From the Department of Cardiovascular Pathology (A.P.B., A.F., Y.-h.L.,
R.V.), Armed Forces Institute of Pathology, Washington, DC; Louisiana State
University, New Orleans (G.T.M.); and the University of Maryland, Baltimore
(J.S.).
Correspondence to Renu Virmani, MD, Department of Cardiovascular Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000.
Methods and Results—We examined 51 cases of sudden
coronary death and 15 hearts from women who died of trauma.
Coronary deaths were divided into four mechanisms of death:
ruptured plaque with acute thrombus (n=8), eroded plaque with acute
thrombus (n=18), stable plaque with healed infarct (n=18), and stable
plaque without infarction (n=7). Vulnerable plaques prone to rupture
were defined as those with a thin, fibrous cap infiltrated by
macrophages and were quantitated in coronary deaths and
control subjects. Total cholesterol (TC), HDL
cholesterol, glycosylated hemoglobin, cigarette smoking,
and hypertension were determined in each case. Compared with control
subjects, women with plaque ruptures had elevated TC (270±55 versus
194±44 mg/dL, P=0.002), and those with erosions were
more likely to be smokers (78% versus 33%, P=0.01).
Women with stable plaque and healed infarct had elevated glycosylated
hemoglobin (10.2±5.0% versus 6.4±0.4% in control subjects,
P=0.001) and were more likely to be hypertensive (50%
versus 15% in control subjects, P=0.03). By
multivariate analysis, cigarette smoking was
associated with plaque erosion (P=0.03, odds ratio
[OR] 21), glycoslyated hemoglobin with stable plaque and healed
infarct (P=0.03, OR 41), TC with plaque rupture
(P=0.02, OR 7), and hypertension with stable plaque with
healed infarct (P=0.02, OR 15). Seven of 8 plaque
ruptures occurred in women >50 years of age versus 3 of 18 erosions
(P=0.001). In cases of coronary death,
vulnerable plaques were associated with elevated
cholesterol (P=0.002) and age >50 years
(P=0.002), independent of other risk factors.
Conclusions—In women, traditional risk factors have distinct
effects on the mechanisms of sudden coronary death, which vary
by menopausal status. Effective risk factor modification may therefore
differ between younger and older women and may be targeting different
mechanisms of plaque instability.
Although the incidence of sudden death is approximately four times
greater in men than women,3 this difference
decreases with advancing age.4 Estrogen has been
implicated as a protective mechanism against the development of
atherosclerosis. The effect of estrogen on the
inhibition of atherosclerosis is poorly understood but
may be related to lipoprotein
metabolism5 or its effect on vascular
smooth muscle.5 6 The protective effect of
estrogen against atherosclerotic vascular disease is one of the major
reasons to prescribe estrogen replacement treatment in postmenopausal
women.7
Coronary risk factors have been well established in men and
include cigarette smoking, dyslipidemia, diabetes mellitus,
and hypertension.3 In women,
hyperlipidemia (elevated total cholesterol
[TC], low HDL-C, and
hypertriglyceridemia), cigarette smoking,
and diabetes mellitus have been linked to coronary artery
disease, sudden death, and myocardial
infarction.2 8 9 10 11 12 13 We have recently shown that in
men, cigarette smoking is associated with coronary thrombosis
and dyslipidemia with plaque
rupture.14 It is unknown whether similar
associations exist for women, especially given the likely effects of
estrogen on the morphology of atherosclerosis.
The purpose of this study was to determine whether risk factors affect
the mechanism of coronary death in women (specifically the
plaque morphology underlying thrombosis and incidence of healed
infarcts) and whether these mechanisms are modified by age >50 years
or <50 years (a likely reflection of menopausal status). The results
of this study should aid in targeting coronary risk factor
modification and therapy in women with coronary artery
disease.
Heart Study and Determination of Death Category
Because deaths referred to the medical examiner are unexpected, all
coronary deaths were classified as sudden as previously
defined.14 16 Sudden death was defined as
symptoms commencing within 6 hours of death (witnessed arrest) or death
that occurred within 24 hours of the time that the victim was last seen
alive in his normal state of health. Coronary deaths with acute
thrombus were further categorized as plaque rupture if serial
sectioning showed a connection between the thrombus and the necrotic
core.
Vulnerable plaques were defined as a fibrous cap thinner than 65
µm infiltrated by macrophages overlying a necrotic core as
previously defined.14 In each heart, the mean
number of vulnerable plaques was tabulated by counting the number of
segments with >50% luminal narrowing with histologic features of
vulnerable plaque. In coronary deaths without acute thrombus,
the category of death was assigned as stable plaque with healed
myocardial infarct and stable plaque without healed
infarct.14
Definition of Plaque Erosion
Determination of Risk Factors and Menopausal Status
Investigators at the scene of death recorded all medications
including estrogens, and autopsy and scene investigation resulted in
knowledge of previous oophorectomy, if any. Dates of last menstrual
periods were not known. An age of 50 years was considered an
approximation for onset of menopause. The gross appearance and presence
of the uterus and ovaries were evaluated in each case.
Statistical Analysis
Of the 51 coronary deaths, 21 occurred in women >50 years of
age and 30 in women
Thirty-six (71%) of coronary deaths were witnessed (11 of 18
plaque erosions, 7 of 8 plaque ruptures, 11 of 18 stable plaques with
healed infarcts, and 7 of 7 stable plaques without healed infarcts). Of
the 36 witnessed coronary deaths, 8 (22%) women had chest
pain, 12 (33%) complained of symptoms other than chest pain
immediately before death, and 16 (45%) did not complained of symptoms.
There was no correlation between category of death and presence of
chest pain. Symptoms in women who did not complain of chest pain
included back pain (2), dizziness (3), nausea and vomiting (1), fever
and chills (1), stomach distention (1), left shoulder tingling (1),
shortness of breath (1), malaise (1), and fatigue (1). None of the
witnessed deaths occurred during exertion. A history of "heart
disease" was present in 9 women with sudden coronary
death (7 of 18 with stable plaque and healed infarcts, 1 of 8 with
plaque rupture, and 1 of 8 with stable plaque without healed infarct),
2 of whom had a documented history of previous myocardial infarction
(both with healed infarcts at autopsy). Other medical conditions
included known hypertension (11), breast carcinoma (1), carotid
endarterectomy (1), depression (3), emphysema (1),
known hypercholesterolemia (1),
insulin-dependent diabetes mellitus (5), asthma (1), alcoholism (2),
glomerulonephritis (1), seizure disorder (1), schizophrenia (1), mitral
valve prolapse (1), and lupus erythematosus
(1). Fifteen women were receiving oral medications; one was receiving
estrogen replacement therapy and 5 were receiving insulin for diabetes
mellitus. Oral medications included amitriptyline, aminophylline,
atenolol, sertraline, clonidine, furosemide, enalapril, alprazolam,
coumadin, dilantin, metoprolol, hydrochlorothiazide,
chlorpromazine, amlodipine, methyldopa,
hydrochlorothiazide, sulfazoxazole, ranitidine,
prednisone, and diltiazem. The patient receiving estrogen replacement
was a 46-year-old woman (status post-hysterectomy/oophorectomy) with an
eroded plaque. Other surgeries included mastectomy (1), hysterectomy
without oophorectomy (1), and cholecystectomy and tubal ligation
(4).
The mean heart weight in hearts with plaque rupture (483±108 g) and
stable plaque with healed myocardial infarct (460±105) exceeded that
of hearts with plaque erosion (372±87 g) (P=0.01). The mean
heart weight in 7 hearts with stable plaque and no myocardial infarct
was 375±128 g.
General Clinical and Pathologic Data: Noncoronary Deaths
Risk Factors and Mechanism of Death
For each of the four categories of coronary deaths, mean age,
TC, HDL-C, body mass index, and percent glycosylated hemoglobin are
presented in Table 1
Compared with control subjects, women with acute ruptures had higher
total cholesterol levels and higher heart weights (Table 2
Incidence of Infarcts and Degree of Coronary Narrowing:
Coronary Deaths
The 26 acute thrombi were located in proximal segments in 16 hearts
(62%): proximal left anterior descending before first diagonal (10),
proximal right before the first large branch or acute angle (5), and
proximal circumflex before the obtuse marginal (1). Eight thrombi were
in the mid portion of the left anterior descending (5) or right
coronary (3); one thrombus was in the distal right. At the site
of thrombus, the percent stenosis was 66±15% in women
Vulnerable Plaques and Risk Factors
Sudden coronary death in the setting of healed myocardial
infarction without acute coronary thrombosis constituted 35%
of coronary deaths in this study. Therefore, a reduction in
sudden coronary deaths in women would need to target that group
of patients as well. Similar to women with plaque rupture, they are
likely to be significantly older than women with plaque erosion. In
addition, these women were more likely to be diabetic or hypertensive,
two risk factors more prevalent in older women in our study. Therefore,
control of hypertension and blood glucose levels may reduce sudden
deaths in women with known coronary disease and a history of
ischemic heart disease.
In addition to establishing a correlation between risk factors and
mechanism of sudden coronary death in women, this study also
demonstrates age-related differences in percent luminal
stenosis at the site of thrombus and extent of coronary
disease. In younger women who died of severe coronary disease,
the mean degree of narrowing by atherosclerotic plaque at the site of
thrombus was only 66% cross-sectional area luminal narrowing
(equivalent to 43% diameter luminal narrowing), and there were
relatively few narrowed segments of coronary arteries compared
with women >50 years of age. The implication of this finding is that
angiography in younger women may underestimate potentially lethal
coronary artery narrowings in younger women.
Although this study demonstrates a clear association between
traditional risk factors and type of coronary plaque morphology
in women who die suddenly, not all women showed these associations.
Seven (14%) died of stable plaque without infarct; this group showed
no association with known risk factors. Furthermore, not all women with
erosions were smokers and not all women with healed infarcts and stable
plaque had evidence of either hypertension or diabetes. Therefore, it
appears that other nontraditional risk factors for
atherosclerosis may independently affect plaque
morphology or interact with traditional risk factors. There is an
evolving list of newer risk factors that have been implicated in
coronary atherosclerosis, including clotting
factors such as plasminogen activator
inhibitor, fibrinogen, von Willebrand factor
antigen, and platelet glycoprotein IIb/IIIa gene
polymorphism and lipid variants such as apolipoprotein E
polymorphism and lipoprotein(a). The possible association of these
risk factors with coronary plaque morphology are
unknown16 and have not been addressed in this
study. Inflammation has been identified as a key component of plaque
instability in both ruptures and erosions,19
suggesting that local inflammation may be a mediator of acute thrombus
with various underlying stimuli. However, the degree of inflammation in
plaque erosion, as assessed by numbers of macrophages and
lymphocytes, is significantly fewer compared with plaque rupture at the
site of thrombosis in our previous study.20
Sex Differences in Coronary Thrombosis
Mechanisms of Sudden Coronary Death in Women
Plaque Calcification and Extent of Luminal Narrowing
Limitations of the Study
Conclusions
Received October 6, 1997;
revision received December 29, 1997;
accepted January 30, 1998.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Effect of Risk Factors on the Mechanism of Acute Thrombosis and Sudden Coronary Death in Women
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Traditional risk factors
have been linked to atherosclerotic heart disease in women. However,
the effect of risk factors and menopausal status on the mechanism of
sudden coronary death is unknown.
Key Words: thrombosis • death, sudden • risk factors • women
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Sudden cardiac death
occurs in 300 000 people in the United States annually, >80% of
which are due to coronary causes.1
Because it has been estimated that up to 50% of coronary
deaths are sudden,1 2 pathologic observations
about sudden coronary death are likely to reflect a fairly
large proportion of patients who suffer from atherosclerotic
coronary disease.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Case Selection
Female victims of sudden death were identified at the Office of
the Chief Medical Examiner of the State of Maryland. When an autopsy
was performed, the heart was examined in consultation with the
Department of Cardiovascular Pathology at the Armed
Forces Institute of Pathology. These cases were evaluated prospectively
in a similar manner during the same time period as previously reported
in men.14 Fifteen control subjects who died of
trauma were collected during the same study period. The trauma cases
were chosen only if the age of the victim fell within the approximate
study range (that is, >35 years of age). Risk factors (with the
exception of age) were not known before inclusion into the study in any
case.
All hearts were studied under supervision of the medical
examiner as previously described.14 Ten cases
were published previously without risk factor data other than
hypertension.15 Briefly, hearts were perfusion
fixed in buffered formalin, and epicardial arteries were serially
sectioned at 2- to 3-mm intervals. Each segment with >50%
cross-sectional area luminal narrowing (estimated at gross examination)
was submitted for histology, including Movat pentachrome
stains. Coronary deaths were defined as natural deaths without
extracardiac cause of death and in which 
1 epicardial
coronary arteries had >75% cross-sectional area lumen
narrowed by atherosclerotic plaque or plaque with superimposed
thrombus. Mean cross-sectional luminal area narrowing was determined by
computerized morphometry of maximal narrowing of any epicardial artery
and plaque underlying acute thrombus (Figure
).
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Figure 1. Substrates of acute coronary thrombosis. a, Plaque
erosion: eccentric plaque with overlying subocclusive thrombus. The
narrowing is not critical, and disruption of the cap is absent. b,
Microscopic illustration of a demonstrates thrombus overlying intact
plaque. The patient was a 58-year-old smoker with a history of
emphysema but no heart disease. She recently complained of chest pain
but was not extensively evaluated. She had an apparent seizure and
developed cardiac arrest from which she could not be resuscitated. c,
Plaque rupture: Critical narrowing of this section of left anterior
descending artery by atheroma rich in
cholesterol crystals. Central hemorrhage into
plaque is continuous with the small residual lumen above. Black
reflects the postmortem injection of contrast material. d, Higher
magnification of c demonstrates rupture site.
Plaque erosions were defined as an acute thrombus without
features of plaque rupture. They consisted of an acute thrombus in
direct contact with intimal plaque rich in smooth muscle cells with
surrounding proteoglycan matrix. Necrotic core was either absent or
poorly defined and when present was not in close proximity to the
luminal thrombus.
The postmortem serum evaluation of TC, HDL-C, and thiocyanate
was performed as previously described.14 17 18 A
thiocyanate level of 90 mg/dL was considered evidence for cigarette
smoking.17 18 The evaluation of glycosylated
hemoglobin on red blood cells and the evaluation of hypertension with
renal morphometric vascular analysis have also been
reported.14 Cases were discarded if there was
gross hemolysis or if evaluation of total protein and serum
albumin indicated hemoconcentration or hemodilution. The body
mass index was estimated with the formula body weight/body
height2 (kg/m2).
Five categories of sudden death were considered, four
coronary and one noncoronary: (1) acute plaque rupture,
(2) acute plaque erosion, (3) stable plaque and healed infarct, (4)
stable plaque and no healed infarct, and (5) trauma deaths. For
univariate analysis, continuous variables (TC,
HDL-C, glycosylated hemoglobin, and age) were compared among these five
groups by comparisons of means (ANOVA means table). Categorical
variables (smoking status, presumed menopausal status, [age >50
years], hypertension) were compared among these five groups by
contingency tables and 
2 analysis. For
multivariate analysis, logistic regression was
performed four times separately to compare the control group with each
of the four coronary death groups by using age and risk factors
as independent variables (dependent variable=coronary
versus control death). TC, HDL-C, and percent glycosylated hemoglobin
were treated as continuous variables for determination of
P values; for determination of odds ratios, a level of 210
mg/dL was used as a normal limit for cholesterol, 45 mg/dL
for a normal limit for HDL-C, and 10% as an upper limit for the
determination of diabetes mellitus.14 To test the
association between vulnerable plaques and risk factors, only
coronary deaths were studied. For univariate
analysis, simple regression was used to test for an association
between numbers of vulnerable plaques and continuous risk factor data
in the four coronary groups. For categorical variables,
mean numbers of vulnerable plaques in each heart were compared by
Student's t test. ANOVA was used to test the association
between the independent risk factor variables on the number of
vulnerable plaques in each heart. Age >50 years was considered a
categorical variable as an indicator of menopausal status.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
General Clinical and Pathologic Data: Coronary Deaths
For sudden unexpected deaths, a total of 105 cases were initially
collected. Seven were eliminated because of incomplete risk factor data
based on hemolysis, hemodilution, or inadequate cells for the
determination of glycohemoglobin. Of the 98 cases with serologic and
blood data, the type of sudden death was determined after full autopsy
and serial coronary artery evaluation. Forty-seven cases were
excluded on the basis of lack of severe coronary disease
(<75% maximal cross-sectional luminal narrowing in the absence of
coronary thrombosis), resulting in 51 coronary deaths.
In addition, 15 cases of traumatic death were studied in an identical
fashion. 
50 years of age. Acute thrombus overlying plaque
erosion was present in 18 hearts (35%), acute thrombus overlying
plaque rupture in 8 (16%), stable plaque with healed myocardial
infarct in 18 (35%), and stable plaque without infarct in 7 (14%).
The mean number of segments studied (those with >50% cross-sectional
luminal narrowing) were 7±5 in cases of plaque erosion, 10±4 in cases
of plaque rupture, 12±8 in cases of stable plaque with healed infarct,
and 7±4 in cases of stable plaque without healed infarct. The number
of segments with >50% cross-sectional luminal narrowing was 12±11 in
women >50 years of age and 7±4 in women younger than <50 years of
age (P=0.05). The number of severely narrowed segments
(>75% cross-sectional luminal narrowing) was 2.7±1.7 in cases of
plaque erosion, 4.0±1.1 in cases of plaque rupture, 4.2±1.3 in cases
of stable plaque with healed infarct, and 3.1±2.0 in cases of stable
plaque without healed infarct. Severely narrowed segments were
significantly fewer in cases of plaque erosion compared with plaque
rupture (P=0.05) and stable plaque with healed infarct
(P=0.004). The total number of coronary histologic
sections examined was 28±13 in cases of acute plaque rupture, 25±14
in cases of plaque erosion, 25±13 in cases of stable plaque with
healed infarct, and 14±5 in cases of stable plaque without healed
infarct.
The 15 trauma cases were 50±19 years of age, with a heart weight
of 384±86 g. The mean heart weight of trauma deaths was significantly
less than that of hearts with plaque rupture (P=0.02) and
stable plaque with healed infarct (P=0.02). The maximum
percent coronary stenosis for the trauma deaths was
13±16%.
In the 66 women, there were no significant differences between TC
in women <50 years of age (194±63 mg/dL) versus women >50 years of
age (221±61 mg/dL, P=0.11). HDL cholesterol was
similar in both groups (47±18 versus 42±24 mg/dL, respectively,
P=0.4), as was the frequency of presumed cigarette smoking
(50% versus 58%, respectively). Percent glycohemoglobin was lower in
young women (7.1±2.4% versus 9.3±5.6%, respectively,
P=0.04), as was the frequency of hypertension (20% versus
48%, P=0.03). Body mass index was similar in young and
older women (29±8.3 kg/m2 versus 28±7
kg/m2, respsectively, P=0.4). The mean
heart weight was greater in women >50 years of age (454±124 g) than
in women 50 years of age (385±84 g, P=0.009). . Women with
plaque rupture were significantly older than women with eroded plaque
and stable plaque without myocardial infarct, and women with plaque
erosion were significantly younger than those with stable plaque and
healed infarct. The TC levels of women with plaque rupture were
significantly elevated compared with women with stable plaque and women
with plaque erosion. HDL-C and TC/HDL did not significantly differ
among the groups. Body mass index was significantly greater in plaque
rupture compared with plaque erosion. Percent glycohemoglobin was
significantly higher in stable plaque with healed infarct compared with
eroded plaque. Heart weight was less in hearts with acute erosion
compared with hearts with stable plaque and healed infarct and hearts
with acute rupture. When taken in relation to body mass index, the
heart weight was greatest in women with stable plaque and healed
infarct.
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Table 1. Risk Factors and Mechanism of Death: 51 Women With
Severe Coronary Atherosclerosis ). TC/HDL-C was significantly higher in
women with stable plaque and healed infarct than in control subjects.
Women with plaque erosion were more likely to be smokers than were
control subjects (Table 2). Women with stable plaque and healed infarct
were more likely to be hypertensive and had elevated glycoslyated
hemoglobin (Table 2). By multivariate analysis,
these associations were independent of other risk factors (Table 3). Compared with control subjects, the
odds ratio of elevated TC >210 mg/dL was 7 in women with plaque
rupture, and the odds ratio of smoking in women with erosion was 21
compared with control subjects. The odds ratio of hypertension was 15,
and the odds ratio of elevated glycosylated hemoglobin >10% was 41 in
women with stable plaque and healed myocardial infarct versus control
subjects. There were no significant associations between risk factors
and stable plaque without healed infarct.
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Table 2. Risk Factors: 15 Control Subjects, Comparison With
Coronary Deaths by Mechanism (Univariate
Analysis)
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Table 3. Risk Factors in Women Who Died of Severe
Coronary Disease: Multivariate Comparison With
Control Subjects by Mechanism of Death
Acute myocardial infarcts were present in 8 of 18 plaque
erosions, 2 of 8 plaque ruptures, 2 of 18 stable plaques with healed
infarcts, and none of 7 stable plaques without healed infarcts. The
maximal percent coronary artery stenosis in any artery
(not necessarily that with thrombus) was 88±10% for stable plaque
with healed infarct, 81±11% for plaque rupture, 81±6% for stable
plaque without healed infarct, and 73±17% for eroded plaque. The
maximal percent coronary artery stenosis was 84±10%
in coronary deaths of women >50 years of age and 78±16% in
women 50 years of age (P>0.1). 50
years of age and 79±7% in women >50 years of age (P=0.02)
and was 77±8% for plaque ruptures and 70±16% for plaque erosions
(P>0.1). Thirteen (50%) of the thrombi were occlusive; 8
(80%) of those in women > 50 years of age and 5 (19%) of those
in women <50 years of age were occlusive (P=0.04). Six of
18 (33%) of eroded versus 7 of 8 (88%) of plaque ruptures were
occlusive (P=0.02).
The mean numbers of vulnerable plaques were associated with TC
(r2=0.3, P=0.002), increasing
age (r2=0.3, P=0.002), and
increased glycohemoglobin (r2=0.2,
P=0.05) by univariate analysis. When
risk factors of hypercholesterolemia (TC >210
and TC/HDL-C >5), diabetes (glycohemoglobin >10), and age (>50
years) were considered as categorical variables, vulnerable plaques
were more numerous in hearts from patients with increased age
(P<0.0001) and abnormal TC and TC/HDL-C (Table 4). By multivariate
analysis, age >50 years and cholesterol were
independently associated with numbers of vulnerable plaques
(F=10.34, P=0.002; F=12.36,
P=0.007, respectively). When age was used as a continuous
variable, its association with mean numbers of vulnerable plaques
was weaker (F=4.4, P=0.04). Other risk factor
variables were not associated with vulnerable plaques
(P>0.15 for all).
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Table 4. Mean Vulnerable Plaques in Hearts From 51 Women Who
Died Suddenly With Severe Coronary Disease, Compared by
Presence of Risk Factors
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
Current Study
This study demonstrates that in women who die suddenly with severe
coronary disease, traditional risk factors and menopausal
status affect the mechanism of sudden death and coronary artery
thrombosis found at autopsy. Because the majority of acute
coronary thrombi caused by plaque erosion occur in young female
smokers without significantly elevated cholesterol levels,
body mass index, or glycohemoglobin levels, it appears that smoking
cessation is the most important risk factor modification indicated for
this group. In older women who are
hypercholesterolemic, plaque rupture plays an important
role in the development of acute coronary thrombosis,
underscoring the need for cholesterol reduction in women
who are postmenopausal. Plaques vulnerable to rupture were far fewer in
younger women who died of severe coronary artery
atherosclerosis than in postmenopausal women,
indicating that the development of the substrate for plaque rupture
appears to be inhibited in premenopausal women.
The current study demonstrates both similarities and differences
between men and women in the relation of acute thrombosis and
coronary risk factors. The link between
hypercholesterolemia and plaque rupture appears
to occur only in women who are postmenopausal; age does not appear to
have an affect on this relation in men.14 In
addition, in women TC is specifically associated with plaque rupture,
whereas in men, elevated TC/HDL-C is a predictor of plaque rupture.
Because of the apparent protective effect of estrogen on plaque
rupture, erosions are more common in women than in
men.20 Furthermore, there appears to be a
stronger link between diabetes and hypertension and sudden death caused
by stable plaque with healed myocardial infarction in women than in
men, for reasons that have yet to be explored.
This study does not address possible cellular mechanisms that
explain the association between risk factors and plaque morphology. The
link between plaque rupture and elevated cholesterol levels
may be explained by increased numbers of lipid-rich macrophages
infiltrating fibrous caps, resulting in plaques vulnerable to rupture.
The fact that premenopausal women appear to be protected in part from
the effects of hyperlipidemia on the formation of
vulnerable plaques suggests that estrogen may interfere with the
accumulating of foam cells in coronary plaques, a hypothesis
that has been supported by studies on nonhuman primates that
demonstrate an inhibitory effect of estrogen replacement
therapy on the uptake and degradation of LDL by the artery
wall.15 The mechanism of formation of eroded
plaques is unknown but may be related to a propensity to thrombosis
that is facilitated by components of cigarette
smoke.20 The apparent increased susceptibility of
the chronically ischemic myocardium (healed
infarction) to the development of fatal arrhythmias in patients
with hypertension and diabetes, as shown in this study, may reflect
microvascular disease that occurs in patients with diabetes and
hypertension.21 22 The mechanism of sudden death
in women with stable plaques and healed infarcts probably is
exacerbated by left ventricular hypertrophy
because the hearts of women with stable plaques and healed infarcts
were significantly heavier than other hearts in this study.
Previous autopsy studies have demonstrated that coronary
artery lesions in young women contain less calcium and dense fibrous
tissue than those of men and older women.23 24
The degree of calcification in ruptured plaques, which in the current
study were found predominantly in older women, has been demonstrated to
exceed that of eroded plaques, which are more common in younger
women.20 Erosions also occur over plaques that
result in a lesser degree of luminal narrowing, and this study
demonstrated that the degree of arterial narrowing at the
site of acute thrombus is less in young women than in older women.
These data suggest that symptomatic coronary
disease in young women may be angiographically less detectable, more
likely to be missed on clinical evaluation, and more likely to be
overlooked by ultrafast computed tomography.
The major limitation of this study is the inherent selection bias
caused by autopsy sampling. It is noteworthy that larger numbers of
sudden coronary death were seen in women <50 years of age,
which is contrary to epidemiologic studies of sudden death in men as
well as women. The most likely explanation for the large proportion of
deaths in younger women is a higher autopsy rate of unexpected death in
younger women without a history of heart disease. Deaths are
investigated with complete autopsy at the medical examiner's office if
there is no medical explanation of sudden death, which is more likely
to occur in younger women without a prior history. However, this
apparent bias is unlikely to effect the observation that in younger
women, plaque rupture and vulnerable plaques are uncommon findings.
These data support the hypothesis that the premenopausal state is
protective against plaque rupture as a mechanism of acute
coronary events.
The mechanisms of sudden coronary death appear to differ
in older women compared with younger women, and risk factors play
different roles in these groups of patients. Young women who die of
coronary artery thrombosis are often smokers with plaque
erosions with relatively little coronary narrowing, whereas
older women who die of coronary artery thrombosis are often
hypercholesterolemic and have plaque ruptures with
relatively severe coronary narrowing. The mechanism of sudden
coronary death in hypertensive women and women with diabetes
mellitus is often associated with healed myocardial infarcts and
cardiomegaly. These data suggest that risk factor modification may be
tailored to specific groups of women for the optimal reduction of
sudden coronary death.
Footnotes
The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the views of the Department of the Army, the Department of the Air Force, or the Department of Defense.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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  W. D. Nelson, A. G. Zenovich, H. C. Ott, C. Stolen, G. J. Caron, A. Panoskaltsis-Mortari, S. A. Barnes III, X. Xin, and D. A. Taylor Sex-Dependent Attenuation of Plaque Growth After Treatment With Bone Marrow Mononuclear Cells Circ. Res., December 7, 2007; 101(12): 1319 - 1327. [Abstract] [Full Text] [PDF]
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 I. Kusama, K. Hibi, M. Kosuge, N. Nozawa, H. Ozaki, H. Yano, S. Sumita, K. Tsukahara, J. Okuda, T. Ebina, et al. Impact of Plaque Rupture on Infarct Size in ST-Segment Elevation Anterior Acute Myocardial Infarction J. Am. Coll. Cardiol., September 25, 2007; 50(13): 1230 - 1237. [Abstract] [Full Text] [PDF]
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 O. C. Raffel, G. J. Tearney, D. D. Gauthier, E. F. Halpern, B. E. Bouma, and I.-K. Jang Relationship Between a Systemic Inflammatory Marker, Plaque Inflammation, and Plaque Characteristics Determined by Intravascular Optical Coherence Tomography Arterioscler. Thromb. Vasc. Biol., August 1, 2007; 27(8): 1820 - 1827. [Abstract] [Full Text] [PDF]
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 S. K. Mehta, J. R. McCrary, A. D. Frutkin, W. J.S. Dolla, and S. P. Marso Intravascular ultrasound radiofrequency analysis of coronary atherosclerosis: an emerging technology for the assessment of vulnerable plaque Eur. Heart J., June 1, 2007; 28(11): 1283 - 1288. [Abstract] [Full Text] [PDF]
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 S. Lavi, A. Prasad, E. H. Yang, V. Mathew, R. D. Simari, C. S. Rihal, L. O. Lerman, and A. Lerman Smoking Is Associated With Epicardial Coronary Endothelial Dysfunction and Elevated White Blood Cell Count in Patients With Chest Pain and Early Coronary Artery Disease Circulation, May 22, 2007; 115(20): 2621 - 2627. [Abstract] [Full Text] [PDF]
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H. Bolooki The Controversy in Clinical Results Among Men and Women After Coronary Bypass Operation J. Am. Coll. Cardiol., April 10, 2007; 49(14): 1559 - 1560. [Full Text] [PDF]
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 M Pasotti, F Prati, and E Arbustini The pathology of myocardial infarction in the pre- and post-interventional era Heart, November 1, 2006; 92(11): 1552 - 1556. [Full Text] [PDF]
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J J Wang, G Liew, T Y Wong, W Smith, R Klein, S R Leeder, and P Mitchell Retinal vascular calibre and the risk of coronary heart disease-related death Heart, November 1, 2006; 92(11): 1583 - 1587. [Abstract] [Full Text] [PDF]
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Developed in Collaboration With the European Heart, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) J. Am. Coll. Cardiol., September 5, 2006; 48(5): e247 - e346. [Full Text] [PDF]
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 Writing Committee Members, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society Europace, September 1, 2006; 8(9): 746 - 837. [Full Text] [PDF]
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R. Virmani, A. P. Burke, A. Farb, and F. D. Kolodgie Pathology of the vulnerable plaque. J. Am. Coll. Cardiol., April 18, 2006; 47(8 Suppl): C13 - C18. [Abstract] [Full Text] [PDF]
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L. J. Shaw, P. Raggi, T. Q. Callister, and D. S. Berman Prognostic value of coronary artery calcium screening in asymptomatic smokers and non-smokers Eur. Heart J., April 2, 2006; 27(8): 968 - 975. [Abstract] [Full Text] [PDF]
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 W. Whang, J. E. Manson, F. B. Hu, C. U. Chae, K. M. Rexrode, W. C. Willett, M. J. Stampfer, and C. M. Albert Physical Exertion, Exercise, and Sudden Cardiac Death in Women JAMA, March 22, 2006; 295(12): 1399 - 1403. [Abstract] [Full Text] [PDF]
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T. S. Perlstein and R. T. Lee Smoking, Metalloproteinases, and Vascular Disease Arterioscler. Thromb. Vasc. Biol., February 1, 2006; 26(2): 250 - 256. [Abstract] [Full Text] [PDF]
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V. Bittner Perspectives on Dyslipidemia and Coronary Heart Disease in Women J. Am. Coll. Cardiol., November 1, 2005; 46(9): 1628 - 1635. [Abstract] [Full Text] [PDF]
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 P. K. MacCallum Markers of Hemostasis and Systemic Inflammation in Heart Disease and Atherosclerosis in Smokers Proceedings of the ATS, April 1, 2005; 2(1): 34 - 43. [Abstract] [Full Text] [PDF]
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F D Kolodgie, R Virmani, A P Burke, A Farb, D K Weber, R Kutys, A V Finn, and H K Gold Pathologic assessment of the vulnerable human coronary plaque Heart, December 1, 2004; 90(12): 1385 - 1391. [Full Text] [PDF]
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 S. Kangavari, S. Matetzky, P. K. Shah, J. Yano, K.-Y. Chyu, M. C. Fishbein, and B. Cercek Smoking Increases Inflammation and Metalloproteinase Expression in Human Carotid Atherosclerotic Plaques Journal of Cardiovascular Pharmacology and Therapeutics, October 1, 2004; 9(4): 291 - 298. [Abstract] [PDF]
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A. P. Burke, F. D. Kolodgie, A. Zieske, D. R. Fowler, D. K. Weber, P. J. Varghese, A. Farb, and R. Virmani Morphologic Findings of Coronary Atherosclerotic Plaques in Diabetics: A Postmortem Study Arterioscler. Thromb. Vasc. Biol., July 1, 2004; 24(7): 1266 - 1271. [Abstract] [Full Text] [PDF]
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E. Durand, A. Scoazec, A. Lafont, J. Boddaert, A. Al Hajzen, F. Addad, M. Mirshahi, M. Desnos, A. Tedgui, and Z. Mallat In Vivo Induction of Endothelial Apoptosis Leads to Vessel Thrombosis and Endothelial Denudation: A Clue to the Understanding of the Mechanisms of Thrombotic Plaque Erosion Circulation, June 1, 2004; 109(21): 2503 - 2506. [Abstract] [Full Text] [PDF]
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J. A. Ambrose and R. S. Barua The pathophysiology of cigarette smoking and cardiovascular disease: An update J. Am. Coll. Cardiol., May 19, 2004; 43(10): 1731 - 1737. [Abstract] [Full Text] [PDF]
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 H. Romo, A. C. K.-B. Amaral, and J.-L. Vincent Effect of Patient Sex on Intensive Care Unit Survival Arch Intern Med, January 12, 2004; 164(1): 61 - 65. [Abstract] [Full Text] [PDF]
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A. Lafont Basic aspects of plaque vulnerability Heart, October 1, 2003; 89(10): 1262 - 1267. [Full Text] [PDF]
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