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https://www.ahajournals.org/doi/pdf/10.1161/01.CIR.65.6.1242
VOL 65, No 6, JUNE 1982
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The Sinus Node in Sudden Infant
Death Syndrome
HARRY P. W. KOZAKEWICH, M.D., BRUCE M. MCMANUS, M.D., PH.D.,
AND GORDON F. VAWTER, M.D.
SUMMARY The sinus node (SN) was examined histologically in 30 infants diagnosed with sudded infant
death syndrome (SIDS) and in 18 age-matched controls who died of known causes. Location, size and
organization of the SN did not differ significantly in the two groups. Petechiae involved the SN region in 20%
of SIDS and 17% of control infants and probably do not represent a primary event. In three SIDS infants
(10%), intimal lesions reduced the lumen of the intranodal SN artery by 63-83% in cross-sectional area. These
resembled the intimal thickenings frequently observed in main epicardial coronary arteries of infants. Whether
the vascular alterations in these three cases had adverse effects upon SN function is unknown.
THE PRIMARY CAUSES of the vast majority of
sudden unexpected deaths in infancy (SIDS) remain
unknown. Sudden cessation of some vital physiologic
function, such as respiratory or cardiac arrest, con-
tinues to be a major hypothesis.'
Studies of the cardiac conduction system in SIDS
are usually directed to the atrioventricular node and
His bundle.2-7 The sinus node (SN) in SIDS has been
described as anatomically normal.2 6 7 Small hemor-
rhages have been common in atrial musculature and
perinodal autonomic ganglia, occasionally occurring
From the Department of Pathology, Children's Hospital Medical
Center and Harvard Medical School, Boston, Massachusetts.
Presented at the International Academy of Pathology meeting,
March 1981, Chicago.
Address for correspondence: Harry P. W. Kozakewich, M.D.,
Department of Pathology, Children's Hospital Medical Center, 300
Longwood Avenue, Boston, Massachusetts 02115.
Received August 20, 1981; accepted September 21, 1981.
Circulation 65, No. 6, 1982.
within the SN itself.2-5 7 Similar hemorrhages are
equally common in controls. James noted degenera-
tive changes in the perinodal autonomic ganglia
associated with the hemorrhages.2
We examined one infant with a documented con-
duction disturbance who died unexpectedly without
demonstrated cause and who had an atrioventricular
bypass tract. This experience and the disparate find-
ings in the literature prompted a new analysis of the
cardiac conduction system in SIDS victims. Studies of
the SN are reported here.
Materials aild Methods
The SN was examined histologically in 30 SIDS
victims and 18 age-matched controls at Children's
Hospital Medical Center, Boston, who died from
1975-1980. SIDS was defined by sudden and unex-
plained death in a previously healthy infant younger
than 18 monthis of age. (Two SIDS infants were ini-
tially resuscitated, but one died 6 hours and the other 4
1242 CIRCULATIONDownloaded from http://ahajournals.org by on June 21, 2022
days later.) The control group of 18 infants had an
equal sex distribution and ranged in age from 1 day to
18 months. In the control group, two patients had dis-
seminated infection, probably viral; two had epi-
dermolysis bullosa; two had multiple congenital
anomalies; and one patient each had meningitis, acute
bronchiolitis, aspiration pneumonitis, bronchopul-
monary dysplasia, purpura fulminans, hemophilia,
Wilms' tumor, hepatoblastoma, infantile polycystic
renal disease, trauma, propionic acidemia and
Zellwegger's syndrome.
At autopsy, in all cases except one, the heart was
fixed in 10% buffered formalin. The entire superior
vena cava-right atrial junction was removed as a ring
of tissue 2.5 cm in height. At the time of paraffin
embedding, the tissue ring was collapsed in an antero-
posterior plane to provide a relatively thin rectangular
tissue block which was serially sectioned at 10 A.
Forty-five cases were sectioned in the sagittal plane
and two in the horizontal plane. All sections were
retained and every fiftieth and adjacent sections
stained with hematoxylin-eosin. After localization of
the SN, all adjacent sections of the complete SN were
stained with hematoxylin-eosin and modified Movat's
pentachrome.8 Sections in selected cases were sub-
mitted for periodic acid-Schiff and reticulin stains. In
one SIDS case, the tissue block was removed from the
fresh heart, quick-frozen, and 10-A cryostat sections
were cut at different levels, primarily for histochem-
ical demonstration of cholinesterase.?
The maximum width (diameter) of the SN in a
plane perpendicular to the endocardial surface of the
superior vena cava was measured by ocular microm-
etry and plotted vs age. The internal and external di-
ameters of the SN artery within the midsegment of the
SN were measured. The ratio of internal to external
diameter of the SN artery (ID: ED) was calculated
and plotted vs age. The coordinates of all measure-
ments were subjected to linear regression analysis for
SIDS and controls separately.
Results
The SN in all cases was situated subepicardially
anterolaterally at the superior vena cava-right atrial
junction in the sulcus terminalis (fig. 1). The centrally
placed artery was surrounded by a prominent col-
lagenous collar, in contrast to the sparse collage-
nous framework in the remainder of the SN. The
nodal cells formed a woven network with occasional
fibers extending to the media of the SN artery. The
transitional fibers at the periphery of the node were
enlarged and blended with the adjacent atrial
musculature. A few lymphocytes, disposed around the
ganglia and within the epicardial fat, were common in
both groups.
The maximum width of the SN was similar in both
groups (fig. 2), with no statistically significant
difference between the respective regression lines (p <
0.05).
Petechial hemorrhages occurred in six SIDS cases
(20%) (perinodally in five and intranodally in one),
and perinodally in three controls (17%7n). No necrosis,
FIGURE 1. The sinus node (SN) (interrupted line) in its
medial two-thirds sectioned in a horizontal plane. The SN
artery is centrally placed. RAA = right atrial appendage;
SVC = superior vena cava. Movat stain; magnification X 2.
nodal cell degeneration, replacement fibrosis or hemo-
siderin deposits were observed in the SN in the SIDS
group. In the control group, the SN was involved
twice as a part of a generalized myocarditis, presum-
ably viral, and once by extension of a fibrinopurulent
pericarditis.
The SN artery in the SIDS group entered the SN
laterally in 21 instances and medially in nine, not
differing significantly from the control group with cor-
responding frequencies of 13 and five, respectively.
There was a moderate variation in SN artery size in
both groups.
1.6 r
1.4 F
E 1 [
= E '-'
-
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3 o 1.0
E v 0.8._ _
2 G.- 0.6
a
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- ** U
4* * 0
- *
04 --*
-
- -
_ .
em mma
a
-- SIDS
--- * Control
I I I J
21
r
0.4 _
0.21-
0 I4
0 3 6 9 12 15 18
Age (months)
FIGURE 2. Maximum width ofsinus node related to age in
sudden infant death syndrome (SIDS) and control infants
with regression lines.
------SsS-S1243Downloaded from http://ahajournals.org by on June 21, 2022VOL 65, No 6, JUNE 1982
Intimal thickenings in the intranodal SN artery,
similar to those in the main coronary arteries of most
infants,'0 were present in approximately three-fourths
of SIDS and control infants and were even more fre-
quent in its extranodal segment. These intimal thick-
enings were primarily musculoelastic membranes
associated with a discontinuous internal elastic lamina
and were of minor degree (figs. 3D and 4B).
In three SIDS cases, almost the entire intranodal
course of the artery was involved (narrowed) by in-
timal lesions within the spectrum of those commonly
observed in main coronary arteries of infants. Figures
3A and 3B depict the SN artery of two SIDS infants
with lumina constricted by intimal hyperplasia of
smooth muscle and elastic fibers. Little internal elastic
lamina remained and the innermost intima displayed
edema with a moderate amount of acid mucopoly-
saccharides on Movat's stain. In the third SIDS infant
(fig. 3C), the intima was markedly expanded by
ground substance staining weakly for acid mucopoly-
saccharides. In these three infants the luminal cross-
sectional area was reduced by 85%, 65%, and 63%,
!4
respectively. One control infant had prominent mus-
culofibroelastic intimal cushions (fig. 4A).
The SN artery ID:ED ratios had a wide range in
SIDS and control infants (fig. 5) reflecting primarily
the variable size of the artery. There was no statistical-
ly significant difference between the regression lines
for the two groups (p < 0.05). In the three SIDS and
single control infants with major (prominent) SN
arterial narrowing, the I: ED ratios exceeded 2 stan-
dard deviations from the means.
Histochemical cholinesterase staining of the SN in
one SIDS infant revealed strong positivity in nodal
cells, autonomic ganglia and nerves and weaker
positivity in atrial muscle. The results are similar to
those observed in our laboratory in infants who die
from other causes (not included in this study). Similar
results have been described by Anderson in the SN of
SIDS and controls quoted by Lie et al.7 and by James
and Spence in the adult SN."
No unusual pre- or postnatal events were recorded
for the three SIDS infants with marked intimal lesions
of the SN artery. The infant whose SN artery is shown
* e-'~e5i
FIGURE 3. Intimal lesions in the sinus node (SN) artery offour infants who died with sudden infant death
syndrome (SIDS). (A and B) Intimal hyperplasia of smooth muscle, elastic fibers and fibroblasts with in-
creased ground substance. Internal elastic lamina is only focally preserved. Movat stain; magnification A, X
110; B, x 160. (C) Intimal expansion by ground substance,fibroblasts and smooth muscle cells. Movat stain;
magnification X 210. (D) Typical low-profile musculoelastic intimal cushions observed in SN artery ofmost
SIDS infants. Movat stain; magnification X 325.
1244 CIRCU LATIONDownloaded from http://ahajournals.org by on June 21, 2022SINUS NODE IN SIDS/Kozakewich et al.
FIGURE 4. Sinus note (SN) artery in two control infants
with intimal cushions. (A) Longitudinal section ofSN artery
with the most prominent intimal musculofibroelastic cush-
ions observed in the control group. Movat stain; magnifi-
cation X 110. (B) More typical, low-profile musculoelastic
intimal cushions observed in SN artery of most control in-
fants. Movat stain; magnification X 110.
in figure 3B was initially resuscitated but died 6 hours
later. ECGs during this period showed irregular sinus
rhythm, elevated ST segments, inverted T waves, and
a corrected QT interval not exceeding 0.42 second.
Intermittent episodes of ventricular tachycardia were
of the torsade de pointes variety. All three infants (two
females and one male) had focal intimal thickening in
the main coronary arteries and in the aorta and its
large abdominal branches, but not greater than usual
for infants at these sites. Increased muscularity of the
pulmonary arterial circulation, as has been described
in most SIDS victims,'2 was present in the two others.
One of the three infants did not have thoracic visceral
petechiae.
The control infant with marked intimal thickening
in her SN artery had hypoplasia of multiple cranial
nerves and diaphragmatic paralysis, necessitating con-
tinuous mechanical ventilatory support. She suffered
a fatal cardiac arrest at 7 months of age. The pul-
monary arteries exhibited medial hypertrophy, but no
peripheral extension of muscle was present. Intimal
thickenings in the coronary arteries and the aorta and
its abdominal branches were not greater than usual for
infants at these sites.
Discussion
The SN in SIDS has been described as structurally
normal in previous reports, although vicinal petechiae
have been common.' 7 In the present study the SN
was normal in location, size and organization. Pete-
chiae were present in 20% of SIDS and 17% of control
infants and probably do not represent a primary event.
Focal thickening of intima is common in the cor-
onary arteries of infants.'0 Similar but mild changes in
SN arteries were common among both SIDS and con-
trol infants in this study. In four infants, three SIDS
and one control, intimal lesions narrowed the luminal
cross-sectional area of the SN artery by 63-83%. The
lesions were more than focal, involving most of the in-
tranodal course of the artery, and differed in quality:
Three involved musculofibroelastic hyperplasia and
one primarily ground substance and edema.
Intimal thickenings in main coronary arteries of in-
fants are considered by some to represent a physio-
logic response to hemodynamic stress, resulting from
a steep pulse wave, prominent pulsation from lack of
adjacent soft tissue support, and tethering at origins of
large branches.'3 Occasionally, the intimal thicken-
ings appear excessive.'0 The reasons for the excessive
intimal thickenings in the SN arteries of the above
four infants is unknown. Hemodynamic stress,
whether mediated by autonomic imbalance or not,
might cause such arterial changes. Cardiac autonomic
imbalance has been a leading hypothesis as a sub-
strate for SIDS.", 1' An abnormality of the autonomic
system could well have been present in addition to
hypoplasia of multiple cranial nerves in the control in-
fant.
The significance of the SN arterial narrowing in the
* 0)
t t
* w
z Z
(o00 *
E E
X IX
I-b
e X
C x
_ w
0
F:
IC
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0 *
.
--- SIDS
---in Control
0 2 4 6 8 10 12 14 16 18
AGE (months)
FIGURE 5. The ratio of internal to external diameter ofthe
SN artery related to age in sudden infant death syndrome
(SIDS) and control infants. SN = sinus node.
1245Downloaded from http://ahajournals.org by on June 21, 2022
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