Sex Differences in the Pathophysiology, Treatment, and Outcomes in IHD
Curr Atheroscler Rep
Sex Differences in the Pathophysiology, Treatment, and Outcomes in IHD
Monika Sanghavi 0 1
Martha Gulati 0 1
0 Department of Internal Medicine (Cardiology) and Department of Clinical Public Health (Epidemiology), The Ohio State University , Columbus, OH , USA
1 Department of Internal Medicine, Division of Cardiology, University of Texas Southwestern Medical Center , 5323 Harry Hines Blvd, Dallas, TX 75390-8830 , USA
Heart disease is the number one killer of women. Although there are many similarities between men and women, the evolving understanding of ischemic heart disease in women allow us to emphasize the important differences that need to be recognized. These differences, including symptoms at presentation, importance of particular risk factors, pathophysiology of disease, and treatments/outcomes, will be discussed in this review.
Ischemic heart disease; Women; Microvascular dysfunction; Cardiovascular disease; Risk factors
Women in the USA are more likely to die of cardiovascular
disease (CVD) than any other cause [1 ]. In fact,
cardiovascular disease claims the life of a woman every minute [1 ].
The statistics are staggering; however, almost 50 % of white
women and three fourths of Hispanic and black women are
still unaware that this is their greatest risk .
Among cardiovascular diseases, coronary heart disease
(CHD) makes up the majority of events for both men and
women below 75 years of age [1 ]. The incidence of CHD
in women lags behind men by 10 years, suggesting a
protective effect in women that is lost with advanced age,
particularly after the onset of menopause. The overall incidence of
CHD is lower in women; however, across all age strata, a
myocardial infarction (MI) is more likely to be fatal in women,
particularly in younger women (under 55 years of age) [1 ].
Although the overall trends suggest a decrease in incident
CHD events and CHD-related deaths over the past 20
25 years in both men and women, the only exception is
younger women (3544 years of age) for whom the mortality has
Previously it was assumed that heart disease in women was
the same as in men, and the underrepresentation of women in
research studies prevented any alternate sex-specific
conclusions. With the emergence of new sex-specific studies and
data, the landscape of heart disease is changing. We now know
that certain risk factors are stronger predictors of heart disease
in women, there are sex differences in symptoms, and there
are differences in the underlying pathophysiology. With the
new understanding of the pathophysiologic differences come
changes in diagnostic testing and treatment strategies.
CHD is traditionally characterized by obstructive
atherosclerosis in the epicardial coronary arteries resulting in
ischemia or decreased myocardial blood flow. However, with the
recognition that there are a variety of disorders that result in
ischemia and ischemic symptoms in women, not just coronary
heart disease, the more-inclusive term ischemic heart disease
(IHD) is considered fitting for this discussion . IHD is a
broader term that encompasses any disorder or disease that
results in myocardial ischemia; this includes Cardiac
Syndrome X, a term used to describe patients with symptoms
and evidence of ischemia but no obstructive coronary artery
disease  and is noted to be more common in women. More
recently, this syndrome has been labeled as female-specific
The following review article will discuss the sex
differences in IHD with a focus on the pathophysiology, treatment,
Angina pectoris is the most common symptom of myocardial
ischemia. The description of Btypical^ angina was based the
presence of classic characteristics of obstructive coronary
disease which included retrosternal chest pressure, exacerbation
with activity, and relief with rest or nitroglycerin, defined in a
population of predominantly men. Of note, other causes of
myocardial ischemia may not present with the same
characteristic presentation, for example, patients with coronary
vasospasm often report pain at rest. The distinction of Btypical^
vs. Batypical^ angina, based on the number of classic
characteristics present, was used by Diamond and Forrester to help
determine the pretest probability of atherosclerotic disease .
More recently, the term Batypical angina^ is often used when
describing symptoms in women since some women can have
prodromal symptoms of shortness of breath, fatigue, and
weakness with ischemia  or other nonclassic descriptions
of pain. However, even though women are more likely to have
atypical symptoms when compared to men, the most common
presentation in acute coronary syndrome is still typical angina
. In a study evaluating anginal symptoms in men and
women with confirmed obstructive coronary artery disease, there
was no difference in the presenting symptoms . In general,
women have a higher prevalence of angina than men  and
more functional impairment from the pain. Interestingly, even
when typical angina is present, women are less likely to have
any evidence of obstructive CAD when angiography is
performed . In women with signs and symptoms of IHD yet
without obstructive CAD, the majority will have repeated
episodes of chest pain requiring hospitalization and repeat
testing which is economically taxing on the healthcare system
Traditional Risk Factors
The absence of traditional cardiac risk factors in midlife is
associated with a low lifetime risk of heart disease [13 ].
However, by the age of 55, a majority of women have at least one
major risk factor putting them at an increased lifetime risk of
cardiovascular disease [13 ]. Traditional cardiac risk factors
play a key role in the development of heart disease in women
and men, but the prevalence of certain risk factors differ
between the sexes and some are stronger predictors of heart
disease in women. Women have lower total cholesterol levels
than men until after the fifth decade of life, thereafter their
values are greater . In general, high-density lipoprotein
cholesterol (HDL-C) levels are higher in women than in
men, but decrease during the menopause transition likely
due to hormonal changes . In addition to dyslipidemia,
postmenopausal women also have a clustering of other risk
factors including obesity and hypertension that could be
related to gender-specific metabolic differences exacerbated by
hormonal imbalances . Diabetes, metabolic syndrome,
hypertension, obesity, and hypertriglyceridemia are all stronger
risk factors for ischemic heart disease in women than men
. A recent meta-analysis reported that women with
diabetes had a 40 % greater risk of incident CHD compared
with men with diabetes . In fact, the presence of diabetes is
thought to take away the relative protection from ischemic
heart disease in young women .
Even though there is a lower prevalence of smoking among
women than men (15.9 % vs. 20.5 %) (1), smoking confers a
higher risk of ischemic heart disease in women. In fact, for a
woman, the risk of CHD mortality from cigarettes is
equivalent to the risk associated with weighing ~42 kg more than her
nonsmoker counterpart . A recent meta-analysis
demonstrated a 25 % higher relative risk of heart disease in women
smokers compared to men .
There is increasing recognition of the importance of
lifestyle on ischemic heart disease. In a recent study evaluating
young women without underlying CVD disease or CV risk
factors, it was noted that 73 % of CHD cases and 46 % of
CVD risk factor cases were attributable to a poor lifestyle
[22 ]. This emphasizes the importance of primordial
prevention with education and lifestyle counseling at a young age.
Physical activity and inactivity are both important
considerations. A recent study found that after the age of 30, the
population risk of heart disease attributable to physical
inactivity outweighed all other risk factors in women . On the
other end of the spectrum, exercise capacity has a strong and
independent positive association with cardiovascular and
allcause mortality . The adjusted hazard ratio for every
1MET decrement in exercise capacity is 1.20 .
Nontraditional Risk Factors
Psychosocial factors are known to be associated with an
increased incidence of IHD as well as recurrent CV events in
patients with established disease  and can prevent
individuals from adopting recommended lifestyle changes .
Psychosocial problems such as depression are twice as common
in women than in men . For women, family conflicts and
obligations, depression and anxiety are all associated with
increased risk of heart disease whereas for men, work
obligations and hostility are more commonly associated with
IHD risk . The differential impact of mental stress on
women compared to men was demonstrated in a recent study
in post-MI patients aged 3860 years, younger women (those
less than 50 years of age) had increased evidence of mental
stress-induced myocardial ischemia as determined by the sum
difference score (SDS) on technetium-99 m perfusion imaging
when compared to young men. There was no difference seen
with exercise-induced ischemia or in the older subjects (those
>50 years of age) .
Inflammatory markers such as high-sensitivity C-reactive
protein (hs-CRP) can be used in addition to traditional cardiac
risk factors for further risk stratification in men and women.
An elevation is associated with a greater risk of IHD even
when accounting for traditional risk factors. High-sensitivity
CRP is consistently higher after puberty in women  and
has been shown to vary with levels of estrogen in
postmenopausal women . It has also been demonstrated to help
stratify higher risk women with metabolic syndrome. In one
study of women with metabolic syndrome , those with
hsCRP >3.0 mg/l had twice the risk of future cardiovascular
events compared to those with hs-CRP <3.0 mg/l.
Autoimmune disorders characterized by chronic
inflammation such as systemic lupus erythematosus (SLE) and
rheumatoid arthritis (RA) primarily affect women and
support the theory that inflammation may be associated with
atherosclerosis. These individuals often manifest ischemic
heart disease at an earlier age and have a rapid progression
of atherosclerosis . Young women with SLE are 50
times more likely to have an acute MI than women of the
same age without it .
Sex-Specific Risk Factors
As mentioned earlier, women have a 10-year relative delay
in the clinical expression of IHD that is not completely
understood. Clinicians suspect that the delay is due to the
protective effects of estrogen during a womans reproductive
years, since estrogen has anti-atherosclerotic and
antiinflammatory effects , as well beneficial effects on lipids
and endothelial vasomotor function . However, despite
making physiologic sense, hormone replacement therapy as
a preventive measure for women has not proven to be
effective for primary or secondary prevention of cardiovascular
disease [38, 39].
There is increasing recognition of pregnancy-related
complications such as preeclampsia, gestational diabetes, and
gestational hypertension as being risk factors for ischemic
heart disease. In fact, women with a history of preeclampsia
have twice the risk of cardiovascular disease and venous
thromboembolism in the decade following their pregnancy
 as well as an increased risk of chronic kidney disease
and diabetes mellitus . Recently, there have also been
associations reported between parity and heart disease.
Multiple pregnancies as well as recurrent pregnancy losses have
been associated with increased risk of future ischemic heart
disease [42, 43]. Interestingly, a recent cohort study
demonstrated that women who successfully used fertility therapy to
get pregnant did not have an increased risk of cardiovascular
disease in the next 10 years, but rather there was a signal
toward benefit .
Ovulation dysfunction has also been associated with
infertility and increased risk of IHD in women. Women with
polycystic ovarian syndrome (PCOS) have an increased
prevalence of glucose intolerance, metabolic syndrome, and
diabetes , which are associated with increased risk of IHD.
Women undergoing cancer treatment such as radiation or
chemotherapy are at increased risk of heart disease. There is a
linear relationship between the dose of ionizing radiation
exposure during breast cancer radiotherapy and the risk of major
coronary events in women . As cancer therapy improves,
this risk is of increasing importance since survivors of breast
cancer are more likely to die of CVD than breast cancer. There
may be ways to minimize the risk associated with
radiotherapy by adjusting dosage and patient position [47 ].
Risk prediction models, such as the Framingham risk score,
are largely age-dependent and only forecast 10-year risk. This
can result in underestimation of the lifetime risk for women,
especially young women. The AHA BEffectiveness-Based
Guidelines for Prevention of Coronary Artery Disease in
Women 2011 Update^ suggested a risk prediction model
that relies on risk factor burden, including sex-specific risk
factors, rather than age to assess a womans risk, and stressed
the importance of taking a pregnancy history as part of the
initial patient evaluation . The atherosclerotic
cardiovascular disease (ASCVD) risk score is a new risk assessment
tool that includes stroke in the outcome. This is especially
important when assessing risk in women. The calculator helps
clinicians determine the need for cholesterol reducing therapy
and also provides a lifetime risk assessment for patient
education. The calculator incorporates the traditional risk factors
used in the Framingham risk score but does not incorporate
sex- specific risk factors as discussed above, so these need to
be evaluated and considered separately.
Differences in the Cardiovascular System
Although the overall coronary vasculature is similar, there are
notable sex differences in the cardiovascular system. Women
have smaller left anterior descending artery and right coronary
artery diameters than men as assessed by computed
tomography . It has also been established that overall women have
less atheromatous burden than men. Interestingly, this
difference is most significantly seen in the coronary vascular bed
and is absent in the aorta and peripheral vasculature .
There are also sex differences in the autonomic nervous
system control of the cardiovascular system . Women have
more parasympathetic activity than men, who have higher
sympathetic activity . These differences are thought to
be mediated by a variety of factors including hormonal
differences , fat distribution , and psychological disorders
. An imbalance in the autonomic regulation in
postmenopausal women has been implicated for takotsubo, a
stressmediated cardiomyopathy affecting predominantly women,
as well as female-specific ischemic heart disease.
Proposed Pathophysiology of Ischemic Heart Disease
The presumption that ischemic heart disease is the same in
men and women was challenged by the Coronary Artery
Surgery Study (CASS) which was a large, multicenter study that
involved close to 25,000 patients of which a quarter were
women. A substantial number of women referred for
angiography did not have evidence of CAD, but many had positive
exercise treadmill stress tests with evidence of ischemia.
Based on these data, one study reported that 53 % of women
vs. 12 % of men had false-positive stress tests , implying
decreased sensitivity of the exercise treadmill test in women.
However, recently, it has been suggested that angiography
may be an imperfect gold standard for assessing ischemic
heart disease, and these Bfalse-positive^ tests are evidence of
myocardial ischemia in part of the coronary vasculature not
visualized by angiography .
The coronary arterial system is a continuous network made
of functionally distinct vessel segments of decreasing size.
The initial large epicardial coronary arteries, which measure
anywhere from 500 m to 23 mm, are followed by the
prearterioles which measure 100 to 500 m and lead to the
intramural arterioles with diameters less than 100 m. The
epicardial arteries have a primary capacitance function with
minimal resistance to coronary flow. Whereas, the arterioles
have a fundamental role in coronary blood flow regulation by
matching myocardial oxygen demand with blood supply via
changes in resistance and dilation .
The underlying pathophysiology of ischemic heart disease
can differ depending on the portion of the coronary
vasculature affected, whether it is the large epicardial vessels or the
smaller microvasculature (Fig. 1). Coronary artery disease,
coronary vasospasm, and coronary artery dissection are all
causes of IHD that primarily affect the epicardial coronary
arteries. In contrast, microvascular dysfunction refers to
dysfunction in the smaller coronary arterioles which can cause
chronic ischemia, acute myocardial infarction, or
Epicardial Coronary Arteries
Typically, coronary artery disease is caused by atherosclerosis
in the epicardial coronary arteries. Obstruction to flow occurs
either by gradual atherosclerosis accumulation or by plaque
rupture resulting in occlusive thrombus formation. The
utilization of coronary angiography for the diagnosis relies upon
luminal obstruction resulting in contrast-void areas during
Even though a large number of women have obstructive
atherosclerosis as a cause of ischemic heart disease, a
substantial number of women do not. The absence of obstructive
disease is identified in up to one third of women during a
myocardial infarction  and close to two thirds of women
being evaluated for ischemic chest pain . Men also have
nonobstructive disease on presentation, but the incidence is
much lower .
Imaging techniques, such as intravascular ultrasound
(IVUS) and optical coherence tomography (OCT) have
allowed for visualization of the vessel wall and a deeper
understanding of the subtle differences in the pathophysiology
which were previously invisible on traditional angiography. In
a prospective study of women with a myocardial infarction
and nonobstructive disease on angiography (defined as <50 %
stenosis in all major vessels), 29 % were noted to have
evidence of plaque rupture and 12 % had plaque erosion with
presumed distal embolization as evidenced by myocardial
edema on MRI . The term plaque disruption is a
comprehensive term used to incorporate any cause of vessel wall
disruption whether it is due to plaque rupture or plaque
erosion. Plaque erosions are more commonly seen in women and
younger individuals .
Coronary vasospasm has also been implicated as a cause of
myocardial ischemia or injury in the absence of obstructive
coronary artery disease. Although, coronary spasms usually
occur in the epicardial vessels, coronary microvascular spasm
can also occur . Its pathogenesis is likely multifactorial
involving smooth muscle hyperreactivity, endothelial
dysfunction, as well as environmental factors such as smoking
or alcohol consumption . Focal vasospasm has been
associated with atherosclerotic lesions with normal coronary flow
reserve (CFR) whereas diffuse vasospasm has been associated
with significantly reduced CFR suggesting a component of
coronary microvascular dysfunction . Coronary
vasospasm is difficult to confirm on angiography and often
requires provocative testing with acetylcholine or ergonovine
due to the transient nature of the disease.
Lastly, spontaneous coronary artery dissection (SCAD) is
an important cause of ischemic heart disease, especially in
young women. In a report containing the largest series of
patients with spontaneous coronary artery dissection and no
atherosclerosis, the authors reported a large female
predominance (82 % of the cases were women) with a 10-year major
Fig. 1 Mechanisms for ischemic heart disease in women. *Plaque disruption denotes plaque rupture or plaque erosion . ** Adapted with permission
from Oxford University Press and the European Society of Cardiology 
adverse cardiac event rate of up to 47 %. The LAD was the
most frequent vessel affected and fibromuscular dysplasia was
noted in half of the femoral angiograms done .
Coronary microvascular dysfunction (CMD) refers to
dysfunction of the coronary arterioles measuring <500 m in
diameter which includes the prearterioles and intramuscular
arterioles . These arterioles are too small to be visualized
by angiography and thus their function cannot be assessed by
this traditional method. It is thought that microvascular
dysfunction is the result of impaired relaxation or increased
sensitivity to vasoconstriction which results in inappropriate
myocardial blood regulation. CMD is highly prevalent in
women with chest pain without obstructive disease. In fact,
in the Womens Ischemia Syndrome Evaluation (WISE)
study, approximately half of the women with chest pain and
ischemia without obstructive CAD had evidence of
microvascular dysfunction . Although microvascular dysfunction
has currently been implicated as a common cause of chest pain
in the absence of obstructive disease in women, whether this is
a sex-specific phenomenon is still debated. Takotsubo, a
stress-mediated cardiomyopathy which disproportionately
affects older women, has recently been associated with
microvascular dysfunction . Additional evidence that
microvascular dysfunction may be a problem that disproportionately
affects women comes from the ARIC study where retinal
artery narrowing was shown to be a marker of microvascular
disease and predicted heart disease in women but not men
. The remaining discussion on diagnostic testing,
management, and outcomes will focus on epicardial atherosclerotic
disease and microvascular dysfunction as the cause of
The diagnostic testing for ischemic heart disease has
historically been the same for men and women. The testing
modalities can be divided into those that diagnose anatomical
disease vs. those that diagnose functional ischemia. Anatomical
disease can be evaluated using CT-angiography, MRI, or
invasive angiography. Functional ischemia can be assessed by a
variety of different stress tests as well as fractional flow
reserve (FFR) measurements in the cardiac catheterization
laboratory. Exercise treadmill testing has been reported as having
a high false-positive rate and thus lower sensitivity in women.
However, there is a shift in thinking that these may not be
false-positive tests but rather evidence of ischemia due to
microvascular dysfunction rather than epicardial coronary
obstruction [68 ]. Other prognostic tools include the Duke
treadmill score which incorporates exercise time,
STsegment deviation, and angina score into an equation to help
predict risk of CAD: it is a better predictor of significant CAD
in women than men . In addition, exercise capacity is a
powerful predictor of CAD. A nomogram has been
established defining age-predicted exercise capacity for
women . The inability to achieve 85 % of age-predicted fitness
level or achieving less than 5 METs is associated with a higher
risk of MI and all-cause mortality [70, 71].
The interest in evaluating microvascular dysfunction in
women has brought to the forefront specific diagnostic
maneuvers to assess the health of the coronary microvascular
circulation. These include coronary reactivity testing (CRT)
during cardiac catheterization with adenosine and
acetylcholine to help diagnose coronary microvascular dysfunction and
d i s t i n g u i s h b e t w e e n e n d o t h e l i u m - i n d e p e n d e n t o r
endothelium-dependent dysfunction, respectively. The
pharmacologic agents are used to induce a hyperemic state.
CMD is defined as coronary volumetric blood flow increases
of less than 2.5 times baseline flow during maximal
hyperemic stimuli .
In addition, noninvasive techniques are being tested to help
make the diagnosis. Women with confirmed microvascular
dysfunction by CRT had decreased myocardial perfusion
reserve index on cardiac MRI in response to adenosine .
Stress cardiac magnetic resonance (CMR) imaging is gaining
interest. Women with chest pain and nonobstructive CAD
who underwent adenosine CMR were found to have
subendocardial ischemia more frequently compared to control
subjects . Lastly, positron-emission tomography (PET) can be
used to assess coronary flow reserve as measured by
myocardial blood flow at peak hyperemia over myocardial blood flow
at baseline. The diagnostic and prognostic significance of
these tests are still being explored.
When choosing a diagnostic test, there are sex-specific
concerns that need to be considered such as the patients age
and radiation exposure given the association between
cumulative exposure and cancer risk in young women [68 ]. The
new noninvasive stress testing guidelines emphasize this
concern and list expected radiation exposure for each test to help
guide clinicians [68 ].
Management of Ischemic Heart Disease
Epicardial Coronary Atherosclerosis
Even though the current treatment of coronary artery disease
is similar for men and women, women are less likely to
receive guideline-based therapy for the treatment of risk factors
 and secondary prevention for known coronary artery
disease [76, 77]. These include medications such as antiplatelet
therapy, statins, beta blockers, and angiotensin-converting
enzyme inhibitors (Table 1). In addition, after disease has been
diagnosed, women are consistently referred less often to
cardiac rehabilitation [78, 79] despite the known benefits.
Recently, there has been increasing research into sex-related
differences in the efficacy of traditional treatments. Aspirin, for
unclear reasons, is more effacious for the primary prevention
of myocardial infarction in men but stroke in women. Also,
one study showed that guideline-based statin therapy resulted
in greater atheroma regression for women than men .
Calcium channel blockers (CCB) are the established therapy
for coronary vasospasm in addition to long-acting nitrates
which can be used alone or as additive therapy to CCB
(Table 1). Magnesium may have a role in acute therapy as
well as prevention . More invasive strategies such as
percutaneous coronary intervention (PCI) and coronary artery
bypass grafting are usually only for patients who are refractory
to medical therapy .
Coronary Artery Dissection
The treatment for coronary artery dissection remains empirical
and controversial. The overall medical treatment for SCAD is
similar to that recommended for patients with ACS (Table 1).
However, the safety and efficacy of these medications for this
specific indication have not been thoroughly evaluated. In
fact, in one registry, statin therapy was associated with
increased risk of recurrent SCAD . This underscores the
need for additional data. Traditionally, an invasive approach
is taken with these patients since they often present with acute
coronary syndrome; however, some are now recommending a
more conservative initial approach due to the high rate of
technical failure [82, 83]
The lack of appropriate treatment and inadequate use of
secondary prevention strategies are exacerbated in patients
without obstructive coronary disease , especially in women
. This is in part to the limited understanding of the disease
process. In those women who are treated for female-specific
ischemic heart disease, the understanding of the
pathophysiology behind microvascular dysfunction has helped the
development of a variety of treatment options. -blockers improve
anginal symptoms as well as functional capacity. They are
more effective than channel blocker and nitrates  and are
considered the first line of treatment. The third-generation beta
blockers, nebivolol and carvedilol, also have
endotheliumdependent vasodilating properties which may make them
Treatment of ischemic heart disease
Epicardial coronary atherosclerosis
Medications Antiplatelet Agent
Recommended for all patients with CAD unless contraindicated
Recommended for all patients with left ventricular ejection fraction <40 % and in those
with hypertension, diabetes, or chronic kidney disease, unless contraindicated.
Therapy should be started and continued for 3 years in all patients with who have had
a myocardial infarction or acute coronary syndrome
Statin therapy should be initiated in all patients with established CAD
Patients with blood pressure >140/90 mmHg should be treated with lifestyle changes
Complete cessation is recommended
Goal BMI is 18.5 to 24.9 kg/m2
Recommendation is 30 min of moderate intensity activity at least 5 days a week
Patients with cardiovascular disease should have an annual influenza vaccination.
Patients with the diagnosis of ACS, coronary artery bypass surgery or PCI, chronic
angina and/or PAD within the past year should be referred to a cardiovascular
CAD coronary artery disease, ACE-I angiotensin converting enzyme inhibitors, BP blood pressure, BMI body mass index, ACS acute coronary
syndrome, PCI percutaneous coronary intervention, PAD peripheral artery disease, CABG coronary artery bypass grafting
a No established guidelines
b Adapted from Coronary Artery Spasm A 2009 Update 
c Adapted from Spontaneous Coronary Artery Dissection 
more effective than traditional -blockers . Statins and
ACE-I have been shown to improve endothelial dysfunction
[88, 89]. A newer agent, ranolazine, has recently been shown
to improve physical functioning, angina symptoms, and
quality of life in women with a positive stress test but no
obstructive CAD . In addition to the medications discussed,
lifestyle changes such as exercise have significant benefit for
symptoms of chest pain . Weight loss, smoking cessation,
and the Mediterranean diet all have been shown to improve
endothelial function  and should be recommended for
appropriate patients. Women with female-specific ischemic
heart disease are thought to have enhanced pain sensitivity
which may respond to xanthine derivatives and tricyclic
antidepressants. Lastly, other nonpharmacologic treatments have
shown some efficacy including cognitive-behavioral therapy,
enhanced external counterpulsation, neurostimulation, and
stellate ganglionectomy .
Epicardial Coronary Atherosclerosis
Women with coronary artery disease report worse health
related quality of life outcomes compared to men . In
addition, there remains a pattern of higher mortality and worse
cardiovascular outcomes in women with ischemic heart
disease [93, 94]. This is partially attributed to the incomplete use
of secondary prevention treatment regimens for coronary
atherosclerosis which improve survival, reduce recurrent
ischemic events, and improve quality of life .
There are also sex differences in invasive strategies during
an ACS presentation. Compared with men, women are at
increased risk of adverse outcomes after acute coronary
syndrome as well as percutaneous coronary interventions [96,
97]. They are also at increased risk of bleeding from medical
therapies used in acute coronary syndrome and the use of
femoral access for PCI [98, 99].
It was originally thought that women with nonobstructive
disease had a benign prognosis ; however, we now know that
this is not the case. Some of the discrepancies in findings can be
attributed to patient selection and the heterogeneity of inclusion
criteria in studies. Women with proven ischemia but no
obstructive coronary artery disease still have increased events
compared to asymptomatic women . In fact, women with
stable angina and nonobstructive CAD are three times more likely
than men to experience a cardiac event within the first year of
cardiac catheterization . In those with ACS and
nonobstructive disease, there is a 2 % risk of death and MI at
30 days . Within the WISE Study, a subset of women
without angiographic CAD but persistent symptoms underwent
magnetic resonance spectroscopy (MRS) to assess for
myocardial ischemia. Those women with no obstructive CAD and a
normal MRS had a 13 % vascular event rate in the following
3 years; whereas those with an abnormal MRS study had a
cardiovascular event rate of 43 % which was similar to the
reference WISE women with obstructive CAD (48 %) .
More research is needed to determine the best diagnostic testing
and treatment strategies for these women.
We have come a long way in the past 25 years since the US
National Institutes of Health (NIH) mandated the inclusion of
women in all NIH-sponsored research in 1990. However, we
are only beginning to scratch the surface in the understanding
of sex differences in the pathophysiology and treatment of
ischemic heart disease. There are important differences that
clinicians should be cognizant of as discussed in this article.
These differences impact our understanding of the disease,
diagnosis, and treatment. In the future, as we continue to
reevaluate our known therapies based on sex, we will be able to
adjust our treatment strategies accordingly. There remain
many biologic, pathophysiologic, and diagnostic sex
differences in ischemic heart disease that have yet to be clarified
and will require additional research.
Compliance with Ethics Guidelines
M Sanghavi and M Gulati both declare no conflicts
Human and Animal Rights and Informed Consent All studies by M
Gulati involving animal and/or human subjects were performed after
approval by the appropriate institutional review boards. When required,
written informed consent was obtained from all participants.
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