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as an Antiarrhythymic Drug
By KEN A. COLLINSWORTH, M.D., SUMNER M. KALMAN, M.D.,
AND DONALD C. HARRISON, M.D.
SUMMARY
This article reviews current knowledge about lidocaine, with reference to its chemistry, metabolism, elec-
trophysiology, hemodynamic effects, antiarrhythmic uses, pharmacokinetics, and side effects. The critical
importance of blood levels and their relation to lidocaine's antiarrhythmic and toxic effects is noted, with
special emphasis given to patients with compromised clearance due to heart failure. On the basis of this in-
formation, we present our current approach to the clinical use of lidocaine in the treatment of ventricular
arrhythmias, with particular reference to patients with acute myocardial infarction.
Hemodynamic effects
Antiarrhythmic actions Side effects Blood levels
LIDOCAINE was first synthesized in 1943 pathway (fig. 1) appears to be conversion to mono-
and was used for many years as a local anes- ethylglycinexylidide by oxidative N-de-ethylation
thetic agent.' Its first reported use as an antiar- followed by hydrolysis to 2,6-xylidine.' Evidence ex-
rhythmic drug was in 1950.2 Anesthesiologists sub- ists for a cyclic intermediate in the N-de-ethylation re-
sequently adopted lidocaine for treating arrhythmias action.7 A stable cyclic form, N'-ethyl-2-methyl-N'-
occurring during surgery, and in 1963 its successful (2,6-dimethylphenyl)-4-imidozolidinine, has also
use in treating arrhythmias occurring during and after been isolated from the urine of humans receiving oral
cardiac operations was described.3 Lidocaine has since lidocaine.7 Further conversion of 2,6-xylidine to 4-
been used extensively in treating ventricular hydroxy-2,6-xylidine appears to occur in man, since
arrhythmias, and administered intravenously is prob- the latter compound excreted in urine over a 24-hour
ably the most widely used agent for the treatment and period has accounted for over 70% of an orally ad-
prevention of cardiac arrhythmias after acute myo- ministered dose of lidocaine.' A number of other
cardial infarction. degradative pathways produce small amounts of 3-hy-
droxylidocaine, 3-hydroxymonoethylglycinexylidide,
Chemistry and Metabolism and glycinexylidide, as well as small amounts of the
The chemical structure of lidocaine is an aromatic intermediate compounds in its major metabolic path-
group, 2,6-xylidine, which is coupled to diethylgly- way, monoethylglycinexylidide and xylidine.' Hy-
cine via an amide bond. Lidocaine appears to be droxylation of the aromatic nitrogen also occurs,
metabolized chiefly by the liver.4 5Studies on hepatic resulting in the formation of N-hydroxylidocaine and
tissue homogenates have shown that the microsomal N-hydroxymonoethylglycinexylidide, both of which
enzyme system is primarily responsible for the hepatic have been identified in the urine of patients given oral
metabolism of lidocaine.' Its major degradative lidocaine.' Lidocaine is a weak base with a pKa' of
7.8510 and up to 10% of lidocaine in unchanged form
may be excreted in the urine, depending on the
From the Divisions of Cardiology and Pharmacology, Stanford urinary pH.'.9 Acid urine results in a larger fraction
University School of Medicine, Stanford, California. being excreted in the urine. Extensive biliary secretion
This work was supported in part by NIH grants nos. HL-5709, of lidocaine metabolites occurs in rats, but most of
HL-5866, and 1-PO1-HL-15833-01. Dr. Collinsworth was supported
in part by the Bay Area Heart Research Committee. these metabolites are absorbed in the intestine and
Dr. Collinsworth's present address is Department of Medicine, then eliminated via the urine.8 There is no evidence
University of California, San Francisco, California 94143. that biliary secretion and intestinal absorption of
Address for reprints: Donald C. Harrison, M.D., Chief, Car- lidoDaine metabolites occur in man.9
diology Division, Stanford University School of Medicine, Stanford,
California 94305. Electrophysiology
Received April 14, 1973; revision accepted for publication August
21, 1974. The electrophysiologic effects of lidocaine on
Circulation, Volume 50, December 1974 1217
1218 1218 ~~~~~~~~~~~~COLLINSWORTH ET AL.
/CH3 CH3
/ OH 0 C2 H5 OHO0 H
<
N-COCH2-N -N -O-CH2-N
C~~~~2H5
OH3 OH3
N-HYDROXY LIDOCAINE N- HYDROXY- MONOETHYGLYCINEXYLIDIDE
OH3 CH CH3
0 H
0 C2H5
-NHOO-H2N NH-C-OH2- N -NH2 HO- "~>-NH2
OH3
C2H5 C2H5
OH3 CH3 OH3
MONOETHYLGLCINEXYLIDIDE 2,6-XYLIDINE 4 HYDROXY- 2,6-XYLIDINE
HO CH3 OH 3 0 CH3
/0 C2H5
1
/~~~~~~~c1
1/1
11~~~~ .0
- NH-0
CH2-N\ -N CH 2 -NH-C-CH2-NH2
1
1
1
0H Ki-el U
CH3 OH
HC N M5
3 CH 3 CH3
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3-HYDROXY LIDOCAINE
N1 ETHYL -2- METHYL -N3 _(2 6-EDMETHYLPHENYL)
-
GLYCINEXYLIDIDE
-4-IMIDAZOLIDINONE
HO\ OH
0 H
NH O2 N
O3 c2H5
3-HYDROXY- MONOETHYLXYLDIDIE
Figure 1
Metabolic pathways of lidocaine degradation.
cardiac tissue have been studied extensively. Though The effect of lidocaine on the duration of cardiac
controversy remains, the results of these studies may action potential and effective refractory period has
be summarized as follows. been studied."11 13, 16, 17 The action potential duration
Lidocaine causes a slight decrease in automaticity in canine Purkinje fibers is decreased at extracellular
(spontaneous phase 4 depolarization) of pacemaker lidocaine concentrations of 2.34 gtg/M1'6' " and 5
tissue in rabbit atrial tissue in tissue baths at lidocaine gtg/Ml."1 Lidocaine also shortens the action potential
concentrations of 3 and 5 ggml," and in rabbit duration in ventricular muscle at extracellular concen-
sinioatrial node at 2.34 gg/Mn1.2 Larger decreases in trations of 3 ug/in1 in tissue from rabbits" and 2.34
automaticity than found in atrial tissue occur in p~g/ml in tissue from dogs.'6,1 A more prominent
canine Purkinje fibers at extracellular lidocaine con- effect is noted on Purkinje fibers than on ventricular
centrations of 2.34 ptg/M1'2 and 5 gg/mL`' These muscle. '7
lidocaine concentrations are in the range of The effective refractory period is relatively
therapeutic blood levels (1.4 to 6.0 j.g/ml) in man prolonged compared to the action potential duration
(discussed below). The diastolic threshold requisite for in both Purkinje fibers and ventricular muscle.'16
depolarization in rabbit atrial tissue is increased at ex- Lidocaine's effect on the maximum rate of depolariza-
tracellular lidocaine concentrations of 3 and 5 tion and membrane responsiveness has been the sub-
9ig/ml." In humans, the ventricular diastolic ject of controversy."` The reported differences are
threshold is either slightly increased' or unchanged 14 probably due to the extracellular potassium concen-
after 1-2 mg/kg intravenous bolus injection. Spon- trations in the tissue baths at which these two proper-
taneous repetitive discharge after a premature ties are measured.", 16, 18, 19 At physiologic potassium
stimulus is prevented by extracellular lidocaine con- levels (5.6 mM), the maximum rate of depolarization
centrations of 5 pg/mI in canine ventricular tissue and and membrane responsiveness in rabbit ventricular
10 gg/ml in canine Purkinje tissue."1, 1` Lidocaine in- muscle is decreased by extracellular lidocaine concen-
creases the ventricular fibrillatory threshold in intact trations of 3 g.g/ml." Hypokalemic solutions (3.0
rabbit hearts at perfusion concentrations of 1.5-6.2 MM), however, cause hyperpolarization of the cell
pAg/ml, and in acutely ischemic hearts in dogs, at membrane so that tenfold increases in lidocaine con-
blood levels of 1.2-5.5 jtg/ml. centration are needed before depression of membrane
Circulation, Volume 50, December 1974
PHARMACOLOGY OF LIDOCAINE 1219
responsiveness or maximum rate of depolarization oc- might have clinical relevance with regard to
curs.1 Conduction velocity in Purkinje fibers in lidocaine's antiarrhythmic mechanism and efficacy,
hypokalemic (3.0 mM) bath preparations appears to since they were noted at extracellular potassium con-
be slightly decreased by lidocaine concentrations of centrations which occur in many clinical instances,
5-50 ,g/ml.l3 i.e., 3mM and 5.6 mM. A summary of the findings of
Atrioventricular (A-V) node and intraventricular electrophysiologic effects of lidocaine from several
conduction time in man are not significantly changed studies is presented in table 1.
after intravenous injections of lidocaine of 1-2 Hemodynamic Effects
mg/kg.20 However, A-V node conduction time is in-
creased in dogs given high-dose intravenous injections The hemodynamic effects of lidocaine have been
of lidocaine (5-20 mg/kg).21 studied in isolated muscle preparations, isolated per-
These electrophysiologic effects cannot be cor- fused hearts, awake and anesthetized animals, animal
related precisely with lidocaine's antiarrhythmic ac- models with acute myocardial infarction, anesthetized
tions in humans at this time, but can be used to man, and in awake man with acute myocardial infarc-
speculate upon its mode of action in certain specific tion.
instances. Ventricular arrhythmias due to acceleration Lidocaine has been shown to depress the contrac-
of ectopic foci may be responsive to lidocaine because tility of bath preparations of isolated guinea pig right
of its effect on decreasing automaticity by slowing the
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In awake patients with acute myocardial infarction, depression of cardiac function in patients with acute
bolus doses of lidocaine, 1-2 mg/kg30 and 100 mg,31 infarction would likely develop. Extrapolating from
caused no significant depression of cardiac output, dog studies, rapid intravenous bolus injections of
heart rate, or arterial pressure. In one patient who lidocaine leading to very high blood levels would be
received a 5 mg/min continuous infusion of lidocaine, more likely to cause depression of cardiac function
a marked fall of arterial pressure was observed and than more slowly administered (1-5 min) bolus injec-
sinus bradyeardia developed.30 In another study in tions, and it should always be administered in the
patients with acute myocardial infarction, continuous latter way in patients with depressed cardiac function.
infusion of lidocaine up to 3 mg/min for up to one
hour caused no significant change in left ventricular Antiarrhythmic Actions
contractility, stroke work index, cardiac output, Lidocaine administered intravenously has been
arterial pressure, or heart rate.32 highly effective in terminating ventricular premature
Lidocaine appears to cause no, or minimal, decrease beats and ventricular tachycardia occurring during
in ventricular contractility, cardiac output, arterial general surgery, during and after cardiac surgery,
pressure, or heart rate. This generalization would following acute myocardial infarction, and in the
seem to apply to normal individuals, patients with car- course of digitalis intoxication. It has also been
diac disease, and patients with acute myocardial in- suggested for the prevention and treatment of ven-
farction. With excessive doses, however, marked tricular arrhythmias occurring during cardiac
Circulation, Volume 50, December 1974
PHARMACOLOGY OF LIDOCAINE 1221
catheterization. However, ventricular fibrillation is administration has been studied in normal healthy
best treated by electrical cardioversion, to be followed humans.38 42 After an intravenous bolus of lidocaine,
by lidocaine infusion. or after discontinuing a constant infusion, the plasma
The general experience has been that lidocaine has concentration changes describe a biphasic curve that
not been very effective in the treatment of atrial can be fitted into two exponential components (fig. 4).
or A-V junctional arrhythmias. In isolated atrial tissue, There is an early rapid fall in concentration, followed
poor response of ectopic tachycardias to lidocaine has by a later slower decrease in plasma concentration. An
been shown.12 average half-life of about 8 min was found in one
Perhaps the most important use for lidocaine after study for the early rapid fall, though considerable
acute myocardial infarction is to suppress ventricular variation was present within the group.38 Another
premature beats which often occur in the early postin- report placed the average value of half-life at 17
farction period. Most cases of ventricular tachycardia m.42 The half-life of the later slow decrease in
and fibrillation after acute infarction are preceded by plasma concentration of drug has been reported to
ventricular premature beats. On the basis of these average 108 minutes38 and 87 minutes41 in normal sub-
observations, criteria have been developed for the jects.
treatment of ventricular arrhythmias occurring after The two-compartment open model (fig. 5) has been
acute infarction.32 3 We have recommended suppres- formulated to explain the biphasic curve observed for
sion of ventricular premature beats when: a) more the plasma disappearance of lidocaine.38 41 The first or
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than five per minute of unifocal origin occur, b) central compartment (CPT 1) includes the in-
R-on-T ventricular premature beats are noted, c) mul- travascular space, though the calculated volume of
tifocal ventricular premature beats occur, d) two or distribution exceeds plasma volume.38 The second or
more ventricular premature beats in a row occur, i.e., peripheral compartment (CPT 2) is larger. When
short bursts of ventricular tachycardia.34 In addition, equilibration is attained for all tissues, the volume of
after ventricular tachycardia or fibrillation has been distribution exceeds total body water,38 and implies
terminated, lidocaine is administered prophylactically intracellular concentration of lidocaine. In rats, tissue
for 24 hours, in an attempt to prevent the recurrence lidocaine levels in numerous organs are higher than
of ventricular arrhythmias. blood levels, tending to confirm the intracellular con-
Several studies have been carried out to determine centration of lidocaine.43
the maintenance dose of intravenous lidocaine
necessary to prevent ventricular premature beats. In BEFORE LUDOCAINE AFTER LIDOCAINE
one study, it was found that ventricular premature
beats above a frequency of five per minute were sup-
pressed or terminated in 80% of patients by a
lidocaine blood level of 1.4 to 6.0 ,g/ml (fig. 2).33 This
level was achieved by constant infusion rates of 20-55
gg/kg/min (1.4-4.0 mg/min in a 70 kg patient) (fig.
3).34 Lower rates are recommended in patients with ha
W
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COLLINSWORTH ET AL.
Figure 3
Relation between the rate of
infusion of lidocaine and the blood
level of lidocaine in 39 patients
receiving a constant infusion. All
levels were measured after at least
two hours of constant infusion in
patients who were not in severe
congestive heart failure or shock.
The area enclosed within the rec-
tangle is considered to be the effec-
tive therapeutic range. [Reprinted
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of lidocaine. Drug distributes between compartments one and two constants,respectively. The closed circles represent observed data,
and is eliminated via compartment one. [Reprinted with permission whereas open circles represent derived data. [Figure reprinted with
of Rowland and Thomson and Ann NY Acad Sci38] permission of Thompson et al. and Am Heart J39]
Circulation, Volume 50, December 1974
PHARMACOLOGY OF LIDOCAINE 1223
CR 1
recovery, when similar rates of infusion were used.'8
W 2.4 p- 1
z 1
3.4 p
U 2.2
0 1
2.0 I.
a0o 1
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1.0 1.5 2.0 2.5 3.0 3.5 40 4.5 1 1
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.-- -.- -1-
CARDiAC INDEX (I/min/m2) 0 250 500 750 1000 1250 1500 1750
Another study has shown higher than expected tion of 1.5 mg/kg, followed by 30 ,ug/kg/min infu-
steady-state plasma levels of lidocaine (i.e., 1.0-2.5 sion, is recommended. These doses correspond ap-
,ug/ml) in a group of patients with acute infarction proximately to a 100 mg dose, followed by a 2 mg/min
and congestive heart failure receiving lidocaine in- infusion in a 70 kg person. Another approach would
fusions of 0.7 mg/min.50 The mean plasma half-life in be to give the two smaller bolus doses of 0.75 mg/kg
these patients was prolonged (T-1/2 = 200 min) each, with the second injection following the first by
following cessation of infusion after steady-state levels about 15 minutes. The drug should always be injected
had been achieved. The long half-life was in part at- over several minutes, since very rapid injection might
tributed to slow release of lidocaine from peripheral lead to transiently high plasma levels, with possible
tissues and impaired hepatic clearance, probably due toxic side effects. Slower rates of injection would tend
to diminished perfusion. The plasma clearance of to prevent such high plasma levels, without reduction
lidocaine was also reduced in these patients40 and in antiarrhythmic effectiveness. In patients with
wide ranges of values were found for the apparent markedly reduced cardiac output or shock, we recom-
volume of distribution. Another group of patients with mend a dose of no more than 0.75 mg/kg, followed by
acute infarction but without severe heart failure have an infusion of 10-20 ,ug/kg/min. This would corres-
been studied in a similar manner.53 In these patients, pond approximately to a 50 mg injection, followed by
mean plateau levels of 2.25 ,g/ml were achieved by an infusion of 0.7 to 1.4 mg/min, in a 70 kg person.
Even these doses may be too high in some in-
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0.5l -~4
(.)z
9
20
-4
0
oto
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urn mu
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30 60 90 120 150 ito 210
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30 60 90 120 150
TIE (mi n) minutes
Figure 11 Figure 12
Plasma levels of lidocaine following 500 mg of oral doses to subjects Effect of high dose intravenous infusion of lidocaine on ventricular
G 0. ( * ) and A.L. (M). Data points represent experimentally deter- premature beats and blood levels is illustrated in this figure. In the
mined plasma computer-calculated levels. [Reprinted with permis- top panel, the number of ventricular premature beats per three
sion of Boyes et al. and Clin Pharmacol Ther"'] minute block of time are shown for one patient. In the center panel,
the dark solid bar represents the period of intermittent infusion of
lidocaine, 130 gg/kg/min. In the bottom panel, the blood level of
Lidocaine Resistance lidocaine achieved during this study is shown. Note that as the
Patients with ventricular arrhythmias resistant to blood level of lidocaine was increased with the intermittent infu-
sion, the frequency of ventricular premature beats decreased to
lidocaine have been reported. A study of such patients zero. As the blood level was allowed to fall by stopping the infusion,
referred to a university hospital has been made.34 the number of ventricular premature beats returned to nearly the
Some patients in the study were responsive, but only same frequency as had been observed in the control period. This
to high blood levels greater than 5 ug/ml, and were was permitted to occur on four separate occasions in this patient, in
refractory to ordinary therapeutic levels (fig. 12). order to determine the threshold dose of lidocaine and the threshold
blood level necessary to suppress ventricular premature beats.
Other patients were considered truly unresponsive to [Reprinted with permission of Harrison and Alderman and Mod
lidocaine, even at elevated blood levels of 10 gg/ml Treatm34]
and after toxic central nervous system side effects
begin to appear. (fig. 13). In some of these patients
unresponsive ventricular arrhythmias were due to a withdrawal of lidocaine and administration of
parasystolic foci. On the other hand, other patients in sedatives. Convulsive disorders respond well to in-
the study were responsive to lidocaine in the usual travenous barbiturates or diazepam. True allergic
therapeutic range, suggesting that lidocaine ad- reactions to lidocaine are probably extremely rare,64 65
ministration was inadequate. Also, failure to ad- though this has been challenged.66
minister a bolus injection before beginning constant The contribution of the metabolic products of
infusion may result in therapeutically ineffective lidocaine degradation to its toxic effects is not clear.
blood levels for several hours, resulting in apparent The N-dealkylation metabolites, monoethylglycine-
unresponsiveness. xylidide and glycinexylidide may be responsible for
Side Effects
central nervous system symptoms in some cases.67 In
one patient who was confused and had visual
Serious toxic side effects on the central nervous hallucinations, the lidocaine plasma level was in a low
system include focal and grand mal seizures, psy- therapeutic range, while levels of both monoethylgly-
chosis, and rarely, respiratory arrest.49' 63 Drowsiness, cinexylidide and glycinexylidide were considerably
decreased hearing, paresthesias, disorientation, and elevated, suggesting an etiologic relationship between
muscle twitching may occur, and some patients the elevated levels of these metabolites and the toxic
become acutely disturbed and agitated. The treat- symptoms.67 These two metabolites are apparently not
ment of central nervous system side effects includes pharmacologically inert. Monoethylglycinexylidide
Circulation, Volume 50, December 1974
1228 COLLINSWORTH ET AL.
z
cant effect of lidocaine on H-V times.74 In another
study,75 patients with prolonged A-H and H-V times
and bilateral bundle branch block were given
0
00
lidocaine, without subsequent significant change in
A-H or H-V times. In both reports, lidocaine sup-
pressed the patients' ventricular premature beats.
These studies would appear to establish that
therapeutic doses of lidocaine may be used safely in
patients with conduction abnormalities. Although
lidocaine may induce heart block or sinus node
30 80 90 120 depression, it probably does so infrequently, and
mainly when toxic doses have been given. Either ab-
TIME IN MINUTES normality should not necessarily be a contraindication
Figure 13 to the cautious use of lidocaine. The failure to sup-
Lack of response of ventricular arrhythmias to high dose lidocaine press ventricular arrhythmias by withholding
infusion. [Reprinted with permission of Harrison and Alderman and lidocaine may place the patient at greater risk of sub-
Mod Treatm341 sequent complications than the risk of inducing heart
block or bradycardia by giving lidocaine. Lidocaine
may be safely used in treating ventricular premature
has been shown to have local anesthetic' and an- beats in patients with artificial ventricular
tiarrhythmic68 actions. pacemakers, without fear of altering pacemaker cap-
In addition, monoethylglycinexylidide causes con- ture, since the threshold response to artificial pacing
vulsions in animals68' 69 and has approximately does not seem to be significantly changed by
equivalent convulsive activity compared to lidocaine. 14
lidocaine.69 The convulsive activities of monoethyl- Acceleration of ventricular response in atrial
glycinexylidide and lidocaine are additive.69 Glycine- tachyarrhythmias after lidocaine administration has
xylidide also has local anesthetic actions.67 While been reported, presumably due to enhanced A-V con-
glycinexylidide causes death in animals before con- duction.76 This would seem paradoxical in view of
vulsions are seen, it does potentiate the convulsive ac- most studies which point out either unchanged or
tivities of monoethylglycinexylidide and lidocaine.69 slightly diminished A-V conduction by lidocaine.20 An
Large bolus doses of lidocaine resulting in toxic increase in the number of ventricular ectopic beats in
levels can produce bradyeardia and hypotension due patients with acute myocardial infarction has been
to decreased myocardial function.30 Also, the ad- reported, using low dose lidocaine infusion.77 In addi-
ministration of large doses of lidocaine has been tion, re-entry ventricular beats were increased by
reported to cause heart block, and second degree lidocaine in animal models of acute infarction in some
heart block has been reported to be converted to com- instances in one study.78 These reports of paradoxical
plete heart block by lidocaine.4 33' 70 In complete effects of lidocaine would appear to need further con-
heart block, subsidiary pacemakers may be slowed.'4 firmation.
Circulation, Volume 50, Decenmber 1974
PHARMACOLOGY OF LIDOCAINE 1229
Acknowledgments mammalian heart muscle. In Lidocaine in the Treatment of
Ventricular Arrhythmias, edited by SCOTT DB, JULIAN DG.
Some of the studies cited were carried out in the Coronary Care Livingstone, Edinburgh, 1971, p 43
Unit at Stanford University Hospital with the collaboration of Dr. 19. General discussion, Electrophysiologic effects of lidocaine. In
Alfred Spivack and the nursing staff, and the cooperation of several Lidocaine in the Treatment of Ventricular Arrhythmias,
former cardiac fellows and faculty, who permitted these studies in edited by SCOTT DB, JULIAN DG. Livingstone, Edinburgh,
their patients. Finally, we have had the excellent editorial assistance 1971, p 59
of Mrs. Dorothy McCain in the preparation of this manuscript. 20. ROSEN K, LAU S, WEISS M, DAMATO A: The effect of lidocaine
on atrioventricular and intraventricular conduction in man.
Am J Cardiol 25: 1, 1971
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Circulation. 1974;50:1217-1230
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