The American Journal of PATHOLOGY JANUARY 1976
-
VOLUME 82, NUMBER 1
Cardiac and Other Abnormalities in the Sudden Infant Death Syndrome Richard L. Naeye, MD, Philip Whalen, MD, Monique Ryser, MD, and Russell Fisher, MD
'Many victims of the sudden infant death symdrome (SIDS) have abnormally- heav% cardiac right ventricles. The degree of this abnormality is directly proportional to: a) the mass of muscle about small pulmonary arteries, b) the amount of brown fat retention about adrenal glands, and c) the presence of hepatic erythropoiesis. The pulmonary- arterial abnormalit is probably the result of chronic alveolar hy poventilation, while brown fat retention and hepatic erythropoiesis are likely consequences of chronic hypoxemia. These abnormalities are found in both SIDS victims who die with and those who die without mild respiratory tract infections. However, there are some differences between the two SIDS groups. Infected victims die at an older age and have smaller thymus glands and larger spleens; there is a greater proportion of males in the infected victims than in the noninfected victims. (Am J Pathol 82:1-8, 1976)
APNSEIC EPISODES during sleep precede death and may be the mechanism of death in some victims of the sudden infant death svndrome (SIDS) 1.3 In other disorders, such apneic episodes are often associated with chronic underventilation of the lungs with resultant alveolar hvpoxia and systemic arterial hypoxemia.45 Many SIDS victims have anatomic markers of chronic alveolar hvpoxia and hvpoxemia. These include increased muscle in pulmonary arteries, an increased volume of adrenal medullarv chromaffin tissue, an abnormal proliferation of brain stem astroglial fibers, and an abnormal retention of extramedullary erythropoiesis and brown fat.-'0 If the hypoventilation hypothesis is corFrom the Department of Pathology. The \Milton S Hershex Mledical Center. lhe Penns\ladnia State U.niversit\ College of \ledicine. Hershe\. Penns\lvania. and the Office of the Chief Medical Examiner of the State of Mlars land. Baltimore. Mlarnland Supported by Grant HL-14297-0:3 and Contract NOL-HD-4-2517 from the L1S Public Health Service Xccepted for publication September 3. 1975. Address repnrnt requests to Dr Richard Naeve. NMilton S. Hershev Nledical Center. Hershev. PA 1 70:33
2
NAEYE ET AL
American Journal of Pathology
rect, many SIDS victims should also have abnormally heavy cardiac right ventricles, a consequence of the increased pulmonary arterial constriction that is induced by chronic alveolar hypoxia. 11-13 'Te current study measured the weights of the cardiac ventricles in SIDS victims and in controls. The cardiac findings were compared with anatomic markers of hypoventilation and hypoxemia. The study also made an attempt to better define the role of the mild infections so commonly present at death in SIDS victims. Materials and Methods The patients included 45 infants, I to 12 months in age, who were categorized as having died of SIDS when the death was sudden, completely unexpected, and unexplained by anv clinical or postmortem findings. Also included were 40 infants who were placed in the category of SIDS with infection when the infants had bronchopneumonia, tracheobronchitis, larvngitis, or otitis media of too mild a degree to explain death.7 Thirty-three nonhypoxic controls were included in the study. Thev were mostlv victims of accidents, fires, or homicides. They were from 1 to 12 months of age at death (Text-figure 1). None lived longer than 4 hours after the acute event that was responsible for death. In all categories, only infants with well-preserved tissues were included in the studv. Heart and other organ weights were calculated as a proportion of body weight for each case. The resultant values for the heart, brain, liver, spleen, thvmus, kidneys, and adrenals did not change in the controls between 1 and 6 months of age, making possible direct comparisons between SIDS victims and controls within this age span (Table 1). In each heart, the free walls of the two ventricles were dissected from the interventricular septum and separately weighed. These weights were then calculated as a proportion of bodv weight. The resultant values did not change between 1 and 6 months of age in the controls, so direct cornparisons were possible between groups within this age period (Text-figure 1). Ventricular weights and all histologic measurements in the study were made in duplicate by two examiners without either knowing an infant's age or diagnosis. Differences between the duplicate analyses were small. The point counting method of Chalkley was used to quantitate the amount of muscle in pulmonary arteries of 100 g or less diameter.'l The ratio of the area of arterial media to the area of arterial intimal nuclei was used as the measure of arterial muscle mass." A minimum of twenty arteries was measured in each infant, and a mean figure recorded as the value for the case. Extramedullary ervthropoiesis was recorded when nests of erythropoietic cells, including normoblasts, were identified between the cords of hepatic parenchymal cells. Periadrenal brown fat is normally replaced by white fat during the first vear of postnatal life. It has recently been found that brown fat is replaced more slowly than normal in infants who are chronically hypoxemic after birth and in SIDS victims.7'0 In the current study, periadrenal fat cells with a clearly defined cytoplasmic reticular infrastructure were counted as brown cells. The proportion of fat cells that were brown was determined in each case by the point-counting method of Chalkley.7' Nonadipose structures, such as blood vessels and connective tissue, were excluded from the final calculations so that brown cells were represented as a percentage of the total volume of fat cells present. The transfornation of brown to white cells is not normally advanced until after 4 months of age, so only infants a months of age and older were included in the fat analyses.7 .0
Results Relative heart weights were greater in SIDS victims than in the controls (Table 1). Both right and left ventricular weights contributed to this
CARDIAC ABNORMALITIES IN SIDS
Vol. 82, No. 1 January 1976 II
I
1.60
1.40
3
0
00
U
CY)
C
0. 0
_4
U *o
*
00
1.20
Lx -I
C-)
.0
0*
z
L> I-
1.00
:
0 e
Om
*
0
-
00
cr
.80
m
0
*.0 0 00~~~~~~~
o0 ~ 0 0~~~~~~~~~~~ -.
*:0
*
C-
ED
0D
*
*~
.60
7-
0L
0
*
.40
.20
IiI
1
2
3
4
5
6
I
7
8
9
10
11
12
AGE IN MONTHS TEx-T-F IGIRE 1-Relatise cardiac right ventricular seights are greater in mans SIDS sictims than in nonh-poxemic controls. The values in the controls decrease after 6 months of age. (SIDS without infection. opeli squares. SIDS with infection. solid squares, controls, solid circles)
finding, the greater abnormality being on the right (Text-figure 1, Tables
2 and 3). Relative right ventricular weights directly correlated with the amount of medial muscle in the small pulmonary arteries (Text-figure 2). None of the SIDS victims who had a right ventricular weight x 103,//body weight ratio below 1.00 had hepatic erythropoiesis, while 44% of those with values greater than 1.00 had such erythropoiesis (P < .03). Brown
cells constituted 20%' of the periadrenal fat in victims who had right ven-
NAEYE ET AL
4
American Journal of Pathology
Table 1-Relative Organ Weights of Infants Between Ages One and Six Months (mean values t 1 SE)
Organ Brain Heart Liver Spleen Thymus Kidneys
Adrenals
Organ weight/body weight SIDS without infection
Controls .1010 .0033 .0055 .0002 .0348 .0012 .0026 .0002 .0053 .0008 .0072 +.0003 .00058 .00004
.1130 + .0035 .0060 + .0001 $ .0360 + .0010 .0027 .0001 .0052 _ .0002 .0067 +.0002 .00064 + .00005
SIDS with infection .0979 .0050 t .0059 + .0001 $ .0353 +.0010 .0039 .000716 .0042 + .0002 t$ .0065 + .0002 $ .00061 _ .00003
< .01 by comparison with controls. tp < .01 by comparison with SIDS without infection. *P < .05 by comparison with controls. §p < .05 by comparison with SIDS without infection. .P
tncular ratios below 1.00 and 44% in those with ratios greater than 1.00 (P < .0.3).
Kidneys were relatively fighter in SIDS victims than in the controls, while brains were relatively heavy in the SIDS victims who did not have evidence of infection (Table 1). Spleens were relativelv heavier and thymus glands lighter in the SIDS victims who had evidence of infection. SIDS victims who had infections died at an older age, and had a greater proportion of males than did noninfected victims (Table 4). The infected victims had less hepatic erythropoiesis, brown fat, and pulmonanr arterial muscle than did the noninfected victims (Table 4). None of these last three differences were statistically significant. Discussion Alveolar hypoxia increases pulmonarv vascular resistance bv causing small arteries to contract. When the stimulus is sustained, the arteries' Table 2-Relative Weight of the Cardiac (mean 1 SE)
Right Ventricle
in SIDS Victims and in Controls
Right ventricle weight x 103/body weight Age 1-6 months SIDS without infection SIDS with infection Controls Age 7-10 months SIDS without infection SlDSwith infection Controls Number of cases are in parentheses. P < .005 by comparison with controls. t P < .05 by comparison with controls. *
1.03 .04 0.99 .03 0.77 .03 0.86
-
(42) (37) (22)
.08 t (3)
0.95: .12t (3) 0.67
.04
(11)
Vol. 82, No. 1 January 1976
CARDIAC ABNORMALITIES IN SIDS
5
Table 3-Relative Weight of the Cardiac Left Ventricle in SIDS Victims and Controls (mean - 1 SE)
Right ventricle weight X 103/body weight Age 1-6 months
SIDS without infection SIDS with infection Controls Age 7-10 months SIDS without infection SIDS with infection Controls Number of cases are in parentheses. * P < .005 by comparison with controls.
1.50 .05 1.56 .06 1.31 -.04
1.16 .09 1.38 .11 1.22- .09
-
*
(42) (37) (22) (3) (3) (1 1)
medial cells undergo both hvperplasia and hypertrophy, wvith resultant increased weight of the cardiac right ventricle. Many SIDS xictims develop these structural abnormalities without any evidence of chronic pulmonary disease, indicating that they probably had chronic alveolar hypoxia before death. Chronic alveolar hypoxia leads to chronic systemic arterial hypoxemia.6-7'1 The finding that SIDS victims wvith the greatest right ventricular abnormality have extramedullarv erythropoiesis and ab-
*.
.
,, o
I~~~~~~~~~~~~~ U* -
g
7-Z
=
.:
=U
1-I-Il
C
-
=
-.
60 _
=
*
z~~~~~
*
1
2
3
-~~~~~~~~~~~z---
U
* -~~~~~~~~~~U -Z
*a
a-
-
*_]
j7 0U
_ U *~ _~~~~~ 6
J
*
*
0
_.*-
-X
- 2
U
4
5
6
7
8
9
AREA MEDIA SMALL PULMONARY ARTERIES MEAN RATIO: AREA INTIMAL NUCLEI
TE\T-FiI-RE 2-Relative cardiac right -entricular waeights increase with increases of medial muscle in the small pulmonar- arteries U sing simple linear regression. the zero order correlation coefficient for these data is 0.60 (SIDS without infection, open squares. SIDS with infection, solid squjares. controls. solid circles I
6
NAEYE ET AL
American Journal of Pathology
Table 4-Comparisons Between Two Categories of SIDS Victims and Controls (mean ± 1 SE) SIDS without infection
SIDS with infection
Controls
Age at death (mons) Ratio of males to females Muscle mass about small
2.26 + 0.25 75:75
3.61 + 0.41 43:22 t
43:38
pulmonaryarteriest
5.5 + 0.2§ 10/43 (23%) 36.2 + 6.211
5.3 - 0.2§ 4/40 (10 /.) 30.3 2.111
4.2 - 0.1 0/33 (0°/a) 13.0 7.3
Hepaticerythropoiesis Periadrenal brown fat (%)
The male:female category includes patients from this and a previous study.7 * P < .01 by comparison with SIDS without infection. t P < .05 by comparison with SIDS without infection. t Area of arterial media/area of intimal nuclei. § P < .01 by comparison with controls. f P < .02 by comparison with controls. I P < .05 by comparison with controls.
normal brown fat retention reinforces the view that they' experienced chronic hypoxemia before death. Both extramedullarv erythropoiesis and abnormal brown fat retention are markers of chronic hvpoxemia.7 Left ventricular weights were also relatively greater in the SIDS victims than in the controls. Since this abnormality was not as severe as that on the right ventricle, the increased work load of the right ventricle may have initiated the changes in the left heart. Left ventricular failure and hypertrophy have previously been reported in some patients with chronic cor pulmonale.' 1-7 Acute experimental right ventricular stress has been reported to stimulate both protein and RNA synthesis in the unstressed left ventricle.'8 Both SIDS victims with and without infection have markers of chronic hvpoventilation, but there are some differences between the two groups. Infected victims have smaller thymus glands, raising the possibilitx of stress-induced cortisol lympholysis. Victims with infections are also older at death, and there is a greater proportion of males in this group. Males are more apt than females to die with a wide variety of postnatal disorders that involve sustained stress.'9 As a group, infected SIDS victims have somewhat milder features of antecedent hypoventilation and hvpoxemia than do noninfected victims. This might indicate that a greater proportion of deaths in infected victims are not related to the hypoventilation-apnea mechanism. However, such infections have been shown to increase both the frequency and duration of apneic episodes during sleep in susceptible infants; abnormalities in the central control of respiration remain a plausible explanation for many deaths in both infected and noninfected victims. 2-20
Vol. 82, No. 1 January 1976
CARDIAC ABNORMALITIES IN SIDS
7
Most of the anatomic markers of hypoventilation and hvpoxemia found in SIDS victims are potentially reversible. The most important abnormality is probably the increased muscle in the pulmonary arteries because it contributes to an increased pulmonary v-ascular resistance. This increase in muscle is not accompanied by any intimal proliferative or sclerotic changes, so the increased vascular resistance would almost certainlv reverse if the alveolar hypoxia was relieved. 13 The same is likely true for the cardiac, adrenal, and brown fat abnormalities. This raises the possibility that a proportion of the deaths from SIDS might be prevented if means could be found to recognize infants Nvho chronically hypoventilate during the early months of life and prevent prolonged apneic episodes in them. However, it is unlikely that all deaths from the syndrome could be prevented in this manner because some of the victims have no evidence of antecedent hvpoventilation and hypoxemia. There is undoubtedly more than one, and most likely mansr, causes of SIDS. References 1. Steinschneider A: Prolonged apnea and the sudden infant death syndrome: Clinical and laboratorv observations. Pediatrics 50:646-654. 1972 2. Stevens LH: Sudden unexplained death in infancy: Observations on a natural mechanism of adoption of a face down position. Am J Dis Child 110:243-247. 1965 3. Geertinger P: Sudden Death in Infancy. Springfield. Ill.. Charles C Thomas Co.. 1968 4. Guilleminault C, Eldridge. FL, Dement W%C: Insomnia with sleep apnea: A new syndrome. Science 181:856-858, 1973 5. Lugaresi E, Coccagna C, Mantovani NI, et al: Hypersomnia with periodic breathing: Periodic apneas and alveolar hypoventilation during sleep. Bull Physiopathol Resp (Nancy) 8:1103-1113, 1972 6. Naeve RL: Pulmonarv arterial abnormalities in the sudden-infant-death syndrome. N Engl J Med 289:1167-1170, 1973 7. Naeve RL: Hypoxemia and the sudden infant death syndrome. Science 186:&37-,&38. 1974 8. Naeve RL, Drage JS: Sudden infant death syndrome: A prospective study. Pediatr Res 9:298, 1975 (Abstr) 9. NMason JN, Nlason LH, Jackson NI, Bell JS, Francisco JT. Jennings BR: Pulmonary vessels in SIDS. N Engl J NIed 292:479, 1975 10. Nlarx JL: Crib death. Some promising leads but no solution y-et. Science 189:367-369, 1975 11. Naeve RL: Alveolar hypoventilation and cor pulmonale secondary to damage to the respiratory center. Arm J Cardiol 8:416-419. 1961 12. Naeye RL: Pulmonary vascular changes with chronic unilateral pulmonary hvpoxia. Circ Res 17:160-167, 1965 1:3. Naeye RL: Pulmonary hypertension and vascular disease. The Heart. Edited by JE Edwards, NI Lev, IBR Abell. Baltimore, WN'illiams & WN'ilkins Co.. 1974 14. Chalkley HNV: Nethod for the quantitative morphologic analysis of tissues. J Natl Cancer Inst 4:47-53, 1943 15. Koutz WN'B. Alexander HL, Prinzmetal NI: The heart in emphysema. Am Heart J 11: 16;3-172. 1936
8
16.
17. 18.
19.
20.
NAEYE ETAL
American Journal of Pathology
Michelson N: Bilateral ventricular hypertrophy due to chronic pulmonary disease. Dis Chest 38:43-446, 1960 Rao BS, Cohn KE, Eldridge FL, Hancock EW: Left ventricular failure secondarv to chronic pulmonary disease. Am J Med 45:229-241, 1968 Zellis R, Wikman-Coffelt J, Kamiyama T, Peng CL: Salel AF, Amsterdam EA, Mason DT: Acute right ventricular stress as a stimulus for left ventricular RNA and protein synthesis. Recent Advances in Studies on Cardiac Structure and Metabolism, Vol 3, NMvocardial Metabolism. Edited by NJ Dhalla. New York, Academic Press, 197-3 Naeye RL, Burt LS, Wright DL, Blanc WA, Tatter D: Neonatal mortality, the male disadvantage. Pediatrics 48:902-906, 1971 Steinschneider A: The concept of sleep apnea as related to SIDS. SIDS 1974, Proceedings Francis E Camps Intemational Symposium on Sudden and Unexpected Deaths in Infancy. Edited by RR Robinson. Toronto, Canadian Foundation for the Study of Infant Death, 1974
-
VOLUME 82, NUMBER 1
Cardiac and Other Abnormalities in the Sudden Infant Death Syndrome Richard L. Naeye, MD, Philip Whalen, MD, Monique Ryser, MD, and Russell Fisher, MD
'Many victims of the sudden infant death symdrome (SIDS) have abnormally- heav% cardiac right ventricles. The degree of this abnormality is directly proportional to: a) the mass of muscle about small pulmonary arteries, b) the amount of brown fat retention about adrenal glands, and c) the presence of hepatic erythropoiesis. The pulmonary- arterial abnormalit is probably the result of chronic alveolar hy poventilation, while brown fat retention and hepatic erythropoiesis are likely consequences of chronic hypoxemia. These abnormalities are found in both SIDS victims who die with and those who die without mild respiratory tract infections. However, there are some differences between the two SIDS groups. Infected victims die at an older age and have smaller thymus glands and larger spleens; there is a greater proportion of males in the infected victims than in the noninfected victims. (Am J Pathol 82:1-8, 1976)
APNSEIC EPISODES during sleep precede death and may be the mechanism of death in some victims of the sudden infant death svndrome (SIDS) 1.3 In other disorders, such apneic episodes are often associated with chronic underventilation of the lungs with resultant alveolar hvpoxia and systemic arterial hypoxemia.45 Many SIDS victims have anatomic markers of chronic alveolar hvpoxia and hvpoxemia. These include increased muscle in pulmonary arteries, an increased volume of adrenal medullarv chromaffin tissue, an abnormal proliferation of brain stem astroglial fibers, and an abnormal retention of extramedullary erythropoiesis and brown fat.-'0 If the hypoventilation hypothesis is corFrom the Department of Pathology. The \Milton S Hershex Mledical Center. lhe Penns\ladnia State U.niversit\ College of \ledicine. Hershe\. Penns\lvania. and the Office of the Chief Medical Examiner of the State of Mlars land. Baltimore. Mlarnland Supported by Grant HL-14297-0:3 and Contract NOL-HD-4-2517 from the L1S Public Health Service Xccepted for publication September 3. 1975. Address repnrnt requests to Dr Richard Naeve. NMilton S. Hershev Nledical Center. Hershev. PA 1 70:33
2
NAEYE ET AL
American Journal of Pathology
rect, many SIDS victims should also have abnormally heavy cardiac right ventricles, a consequence of the increased pulmonary arterial constriction that is induced by chronic alveolar hypoxia. 11-13 'Te current study measured the weights of the cardiac ventricles in SIDS victims and in controls. The cardiac findings were compared with anatomic markers of hypoventilation and hypoxemia. The study also made an attempt to better define the role of the mild infections so commonly present at death in SIDS victims. Materials and Methods The patients included 45 infants, I to 12 months in age, who were categorized as having died of SIDS when the death was sudden, completely unexpected, and unexplained by anv clinical or postmortem findings. Also included were 40 infants who were placed in the category of SIDS with infection when the infants had bronchopneumonia, tracheobronchitis, larvngitis, or otitis media of too mild a degree to explain death.7 Thirty-three nonhypoxic controls were included in the study. Thev were mostlv victims of accidents, fires, or homicides. They were from 1 to 12 months of age at death (Text-figure 1). None lived longer than 4 hours after the acute event that was responsible for death. In all categories, only infants with well-preserved tissues were included in the studv. Heart and other organ weights were calculated as a proportion of body weight for each case. The resultant values for the heart, brain, liver, spleen, thvmus, kidneys, and adrenals did not change in the controls between 1 and 6 months of age, making possible direct comparisons between SIDS victims and controls within this age span (Table 1). In each heart, the free walls of the two ventricles were dissected from the interventricular septum and separately weighed. These weights were then calculated as a proportion of bodv weight. The resultant values did not change between 1 and 6 months of age in the controls, so direct cornparisons were possible between groups within this age period (Text-figure 1). Ventricular weights and all histologic measurements in the study were made in duplicate by two examiners without either knowing an infant's age or diagnosis. Differences between the duplicate analyses were small. The point counting method of Chalkley was used to quantitate the amount of muscle in pulmonary arteries of 100 g or less diameter.'l The ratio of the area of arterial media to the area of arterial intimal nuclei was used as the measure of arterial muscle mass." A minimum of twenty arteries was measured in each infant, and a mean figure recorded as the value for the case. Extramedullary ervthropoiesis was recorded when nests of erythropoietic cells, including normoblasts, were identified between the cords of hepatic parenchymal cells. Periadrenal brown fat is normally replaced by white fat during the first vear of postnatal life. It has recently been found that brown fat is replaced more slowly than normal in infants who are chronically hypoxemic after birth and in SIDS victims.7'0 In the current study, periadrenal fat cells with a clearly defined cytoplasmic reticular infrastructure were counted as brown cells. The proportion of fat cells that were brown was determined in each case by the point-counting method of Chalkley.7' Nonadipose structures, such as blood vessels and connective tissue, were excluded from the final calculations so that brown cells were represented as a percentage of the total volume of fat cells present. The transfornation of brown to white cells is not normally advanced until after 4 months of age, so only infants a months of age and older were included in the fat analyses.7 .0
Results Relative heart weights were greater in SIDS victims than in the controls (Table 1). Both right and left ventricular weights contributed to this
CARDIAC ABNORMALITIES IN SIDS
Vol. 82, No. 1 January 1976 II
I
1.60
1.40
3
0
00
U
CY)
C
0. 0
_4
U *o
*
00
1.20
Lx -I
C-)
.0
0*
z
L> I-
1.00
:
0 e
Om
*
0
-
00
cr
.80
m
0
*.0 0 00~~~~~~~
o0 ~ 0 0~~~~~~~~~~~ -.
*:0
*
C-
ED
0D
*
*~
.60
7-
0L
0
*
.40
.20
IiI
1
2
3
4
5
6
I
7
8
9
10
11
12
AGE IN MONTHS TEx-T-F IGIRE 1-Relatise cardiac right ventricular seights are greater in mans SIDS sictims than in nonh-poxemic controls. The values in the controls decrease after 6 months of age. (SIDS without infection. opeli squares. SIDS with infection. solid squares, controls, solid circles)
finding, the greater abnormality being on the right (Text-figure 1, Tables
2 and 3). Relative right ventricular weights directly correlated with the amount of medial muscle in the small pulmonary arteries (Text-figure 2). None of the SIDS victims who had a right ventricular weight x 103,//body weight ratio below 1.00 had hepatic erythropoiesis, while 44% of those with values greater than 1.00 had such erythropoiesis (P < .03). Brown
cells constituted 20%' of the periadrenal fat in victims who had right ven-
NAEYE ET AL
4
American Journal of Pathology
Table 1-Relative Organ Weights of Infants Between Ages One and Six Months (mean values t 1 SE)
Organ Brain Heart Liver Spleen Thymus Kidneys
Adrenals
Organ weight/body weight SIDS without infection
Controls .1010 .0033 .0055 .0002 .0348 .0012 .0026 .0002 .0053 .0008 .0072 +.0003 .00058 .00004
.1130 + .0035 .0060 + .0001 $ .0360 + .0010 .0027 .0001 .0052 _ .0002 .0067 +.0002 .00064 + .00005
SIDS with infection .0979 .0050 t .0059 + .0001 $ .0353 +.0010 .0039 .000716 .0042 + .0002 t$ .0065 + .0002 $ .00061 _ .00003
< .01 by comparison with controls. tp < .01 by comparison with SIDS without infection. *P < .05 by comparison with controls. §p < .05 by comparison with SIDS without infection. .P
tncular ratios below 1.00 and 44% in those with ratios greater than 1.00 (P < .0.3).
Kidneys were relatively fighter in SIDS victims than in the controls, while brains were relatively heavy in the SIDS victims who did not have evidence of infection (Table 1). Spleens were relativelv heavier and thymus glands lighter in the SIDS victims who had evidence of infection. SIDS victims who had infections died at an older age, and had a greater proportion of males than did noninfected victims (Table 4). The infected victims had less hepatic erythropoiesis, brown fat, and pulmonanr arterial muscle than did the noninfected victims (Table 4). None of these last three differences were statistically significant. Discussion Alveolar hypoxia increases pulmonarv vascular resistance bv causing small arteries to contract. When the stimulus is sustained, the arteries' Table 2-Relative Weight of the Cardiac (mean 1 SE)
Right Ventricle
in SIDS Victims and in Controls
Right ventricle weight x 103/body weight Age 1-6 months SIDS without infection SIDS with infection Controls Age 7-10 months SIDS without infection SlDSwith infection Controls Number of cases are in parentheses. P < .005 by comparison with controls. t P < .05 by comparison with controls. *
1.03 .04 0.99 .03 0.77 .03 0.86
-
(42) (37) (22)
.08 t (3)
0.95: .12t (3) 0.67
.04
(11)
Vol. 82, No. 1 January 1976
CARDIAC ABNORMALITIES IN SIDS
5
Table 3-Relative Weight of the Cardiac Left Ventricle in SIDS Victims and Controls (mean - 1 SE)
Right ventricle weight X 103/body weight Age 1-6 months
SIDS without infection SIDS with infection Controls Age 7-10 months SIDS without infection SIDS with infection Controls Number of cases are in parentheses. * P < .005 by comparison with controls.
1.50 .05 1.56 .06 1.31 -.04
1.16 .09 1.38 .11 1.22- .09
-
*
(42) (37) (22) (3) (3) (1 1)
medial cells undergo both hvperplasia and hypertrophy, wvith resultant increased weight of the cardiac right ventricle. Many SIDS xictims develop these structural abnormalities without any evidence of chronic pulmonary disease, indicating that they probably had chronic alveolar hypoxia before death. Chronic alveolar hypoxia leads to chronic systemic arterial hypoxemia.6-7'1 The finding that SIDS victims wvith the greatest right ventricular abnormality have extramedullarv erythropoiesis and ab-
*.
.
,, o
I~~~~~~~~~~~~~ U* -
g
7-Z
=
.:
=U
1-I-Il
C
-
=
-.
60 _
=
*
z~~~~~
*
1
2
3
-~~~~~~~~~~~z---
U
* -~~~~~~~~~~U -Z
*a
a-
-
*_]
j7 0U
_ U *~ _~~~~~ 6
J
*
*
0
_.*-
-X
- 2
U
4
5
6
7
8
9
AREA MEDIA SMALL PULMONARY ARTERIES MEAN RATIO: AREA INTIMAL NUCLEI
TE\T-FiI-RE 2-Relative cardiac right -entricular waeights increase with increases of medial muscle in the small pulmonar- arteries U sing simple linear regression. the zero order correlation coefficient for these data is 0.60 (SIDS without infection, open squares. SIDS with infection, solid squjares. controls. solid circles I
6
NAEYE ET AL
American Journal of Pathology
Table 4-Comparisons Between Two Categories of SIDS Victims and Controls (mean ± 1 SE) SIDS without infection
SIDS with infection
Controls
Age at death (mons) Ratio of males to females Muscle mass about small
2.26 + 0.25 75:75
3.61 + 0.41 43:22 t
43:38
pulmonaryarteriest
5.5 + 0.2§ 10/43 (23%) 36.2 + 6.211
5.3 - 0.2§ 4/40 (10 /.) 30.3 2.111
4.2 - 0.1 0/33 (0°/a) 13.0 7.3
Hepaticerythropoiesis Periadrenal brown fat (%)
The male:female category includes patients from this and a previous study.7 * P < .01 by comparison with SIDS without infection. t P < .05 by comparison with SIDS without infection. t Area of arterial media/area of intimal nuclei. § P < .01 by comparison with controls. f P < .02 by comparison with controls. I P < .05 by comparison with controls.
normal brown fat retention reinforces the view that they' experienced chronic hypoxemia before death. Both extramedullarv erythropoiesis and abnormal brown fat retention are markers of chronic hvpoxemia.7 Left ventricular weights were also relatively greater in the SIDS victims than in the controls. Since this abnormality was not as severe as that on the right ventricle, the increased work load of the right ventricle may have initiated the changes in the left heart. Left ventricular failure and hypertrophy have previously been reported in some patients with chronic cor pulmonale.' 1-7 Acute experimental right ventricular stress has been reported to stimulate both protein and RNA synthesis in the unstressed left ventricle.'8 Both SIDS victims with and without infection have markers of chronic hvpoventilation, but there are some differences between the two groups. Infected victims have smaller thymus glands, raising the possibilitx of stress-induced cortisol lympholysis. Victims with infections are also older at death, and there is a greater proportion of males in this group. Males are more apt than females to die with a wide variety of postnatal disorders that involve sustained stress.'9 As a group, infected SIDS victims have somewhat milder features of antecedent hypoventilation and hvpoxemia than do noninfected victims. This might indicate that a greater proportion of deaths in infected victims are not related to the hypoventilation-apnea mechanism. However, such infections have been shown to increase both the frequency and duration of apneic episodes during sleep in susceptible infants; abnormalities in the central control of respiration remain a plausible explanation for many deaths in both infected and noninfected victims. 2-20
Vol. 82, No. 1 January 1976
CARDIAC ABNORMALITIES IN SIDS
7
Most of the anatomic markers of hypoventilation and hvpoxemia found in SIDS victims are potentially reversible. The most important abnormality is probably the increased muscle in the pulmonary arteries because it contributes to an increased pulmonary v-ascular resistance. This increase in muscle is not accompanied by any intimal proliferative or sclerotic changes, so the increased vascular resistance would almost certainlv reverse if the alveolar hypoxia was relieved. 13 The same is likely true for the cardiac, adrenal, and brown fat abnormalities. This raises the possibility that a proportion of the deaths from SIDS might be prevented if means could be found to recognize infants Nvho chronically hypoventilate during the early months of life and prevent prolonged apneic episodes in them. However, it is unlikely that all deaths from the syndrome could be prevented in this manner because some of the victims have no evidence of antecedent hvpoventilation and hypoxemia. There is undoubtedly more than one, and most likely mansr, causes of SIDS. References 1. Steinschneider A: Prolonged apnea and the sudden infant death syndrome: Clinical and laboratorv observations. Pediatrics 50:646-654. 1972 2. Stevens LH: Sudden unexplained death in infancy: Observations on a natural mechanism of adoption of a face down position. Am J Dis Child 110:243-247. 1965 3. Geertinger P: Sudden Death in Infancy. Springfield. Ill.. Charles C Thomas Co.. 1968 4. Guilleminault C, Eldridge. FL, Dement W%C: Insomnia with sleep apnea: A new syndrome. Science 181:856-858, 1973 5. Lugaresi E, Coccagna C, Mantovani NI, et al: Hypersomnia with periodic breathing: Periodic apneas and alveolar hypoventilation during sleep. Bull Physiopathol Resp (Nancy) 8:1103-1113, 1972 6. Naeve RL: Pulmonarv arterial abnormalities in the sudden-infant-death syndrome. N Engl J Med 289:1167-1170, 1973 7. Naeve RL: Hypoxemia and the sudden infant death syndrome. Science 186:&37-,&38. 1974 8. Naeve RL, Drage JS: Sudden infant death syndrome: A prospective study. Pediatr Res 9:298, 1975 (Abstr) 9. NMason JN, Nlason LH, Jackson NI, Bell JS, Francisco JT. Jennings BR: Pulmonary vessels in SIDS. N Engl J NIed 292:479, 1975 10. Nlarx JL: Crib death. Some promising leads but no solution y-et. Science 189:367-369, 1975 11. Naeve RL: Alveolar hypoventilation and cor pulmonale secondary to damage to the respiratory center. Arm J Cardiol 8:416-419. 1961 12. Naeye RL: Pulmonary vascular changes with chronic unilateral pulmonary hvpoxia. Circ Res 17:160-167, 1965 1:3. Naeye RL: Pulmonary hypertension and vascular disease. The Heart. Edited by JE Edwards, NI Lev, IBR Abell. Baltimore, WN'illiams & WN'ilkins Co.. 1974 14. Chalkley HNV: Nethod for the quantitative morphologic analysis of tissues. J Natl Cancer Inst 4:47-53, 1943 15. Koutz WN'B. Alexander HL, Prinzmetal NI: The heart in emphysema. Am Heart J 11: 16;3-172. 1936
8
16.
17. 18.
19.
20.
NAEYE ETAL
American Journal of Pathology
Michelson N: Bilateral ventricular hypertrophy due to chronic pulmonary disease. Dis Chest 38:43-446, 1960 Rao BS, Cohn KE, Eldridge FL, Hancock EW: Left ventricular failure secondarv to chronic pulmonary disease. Am J Med 45:229-241, 1968 Zellis R, Wikman-Coffelt J, Kamiyama T, Peng CL: Salel AF, Amsterdam EA, Mason DT: Acute right ventricular stress as a stimulus for left ventricular RNA and protein synthesis. Recent Advances in Studies on Cardiac Structure and Metabolism, Vol 3, NMvocardial Metabolism. Edited by NJ Dhalla. New York, Academic Press, 197-3 Naeye RL, Burt LS, Wright DL, Blanc WA, Tatter D: Neonatal mortality, the male disadvantage. Pediatrics 48:902-906, 1971 Steinschneider A: The concept of sleep apnea as related to SIDS. SIDS 1974, Proceedings Francis E Camps Intemational Symposium on Sudden and Unexpected Deaths in Infancy. Edited by RR Robinson. Toronto, Canadian Foundation for the Study of Infant Death, 1974
