Download Potential Role of QT Interval Prolongation in Sudden

QT INTERVAL IN SIDS/Maron, Clark, Goldstein, Epstein
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Potential Role of QT Interval Prolongation in
Sudden Infant Death Syndrome
BARRY J. MARON, M.D., CHESTER E. CLARK, M.D.,
ROBERT E. GOLDSTEIN, M.D., AND STEPHEN E. EPSTEIN, M.D.
SUMMARY To investigate the possibility that a genetically
transmitted cardiac abnormality is involved in the genesis of the
sudden infant death syndrome (SIDS), 42 sets of parents who had at
least one infant with SIDS were studied by electrocardiography.
Prolongation of the QT interval was present in at least one member of
11 (26%) sets of parents. In families in which QT interval prolongation was found in a parent, prolonged QT interval was also present in
39% of the siblings of infants with SIDS, suggesting an autosomal
dominant pattern of inheritance. In addition, an infant with "nearmiss" SIDS showed marked prolongation of the QT interval. Thus,
our data suggest that prolonged QT interval may play a role in a considerable proportion of sudden and unexpected infant deaths.
However, definitive confirmation of the relation between QT interval
prolongation and SIDS will require large prospective investigations.
SUDDEN INFANT DEATH SYNDROME (SIDS) is the
largest single cause of death between one week and one year
of age in the United States, accounting for the deaths of approximately 10,000 apparently well infants annually." 2
Although numerous theories have been proposed,2' the
primary mechanisms responsible for SIDS are still un-
known. Recently, many investigators have incriminated
respiratory and cardiac mechanisms such as chronic hypoxemia,6+ 7 prolonged apnea,' dysfunction of central nervous
system reflexes that are responsible for stabilization of cardiac rate,9 or cardiac arrhythmias"' 11 as the cause of SIDS.
We have considered the possibility that prolonged QT interval syndrome,"'-13 a genetically transmitted cardiac condition known to cause sudden death in children"'-" and in infants,'4-21 is related to SIDS. The present study describes our
investigation into the possible relation between prolonged
QT interval syndrome and sudden, unexplained death in infancy.
From the Cardiology Branch, National Heart and Lung Institute,
Bethesda, Maryland.
Address for reprints: Dr. Barry J. Maron, Cardiology Branch, National
Heart and Lung Institute, Building 10, Room 7B-15, Bethesda, Maryland
20014.
Received January 5, 1976; revision accepted April 29, 1976.
424
CIRCULATION
Methods
Family Studies
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Since prolonged QT interval syndrome'4 22-24 may be
transmitted as an autosomal dominant trait, we hypothesized that evidence of this disease might be present in
parents of infants with SIDS, if this condition was responsible for the infant's death. Therefore, 42 sets of parents who
had at least one infant with SIDS (documented by the
characteristic clinical and pathologic features of this condition25) were studied by electrocardiography. Subjects were
selected from organizations (in the Washington, Baltimore
and Philadelphia metropolitan areas) of parents who had an
infant with SIDS. All parents in these organizations were informed of this investigation and those who volunteered were
included in the study. Parents ranged in age from 19 to 59
years (mean 32). Electrocardiograms were also performed
on all siblings of infants with SIDS from eight families (23
siblings) in which one parent was shown to have a prolonged
QT interval and on all siblings of infants with SIDS from
seven other families (18 siblings) in which neither parent had
a prolonged QT interval. The siblings ranged in age from 2
to 15 years (mean 8).
Standard 12 lead electrocardiograms were recorded in
each subject in the supine position under basal conditions in
the waking state. Marquette series 3000-A and Sanborn 100
Viso-Cardette electrocardiograph recorders were used. All
electrocardiograms were recorded at a speed of 25 mm/second. Calibration of the electrocardiographic recorders used
in this study demonstrated that the paper speed of each
recorder was within 2% of 25 mm/sec. The frequency
response of the electrocardiographic recorders was uniform
(at ± 3 dB) from 0.05 Hz to 80 Hz.
Each parent with prolongation of the QT interval (as
described below) had normal serum potassium, calcium,
sodium, chloride, carbon dioxide and magnesium. No subject was, at the time of study, receiving medications known
to alter the QT interval. Furthermore, no subject had
evidence of cardiovascular abnormalities known to alter the
QT interval such as conduction defect, left ventricular
hypertrophy, congestive heart failure, myocardial or
valvular disease, pericarditis, cor pulmonale, cerebral disorder, or previous myocardial infarction.
Measurement of QT Interval
QT intervals were measured in standard lead II. The maximal QT interval and an average of QT intervals (derived by
measuring six to fourteen consecutive beats) were obtained
for each subject. These methods of measurement were
employed to permit comparison of our values with those
reported in several commonly used studies that define the
normal QT interval.26 32
The QT interval was measured from the onset of the Q
wave (or from the onset of the R wave if no Q wave was
present) to the termination of the T wave (at the point where
the downslope of the T wave met the isoelectric baseline).
Care was taken to avoid including U or P waves in the
measurement of QT intervals." We considered unsatisfactory for measurement any beat in which: 1) the QRS
complex was abnormally wide, 2) T waves were notched,
VOL 54, No 3, SEPT'EMBER 1976
bifid, biphasic, flat or inverted, or 3) muscle tremor artifact
was present or the baseline was irregular. Furthermore, QT
intervals were not measured in premature beats or in areas
of the tracing showing marked sinus arrhythmia. Heart rate
was calculated over five consecutive beats in the same segment of the tracing that the QT interval was measured.
QT intervals were measured in the majority of tracings on
two to four different occasions by the same observer without
knowledge of the previous measurements. Only slight deviations (± 0.02 sec) in the duration of the QT interval were
noted among the measurements; on no occasion did these
slight variations in the measurement of QT interval constitute the difference between a normal or abnormal QT interval.
Because there is no general agreement regarding the standards of normal QT interval, our measured values for adults
were compared to two normal populations and our values
for children were compared to three normal populations.
For adult subjects (18 years of age and older), the maximal
measured QT interval in lead II was compared to the normal
standards of Simonson et al.;29 the average QT interval in
lead II was compared to the normal standards of Ashman
and Hull.26 27 QT intervals in adults were considered
prolonged if the maximal measured QT interval was at or
exceeded the 97.5 percentile of Simonson's normal population29 or if the average QT interval was at or exceeded the
97th percentile of Ashman and Hull's normal population.26 27 In addition, the maximal and average QT intervals were corrected for heart rate (QT,) by dividing the
measured QT interval by the square root of the RR interval
(a method first described by Bazett34).
For children and infants, the maximal QT, was compared
to the normal standards of McCammon.28 The average QT
interval was compared to the normal standards of
Alimurung et al.32 and of Fraser et al.30 3' QT intervals in
children were considered prolonged if the maximal QT, was
at or exceeded the 97th percentile of McCammon's normal
population,28 if the average QT interval was at or exceeded
the 97th percentile of Alimurung's normal population,32 or if
the average QT interval exceeded the expected value by two
standard errors, using the method of Fraser et al.30 31 Since
the study of McCammon28 does not provide data for percentiles over the 90th, the 97th percentile was estimated assuming the McCammon results were derived from a normally
distributed data base. Where appropriate, data were
analyzed statistically using the two-tailed Fisher's exact test.
Infant with "Near-miss" SIDS
We hypothesized that if prolonged QT interval were
responsible for some instances of SIDS, then the presence of
this electrocardiographic abnormality during life in infants
with "near-miss" SIDS35 36 would provide some evidence
for our hypothesis. Therefore, an apparently normal infant
who survived a cardiorespiratory arrest at seven weeks of
age was studied. Electrocardiograms obtained in this infant
in the waking state were recorded and interpreted in the
same manner as described above. Electrocardiograms were
also obtained in 18 other members of the infant's family, including her parents and siblings.
425
QT INTERVAL IN SIDS/Maron, Clark, Goldstein, Epstein
TABLE 1. QT Interval Prolongation in Parents of Infants with SIDS
S.G. / 39 / F
67
95
C.M./ 40 / M
E.W./
R.M./
F.H. /
C.W./
A.M./
R.R./
S.K./
D.C./
P.C./
E.K./
R.L./
Maximal
QT
(see)
HR
(beats/min)
Age
Subject/(yrs)/Sex
35 / M
32 /M
26 / F
34 / F
31 / F
59 / M
26 / F
36 / M
20 / F**
39 / M
23 / F
Maximal QT
UL*
(Simonson)
0.46
0.38
0.40
0.46
0.40
0.42
0.38
0.44
0.41
0.41
0.38
0.40
0.41
84
61
78
71
90
64
77
73
84
73
69
Maximal
QT.t
Average
QT
(sec)
0.49
0.48
0.47
0.47
0.46
0.46
0.46
0.46
0.46
0.45
0.45
0.44
0.44
0.44
0.36
0.38
0.44
0.38
0.40
0.38
0.41
0.39
0.40
0.36
0.39
0.39
(see)
0.41
0.39
0.38
0.43
0.39
0.41
0.38
0.42
0.39
0.40
0.38
0.40
0.41
Average
QT ULT
(Ashman
& Hull)
0.41
0.35
0.37
0.42
0.39
0.40
0.36
0.41
0.39
0.39
0.37
0.39
0.41
Average
QTct
(sec)
0.47
0.45
0.45
0.45
0.43
0.44
0.46
0.43
0.44
0.44
0.43
0.43
0.42
Prolonged§
(Simonson)
+
0
+
+
+
+
+
+
+
+
+
+
+
Prolongedl
(Ashman
& Hull)
+
+
+
+
0
+
+
+
+
+
0
+
0
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Subjects with initials in itali cs are husband and wife.
*Values given are those for the 97.5 percentile of the normal population of Simonson et al.29
tQT, calculated by dividing the measured QT interval by the square root of the RR interval (method initially described by Bazett34).
tValues given are those for the 97th percentile of the normal population of Ashman and Hu1126 27
' Prolonged QT interval is defined as a value at or beyond the 97.5 percentile.
Prolonged QT interval is defined as a value at or beyond the 97th percentile.
**Mother of two infants with SIDS; all other parents included in the table had one infant with SIDS.
+ = QT interval prolonged; 0 = QT interval normal.
Abbreviations: HR = heart rate (beats per minute); UL = upper limits of normal.
mal QT intervals about the predicted mean tends to dispute
the possibility that the 12 instances of QT prolongation are
due to differences between our technique of QT interval
measurement and that of Simonson: 1) a systematically long
reading of QT intervals relative to Simonson would displace
all QT intervals upward relative to the prediction line, and 2)
if our prevalence of prolonged QT interval represented an
artifact due to a greater degree of scatter than experienced
by Simonson, then we might have expected to show a greater
number of shorter as well as longer QT intervals in our study
population.
When the relatively small number of 12 individuals in our
study group with QT interval prolongation are excluded, the
remaining population with normal QT intervals can be com-
Results
Family Studies
Using the normal standards of Simonson et al.29 for comparison, electrocardiograms showed relatively mild
prolongation of the QT interval in one member of ten sets of
parents. In one other parental set both members had
prolongation of the QT interval (table 1). Maximal QT intervals for all parents are plotted against corresponding R-R
intervals in figure 1. While the QT intervals of most parents
cluster about the predicted mean (from the linear regression
analysis of Simonson29), those considered abnormal appear
to stand apart as a separate population.
The symmetrical and relatively close grouping of the nor.46
0
r
o
.44
*
0
QT Normal
.42
0
0
.40
0
QT at or Above 97.5 Percentile
F
0
.38 F
0
0
FIGURE 1. Maximal QT interval (vertical axis)
each of the 84 parents studied is plotted
against corresponding R-R interval (horizontal
axis). QT interval lengths at or above the 97.5
percentile defined by the data ofSimonson et al.29
are designated by unfilled circles while the
remaining QT intervals are shown as filled circles.
Two subjects with normal QT interval appear to
be among the subjects with prolonged QT interval
due to the effect of age on normal QT interval. A
regression line calculatedfrom Simonson's results
in 960 normal subjects29 indicates the predicted
0
*
60
0
ffor
I
0
.-A
.36'
*
1
0
0
*
*
0
x
*
.34
.
0
.32
*
.
I
I
*0
mean.
.30
6Z
' .60
.65
.70
.80
.85
.75
RR Interval (sec.)
.90
.95
1.0
1.05
1.10
426
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pared to the published normal population of Simonson et
al.29 Thus, QT intervals in the apparently normal portion of
our population yield a regression line of QT interval related
to RR interval (slope = 0.130; intercept = 0.246) that is indistinguishable from a similar line (slope = 0.140; intercept = 0.242) that Simonson et al.29 derived from their
population of 960 normal adults. Furthermore, the standard
error of the estimate was similar for the apparently normal
portion of the present study group (0.020) and the normal
population of Simonson et al. (0.016).29 QT prolongation
was not associated with any particular R-R interval length,
although subjects with the slowest heart rates tended to exhibit the greatest degree of abnormality. Using the normal
standards of Ashman and Hu1126 27 for comparison, at least
one member of nine sets of parents showed prolonged QT interval, including nine parents identified as abnormal by
Simonson's criteria and one parent in whom the QT interval
was at the upper limits of normal compared to the standards
of Simonson et al.29
Thus, the prevalence of QT interval prolongation in our
study population was 12 of 84 subjects (14%) using the standards of Simonson et al.29 and ten of 84 subjects (12%) using
the standards of Ashman and Hull.26' 27 The prevalence of
QT interval prolongation, using either standard, differed
significantly (P < 0.001) from that expected (2.5%) when the
97.5 percentile is employed as the upper limit of normal.
Subjects with QT interval prolongation did not differ
significantly in age from subjects with normal QT intervals.
Two of the subjects with QT interval prolongation had
other electrocardiographic abnormalities, including one subject with left anterior hemiblock and nonspecific STsegment and T-wave abnormalities and one with nonspecific
ST-segment and T-wave abnormalities. Electrocardiograms with QT interval prolongation showed normal sinus
rhythm without frequent premature beats or other arrhythmias. In no tracing were T waves abnormally peaked; electrical alternation of the T wave37 was not present. One
member of three other parental sets (in which QT interval
was not prolonged) showed electrocardiographic abnormalities, including one with left anterior hemiblock, one
42i
#QT
ST-T
*QT
LAH
NL.
1°AVB
with first degree atrioventricular block, and one with nonspecific ST-segment and T-wave abnormalities. The electrocardiographic findings in the 42 sets of parents who had infants with SIDS are summarized in figure 2.
To investigate further the possible genetic transmission of
prolonged QT interval, electrocardiograms were performed
in 23 siblings of infants with SIDS; these siblings were
members of eight families in which one parent had a
prolonged QT interval. Electrocardiograms showed
relatively mild QT interval prolongation in nine (39%) of the
23 siblings using the normal standards of McCammon28 for
comparison (fig. 3). Maximal QT, in these nine children
ranged from 0.43 to 0.48 sec (mean 0.45). Children with
prolonged QT interval were found in six of the eight families
studied. When the normal standards of Fraser et al.30 3
were used for comparison, eight children showed a
prolonged QT interval, including six children who were abnormal by McCammon's criteria and two children in whom
the QT interval was at the upper limits of normal compared
to the standards of McCammon.28 When the normal standards of Alimurung et al.32 were used, two children showed
prolonged QT interval; both of these children also had
prolonged QT interval by the criteria of McCammon28 or
Fraser et al.30 '3 The electrocardiograms of children with
prolonged QT interval showed normal sinus rhythm without
marked sinus arrhythmia, premature beats, or other
arrhythmias. In no tracing were the T waves abnormally
2
SETS OF PARENTS
Abn.
ST-T
VOL 54, No 3, SEPTEMBER 1976
CIRCULATION
ECG
#QT
D
C
E
Q
NORMAL
AFFECTED
LAH
ST-T
FIGURE 2. Diagram summarizing electrocardiographic data in 42
sets of parents who had infants with SIDS. Abn = abnormal;
NL = normal; ST-T = nonspecific ST-segment and T- wave abnormalities; tQT = prolongation of QT interval; LAH = left anterior
hemiblock; 1° A VB =first degree atrioventricular block. Numbers
in circles refer to parental sets in which at least one member had an
electrocardiographic abnormality.
DEAD OF SIDS
t
FIGURE 3. Two family diagrams showing distribution of affected
(prolonged QT interval) and unaffected (normal QT interval)
members. In the family diagram in the bottom panel, offspring 3
with prolonged QT interval and ofspring 4 with SIDS arefraternal
twins. Age (in years) ofeach subject is shown in parentheses; longest
QT, for children and average QT, for adults are shown under the
age.
<> ^k _LwvR =.50
QT INTERVAL IN SIDS/Maron, Clark, Goldstein, Epstein
peaked or markedly inverted. Each electrocardiogram performed on 18 siblings of infants with SIDS from seven
families in which neither parent had prolonged QT interval
showed normal QT interval. The difference in the prevalence
of prolonged QT interval in the siblings from families with
an affected parent (9 of 23) compared to the prevalence of
prolonged QT interval in siblings from families without
affected parents (O of 18) was significant (P < 0.01). QT interval data in siblings of infants with SIDS are summarized
in table 2.
None of the adults or children studied had overt clinical
evidence of a hearing deficit, nor was a family history of
deafness present in other members of their families. In 37 of
the 42 families studied no parent or child (other than the infants who were the index cases in this study) had experienced
0 7c 57
RRt_
c.5
3/14/73
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3/16/73-_ _ 1____t_ LI:-I
OTc =. 55
RR=. 51
OTC= . 50
RR= .44
i':..'...--
3 /197/ 7 3 il
- - a'1da11
ll
427
TABLE 2. Prevalence of QT Interval Prolongation in Siblings
of Infants with SIDS
Normal standards used
Parental QT
interval
A) Prolonged*
(8 families)
B) Normalt
(7 families)
McCammon2s
9/23
(39%)
0/18
P < 0.01
(A vs B)
Fraser et al.30 ,31
Alimurung
et al.32
8/23
(35%)
0/18
2/23
(9%)
0/18
P < 0.025
(A vs B)
P > 0.05
(A vs B)
*Refers to prolonged QT interval in at least one member of the parental
set.
tRefers to normal QT interval in both members of the parental set.
syncope or sudden death. In two families (including one in
which QT interval prolongation was present) one sibling of
the index case had documented SIDS. In three other
families (including two in which QT interval prolongation
was present) an infant who was a cousin of the index case
died suddenly and unexpectedly (necropsy examination was
not performed).
"Near-miss" SIDS
Electrocardiograms from the infant with "near-miss"
SIDS showed marked prolongation of the QT interval
following a cardiorespiratory arrest with ECG documented
asystole at 7 weeks of age (fig. 4); the electrocardiograms
were otherwise normal (fig. 5). There was no clinical
evidence of heart disease and the patient was not given
medications known to prolong the QT interval. The parents
of this infant had normal QT intervals (mother's maximal
QT, = 0.41 sec; father's maximal QT, = 0.38 sec); a mildly
OTC =.5/
ilt;
RR = .59
QTC= .52
RR =.56
6/1 73
0Q =.50
:'
RR = . 44
(longest QT1
1/22/75
-~
_
~ ..I
.ft i,
_
_|_r-Iu
_ :z
_
_
OTc=.46
fant wit
standard
1in
lead II
_
0.53second).
VI
V2
V3
4"nearmis
1.
SID fou day afe
il0.;3.
'Z, .38
34.t s*Ii
cardiorespira|''
tory
RR =
.43
e~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
arrst Train isnraxetfrpoog tionofthe Tin-tera
FIGURE 4. Serial electrocardiographic tracings (standard lead HI)
from infant with "near-miss" SIDS. Cardiorespiratory arrest occurred on 3-12-73 (7 weeks of age). Five tracings at the top were
taken during the subsequent hospitalization. The two tracings at the
bottom (6-1-73 and 1-22-75) were taken during outpatient
evaluations at four months and two years of age, respectively. Electrocardiographic tracings were retouched for enhanced clarity.
V4
V5
v6
FIGURE 5. Standard 12 lead electrocardiogram recorded in the infant with "near-miss" SIDS four days after cardiorespiratory
arrest. Tracing is normal except forprolongation of the Q T interval
(longest QT, in standard lead II = 0.53 second).
CIRCULATION
428
prolonged QT interval (maximal QT, 0.45 sec) was present in only one of 18 family members surveyed, a 10-monthold nephew of the infant. Because of the unique aspects of
this case, the clinical features are described.
=
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This female child was the product of a full-term pregnancy complicated by premature rupture of the membranes. Delivery was uncomplicated and the birth weight was 7 lbs. 1 oz. The infant was examined by her pediatrician at six weeks of age and was thought to be
in good health. One week later the child was sleeping in a sitting
position (in an infant seat) when she was noted by her parents to
make a "throaty noise" followed by several inspiratory gasps. The
child was initially rigid but soon became limp. Her color became
ashen gray. At this time, the parents noted that the infant was not
breathing and attempted to revive her by mouth-to-mouth resuscitation and external cardiac massage. The infant was taken by ambulance and reached the local hospital emergency room in about 30
minutes. At this time, she was apneic and there were no audible
heart sounds. An electrocardiogram revealed asystole. Emergency
measures were instituted immediately, including intracardiac epinephrine and intravenous sodium bicarbonate, atropine, lidocaine
and isuprel. These therapeutic measures produced ventricular fibrillation within a few minutes. Electrical DC defibrillation restored
normal sinus rhythm.
Cardiovascular examination performed two hours after admission with the patient in relatively stable condition showed blood
pressure 105/60 mm Hg, heart rate 150/min, respiratory rate
60/min and temperature 99°. Lung fields were clear to auscultation. First and second heart sounds were normal; no murmurs were
audible. There was no evidence of congestive heart failure.
Normal results were obtained from the following laboratory
studies: white blood cell count, serum calcium, sodium, chloride,
blood urea nitrogen and glucose. Serum potassium ranged from 4.0
to 5.5 mEq/L (normal 3.5 to 5.3 mEq/L) on seven different determinations. Lumbar puncture was performed; analysis of the
cerebrospinal fluid showed no abnormalities. Urinalysis was normal. Chest radiograph showed a normal heart size, normal
pulmonaryvascular markings and a mild right perihilar infiltrate.
Cultures of cerebrospinal fluid, blood, throat and nasopharynx
showed no growth of organisms.
Representative electrocardiographic tracings of standard lead II
obtained during the hospitalization and the period of follow-up are
shown in figure 4. Maximal QTc ranged from 0.50 to 0.57 second
during the period of hospitalization; a trend toward diminishing QT
interval with time was apparent. In each instance the QT interval
was markedly prolonged compared to normal standards.28 30-32 The
heart rate during hospitalization ranged from 90 to 160 beats/min
(normal range 115 to 180). We cannot exclude the possibility that
the prolonged QT interval present in this infant was an effect rather
than a cause of the cardiac arrest, since little is known of the effect
of cardiac arrest on QT interval. However, an electrocardiogram
performed at a follow-up examination at 4 months of age (over two
months after the cardiac arrest) (fig. 4) showed persistent prolongation of the QT interval (longest QT, 0.50 second). Furthermore,
none of the electrocardiograms recorded in this infant showed
evidence of myocardial ischemia or injury. The patient has
remained in good health, exhibited normal developmental landmarks, and has had no overt clinical evidence of a hearing deficit. At
2 years of age she was evaluated at the National Heart and Lung
Institute. An echocardiogram was normal with the ventricular septum and posterobasal left ventricular wall each 5 mm in thickness.
Electrocardiogram (fig. 4) showed a QT interval at the upper limits
of normal. Physical examination was normal. There is no family
history of sudden death, syncope or deafness in the family.
=
=
Discussion
The results of this study suggest that a considerable
proportion of first degree relatives of infants with SIDS have
prolongation of the QT interval on electrocardiogram.
Prolonged QT interval syndrome"'-",12
39
is
an inherit-
able condition that is manifested by cardiac arrhythmias,
syncopal spells and sudden death (in addition to an abnor-
VOL 54, No 3, SEPTEMBER 1976
mally long QT interval on electrocardiogram). When
prolonged QT interval syndrome is associated with congenital bilateral high frequency deafness it is apparently
transmitted as an autosomal recessive trait and is known as
Jervell and Lange-Nielson syndrome;38 when not associated
with deafness prolonged QT interval syndrome is
transmitted as an autosomal dominant trait and is referred
to as Romano-Ward syndrome.14 22 The syncopal spells
(and presumably sudden death) in prolonged QT interval
syndrome are due to arrhythmias (i.e., asystole, ventricular
fibrillation or ventricular tachycardia)'8 17, 40 that are
probably initiated by premature beats arriving during the
lengthened vulnerable period of electrical recovery.17 41. 42
Most reported sudden deaths in patients with prolonged QT
interval syndrome occurred in older children or adults;
however, several infants from families with this condition
have been reported to die suddenly or experience their initial
episode of syncope during the first year of life (i.e., in the
SIDS age group).'4 21 Other authors have noted an association of sudden death and prolonged QT interval syndrome in
infancy and have postulated a pathogenic link between
SIDS and prolonged QT interval syndrome.43-45
Our finding that relatively mild QT interval prolongation
is present in parents and siblings of infants with SIDS
suggests a relation to the Romano-Ward type of prolonged
QT interval syndrome. It should be emphasized, however,
that major differences exist between families with infants dying of SIDS and those with Romano-Ward syndrome: 1) unlike families with Romano-Ward syndrome, those with
SIDS rarely have members (other than the infant with
SIDS) who experience syncopal episodes or sudden death;
and 2) the magnitude of QT interval prolongation present in
asymptomatic first degree relatives of infants with SIDS, as
demonstrated in this study, was less than that reported for
asymptomatic relatives of patients with Romano-Ward syndrome in some studies.23 24 However, other studies of the
Romano-Ward syndrome have shown that asymptomatic
relatives have mild QT interval prolongation'2' 46,47 similar
to the values we observed in the relatives of infants with
SIDS.
It has been suggested that the QT interval is normally
lengthened in infants during sleep.36 However, all electrocardiograms that we obtained in adults, children, and the
'near-miss" infant were recorded inthe waking state. This
excludes the possibility that the QT interval prolongation
reported in this study was due to the sleeping state.
There are obvious interpretative uncertainties in linking
the relatively mild prolongation of the QT interval present in
first degree relatives of certain infants with SIDS demonstrated in this study to the mechanism responsible for the infant's death. Obviously, definitive evidence that these conditions are linked requires data obtained directly from the
infants during life. However, since infants with SIDS are invariably considered to be healthy prior to their death, electrocardiograms are almost never obtained in these babies.
In this regard, our finding of marked prolongation of the
QT interval in an infant with "near-miss" SIDS is confirmatory data that an association between SIDS and
prolonged QT interval may exist in some infants. Indeed had
this patient died, she most certainly would have been considered an example of SIDS. The absence of QT interval
QT INTERVAL IN SIDS/Maron, Clark, Goldstein, Epstein
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prolongation in most members of this infant's family
suggests that either the genetic penetrance of QT interval
prolongation in this family was incomplete or that the
"near-miss" infant demonstrates a nongenetic form of QT
interval prolongation. Indeed, there have been reports of
families in which one member demonstrated typical QT syndrome, but all other family members were asymptomatic
and had normal QT intervals.'2 43
Nevertheless, prospective studies in which electrocardiograms can be obtained in large numbers of apparently normal newborns will be necessary to confirm a causal relation
between prolonged QT interval and SIDS. Furthermore, it
should be emphasized that it is likely that SIDS is not a
single clinicopathologic entity and that several etiologic
mechanisms (in addition to prolonged QT interval) may be
capable of inducing sudden death during this particularly
vulnerable period of infancy.
If prolonged QT interval is an important factor in SIDS,
it may operate in the following ways: 1) the abnormally long
QT interval may be a primary mechanism causing death in
infants with SIDS in much the same way that it does in
patients with prolonged QT interval syndrome (i.e.,
presumably by predisposing to ventricular arrhythmias); 2)
prolonged QT interval may convey susceptibility to ventricular arrhythmias or sudden death that is ultimately triggered
by an environmental factor (e.g., respiratory infection); 3)
prolonged QT interval may be a secondary manifestation of
a primary central nervous system abnormality.
It has been demonstrated that the QT interval lengthens in
certain cerebral disorders.48' 49 Furthermore, the intimate
relation of the sympathetic nervous system and the QT inter-
val is well known.'2',13 37,44, 50, 5 Stimulation of the left
stellate ganglion or ablation of the right stellate ganglion in
dogs produces prolongation of the QT interval,50 and cooling
or ablation of the right stellate ganglion in dogs lowers the
ventricular fibrillation threshold."2 The fact that syncopal
spells in patients with prolonged QT interval syndrome often
are
precipitated by excitement, fright
or
physical exertion
suggests that in those patients and conceivably in certain in-
fants with SIDS (who may have QT interval prolongation)
ventricular arrhythmias may be induced by sudden sympathetic neural stimulation of the myocardium.4
The analysis of our data is based on the assumption that
clear distinctions can be made between normal and abnormal QT intervals. However, it should be emphasized that
certain difficulties are associated with measurement and interpretation of the QT interval. In both normal subjects and
patients with prolonged QT interval syndrome, the QT interval is relatively labile,"' 23, 28, 53 tends to decrease with age,
and appears to be influenced by central nervous and sympathetic neural activity. In addition, the difficulties in exact
determination of the beginning and end of the QT interval in
a given complex are well recognized.33 Therefore, although
the results of this study suggest a role for prolonged QT interval in some instances of SIDS, our conclusions regarding
the importance of this association should be considered with
these reservations in mind.
In conclusion, we have found that a considerable number
of first degree relatives of infants with SIDS, as well as an
infant with "near-miss" SIDS, showed prolonged QT interval on electrocardiogram. Although our results are not
429
definitive, they do suggest that cardiac mechanisms related
to prolonged QT interval syndrome are causally related to a
substantial number of sudden and unexplained infant deaths.
Most importantly, these data suggest a potentially important area for future prospective investigations.
Acknowledgments
We wish to acknowledge the fine technical assistance of Ms. Cora Burn,
R.N., and Mrs. Joyce McKay, R.N. We are particularly indebted to the
assistance provided by the International Guild for Infant Survival, Sylvia and
Saul Goldberg, and the many parents of infants with SIDS who volunteered
their time. We also appreciate the assistance of Mrs. Mary Lou Climpson in
typing the manuscript.
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VOL 54, No 3, SEPTEMBER 1976
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Paroxysmal Supraventricular Tachycardia
Is
the Atrium
a
MARK E. JOSEPHSON, M.D.,
Necessary Link?
AND
JOHN A. KASTOR, M.D.
SUMMARY Whether or not the atrium plays an essential role in
initiating and/or sustaining atrioventricular (A-V) nodal re-entrant
tachycardia was evaluated in eight patients. In all eight patients, the
atrium could be rendered refractory to retrograde atriai echoes during the tachycardia without interrupting the arrhythmia. This was accomplished by introducing atrial premature depolarizations prior to
the time the atrium would normally be retrogradely depolarized by
atrial echoes. In one patient, two atrial premature depolarizations
could be introduced, producing A-V dissociation, without termatig
the tachycardia. In another patient, the tachycardia could be initiated
without an atrial echo.
Our data suggest that most, if not all of the atrium is unnecessary
for the initiation and maintenance of A-V nodal re-entrant supraventricular tachycardia.
MOST CASES of paroxysmal supraventricular tachycardia are initiated and sustained through re-entry within
the atrioventricular (A-V) node.' Whether or not the atria
form a portion of the re-entrant pathway remains unsettled.
The present investigation of eight patients demonstrated
that in each case no portion of the atrium recorded by our
electrode catheters was required to sustain A-V nodal re-
entrant supraventricular tachycardia and in one the atrium
did not play an essential role in initiating the arrhythmia.
From the Cardiac Clinical Electrophysiology Laboratory, Hospital of the
University of Pennsylvania; the Cardiovascular Section, Department of
Medicine, University of Pennsylvania School of Medicine, Philadelphia,
Pennsylvania.
Presented at the 25th Annual Scientific Session of the American College of
Cardiology, February 24, 1976, New Orleans, Louisiana.
Supported in part by grants from the USPHS, NIH, HL 14807, and the
American Heart Association, Southeastern Pennsylvania Affiliate.
Address for reprints: Dr. Mark E. Josephson, Director, Electrophysiology
Laboratories, 669 White Building, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, Pennsylvania 19104.
Received March 5, 1975; revision accepted March 29, 1976.
Methods, Materials, and Clinical Patient Information
Eight patients were studied in the nonsedated postabsorptive state after informed consent was obtained (table
1). All had symptomatic supraventricular tachycardia
(SVT), and none demonstrated evidence of pre-excitation.
No patient was taking antiarrhythmic drugs at the time of
the study.
A quadripolar electrode catheter was introduced percutaneously into an antecubital and/or femoral vein and
positioned under fluoroscopic control against the lateral wall
of the high right atrium and/or the coronary sinus. The
proximal pair of electrodes was used to record a high right
atrial or coronary sinus electrogram, while the distal pair
was used for atrial stimulation. A bipolar electrode catheter
Potential role of QT interval prolongation in sudden infant death syndrome.
B J Maron, C E Clark, R E Goldstein and S E Epstein
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Circulation. 1976;54:423-430
doi: 10.1161/01.CIR.54.3.423
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1976 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
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