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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
SINUS NODE IN SIDS/Kozakewich et al.days later.) The control group of 18 infants had anequal sex distribution and ranged in age from 1 day to18 months. In the control group, two patients had dis-seminated infection, probably viral; two had epi-dermolysis bullosa; two had multiple congenitalanomalies; and one patient each had meningitis, acutebronchiolitis, aspiration pneumonitis, bronchopul-monary dysplasia, purpura fulminans, hemophilia,Wilms' tumor, hepatoblastoma, infantile polycysticrenal disease, trauma, propionic acidemia andZellwegger's syndrome.At autopsy, in all cases except one, the heart wasfixed in 10% buffered formalin. The entire superiorvena cava-right atrial junction was removed as a ringof tissue 2.5 cm in height. At the time of paraffinembedding, the tissue ring was collapsed in an antero-posterior plane to provide a relatively thin rectangulartissue block which was serially sectioned at 10 A.Forty-five cases were sectioned in the sagittal planeand two in the horizontal plane. All sections wereretained and every fiftieth and adjacent sectionsstained with hematoxylin-eosin. After localization ofthe SN, all adjacent sections of the complete SN werestained with hematoxylin-eosin and modified Movat'spentachrome.8 Sections in selected cases were sub-mitted for periodic acid-Schiff and reticulin stains. Inone SIDS case, the tissue block was removed from thefresh heart, quick-frozen, and 10-A cryostat sectionswere cut at different levels, primarily for histochem-ical demonstration of cholinesterase.?The maximum width (diameter) of the SN in aplane perpendicular to the endocardial surface of thesuperior 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 theSN were measured. The ratio of internal to externaldiameter of the SN artery (ID: ED) was calculatedand plotted vs age. The coordinates of all measure-ments were subjected to linear regression analysis forSIDS and controls separately.ResultsThe SN in all cases was situated subepicardiallyanterolaterally at the superior vena cava-right atrialjunction in the sulcus terminalis (fig. 1). The centrallyplaced artery was surrounded by a prominent col-lagenous collar, in contrast to the sparse collage-nous framework in the remainder of the SN. Thenodal cells formed a woven network with occasionalfibers extending to the media of the SN artery. Thetransitional fibers at the periphery of the node wereenlarged and blended with the adjacent atrialmusculature. A few lymphocytes, disposed around theganglia and within the epicardial fat, were common inboth groups.The maximum width of the SN was similar in bothgroups (fig. 2), with no statistically significantdifference 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 itsmedial two-thirds sectioned in a horizontal plane. The SNartery 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 SIDSgroup. In the control group, the SN was involvedtwice as a part of a generalized myocarditis, presum-ably viral, and once by extension of a fibrinopurulentpericarditis.The SN artery in the SIDS group entered the SNlaterally in 21 instances and medially in nine, notdiffering significantly from the control group with cor-responding frequencies of 13 and five, respectively.There was a moderate variation in SN artery size inboth groups.1.6 r1.4 FE 1 [= E '-'-:,%.3 o 1.0E v 0.8._ _2 G.- 0.6a* *@- ** U4* * 0- *04 --*-- -_ .em mmaa-- SIDS--- * ControlI I I J21r0.4 _0.21-0 I40 3 6 9 12 15 18Age (months)FIGURE 2. Maximum width ofsinus node related to age insudden infant death syndrome (SIDS) and control infantswith regression lines.------SsS-S1243Downloaded from http://ahajournals.org by on June 21, 2022VOL 65, No 6, JUNE 1982Intimal thickenings in the intranodal SN artery,similar to those in the main coronary arteries of mostinfants,'0 were present in approximately three-fourthsof SIDS and control infants and were even more fre-quent in its extranodal segment. These intimal thick-enings were primarily musculoelastic membranesassociated with a discontinuous internal elastic laminaand were of minor degree (figs. 3D and 4B).In three SIDS cases, almost the entire intranodalcourse of the artery was involved (narrowed) by in-timal lesions within the spectrum of those commonlyobserved in main coronary arteries of infants. Figures3A and 3B depict the SN artery of two SIDS infantswith lumina constricted by intimal hyperplasia ofsmooth muscle and elastic fibers. Little internal elasticlamina remained and the innermost intima displayededema with a moderate amount of acid mucopoly-saccharides on Movat's stain. In the third SIDS infant(fig. 3C), the intima was markedly expanded byground substance staining weakly for acid mucopoly-saccharides. In these three infants the luminal cross-sectional area was reduced by 85%, 65%, and 63%,!4respectively. One control infant had prominent mus-culofibroelastic intimal cushions (fig. 4A).The SN artery ID:ED ratios had a wide range inSIDS and control infants (fig. 5) reflecting primarilythe variable size of the artery. There was no statistical-ly significant difference between the regression linesfor the two groups (p < 0.05). In the three SIDS andsingle control infants with major (prominent) SNarterial narrowing, the I: ED ratios exceeded 2 stan-dard deviations from the means.Histochemical cholinesterase staining of the SN inone SIDS infant revealed strong positivity in nodalcells, autonomic ganglia and nerves and weakerpositivity in atrial muscle. The results are similar tothose observed in our laboratory in infants who diefrom other causes (not included in this study). Similarresults have been described by Anderson in the SN ofSIDS and controls quoted by Lie et al.7 and by Jamesand Spence in the adult SN."No unusual pre- or postnatal events were recordedfor the three SIDS infants with marked intimal lesionsof the SN artery. The infant whose SN artery is shown* e-'~e5iFIGURE 3. Intimal lesions in the sinus node (SN) artery offour infants who died with sudden infant deathsyndrome (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, X110; 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 ofmostSIDS 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 infantswith intimal cushions. (A) Longitudinal section ofSN arterywith the most prominent intimal musculofibroelastic cush-ions observed in the control group. Movat stain; magnifi-cation X 110. (B) More typical, low-profile musculoelasticintimal cushions observed in SN artery of most control in-fants. Movat stain; magnification X 110.in figure 3B was initially resuscitated but died 6 hourslater. ECGs during this period showed irregular sinusrhythm, elevated ST segments, inverted T waves, anda corrected QT interval not exceeding 0.42 second.Intermittent episodes of ventricular tachycardia wereof the torsade de pointes variety. All three infants (twofemales and one male) had focal intimal thickening inthe main coronary arteries and in the aorta and itslarge abdominal branches, but not greater than usualfor infants at these sites. Increased muscularity of thepulmonary arterial circulation, as has been describedin most SIDS victims,'2 was present in the two others.One of the three infants did not have thoracic visceralpetechiae.The control infant with marked intimal thickeningin her SN artery had hypoplasia of multiple cranialnerves and diaphragmatic paralysis, necessitating con-tinuous mechanical ventilatory support. She suffereda fatal cardiac arrest at 7 months of age. The pul-monary arteries exhibited medial hypertrophy, but noperipheral extension of muscle was present. Intimalthickenings in the coronary arteries and the aorta andits abdominal branches were not greater than usual forinfants at these sites.DiscussionThe SN in SIDS has been described as structurallynormal in previous reports, although vicinal petechiaehave been common.' 7 In the present study the SNwas normal in location, size and organization. Pete-chiae were present in 20% of SIDS and 17% of controlinfants 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 inSN arteries were common among both SIDS and con-trol infants in this study. In four infants, three SIDSand one control, intimal lesions narrowed the luminalcross-sectional area of the SN artery by 63-83%. Thelesions were more than focal, involving most of the in-tranodal course of the artery, and differed in quality:Three involved musculofibroelastic hyperplasia andone 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 froma steep pulse wave, prominent pulsation from lack ofadjacent soft tissue support, and tethering at origins oflarge branches.'3 Occasionally, the intimal thicken-ings appear excessive.'0 The reasons for the excessiveintimal thickenings in the SN arteries of the abovefour infants is unknown. Hemodynamic stress,whether mediated by autonomic imbalance or not,might cause such arterial changes. Cardiac autonomicimbalance has been a leading hypothesis as a sub-strate for SIDS.", 1' An abnormality of the autonomicsystem could well have been present in addition tohypoplasia of multiple cranial nerves in the control in-fant.The significance of the SN arterial narrowing in the* 0)t t* wz Z(o00 *E EX IXI-be XC x_ w0F:IC0.90.80.70.60.50.40.30.20.10 *.--- SIDS---in Control0 2 4 6 8 10 12 14 16 18AGE (months)FIGURE 5. The ratio of internal to external diameter oftheSN 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
