly sensitive, specific, and predictive of malignant ventricular arrhythmias . Both R-wave amplitude changes and malignant arrhythmias may be related to the marked delay in intramyocardial conduction that occurs acutely in the ischemic zone . Clinical investigation of this phenomenon should be of considerable interest in the identification of patients at increased risk for sudden death .

Acknowledgment We gratefully thank John Neilands, biomedical engineer, and Charles Sauermelch, for expert technical assistance ; Douglas Thayer for help with illustrative material ; and Rose Marie Wells and Marie Sciocchetti fur manuscript preparation .

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References 1 . Bonorls PE, Greenberg PS, Christison GW, Castellanet MJ, Ellestad MN . Evaluation of R wave amplitude changes versus ST-segment depression in stress testing Circulation 1978 ;57 904-910 . 2 . Bonorls PE, Greenberg PS, Castellanet MJ, Ellestad MN . Significance of changes in R wave amplitude during treadmill stress testing' angiographic correlation . Am J Cardiol 1978;41 :846-851 . 3. DeCaprlo L, Cuomo S, Belloli P, al al . R wave amplitude changes during stress testing Comparison with ST segment depression and angiographic correlation . Am Heart J 1980;99 :413-418 4. Simoon ML. CRS changes in coronary artery disease Circulation 1979 ; 59:841-843 . S. Berman JL, Wynne J, Cohn PF . Multiple lead ORS changes with exercise testing . Diagnostic value and hemodynamic implications. Circulation 1980 ;61 :53-61 6. Baron DW, llsley C, Sheiban I, Poole-Wilson PA, Rickards AF . R wave amplitude during exercise . Relation to left ventricular function and coronary artery disease . Br Heart J 1980;44 :512-517 7 . Wagner S, Cohn K, Selzer A . Unreliability of exercise induced R wave changes as indexes of coronary artery disease . Am J Cardiol 1979 :44 . 1241-1246 8 . Battler A, Froelicher V, Slulsky R, Ashburn W. Relationship of ORS amplitude changes during exercise to left ventricular function and volumes and the diagnosis of coronary artery disease Circulation 1979 :60 : 1004-1013 . 9 . David D, Kitchen JG, Chen CC, et al . The significance of biphasic R wave amplitude changes during incremental atrial pacing : sensitive and specific marker for acute myocardial ischemia (abstr) Am J Cardiol 1981 ;47 . 423 10 . Refills L, Borduas JL, Rothman S, Pr/nzmelal M . Studies on the mechanism of ventricular activity . XII Early changes in the RS-T segment and ORS complex following acute coronary artery occlusion : experimental study and clinical implications . Am Heart J 1954 ;48 :351-372 . 11 . David D, Nalto M, Chen CC, Michelson EL, Morganroth J, Schaffenburg M . R wave variations during acute experimental myocardial ischemia an inadequate index for changes in intracardiac volume Circulation 1981 ; 63 :1364-1371 12 . David 0, Nallo M, Michelson EL, et al. Intramyocardial conduction : a mayor determinant of R wave amplitude alterations during acute myocardial ischemia . Circulation 1981 ;65 :161-167 . 13 . Leviles R, Banks VS, Hellant RH . Electrophysiologic effects of coronary occlusion and reperfusion : observations of dispersion of refractoriness and ventricular automaticity . Circulation 1975,52 :760-765 . 14 . Corbalan R, Varrler RL, Lown B. Differing mechanisms for ventricular vulnerability during coronary artery occlusion and release Am Heart J 1976;92 :223-230 . 15 . Scherlag BJ, HeitaM RH, Haft JI, Damato AN . Electrophysiology underlying ventricular arrhythmias due to coronary ligation . Am J Physiol 1970 ;219 : 1665-1671 16 . Boineau JP, Cox JL . Slow ventricular activation in acute myocardial infarction' a source of reentrant premature ventricular contraction Circulation 1973,48 :702-713 17 . Waldo AL, Kaiser GA. A study of ventricular arrhythmias associated with acute myocardial infarction in the canine heart . Circulation 1973 ;47 : 1222-1228 . 18 . Scherlag BJ, EI-Sherif N, Hope R, Lazzara R . Characterization and localization of ventricular arrhythmias resulting from myocardial ischemia and infarction . Circ Res 1974 ;35 :372-383 . 19 . Kapllnsky E, Ottawa S, Balks CW, Drelfus LS. Two periods of early ventricular arrhythmia in the canine acute myocardial infarction model Circulation 1979;60 397-403 20 . Hill JD. The significance of foreleg positions in the interpretation of electrocardiograms and vectorcardiograms from research animals . Am Heart J 1968 ;75'518-527 21 . Galen RS. Statistics In Sonnenwirth AC, Jarett L, ads Gradwohl's Clinical Laboratory Methods and Diagnosis . St . Louis : CV Mosby, 1980:41-68 22. Bigger JT Jr, Dresdale RJ, Heissenbuttel RH, Weld FM, Wit AL Ventricular arrhythmias in ischemic heart disease' mechanism, prevalence, significance and management Prog Cardiovasc Dis 1977 ;19:255-300 . 23 . Drelfus LS, Nalto M, Michelson EL. What animal models should be used to define antiarrhythmic efficacy? Acute dog models . In : Morganroth J, Moore EN, Drelfus Its, Michelson EL, eds . The Evaluation of New Artierrhythmic Drugs . The Hague : Martinus Nijhoff, 1981 :17-32 . 24 . Madias JE, Krikelis EN. Transient giant R waves in the early phase of acute myocardial infarction association with ventricular fibrillation . Clin Cardiol 1981 ;4 :339-349

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