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Chronic Coronary Syndromes in Women

Challenges in Diagnosis and Management
  • Matthias R. Meyer
    Correspondence
    Correspondence: Address to Matthias R. Meyer, MD, Division of Cardiology, Triemli Hospital, Birmensdorferstrasse 497, 8063 Zurich, Switzerland.
    Affiliations
    Division of Cardiology, Triemli Hospital, Zurich, Switzerland

    Division of Gender Medicine, Institute of Primary Care, University of Zurich, Switzerland
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      Abstract

      Sex matters in science. This particularly applies to ischemic heart disease, which displays key differences in pathophysiology, presentation, and effectiveness in diagnostic strategies and management between women and men. However, underrepresentation of women in randomized trials has led to an evidence gap in clinical practice. Nevertheless, it has become clear that women present with a higher burden of symptoms and comorbidities, experience worse outcomes, but are less likely to have flow-limiting stenosis in epicardial coronary arteries than men. A major contributor to this paradox is coronary microvascular disease, a heterogeneous disorder with multifactorial etiology that predominantly affects women. There is a significant interplay between coronary microvascular disease, obstructive coronary artery disease, and the cardiovascular risk associated with it, with impaired vasomotor function often preceding the development of advanced atheroma. This novel concept has recently been referred to as chronic coronary syndromes, which better meets the female phenotype of ischemic heart disease, questioning current management recommendations that still largely apply to flow-limiting stenoses in epicardial coronary arteries typically found in men. The goal of this review is to highlight the most recent scientific advances in understanding chronic coronary syndromes in women. It provides practical advice with focus on challenges in diagnosis and management, and discusses perspectives towards the implementation of sex-specific, safer, and more effective therapeutic strategies.

      Abbreviations and Acronyms:

      CAD (coronary artery disease), CMD (coronary microvascular disease), CMR (cardiac magnetic resonance), CCTA (coronary computed tomography angiography), INOCA (ischemia with no obstructive coronary artery disease), PET (positron emission tomography), SPECT (single-photon emission computed tomography)
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      Learning Objectives: On complication of this article, the reader should be able to: (1) differentiate coronary microvascular disease and obstructive coronary artery disease as frequent causes of myocardial ischemia in women; ((2) select appropriate testing in women with angina; and (3) employ specific treatment considering both adverse drug reactions and undertreatment of women with chronic coronary syndromes.
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      Article Highlights
      • Chronic coronary syndromes range from coronary microvascular disease to flow-limiting stenoses in epicardial coronary arteries, which both are frequent causes of myocardial ischemia in women.
      • Detection of obstructive atheroma on coronary angiography is not a sine qua non for the diagnosis of a chronic coronary syndrome, hence both epicardial and microvascular disease must be considered when selecting diagnostic tests.
      • Patients with myocardial ischemia but no obstructive coronary artery disease are at increased risk for cardiovascular events, have impaired quality of life, and repeatedly use health care resources, thus warranting specific management.
      • Sex differences in pharmacokinetics and pharmacodynamics must be considered when prescribing cardiovascular drugs to avoid adverse reactions and undertreatment of women with chronic coronary syndromes.
      In the United States and Europe, cardiovascular diseases claim more lives of women than cancer and chronic lung disease combined.
      • Timmis A.
      • Townsend N.
      • Gale C.
      • et al.
      European Society of Cardiology: cardiovascular disease statistics 2017.
      ,
      • Virani S.S.
      • Alonso A.
      • Benjamin E.J.
      • et al.
      Heart disease and stroke statistics 2020 update: a report from the American Heart Association.
      Ischemic heart disease in women exceeds, for example, breast cancer mortality by six-fold.
      • Timmis A.
      • Townsend N.
      • Gale C.
      • et al.
      European Society of Cardiology: cardiovascular disease statistics 2017.
      Nevertheless, women continue to be labeled as a special population in many guidelines, are evaluated and treated less aggressively, and experience more adverse events when receiving therapy.
      • Gulati M.
      Improving the cardiovascular health of women in the nation: moving beyond the bikini boundaries.
      This may result from the fact that the community in medical practice and research tends to focus on diseases involving the breasts and the reproductive organs, while essentially ignoring many other organ systems, in particular the cardiovascular system and its diseases, as determinants of women's health.
      • Wenger N.K.
      You've come a long way, baby: cardiovascular health and disease in women: problems and prospects.
      Indeed, inclusion rates of women are as low as 30% in cardiovascular clinical trials,
      • Gong I.Y.
      • Tan N.S.
      • Ali S.H.
      • et al.
      Temporal trends of women enrollment in major cardiovascular randomized clinical trials.
      reducing the utility of the results for the diseased population and leading to an evidence gap in diagnostic algorithms and management guidelines. Furthermore, sex-related reporting is done in less than 50% of clinical studies, and is associated with publishing in journals with lower impact factors.
      • Sugimoto C.R.
      • Ahn Y.Y.
      • Smith E.
      • Macaluso B.
      • Lariviere V.
      Factors affecting sex-related reporting in medical research: a cross-disciplinary bibliometric analysis.
      However, increased awareness and ongoing research efforts in recent years have grown our knowledge about the roles of sex and gender in ischemic heart disease, thus challenging current diagnostic and therapeutic strategies that largely focus on flow-limiting coronary stenoses typically found in men. Therefore, the goal of this review is to highlight most recent scientific advances that are changing existing approaches and may enable a safer and more effective management of women with ischemic heart disease.

      Literature Search

      PubMed and Google Scholar were searched to identify published literature written in English between January 2000 and July 2020, using the following key words: ischemic heart disease, coronary artery disease, sex, and gender. From these initially identified articles, publications were selected based on perceived clinical importance. Cited references were also used to identify the relevant literature.

      Sex and Gender in the Pathophysiology of Ischemic Heart Disease

      Numerous experimental and clinical studies have consistently shown major sex- and gender-based genetic, cellular, biochemical, and physiological differences in cardiovascular health and disease.
      • Meyer M.R.
      • Barton M.
      Estrogens and coronary artery disease: new clinical perspectives.
      ,
      • Regitz-Zagrosek V.
      • Oertelt-Prigione S.
      • Prescott E.
      • et al.
      Gender in cardiovascular diseases: impact on clinical manifestations, management, and outcomes.
      Sex differences result from differential effects of sex chromosomes and sex hormones in males and females. Gender differences are based on sociocultural environments and thus unique to humans, such as differences in socioeconomic position, social support, culture, health behaviors, or access and attitudes towards treatment and prevention.
      • O'Neil A.
      • Scovelle A.J.
      • Milner A.J.
      • Kavanagh A.
      Gender/sex as a social determinant of cardiovascular risk.
      The role of gender as a social determinant shaping cardiovascular risk has recently been reviewed elsewhere.
      • O'Neil A.
      • Scovelle A.J.
      • Milner A.J.
      • Kavanagh A.
      Gender/sex as a social determinant of cardiovascular risk.
      Examples include less physical mobility but a more frequent use of smoking as a weight loss tool in women compared with men, poor workplace conditions such as low job control and high demand that increase cardiovascular risk in men, and poor-quality marriages or high-intensity caregiving for relatives that can increase the prevalence of cardiovascular risk factors in women.
      • O'Neil A.
      • Scovelle A.J.
      • Milner A.J.
      • Kavanagh A.
      Gender/sex as a social determinant of cardiovascular risk.
      With regard to sex as a determinant of cardiovascular risk, endogenous estrogens play a unique role as potent inhibitors of atherosclerosis due to anti-inflammatory, antioxidative and vasodilator effects, inhibition of vascular smooth muscle cell growth and proliferation, as well as beneficial effects on lipid, glucose metabolism, and coagulation.
      • Meyer M.R.
      • Barton M.
      Estrogens and coronary artery disease: new clinical perspectives.
      In the cardiovascular system, estrogens activate at least three different estrogen receptors, which either act as nuclear transcription factors regulating gene transcription, or induce rapid, non-genomic cellular signaling cascades.
      • Meyer M.R.
      • Barton M.
      Estrogens and coronary artery disease: new clinical perspectives.
      Interestingly, there is evidence that estrogen receptor signaling detrimentally changes with declining endogenous estrogen levels following menopause, the aging of the vascular wall, and the progression of atherosclerosis.
      • Meyer M.R.
      • Barton M.
      ERalpha, ERbeta, and gpER
      novel aspects of oestrogen receptor signalling in atherosclerosis.
      Thus, menopause has emerged as a particularly vulnerable phase in women's health.
      • Barrett-Connor E.
      Menopause, atherosclerosis, and coronary artery disease.
      Because of the protective cardiovascular effects of endogenous estrogens, women are 8 to 10 years older than men when first diagnosed with obstructive coronary artery disease (CAD), and have more comorbidities.
      • Berger J.S.
      • Elliott L.
      • Gallup D.
      • et al.
      Sex differences in mortality following acute coronary syndromes.
      Nevertheless, even when accounting for age and concomitant conditions, women undergoing treatment still experience unfavorable outcomes compared with men,
      • Regitz-Zagrosek V.
      • Oertelt-Prigione S.
      • Prescott E.
      • et al.
      Gender in cardiovascular diseases: impact on clinical manifestations, management, and outcomes.
      ,
      • Berger J.S.
      • Elliott L.
      • Gallup D.
      • et al.
      Sex differences in mortality following acute coronary syndromes.
      • Ubrich R.
      • Barthel P.
      • Haller B.
      • et al.
      Sex differences in long-term mortality among acute myocardial infarction patients: results from the ISAR-RISK and ART studies.
      • McSweeney J.C.
      • Rosenfeld A.G.
      • Abel W.M.
      • et al.
      Preventing and experiencing ischemic heart disease as a woman: state of the science: a scientific statement from the American Heart Association.
      indicating differences in the pathophysiology of atherosclerosis and/or worse performance of currently used diagnostic algorithms and management strategies.
      The pathophysiology of atherosclerosis in women is characterized by unique differences compared with men, who predominantly present with focal, flow-limiting stenoses in major epicardial coronary arteries. Whereas premenopausal women are largely protected from coronary artery disease, estrogen loss following menopause leads to a rapid clustering of risk factors such as hypertension, dyslipidemia, and adverse changes in glucose metabolism (Figure 1).
      • Shaw L.J.
      • Bugiardini R.
      • Merz C.N.
      Women and ischemic heart disease: evolving knowledge.
      These risk factors propagate inflammatory changes in the vascular wall, which may be amplified by concomitant chronic autoimmune diseases affecting mostly women, such as rheumatoid arthritis and systemic lupus erythematosus.
      • Shaw L.J.
      • Bugiardini R.
      • Merz C.N.
      Women and ischemic heart disease: evolving knowledge.
      Resulting early atherosclerotic changes often diffusely affect the coronary circulation, promote abnormal coronary vasomotor function characterized by detrimental changes in endothelial and microvascular vasoreactivity,
      • Barton M.
      • Baretella O.
      • Meyer M.R.
      Obesity and risk of vascular disease: importance of endothelium-derived vasoconstriction.
      as well as positive coronary remodeling, plaque erosion, and embolization.
      • Shaw L.J.
      • Bugiardini R.
      • Merz C.N.
      Women and ischemic heart disease: evolving knowledge.
      Subsequently, these structural and functional changes of the artery wall may lead to ischemia with no obstructive coronary artery disease (INOCA), a heterogeneous syndrome characterized by coronary microvascular disease (CMD).
      • Ford T.J.
      • Berry C.
      Angina: contemporary diagnosis and management.
      ,
      • Bairey Merz C.N.
      • Pepine C.J.
      • Walsh M.N.
      • Fleg J.L.
      Ischemia and no obstructive coronary artery disease (INOCA): developing evidence-based therapies and research agenda for the next decade.
      Obstructive CAD, the phenotype typically observed in men already at younger age, may often not develop in women until 20 years after menopause (Figure 1). However, it is important to recognize that the pathological process of ischemic heart disease in women usually begins with detrimental vasomotor changes that may progress to clinical CMD before flow-limiting atherosclerotic lesions may develop later in life. This concept of an evolving disease has recently been referred to as chronic coronary syndromes.
      • Ford T.J.
      • Berry C.
      Angina: contemporary diagnosis and management.
      ,
      • Knuuti J.
      • Wijns W.
      • Saraste A.
      • et al.
      2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes.
      Indeed, functional alterations in the epicardial and microvascular coronary circulation may alone lead to angina, particularly in women.
      • Ford T.J.
      • Berry C.
      Angina: contemporary diagnosis and management.
      ,
      • Bairey Merz C.N.
      • Pepine C.J.
      • Walsh M.N.
      • Fleg J.L.
      Ischemia and no obstructive coronary artery disease (INOCA): developing evidence-based therapies and research agenda for the next decade.
      Hence, the detection of obstructive atheroma on coronary angiography should not be considered a sine qua non for the diagnosis of a chronic coronary syndrome, which rather can be made in patients both with CMD or/and obstructive CAD. Thus, established algorithms that focus on the detection of flow-limiting stenoses in epicardial coronary arteries alone must be reconciled with the phenotype of ischemic heart disease found in women.
      Figure thumbnail gr1
      Figure 1Role of risk factors, menopause, and age in the pathogenesis of coronary microvascular disease and obstructive atherosclerosis in chronic coronary syndromes. RA = rheumatoid arthritis; SLE = systemic lupus erythematosus.

      Assessing the Clinical Likelihood of Obstructive CAD in Women

      The cardinal manifestation of chronic coronary syndromes is angina, although it is impossible to distinguish between obstructive CAD and CMD based on symptoms alone. In his first detailed descriptions of angina, British physician William Heberden (1710–1801) noted that chest pain is less frequently reported among middle-aged women compared with men.
      • Heberden W.
      Some account of a disorder of the breast.
      However, this reflects differences in disease prevalence in that age group
      • Berger J.S.
      • Elliott L.
      • Gallup D.
      • et al.
      Sex differences in mortality following acute coronary syndromes.
      rather than the historical assumption that women commonly experience atypical angina. In fact, based on standardized analyses of chest pain characteristics, pain in areas outside the chest region, and accompanying symptoms, complaints are remarkably similar among men and women with stable obstructive CAD.
      • Kreatsoulas C.
      • Shannon H.S.
      • Giacomini M.
      • Velianou J.L.
      • Anand S.S.
      Reconstructing angina: cardiac symptoms are the same in women and men.
      However, there may be gender-based differences in communicating discomfort, with women choosing more diverse, detailed, and emotional terms and a broader spectrum of presenting symptoms compared with men when expressing their complaints (referred to as gendered language).
      • Kreatsoulas C.
      • Shannon H.S.
      • Giacomini M.
      • Velianou J.L.
      • Anand S.S.
      Reconstructing angina: cardiac symptoms are the same in women and men.
      Furthermore, more variable chest pain characteristics in women may be explained by the higher prevalence of CMD, which causes a wide spectrum of clinical manifestations including angina at rest.
      • McSweeney J.C.
      • Rosenfeld A.G.
      • Abel W.M.
      • et al.
      Preventing and experiencing ischemic heart disease as a woman: state of the science: a scientific statement from the American Heart Association.
      ,
      • Bairey Merz C.N.
      • Pepine C.J.
      • Walsh M.N.
      • Fleg J.L.
      Ischemia and no obstructive coronary artery disease (INOCA): developing evidence-based therapies and research agenda for the next decade.
      This may lead to difficulties in clinical practice when characterizing symptoms as typical, atypical, or non-anginal, a classification that — in addition to age and sex — is commonly used to estimate the likelihood of obstructive CAD and thus the usefulness of referral for further diagnostic testing.
      • Knuuti J.
      • Wijns W.
      • Saraste A.
      • et al.
      2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes.
      ,
      • Fihn S.D.
      • Gardin J.M.
      • Abrams J.
      • et al.
      2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.
      However, although the detection of obstructive coronary atheroma allows evidence-based medical treatment and myocardial revascularization, clinicians should be aware that such a “stenosis-centric” approach carries the risk of underdiagnosing and undertreating patients with INOCA. These patients often rightfully seek an explanation for their symptoms and effective treatment options.
      Although the possibility of CMD should always be considered, diagnostic strategies to detect obstructive CAD remain of key importance. However, they impose many pitfalls when assessing women. Current major international guidelines favor a Bayesian approach indicating that the performance of diagnostic testing is best when the pretest probability of obstructive CAD is intermediate, currently defined as 10% to 90% in American and greater than 15% in European guidelines.
      • Knuuti J.
      • Wijns W.
      • Saraste A.
      • et al.
      2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes.
      ,
      • Fihn S.D.
      • Gardin J.M.
      • Abrams J.
      • et al.
      2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.
      According to the European guidelines, testing may also be considered in low-intermediate likelihoods of 5% to 15%, which applies to most symptomatic women based on the updated, contemporary prevalence of obstructive CAD that is much lower compared with previously used models dating back to the last century.
      • Knuuti J.
      • Wijns W.
      • Saraste A.
      • et al.
      2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes.
      However, estimation of the pretest probability based on the nature of symptoms may work well in men given differences of approximately 20% between patients with typical and non-anginal chest pain, whereas the discriminatory capacity is much poorer in women. Indeed, a markedly reduced performance of these prediction models for obstructive CAD in women compared with men has been confirmed in a large multinational coronary computed tomography angiography (CCTA) registry.
      • Cheng V.Y.
      • Berman D.S.
      • Rozanski A.
      • et al.
      Performance of the traditional age, sex, and angina typicality-based approach for estimating pretest probability of angiographically significant coronary artery disease in patients undergoing coronary computed tomographic angiography: results from the multinational coronary CT angiography evaluation for clinical outcomes: an international multicenter registry (CONFIRM).
      In an attempt to address these discrepancies, the American Heart Association has published a consensus statement on the diagnostic evaluation of CAD specifically in women.
      • Mieres J.H.
      • Gulati M.
      • Bairey Merz N.
      • et al.
      Role of noninvasive testing in the clinical evaluation of women with suspected ischemic heart disease: a consensus statement from the American Heart Association.
      Instead of focusing on chest pain characteristics, this statement estimates the risk for coronary events in women based on age alone (and thus time since the loss of estrogen-mediated protection following menopause). Women in their fifth and sixth decade of life are considered at low and intermediate risk, respectively, whereas women greater than 70 years old with suspected ischemic symptoms are considered at high risk for coronary events. In women with extensive comorbidities, multiple risk factors or functional disability, this risk estimation may be elevated by 1 category (Figure 2).
      • Mieres J.H.
      • Gulati M.
      • Bairey Merz N.
      • et al.
      Role of noninvasive testing in the clinical evaluation of women with suspected ischemic heart disease: a consensus statement from the American Heart Association.
      Figure thumbnail gr2
      Figure 2Flowchart depicting an approach to estimate the risk for obstructive coronary artery disease and the need for further testing in symptomatic women. Risk categorization based on age with adjustments in women with clinical risk markers has been proposed in a consensus statement from the American Heart Association.
      • Mieres J.H.
      • Gulati M.
      • Bairey Merz N.
      • et al.
      Role of noninvasive testing in the clinical evaluation of women with suspected ischemic heart disease: a consensus statement from the American Heart Association.
      CAD = coronary artery disease; CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease; INOCA = ischemia with no obstructive coronary artery disease; METs = metabolic equivalents; PAD = peripheral artery disease.
      Several cardiovascular risk factors including diabetes, smoking, and hypertension are more impactful in women compared with men, while others predominantly affect women, such as rheumatoid arthritis and systemic lupus erythematosus.
      • McSweeney J.C.
      • Rosenfeld A.G.
      • Abel W.M.
      • et al.
      Preventing and experiencing ischemic heart disease as a woman: state of the science: a scientific statement from the American Heart Association.
      ,
      • Schmidt K.M.T.
      • Nan J.
      • Scantlebury D.C.
      • Aggarwal N.R.
      Stable ischemic heart disease in women.
      Furthermore, specific risk factors in women have been established (Figure 1) including estrogen deficiency due to premature ovarian failure, ovariectomy (surgical menopause), polycystic ovarian syndrome, or hypothalamic amenorrhea. In addition, hypertensive disorders of pregnancy, preterm delivery, and gestational diabetes indicate premature vascular dysfunction and are associated with increased cardiovascular risk later in life.
      • McSweeney J.C.
      • Rosenfeld A.G.
      • Abel W.M.
      • et al.
      Preventing and experiencing ischemic heart disease as a woman: state of the science: a scientific statement from the American Heart Association.
      ,
      • Schmidt K.M.T.
      • Nan J.
      • Scantlebury D.C.
      • Aggarwal N.R.
      Stable ischemic heart disease in women.
      Finally, exposing coronary arteries to ionizing radiation during breast cancer radiotherapy and/or administration of chemotherapy such as anthracyclines or trastuzumab increases cardiovascular risk even more than 10 years later in life.
      • Bradshaw P.T.
      • Stevens J.
      • Khankari N.
      • Teitelbaum S.L.
      • Neugut A.I.
      • Gammon M.D.
      Cardiovascular disease mortality among breast cancer survivors.
      Despite sound scientific evidence supporting that physicians assessing women with suspected myocardial ischemia should obtain a history of the patient’s hormonal life through pregnancy and menopause, no cardiovascular risk score to date has incorporated these factors.
      • Schmidt K.M.T.
      • Nan J.
      • Scantlebury D.C.
      • Aggarwal N.R.
      Stable ischemic heart disease in women.
      Currently used risk scores endorsed by the American College of Cardiology/American Heart Association and the European Society of Cardiology overestimate the actual cardiovascular risk and have only modest ability to discriminate between individuals with and without clinical events independent of sex.
      • Kavousi M.
      • Leening M.J.
      • Nanchen D.
      • et al.
      Comparison of application of the ACC/AHA guidelines, Adult Treatment Panel III guidelines, and European Society of Cardiology guidelines for cardiovascular disease prevention in a European cohort.
      ,
      • Rana J.S.
      • Tabada G.H.
      • Solomon M.D.
      • et al.
      Accuracy of the atherosclerotic cardiovascular risk equation in a large contemporary, multiethnic population.
      However, there is concern that they may underestimate the true risk of women classified as intermediate to high-risk category.
      • Schmidt K.M.T.
      • Nan J.
      • Scantlebury D.C.
      • Aggarwal N.R.
      Stable ischemic heart disease in women.
      ,
      • Santos-Ferreira C.
      • Baptista R.
      • Oliveira-Santos M.
      • Moura J.P.
      • Goncalves L.
      A 10- and 15-year performance analysis of ESC/EAS and ACC/AHA cardiovascular risk scores in a Southern European cohort.
      It ultimately remains of great importance that patients and physicians both recognize symptoms indicative of chronic coronary syndromes, and that clinicians suspecting them as potentially related to ischemic heart disease are aware that the diagnostic tools used may not be adequately sensitive or specific.
      • McSweeney J.C.
      • Rosenfeld A.G.
      • Abel W.M.
      • et al.
      Preventing and experiencing ischemic heart disease as a woman: state of the science: a scientific statement from the American Heart Association.
      ,
      • Hemal K.
      • Pagidipati N.J.
      • Coles A.
      • et al.
      Sex differences in demographics, risk factors, presentation, and noninvasive testing in stable outpatients with suspected coronary artery disease: insights from the PROMISE trial.
      ,
      • Bairey Merz C.N.
      • Andersen H.
      • Sprague E.
      • et al.
      Knowledge, attitudes, and beliefs regarding cardiovascular disease in women: the Women's Heart Alliance.

      Selecting Appropriate Testing for Myocardial Ischemia in Women

      About two-thirds of women referred for invasive coronary angiography based on clinically assessed likelihood of stable CAD alone have no obstructive atherosclerotic stenosis,
      • Jespersen L.
      • Hvelplund A.
      • Abildstrom S.Z.
      • et al.
      Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events.
      highlighting the importance of appropriate testing for myocardial ischemia considering both the epicardial and microvascular coronary circulation, especially in younger women. Of note, a substantial proportion of these patients may have INOCA that is associated with reduced quality of life, more frequent office visits, and greater health care costs.
      • Ford T.J.
      • Berry C.
      Angina: contemporary diagnosis and management.
      ,
      • Bairey Merz C.N.
      • Pepine C.J.
      • Walsh M.N.
      • Fleg J.L.
      Ischemia and no obstructive coronary artery disease (INOCA): developing evidence-based therapies and research agenda for the next decade.
      ,
      • Olson M.B.
      • Kelsey S.F.
      • Matthews K.
      • et al.
      Symptoms, myocardial ischaemia and quality of life in women: results from the NHLBI-sponsored WISE study.
      Nevertheless, noninvasive anatomical testing using multidetector CCTA has recently been more strongly advocated for in international guidelines,
      • Knuuti J.
      • Wijns W.
      • Saraste A.
      • et al.
      2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes.
      ,
      • Fihn S.D.
      • Gardin J.M.
      • Abrams J.
      • et al.
      2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.
      with the British National Institute of Health and Care Excellence guidelines even recommending its use as first-line diagnostic strategy in all patients with stable chest pain.

      National Institute for Health and Care Excellence (NICE) clinical guideline CG 95. Recent-onset chest pain of suspected cardiac origin: assessment and diagnosis. https://www.nice.org.uk/guidance/CG95. Accessed April 2, 2020.

      Although the exclusion of significant obstructive CAD by CCTA with high certainty may seem attractive in many women with angina considered to be at low-intermediate risk, clinicians may also give false reassurance to those patients with INOCA forgoing additional functional tests. In fact, the number of nonobstructive plaques detected by CCTA predicts death in women, even when adjusting for obstructive CAD, findings not replicated in men.
      • Shaw L.J.
      • Min J.K.
      • Narula J.
      • et al.
      Sex differences in mortality associated with computed tomographic angiographic measurements of obstructive and nonobstructive coronary artery disease: an exploratory analysis.
      Given that symptomatic women may have INOCA that in turn increases their cardiovascular risk, they might represent a significant group disparately affected by an anatomical diagnostic strategy. Performance of CCTA was associated with lack of improvement in angina, physical limitation, and quality of life when compared with standard care alone in a large randomized trial,
      • Williams M.C.
      • Hunter A.
      • Shah A.
      • et al.
      Symptoms and quality of life in patients with suspected angina undergoing CT coronary angiography: a randomised controlled trial.
      suggesting the possibility of underdiagnosing and undertreating the INOCA patients undergoing anatomical testing for CAD.
      Depending on local availability and expertise, noninvasive functional diagnostic tests detect myocardial ischemia through exercise-induced electrocardiogram changes, regional wall motion abnormalities during stress echocardiography, stress-induced perfusion changes assessed by cardiac magnetic resonance (CMR) or single-photon emission computed tomography (SPECT), and metabolic alterations revealed by positron emission tomography (PET).
      • Baldassarre L.A.
      • Raman S.V.
      • Min J.K.
      • et al.
      Noninvasive imaging to evaluate women with stable ischemic heart disease.
      Exercise electrocardiography, although widely used, has even lower diagnostic accuracy in women (sensitivity and specificity between 60% and 70%) compared with men (approximately 75%).
      • Mieres J.H.
      • Gulati M.
      • Bairey Merz N.
      • et al.
      Role of noninvasive testing in the clinical evaluation of women with suspected ischemic heart disease: a consensus statement from the American Heart Association.
      This may result in part from lower physical capacity precluding adequate exercise-induced stress that is more frequently observed in women. Furthermore, hormonal changes during the menstrual cycle have been associated with ST-segment depression during exercise.
      • Grzybowski A.
      • Puchalski W.
      • Zieba B.
      • et al.
      How to improve noninvasive coronary artery disease diagnostics in premenopausal women? The influence of menstrual cycle on ST depression, left ventricle contractility, and chest pain observed during exercise echocardiography in women with angina and normal coronary angiogram.
      However, a negative exercise electrocardiography test in low-risk women with good physical capacity and normal rest electrocardiogram yields a good prognosis that is similar to a normal SPECT result.
      • Shaw L.J.
      • Mieres J.H.
      • Hendel R.H.
      • et al.
      Comparative effectiveness of exercise electrocardiography with or without myocardial perfusion single photon emission computed tomography in women with suspected coronary artery disease: results from the What Is the Optimal Method for Ischemia Evaluation in Women (WOMEN) trial.
      In contrast, the positive predictive value of an abnormal exercise electrocardiography is only 47%,
      • Mieres J.H.
      • Gulati M.
      • Bairey Merz N.
      • et al.
      Role of noninvasive testing in the clinical evaluation of women with suspected ischemic heart disease: a consensus statement from the American Heart Association.
      which together with equivocal results frequently lead to physician uncertainty and contribute to further, perhaps unnecessary, testing of women.
      As opposed to exercise electrocardiography, noninvasive imaging using pharmacological stress has significantly higher sensitivity to detect flow-limiting epicardial coronary stenoses, some also offering the possibility to study microvascular function (Figure 3).
      • Baldassarre L.A.
      • Raman S.V.
      • Min J.K.
      • et al.
      Noninvasive imaging to evaluate women with stable ischemic heart disease.
      Although dependent on the experience of the operator, stress echocardiography is a widely available test with minimal side effects and high diagnostic accuracy if good acoustic windows are available.
      • Baldassarre L.A.
      • Raman S.V.
      • Min J.K.
      • et al.
      Noninvasive imaging to evaluate women with stable ischemic heart disease.
      The detection of abnormal diastolic function may also help to explain nonspecific symptoms such as dyspnea and exercise intolerance, yet the extent to which this finding may be due to CMD in women remains uncertain. In addition, Doppler echocardiography of the left anterior descending coronary artery may be used to quantify velocities at rest and at peak hyperemia to estimate coronary flow reserve, and thus the presence of CMD.
      • Gan L.M.
      • Svedlund S.
      • Wittfeldt A.
      • et al.
      Incremental value of transthoracic doppler echocardiography-assessed coronary flow reserve in patients with suspected myocardial ischemia undergoing myocardial perfusion scintigraphy.
      Alternatively, CMR imaging is less operator-dependent and provides not only accurate evaluation of myocardial ischemia, viability, and scars, but also of other structural and functional cardiac pathologies. Stress perfusion CMR has a high (>90%) diagnostic accuracy for significant obstructive CAD particularly in women.
      • Hamada S.
      • Gotschy A.
      • Wissmann L.
      • et al.
      Multi-centre study of whole-heart dynamic 3D cardiac magnetic resonance perfusion imaging for the detection of coronary artery disease defined by fractional flow reserve: gender based analysis of diagnostic performance.
      In addition, CMR can detect a lack of appropriately increased subendocardial perfusion in response to stress, a semiquantitative approach (myocardial perfusion reserve index) indicating CMD in patients with INOCA,
      • Panting J.R.
      • Gatehouse P.D.
      • Yang G.Z.
      • et al.
      Abnormal subendocardial perfusion in cardiac syndrome X detected by cardiovascular magnetic resonance imaging.
      yet these techniques are technically demanding and not widespread available. Alternatively, CMD resulting in impaired coronary flow reserve can be assessed using myocardial perfusion PET, which provides a highly accurate, reproducible measurement of coronary blood flow that may be the best validated noninvasive approach.
      • Baldassarre L.A.
      • Raman S.V.
      • Min J.K.
      • et al.
      Noninvasive imaging to evaluate women with stable ischemic heart disease.
      Impaired coronary flow reserve detected by PET, even in the presence of normal stress perfusion imaging, has emerged as a predictor for adverse cardiac events.
      • Murthy V.L.
      • Naya M.
      • Taqueti V.R.
      • et al.
      Effects of sex on coronary microvascular dysfunction and cardiac outcomes.
      However, PET may not be universally available and is associated with radiation exposure and high cost. Stress myocardial perfusion SPECT imaging also exposes women to ionizing radiation, and may have reduced accuracy than in men due to soft-tissue attenuation artifacts resulting from fat deposits or breast tissue (approximately 80% sensitivity and specificity).
      • Baldassarre L.A.
      • Raman S.V.
      • Min J.K.
      • et al.
      Noninvasive imaging to evaluate women with stable ischemic heart disease.
      Moreover, when referring women to diagnostic procedures that involve ionizing radiation, physicians should balance the benefit of myocardial ischemia detection against the small projected cancer risk associated with it.
      • Mieres J.H.
      • Gulati M.
      • Bairey Merz N.
      • et al.
      Role of noninvasive testing in the clinical evaluation of women with suspected ischemic heart disease: a consensus statement from the American Heart Association.
      Figure thumbnail gr3
      Figure 3Tests for epicardial and microvascular disease in women with suspected myocardial ischemia. “+" indicates that the test is of value, "-" indicates that the test is not of value. CCTA = coronary computed tomography angiography; CFR = coronary flow reserve; CMR = cardiac magnetic resonance; FFR = fractional flow reserve; LAD = left anterior descending coronary artery; MPRI = myocardial perfusion reserve index; PET = positron emission tomography; SPECT = single-photon emission computed tomography.
      Together, exercise electrocardiography is of limited diagnostic value except for functional capacity as well as blood pressure and heart rate responses. To establish the diagnosis of a chronic coronary syndrome, noninvasive functional tests for myocardial ischemia may be preferably used in symptomatic women, particularly if INOCA is considered that would be missed with CCTA. However, the selection of a test also depends on other patient characteristics such as heart rate, as well as local expertise and availability as discussed elsewhere,
      • Knuuti J.
      • Wijns W.
      • Saraste A.
      • et al.
      2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes.
      and must be tailored to the individual patient depending on the perceived likelihood for obstructive CAD and CMD. It is also a good opportunity for patient-physician shared decision-making.
      • Mieres J.H.
      • Gulati M.
      • Bairey Merz N.
      • et al.
      Role of noninvasive testing in the clinical evaluation of women with suspected ischemic heart disease: a consensus statement from the American Heart Association.
      Ultimately, exclusion of significant obstructive CAD by invasive coronary angiography can be important for high-quality diagnosis and patient management, and at the same time allows invasive evaluation of INOCA by studying coronary vasomotor function.

      Challenging Diagnosis and Management of INOCA

      The prognosis of patients with angina, in whom no significantly obstructing CAD is found, is not necessarily benign.
      • Jespersen L.
      • Hvelplund A.
      • Abildstrom S.Z.
      • et al.
      Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events.
      ,
      • Maddox T.M.
      • Stanislawski M.A.
      • Grunwald G.K.
      • et al.
      Nonobstructive coronary artery disease and risk of myocardial infarction.
      ,
      • Kenkre T.S.
      • Malhotra P.
      • Johnson B.D.
      • et al.
      Ten-year mortality in the WISE study (Women's Ischemia Syndrome Evaluation).
      In fact, patients with INOCA are at elevated risk for cardiovascular events similar to individuals with single CAD,
      • Jespersen L.
      • Hvelplund A.
      • Abildstrom S.Z.
      • et al.
      Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events.
      ,
      • Maddox T.M.
      • Stanislawski M.A.
      • Grunwald G.K.
      • et al.
      Nonobstructive coronary artery disease and risk of myocardial infarction.
      and appear to be at higher risk for myocardial infarction with no obstructive coronary arteries and heart failure with preserved ejection fraction later in life.
      • Taqueti V.R.
      • Di Carli M.F.
      Coronary microvascular disease pathogenic mechanisms and therapeutic options: JACC state-of-the-art review.
      They may have substantially impaired quality of life and repeatedly use health care resources for diagnostic testing, cardiac catheterization, and therapy.
      • Bairey Merz C.N.
      • Pepine C.J.
      • Walsh M.N.
      • Fleg J.L.
      Ischemia and no obstructive coronary artery disease (INOCA): developing evidence-based therapies and research agenda for the next decade.
      Mechanisms contributing to INOCA are multifactorial but mainly involve impaired regulation of coronary blood flow due to microvascular remodeling, endothelial dysfunction, impaired microvascular vasodilation, and/or spasm, which has been referred to as CMD.
      • Bairey Merz C.N.
      • Pepine C.J.
      • Walsh M.N.
      • Fleg J.L.
      Ischemia and no obstructive coronary artery disease (INOCA): developing evidence-based therapies and research agenda for the next decade.
      ,
      • Taqueti V.R.
      • Di Carli M.F.
      Coronary microvascular disease pathogenic mechanisms and therapeutic options: JACC state-of-the-art review.
      Diabetes and other traditional risk factors for atherosclerosis, vascular stiffness, and inflammation have been implicated in dysregulation of myocardial blood flow, which may explain why CMD is often linked to atherosclerosis in the macrocirculation.
      • Taqueti V.R.
      • Di Carli M.F.
      Coronary microvascular disease pathogenic mechanisms and therapeutic options: JACC state-of-the-art review.
      Indeed, despite normal-appearing angiograms, almost all patients with INOCA have some coronary atherosclerosis detectable by coronary imaging with intravascular ultrasound or optical coherence tomography.
      • Khuddus M.A.
      • Pepine C.J.
      • Handberg E.M.
      • et al.
      An intravascular ultrasound analysis in women experiencing chest pain in the absence of obstructive coronary artery disease: a substudy from the National Heart, Lung and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE).
      Thus, a detailed assessment of cardiovascular risk may be an important clue to the diagnosis.
      • Taqueti V.R.
      • Di Carli M.F.
      Coronary microvascular disease pathogenic mechanisms and therapeutic options: JACC state-of-the-art review.
      Additional problems that should be addressed with conventional diagnostic testing include reduced myocardial oxygen supply due to anemia or hypoxemia, cardiac factors (left ventricular hypertrophy, aortic stenosis, and heart failure with elevated left ventricular end-diastolic pressure), systemic factors such as high blood pressure and/or heart rate, and thyroid function disorders (Figure 4).
      • Taqueti V.R.
      • Di Carli M.F.
      Coronary microvascular disease pathogenic mechanisms and therapeutic options: JACC state-of-the-art review.
      Since the coronary microcirculation is too small to be directly imaged, conventional stress testing is neither sensitive nor specific for CMD unless methods that detect an impaired functional capacity in regulating myocardial blood flow are used. However, stress imaging tests occasionally show regional abnormalities that may not follow typical vascular distributions.
      • Bairey Merz C.N.
      • Pepine C.J.
      • Walsh M.N.
      • Fleg J.L.
      Ischemia and no obstructive coronary artery disease (INOCA): developing evidence-based therapies and research agenda for the next decade.
      ,
      • Taqueti V.R.
      • Di Carli M.F.
      Coronary microvascular disease pathogenic mechanisms and therapeutic options: JACC state-of-the-art review.
      Figure thumbnail gr4
      Figure 4Flowchart depicting an approach to diagnostic evaluation and treatment of patients with angina and no obstructive CAD. ACE = angiotensin-converting enzyme; CAD = coronary artery disease; CFR = coronary flow reserve; CMD = coronary microvascular disease; CMR = cardiac magnetic resonance; INOCA = ischemia with no obstructive coronary artery disease; LV = left ventricle; LVEDP = left ventricular end-diastolic pressure; MPRI = myocardial perfusion reserve index; PET = positron emission tomography.
      Although not all patients with nonobstructive coronary arteries on angiography have INOCA, the diagnosis should be considered in those with a compatible history. The diagnosis of INOCA may be made in patients with angina, exclusion of underlying obstructive CAD, but objective evidence of CMD based on the detection of impaired myocardial perfusion reserve index by CMR, impaired coronary flow reserve by PET, or invasive studies of coronary vasomotor function, which currently allows the most comprehensive assessment for INOCA (Figure 4).
      • Bairey Merz C.N.
      • Pepine C.J.
      • Walsh M.N.
      • Fleg J.L.
      Ischemia and no obstructive coronary artery disease (INOCA): developing evidence-based therapies and research agenda for the next decade.
      ,
      • Taqueti V.R.
      • Di Carli M.F.
      Coronary microvascular disease pathogenic mechanisms and therapeutic options: JACC state-of-the-art review.
      These measures of CMD indicate impaired myocardial blood flow augmentation in response to stress in the absence of obstructive CAD, reflecting downstream vasomotor dysfunction that leads to myocardial ischemia.
      • Bairey Merz C.N.
      • Pepine C.J.
      • Walsh M.N.
      • Fleg J.L.
      Ischemia and no obstructive coronary artery disease (INOCA): developing evidence-based therapies and research agenda for the next decade.
      ,
      • Taqueti V.R.
      • Di Carli M.F.
      Coronary microvascular disease pathogenic mechanisms and therapeutic options: JACC state-of-the-art review.
      Atypical symptoms such as angina at rest may be present, while CMD-mediated left-ventricular diastolic dysfunction may cause exertional dyspnea. The diagnosis of INOCA requires a high level of clinical suspicion given the strong temptation to reclassify noninvasive functional tests as false-positive when a normal-appearing angiogram has been obtained. Although conventional stress imaging may have technical artifact issues related to breast tissue, obesity, and poor exercise capacity, a high rate of false-positive findings in women (ie, abnormal stress test results with nonobstructive CAD) is a misconception prompting greater uncertainty on the part of the treating physician.
      • Mieres J.H.
      • Gulati M.
      • Bairey Merz N.
      • et al.
      Role of noninvasive testing in the clinical evaluation of women with suspected ischemic heart disease: a consensus statement from the American Heart Association.
      ,
      • Baldassarre L.A.
      • Raman S.V.
      • Min J.K.
      • et al.
      Noninvasive imaging to evaluate women with stable ischemic heart disease.
      Such patients are often reassured but neither offered further testing for CMD nor specific management. Instead, stress tests showing myocardial ischemia in symptomatic women with nonobstructive CAD should be classified as abnormal, and patients should be noted as being at an elevated cardiovascular risk.
      • Mieres J.H.
      • Gulati M.
      • Bairey Merz N.
      • et al.
      Role of noninvasive testing in the clinical evaluation of women with suspected ischemic heart disease: a consensus statement from the American Heart Association.
      ,
      • Baldassarre L.A.
      • Raman S.V.
      • Min J.K.
      • et al.
      Noninvasive imaging to evaluate women with stable ischemic heart disease.
      A correct INOCA diagnosis and subsequently tailored management has been shown to reduce angina burden and improve quality of life.
      • Ford T.J.
      • Stanley B.
      • Good R.
      • et al.
      Stratified medical therapy using Invasive coronary function testing in angina: the CorMicA trial.
      Nevertheless, treatment of CMD is challenging because its etiology is multifactorial, because there are no therapies specifically targeting CMD, and because there are currently no large randomized clinical trials available. Furthermore, the coronary microcirculation differs both structurally and functionally from the epicardial conduit arteries: while microvessels have a well-developed vascular smooth muscle layer, conduit arteries have more elastic properties.
      • Beltrame J.F.
      • Horowitz J.D.
      Why do nitrates have limited efficacy in coronary microvessels?: Editorial to: "Lack of nitrates on exercise stress test results in patients with microvascular angina" by G. Russo et al.
      In addition, endothelium-dependent, nitric oxide–mediated vasodilation plays a greater role in the conduit arteries, whereas endothelium-dependent hyperpolarization is more important in the microvasculature.
      • Beltrame J.F.
      • Horowitz J.D.
      Why do nitrates have limited efficacy in coronary microvessels?: Editorial to: "Lack of nitrates on exercise stress test results in patients with microvascular angina" by G. Russo et al.
      Such anatomical and functional differences likely explain the differential effectiveness of pharmacological treatments for CMD and obstructive CAD. Nevertheless, first-line therapeutics for INOCA are considered β-blockers (for example, nebivolol
      • Erdamar H.
      • Sen N.
      • Tavil Y.
      • et al.
      The effect of nebivolol treatment on oxidative stress and antioxidant status in patients with cardiac syndrome-X.
      ,
      • Ong P.
      • Athanasiadis A.
      • Sechtem U.
      Pharmacotherapy for coronary microvascular dysfunction.
      ) and calcium antagonists if the former are not tolerated or efficacious (Figure 4). Amlodipine may be added to β-blockers if blood pressure permits. Short-acting nitrates should be used for immediate relief of angina or before performing activities known to bring angina,
      • Ford T.J.
      • Berry C.
      Angina: contemporary diagnosis and management.
      while long-acting nitrates are ineffective or even detrimental.
      • Ford T.J.
      • Berry C.
      Angina: contemporary diagnosis and management.
      ,
      • Bairey Merz C.N.
      • Pepine C.J.
      • Walsh M.N.
      • Fleg J.L.
      Ischemia and no obstructive coronary artery disease (INOCA): developing evidence-based therapies and research agenda for the next decade.
      ,
      • Taqueti V.R.
      • Di Carli M.F.
      Coronary microvascular disease pathogenic mechanisms and therapeutic options: JACC state-of-the-art review.
      ,
      • Beltrame J.F.
      • Horowitz J.D.
      Why do nitrates have limited efficacy in coronary microvessels?: Editorial to: "Lack of nitrates on exercise stress test results in patients with microvascular angina" by G. Russo et al.
      ,
      • Russo G.
      • Di Franco A.
      • Lamendola P.
      • et al.
      Lack of effect of nitrates on exercise stress test results in patients with microvascular angina.
      Limited efficacy of long-acting nitrates in patients with CMD may be due to steal syndromes through myocardial regions without CMD, reduced responsiveness of nitrates in the microvasculature, nitrate-induced oxidative stress, and endothelial dysfunction.
      • Ford T.J.
      • Berry C.
      Angina: contemporary diagnosis and management.
      ,
      • Beltrame J.F.
      • Horowitz J.D.
      Why do nitrates have limited efficacy in coronary microvessels?: Editorial to: "Lack of nitrates on exercise stress test results in patients with microvascular angina" by G. Russo et al.
      ,
      • Russo G.
      • Di Franco A.
      • Lamendola P.
      • et al.
      Lack of effect of nitrates on exercise stress test results in patients with microvascular angina.
      If INOCA is mainly due to vasospasms, therapy consists of calcium antagonists at high doses and nitrates.
      • Taqueti V.R.
      • Di Carli M.F.
      Coronary microvascular disease pathogenic mechanisms and therapeutic options: JACC state-of-the-art review.
      ,
      • Ford T.J.
      • Berry C.
      How to diagnose and manage angina without obstructive coronary artery disease: lessons from the British Heart Foundation CorMicA trial.
      Nicorandil may be used as third-line therapy in both scenarios.
      • Taqueti V.R.
      • Di Carli M.F.
      Coronary microvascular disease pathogenic mechanisms and therapeutic options: JACC state-of-the-art review.
      ,
      • Ford T.J.
      • Berry C.
      How to diagnose and manage angina without obstructive coronary artery disease: lessons from the British Heart Foundation CorMicA trial.
      In addition, management of underlying cardiovascular risk factors and disease-modifying therapies such as angiotensin-converting enzyme inhibitors and statins should be considered, especially in patients with diffuse nonobstructive CAD.
      • Ford T.J.
      • Berry C.
      Angina: contemporary diagnosis and management.
      ,
      • Bairey Merz C.N.
      • Pepine C.J.
      • Walsh M.N.
      • Fleg J.L.
      Ischemia and no obstructive coronary artery disease (INOCA): developing evidence-based therapies and research agenda for the next decade.
      ,
      • Taqueti V.R.
      • Di Carli M.F.
      Coronary microvascular disease pathogenic mechanisms and therapeutic options: JACC state-of-the-art review.
      Multiple other substances have been proposed for the treatment of INOCA, such as endothelin-receptor antagonists and Rho-kinase inhibitors, yet they have not been tested in a clinical study.
      • Bairey Merz C.N.
      • Pepine C.J.
      • Walsh M.N.
      • Fleg J.L.
      Ischemia and no obstructive coronary artery disease (INOCA): developing evidence-based therapies and research agenda for the next decade.
      Additional interventions include tricyclic antidepressants to counteract enhanced pain perception, cardiac rehabilitation, and cognitive behavioral therapy (Figure 4).
      • Taqueti V.R.
      • Di Carli M.F.
      Coronary microvascular disease pathogenic mechanisms and therapeutic options: JACC state-of-the-art review.
      ,
      • Ford T.J.
      • Berry C.
      How to diagnose and manage angina without obstructive coronary artery disease: lessons from the British Heart Foundation CorMicA trial.

      Revascularization in Women With Obstructive CAD

      Although there is a significant interplay between CMD, obstructive CAD, and the cardiovascular risk associated with it, coronary revascularization of obstructive, flow-limiting stenoses improves symptoms and quality of life in these patients.
      • Knuuti J.
      • Wijns W.
      • Saraste A.
      • et al.
      2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes.
      ,
      • Fihn S.D.
      • Gardin J.M.
      • Abrams J.
      • et al.
      2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.
      At the same time, optimal medical therapy remains a cornerstone in management.
      • Knuuti J.
      • Wijns W.
      • Saraste A.
      • et al.
      2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes.
      ,
      • Fihn S.D.
      • Gardin J.M.
      • Abrams J.
      • et al.
      2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.
      In stable patients without heart failure or significant left main disease, the International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) trial found no sex differences in cardiovascular outcomes when myocardial ischemia was treated with coronary revascularization or medical therapy.
      • Maron D.J.
      • Hochman J.S.
      • Reynolds H.R.
      • et al.
      Initial invasive or conservative strategy for stable coronary disease.
      In contrast to stable CAD, there is accumulating evidence for a sex-specific management of acute coronary syndromes, because men present more frequently with plaque rupture of a thin-cap fibroatheroma, whereas plaque erosions and other causes of myocardial infarction with no obstructive coronary arteries are observed more often in women.
      • Baldassarre L.A.
      • Raman S.V.
      • Min J.K.
      • et al.
      Noninvasive imaging to evaluate women with stable ischemic heart disease.
      These findings also suggest that there is still much to learn about mechanisms of atherogenesis and ischemia as contributors to symptoms and cardiovascular risk.
      In patients undergoing percutaneous coronary interventions with implantation of drug-eluting stents, sex is not an independent predictor of major adverse cardiovascular events.
      • Grines C.L.
      • Schreiber T.
      Sex differences in the drug-eluting stent era: do they still exist?.
      ,
      • Husted S.
      • James S.K.
      • Bach R.G.
      • et al.
      The efficacy of ticagrelor is maintained in women with acute coronary syndromes participating in the prospective, randomized, PLATelet inhibition and patient Outcomes (PLATO) trial.
      In fact, second- and third-generation drug-eluting stents are equally effective at improving outcomes in women and men with similarly low target-vessel revascularization rates during follow-up,
      • Stefanini G.G.
      • Kalesan B.
      • Pilgrim T.
      • et al.
      Impact of sex on clinical and angiographic outcomes among patients undergoing revascularization with drug-eluting stents.
      likely due to their low profile, thin strut designs that may enhance stent deliverability in small, tortuous coronary arteries found in some women.
      • Grines C.L.
      • Schreiber T.
      Sex differences in the drug-eluting stent era: do they still exist?.
      Moreover, routine use of radial access can eliminate femoral access site complications that occur more frequently in women than in men.
      • Chacko Y.
      • Parikh R.V.
      • Tremmel J.A.
      Vascular access-related complications in women: temporal trends, emerging data, and the current state of interventional cardiology practice.
      Women who undergo coronary artery bypass grafting have more incomplete revascularization, bleeding complications, and greater hospital and long-term mortality compared with men.
      • Swaminathan R.V.
      • Feldman D.N.
      • Pashun R.A.
      • et al.
      Gender differences in in-hospital outcomes after coronary artery bypass grafting.
      ,
      • Johnston A.
      • Mesana T.G.
      • Lee D.S.
      • Eddeen A.B.
      • Sun L.Y.
      Sex differences in long-term survival after major cardiac surgery: a population-based cohort study.
      Likely due to the generally more diffuse atherosclerotic changes with positive remodeling of the coronary artery wall as well as concomitant CMD, residual angina after revascularization procedures
      • Weintraub W.S.
      • Spertus J.A.
      • Kolm P.
      • et al.
      Effect of PCI on quality of life in patients with stable coronary disease.
      • Tonino P.A.
      • De Bruyne B.
      • Pijls N.H.
      • et al.
      Fractional flow reserve versus angiography for guiding percutaneous coronary intervention.
      may be more frequent in women than in men, underscoring the need for optimal medical therapy.

      Sex and Gender Differences in Pharmacological Management

      Contemporary pharmacotherapy of angina has recently been reviewed elsewhere.
      • Ford T.J.
      • Berry C.
      Angina: contemporary diagnosis and management.
      Although optimal medical therapy is a cornerstone in the management of chronic coronary syndromes,
      • Knuuti J.
      • Wijns W.
      • Saraste A.
      • et al.
      2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes.
      ,
      • Fihn S.D.
      • Gardin J.M.
      • Abrams J.
      • et al.
      2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.
      important sex differences exist that explain the more frequently observed adverse drug reactions in women compared with men.
      • Rosano G.M.
      • Lewis B.
      • Agewall S.
      • et al.
      Gender differences in the effect of cardiovascular drugs: a position document of the Working Group on Pharmacology and Drug Therapy of the ESC.
      ,
      • Tamargo J.
      • Rosano G.
      • Walther T.
      • et al.
      Gender differences in the effects of cardiovascular drugs.
      There are multiple known sex differences in pharmacokinetics (ie, the absorption, distribution, metabolism, and excretion of drugs) and pharmacodynamics (ie, the relationship between drug concentration and clinical responses at the site of action) for many cardiovascular drugs, however, the knowledge about their sex-related safety and efficacy may be limited because women are underrepresented in clinical trials.
      • Rosano G.M.
      • Lewis B.
      • Agewall S.
      • et al.
      Gender differences in the effect of cardiovascular drugs: a position document of the Working Group on Pharmacology and Drug Therapy of the ESC.
      ,
      • Tamargo J.
      • Rosano G.
      • Walther T.
      • et al.
      Gender differences in the effects of cardiovascular drugs.
      For example, intake of equal doses of aspirin, β-blockers, or statins yields higher plasma levels in women, partly due to smaller distribution volume and lower clearance compared with men.
      • Rosano G.M.
      • Lewis B.
      • Agewall S.
      • et al.
      Gender differences in the effect of cardiovascular drugs: a position document of the Working Group on Pharmacology and Drug Therapy of the ESC.
      ,
      • Tamargo J.
      • Rosano G.
      • Walther T.
      • et al.
      Gender differences in the effects of cardiovascular drugs.
      With regard to pharmacodynamics, aspirin more potently inhibits platelet aggregation
      • Patti G.
      • De Caterina R.
      • Abbate R.
      • et al.
      Platelet function and long-term antiplatelet therapy in women: is there a gender-specificity? A 'state-of-the-art' paper.
      and β-blockers more efficiently reduce exercise-induced angina in men.
      • Cocco G.
      • Chu D.
      The anti-ischemic effect of metoprolol in patients with chronic angina pectoris is gender-specific.
      Of note, women have a 1.5- to 1.7-fold greater incidence of adverse drug reactions than men.
      • Rosano G.M.
      • Lewis B.
      • Agewall S.
      • et al.
      Gender differences in the effect of cardiovascular drugs: a position document of the Working Group on Pharmacology and Drug Therapy of the ESC.
      ,
      • Tamargo J.
      • Rosano G.
      • Walther T.
      • et al.
      Gender differences in the effects of cardiovascular drugs.
      Indeed, inadequate consideration of sex differences in pharmacokinetics and pharmacodynamics may have serious consequences: Of 10 prescription drugs withdrawn from the market in the United States between 1997 and 2001, 8 posed greater health risks for women, including mibefradil dihydrochloride (Posicor®, Roche Laboratories, Nutley, NJ), which was approved for treatment of hypertension and angina and increased the risk for severe bradycardia, especially among elderly women.
      United States General Accounting Office
      Drug safey: most drugs withdrawn in recent years had greater health risks for women. GAO-01-286R: published January 19, 2001.
      Examples of sex differences in adverse cardiovascular drug reactions are shown in Table.
      TableAdverse Reactions to Cardiovascular Drugs More Frequently Observed in Women
      ACE inhibitors = angiotensin-converting enzyme inhibitors.
      Drug classAdverse drug reactions
      AntiplateletsBleeding
      ACE inhibitorsDry cough, renal dysfunction
      β-blockersBradycardia, hypotension
      Calcium channel blockersHypotension, edema
      DigoxinMortality
      DiureticsHyponatremia, hypokalemia, torsades de pointes
      HeparinBleeding
      Oral anticoagulantsBleeding
      StatinsMyalgias, diabetes
      a ACE inhibitors = angiotensin-converting enzyme inhibitors.
      Women treated with antiplatelet drugs experience more bleeding complications than men, probably because they are generally older, have worse renal function, and more comorbidities.
      • Husted S.
      • James S.K.
      • Bach R.G.
      • et al.
      The efficacy of ticagrelor is maintained in women with acute coronary syndromes participating in the prospective, randomized, PLATelet inhibition and patient Outcomes (PLATO) trial.
      ,
      • Tamargo J.
      • Rosano G.
      • Walther T.
      • et al.
      Gender differences in the effects of cardiovascular drugs.
      While increasing the risk of bleeding, aspirin used as primary prevention reduces the risk of ischemic stroke in women and myocardial infarction in men.
      • Berger J.S.
      • Roncaglioni M.C.
      • Avanzini F.
      • Pangrazzi I.
      • Tognoni G.
      • Brown D.L.
      Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials.
      • Baigent C.
      • Blackwell L.
      • Collins R.
      • et al.
      Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.
      • Xie M.
      • Shan Z.
      • Zhang Y.
      • et al.
      Aspirin for primary prevention of cardiovascular events: meta-analysis of randomized controlled trials and subgroup analysis by sex and diabetes status.
      When used as secondary prevention, aspirin yields a greater reduction in cardiovascular events that seems similar for women and men.
      • Tamargo J.
      • Rosano G.
      • Walther T.
      • et al.
      Gender differences in the effects of cardiovascular drugs.
      ,
      • Baigent C.
      • Blackwell L.
      • Collins R.
      • et al.
      Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.
      In a large meta-analysis on data from 27 trials (47,000 women) of statin therapy, proportional reductions in vascular events per 1.0 mmol/L reduction in low-density lipoprotein cholesterol were similar for women and men, and likewise, proportional reductions in coronary events, revascularization, and stroke did not differ by sex.
      • Fulcher J.
      • O'Connell R.
      • Voysey M.
      • et al.
      Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials.
      However, female sex is an established risk factor for statin-associated muscle symptoms and new-onset diabetes.
      • Tamargo J.
      • Rosano G.
      • Walther T.
      • et al.
      Gender differences in the effects of cardiovascular drugs.
      Clinical trials studying effects of angiotensin-converting enzyme inhibitors, β–blockers, calcium antagonists, or PCSK9 inhibitors found no major differences in clinical outcomes between women and men, although women were often underrepresented.
      • Tamargo J.
      • Rosano G.
      • Walther T.
      • et al.
      Gender differences in the effects of cardiovascular drugs.
      Although there is no difference between women and men in the reduction of cardiovascular events due to secondary prevention measures, such as lipid- and blood pressure-lowering therapies,
      • Mach F.
      • Baigent C.
      • Catapano A.L.
      • et al.
      2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.
      ,
      • Williams B.
      • Mancia G.
      • Spiering W.
      • et al.
      2018 ESC/ESH guidelines for the management of arterial hypertension.
      there are important gender differences in prescription rates of cardiovascular drugs, with women being less aggressively treated with guideline-recommended medication than men.
      • Lee C.M.Y.
      • Mnatzaganian G.
      • Woodward M.
      • et al.
      Sex disparities in the management of coronary heart disease in general practices in Australia.
      ,
      • Zhao M.
      • Woodward M.
      • Vaartjes I.
      • et al.
      Sex differences in cardiovascular medication prescription in primary care: a systematic review and meta-analysis.
      Importantly, women with chronic coronary syndromes receive less antiplatelets, lipid-lowering drugs, inhibitors of the renin-angiotensin-aldosterone system, β-blockers, and nitrates than men.
      • Lee C.M.Y.
      • Mnatzaganian G.
      • Woodward M.
      • et al.
      Sex disparities in the management of coronary heart disease in general practices in Australia.
      ,
      • Zhao M.
      • Woodward M.
      • Vaartjes I.
      • et al.
      Sex differences in cardiovascular medication prescription in primary care: a systematic review and meta-analysis.
      As a result, cardiovascular risk factors in secondary prevention are evaluated less frequently and treatment goals less often reached in women than men,
      • Lee C.M.Y.
      • Mnatzaganian G.
      • Woodward M.
      • et al.
      Sex disparities in the management of coronary heart disease in general practices in Australia.
      possibly reflecting in part the worse drug safety profile in women. This underscores the need to identify sex differences in dosing, efficacy, and safety of cardiovascular drugs that likely will result in better adherence and reduced adverse drug reactions as opposed to administration of fixed doses in women and men alike.
      • Rosano G.M.
      • Lewis B.
      • Agewall S.
      • et al.
      Gender differences in the effect of cardiovascular drugs: a position document of the Working Group on Pharmacology and Drug Therapy of the ESC.
      ,
      • Tamargo J.
      • Rosano G.
      • Walther T.
      • et al.
      Gender differences in the effects of cardiovascular drugs.
      Implementation of sex-specific pharmacological guidelines may ultimately improve the reach of guideline-recommended treatment goals. Furthermore, establishing evidence-based treatment guidelines for patients with INOCA may help to improve risk reduction in women with chronic coronary syndromes.

      Conclusion

      Chronic coronary syndromes in women are characterized by a coexistence of both CMD and the development of obstructive atherosclerotic lesions. Nevertheless, current strategies in diagnosis and management largely focus on a "stenosis-centric" approach evaluated in clinical trials that predominantly included middle-aged men. Therefore, future clinical studies should be designed with an adequate number of women to analyze sex-related cardiovascular outcomes. We should aim for a better understanding of sex-dependent risk factors for the development of chronic coronary syndromes, as well as sex-related differences in the efficacy and safety of diagnostic and therapeutic strategies. This particularly applies to the heterogeneous group of patients with INOCA. Studies should include cost-effectiveness analyses and quality of life outcomes evaluated by gender. Ultimately, sex- and gender-related differences in chronic coronary syndromes should become an integral part of medical education, enabling the implementation of safer and more effective personalized diagnostic and therapeutic strategies in women and men.

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      • In the Limelight: April 2021
        Mayo Clinic ProceedingsVol. 96Issue 4
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          This month’s feature highlights five articles, four of which focus on COVID-19, that appear in the current issue of Mayo Clinic Proceedings. These articles are also featured on the Mayo Clinic Proceedings’ YouTube Channel ( https://youtu.be/mt3zfdaokyu ).
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