Ischemic Heart Disease in Women

Nida Waheed,MD,MPH ,Nicholas Kaufman,BS ,Jonathon Seawright,MD and Ki Park,MD,MS

1 University of Florida,College of Medicine,1600 SW Archer Rd,Gainesville,FL 32610,USA

Abstract

Keywords: Angina;microvascular angina;chest pain;ischemic heart disease;coronary microvascular dysfunction

Introduction

The leading cause of deaths related to cardiovascular disease (CVD)in 2013 was ischemic heart disease,and an estimated 3.8 million such deaths occurred among women worldwide [1].Advances in the prevention and treatment of CVD have resulted in a decline in CVD deaths overall;however,younger individuals less than age 40,especially women,have not experienced as great a proportional decline in CVD mortality [2].Women develop ischemic heart disease (IHD)at an older age than men and tend to have more comorbidities such as heart failure,hypertension,and diabetes at IHD onset than men [3].A study including 388 US hospitals found higher in-hospital CVD mortality rates among women and a 1.34-fold higher risk of death among white women presenting with stable angina compared to white men with angina [4].Women with stable angina and IHD are approximately twice as likely to die or have a nonfatal myocardial infarction (MI)1 year after diagnosis compared to men with IHD.A higher proportion of women with IHD die of sudden cardiac death (52%)before hospital arrival compared to men with IHD (42%)[5].Women with IHD often have persistent symptoms,are hospitalized because of recurrent symptoms,and have lower general wellbeing and greater limitations in performing activities of daily living compared to men with IHD [5].However,they are less likely to under go an exercise stress test and are less likely to be referred for coronary angiography following a positive stress test result compared to men.They are also less likely to be taking appropriate evidence-based medications such as antiplatelet and statin therapies compared to men with IHD [6].Overall,IHD in women presents a diff cult challenge for clinicians because of greater symptom burden,greater functional disability,increased health care use,and more adverse outcomes than in men with IHD.

Differences in Ischemia by Sex

In women compared with men,IHD is character -ized by a number of structural and functional differences in coronary vasculature.Structurally,women tend to have smaller coronary vessels,increased vessel stiffness,more diffuse coronary disease,and microemboli [5,7].Women are predisposed to having more plaque erosion as opposed to plaque rupture,which more commonly occurs in men [5,7,8].Plaque rupture is often seen in calcif ed plaques and is associated with hypercholesterolemia.On the other hand,plaque erosion is not associated with elevated cholesterol levels and is character -ized by an abundance of surface smooth muscle cells and proteoglycans [9].Atherosclerotic plaque rupture with lumen thrombosis is the most common mechanism for acute coronary syndromes and sudden cardiac death.Plaque erosion is more common in women than in men,especially in individuals younger than 50 years [10].In a study comparing coronary plaque rupture with coronary plaque erosion in 74 coronary specimens obtained at autopsy,levels of inf ammatory markers and apoptosis were signif cantly lower in plaque erosion compared with plaque rupture [11].The plaque erosion samples most closely resembled thick-cap f broatheromas,whereas plaque rupture was more closely associated with thin-cap f broatheromas.This suggests two dif ferent pathophysiological processes and that women could potentially benef t from therapeutic approaches tar geted to prevent plaque erosion.Women are also more likely than men to have endothelial dysfunction,smooth muscle dysfunction,and inf ammation [7].

In the setting of myocardial ischemia,there is diminished ventricular compliance,diastolic and systolic dysfunction,electrocardiographic changes,and increased ventricular pressure [12].This can ultimately lead to angina,but approximately 25-50% of patients with angina also experience episodes of asymptomatic (silent)ischemia,and these may outnumber symptomatic episodes by a ratio of more than 20:1 [13].Postmenopausal women have a higher incidence of silent ischemia than men,although whether there are different mechanisms driving asymptomatic myocardial ischemia in men and women is unknown [14,15].Women with silent ischemia report more nonanginal symptoms than men and experience a higher frequency of fatigue,shortness of breath,diaphoresis,muscle tension,and headaches [16].A review of asymptomatic myocardial ischemia by sex highlighted the need to study women-only cohorts to better understand the physiology and risk of adverse outcomes in these patients [15].

Risk Assessment of Ischemic Heart Disease in Women

Historically,risk factors for IHD have been lar gely based on research conducted predominantly in male participants.This has led to underestimation of risk,and,therefore,undertreatment of women with heart disease risk factors.There are several tools designed to aid physicians in risk stratifying patients to guide treatment and predict prognosis for IHD.However,these tools are often based on traditional risk factors in men relying on outdated research.

While these traditional risk factors were identif ed by research involving predominantly male participants,they still hold value in risk stratifying women.All-cause,coronary heart disease,and CVD mortality increase with increasing number of traditional risk factors in young women less than age 40.CVD mortality rates increase from 1.5% among women at low risk of cardiovascular events to 9.0% among those with at least two CVD risk factors [17].One study found 97% of women with obstructive coronary artery disease (CAD)had at least one conventional cardiovascular risk factor,but the odds ratios for CAD for diabetes,hypertension,and smoking were signif cantly greater in women than in men [18].Thus,traditional risk factors should be considered when one is stratifying female patients;however,they may not hold the same signif cance.For example,when the association of angina with mortality in men and postmenopausal women was compared,women had nearly 50 and 150% higher hazard ratios for glucose intolerance and type 2 diabetes,respectively [19].If a man and a woman are both determined to have the same risk factor,their degree of risk attributable to that risk factor may not be proportional on the basis of sex.

These factors may lead to underrecognition and treatment of IHD in women,leading to increased disparity in outcomes.Despite traditional risk factors often having greater health impacts on women than men,these risk factors are treated less often and less aggressively in women because of decreased awareness among patients and physicians.Nearly 75% of all coronary heart disease deaths among women could be avoided if these risk factors are adequately treated [20].

Traditional Risk Factors

Traditional risk factors should not be totally discounted since they are useful in predicting CVD in both men and women.However,there is a need to reexamine the impact of these risk factors on women specif cally to better risk stratify patients and decrease sex-related health care inequity.

Nontraditional Risk Factors

It has been increasingly recognized that traditional risk factors and the widely used Framingham Risk Score likely underestimate stable IHD risk in women.Consequently,there have been increasing efforts to identify novel risk factors specif c to women and include them in newer risk stratif cation tools.These novel risk factors include abdominal obesity,metabolic syndrome,low estrogen levels,elevated testosterone levels,elevated C-reactive protein levels,and polycystic ovarian syndrome [5,21].

Hormone regulation seems to be particularly inf uential in CVD risk in women.Disruption of ovulatory cycling-indicated by estrogen def ciency and hypothalamic dysfunction or irregular menstrual cycling-in premenopausal women is associated with increased risk of coronary atherosclerosis and adverse CVD events.In postmenopausal women,combinations of insulin resistance,dyslipidemia (increased levels of triglycerides,decreased HDL levels),hypertension,or abdominal obesity are frequently associated with alterations in endogenous estrogens and androgens in women i.e.,changes in levels of hormones [5,21,22].Despite the benef t of identifying ovulatory cycling as a novel risk factor,much more research is required to determine how to best use the data for risk stratifying female patients.

The Reynolds Risk Score is a cardiovascular risk assessment tool developed specif cally for use in women from a cohort of nearly 25,000 patients [23].This tool reclassif ed more than 40% of women into higher- or lower-risk categories,which correlated more closely with actual CVD event rates than the Framingham Risk Score.The Reynolds Risk Score is clinically simple and is based on age,systolic blood pressure,high-sensitivity C-reactive protein level,total cholesterol level,HDL cholesterol level,smoking status,and family history of premature MI [24].This risk stratif cation tool is clearly a step in the right direction for better predicting CVD events in women,but more work needs to be done to incorporate female-specif c risk factors.

The American College of Cardiology and American Heart Association created a new calculator for cardiovascular event risk estimation.This calculator includes sex and is specif c for whites and African Americans.The Pooled Cohort Equation provides the 10-year and lifetime risk of CVD.Although it better estimates women’s higher lifetime CVD risk [25],the calculator also does not account for female-specif c risk factors.

The American Heart Association and American Stroke Association presented new guidelines in 2014 identifying stroke risk factors that are unique and more common in women.The sex-specif c risk factors include pregnancy,preeclampsia,gestational diabetes,oral contraceptive use,postmenopausal hormone use,and changes in hormonal status.The risk factors more prevalent or stronger in women include migraine with aura,atrial f brillation,diabetes mellitus,hypertension,depression,and psychosocial stress [26].

Ideally,physicians should use a cardiovascular risk assessment such as the American College of Cardiology and American Heart Association Pooled Cohort Equation and incorporate risk factors unique to or predominant in women.These risk factors include preeclampsia,gestational diabetes,smoking and oral contraceptive use,polycystic ovarian syndrome,depression,and anxiety [25].While preeclampsia and gestational diabetes are thought to be transient conditions of pregnancy,they may have lasting effects on the long-term risk of developing CVD in women.When an attempt was made to incorporate hypertensive disorders of pregnancy and parity in an established risk score for low-risk patients,unfortunately reclassif cation of risk did not improve [27].Thus,the optimal use of femalespecif c risk factors has not yet been determined.

There has also been increased interest in deter -mining novel biomarkers in the prediction of car -diovascular risk.Use of high-sensitivity troponin and coronary artery calcium levels improved the prediction of coronary heart disease in women alone.Apolipoprotein A-1,apolipoprotein B-100,lipoprotein(a),lipoprotein-associated phospholipase A2,brain natriuretic peptide,N-terminal prohormone of brain natriuretic peptide,and genetic markers have also been identif ed to effect CVD in women [28].

The identif cation of novel risk factors and incorporation of them into new risk stratif cation tools are necessary steps to ending the disparity in diagnosing and treating heart disease in both men and women.However,novel risk factors such as history of pregnancy complications are emer ging to improve risk stratif cation in women.Research efforts to this end should continue to study the utility of these nontraditional risk factors and how they may impact our ability to risk stratify women for CVD.

Symptoms

Chest pain is characterized into three categories: typical,or classic,angina;atypical angina,termedanginal equivalents,which are symptoms of myocardial ischemia without the presence of angina;and nonanginal chest pain,which has no anginal features that denote cardiac involvement.Typical angina presents as a sensation of chest discomfort over or near the sternum described as squeezing,heaviness,or pressure-like,radiates to either shoulder or arm,and can arise in the neck,jaw,or epigastrium.Onset of symptoms is relatively predictable,and they last approximately 2-5 minutes and abate when the stressor is gone or after nitroglycerin use.Precipitating factors may include exercise or emotional distress.The presentation of angina pectoris in women is often atypical in location,frequency,and intensity.Anginal “ equivalents ” of fatigue,shortness of breath,lightheadedness,nausea,and indigestion are also more likely to be reported in women than in men [29,30].D’Antono et al.[31] conducted a prospective study in men and women with myocardial perfusion imaging showing evidence of ischemia during exercise.This study showed that women rated their angina as more

intense than men,described it as throbbing or sharp in nature,and reported pain more often in the neck.Inf ammation and hormonal alterations may play a signif cant role in the presentation of symptoms and may also explain the higher prevalence of observed atypical symptoms and adverse outcomes seen in women [5].

Therapy for Angina

Management of angina is aimed at reducing ischemia,alleviating symptoms,and improving quality of life [32,33].Beta blockers (especially in patients with prior MI or heart failure)or longacting calcium channel blockers,alone or in combination with each other,are the preferred therapies for initial control of anginal symptoms.One metaanalysis compared the eff cacy and tolerability of beta blockers and calcium channel blockers for patients with stable angina and found no signif cant difference in rates of cardiac death or MI between the treatment groups but showed fewer episodes of angina per week with beta blockers than with calcium channel antagonists [34].Aspirin,angiotensin-converting enzyme inhibitors (ACEIs;in patients with diabetes and left ventricular dysfunction),statins,and sublingually administered nitroglycerin (for immediate relief of symptoms)work to reduce cardiovascular risk factors and alleviate symptoms.Ranolazine,a late sodium channel inhibitor,is another FDA-approved medication for the treatment of angina.One study evaluated the antianginal ef fects of ranolazine in combination with amlodipine in patients who were experiencing more than three episodes of angina a week despite receiving treatment with amlodipine daily.Patients in the combination arm had signif cant reductions in anginal frequency and nitrate use at 7 weeks compared with patients in the amlodipine-alone arm [35].Adequate trials of medical therapy are recommended to control symptoms before revascularization is considered to relieve persistent symptoms [32].The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE)trial compared optimal medical therapy alone with percutaneous coronary intervention in combination with optimal medical therapy to determine if there was a reduction in the risk of death or nonfatal MI in patients with stable CAD.The study found no signif cant difference between men and women in regard to the relative risk of death or nonfatal MI between the two groups [36].

Diagnostic Testing for Ischemia

In guidelines published by the American College of Cardiology,noninvasive stress testing is appropriate in most patients with suspected IHD for diagnosis and risk stratif cation [37].Coronary angiography is considered the gold standard for the diagnosis of IHD,although there are limitations and risks associated with the procedure [38].Coronary angiography is considered an appropriate initial test when the information derived from the procedure signif -cantly inf uences patient treatment and the benef ts outweigh the risks [38].After initial ECG testing,patients who are able to exercise,have an interpretable ECG,and are to low to intermediate risk of IHD should undergo standard exercise ECG testing,while those at high risk of IHD or who have a noninterpretable ECG should under go exercise stress with either nuclear myocardial perfusion imaging or echocardiography [32].In patients who are unable to exercise,pharmacologic stress myocardial perfusion imaging or echocardiography is recommended [32].Coronary computed tomography angiography may also be performed to evaluate patients with suspected CAD [39,40].In a recent systematic review and meta-analysis,coronary computed tomography angiography was compared with functional stress testing and was associated with a reduced incidence of MI and an increased incidence of CAD diagnosis,prescriptions for aspirin and statins,and invasive coronary angiography [40].

There are a number of factors affecting the accuracy of diagnostic testing in women [5].The evaluation of women with symptoms suggestive of IHD is challenging because women report more angina despite lower rates of obstructive CAD [41].In premenopausal women,estrogen may provoke ST-segment changes resulting in a false positive exercise ECG,while in postmenopausal women the prevalence of IHD increases,resulting in higher predictive accuracy [5].Angina and ischemia severity have also been shown to vary during menstrual cycles.Higher rates of ischemia and reduced time to ischemia onset have been seen during the luteal phase because of lower levels of estradiol [21].During exercise stress testing,reduced functional capacity or an inability to achieve f ve metabolic equivalents,a measure of oxygen uptake during exercise,diminishes the ability to elicit ischemia and requires retesting with pharmacologic stress imaging in women [21].Further studies show that in comparison with men,in women the diagnostic accuracy of exercise stress ECG is lower [39].The presence of signif cant resting ST-T wave changes on ECG has been shown to diminish the accuracy of identifying peak exertional changes,with current guidelines recommending cardiac imaging in men and women with signif cant ST-T wave changes on resting ECG [21].

Prognosis

It is estimated that approximately nine million adults in the USA have chronic angina [37].The cost of CAD,direct and indirect,is estimated to have topped $177 billion in the USA in 2010 [32].One study found that the annual mortality of patients with angina was twice as high as that of a cohort of matched asymptomatic patients [42].Using data from the Finnish health care system,women with angina had higher mortality rates up to age 75 years compared to men [43].Self-reported angina may also be predictive of cardiovascular death as demonstrated by a Veterans Affairs study showing a fourfold increase in the risk of death in patients reporting severe symptoms in comparison with those with minimal symptoms [44].In patients with stable chronic angina,the clinical outcomes can differ greatly depending on the patient’s characteristics.Women with CAD have higher rates of adverse cardiovascular outcomes,with 42% experiencing sudden cardiac death before arrival at a hospital compared with 25% of men with CAD [5].The CONFIRM study demonstrated that women compared with men have an increased prevalence of CAD with increasing age,greater number of risk factors,and higher rates of atypical anginal symptoms,but that there is no sex difference in mortality.It also found that the Framingham risk estimate underestimates risk in women [45].Alexander et al.[46] tested the prognostic value of the Duke treadmill score (DTS)in men and women referred for evaluation of chest pain who underwent exercise treadmill testing and subsequent diagnostic cardiac catheterization and found that women compared with men had a higher DTS,lower prevalence of CAD,and lower 2-year mortality,concluding that by combining several aspects of treadmill testing,the DTS can effectively stratify women into diagnostic and prognostic risk categories.Exercise stress test scoring improves prognostication in women;however,exercise duration is the strongest predicative parameter from the treadmill test [21].Women who achieve less than f ve metabolic equivalents are also at increased risk of cardiac events [21].Carpiuc et al.[19] demonstrated that impaired glucose tolerance or type 2 diabetes is signif cantly associated with greater risk of CHD death in postmenopausal women compared with men.Further studies show that disruptions in estrogen levels increase the risk of CAD and CVD events in premenopausal women,and in postmenopausal women clustering of risk factors,due to reduced estrogen levels,are common and result in increased risk of all-cause death and CVD death,which increases as the number of traditional risk factors increases [5,17,21].

Coronary Microvascular Dysfunction and Symptom Presentation

Angina in the absence of clinically signif cant CAD is a common clinical scenario in women and remains a challenge for providers caring for these patients.The pathophysiology of angina with nonobstructive (i.e.,less than 50% epicardial stenosis)CAD is poorly understood,but coronary microvascular dysfunction (CMD),or microvascular angina,may play a role.CMD is typically def ned as impaired vasodilation of arterioles,leading to an inadequate increase in blood fow from rest to stress [47].Between 50 and 65% of patients with anginal symptoms and nonobstructive CAD have CMD [48].

Previously,patients with signs and symptoms of myocardial ischemia in the absence of CAD were often labeled as having cardiac syndrome X.The Women’s Ischemia Syndrome Evaluation (WISE)study def ned a major subset of patients with car -diac syndrome X to have microvascular angina as they had vascular dysregulation capable of causing ischemia with provocative testing.These patients are now usually described as having CMD.Shaw et al.[5] coined the termmicrovascular anginafor symptoms occurring as a result of CMD that resulted in myocardial ischemia.Microvascular angina can be indistinguishable from symptoms caused by atherosclerotic epicardial CAD,also known asobstructive CAD.However,the presentation of angina in women is often atypical in location,frequency,and quality.Anginal “ equivalents ” of fatigue,shortness of breath,lightheadedness,nausea,and indigestion are more likely to be reported by women than men [49,50].There also appears to be no correlation between the severity of angina and the extent of CAD as determined by angiography [51].The COURAGE and WISE studies have shown that women have less extensive angiographic CAD than men but are more likely to have moderate to severe angina [21,52].The WISE study has served as the backbone of our understanding of microvascular dysfunction and female-specif c myocardial ischemia pathophysiology.

Persistent angina is also highly prevalent in women with signs and symptoms of ischemia and nonobstructive CAD.A randomized controlled trial found that short-acting ranolazine was not ef fective in treating angina in women with CMD [53].However,a cohort study of 229 women with nonobstructive CAD found limited reduction in angina frequency compared to usual-care antianginal therapy after 1 year of follow-up [54].Moreover,most patients continued to have angina despite traditional antianginal therapy.Thus,more therapeutic options are needed in this population.

Diagnosis of Coronary Microvascular Dysfunction

Multiple techniques have been evaluated to assess microvascular function.CMD is most commonly diagnosed by invasive testing (i.e.,coronary reactivity testing,CR T),myocardial perfusion reserve using positron-emission tomography (PET),and cardiovascular magnetic resonance imaging (cMRI).Unlike epicardial coronary arteries,the coronary microvasculature cannot be directly observed by coronary angiography.CRT is the gold standard for diagnosing CMD and endothelial dysfunction.CRT uses coronary fow reserve (CFR),which is the magnitude of the increase in coronary blood fow that can be achieved from the basal coronary perfusion to maximal coronary vasodilation assessed by an intracoronary Doppler fow wire.It serves as a measure of the ability of the coronary microvasculature to respond to a stimulus and can accurately assess a patient for CMD if no signif cant epicardial coronary disease is present [47,55].CFR is expressed as the ratio of peak hyperemic myocardial blood fow (MBF)to rest MBF,and a CFR of less than 2.0-.5 is generally considered abnormal.

In 100 female patients with angina and nonobstructive coronary disease per standard angiography,intravascular ultrasonography (IVUS)revealed nonobstructive atherosclerotic plaques in approximately 80% of patients [56].Another substudy of the WISE study also evaluated CFR and IVUS of the left coronary segment to better assess the relationship between microvascular bed size and conduit arter -ies (macrovasculature).It found three IVUS measures correlated with CFR (lumen volume,maximal luminal cross-sectional area,and minimal inter -nal elastic lamina cross-sectional area),suggesting IVUS-derived measures of conduit coronary artery size could predict coronary microvasculature size [57].Although CRT is considered safe and effective [58],the advent of noninvasive testing,including PET and cMRI,has increased the feasibility of diagnosing CMD while decreasing the risk associated with invasive techniques [48].PET has been used and validated to diagnose CMD.It uses radioisotope signaling to estimate MBF and thus CFR.However,there is variability among the tracers and variance in methods,even when the same tracer is used,which can signif cantly affect results [48,59].

Cardiovascular magnetic resonance imaging (cMRI)has been used to evaluate myocardial per -fusion with high resolution to detect ischemia in patients with obstructive epicardial CAD [60,61],but it is increasingly being used to assess patients for microvascular disease [62,63].A recent study aimed to evaluate whether cMRI could be used to diagnose microvascular angina or CMD.Fifty patients with nonobstructive CAD underwent adenosine stress and rest perfusion and late gadolinium enhancement imaging followed by invasive coronary angiography 7 days later.This study found that stress perfusion cMRI could noninvasively assess microvascular angina as compared with coronary angiography [64].This provides a promising alternative to invasive testing,especially as cMRI becomes more widely available.

Reynolds et al.[65] evaluated the mechanism of MI in women without obstructive CAD using a variety of imaging techniques IVUS was performed during angiography and cMRI was performed within 1 week to determine the presence and pattern of myocardial injury.This study showed that plaque rupture and ulceration are common in women with nonobstructive CAD.It also found that late gadolinium enhancement was common in this population and showed ischemic patterns of injury.Vasospasm and microembolism are thought to be possible mechanisms of ischemic late gadolinium enhancement without plaque disruption.Since women are much more likely than men to develop ischemia due to endothelial and/or microvascular dysfunction,vasospasm was thought to represent an extreme form of endothelial dysfunction.IVUS and cMRI thus provide complementary mechanistic insights into the pathophysiology of MI in women without obstructive CAD and may be useful in identifying potential causes and therapies.

Prognosis for Women with Coronary Microvascular Dysfunction

Symptomatic women with nonobstructive CAD were previously considered to be at low risk of cardiovascular events.However,studies have found this condition to be associated with increased risk of cardiovascular morbidity and death [66-68].The WISE study demonstrated an increased risk of major adverse cardiac events (MACEs),such as MI,stroke,congestive heart failure,and death related to CVD in this population.In a substudy comparing 540 symptomatic women without obstructive CAD and 1000 age- and race-matched asymptomatic women,16% of the symptomatic group developed a MACE compared with 2.4% of controls in a 5-year follow-up period [68].Another study found that among women without obstructive CAD,patients with persistent symptoms were twice as likely (20.5 vs.10.1%,P = 0.03)as patients without symptoms to have a MACE.These f ndings suggest that,contrary to popular belief,women with nonobstructive CAD but persistent chest pain have increased morbidity and mortality and may need aggressive risk factor reduction and follow-up [69].

Women with nonobstructive CAD were also noted to have decreased quality of life and functional disability due to chest pain compared with women with obstructive CAD.Over the lifetime of these patients,the persistence of symptoms resulted in extensive health care use,including repeated evaluations and hospitalizations,estimated to cost $767,288 [70].

Therapy for Coronary Microvascular Dysfunction

Currently,there are no evidence-based guidelines for treating patients with nonobstructive CAD.The WISE study compared women with persistent chest pain and nonobstructive CAD with women without chest pain and nonobstructive CAD and found that the 6-year incidence of all cardiovascular events (MI,stroke,congestive heart failure,and cardiovascular deaths)was twice as high in women with persistent chest pain and no evidence of obstructive CAD [69].These f ndings highlight the need for aggressive risk factor modif cation and treatment of angina in women with persistent chest pain and no evidence of obstructive CAD.

Mehta et al.[71] conducted a pilot study to evaluate the impact of ranolazine in women with microvascular angina.Compared with placebo,ranolazine was found to signif cantly increase Seattle Angina Questionnaire subscale scores for physical functioning,angina stability,and quality of life.Another study evaluated whether an ACEI increased CFR and relieved anginal symptoms among women with CMD.CFR was evaluated after 16 weeks,and women receiving an ACEi had not only increased CFR but also relief of anginal symptoms,supporting the use of an ACEi in treatment of patients with CMD [72].Furthermore,a meta-analysis found that statin therapy was associated with signif -cant improvement in both peripheral and coronary endothelial function [73].

Currently,the Women’s Ischemia Trial to Reduce Events in Non-Obstructive CAD (W ARRIOR),a multicenter randomized controlled trial,aims to evaluate whether statins,ACEIs,and aspirin modify risk factors,vascular function,and MACEs.This study aims to inform future guidelines regarding how best to treat symptomatic women with nonobstructive CAD [74].

Conclusion

Women share similar cardiovascular risk factors for IHD with men,but there are important sex differences,especially in the prevalence of obstructive coronary disease and coronary vascular disease.Use of risk scores for women,such as the Reynolds Risk Score,improve risk detection,and novel risk markers,including reproductive sex hormones and inf ammatory markers,may provide insight for identifying at-risk women.New imaging techniques,such as cMRI,also hold promise for increasing the detection of ischemia in those with atypical angina,silent ischemia,or CMD.Further investigations are needed to inform guidelines for sex-specif c ischemia management,especially in regard to diagnosis and therapy,to improve outcomes for both women and men.

Conflict of interest

The authors declare no confict of interest.