From the Department of Medicine, Vascular Biology and Hypertension
Program, University of Alabama at Birmingham.
Correspondence to Suzanne Oparil, MD, 1034 Zeigler Research Bldg, 703 S 19th St, Birmingham, AL 35294-0007. E-mail Soparil{at}uab.edu
Despite major
progress in detection, prevention, and treatment, coronary
artery disease remains the leading cause of death in the world. More
than half of all coronary deaths are sudden and unexpected,
occurring within 6 hours of the onset of symptoms and usually outside
the hospital.1 Coronary artery disease is
by far the most common pathology underlying the 300 000 cases of
sudden cardiac death occurring in the United States each
year.2 The insidious nature of sudden cardiac
death and the finality of the outcome represent major barriers
to development of effective preventative and therapeutic strategies.
This is a particular problem in women, in whom the risk of
coronary artery disease and of sudden death is lower than in
men and in whom the index of suspicion of serious
cardiovascular pathology remains low. Data from
carefully conducted postmortem studies of victims of sudden cardiac
death provide important insights into the pathogenesis of sudden
cardiac death and the risk factors that predispose to it.
In a study reported in the current issue of
Circulation, Burke et al relate cardiac pathology in 51
female victims of sudden death identified at the Office of the Chief
Medical Examiner of the State of Maryland to antecedent symptoms and
cardiac risk factors and compare these to findings in 15 female victims
of fatal trauma as control subjects.3 Several
striking findings emerge from the study: (1) Of the 36 deaths that were
witnessed, only 8 (22%) were preceded by chest pain; 12 (33%) were
preceded by other, nonspecific symptoms, including back pain,
dizziness, nausea and vomiting, shortness of breath, malaise, fatigue,
fever and chills, stomach distension, and tingling of the left
shoulder; and 16 (45%) were preceded by no symptoms whatsoever. (2)
Only one patient was receiving hormone replacement therapy. (3)
Coronary anatomy was different in younger (presumably
premenopausal) women, in whom acute coronary thrombosis was
most commonly related to plaque erosion versus older (presumably
postmenopausal) women in whom plaque rupture or healed myocardial
infarction without acute coronary thrombosis was the dominant
lesion. (4) Cardiac risk factors differed in the younger versus the
older women, with smoking predominant in the younger group and
hypercholesterolemia, hypertension, and
diabetes in the older.
Thirty of the 51 sudden coronary deaths in the Burke series
occurred in women <50 years of age, a surprising finding considering
the low incidence of coronary artery disease in this age/sex
group. In part this finding reflects, as the authors acknowledge,
inherent selection bias as the result of autopsy sampling. More
importantly, however, this calls attention to the lethal nature of
myocardial infarction in young women. The 26-year follow-up date from
the Framingham Heart Study demonstrated that women of all ages have an
excess risk over men of death caused by myocardial infarction, with
overall case-fatality rates of 32% for women versus 27% for
men.4 Furthermore, case-fatality rates for
myocardial infarction in women were higher at either extreme of the age
span, reaching 50% in the 35- to 44-year group and 46% in the 75- to
84-year group, far exceeding case-fatality rates for middle-aged women
or men of any age. Thus a myocardial infarction is a relatively rare
but deadly event in young women.
In the Framingham cohort, women had a lower incidence of sudden
coronary death than men, but in two thirds of women who died
suddenly, sudden cardiac death was the first clinical manifestation of
coronary heart disease.5 The absence of
typical premonitory symptoms of coronary heart disease in women
probably denied them the benefit of closer periodic
electrocardiographic surveillance and preventive medical interventions
that might have been lifesaving.
In the Burke series, women who died before age 50 years of
coronary causes were generally free of the risk factors most
commonly associated with heart disease in women: Only 20% were
hypertensive; mean total cholesterol was 194 mg/dL; HDL
cholesterol was 47 mg/dL; and mean glycosylated hemoglobin
was 7.1%. These values were similar to those seen in the trauma
control subjects. The most common risk factor in this group was
cigarette smoking (assessed by postmortem serum thiocyanate level) in
50% of subjects. Not assessed in the Burke study were some of the
newer, nontraditional cardiovascular risk factors,
including homocysteine levels, clotting factors such as
plasminogen activator inhibitor,
fibrinogen and von Willebrand factor, lipoprotein [a], and
chronic infections. Further study of the newer risk factors in
populations may be useful in identifying the population of young women
at increased risk for coronary events.
Cigarette smoking is clearly a powerful risk factor for myocardial
infarction and sudden cardiac death in women, probably by altering
clotting factors and platelet function as well as by accelerating
atherosclerosis and stimulating the sympathetic nervous
system. In one epidemiologic study, cigarette smoking was the strongest
risk factor for sudden cardiac death among women; all of those
Inhaled cigarette smoke has a variety of effects on clotting factors
and platelet function that could predispose to acute
coronary events. Data from Framingham have shown significantly
higher fibrinogen levels in the smoking than in the nonsmoking
population, and fibrinogen levels are an independent risk factor for
coronary artery disease.8 Smokers also
have increased platelet aggregation and prolonged clotting
times.9 Furthermore, and most importantly,
cigarette smoking appears to damage the endothelium,
decreasing prostacyclin synthesis and/or release, thus favoring
platelet aggregation and thrombosis.10
The most common lesion found in cigarette smokers in the Burke study
was plaque erosion. The average age of the 18 women with plaque erosion
was 45 years, and 14 of the 18 (78%) were smokers. Eroded
coronary artery plaques that were rich in smooth muscle cells
and proteoglycans but lacked a superficial lipid core and had not
ruptured into the lumen were recently described by this group in
victims of sudden cardiac death.11 Eroded plaques
accounted for 44% of a series of 50 consecutive cases of sudden death
caused by coronary thrombosis.11 In all
cases, thrombi were adherent to the eroded plaque. Patients with plaque
erosion were younger (44 versus 53 years) and more likely to be women
(50% versus 18%) than those with plaque rupture and had less luminal
narrowing and plaque calcification (23% versus 69%). Smooth muscle
cells predominated in the eroded plaques, whereas lipid-laden
macrophages, T-cells, and HLA-DR–positive cells (marker of
cell activation) were present in large numbers at the luminal
surface in the vicinity of the rupture site in ruptured plaques. The
finding of more cellular fibrous tissue and less dense calcified
fibrous tissue in coronary lesions in women is
consistent with earlier findings in both native and
coronary arteries and saphenous vein grafts of women compared
with men.12 Cellular fibrous plaques are
associated with an earlier stage of atherosclerosis
than dense, hypercellular, lipid-laden plaques, consistent with
the concept that atherosclerotic plaque formation is delayed in women
by 10 to 20 years, presumably because of the protective effects of
ovarian hormones.
Eroded plaques have an irregular surface and lack a protective covering
of endothelial cells. The authors postulated that
endothelial injury leads to platelet deposition
followed by smooth muscle cell proliferation and extracellular matrix
synthesis within the plaque. Procoagulant proteoglycans within the
plaque, in addition to endothelial
dysfunction/denudation and, particularly in smokers, activated
platelets and circulating clotting factors, would increase the risk
of arterial thrombosis. Further study is needed to identify
the specific factors that predispose to plaque erosion.
Coronary lesions in the older (postmenopausal and not hormone
replaced) women in the Burke study more closely resembled those usually
reported in men, for example, plaque rupture. Rupture of lipid-laden
plaques is the most common cause of acute coronary thrombosis
and associated clinical events, including unstable angina, acute
myocardial infarction, and sudden cardiac
death.13 Atherosclerotic plaques that are
vulnerable to rupture contain a dense infiltrate of lipid-laden
macrophages and lymphocytes within a fibrous cap that overlies
an acellular mass of lipids. Thinning and disruption of the fibrous cap
caused by release of metalloproteases from activated
macrophages within the plaque and/or other factors can lead to
plaque rupture and generation of a thrombogenic surface that may form
the nidus of an occlusive clot.
Hypercholesterolemia (mean total
cholesterol, 270 mg/dL) was the predominant risk factor in
women with plaque rupture. Recent clinical trials have shown that women
as well as men who have hypercholesterolemia
and/or have had previous coronary events benefit from
aggressive cholesterol lowering, presumably by removing
cholesterol from lipid-laden plaques and reducing the
probability of rupture.
Eighteen (35%) hearts in the Burke study showed evidence of healed
myocardial infarctions with stable plaques. Half of these women were
hypertensive, and the mean glycosylated hemoglobin in this group was
10.2%, suggesting a high prevalence of diabetes. These findings are
consistent with epidemiologic and clinical trial evidence that
elevated systolic and diastolic blood pressures are
independent risk factors for acute coronary events and
cardiovascular mortality rates in women. Successful
antihypertensive treatment reduces the risk of major
cardiovascular events in women as well as
men.14
Diabetes is a more important risk factor for coronary heart
disease in women than in men, negating much of the protective effects
of female sex.15 The Nurses' Health Study showed
that maturity-onset diabetes was associated with a threefold to
sevenfold increase in risk of a cardiovascular event,
and 14-year follow-up data from the Rancho Bernardo Study showed a
strong relation between fasting plasma glucose levels and
coronary heart disease mortality rates in women. The relative
hazard of ischemic heart disease death in diabetic subjects
versus nondiabetic subjects was 1.7 in men and 3.3 in women after
adjusting for age, systolic blood pressure,
cholesterol, body mass index, and cigarette smoking, by use
of the Cox regression model. Thus diabetes imposes a greater risk of
heart disease in women than in men, and the sex difference is
independent of other cardiovascular risk
factors,15 although both men and women with
diabetes tend to be more hyperlipidemic, more
hypertensive, and more obese than nondiabetic subjects. The mechanisms
by which diabetes accelerates the natural history of vascular disease
are poorly understood and probably do not relate to hyperglycemia per
se. Further study is urgently needed in this area.
Finally, it is remarkable that only one patient in the Burke study was
receiving hormone replacement therapy. Ovarian hormones are not
a panacea, as clearly evidenced by the appearance of fatal
coronary artery disease in women in the premenopausal age
group. Nevertheless, overwhelming epidemiologic evidence indicates that
ovarian hormones, particularly estrogen, protect against both
atherosclerosis and coronary events, which are
related to thrombus formation as well as
atherosclerosis per se.16 17 The
vasoprotective effects of estrogen are numerous, including stimulation
of endothelial repair in damaged vessels, restoration
of endothelium-dependent vasomotor mechanisms,
termination of lipid peroxidation, inhibition of platelet adhesion,
lipid lowering, inhibition of clotting factor synthesis, and many
others.18 19 Even while controlled clinical
trials are ongoing to more precisely delineate the benefits and risks
of hormone replacement therapy, it is important to exploit the known
benefits of these agents in protecting women from coronary
artery disease–related death.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
1.
Demirovic J, Myerburg RJ.
Epidemiology of sudden coronary death:
an overview. Prog Cardiovasc Dis. 1994;1:39–48.
2.
Virmani R, Roberts WC. Sudden cardiac death. Hum
Pathol. 1987;18:485–492.[Medline]
[Order article via Infotrieve]
3.
Burke AP, Farb A, Malcom GT, Liang Y, Smialek J,
Virmani R. Effect of risk factors on the mechanism of acute thrombosis
and sudden coronary death in women. Circulation. 1998;97:2110–2116.
4.
Lerner DJ, Kannel WB. Patterns of coronary
heart disease morbidity and mortality in the sexes: a 26-year follow-up
of the Framingham population. Am Heart J. 1986;111:383–390.[Medline]
[Order article via Infotrieve]
5.
Schatzkin A, Cupples LA, Heeren T, Morelock S, Kannel
WB. Sudden death in the Framingham Heart Study: differences in
incidence and risk factors by sex and coronary disease status.
Am J Epidemiol. 1984;120:888–899.
6.
Talbott E, Kuller LH, Perper J, Murphy PA. Sudden
unexpected death in women: biologic and psychosocial origins.
Am J Epidemiol. 1981;114:671–681.
7.
Schatzkin A, Cupples LA, Heeren T, Morelock S, Kannel
WB. The epidemiology of sudden unexpected
death: risk factors for men and women in the Framingham Heart Study.
Am Heart J. 1984;107:1300–1306.[Medline]
[Order article via Infotrieve]
8.
Kannel WB, D'Agostino RB, Belanger AJ. Fibrinogen,
cigarette smoking, and the risk of cardiovascular
disease: insights from the Framingham Study. Am Heart
J. 1987;113:1006–1010.[Medline]
[Order article via Infotrieve]
9.
Meade TW, Imeson J, Stirling Y. Effects of changes in
smoking and other characteristics on clotting factors and the risk of
ischemic heart disease. Lancet. 1987;2:986–988.[Medline]
[Order article via Infotrieve]
10.
Nowak J, Murray JJ, Oats JA, FitzGerald GA. Biochemical
evidence of a chronic abnormality in platelet and vascular function
in healthy individuals who smoke cigarettes. Circulation. 1987;76:6–14.
11.
Farb A, Burke AP, Tang AL, Liang Y, Mannan P, Smialek
J, Virmani R. Coronary plaque erosion without rupture into a
lipid core: a frequent cause of coronary thrombosis in sudden
coronary death. Circulation. 1996;93:1354–1363.
12.
Mautner SL, Lin F, Mautner GC, Roberts WC. Comparison
in women versus men of composition of atherosclerotic plaques in native
coronary arteries and saphenous veins used as
aortocoronary conduits. J Am Coll Cardiol. 1993;21:1312–1318.[Abstract]
13.
Davies M, Thomas AC. Plaque fissuring: the cause of
acute myocardial infarction, sudden ischemic death, and
crescendo angina. Br Heart J. 1985;53:363–373.
14.
Gueyffier F, Boutitie F, Boissel J-P, Pocock S, Coope
J, Cutler J, Ekbom T, Fagard R, Friedman L, Perry M, Prineas R, Schron
E. Effect of antihypertensive drug treatment on
cardiovascular outcomes in men and women. Ann
Intern Med. 1997;126:761–767.
15.
Barrett-Connor EL, Cohn BA, Wingard DL, Edelstein SL.
Why is diabetes mellitus a stronger risk factor for fatal
ischemic heart disease in women than in men? The Rancho
Bernardo Study. JAMA. 1991;265:627–631.
16.
Grady D, Rubin SM, Petitti DB, Fox CS, Black D,
Ettinger B, Ernster VL, Cummings SR. Hormone therapy to prevent disease
and prolong life in postmenopausal women. Ann Intern Med. 1992;117:1016–1037.
17.
Grodstein F, Stampfer MJ, Colditz GA, Willett WC,
Manson JE, Joffe M, Rosner B, Fuchs C, Hankinson SE, Hunter DJ,
Hennekens CH, Speizer FE. Postmenopausal hormone therapy and mortality.
N Engl J Med. 1997;336:1769–1775.
18.
White CR, Darley-Usmar V, Oparil S. Gender and
cardiovascular disease: recent insights. Trends
Cardiovasc Med. 1997;7:94–100.
19.
Kon Koh K, Mincemoyer R, Bui MN, Csako G, Pucino
F, Guetta V, Waclawiw M, Cannon RO. Effects of hormone-replacement
therapy on fibrinolysis in postmenopausal women.
N Engl J Med. 1997;336:683–690.
© 1998 American Heart Association, Inc.
Editorial
Pathophysiology of Sudden Coronary Death in Women
Implications for Prevention
Key Words: Editorials • death, sudden • women • thrombosis
45
years of age who died suddenly were heavy (>1 pack per day)
smokers.6 Furthermore, in the Framingham cohort,
the strongest predictors of sudden coronary death in women were
an increased hematocrit level and a decreased vital
capacity.7 Although cigarette smoking was not a
significant predictor of sudden unexpected death in this population,
the authors raised the possibility that smoking may have acted through
hematocrit or some other hematologic mechanism to increase risk.
This article has been cited by other articles:
 |
|
 |
|
  I. Goldenberg, M. Jonas, A. Tenenbaum, V. Boyko, S. Matetzky, A. Shotan, S. Behar, and H. Reicher-Reiss Current Smoking, Smoking Cessation, and the Risk of Sudden Cardiac Death in Patients With Coronary Artery Disease Arch Intern Med, October 27, 2003; 163(19): 2301 - 2305. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Bolego, A. Poli, and R. Paoletti Smoking and gender Cardiovasc Res, February 15, 2002; 53(3): 568 - 576. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||