Cardiovascular Research 53 (2002) 538549

www.elsevier.com/ locate/ cardiores

Review
Risk factors for coronary heart disease: implications of gender
a b b
Jeanine E. Roeters van Lennep , H. Tineke Westerveld , D. Willem Erkelens , Ernst E. van
a ,
*
der Wall
a
Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
b
Department of Internal Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands
Received 10 January 2001; accepted 21 May 2001
Abstract
It has been recognized over the past years that women form a distinct subpopulation within patients with coronary heart disease. This
phenomenon should be acknowledged in the management and in the assessment of coronary heart disease. Over the past years remarkable
progress has been made concerning our knowledge of cardiovascular risk factors related to gender. For instance, diabetes, high density
lipoproteins and triglycerides levels have been found to have a greater impact on coronary heart disease risk in women compared to men.
On the other hand, evidence showing that lipoprotein (a) is a cardiovascular risk factor seems to be stronger in men than in women. For
optimal treatment and prevention of coronary heart disease it is necessary to acknowledge that it is not self-evident that women and men
show simular responses to risk factors or to treatment. This review article addresses the role of cardiovascular risk factors focusing on the
differential impact they might have on men and women. 2002 Elsevier Science B.V. All rights reserved.
Keywords: Coronary disease; Epidemiology; Gender
1. Introduction both men and women [10,11], the impact of individual risk
factors might be different. The inuence of the menopause
Traditionally, coronary heart disease (CHD) has been on both cardiovascular risk factors and CHD is unique for
considered as a disease predominantly affecting men and women. Hence, women form a distinct subpopulation
for a long time women were not included in cardiovascular within patients with CHD. This should be acknowledged in
research programs. Although the life-time risk of CHD is the management and assessment of CHD. In the past years
one in three for women [1], they are still not fully aware of remarkable progress has been made concerning our knowl-
their risk of CHD and perceive the chance of dying of edge of cardiovascular risk factors. In this review we
breast cancer as far more likely than of CHD [2,3]. In the discuss the role of cardiovascular risk factors focusing on
early 1990s more attention was focused on women with the differential impact they have on men and women
CHD. Since then an increasing number of studies have (Table 1).
been published concerning womens cardiovascular health.
Several studies reported the existence of a gender differ-
ence in the use of diagnostic and therapeutic procedures 2. Epidemiology
for CHD. Women were less likely to be referred for
diagnostic and therapeutic procedures [46]. Also the CHD is the leading cause of death worldwide [12]. The
prognosis for women with CHD was worse than for men lifetime risk of developing CHD at age 40 years is 50% for
[79]. Although most risk factors contribute to CHD in men and 33% for women [1]. Over the past decades there
seems to be a trend towards a decrease in cardiovascular
mortality in North America and Western Europe [13].
*Corresponding author. Building 1, C5-P 28, PO Box 9600, Leiden
Most studies [1315] found that this change in mortality
University Medical Center, Albinusdreef 2, 2300 RC Leiden, The
Netherlands. Tel.: 131-71-526-2038; fax: 131-71-524-8116.
E-mail address: e.e.van der wall@lumc.nl (E.E. van der Wall). Time for primary review 36 days.
] ]
0008-6363/ 02/ $ see front matter 2002 Elsevier Science B.V. All rights reserved.
PI I : S0008- 6363( 01) 00388- 1

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J.E. Roeters van Lennep et al. / Cardiovascular Research 53 (2002) 538549 539
Table 1
upregulating agents [26]. In the presence of low endogen-
Risk factors for men and women
ous estrogen levels, LDL receptor activity is reduced. This
Risk factor Men Women
leads to the elevated LDL concentration observed in
postmenopausal women [27]. Elevated total cholesterol
Total cholesterol 111 111
LDL 111 111 and LDL levels are major risk factors for CHD in both
HDL 11 111
men and women [28,29]. Recent studies included a suf-
Triglycerides 1 11
cient number of women to show that they respond at least
Apo A-I 111 111
as well as men to cholesterol lowering therapy [3033].
Apo-B 111 111
The Scandinavian Simvastatin Survival Study (4S) showed
Apo(a) 11 1(1)
Smoking 11 11(1) that a reduction of high cholesterol level (range 5.58.0
Diabetes 11 111
mmol / l) in patients with CHD reduced major coronary
events by 34% in both men and women [33]. In the
Obesity
BMI 11 11
Cholesterol And Recurrent Events (CARE) trial [34],
WHR 111 111
which addressed the effect of pravastatin in patients with
Hypertension 11 11 average cholesterol levels (6.2 mmol / l), women had a risk
Family History 11 11(1)
reduction of major coronary events which was twice as
Hormones 111
large as that in men (46 vs. 20%, P50.048). Most of the
Homocysteine 1 1
primary prevention trials included only middle-aged men.
Fibrinogen 11 11
The Air Force/ Texas Coronary Atherosclerosis Prevention
Inammation (CRP) 1 11
Infection (HP, ChP) Study (AFCAPS/ TexCAPS) is the only study with a
Psychosocial factors 1 1
considerable number of women [35]. This study assessed
the effect of lipid lowering therapy in men and women
Apo(a), apolipoprotein (a); Apo A-I, apolipoprotein A-I; Apo B,
apolipoprotein B; BMI, body mass index; ChP, Chlamydia pneumoniae;
without clinically evident cardiovascular disease and with
CRP, C-reactive protein; HDL, high density lipoprotein cholesterol; HP,
average cholesterol (mean total cholesterol 5.71 mmol / l)
Helicobacter pylori; LDL, low-density lipoprotein cholesterol; WHR,
and LDL levels (mean LDL 3.89 mmol / l), but below-
waist hip ratio.
average high-density lipoprotein cholesterol (HDL) levels
was similar for men and women, although other reports (0.94 mmol / l for men and 1.03 mmol / l for women). This
showed that mortality trends are more favorable in women study included 997 women (15% of the study population).
than in men [1519]. Controversy exists about the causes After a follow-up period of 5.2 years, the incidence of rst
of this decline in mortality. Several studies [13,20] showed acute major coronary events was reduced by 37% in the
no decline in the incidence of hospitalization for a rst group who received lovastatin compared to those who
myocardial infarction, suggesting an important contribu- received placebo. Although the benecial effect of treating
tion of improvement in medical treatment and secondary elevated levels of cholesterol and LDL in both genders is
prevention of myocardial infarction. On the other hand, well established in secondary prevention, the use of lipid
data from the World Health Organization Multinational lowering drugs in primary prevention will probably be
Monitoring of Trends and Determinants in Cardiovascular reserved for high-risk patients for economic reasons.
Disease (WHO MONICA) project indicate that the decline
in case fatality of acute myocardial infarction can be 3.1.2. High-density lipoprotein cholesterol
explained by an absolute reduction in the incidence of this High-density cholesterol (HDL) levels are reported to
disease [16,19]. This effect might be the result of primary correlate closely and inversely with the risk of CHD
prevention and the modication of risk factors. [3638]. HDL levels are higher in women than in men
from young adulthood onwards [24,39,40]. Some studies
[41,42], but not all [24,25,43], have described a decrease in
3. Risk factors HDL levels following the menopause. The loss of protec-
tion from HDL is considered to be a major factor for the
3.1. Lipids increased coronary risk in postmenopausal women. It has
been suggested that low levels of HDL are more predictive
3.1.1. Total cholesterol and low-density lipoprotein of coronary artery disease in women than in men [38].
cholesterol Because of the higher level of HDL in women, a modi-
Total cholesterol and low-density lipoprotein cholesterol cation of the current National Cholesterol Education
(LDL) levels in men and women are similar up to |20 Program (NCEP) guidelines has been proposed with more
years of age [21]. In the third and fourth decades, aggressive targets for HDL in women [44]. Although it
cholesterol levels increase more sharply in men than in was initially presumed that low HDL levels pose no risk in
women [22]. Total cholesterol and LDL levels in women the absence of elevated LDL cholesterol, total cholesterol
rise or even exceed the levels in men following the or elevated triglyceride levels, several studies have recent-
menopause [2325]. Estrogens are potent LDL receptor- ly shown that an isolated low HDL level represents a

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540 J.E. Roeters van Lennep et al. / Cardiovascular Research 53 (2002) 538549
signicant risk of CHD [4547]. The Veterans Affairs marker for functional reverse cholesterol transport than
Cooperative Studies Program High-Density Lipoprotein HDL. Because HDL appears to be a less adequate predic-
Cholesterol Intervention Trial (VA-HIT) showed that a tor for CHD for men than for women, apo A-I measure-
modest increase in HDL levels in men with CHD and ment might be particularly valuable for men. This was
normal LDL levels (#3.6 mmol / l) resulted in a signicant supported by data from Kwiterovich et al. who found that
reduction in the risk of major cardiovascular events [46]. the level of apo A-I but not the level of HDL was an
So far, similar data for women are not available. In indicator of future CHD in 99 men and 104 women [59].
conclusion, the HDL level is an important factor affecting Atherogenic lipoproteins including LDL particles, very
atherosclerosis. It might be appropriate to apply a gender low density lipoprotein (VLDL) particles, and remnants of
specic approach in interpreting HDL levels because of the triglyceride-rich particles each contain one molecule of apo
higher absolute levels and possible greater impact of HDL B [63]. Consequently, apo B gives an accurate estimation
in women. of the total number of atherogenic particles [64]. The
composition of LDL particles, each containing one mole-
cule of apo B, is heterogeneous because of the variable
3.1.3. Triglycerides content of cholesterol. Smaller and denser LDL particles
Elevated levels of triglycerides have been associated are more atherogenic than larger, more buoyant ones
with an increased risk of CHD in men and women [48,49]. [65,66]. Therefore, apo B could be superior compared to
However, the role of plasma triglycerides as an indepen- LDL in determining CHD risk. This impression has been
dent risk factor is still elusive. First, there are methodo- supported by a number of studies in both women and men
logical difculties in interpreting triglyceride levels be- [59,67,68].
cause of high biologic intra- and inter-individual vari- Former problems with measuring these apolipoproteins
ability. Second, strong interactions exist between tri- have been overcome with the standardization of apo A-I
glycerides and other lipid factors. Elevated triglycerides and apo B [69,70]. In conclusion, both apo A-1 and apo B
are often seen with lower HDL levels and this combination might be better predictors for CHD in men and women and
has been associated with increased CHD risk [50]. A may therefore be more suitable for cardiovascular risk
meta-analysis including more than 46 000 men and nearly assessment than traditional lipid factors.
11 000 women showed for men and women, respectively,
a 32 and 76% increase in cardiovascular risk associated
with a 1-mmol / l increase in triglycerides. After adjustment 3.1.5. Lipoprotein(a)
for HDL and other risk factors, these risks were decreased Lipoprotein(a) consists of an LDL particle bound by a
to 14% in men and 37% in women, but this remained disulde bridge to apolipoprotein(a) that has a structure
statistically signicant for both genders [51]. It seems that resembling plasminogen. Lipoprotein(a) levels are indepen-
elevated triglycerides increase cardiovascular risk more in dent of other lipid parameters [71]. In women, circulating
women than in men, implying a gender difference in the lipoprotein(a) levels increase after the menopause just like
role of triglycerides in atherosclerosis [52]. Therefore, the other lipid parameters (triglycerides, LDL and total
analogous to the gender-specic approach for HDL, the cholesterol) [72].
latest NCEP guidelines have suggested that that the Most cross-sectional, case-control studies and prospec-
optimal levels for triglycerides may be lower for women tive studies show that lipoprotein(a) is a risk factor for
[44]. There is accumulating evidence that postprandial CHD. Prospective studies have reported that elevated
triglyceride levels are of major importance in determining levels of lipoprotein(a) (in particular of lipoprotein(a)
cardiovascular risk [5355] and that premenopausal levels of .0.30 g/ l) are associated with an increase in
women have lower triglyceride levels than men and CHD even after adjustment for other cardiovascular risk
postmenopausal women [5658]. factors in men [7375] and in women [73,76]. Other data
indicate that lipoprotein(a) is not as strong a risk factor for
CHD in women as in men [77,78] The results of these
3.1.4. Apolipoproteins A-I and B studies might have been biased because of the low CHD
Apolipoprotein A-I (apo A-I) is the major apolipoprotein event rate in women. Elevated lipoprotein(a) levels are
of HDL. Apo A-I has previously been reported to be a difcult to treat. The only drugs that lower lipoprotein(a)
better marker for CHD than HDL [5961]. Biologically, levels are nicotinic acid, and, as recently shown, hormone
this nding is plausible because not all HDL particles are replacement therapy (HRT) [79]. The reports on the effect
equal in size. Two subclasses of HDL can be recognized, of brate therapy on the synthesis of lipoprotein(a) are
HDL particles that only contain apo A-I, lipoprotein A-I, conicting [8082]. In conclusion, lipoprotein(a) can be
and particles that contain both apo A-I and apo A-II, regarded as a cardiovascular risk factor, but the evidence in
lipoprotein A-I /A-II. In general, lipoprotein A-I is consid- women is not as strong as in men. More data are necessary
ered to be more protective against CHD than lipoprotein to determine whether gender-related differences are clini-
AI /A-II [62]. Therefore, apo A-I levels may be a better cally relevant.

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J.E. Roeters van Lennep et al. / Cardiovascular Research 53 (2002) 538549 541
3.2. Smoking ceptives, elderly individuals and persons with isolated
hypertension [105]. However, with the large number of
Smoking is the most important preventable cause for the persons who are now considered for anti-hypertensive
development of CHD among men and women [83]. In the treatment, risk stratication is necessary for this treatment
United States 23.9% of women and 27.3% of men older to remain cost-effective. In conclusion, hypertension is a
than 18 years are current smokers [84]. A clear dose highly prevalent risk factor, especially in the elderly.
response relationship exists between the number of cigaret- Because of the tendency of risk factor clustering in the
tes smoked and the increase of risk of CHD [85,86]. presence of elevated blood pressure, hypertension is an
Fortunately, smoking cessation can considerably reduce important marker for patients with a high-risk prole. The
the risk of CHD in both genders [87,88]. After 23 years current guidelines for the treatment of hypertension have
of abstinence the level of risk of ex-smokers is similar to incorporated this view and emphasize risk factor interven-
that of never smokers regardless of the amount or duration tion [105,106].
of cigarettes smoked or the age at which they stopped
smoking [87]. This benecial effect is sustained at an older 3.4. Diabetes
age [89,90]. A number of studies [10,85,91] showed that
smoking appears to be a stronger risk factor for myocardial Diabetes is a powerful risk factor for CHD. Up to
infarction in middle-aged women than in men. Smoking 7580% of adult diabetic patients die of cardiovascular
has also been associated with an early menopause [9294]. diseases, and 75% of these deaths are caused by CHD
A recent study showed that current smoking decreased the [107]. Compared to diabetic men, who have a two-fold to
age of the natural menopause by 2 years and past smoking three-fold increased risk of CHD, diabetic women are
by 1 year [94]. In both men and women smoking has an reported to have a three-fold to seven-fold increased risk
unfavorable affect on plasma lipoproteins, in particular a [108111]. Thus, diabetes seems to eliminate the pre-
decrease in HDL [10,91,95]. Some studies have suggested menopausal female advantage in the prevalence of CHD
that this harmful effect on HDL is more pronounced in [112]. Mortality from myocardial infarction is signicantly
female smokers than in male smokers [10,95]. In conclu- higher in diabetic women than in non-diabetic women and
sion, smoking is a very important modiable risk factor in men with or without diabetes [113]. Lipid abnormalities
that seems to have at least a similar impact in women and frequently found in patients with diabetes type II are
men. elevated triglycerides, low HDL levels and small dense
LDL [114]. Goldschmidt et al. [108] showed that de-
3.3. Hypertension creased HDL and very low-density lipoprotein levels
predict CHD mortality in diabetic women but not in
Elevated systolic blood pressure is, as risk factor, at non-diabetic women or diabetic and non-diabetic men.
least as powerful as diastolic blood pressure [96,97]. Because of the poor prognosis for women with diabetes,
Isolated systolic hypertension, dened as a systolic blood aggressive treatment of cardiovascular risk factors, such as
pressure $160 mmHg and a diastolic blood pressure ,90 dyslipidemia, should be a high priority.
mmHg [98], is associated with an increased risk of
cardiovascular disease, stroke and all-cause mortality in 3.5. Obesity
men and women independent of other risk factors [99,100].
Isolated systolic hypertension is an indication of loss of Obesity is an independent risk factor for CHD in women
arterial elasticity, and its prevalence increases with age for as well as in men [115,116]. Willet and colleagues [115]
both sexes [101]. However, the rise in prevalence of showed in data from the Nurses Health Study that even
isolated systolic hypertension is steeper for women than women with a modestly increased body mass index (.25
2
for men $55 years of age [102]. Isolated systolic hyperten- and ,29 kg/ m ) had twice the risk of CHD as the leanest
2
sion is a common nding in elderly women, with a women (body mass index ,21 kg/ m ). Independent of
prevalence of 30% in women over 65 years of age [103]. overall obesity, the distribution of body fat is a deter-
The Systolic Hypertension in the Elderly Program (SHEP) minant of cardiovascular risk. It has been shown that
[98] has shown that both men and women with isolated truncal obesity, the so-called android habitus, confers a far
systolic hypertension benet from blood pressure control. higher risk than the peripheral or gynecoid body fat
Antihypertensive treatment reduced the incidence of stroke distribution [117119]. Waist-hip ratio and waist circum-
and non-fatal myocardial infarction (36 and 27%, respec- ference are highly correlated to the risk of CHD [117].
tively). Large long-term clinical trials have included both Rexrode and colleagues showed that women with a waist-
men and women and a meta-analysis of these studies did hip ratio of 0.76 or higher or waist circumference of $76.2
not show signicant gender differences in blood pressure cm had a markedly increased cardiovascular risk even after
and clinical outcome [104]. The current guidelines recom- adjustment for hypertension, diabetes and elevated choles-
mend antihypertensive therapy for a heterogeneous popula- terol levels [117]. Weight reduction was associated with an
tion including pregnant women or women on oral contra- improvement in risk factors and favorable changes in

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542 J.E. Roeters van Lennep et al. / Cardiovascular Research 53 (2002) 538549
triglycerides, high and low-density lipoprotein levels and 3.7. Homocysteine
blood pressure [120,121]. These observations suggest a
benecial effect of weight reduction, but direct evidence Over the past 10 years many studies have demonstrated
that weight loss reduces the risk of CHD is currently not a relationship between elevated levels of total plasma
available. Because of the difculty of achieving and homocysteine and increased risk of CHD [130]. For a long
maintaining weight loss, the prevention of obesity is of time data in women were scarce. When women were
utmost importance. included, they often formed a small percentage of the
population. In addition, in most cases estimations of
3.6. Family history vascular disease risk were given for the pooled sexes
[131]. Several studies that did include women have shown
Familial aggregation of CHD has been studied in both that the risk of vascular disease associated with elevated
women and men [122124]. Research on family history as homocysteine levels was at least as strong in women as in
a cardiovascular risk factor is complicated by methodo- men [131134]. Meta-analysis showed that the summary
logical factors such as identication and the denition of a odds ratio, based on a 5-mmol / l increment in plasma
positive family history and endpoints. These factors can homocysteine, was 1.6 for men and 1.8 for women [134].
act as confounding elements in comparing study results. Homocysteine levels rise with age, and fasting homo-
Also, the interaction between known risk factors and cysteine levels appear to be generally lower in women than
family history is evident. Therefore, the underlying mecha- in men [131]. Higher homocysteine levels in men might be
nism of how family history acts as a risk factor and the due to both their larger muscle mass since most plasma
separate impact of genetic and environmental factors is homocysteine is formed in conjunction with creatine-
still controversial. Several studies showed that a parental creatinine synthesis. Furthermore, a homocysteine-lower-
history of CHD increases the chance of premature onset of ing effect of estrogens has been reported in some studies
CHD in men [125]. As with most risk factors, results in [135,136]. This latter mechanism might also explain why
women became available much later. An early study some studies found that the levels of homocysteine in
showed that an independent effect on cardiovascular death postmenopausal women were higher than in premenopaus-
was only present in men of ,60 years but not in women al women and even men of a similar age [137,138]. It has
[126]. This study, however did not include a sufcient been suggested that the lower levels of homocysteine in
enough number of women to detect a signicant relation- premenopausal women contribute to the lower incidence of
ship between family history and risk of CHD. More recent vascular disease [139]. However, controversy still exists as
studies have reported that a family history of CHD is also to whether elevated homocysteine is a cause or a conse-
a risk factor for women [122124,127,128]. The Nurses quence of CHD. The majority of prospective studies in
Health Study showed an age-adjusted risk of non-fatal individuals initially free of CHD failed to show a signi-
CHD of 2.8 and an age-adjusted risk of fatal CHD of 5.0 cant association between elevated homocysteine and CHD
in women with a parental history of myocardial infarction incidence [140]. On the other hand, recent evidence
before 60 years of age [127]. Recently, some studies suggests that hyperhomocysteinemia is an independent risk
showed that the risk of premature CHD was higher in factor for arterial endothelial dysfunction and might there-
women compared to men [122,124,129]. A Finnish study fore act as pathogenic factor in the development of
showed that 76% of the women and 62% of the men who vascular disease [141].
survived a myocardial infarction had rst degree relatives
with CHD at ,65 years of age. In particular, the sisters of 3.8. Fibrinogen
female patients were at risk for CHD [124]. Jousilahti et al.
[122] showed that the adjusted risk of a rst coronary The haemostatic system plays an important role in the
event was markedly higher for women than for men pathogenesis of atherosclerosis. Several studies have dem-
(relative risk 2.64 vs. 1.64, respectively). However, the onstrated a signicant association of brinogen level and
practical implications of identifying a positive family cardiovascular disease in men and women [142144].
history as a risk factor are uncertain. At this moment the Plasma brinogen levels are higher in women and increase
only application is identifying individuals who are at risk. with smoking, age, post-menopausal status, obesity and
In the future genetic research may be able to identify use of oral contraceptives [145147]. Smoking cessation,
different subtypes in the familial risk and this could be alcohol use and weight loss have a lowering effect on
used for targeted counseling and therapy to prevent CHD. binogen levels [145,146]. In the Framingham study, the
In conclusion, women and men with a positive family risk for CHD associated with brinogen diminished with
history have an increased risk of premature coronary age in women but not in men [148]. After the menopause,
events. Recent results indicated that this risk might be levels of brinogen increase, but as antithrombotic factors
higher in women compared to men. To date, neither the like antithrombin III and plasminogen increase, the net
evaluation nor the interpretation of family history as a risk effect of the menopause is unclear [149]. Several drugs
factor for CHD are completely established. including brates, propranolol, nislodipine and ticlopidine

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J.E. Roeters van Lennep et al. / Cardiovascular Research 53 (2002) 538549 543
[150] and HRT have been reported to lower binogen 3.11. Psychosocial factors
levels [151]. In conclusion, brinogen is an important
cardiovascular risk factor that can be modied by external Psychosocial factors such as socio-economic status and
factors (e.g. drug therapy), life style and the female social support have been frequently linked to CHD in both
hormonal status. men and women [169172]. Although initially data for
women were scarce and inconclusive, several studies have
addressed the role of psychosocial issues for women
3.9. Infections
[169,172,173]. A low education level has been associated
with an increased incidence of CHD, mainly because of the
The possible role of chronic infections and CHD has
strong inverse correlation of atherogenic risk factors and
been investigated in a number of studies. Most of these
education attainment. It is a consistent nding that men
studies relate to Helicobacter pylori and Chlamydia pneu-
and women with lower education have a higher incidence
moniae. A great number of studies found evidence for an
of elevated blood pressure, total cholesterol, body mass
association between C. pneumoniae antibodies and CHD
index and current smoking [174176]. The psychosocial
[152]. More recently, C. pneumoniae studies have been
work environment also seems predictive for future CHD.
published both supporting [153,154] and refuting [155
The Whitehall II study showed that men and women with
157] its role in the pathogenesis of CHD. Most of these
low job control, either self-reported or independently
studies have only included men or did not consider women
assessed, had a higher risk of newly diagnosed CHD [177].
separately. Two studies carried out a separate analysis for
Subjects with low job control had an odds ratio for any
men and women. One study found a possible association
subsequent coronary event of 1.93 compared to subjects
between circulating C. pneumoniae DNA and CHD in men
with high job control. This association could not be
only [153]. The other study found that serological evidence
explained by employment grade or classic coronary risk
of an C. pneumoniae infection was associated with an
factors [177]. In conclusion, these ndings support the
atherogenic lipid prole in men but not in women [158].
signicance of psychosocial factors for CHD for both men
However, because of the relatively small number of
and women.
women included, these results might be coincidental and
lack statistical power. Therefore, further research is needed
3.12. Estrogens
to investigate these associations. Of the ve prospective
studies [159163] which examined whether H. pylori was
Unique to women is the inuence of their hormonal
associated with cardiovascular disease, three studies
status on CHD. In comparison with men of a similar age
[159,161,163] included women. None of these prospective
and postmenopausal women, the incidence of CHD is
studies found any statistically signicant evidence for a
signicantly lower in premenopausal women suggesting
relationship between CHD and H. pylori infection. In
that endogenous estrogens have a protective effect on the
summary, data are not available to show that infective
development of CHD [94,178,179]. Estrogens affect the
agents are of major importance as risk factors for CHD in
atherosclerotic process through a variety of mechanisms.
either men or women.
Estrogens have been reported to have a lowering effect on
total cholesterol and LDL [23,25,180], lipoprotein(a) [72]
3.10. Inammation and homocysteine [135,136] levels. HDL levels are in-
creased [181184] and postprandial lipid metabolism
Inammation as assessed by C-reactive protein (CRP) improved by estrogens [185]. Moreover, estrogens have an
levels has been demonstrated to predict cardiovascular acute vasodilatory effect on the vessel wall and an
events in healthy middle-aged [164,165] and elderly [166] atheroprotective effect involving inhibition of smooth-mus-
men. Recently, the predictive value of CRP has been cle cell proliferation [186]. The role of exogenous es-
investigated in middle-aged and elderly women [166,167]. trogens is controversial. Meta-analyses of multiple ob-
Interestingly, both studies found that the relative risks servational studies suggested a 3550% reduction of CHD
associated with CRP were higher for women than for men. associated with the use of estrogens after the menopause
It remains to be investigated whether these results reect [187]. However, two double blind randomized trials
true sex differences or whether they are chance. In a recent [181,184] addressing this topic both failed to demonstrate
study, Ridker et al. [168] raised the possibility of adding a favorable effect of HRT for the secondary prevention of
CRP measurements to the standard lipid screening, since CHD. The Hormone Estrogen Replacement Study (HERS)
CRP was the most signicant and strongest risk factor for [184], which compared HRT consisting of estrogen plus
cardiovascular events in healthy middle-aged women progestin with placebo in women with CHD showed no
compared to measurements of homocysteine, lipids and overall benet of HRT on coronary death and non-fatal
apolipoproteins. In conclusion, evidence of the importance myocardial infarction, despite an 11% decrease in LDL
of CRP as marker for future CHD is becoming more and a 10% increase in HDL. Moreover, an increase was
convincing for women. seen in the relative risk of venous thrombotic events and

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544 J.E. Roeters van Lennep et al. / Cardiovascular Research 53 (2002) 538549
gallbladder disease of 2.89 and 1.38, respectively. Interest- that risk factors such as smoking, family history and
ingly, a time trend was seen with more coronary events in inammation characterized as C-reactive protein, have a
the 1st year with HRT, and fewer in years 4 and 5. more negative inuence on CHD in women than in men.
Therefore, the HERS investigators recommended not On the other hand the evidence showing that lipoprotein(a)
initiating this hormone regiment for secondary prevention is a cardiovascular risk factor seems to be stronger in men
of CHD, but given the late benet of long-term use, it than in women. The majority of cardiovascular risk factors
could be appropriate to continue HRT for women who show no important differences between the genders. For
already use this therapy. Recently a double-blind placebo optimal treatment and prevention of CHD it is necessary to
controlled trial examined the effect of estrogen, estrogen acknowledge that it is not self-evident that women and
with progesterone or placebo on the progression of cor- men show a similar response to risk factors or to treatment.
onary atherosclerosis in women with CHD [181]. No effect Therefore, it is essential that studies present results accord-
was found for estrogen alone or estrogen in combination ing to gender, in order to comprehend to what extent CHD
with progesterone on the progression of coronary athero- prevention measures are similar for men and women.
sclerosis. Despite these landmark studies, many issues
concerning hormone use in postmenopausal women are
still unresolved. Estrogen therapy might be more protective
References
in preventing atherosclerosis than in slowing down the
progression of established disease. No data for estrogen
[1] Lloyd-Jones DM, Larson MG, Beiser A, Levy D. Lifetime risk of
therapy in primary prevention are currently available. The
developing coronary heart disease. Lancet 1999;353:8992.
Womens Health Initiative has randomized 27 500 post-
[2] Legato MJ, Padus E, Slaughter E. Womens perceptions of their
general health, with special reference to their risk of coronary artery
menopausal women to conjugated equine estrogen with
disease: results of a national telephone survey. J Womens Health
continuous progestin in a primary prevention trial; results
1997;6:189198.
are awaited in 2005 [188]. A new therapeutic approach is
[3] Pilote L, Hlatky MA. Attitudes of women toward hormone therapy
the use of Selective Estrogen Receptor Modulators
and prevention of heart disease. Am Heart J 1995;129:12371238.
(SERMs), non-hormonal agents which share the effects of
[4] Tobin JN, Wassertheil SS, Wexler JP et al. Sex bias in considering
coronary bypass surgery. Ann Intern Med 1987;107:1925. estrogen that are favorable on bone and the cardiovascular
[5] Ayanian JZ, Epstein AM. Differences in the use of procedures
system but not in other tissues such as the breast and
between women and men hospitalized for coronary heart disease.
endometrium [189]. In healthy menopausal women ralox-
New Engl J Med 1991;325:221225.
ifen had a favorable effect on cardiovascular risk by
[6] Steingart RM, Packer M, Hamm P et al. Sex differences in the
decreasing LDL, brinogen and lipoprotein(a) levels [189].
management of coronary artery disease. Survival and Ventricular
Currently ongoing is the RUTH (Raloxifen Use for the Enlargement Investigators. New Engl J Med 1991;325:226230.
[7] Kostis JB, Wilson AC, ODowd K et al. Sex differences in the
Heart) trial which aims to enroll 10 000 post-menopausal
management and long-term outcome of acute myocardial infarction.
women, with a scheduled follow-up period of |5 years
A statewide study. MIDAS Study Group. Myocardial Infarction
[190]. In conclusion, at this time the benet of exogenous
Data Acquisition System. Circulation 1994;90:17151730.
estrogens for the prevention of CHD is unconvincing.
[8] Marrugat J, Sala J, Masia R et al. Mortality differences between men
Therefore, the use of HRT is as yet not recommended, and women following rst myocardial infarction. RESCATE Inves-
tigators. Recursos Empleados en el Sindrome Coronario Agudo y
particularly since there are other agents (e.g. statins) that
Tiempo de Espera. J Am Med Assoc 1998;280:14051409.
have been indisputably proven to be benecial in risk
[9] Nettleman MD, Banitt L, Barry W, Awan I, Gordon EE. Predictors
factor management. However, it should be realized that in
of survival and the role of gender in postoperative myocardial
the decision whether or not to prescribe HRT, cardiovascu-
infarction. Am J Med 1997;103:357362.
lar issues are only one factor among others such as [10] Njolstad I, Arnesen E, Lund-Larsen PG. Smoking, serum lipids,
blood pressure, and sex differences in myocardial infarction. A
osteoporosis, peri-menopausal symptoms and cancer con-
12-year follow-up of the Finnmark Study. Circulation 1996;93:450
cerns.
456.
[11] Jousilahti P, Vartiainen E, Tuomilehto J, Puska P. Sex, age, car-
diovascular risk factors, and coronary heart disease: a prospective
4. Conclusions follow-up study of 14 786 middle-aged men and women in Finland.
Circulation 1999;99:11651172.
[12] Murray CJ, Lopez AD. Mortality by cause for eight regions of the
In this review an update is provided on the role of a
world: Global Burden of Disease Study. Lancet 1997;349:1269
number of risk factors with emphasis on possible differ-
1276.
ences between men and women. Except for female hor-
[13] Rosamond WD, Chambless LE, Folsom AR et al. Trends in the
monal status, no risk factor has been recognized as acting incidence of myocardial infarction and in mortality due to coronary
heart disease, 19871994. New Engl J Med 1998;339:861867.
on one gender but not on the other. This nding indicates
[14] Khaw KT. Epidemiology of coronary heart disease in women. In:
that the pathogenesis of CHD is very similar for men and
Julian DG, Wenger NK, editors, Women and heart disease, St. Louis,
women. Yet, diabetes, HDL and triglycerides levels have
MO, Mosby, 1997, pp. 720.
been found to have a greater impact on CHD risk in
[15] Sytkowski PA, DAgostino RB, Belanger A, Kannel WB. Sex and
women compared to men. In addition, there are indications time trends in cardiovascular disease incidence and mortality: the

b
y

g
u
e
s
t

o
n

N
o
v
e
m
b
e
r

9
,

2
0
1
3
h
t
t
p
:
/
/
c
a
r
d
i
o
v
a
s
c
r
e
s
.
o
x
f
o
r
d
j
o
u
r
n
a
l
s
.
o
r
g
/
D
o
w
n
l
o
a
d
e
d

f
r
o
m

J.E. Roeters van Lennep et al. / Cardiovascular Research 53 (2002) 538549 545
Framingham Heart Study, 19501989. Am J Epidemiol angina pectoris: ndings from the Scandinavian Simvastatin Surviv-
1996;143:338350. al Study (4S). Circulation 1997;96:42114218.
[16] Sans S, Kesteloot H, Kromhout D. The burden of cardiovascular [34] Randomised trial of cholesterol lowering in 4444 patients with
diseases mortality in Europe. Task Force of the European Society of coronary heart disease: the Scandinavian Simvastatin Survival Study
Cardiology on Cardiovascular Mortality and Morbidity Statistics in (4S). Lancet 1994;344:13831389.
Europe. Eur Heart J 1997;18:12311248. [35] Downs JR, Cleareld M, Weis S et al. Primary prevention of acute
[17] Morbidity and mortality: 1996 chartbook on cardiovascular, lung, coronary events with lovastatin in men and women with average
and blood diseases, Bethesda, MD, National Institutes of Health, cholesterol levels: results of AFCAPS/ TexCAPS. Air Force/ Texas
1996. Coronary Atherosclerosis Prevention Study. J Am Med Assoc
1998;279:16151622. [18] Marmot MG. Socio-economic factors in cardiovascular disease. J
Hypertens 1996;14(Suppl):S201S205. [36] Jacobs Jr. DR, Mebane IL, Bangdiwala SI, Criqui MH, Tyroler HA.
High density lipoprotein cholesterol as a predictor of cardiovascular [19] Tunstall-Pedoe H, Kuulasmaa K, Mahonen M et al. Contribution of
disease mortality in men and women: the follow-up study of the trends in survival and coronary-event rates to changes in coronary
Lipid Research Clinics Prevalence Study. Am J Epidemiol heart disease mortality: 10-year results from 37 WHO MONICA
1990;131:3247. project populations. Monitoring trends and determinants in car-
diovascular disease. Lancet 1999;353:15471557. [37] Gordon DJ, Probsteld JL, Garrison RJ et al. High-density lipopro-
tein cholesterol and cardiovascular disease. Four prospective Ameri- [20] McGovern PG, Pankow JS, Shahar E et al. Recent trends in acute
can studies. Circulation 1989;79:815. coronary heart disease mortality, morbidity, medical care, and
risk factors. The Minnesota Heart Survey Investigators. New Engl J [38] Stensvold I, Urdal P, Thurmer H et al. High-density lipoprotein
Med 1996;334:884890. cholesterol and coronary, cardiovascular and all cause mortality
among middle-aged Norwegian men and women. Eur Heart J [21] Trends in serum cholesterol levels among US adults aged 20 to 74
1992;13:11551163. years. Data from the National Health and Nutrition Examination
Surveys, 1960980. National Center for Health Statistics-National [39] Donahue RP, Orchard TJ, Becker DJ, Kuller LH, Drash AL.
Heart, Lung, and Blood Institute Collaborative Lipid Group. J Am Physical activity, insulin sensitivity, and the lipoprotein prole in
Med Assoc 1987;257:937942. young adults: the Beaver County Study. Am J Epidemiol
1988;127:95103. [22] Kuhn FE, Rackley CE. Coronary artery disease in women. Risk
factors, evaluation, treatment, and prevention. Arch Intern Med [40] Laurier D, Chau NP, Segond P. Cholesterol and other cardiovascular
1993;153:26262636. risk factors in a working population in Ile-de-France (France): rst
results of the PCV-METRA study. Eur J Epidemiol 1992;8:693 [23] Tremollieres FA, Pouilles JM, Cauneille C, Ribot C. Coronary heart
701. disease risk factors and menopause: a study in 1684 French women.
Atherosclerosis 1999;142:415423. [41] Jensen J, Nilas L, Christiansen C. Inuence of menopause on serum
[24] Brown SA, Hutchinson R, Morrisett J et al. Plasma lipid, lipoprotein lipids and lipoproteins. Maturitas 1990;12:321331.
cholesterol, and apoprotein distributions in selected US com- [42] Matthews KA, Meilahn E, Kuller LH et al. Menopause and risk
munities. The Atherosclerosis Risk in Communities (ARIC) Study. factors for coronary heart disease. New Engl J Med 1989;321:641
Arterioscler Thromb 1993;13:11391158. 646.
[25] Davis CE, Pajak A, Rywik S et al. Natural menopause and [43] Peters HW, Westendorp IC, Hak AE et al. Menopausal status and
cardiovascular disease risk factors. The Poland and US Collabora- risk factors for cardiovascular disease. J Intern Med 1999;246:521
tive Study on Cardiovascular Disease Epidemiology. Ann Epidemiol 528.
1994;4:445448. [44] Mosca L, Grundy SM, Judelson D et al. Guide to Preventive
[26] Parini P, Angelin B, Rudling M. Importance of estrogen receptors in Cardiology for Women. AHA/ACC Scientic Statement Consensus
hepatic LDL receptor regulation. Arterioscler Thromb Vasc Biol panel statement. Circulation 1999;99:24802484.
1997;17:18001805. [45] Goldbourt U, Yaari S, Medalie JH. Isolated low HDL cholesterol as
[27] Abbey M, Owen A, Suzakawa M, Roach P, Nestel PJ. Effects of a risk factor for coronary heart disease mortality. A 21-year follow-
menopause and hormone replacement therapy on plasma lipids, up of 8000 men. Arterioscler Thromb Vasc Biol 1997;17:107113.
lipoproteins and LDL-receptor activity. Maturitas 1999;33:259269. [46] Rubins HB, Robins SJ, Collins D et al. Gembrozil for the
[28] Stamler J, Dyer AR, Shekelle RB, Neaton J, Stamler R. Relationship secondary prevention of coronary heart disease in men with low
of baseline major risk factors to coronary and all-cause mortality, levels of high-density lipoprotein cholesterol. Veterans Affairs High-
and to longevity: ndings from long-term follow-up of Chicago Density Lipoprotein Cholesterol Intervention Trial Study Group.
cohorts. Cardiology 1993;82:191222. New Engl J Med 1999;341:410418.
[29] Manolio TA, Pearson TA, Wenger NK et al. Cholesterol and heart [47] Miller M, Seidler A, Kwiterovich PO, Pearson TA. Long-term
disease in older persons and women. Review of an NHLBI predictors of subsequent cardiovascular events with coronary artery
workshop. Ann Epidemiol 1992;2:161176. disease and desirable levels of plasma total cholesterol. Circulation
[30] Waters D, Higginson L, Gladstone P et al. Effects of cholesterol 1992;86:11651170.
lowering on the progression of coronary atherosclerosis in women. [48] Bass KM, Newschaffer CJ, Klag MJ, Bush TL. Plasma lipoprotein
A Canadian Coronary Atherosclerosis Intervention Trial (CCAIT) levels as predictors of cardiovascular death in women. Arch Intern
substudy. Circulation 1995;92:24042410. Med 1993;153:22092216.
[31] Prevention of cardiovascular events and death with pravastatin in [49] LaRosa JC. Triglycerides and coronary risk in women and the
patients with coronary heart disease and a broad range of initial elderly. Arch Intern Med 1997;157:961968.
cholesterol levels. The Long-Term Intervention with Pravastatin in [50] Gaziano JM, Hennekens CH, ODonnell CJ, Breslow JL, Buring JE.
Ischaemic Disease (LIPID) Study Group. New Engl J Med Fasting triglycerides, high-density lipoprotein, and risk of myocar-
1998;339:13491357. dial infarction. Circulation 1997;96:25202525.
[32] Lewis SJ, Sacks FM, Mitchell JS et al. Effect of pravastatin on [51] Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor
cardiovascular events in women after myocardial infarction: the for cardiovascular disease independent of high-density lipoprotein
Cholesterol And Recurrent Events (CARE) trial. J Am Coll Cardiol cholesterol level: a meta-analysis of population-based prospective
1998;32:140146. studies. J Cardiovasc Risk 1996;3:213219.
[33] Miettinen TA, Pyorala K, Olsson AG et al. Cholesterol-lowering [52] Stensvold I, Tverdal A, Urdal P, Graff-Iversen S. Non-fasting serum
therapy in women and elderly patients with myocardial infarction or triglyceride concentration and mortality from coronary heart disease

b
y

g
u
e
s
t

o
n

N
o
v
e
m
b
e
r

9
,

2
0
1
3
h
t
t
p
:
/
/
c
a
r
d
i
o
v
a
s
c
r
e
s
.
o
x
f
o
r
d
j
o
u
r
n
a
l
s
.
o
r
g
/
D
o
w
n
l
o
a
d
e
d

f
r
o
m

546 J.E. Roeters van Lennep et al. / Cardiovascular Research 53 (2002) 538549
and any cause in middle aged Norwegian women. Br Med J [72] Brown SA, Morrisett JD, Boerwinkle E, Hutchinson R, Patsch W.
1993;307:13181322. The relation of lipoprotein(a) concentrations and apolipoprotein(a)
phenotypes with asymptomatic atherosclerosis in subjects of the [53] Ebenbichler CF, Kirchmair R, Egger C, Patsch JR. Postprandial
Atherosclerosis Risk in Communities (ARIC) Study. Arterioscler state and atherosclerosis. Curr Opin Lipidol 1995;6:286290.
Thromb 1993;13:15581566. [54] Bjorkegren J, Boquist S, Samnegard A et al. Accumulation of
[73] Nguyen TT, Ellefson RD, Hodge DO et al. Predictive value of apolipoprotein C-I-rich and cholesterol-rich VLDL remnants during
electrophoretically detected lipoprotein(a) for coronary heart disease exaggerated postprandial triglyceridemia in normolipidemic patients
and cerebrovascular disease in a community-based cohort of 9936 with coronary artery disease. Circulation 2000;101:227230.
men and women. Circulation 1997;96:13901397. [55] Weintraub MS, Grosskopf I, Rassin T et al. Clearance of chylomic-
[74] Schaefer EJ, Lamon-Fava S, Jenner JL et al. Lipoprotein(a) levels ron remnants in normolipidaemic patients with coronary artery
and risk of coronary heart disease in men. The Lipid Research disease: case control study over 3 years. Br Med J 1996;312:936
Clinics Coronary Primary Prevention Trial. J Am Med Assoc 939.
1994;271:9991003. [56] Halkes CJM, Castro Cabezas M, van Wijk JPH, Erkelens DW.
[75] Assmann G, Schulte H, von Eckardstein A. Hypertriglyceridemia Obesity overrules the benecial gender effects on triglyceride
and elevated lipoprotein(a) are risk factors for major coronary events metabolism in non-obese subjects. Atherosclerosis 2000;151:S97.
in middle-aged men. Am J Cardiol 1996;77:11791184. [57] Couillard C, Bergeron N, Prudhomme D et al. Gender difference in
[76] Bostom AG, Gagnon DR, Cupples LA et al. A prospective postprandial lipemia: importance of visceral adipose tissue accumu-
investigation of elevated lipoprotein (a) detected by electrophoresis lation. Arterioscler Thromb Vasc Biol 1999;19:24482455.
and cardiovascular disease in women. The Framingham Heart Study. [58] van Beek AP, Ruijter-Heijstek FC, Erkelens DW, de Bruin TW.
Circulation 1994;90:16881695. Menopause is associated with reduced protection from postprandial
[77] Wild SH, Fortmann SP, Marcovina SM. A prospective case-control lipemia. Arterioscler Thromb Vasc Biol 1999;19:27372741.
study of lipoprotein(a) levels and apo(a) size and risk of coronary [59] Kwiterovich PO, Coresh J, Smith HH et al. Comparison of the
heart disease in Stanford Five-City Project participants. Arterioscler plasma levels of apolipoproteins B and A-1, and other risk factors in
Thromb Vasc Biol 1997;17:239245. men and women with premature coronary artery disease. Am J
[78] Seman LJ, de Luca C, Ordovas JM et al. Lipoprotein(a)-cholesterol Cardiol 1992;69:10151021.
compared with sinking prebeta lipoprotein and associated relative [60] OBrien T, Nguyen TT, Hallaway BJ et al. The role of lipoprotein
risk of heart disease in the Framingham Heart Study. Circulation A-I and lipoprotein A-I /A-II in predicting coronary artery disease.
1997;96(Suppl):I-304. Arterioscler Thromb Vasc Biol 1995;15:228231.
[79] Noma A, Maeda S, Okuno M, Abe A, Muto Y. Reduction of serum [61] Genest Jr. J, McNamara JR, Ordovas JM et al. Lipoprotein
lipoprotein(a) levels in hyperlipidaemic patients with alpha- cholesterol, apolipoprotein A-I and B and lipoprotein (a) abnor-
tocopheryl nicotinate. Atherosclerosis 1990;84:213217. malities in men with premature coronary artery disease. J Am Coll
Cardiol 1992;19:792802. [80] Neele DM, Kaptein A, Huisman H, de Wit EC, Princen HM. No
[62] Colvin PL, Parks JS. Metabolism of high density lipoprotein effect of brates on synthesis of apolipoprotein(a) in primary
subfractions. Curr Opin Lipidol 1999;10:309314. cultures of cynomolgus monkey and human hepatocytes: apolipo-
[63] Beisiegel U. Lipoprotein metabolism. Eur Heart J 1998;19(Suppl protein A-I synthesis increased. Biochem Biophys Res Commun
A):A20A23. 1998;244:374378.
[64] Sniderman AD, Cianone K. Measurement of apoproteins: time to [81] Shlipak MG, Simon JA, Vittinghoff E et al. Estrogen and progestin,
improve the diagnosis and treatment of the atherogenic dyslipo- lipoprotein(a), and the risk of recurrent coronary heart disease events
proteinemias. Clin Chem 1996;42:489491. after menopause. J Am Med Assoc 2000;283:18451852.
[65] Zambon A, Hokanson JE, Brown BG, Brunzell JD. Evidence for a [82] Espeland MA, Marcovina SM, Miller V et al. Effect of post-
new pathophysiological mechanism for coronary artery disease menopausal hormone therapy on lipoprotein(a) concentration. PEPI
regression: hepatic lipase-mediated changes in LDL density. Circu- Investigators. Postmenopausal Estrogen/ Progestin Interventions.
lation 1999;99:19591964. Circulation 1998;97:979986.
[66] Lamarche B, Tchernof A, Moorjani S et al. Small, dense low- [83] Hennekens CH. Coronary disease: risk intervention. In: Julian DG,
density lipoprotein particles as a predictor of the risk of ischemic Wenger NK, editors, Women and heart disease, 1st ed., London:
heart disease in men. Prospective results from the Quebec Car- Martin Dunitz, 1997, pp. 3948.
diovascular Study. Circulation 1997;95:6975. [84] 2000 Heart and Stroke Statistical Update. Dallas, TX, American
[67] Lamarche B, Moorjani S, Lupien PJ et al. Apolipoprotein A-I and B Heart Association 2000.
levels and the risk of ischemic heart disease during a 5-year [85] Nyboe J, Jensen G, Appleyard M, Schnohr P. Smoking and the risk
follow-up of men in the Quebec cardiovascular study. Circulation of rst acute myocardial infarction. Am Heart J 1991;122:438447.
1996;94:273278. [86] Willett WC, Green A, Stampfer MJ et al. Relative and absolute
[68] Westerveld HT, van Lennep JE, van Lennep HW et al. Apolipo- excess risks of coronary heart disease among women who smoke
protein B and coronary artery disease in women: a cross-sectional cigarettes. New Engl J Med 1987;317:13031309.
study in women undergoing their rst coronary angiography. [87] Kawachi I, Colditz GA, Stampfer MJ et al. Smoking cessation in
Arterioscler Thromb Vasc Biol 1998;18:11011107. relation to total mortality rates in women. A prospective cohort
[69] Marcovina SM, Albers JJ, Kennedy H et al. International Federation study. Ann Intern Med 1993;119:9921000.
of Clinical Chemistry standardization project for measurements of [88] van Berkel TF, Boersma H, Roos-Hesselink JW, Erdman RA,
apolipoproteins A-I and B. IV. Comparability of apolipoprotein B Simoons ML. Impact of smoking cessation and smoking interven-
values by use of international reference material. Clin Chem tions in patients with coronary heart disease. Eur Heart J
1994;40:586592. 1999;20:17731782.
[70] Marcovina SM, Albers JJ, Henderson LO, Hannon WH. Internation- [89] LaCroix AZ, Lang J, Scherr P et al. Smoking and mortality among
al Federation of Clinical Chemistry standardization project for older men and women in three communities. New Engl J Med
measurements of apolipoproteins A-I and B. III. Comparability of 1991;324:16191625.
apolipoprotein A-I values by use of international reference material. [90] Hermanson B, Omenn GS, Kronmal RA, Gersh BJ. Benecial
Clin Chem 1993;39:773781. 6-year outcome of smoking cessation in older men and women with
[71] Scanu AM, Lawn RM, Berg K. Lipoprotein(a) and atherosclerosis. coronary artery disease. Results from the CASS registry. New Engl
Ann Intern Med 1991;115:209218. J Med 1988;319:13651369.

b
y

g
u
e
s
t

o
n

N
o
v
e
m
b
e
r

9
,

2
0
1
3
h
t
t
p
:
/
/
c
a
r
d
i
o
v
a
s
c
r
e
s
.
o
x
f
o
r
d
j
o
u
r
n
a
l
s
.
o
r
g
/
D
o
w
n
l
o
a
d
e
d

f
r
o
m

J.E. Roeters van Lennep et al. / Cardiovascular Research 53 (2002) 538549 547
[91] Cullen P, Schulte H, Assmann G. Smoking, lipoproteins and [111] Donahue RP, Goldberg RJ, Chen Z, Gore JM, Alpert JS. The
coronary heart disease risk. Data from the Munster Heart Study inuence of sex and diabetes mellitus on survival following acute
(PROCAM). Eur Heart J 1998;19:16321641. myocardial infarction: a community-wide perspective. J Clin
[92] Kato I, Toniolo P, Akhmedkhanov A et al. Prospective study of Epidemiol 1993;46:245252.
factors inuencing the onset of natural menopause. J Clin Epidemiol
[112] Haffner SM, Valdez RA, Morales PA, Hazuda HP, Stern MP.
1998;51:12711276.
Decreased sex hormone-binding globulin predicts non-insulin-de-
[93] Cramer DW, Harlow BL, Xu H, Fraer C, Barbieri R. Cross-sectional
pendent diabetes mellitus in women but not in men. J Clin
and case-controlled analyses of the association between smoking
Endocrinol Metab 1993;77:5660.
and early menopause. Maturitas 1995;22:7987.
[113] Sowers JR. Diabetes mellitus and cardiovascular disease in women.
[94] Hu FB, Grodstein F, Hennekens CH et al. Age at natural menopause
Arch Intern Med 1998;158:617621.
and risk of cardiovascular disease. Arch Intern Med 1999;159:1061
[114] Kaseta JR, Skafar DF, Ram JL, Jacober SJ, Sowers JR. Car-
1066.
diovascular disease in the diabetic woman. J Clin Endocrinol
[95] Taylor KG, Carter TJ, Valente AJ et al. Sex differences in the
Metab 1999;84:18351838.
relationships between obesity, alcohol consumption and cigarette
[115] Willett WC, Manson JE, Stampfer MJ et al. Weight, weight change,
smoking and serum lipid and apolipoprotein concentrations in a
and coronary heart disease in women. Risk within the normal
normal population. Atherosclerosis 1981;38:1118.
weight range. J Am Med Assoc 1995;273:461465.
[96] Rutan GH, McDonald RH, Kuller LH. A historical perspective of
[116] Manson JE, Colditz GA, Stampfer MJ et al. A prospective study of
elevated systolic versus diastolic blood pressure from an epi-
obesity and risk of coronary heart disease in women. New Engl J
demiological and clinical trial viewpoint. J Clin Epidemiol
Med 1990;322:882889.
1989;42:663673.
[117] Rexrode KM, Carey VJ, Hennekens CH et al. Abdominal adiposity
[97] Stamler J, Neaton JD, Wentworth DN. Blood pressure (systolic and
and coronary heart disease in women. J Am Med Assoc
diastolic) and risk of fatal coronary heart disease. Hypertension
1998;280:18431848.
1989;13:I2I12.
[118] Larsson B, Bengtsson C, Bjorntorp P et al. Is abdominal body fat
[98] Prevention of stroke by antihypertensive drug treatment in older
distribution a major explanation for the sex difference in the
persons with isolated systolic hypertension. Final results of the
incidence of myocardial infarction? The study of men born in 1913
Systolic Hypertension in the Elderly Program (SHEP). SHEP
and the study of women, Goteborg, Sweden. Am J Epidemiol
Cooperative Research Group. J Am Med Assoc 1991;265:3255
1992;135:266273.
3264.
[119] Prineas RJ, Folsom AR, Kaye SA. Central adiposity and increased
[99] Antikainen R, Jousilahti P, Tuomilehto J. Systolic blood pressure,
risk of coronary artery disease mortality in older women. Ann isolated systolic hypertension and risk of coronary heart disease,
Epidemiol 1993;3:3541. strokes, cardiovascular disease and all-cause mortality in the middle-
[120] Van Gaal LF, Wauters MA, De Leeuw IH. The benecial effects of aged population. J Hypertens 1998;16:577583.
[100] Colandrea MA, Friedman GD, Nichaman MZ, Lynd CN. Systolic modest weight loss on cardiovascular risk factors. Int J Obes Relat
hypertension in the elderly. An epidemiologic assessment. Circula- Metab Disord 1997;21(Suppl 1):S5S9.
tion 1970;41:239245. [121] Wood PD, Stefanick ML, Williams PT, Haskell WL. The effects on
[101] Staessen J, Amery A, Fagard R. Isolated systolic hypertension in plasma lipoproteins of a prudent weight-reducing diet, with or
the elderly. J Hypertens 1990;8:393405. without exercise, in overweight men and women. New Engl J Med
[102] Kannel WB, Dawber TR, McGee DL. Perspectives on systolic 1991;325:461466.
hypertension. The Framingham study. Circulation 1980;61:1179 [122] Jousilahti P, Rastenyte D, Tuomilehto J, Sarti C, Vartiainen E.
1182. Parental history of cardiovascular disease and risk of stroke. A
[103] Saltzberg S, Stroh JA, Frishman WH. Isolated systolic hyperten- prospective follow-up of 14 371 middle-aged men and women in
sion in the elderly: pathophysiology and treatment. Med Clin North Finland. Stroke 1997;28:13611366.
Am 1988;72:523547. [123] Marenberg ME, Risch N, Berkman LF, Floderus B, de Faire U.
[104] Gueyfer F, Boutitie F, Boissel JP et al. Effect of antihypertensive Genetic susceptibility to death from coronary heart disease in a
drug treatment on cardiovascular outcomes in women and men. A study of twins. New Engl J Med 1994;330:10411046.
meta-analysis of individual patient data from randomized, con- [124] Pohjola-Sintonen S, Rissanen A, Liskola P, Luomanmaki K.
trolled trials. The INDANA Investigators. Ann Intern Med Family history as a risk factor of coronary heart disease in patients
1997;126:761767. under 60 years of age. Eur Heart J 1998;19:235239.
[105] The sixth report of the Joint National Committee on prevention, [125] Snowden CB, McNamara PM, Garrison RJ et al. Predicting
detection, evaluation, and treatment of high blood pressure. Arch coronary heart disease in siblings a multivariate assessment: the
Intern Med 1997;57:24132446. Framingham Heart Study. Am J Epidemiol 1982;115:217222.
[106] Ramsay LE, Williams B, Johnston GD et al. British Hypertension [126] Barrett-Connor E, Khaw K. Family history of heart attack as an
Society guidelines for hypertension management 1999: summary. independent predictor of death due to cardiovascular disease.
Br Med J 1999;319:630635. Circulation 1984;69:10651069.
[107] Bonow RO, Bohannon N, Hazzard W. Risk stratication in [127] Colditz GA, Stampfer MJ, Willett WC et al. A prospective study of
coronary artery disease and special populations. Am J Med parental history of myocardial infarction and coronary heart disease
1996;101:4A17S22S. in women. Am J Epidemiol 1986;123:4858.
[108] Goldschmid MG, Barrett-Connor E, Edelstein SL et al. [128] Myers RH, Kiely DK, Cupples LA, Kannel WB. Parental history is
Dyslipidemia and ischemic heart disease mortality among men and an independent risk factor for coronary artery disease: the Framin-
women with diabetes. Circulation 1994;89:991997. gham Study. Am Heart J 1990;120:963969.
[109] Seeman T, Mendes de Leon C, Berkman L, Ostfeld A. Risk factors [129] Schildkraut JM, Myers RH, Cupples LA, Kiely DK, Kannel WB.
for coronary heart disease among older men and women: a Coronary risk associated with age and sex of parental heart disease
prospective study of community-dwelling elderly. Am J Epidemiol in the Framingham Study. Am J Cardiol 1989;64:555559.
1993;138:10371049. [130] Jacobsen DW. Homocysteine and vitamins in cardiovascular dis-
[110] Barrett Connor EL, Cohn BA, Wingard DL, Edelstein SL. Why is ease. Clin Chem 1998;44:18331843.
diabetes mellitus a stronger risk factor for fatal ischemic heart [131] Verhoef P, Meleady R, Daly LE et al. Homocysteine, vitamin status
disease in women than in men? The Rancho Bernardo Study. J Am and risk of vascular disease: effects of gender and menopausal
Med Assoc 1991;265:627631. status. Eur Heart J 1999;20:12341244.

b
y

g
u
e
s
t

o
n

N
o
v
e
m
b
e
r

9
,

2
0
1
3
h
t
t
p
:
/
/
c
a
r
d
i
o
v
a
s
c
r
e
s
.
o
x
f
o
r
d
j
o
u
r
n
a
l
s
.
o
r
g
/
D
o
w
n
l
o
a
d
e
d

f
r
o
m

548 J.E. Roeters van Lennep et al. / Cardiovascular Research 53 (2002) 538549
[132] Folsom AR, Nieto FJ, McGovern PG et al. Prospective study of [154] Strachan DP, Carrington D, Mendall MA et al. Relation of
coronary heart disease incidence in relation to fasting total homo- Chlamydia pneumoniae serology to mortality and incidence of
cysteine, related genetic polymorphisms, and B vitamins: the ischaemic heart disease over 13 years in the Caerphilly prospective
Atherosclerosis Risk in Communities (ARIC) study. Circulation heart disease study. Br Med J 1999;318:10351039.
1998;98:204210.
[155] Ridker PM, Kundsin RB, Stampfer MJ, Poulin S, Hennekens CH.
[133] Robinson K, Mayer EL, Miller DP et al. Hyperhomocysteinemia
Prospective study of Chlamydia pneumoniae IgG seropositivity
and low pyridoxal phosphate. Common and independent reversible
and risks of future myocardial infarction. Circulation
risk factors for coronary artery disease. Circulation 1995;92:2825
1999;99:11611164.
2830.
[156] Danesh J, Wong Y, Ward M, Muir J. Chronic infection with
[134] Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantita-
Helicobacter pylori, Chlamydia pneumoniae, or cytomegalovirus:
tive assessment of plasma homocysteine as a risk factor for
population based study of coronary heart disease. Heart
vascular disease. Probable benets of increasing folic acid intakes.
1999;81:245247.
J Am Med Assoc 1995;274:10491057.
[157] Nieto FJ, Folsom AR, Sorlie PD et al. Chlamydia pneumoniae
[135] Giltay EJ, Hoogeveen EK, Elbers JM et al. Effects of sex steroids
infection and incident coronary heart disease: the Atherosclerosis
on plasma total homocysteine levels: a study in transsexual males
Risk in Communities Study. Am J Epidemiol 1999;150:149156.
and females. J Clin Endocrinol Metab 1998;83:550553.
[158] Murray LJ, OReilly DP, Ong GM et al. Chlamydia pneumoniae
[136] Steegers-Theunissen RP, Boers GH, Steegers EA et al. Effects of
antibodies are associated with an atherogenic lipid prole. Heart
sub-50 oral contraceptives on homocysteine metabolism: a pre-
1999;81:239244.
liminary study. Contraception 1992;45:129139.
[159] Folsom AR, Nieto FJ, Sorlie P, Chambless LE, Graham DY.
[137] Wouters MG, Moorrees MT, van der Mooren MJ et al. Plasma
Helicobacter pylori seropositivity and coronary heart disease
homocysteine and menopausal status. Eur J Clin Invest
incidence. Atherosclerosis Risk In Communities (ARIC) Study
1995;25:801805.
Investigators. Circulation 1998;98:845850.
[138] Hak AE, Polderman KH, Westendorp IC et al. Increased plasma
[160] Whincup PH, Mendall MA, Perry IJ, Strachan DP, Walker M.
homocysteine after menopause. Atherosclerosis 2000;149:163
Prospective relations between Helicobacter pylori infection, cor-
168.
onary heart disease, and stroke in middle aged men. Heart
[139] Boers GH, Smals AG, Trijbels FJ, Leermakers AI, Kloppenborg
1996;75:568572.
PW. Unique efciency of methionine metabolism in premenopausal
[161] Strandberg TE, Tilvis RS, Vuoristo M, Lindroos M, Kosunen TU.
women may protect against vascular disease in the reproductive
Prospective study of Helicobacter pylori seropositivity and car-
years. J Clin Invest 1983;72:19711976.
diovascular diseases in a general elderly population. Br Med J
[140] Verhoef P, Hennekens CH, Allen RH et al. Plasma total homo-
1997;314:13171318. cysteine and risk of angina pectoris with subsequent coronary
[162] Wald NJ, Law MR, Morris JK, Bagnall AM. Helicobacter pylori artery bypass surgery. Am J Cardiol 1997;79:799801.
[141] Woo KS, Chook P, Lolin YI et al. Hyperhomocyst(e)inemia is a infection and mortality from ischaemic heart disease: negative
risk factor for arterial endothelial dysfunction in humans. Circula- result from a large, prospective study. Br Med J 1997;315:1199
tion 1997;96:25422544. 1201.
[142] Smith FB, Lee AJ, Fowkes FG et al. Hemostatic factors as [163] Aromaa AA, Knekt P, Reunanen A, Rautelin HI, Kosunen TU.
predictors of ischemic heart disease and stroke in the Edinburgh Helicobacter pylori and the risk of myocardial infarction. Gut
Artery Study. Arterioscler Thromb Vasc Biol 1997;17:33213325. 1996;39(Suppl 2):A91.
[143] Kalaria VG, Zareba W, Moss AJ et al. Gender-related differences in [164] Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH.
thrombogenic factors predicting recurrent cardiac events in patients Inammation, aspirin, and the risk of cardiovascular disease in
after acute myocardial infarction. Am J Cardiol 2000;85:1401 apparently healthy men. New Engl J Med 1997;336:973979.
1408. [165] Ridker PM, Glynn RJ, Hennekens CH. C-reactive protein adds to
[144] Eriksson M, Egberg N, Wamala S et al. Relationship between the predictive value of total and HDL cholesterol in determining
plasma brinogen and coronary heart disease in women. Arterios- risk of rst myocardial infarction. Circulation 1998;97:20072011.
cler Thromb Vasc Biol 1999;19:6772. [166] Tracy RP, Lemaitre RN, Psaty BM et al. Relationship of C-reactive
[145] Lip GY. Fibrinogen and cardiovascular disorders. QJM protein to risk of cardiovascular disease in the elderly. Results from
1995;88:155165. the Cardiovascular Health Study and the Rural Health Promotion
[146] Ernst E, Resch KL. Fibrinogen as a cardiovascular risk factor: a Project. Arterioscler Thromb Vasc Biol 1997;17:11211127.
meta-analysis and review of the literature. Ann Intern Med [167] Ridker PM, Buring JE, Shih J, Matias M, Hennekens CH.
1993;118:956963. Prospective study of C-reactive protein and the risk of future
[147] Folsom AR, Wu KK, Rosamond WD, Sharrett AR, Chambless LE. cardiovascular events among apparently healthy women. Circula-
Prospective study of hemostatic factors and incidence of coronary tion 1998;98:731733.
heart disease: the Atherosclerosis Risk in Communities (ARIC) [168] Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein
Study. Circulation 1997;96:11021108. and other markers of inammation in the prediction of car-
[148] Kannel WB, DAgostino RB, Belanger AJ. Fibrinogen, cigarette diovascular disease in women. New Engl J Med 2000;342:836
smoking, and risk of cardiovascular disease: insights from the 843.
Framingham Study. Am Heart J 1987;113:10061010. [169] Brezinka V, Kittel F. Psychosocial factors of coronary heart disease
[149] Meade TW, Dyer S, Howarth DJ, Imeson JD, Stirling Y. Anti- in women: a review. Soc Sci Med 1996;42:13511365.
thrombin III and procoagulant activity: sex differences and effects [170] Kawachi I, Colditz GA, Ascherio A et al. A prospective study of
of the menopause. Br J Haematol 1990;74:7781. social networks in relation to total mortality and cardiovascular
[150] Ernst E. Fibrinogen. Br Med J 1991;303:596597. disease in men in the USA. J Epidemiol Community Health
[151] Seed M. Hormone replacement therapy and cardiovascular disease. 1996;50:245251.
Curr Opin Lipidol 1999;10:581587. [171] Orth-Gomer K, Rosengren A, Wilhelmsen L. Lack of social
[152] Danesh J, Collins R, Peto R. Chronic infections and coronary heart support and incidence of coronary heart disease in middle-aged
disease: is there a link? Lancet 1997;350:430436. Swedish men. Psychosom Med 1993;55:3743.
[153] Wong YK, Dawkins KD, Ward ME. Circulating Chlamydia pneu- [172] Orth-Gomer K, Horsten M, Wamala SP et al. Social relations and
moniae DNA as a predictor of coronary artery disease. J Am Coll extent and severity of coronary artery disease. The Stockholm
Cardiol 1999;34:14351439. Female Coronary Risk Study. Eur Heart J 1998;19:16481656.

b
y

g
u
e
s
t

o
n

N
o
v
e
m
b
e
r

9
,

2
0
1
3
h
t
t
p
:
/
/
c
a
r
d
i
o
v
a
s
c
r
e
s
.
o
x
f
o
r
d
j
o
u
r
n
a
l
s
.
o
r
g
/
D
o
w
n
l
o
a
d
e
d

f
r
o
m

J.E. Roeters van Lennep et al. / Cardiovascular Research 53 (2002) 538549 549
[173] Eaker ED. Psychosocial risk factors for coronary heart disease in [183] Darj E, Crona N, Nilsson S. Effects on lipids and lipoproteins in
women. Cardiol Clin 1998;16:103111. women treated with oestradiol and progesterone. Maturitas
[174] Winkleby MA, Fortmann SP, Barrett DC. Social class disparities in 1992;15:209215.
risk factors for disease: 8-year prevalence patterns by level of [184] Hulley S, Grady D, Bush T et al. Randomized trial of estrogen plus
education. Prev Med 1990;19:112. progestin for secondary prevention of coronary heart disease in
[175] Diez-Roux AV, Nieto FJ, Tyroler HA, Crum LD, Szklo M. Social postmenopausal women. Heart and Estrogen/ Progestin Replace-
inequalities and atherosclerosis. The atherosclerosis risk in com- ment Study (HERS) Research Group. J Am Med Assoc
munities study. Am J Epidemiol 1995;141:960972. 1998;280:605613.
[176] Bobak M, Hertzman C, Skodova Z, Marmot M. Socioeconomic [185] Westerveld HT, Kock LA, van Rijn HJ, Erkelens DW, de Bruin
status and cardiovascular risk factors in the Czech Republic. Int J TW. 17 beta-Estradiol improves postprandial lipid metabolism in
Epidemiol 1999;28:4652. postmenopausal women. J Clin Endocrinol Metab 1995;80:249
[177] Bosma H, Marmot MG, Hemingway H et al. Low job control and 253.
risk of coronary heart disease in Whitehall II (prospective cohort) [186] Mendelsohn ME, Karas RH. Estrogen and the blood vessel wall.
study. Br Med J 1997;314:558565. Curr Opin Cardiol 1994;9:619626.
[178] Barrett Connor E, Bush TL. Estrogen and coronary heart disease in [187] Grady D, Rubin SM, Petitti DB et al. Hormone therapy to prevent
women. J Am Med Assoc 1991;265:18611867. disease and prolong life in postmenopausal women. Ann Intern
[179] van der Schouw YT, van der GY, Steyerberg EW, Eijkemans JC, Med 1992;117:10161037.
Banga JD. Age at menopause as a risk factor for cardiovascular [188] Design of the Womens Health Initiative clinical trial and observa-
mortality. Lancet 1996;347:714718. tional study. The Womens Health Initiative Study Group. Control
[180] Stevenson JC, Crook D, Godsland IF. Inuence of age and Clin Trials 1998;19:61109.
menopause on serum lipids and lipoproteins in healthy women. [189] Walsh BW, Kuller LH, Wild RA et al. Effects of raloxifene on
Atherosclerosis 1993;98:8390. serum lipids and coagulation factors in healthy postmenopausal
[181] Herrington DM, Reboussin DM, Brosnihan KB et al. Effects of women. J Am Med Assoc 1998;279:14451451.
estrogen replacement on the progression of coronary-artery athero- [190] Barrett-Connor E, Wenger NK, Grady D et al. Hormone and
sclerosis. New Engl J Med 2000;343:522529. non-hormone therapy for the maintenance of postmenopausal
[182] Effects of estrogen or estrogen/ progestin regimens on heart disease health: the need for randomized controlled trials of estrogen and
risk factors in postmenopausal women. The Postmenopausal Es- raloxifene. J Womens Health 1998;7:839847.
trogen/ Progestin Interventions (PEPI) Trial. The Writing Group for
the PEPI Trial. J Am Med Assoc 1995;273:199208.

b
y

g
u
e
s
t

o
n

N
o
v
e
m
b
e
r

9
,

2
0
1
3
h
t
t
p
:
/
/
c
a
r
d
i
o
v
a
s
c
r
e
s
.
o
x
f
o
r
d
j
o
u
r
n
a
l
s
.
o
r
g
/
D
o
w
n
l
o
a
d
e
d

f
r
o
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