Cardiopatia isquemica en la mujer. Med Clin N Am, 2024
Cardiopatia isquemica en la mujer. Med Clin N Am, 2024
Cardiopatia isquemica en la mujer. Med Clin N Am, 2024
Wo m en
a b,
Eleonore Grant, MD , Monika Sanghavi, MD *
KEYWORDS
Ischemic heart disease women’s cardiovascular health
MI with no obstructive coronary arteries Spontaneous coronary artery dissection
acute coronary syndrome
KEY POINTS
Women have a unique clinical phenotype of ischemic heart disease with higher prevalence
of non-occlusive disease, and decreased burden of obstructive atherosclerosis.
Women share a disproportionate burden of traditional risk-factors for heart disease and
have sex-specific risk-factors that are not incorporated into commonly used risk scores.
Ischemia with non-Obstructive Coronary Arteries (INOCA) is a clinical entity grouping
several endotypes including microvascular disease, vasospasm, and myocardial bridging
and is more common in women.
There is a burgeoning understanding of the discordance between angina and ischemia in
women, especially in INOCA and this should be carefully considered in treatment
strategies.
INTRODUCTION
The landscape of ischemic heart disease in women has expanded significantly with
attention to sex-specific differences. The focus has shifted from obstructive epicardial
atherosclerosis to a spectrum of ischemic heart disease including nonobstructive eti-
ologies. Better appreciation of the different phenotypes of ischemic heart disease may
help reduce disparities between the sexes. Women with ischemic heart disease are
reported to have a higher prevalence of angina,1 lower health-related quality of life,2
higher emergency room visits,3 and increased short- and long-term mortality than
men.4 This article reviews the current understanding of ischemic heart disease high-
lighting sex-specific differences.
a
Department of Internal Medicine, University of Pennsylvania, 3400 Civic Center Boulevard,
Philadelphia, PA 19104, USA; b Division of Cardiology, University of Pennsylvania, 3400 Civic
Center Boulevard, Philadelphia, PA 19104, USA
* Corresponding author.
E-mail address: Monika.Sanghavi@pennmedicine.upenn.edu
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568 Grant & Sanghavi
BIOLOGIC DIFFERENCES
RISK FACTORS
Traditional Risk Factors, Differing Burden of Disease
Women share many of the same traditional cardiovascular risk factors as men (hyper-
lipidemia, hypertension [HTN], diabetes mellitus [DM], abdominal obesity, smoking,
and physical inactivity).10 However, HTN, DM, and smoking are more potent risk fac-
tors in women than men (odds ratio of 1.5, 1.6, and 2.0, respectively).10 Possible rea-
sons for this have been theorized: (1) HTN is often undertreated in women as
compared with men;11 (2) DM may cause heightened impairment of endothelium-
dependent vasodilation which may disproportionally affect women11; and (3) smoking
risk is potentiated by use of combined oral contraceptive pills (tenfold increase in
myocardial infarction (MI) and threefold increase in stroke).12 This underscores the
need to target these modifiable risk factors in primary and secondary prevention of
Ischemic Heart Disease (IHD) in women.
Hormonal factors
Endogenous estrogen is cardioprotective due to a myriad of positive effects on the
metabolic and vascular system19 and is theorized to be the reason for the 10-year
delay in atherosclerotic events in women compared with men. The loss of endogenous
estrogen production during menopause has been associated with increased cardio-
vascular risk, redistribution of body fat, reduced glucose tolerance, abnormal lipids,
and increased blood pressure and arterial stiffening.19–21 Still, exogenous estrogen
replacement has not been proven as a reliable mechanism to reduce cardiovascular
risk.20
Polycystic ovarian syndrome (PCOS) is associated with adverse cardio-metabolic
health and higher incidence of IHD. Although the association is well-established, it
is still debated whether PCOS is an independent a risk factor for IHD or if it is due
to the adverse metabolic effects (dyslipidemia, insulin resistance, weight gain).17
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Ischemic Heart Disease in Women 569
Rheumatologic conditions
Women are also disproportionately affected by inflammatory and autoimmune condi-
tions which confer a higher lifetime risk of IHD and are also considered ASCVD risk
enhancers. Patients with lupus have a three- to fourfold increased risk of CV events
and death.22 Inflammation is important in the pathogenesis of atherosclerosis and
may explain the increased risk in these patients.
Other risk factors affecting women disproportionately include chest wall radiation in
patients with breast cancer, psychosocial risk factors,23 including poor mental
health24 and low socioeconomic status.25
PRESENTATION
Ischemic heart disease can present as acute coronary syndrome (ACS) or as chronic
disease with stable symptoms of angina pectoris. The definition of “typical” angina
pectoris is based on the traditional paradigm of obstructive coronary artery disease
that was commonly noted in men. Although chest pain is the most common presen-
tation for both sexes, there are important differences that need to be considered.
Highlighted in the following sections are sex differences in the presentation of acute
coronary syndrome and chronic ischemic heart disease.
Acute Presentations
The most common symptom of acute ischemic heart disease is chest discomfort; how-
ever, women are known to have a broader range of symptoms on presentation. Young
women (aged 35–54 years) are 50% more likely than similarly aged men to present
without chest pain when they have an ST elevation MI (STEMI).26,27 Although many
women with acute myocardial infarction (AMI) have nonobstructive disease (as dis-
cussed below), women with obstructive epicardial disease are more likely to suffer
from plaque erosion and embolization compared with plaque rupture in men.27 Of
note, women presenting with AMI are much less likely to receive guideline-
recommended therapies than men (lipid-lowering medications, dual antiplatelet ther-
apy, beta-blockers, angiotensin-converting enzyme [ACE]/angiogensin receptor
block [ARB]), and less likely to achieve door to balloon time of less than 90 minutes.2
This discrepancy is likely multifactorial from delayed diagnosis and incomplete under-
standing of the spectrum of ischemic disease, these discrepancies are even more sig-
nificant in young women.
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570 Grant & Sanghavi
Chronic Presentations
Chronic IHD in women most commonly presents as stable angina, independent of un-
derlying etiology.40 However, compared with men, women report broader symptomol-
ogy (ie, shortness of breath, nausea, epigastric pain) and are more likely to report
atypical symptoms such as fatigue, jaw pain, or dyspnea. Women present later into
their symptom onset or will have repeated visits with the medical system before diag-
nosis. Women with nonobstructive disease will have had a myriad of tests (stress test,
invasive angiography, computed tomography angiography [CTA]) and may be falsely
reassured or dismissed if they are negative.41
PATHOPHYSIOLOGY
Differences in Types of Disease
Although chronic IHD from obstructive epicardial disease is common, women with
angina disproportionally suffer from nonobstructive etiologies of ischemic heart
disease.3,18,40,42–44
Under the umbrella term of open artery ischemia (OAI),45 several stable clinical phe-
notypes have emerged.45
1. ANOCA (angina with non-obstructive coronary arteries)
2. INOCA (ischemia with non-obstructive coronary arteries)46
These clinical phenotypes are manifestations of several endotypes of disease (cor-
onary spasm, myocardial bridge, endothelial dysfunction, coronary microvascular
dysfunction [CMD], and microvascular spasm). These endotypes can be divided
anatomically into disease of the epicardial and microvascular circulation as discussed
below (Fig. 1).
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Ischemic Heart Disease in Women 571
Epicardial Circulation
Atherosclerosis
Women are more likely to have diffuse and nonobstructive atherosclerosis noted on cor-
onary angiogram. Although focally nonobstructive, diffuse disease can be functionally
significant. The WISE study, in women with stable symptomatic CAD, demonstrated
that 57% of women with symptoms and signs of ischemia had nonobstructive CAD
on angiography.47 Nonobstructive CAD is defined as less than 50% diameter stenosis
of all major epicardial vessels and is at least twice as prevalent in women compared
with men.15 The sex-specific difference in incidence of obstructive atherosclerosis is
most notable earlier in life and becomes less significant with age (and menopause).5
Epicardial artery vasospasm and endothelial dysfunction
Prinzmetal angina is a clinical syndrome of recurrent angina associated with myocardial
ischemia from coronary spasm. Chest pain often occurs at rest or at night; however, ex-
ertional symptoms in the morning have also been reported.46 Smoking is an established
risk factor where diabetes and HTN are not. On invasive testing, coronary spasm is
defined as severe (>90%) constriction of the coronary artery after administration of
acetylcholine with ECG changes indicative of ischemia and associated angina.
Endothelial dysfunction is also diagnosed on invasive testing with administration of
acetylcholine and is diagnosed in the setting of constriction of the epicardial vessel
(>0% to <90%) with acetylcholine instead of the expected vasodilation in normal
vasculature.
Myocardial bridge
This is a congenital anomaly where a segment of epicardial vessel traverses through
the myocardium and is thus compressed during systole. The degree of compression is
not predictable of the hemodynamic effects. Most commonly, the bridge overlies the
left anterior descending artery. Myocardial bridges are common and are reported in
25% of autopsies and CT angiograms. Although most are not hemodynamically or
clinically significant, they can been associated with acute and chronic IHD.37
Microcirculation
Microvascular spasm
Vasospastic angina can also be due to microvascular spasm. Challenging to diag-
nose, microvascular spasm is diagnosed by ECG changes and angina in the absence
of epicardial constriction with administration of acetylcholine invasively; however,
functionally should show decreased coronary blood flow and increased sinus lactate
accumulation after administration of acetylcholine.
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572 Grant & Sanghavi
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Ischemic Heart Disease in Women 573
Management
Historically, ischemic burden on testing and angina symptoms have thought to be
closely linked and targeting ischemia would also treat angina.
However, recent studies have shown that angina symptoms/severity are not directly
associated with the presence of ischemia: a discordance not well understood. In the
CIAO-ISCHEMIA trial, it was found that among women with INOCA, improvement in
ischemia (23%) and angina (43%) were common at 1 year but were not correlated.57
This highlights the importance of considering both ischemia and angina when manag-
ing a patient with ischemic heart disease.
Pharmacotherapy
For traditional atherosclerotic disease, women should be treated aggressively with
secondary prevention interventions such aspirin, statins, cardiac rehabilitation.
Pharmacotherapy for OAI should target the underlying endotype (Fig. 2). The Cor-
MICA trial tested the use of an invasive diagnostic strategy in angina and nonobstruc-
tive coronary artery disease and was able to show an improvement in Seattle Angina
Questionnaire and Quality of life.58
Fig. 2. Treatment pathways for patients with ANOCA. This figure includes therapies for pa-
tients with ANOCA based on endotype. ACE, angiotensin-converting enzyme; ANOCA,
angina with nonobstructive coronary arteries; CCBs, calcium channel blockers; EECP,
enhanced external counterpulsation; GLP-1, glucagon-like peptide-1; PDE-5, phosphodies-
terase 5 inhibitors; SLNTG, sublingual nitroglycerin; TCA/SSRI, tricyclic antidepressants/selec-
tive serotonin reuptake inhibitors. (Adapted from Smilowitz NR, Prasad M, Widmer RJ, et al.
Comprehensive Management of ANOCA, Part 2—Program Development, Treatment, and
Research Initiatives. J Am Coll Cardiol. 2023;82(12):1264-1279. https://doi.org/10.1016/j.
jacc.2023.06.044)
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574 Grant & Sanghavi
The recent JACC State of the Art Review of ANOCA outlines treatment strategies for
individual endotypes (see Fig. 2). Lifestyle changes and statins are the cornerstone
therapy for all endotypes, but additional treatment needs to be individualized.59
For coronary microvascular dysfunction, first-line therapy includes nonselective
beta blockade, angiotensin converting enzyme inhibitor (ACE-I), and sublingual nitro-
glycerin. Ranolazine, calcium channel blockers, and ivabradine can also be consid-
ered. The second line includes ranolazine, calcium channel blockers, and nitrates.59
For vasospasm (both epicardial and microvascular), the mainstay of therapy in-
cludes calcium channel blockers and short-acting nitrates.59 For microvascular
spasm, ACE-inhibitors should also be considered.
For myocardial bridging, beta blockade or calcium channel blockers are the treat-
ment of choice and nitrates should be avoided as it is thought to dilate the proximal
and distal segments of the compressed artery and can worsen the resulting systolic
stenosis. Percutaneous coronary intervention (PCI) or surgical myotomy is the surgical
intervention of choice and should be considered on a case-by-case basis.36,37
For endothelial dysfunction, nitrates and calcium channel blockers should be
considered.
Considerations in Pregnancy
Acute presentation in pregnancy
AMI is uncommon in women of reproductive age. However, pregnancy increases the
risk three- to fourfold and is associated with significant morbidity and mortality.60–62
The recent reported case fatality rate is approximately 5%.60 There is a higher inci-
dence of myocardial infarction with increasing maternal age.60 Acute MIs are most
common in the third trimester or postpartum period. Approximately 25% of women
present with an STEMI and 75% with an non-ST elevation MI (NSTEMI). The anterior
wall is most commonly involved (69% of cases). The mechanism of injury is most
commonly due to coronary dissection (43%), followed by atherosclerosis (27%) and
thrombosis (17%).63
SUMMARY
Over the last decade, we have gained a better understanding of sex-based differences
in ischemic heart disease but application in clinical practice is still limited. With
increased testing availability, improved insurance coverage for testing, and develop-
ment of more targeted treatment options, there is hope that the entire spectrum of
ischemic heart disease will be better understood and optimally treated.
Review sex-specific risk factors when evaluating a woman’s risk for ischemic heart disease.
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Ischemic Heart Disease in Women 575
Consider the entire spectrum of ischemic heart disease in patients presenting with angina.
MINOCA is a working diagnosis requiring further investigation.
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