A Cause of Paired Ventricular Extrasystoles

SHINJI KINOSHITA, M.D., KOUSUKE FUJITA, M.D., KouICHI KANDA, M.D.,

YOSHINORI TANABE, M.D., AND TAKESHI KAWASAKI, M.D.

SUMMARY Eight patients with ventricular extrasystoles are reported in whom coupling intervals of the ex-
trasystoles to the preceding sinus beats were variable and in whom paired ventricular extrasystoles were oc-
casionally seen. In all patients, paired ventricular extrasystoles were initiated only by comparatively late
coupled ventricular extrasystoles. However, the interval between the first and the second of these paired ex-
trasystoles was always much shorter than the coupling interval of this first extrasystole to the preceding sinus
beat, so that the latter extrasystole often interrupted the T wave of the first one, indicating the R-on-T
phenomenon. In two patients there was a gap between the ranges of coupling intervals for single extrasystoles
and for the first ones of paired extrasystoles. These observations suggest the presence of longitudinal dissocia-
tion in the reentrant pathway as one of the causes of paired ventricular extrasystoles.

CLOSE COUPLED ventricular extrasystoles in-
terrupting the T wave (the R-on-T phenomenon) have
been considered to initiate ventricular tachycardia and
fibrillation.'`5 However, some recent data in acute
myocardial infarction have shown that late coupled
ventricular extrasystoles also often initiate such ven-
tricular tachycarhythmias.6-10 The cause of the latter
phenomenon is not known. Therefore, we studied
possible causes of paired ventricular extrasystoles.
Eight patients with ventricular extrasystoles are re-
ported in whom coupling intervals of the extra-
systoles to the preceding beats were variable and
paired ventricular extrasystoles were occasionally
seen. We investigated the relationship between the
coupling interval and the appearance of paired extra-
systoles.
Materials and Methods
Electrocardiograms continuously recorded from
eight patients were selected because: 1) ventricular ex-
trasystoles with the same configuration were fre-
quently found; 2) coupling intervals of the ex-
trasystoles to the preceding beats of the basic rhythm
showed a marked variation of 0.08 second or longer;
and 3) in one or more parts of the continuous record-
ing the extrasystoles occurred in pairs. The clinical
data of these patients and the lengths of the con-
tinuous recordings are presented in table 1. The
patients were seen between September 1976 and
January 1979. Three of these patients had congenital
heart disease and one was studied 6 hours after the
onset of an anterior myocardial infarction. The other
four patients had no organic heart disease. When elec-
trocardiographic data were obtained (table 1), none of
the patients was undergoing digitalis therapy or other
From the Second Department of Medicine and the Department
of Cardiovascular Medicine, Hokkaido University School of
Medicine, and the Department of Medicine, Sapporo Teishin
Hospital, Sapporo, Japan.
Supported in part by a grant from the Education Ministry of the
Japanese government.
Address for correspondence: Shinji Kinoshita, M.D., Second
Department of Medicine, Hokkaido University School of Medicine,
Sapporo, Japan.
Received November 27, 1978; revision accepted May 15, 1979.
Circulation 60, No. 6, 1979.
1395
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antiarrhythmic therapy, though one patient with acute
myocardial infarction was administered i.v. lidocaine
when short runs of ventricular tachycardia occurred.
All patients were in basic sinus rhythm. Though
coupling intervals showed marked variation, no fusion
beats were found and we could not discern in-
dependence of the ectopic rhythm from the basic
rhythm in any part of the recording. Following the
classic criteria," the above factors make parasystole
unlikely, though these criteria are not always useful in
differentiating parasystole from ordinary extrasystolic
rhythm.'2-15
ECGs were continuously recorded by a direct-
writing instrument. All coupling intervals of the ex-
trasystoles were measured by a single observer, and
the relationship between the coupling interval and the
appearance of paired extrasystoles was investigated.
In six patients in whom we saw two or more pairs of
extrasystoles in a continuous recording, the difference
between the mean coupling interval for single ex-
trasystoles and that for the first ones of paired ex-
trasystoles was statistically analyzed using the t test.
Results
The results are summarized in table 1 and figure 1.
We saw a remarkable relationship between the cou-
pling interval to the preceding sinus beat and the
appearance of paired ventricular extrasystoles. In all
cases paired ventricular extrasystoles were initiated
only by comparatively late coupled ventricular ex-
trasystoles. When an extrasystole occurred beyond a
certain critical length after the preceding sinus beat,
this extrasystole was often followed by another ex-
trasystole. However, when an extrasystole occurred
within this critical length after the sinus beat, the ex-
trasystole was never followed by another extrasystole.
In all cases this critical length was longer than the
middle value between the shortest and the longest
coupling interval to the preceding sinus beat. In all of
five cases in which three or more pairs of extrasystoles
were found in a continuous recording, the mean cou-
pling interval for the first paired extrasystoles
was significantly longer than that for single extrasys-
toles (p < 0.01).
In cases 4-7, when an extrasystole following the
sinus beat occurred with a coupling longer than the
1396 1396 CIRCULATION
CIRCULATION ~~~~~~~~~~VOL
60, No 6, DECEMBER 1979

TABLE~1. Electrcardiographice Data in Eight Patmients wlit h Occaosionally Pairedi Ventricular Exrtrasystoles

Age/Sex
Organic
heart, LengthRaieofcultg'trvs(e)
of ECG Ragso opInitevl(s)
(years) disease (min) SE SE, SE, E1E2
Case 1 58/1F PDA 1 0.39-0.54 0.39-0.54 0.49-0.52t 0.30-0.34
Case 2 31/F no 17 0.39-0.6S 0.39-0.68 0.64 0.50
Case 3 .5 4/-M no 15 0. 4 5 -0. 53 0.45 -0. 53 0.52-0.53 0.41-0.44
Case 4 3 5 /M-N PS 4 0.41-0.60 0.41-0.50 0.51-0.60* 0.36-0.40
Case 5 20/M no 15 0.44-0.63 0.44-0.56 0.63 0.38
Case 6 20/M no 5 0.43-0.59 0.43-0.47 0.53-0.59t 0.38-0.46
Case 7 28/F ASD 3 0.40-0.5-2 0.40-0.44 0.45-0.52t 0.34-0.37
Case 8 63/M ml 60 0.39-0.73 0.39-0.73 0.57-0.72* 0.34-0.48
*p <0.01, SE, vs, SE, (unpaired t test).
tp <0.001, SE, vs SE, (unpaired t test).
Abbreviations: SE =initerval between the sinus beat and the next extrasystole, regardless of whether
the extrasystole was single or paired; SE,, interval between- the sinus beat and the next single extrasystole;
SE,1 iaterval betweeni the sinus beat and the first of the followinig paired extrasystoles; EIE2 interval =

between the first and the latter of paired extrasystoles; PDA =patent ductus arteriosus; PS = pulmonary
stenosis; ASD =auricular .septal defect; MJ myocardial infarctionl. =

critical length, it always initiated paired extrasystoles. recording from case 6. In this case, when the ex-
On the other hand, in cases 1, 2, 3 and 8, even when trasystole was single, its coupling interval was always
the extrasystole occurred with a coupling longer than shorter than 0.48 second (fig. 2, upper strip). On the
the critical length, it sometimes did not initiate paired other hand, when paired extrasystoles occurred, the
extrasystoles. In cases 6 and 7, there was a gap coupling interval of the first of them was always longer
between the ranges of coupling intervals for single ex- than 0.52 second (fig. 2, lower strip). The extrasystole
trasystoles and for the first ones of paired ex- with a coupling interval between 0.48-0.52 second was
trasystoles (fig. I). Figure 2 shows portions of a never seen.

COUPLING INTERVALS (hundredths of a second)

40 45 50 55 60 I
65 70
I I I

CASE 1 008 oo 0 0 00 00 0 0

0 0j3f

CASE 2 88o§§§o8o 8o8ooo oooo8oo8o 0 0 000 0 0 0 0

CASE 3 00 888880III18§880§§o80
CAS E 4 0 00 8o8 00000 800 0o 0 S 0
CASE 5 0 0 0 0 00 0 0 0 00 0 0 0

CASE 6 008~8§8o8808888o88 HLIt 0 0

CAS E 7 0 ooo0
0 00 00 ... 00

CASE 8 o8ooo080 0o 0 00 00 0 0 0 0 0 0 0 @00 000 0 0 00 0 0 00 000 000 00 0

FIGURE 1. Relationship of the coupling interval to the preceding sinus beat and the appearance of paired ventricular ex-

tras v-stoles. Open circles indicate coupling intervals between the sinus beat and the single ext rasystole, and solid circles indicate
those between the sinus beat and the first of paired extras Ystoles.

V6 5
6.
FIGURE 2. Case 6. Ventricular extrasystoles occasionally occur in pairs. The two strips are not continuous. Coupling intervals

of ventricular extrasystoles to the preceding sinus beats are indicated in hundredths of a second.

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 PAIRED VENTRICULAR EXTRASYSTOLES/Kinoshita et al.
V3 39
V3 59
FIGURE 3. Case 8. Short runs of ventricular tachycardia
initiated by late coupled ventricular extrasystoles in acute
myocardial infarction. Coupling intervals of ventricular ex-
trasystoles to the preceding sinus beats are indicated in hun-
dredths of a second. The four strips are parts of a long con-
tinuous ECG that was taken after the recording shown in
figure I with a long-term ECG recording system, (Car-
diologger'6). In this recording, 12 short runs of ventricular
tachycardia were found in the 4 hours before i.v. administra-
tion of lidocaine. After lidocaine, ventricular tachycardia
was not found. Three to six (mean 3.8) consecutive ven-
tricular extrasystoles occurred in a run. Coupling intervals
to the preceding sinus beats for the first of these consecutive
extrasystoles ranged from 0.57-0.92 second. The mean
coupling interval for these first ones (mean + SD =
0.675 ± 0.088 second) was significantly longer than that for
single extrasystoles appearing during the same period
(0.545 0.124 second; n = 82; p < 0.001).
Although paired extrasystoles were initiated only by
comparatively late coupled extrasystoles, the interval
between the first and the second of these paired ex-
trasystoles (E,E2 interval in table 1) was always much
shorter than the coupling interval of this first ex-
trasystole to the preceding sinus beat. Usually the in-
tervals between paired extrasystoles were shorter than
the shortest coupling interval between the sinus beat
and the extrasystole, and the latter of paired ex-
trasystoles often interrupted the T wave of the first
one, indicating the R-on-T phenomenon.
In case 8 the ECG, taken 6 hours after an anterior
myocardial infarction, showed occasional paired ven-
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1 397
tricular extrasystoles. The critical coupling interval in-
ducing these paired extrasystoles was about 0.56 sec-
ond (fig. 1). After that, the ECG was continuously
observed with a long-term ECG recording system
(Cardiologger, San-Ei Instrument Company, Tokyo,
Japan).'6 Figure 3 shows parts of this long recording.
When extrasystoles occurred with couplings longer
than the critical length of 0.56 second, they often ini-
tiated short runs of ventricular tachycardia. Case 5
also had occasional tachycardia that continued for a
minute, though the ECG during the attack could not
be taken. The other patients had no tachycardia.
Discussion
Mechanism of Paired Extrasystoles
The above observations in this study suggest a cause
for paired ventricular extrasystoles (figs. 4 and 5). The
explanations we discuss are valid regardless of
whether the conduction disturbance occurs in the reen-
trant pathway or in the junction between an ectopic
focus and the surrounding ventricular myocardium.
However, in this study, the explanations are made
only with regard to the reentrant pathway, because we
believe that such ventricular extrasystoles with
variable coupling are caused by the reentrant
mechanism 14, 17
Figure 4 shows part of the recording in case 1. In
this figure the sinus beat S4 is followed by the ex-
trasystole E, with a comparatively short coupling of
0.40 second. The sinus beat S5 is followed by the ex-
trasystole E4 with a comparatively long coupling of
0.48 second. The next sinus impulse, S6, is not con-
ducted to the ventricles; it is blocked at the atrioven-
tricular (AV) junction. After that, the sinus beat S7 is
not followed by a manifest extrasystole, suggesting
that an event similar to the Wenckebach phenomenon
occurs in the reentrant pathway; in this case, however,
a block subsequent to the progressively increasing
conduction delay occurs at the AV junction. The
diagram below the strip shows that after the
progressively increasing conduction delay in the reen-
trant pathway, a block of the sinus impulse (S6) occurs
at the AV junction and, in the subsequent sinus im-
pulse, S7, conduction in the reentrant pathway
recovers. Because of insufficient conduction delay, the
sinus impulse S7 becomes a concealed ventricular ex-
trasystole due to interference at the distal end of the
reentrant pathway.'8 Figures 5A and B illustrate such
concealed and manifest reentrant extrasystoles. The
upper end of the illustrated reentrant pathway in-
dicates the distal end of the pathway at which uni-
directional block occurs. The impulse can enter the
reentrant pathway only through the lower end of the
illustrated pathway.
In the lower strip of figure 4, the sinus beat S1, is
followed by the extrasystole E,2 with a coupling of
0.42 second. The sinus beat S16 is followed by no
manifest extrasystole, suggesting that this sinus im-
pulse is blocked at the reentrant pathway. However,
the next sinus beat, S,7, is followed by the extrasystole
E,4, with a comparatively long coupling of 0.47 sec-
1 398 CIRCULATION VOL 60, No 6, DECEMBER 1979

RP If1
RI' a1 1 I 1I1
T4AV~~~IIJI I

-T-+ I t- E1
- (Ei3) - -Ej4 -- - -- El-,:]
j . . _
T441 8 t1 l.1
_M
f2_
-l '_>4~~~2
I
-
_V.
R . 4 .~ H, _ 1- -471. -E29 . ;.5'-
1 i

V
9I 1 1.
k I
I~
;4

FIGURE 4. Case 1. Ventricular extrasystoles with variable coupling, occasionally occurring in pairs. The two strips are con-
tinuous. The numbers within the strips indicate coupling intervals of extrasystoles to the preceding sinus beats. Time intervals
are expressed in hundredths of a second. S and (S) = sinus beats (or impulses) conducted and nonconducted to the ventricles,
respectively; E and (E) manifest and concealed extrasystolic beats (or impulses), respectively; V = ventricles; RP = reen-
trant pathway. Intraventricular conduction of the impulse leading to the reentrant pathway is indicated by dashed lines in the
diagrams below the strips.

ond. This finding suggests that after the sinus impulse
S,, invades a considerably large part of the reentrant
pathway, it becomes a concealed ventricular ex-
trasystole due to exit block within the reentrant
pathway.'8' 19 Figure 5C illustrates such a concealed
extrasystole. El-Sherif et al.20 recently demonstrated
the presence of manifest and concealed reentrant ven-
tricular extrasystoles in the late myocardial infarction
period in dogs.
The findings shown in figure 4 indicate that the ab-
solute refractory period at a distal level of the reen-
trant pathway is about equal to or slightly longer than
the sinus cycle length in this figure. In the upper strip,
after conduction in the reentrant pathway recovers in
the sinus impulse S7, conduction delay in the pathway
again increases. After marked delay in the pathway,
the sinus impulse S9 reenters the ventricles and be-
comes the extrasystole E7. The coupling interval of the
extrasystole E7 to the sinus beat S (0.50 second) is
markedly prolonged but still much shorter than the
sinus cycle length. This indicates that the interval SqE7
is much shorter than the absolute refractory period at
the distal level of the reentrant pathway. Despite this,
the extrasystole E7 is followed by another extrasystole,
E8. If the extrasystole E7 occurred after the sinus im-
pulse S9 stimulated all the parts of the reentrant
pathway, the extrasystolic impulse E7 could not pass
again through the pathway, and the extrasystole E8
would not occur. Therefore, we must assume that the
sinus impulse Sg does not stimulate all the parts of the
pathway; that is, that the extrasystole E7 occurs after
the sinus impulse S9 passes through only a part of the
pathway. Longitudinal dissociation in the reentrant
pathway is strongly suggested. Paired ventricular ex-
trasystoles E17 and E,8 in the lower strip also suggest
such longitudinal dissociation.
Diagram D, in figure 5 illustrates longitudinal dis-
sociation in the reentrant pathway, in which the ab-
solute refractory period of one lateral part (the left
side) is slightly longer than that of the other lateral
part (the right side), and the sinus impulse passes
through the right side only. Thereafter, it becomes a
manifest extrasystole with a prolonged coupling.
Diagram D2 illustrates the stage after diagram D,.
In this stage the left side of the reentrant pathway
recovers from the absolute refractory phase. Diagram
D2 shows that after the extrasystolic impulse becomes
manifest in diagram D, it reaches the reentrant
pathway again and, passing through the left side of the
pathway, becomes another manifest extrasystole. In
diagram D2 the impulse falls considerably after the ab-
solute refractory period of the left side, and therefore
reaches the distal end of the pathway after a com-
paratively short conduction time. As a result, the
latter of paired extrasystoles occasionally interrupts
the T wave of the first one, indicating the R-on-T
phenomenon.
In case 2 ventricular extrasystoles usually showed
concealed bigeminal rhythm. This rhythm suggests
2:1 exit block due to the long absolute refractory
period in the reentrant pathway.18' 20 This period in
case 2 was considered to be about 0.85 second, which

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 PAIRED VENTRICULAR EXTRASYSTOLES/Kinoshita et al. 1 399

A
7 B C

RP
, -
T1

D3 I
I
I I

RP I,
I
I
I I

FIGURE 5. Diagrams oflongitudinal dissociation in the reentrant pathway as a mechanism responsible for
genesis ofpaired ventricular extrasystoles. Slow conduction in the reentrant pathway is indicated by zigzag
lines. RP = reentrant pathway.

was much longer than the coupling interval of the first
of paired extrasystoles (0.64 second). As in case 1, this
suggests longitudinal dissociation in the reentrant
pathway.
A discontinuous AV nodal conduction curve during
the atrial extrastimulus examination suggests dual AV
nodal pathways.2' As in figure 5, if there is some
difference not only in the absolute refractory period,
but also in the conduction velocity between the right
and left sides of the reentrant pathway, and if the con-
duction velocity in the right side is slower than that in
the left side, the discontinuity as seen in the AV nodal
conduction will also occur in conduction in the reen-
trant pathway. A gap will be found between the range
of coupling intervals shown in the stage of diagram B
and that in the stage of diagram D1. Actually, such a
gap was found in cases 6 and 7 (fig. 1). This reinforces
the presence of longitudinal dissociation in the reen-
trant pathway.
In the other four cases, neither the presence of such
a gap between the ranges of coupling intervals nor the
presence of concealed extrasystolic rhythm could be
disclosed. However, the fact that paired extrasystoles
were initiated only by comparatively late coupled ex-
trasystoles suggests that in these cases too, lon-
gitudinal dissociation in the reentrant pathway might
be the cause of paired extrasystoles. In these four
cases the interval between paired extrasystoles E, and
E2 was much shorter than the interval between the pre-
ceding sinus beat S and the extrasystole E,; the
difference between them was markedly long. If the ex-
trasystoles E1 and E2 were caused by reentry using the
same pathway, the markedly long difference would in-
dicate that the impulse S could not reach the entrance
of this reentrant pathway without passing through a
region showing abnlormally prolonged conduction
delay, but that the impulse E1 could reach the same en-
trance without passing through this region. The above
assumption also indicates that a form of dual path-
ways was present as a cause of paired ventricular ex-
trasystoles. Some recent data in animal experiments
suggests that longitudinal dissociation occurs in the in-
traventricular conduction system.22-25
In figure 5, if the conduction time in the left side of
diagram D2 shortens further, the impulse will become
a concealed extrasystole due to interference at the dis-
tal end of the pathway. Diagram D' shows such a
state. This might explain some of the single ex-
trasystoles with long couplings in cases 1, 2, 3 and 8, in
whom even when an extrasystole occurred beyond the
critical length after the sinus beat, it sometimes failed
to initiate paired extrasystoles.

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1400 CIRCULATION
Relationship to Initiation of Ventricular
Tachycardia and Fibrillation
2.
The patient with acute myocardial infarction (case
8) showed short runs of ventricular tachycardia. In all
of the other cases, an ECG showing ventricular 3.
tachycardia could not be obtained. Therefore, we can-
not discuss general mechanisms that cause ventricular
tachycardia and fibrillation initiated by late coupled 4.
ventricular extrasystoles in acute myocardial infarc-
tion. However, these observations for paired ex- 5.
trasystoles suggest the possibility that in some patients
with acute myocardial infarction, similar longitudinal
dissociation in the reentrant pathway might occur dur- 6.
ing the initiation of ventricular tachyarrhythmias. In
recent animal experiments, El-Sherif et al.20 26 showed
functional dissociation of conduction in the infarction 7.
zone. An explanation for initiation of ventricular
tachyarrhythmias is discussed below. 8.
Diagram D3 in figure 5 illustrates the stage after
diagram D2. Diagram D, shows that after the ex-
trasystolic impulse becomes manifest (diagram D2), it
usually cannot reenter the pathway through either 9.
side, because the conduction time in the left side at the
stage of diagram D2 is comparatively short. This may 10.
be why, in usual cases of paired ventricular extrasys-
toles, ventricular tachycardia does not occur. ] .
However, if such paired extrasystoles originate in the 12.
infarction zone with its increased vulnerability, ven-
tricular fibrillation or tachycardia with a considerably
rapid rate may be initiated by the latter of paired ex-
trasystoles (diagram D2) which is closely coupled to 13.
the first one. The reentrant circuit for such tachy-
arrhythmia with a rapid rate is probably different 14.
from the reentrant pathway for paired extrasystoles;
the circuit may be located in the region adjacent to the 15.
distal end of the pathway for paired extrasystoles.
Diagram D' shows that if, alternatively, the 16.
manifested extrasystolic impulse in diagram D2 can
reenter the pathway through the right side, it will 17.
become a third manifest extrasystole, and a ven-
18.
tricular rhythm will be initiated and maintained for
some time; however, the rate of this ventricular 19.
rhythm may be relatively slow because of the long ab-
solute refractory period in the pathway.
Our observations suggest that in some patients with 20.
ventricular tachycardia or fibrillation, dual reentrant
pathways due to longitudinal dissociation may initiate
the tachyarrhythmias, although most patients with
ventricular tachyarrhythmias do not have such dual 21.
pathways. In fact, in many animal and clinical cases of
El-Sherif et al.27 and Wellens et al.,28 29 electrically in-
duced ventricular tachycardia can be explained by the
same reentrant pathway. However, the reentrant 22.
mechanism using the same reentrant pathway cannot
explain the fact that ventricular tachycardia or paired 23.
extrasystoles were initiated only by late coupled ven-
tricular extrasystoles.
24.
References 25.
1. Wiggers GJ, Wegria R: Ventricular fibrillation due to single,
localized induction and condenser shocks applied during the 26.
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VOL 60, No 6, DECEMBER 1979
vulnerable phase of ventricular systole. Am J Physiol 128: 500,
1940
Smirk FH, Palmer DG: A myocardial syndrome: with par-
ticular reference to the occurrence of sudden death and of
premature systoles interrupting antecedent T waves. Am J Car-
diol 6: 620, 1960
Lown B, Fakhro AM, Hood WP, Thorn GW: The coronary
care unit: new perspectives and directions. JAMA 199: 156,
1967
Axelrod PJ, Verrier RL, Lown B: Vulnerability to ventricular
fibrillation during acute coronary arterial occlusion and release.
Am J Cardiol 36: 776, 1975
Goel BG, Han J, Fabregas RA, Yoon MS: Ventricular
tachyarrhythmias induced by premature beats during acute cor-
onary occlusion. J Electrocardiol 11: 33, 1978
De Soyza N, Bissett JK, Kane JJ, Murphy ML, Doherty JE:
Ectopic ventricular prematurity and its relationship to ven-
tricular tachycardia in acute myocardial infarction in man. Cir-
culation 50: 529, 1974
Lie KI, Wellens HJJ, Downar E, Durrer D: Observations on
patients with primary ventricular fibrillation complicating acute
myocardial infarction. Circulation 52: 755, 1975
EI-Sherif N, Myerburg RJ, Scherlag BJ, Befeler B, Aranda
JM, Castellanos A, Lazzara R: Electrocardiographic ante-
cedents of primary ventricular fibrillation: value of the R on T
phenomenon in myocardial infarction. Br Heart J 38: 415, 1976
Rothfeld EL, Parsonnet J. McGorman W, Linden S: Har-
bingers of paroxysmal ventricular tachycardia in acute myocar-
dial infarction. Chest 71: 142, 1977
Chou T, Wenzke F: The importance of R on T phenomenon.
Am Heart J 96: 191, 1978
Chung EK: Principles of Cardiac Arrhythmias. Baltimore,
Williams & Wilkins Co, 1971, p 363
Pick A: The electrocardiographic basis of parasystole and its
variants. In The Conduction System of the Heart: Structure,
Function and Clinical Implications, edited by Wellens HJJ, Lie
KI, Janse MJ. Leiden, Stenfert Kroese, 1976, p 143
Moe GK, Jalife J, Mueller WJ, Moe B: A mathematical model
of parasystole and its application to clinical arrhythmias. Cir-
culation 56: 968, 1977
Kinoshita S: Mechanisms of ventricular parasystole. Circula-
tion 58: 715, 1978
Michelson EL, Morganroth J, Spear JF, Kastor JA, Josephson
ME: Fixed coupling: different mechanisms revealed by exercise-
induced changes in cycle length. Circulation 58: 1002, 1978
Shimizu N: A long term recording system. Keisoku-Gijutsu 6:
52, 1978 (in Japanese)
Kinoshita S: Intermittent parasystole originating in the reen-
trant path of ventricular extrasystoles. Chest 72: 201, 1977
Kinoshita S: Concealed ventricular extrasystoles due to in-
terference and due to exit block. Circulation 52: 230, 1975
Kinoshita S, Fujita K, Kawaguchi H, Kanda K, Tanabe Y:
Concealed (proximal) Wenckebach phenomenon with distal 2: 1
exit block in the ectopic-ventricular junction. Chest 73: 198,
1978
El-Sherif N, Lazzara R, Hope RR, Scherlag BJ: Re-entrant
ventricular arrhythmias in the late myocardial infarction
period. 3. Manifest and concealed extrasystolic grouping. Cir-
culation 56: 225, 1977
Rosen KM, Denes P, Wu D, Dhingra RC: Electrophysiological
diagnosis and manifestation of dual A-V nodal pathways. In
The Conduction System of the Heart: Structure, Function and
Clinical Implications, edited by Wellens HJJ, Lie KI, Janse
MJ. Leiden, Stenfert Kroese, 1976, p 453
Anderson GJ, Greenspan K, Bandura JP, Fisch C: Asynchrony
of conduction within the canine specialized Purkinje fiber
system. Circ Res 27: 691, 1970
Spach MS, Barr RC, Serwer GS, Johnson EA, Kootsey JM:
Collision of excitation waves in the dog Purkinje system: ex-
tracellular identification. Circ Res 29: 499, 1971
Myerburg RJ, Nilsson K, Befeler B, Castellanos A, Gelband H:
Transverse spread and longitudinal dissociation in the distal A-
V conduction system. J Clin Invest 52: 885, 1973
Walston A, Boineau JP, Alexander JA, Sealy WC: Dissocia-
tion and delayed conduction in the canine right bundle branch.
Circulation 53: 605, 1976
El-Sherif N, Scherlag BJ, Lazzara R, Hope RR: Re-entrant
 SUDDEN DEATH IN AVID DIETERS/Isner et al. 1401

ventricular arrhythmias in the late myocardial infarction
period. 1. Conduction characteristics in the infarction zone.
Circulation 55: 686, 1977
7. El-Sherif N, Hope RR, Scherlag BJ, Lazzara R: Re-entrant
ventricular arrhythmias in the late myocardial infarction
period. 2. Patterns of initiation and termination of re-entry.
Circulation 55: 702, 1977
28. Wellens HJJ, Schuilenburg RM, Durrer D: Electrical stimula-
tion of the heart in patients with ventricular tachycardia. Cir-
culation 46: 216, 1972
29. Wellens HJJ, Dgren DR, Lie KI: Observations on mechanisms
of ventricular tachycardia in man. Circulation 54: 237, 1976

Sudden, Unexpected Death in Avid Dieters

Using the Liquid-Protein-Modified-Fast Diet
Observations in 17 Patients and the Role
of the Prolonged QT Interval
JEFFREY M. ISNER, M.D., HAROLD E. SOURS, M.D., ALLEN L. PARIS, M.D.,
VICTOR J. FERRANS, M.D., AND WILLIAM C. ROBERTS, M.D.

SUMMARY Clinical and morphologic findings are described in 17 patients who died suddenly and unex-
pectedly during or shortly after use of the liquid-protein-modified-fast diet. Of the 17 patients, 16 were women,
most were young (average age 37 years), and most lost a massive amount of weight (average 41 kg or 35% of
their prediet weight) over a short period of time (average 5 months). Eight had one or more episodes of syn-
cope. Multiple-lead ECGs were recorded in 10 patients. All had normal sinus rhythm; all had episodes of ven-
tricular tachycardia; nine and possibly 10 patients had prolongation of the QT interval, unassociated with the
recognized causes of QT interval prolongation in at least seven of the nine patients; and nine had diminished
amplitude of the QRS complexes ("low voltage"). Histologic study of left ventricular myocardium in 14 pa-
tients disclosed attenuated myocardial fibers in 12, increased lipofuscin pigment in 11, and mononuclear-cell
myocarditis in one. Similar histologic findings, however, also were found in 16 cachectic control subjects
studied in similar fashion, but ECGs in them showed no prolongation of QT intervals or episodes of ventricular
tachycardia. Thus, semistarvation, particularly in the face of antecedent obesity, is a cause of acquired QT in-
terval prolongation, and repeated ECGs are recommended in patients on semistarvation diets for treatment of
obesity.

IN 1976 a book entitled The Last Chance Diet' was
published and almost immediately, several liquid-pro-
tein-modified-fast (LPMF) diets became very popular
and fashionable as means of rapid weight reduction.
These diets were intended to serve as the dieter's only
source of calories. Between January 1, 1977 and
December 31, 1977, it was estimated that more than
100,000 persons had used one or more of the LPMF
diets as their sole source of nourishment for at least 1
month.2 By August 1977, however, sudden death in
several young LPMF diet users was reported to either
the Food and Drug Administration (FDA) or the
Center for Disease Control (CDC), and between July
1977 and January 1978 at least 60 deaths among avid
users of the LPMF diet were reported to the FDA and
CDC.' In 28 of these 60 patients, there was clinical or
From the Pathology Branch, National Heart, Lung, and Blood
Institute, Bethesda, Maryland, and the Center for Disease Control,
Atlanta, Georgia.
Address for correspondence: William C. Roberts, M.D., Building
IOA, Room 3E30, National Institutes of Health, Bethesda,
Maryland 20205.
Received April 2, 1979; revision accepted June 4, 1979.
Circulation 60, No. 6, 1979.
Downloaded from http://circ.ahajournals.org/ by guest on June 21, 2016
necropsy evidence of an underlying disorder that may
have contributed to the patient's death, and in 15 other
patients information regarding the circumstances of
death was incomplete. This report focuses on the other
17 patients who before LPMF dieting were healthy
and in whom detailed clinical and/or necropsy infor-
mation was available. Attention is called to a poorly
documented cause of QT interval prolongation and
sudden death.
Patients
Certain clinical and morphologic findings in the 17
patients are summarized in table 1. Patients 3 and 5,4
8,5 and 106 have been reported by other investigators.
Symptoms attributable to cardiac dysfunction were
minimal to absent in all 17 patients. None had
evidence of congestive cardiac failure. Only four pa-
tients (6, 9, 11 and 12) (table 1) had evidence of
systemic hypertension at some time. Death was
sudden and occurred outside the hospital in six pa-
tients. Of the other II patients, eight presented with
syncope and subsequently died in the hospital; the
other three were comatose upon admission to the
hospital and each died soon thereafter.
 A cause of paired ventricular extrasystoles.
S Kinoshita, K Fujita, K Kanda, Y Tanabe and T Kawasaki

Circulation. 1979;60:1395-1401
doi: 10.1161/01.CIR.60.6.1395
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1979 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539

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