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Evolving knowledge regarding sex differences in coronary heart disease (CHD) is emerging. Given the lower burden of obstructive coronary artery disease (CAD) and preserved systolic function in women contrasted by higher rates of myocardial ischemia and near-term mortality compared to men, we propose the term ischemic heart disease (IHD) as appropriate for this discussion specific to women, rather than CAD or CHD. This paradoxical difference where women have lower rates of anatomical CAD but more symptoms, ischemia, and outcomes appear linked to coronary reactivity which includes microvascular dysfunction. Novel risk factors can improve the Framingham risk score, including inflammatory markers and reproductive hormones, as well as noninvasive imaging and functional capacity measurements. Risk for women with obstructive CAD is elevated compared to men, yet women are less likely to receive guideline-indicated therapies. In the setting of non-ST elevation acute myocardial infarction, interventional strategies are equally effective in biomarker positive women and men, while conservative management is indicated for biomarker negative women. For women with evidence of ischemia but no obstructive CAD, anti-anginal and anti-ischemic therapies can improve symptoms, endothelial function, and quality of life; however trials evaluating adverse outcomes are needed. We hypothesize that women experience more adverse outcomes compared to men because obstructive CAD remains the current focus of therapeutic strategies. Continued research is indicated to devise therapeutic regimens to improve symptom burden and reduce risk in women with IHD.
Over the past several decades, an evolving knowledge regarding sex differences in coronary heart disease (CHD) has emerged. Prevalence, symptom manifestation, and pathophysiology for CHD vary between women and men. Annual CHD population statistics continue to report a higher number of deaths for women than men (455,000 versus 410,000) (1). While recent reports document declines in CHD mortality for females, reductions lag behind those realized for men (2), including mortality increases among younger women (3). The most recent Center for Disease Control data reveal that 1 in 2.6 women die from CHD contrasted to 1 in 4.6 from cancer (4). Current projections indicate a continued increase in CHD given our aging population and epidemics of obesity, diabetes, and the cardiometabolic syndrome (1,2,5-6). Notably, cardiac death remains the leading killer of women at all ages (1,7-8).
Among clinical cohorts, paradoxical sex differences are observed where women have less anatomical obstructive coronary artery disease (CAD) and relatively preserved left ventricular function yet higher rates of myocardial ischemia and mortality compared to similarly-aged males (5,9-11). Accordingly, the term ischemic heart disease (IHD) is more appropriate for a discussion specific to women; rather than CAD or CHD. Data from the NIH-NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE) and related studies implicate adverse coronary reactivity (12), microvascular dysfunction (13), and plaque erosion/distal micro-embolization (14-15) as contributory to a female-specific IHD pathophysiology. Thus, knowledge beyond an anatomical description of obstructive CAD may provide important clues to IHD risk detection and treatment for women.
This review outlines our evolving knowledge of pathophysiology and mechanisms of IHD in women. We include clinical studies addressing gender-specific issues in IHD prevalence and prognosis, traditional and novel risk factors, screening and diagnostic testing, as well as therapeutic management strategies. We propose models for application of our emerging knowledge on IHD in women to clinical practice, as well as forward novel hypotheses for investigation. Finally, while it is unknown to what extent the described issues are female-specific or simply more prevalent in women, it is likely that the outlined concepts should also be applicable for men.
In addition to an absolute greater number of women dying from IHD, a higher proportion of women die of sudden cardiac death prior to hospital arrival (52%) contrasted with 42% of men (16-17). Recent data report significant declines in sudden cardiac death in men with (essentially) no change in women (18). Symptomatic women more often have persistent symptoms requiring more hospitalizations compared to men, accompanied by lower ratings of general well-being and limitations in their abilities to perform activities of daily living (19-20). Notably, these adverse outcomes are experienced by women of all ages despite a lesser extent and severity of obstructive CAD and better systolic function compared to men (11). Relatively higher CAD healthcare costs are incurred in women where resource consumption patterns are characterized by: 1) more frequent diagnoses of angina, office visits, and hospitalizations; 2) higher MI mortality; and 3) higher rates of heart failure hospitalization as compared with men (22-24).
Thus, IHD in women presents a unique and difficult challenge for clinicians due to a greater symptom burden, functional disability, greater healthcare needs, and more adverse outcomes as compared to men despite a lower prevalence and severity of anatomical CAD.
Over 80% of midlife women have 1 or more traditional cardiac risk factors (25). Women have higher (average) blood cholesterol levels than men after their 5th decade of life (10) and exhibit mild declines in HDL-cholesterol following menopause (1,26). Obesity is prevalent in one-third of women including 7% having a body mass index (BMI) ≥40 kg/m2 with associated increased mortality (27-28). Hypertriglyceridemia is a more potent independent risk factor for women as compared to men (26, 29). Diabetic women have significantly higher IHD mortality compared with diabetic men (30-31), and an elevated 3.3-fold IHD risk compared to non-diabetic women (32). Importantly, 30-year trends reveal marked CVD mortality reduction for diabetic men but not for diabetic women (33).
IHD mortality increases with the number of traditional cardiac risk factors, with 30-year death rates (per 10,000 person-years) ranging from 1.5 to 9.1 for women with 0 to ≥2 risk factors (34). Clustering risk factors is common post-menopause, notably the combination of obesity, hypertension, and dyslipidemia (35-39); potentially related to hormonally-mediated metabolic disturbances.
Traditional risk factors and the Framingham risk score (FRS) underestimate IHD risk in women (40-45), while novel risk markers improve risk detection (13,46,48-49). Females have, on average, higher mean C-reactive protein (CRP) measures compared with males; a sex difference apparent at the time of puberty (50). This difference in CRP is consistent with the 2- to 50-fold greater frequency of inflammatory-mediated autoimmune diseases, such as rheumatoid arthritis or systemic lupus erythematosis, in women as compared to men (51) suggesting a prominent role for inflammation in IHD sex differences. Indeed, the relative risk of future IHD events increases proportionally with rising levels of high sensitivity CRP (hsCRP), acting synergistically with other risk factors to accelerate IHD risk in women (47,48,52-55). A number of inflammatory measures, including hsCRP, are related to other IHD risk markers such as the cardiometabolic syndrome, type 2-diabetes, and heart failure (53,56,57). The use of multiple biomarkers improves IHD risk assessment in women (58-60).
We and others have further demonstrated that disruption of ovulatory cycling, indicated by estrogen deficiency and hypothalamic dysfunction (61) or irregular menstrual cycling (62) in premenopausal women is associated with an increased risk of coronary atherosclerosis and adverse CVD events. Polycystic ovary syndrome (PCOS) is prevalent in 10-13% of females and is linked with a clustering of risk factors, incident type-2 diabetes mellitus (63), and adverse IHD events postmenopausally (64). The cardiometabolic syndrome is a clustering of risk factors including at least 3 of the following: insulin resistance, dyslipidemia (elevated triglycerides, low HDL cholesterol), hypertension, or abdominal obesity and is frequently associated with alterations in endogenous estrogens and androgens in women (36,62,65).
Investigation into the optimal utilization of novel risk factors for IHD risk stratification in women is needed.
The FRS is used to classify patients’ 10-year risk of CAD death or MI to determine the appropriate level of therapeutic intervention for both LDL cholesterol and hypertension (66-67). Patients at highest risk should receive the most intensive therapeutic and lifestyle recommendations (i.e., secondary prevention goals). However, the FRS classifies >90% of women as low risk, with very few assigned high risk status before age 70 (41). The FRS is best used to risk stratify populations and underestimates individual patient risk, notably for women (43-45).
The Reynolds risk score is a sex-specific tool recently devised from large derivation (n=24,588) and validation (n=8,158) cohorts of women (68). This score uses the following equation: 0.0799 × age + 3.137 × natural logarithm (systolic blood pressure) + 0.180 × natural logarithm (hsCRP) + 1.382 × natural logarithm (total cholesterol) − 1.172 × natural logarithm (high-density lipoprotein cholesterol) + 0.134 × hemoglobin A1c (%) (if diabetic) + 0.818 (if current smoker) + 0.438 (if family history of premature MI). When compared to the FRS, use of the Reynold’s score resulted in risk re-classification in >40% of intermediate FRS women (68).
Several recent reports have also examined the prevalence of subclinical atherosclerosis within female FRS subsets (43-44). In a recent cross-sectional study of 2,447 consecutive, clinically-referred asymptomatic, non-diabetic women, 84% of those with significant coronary artery calcification (CAC) were classified with a low FRS (43). These data underscore the imprecision of FRS estimates in women and the prevalent, undetected burden of atherosclerosis in females.
There is a growing body of evidence on the use of atherosclerotic imaging. In women, the prevalence of an ankle brachial index ≤0.90 increases with age (ranging <5% for <60 years to 10-35% for 60-80 years) and is more prevalent in Black and Hispanic females (69-70). The hazard for death with an ankle brachial index ≤0.90 is 2.7 (95% CI=2.0-3.6) for women and 3.3 (95% CI=2.7-4.1) for men (71). Carotid intima-media thickness (cIMT) is another imaging marker that is a validated measure of risk for both women and men (72-74). A low risk cIMT is associated with a ~1% 10-year IHD risk vs. ~10% for a high risk cIMT (75); with a relatively higher risk predicted for women than men (76). CAC is another imaging measure that is highly correlated with traditional risk factors (77) but uncorrelated with hsCRP (78). CAC lags by nearly a decade in incidence for women; similar to obstructive CAD (49,79-84). From the NHLBI Multi-Ethnic Study of Atherosclerosis study (44), women with a CAC Score ≥300 had an annual IHD event rate of 2.2%; thus achieving NCEP CHD risk-equivalent status. The IHD event risk for women with a high risk CAC score and multiple risk factors is 10% higher in women than men (49,83); supporting the notion that comorbidity disproportionately accelerates risk in women.
Evaluation of women with symptoms suggestive of IHD is hampered by the definition of “typical” angina, derived from largely male populations where exertional components are more reflective of male patterns of presentation (85-86). Women report more angina despite lower rates of obstructive CAD (11,87-89). In a recent meta-analysis of 74 reports from 13,311 women and 11,511 men, angina prevalence was 11-27% higher for women <65 years of age yet similar in the elderly ≥75 years (90). Women with typical or atypical chest pain symptoms (non-exertional or prolonged discomfort unrelieved by rest) have calculated obstructive CAD probabilities substantially less than that of men (91-93) and among those undergoing coronary angiography, as much as 50% of females do not have obstructive CAD (93-94). Over half of symptomatic women without obstructive CAD continue to have signs and symptoms of ischemia, undergo repeat hospitalization and coronary angiography, with continued consumption of CAD healthcare resources often due to diagnostic and therapeutic uncertainty (20,24). Data from the Women’s Health Initiative document that women with non-specific chest pain have a 2-fold higher risk for nonfatal MI (95), while WISE data demonstrate elevated mortality in women with chest pain and no obstructive CAD (96), underscoring that prognosis in these women is not benign.
“Normal” coronary angiograms, defined as no visible obstructive CAD (luminal irregularities <50% stenosis) are also reported more frequently in women with acute coronary syndromes (ACS). In a recent large series from 600 US hospitals in 459,941 acute coronary syndrome (ACS) patients, the adjusted odds for obstructive CAD were 50% lower for women as compared to men (11). For women presenting with ACS/ST segment elevation MI (STEMI), 10-25% of women as compared to 6-10% of men have no obstructive CAD (97-100). Of the estimated 1.4 million patients discharged following an ACS each year, 600,000 are women (1). Among women, the 10-25% rate of “normal” angiography (101) translates into 60,000-150,000 women with ACS/MI having nonobstructive CAD. Specific investigation is needed to understand the paradox whereby women have less obstructive CAD and less severe MIs yet worsening clinical outcomes. The higher mortality compared to men has been attributed to advanced age, comorbidity (5,10,102,103), and underutilization of guideline care among women (104); yet the largest mortality gap is seen in younger women with a number of studies demonstrating persistent sex differences despite covariate adjustment (105-106).
Clinicians often rely on exercise electrocardiography (ECG) to assess IHD risk. The exercise ECG has a lower sensitivity and specificity (≥1 mm ST segment depression 65%) for detection of obstructive CAD in women compared to men (107), in part due to the lower obstructive CAD prevalence (i.e., Bayesian theory). In several large female cohorts, significant exertional ST segment depression did not differ between survivors and non-survivors (108-109); although marked ST segment changes (≥2 mm horizontal or downsloping) occurring at low workloads or persisting into recovery confirm high risk status for women (110). Combining variables such as exercise duration and ST segment changes into the Duke Treadmill Score (DTS) accurately predicts IHD mortality in women (111-112). From the St. James Women Take Heart Study of 5,392 asymptomatic women, the risk of death decreased by 9% for every unit increase in the DTS; while each MET increase in exercise capacity decreased mortality by 17% (p<0.001) (111). Women undergoing exercise testing using common treadmill protocols are often incapable of performing >5 metabolic equivalents (METs) (112), a level equivalent to performing routine activities of daily living (113), elevating their risk of IHD death or MI by ~3-fold (108-110,114). Reduced functional capacity (≤7 METs) portends worsening outcome equally among lean and obese women (115). A female sex-specific nomogram of exercise capacity (in METs) has been devised and can be applied to estimate average functional abilities for women of diverse ages (116).
Stress-induced changes in regional myocardial perfusion or wall motion are accurate markers of IHD risk in women (110,117-120). Although the sensitivity of echocardiographic wall motion abnormalities is diminished in the setting of an intermediate stenosis or single vessel obstructive CAD, the test’s high negative predictive value renders it useful for younger women (110). Stress-induced changes in myocardial perfusion have been extensively evaluated in women; largely employing SPECT imaging with more recent use of positron emission tomography (PET) and cardiovascular magnetic resonance (CMR) techniques (110).
The evidence is substantial that myocardial perfusion imaging effectively risk stratifies women (110,119-120). Pooled myocardial perfusion data in >7,500 women reveals a low annual IHD event rate of 0.6% in the setting of a normal study (119). Survival worsens for women with multivessel ischemia (120) or moderate-severe perfusion abnormalities yielding a 5% annual IHD mortality for women (121). Because SPECT flow is comparatively assessed across the myocardium, it can appear normal in the setting of global reductions in perfusion attributable to severe multivessel CAD but also to endothelial or microvascular dysfunction, left ventricular hypertrophy, or cardiomyopathy. Additional challenges for SPECT in women include: 1) limited spatial resolution where minor perfusion abnormalities may go undetected in smaller hearts and 2) breast tissue artifact. With regards to the latter, contemporary techniques using Tc-99m agents, prone imaging, and/or attenuation correction algorithms diminish artifact frequency (110). Thus, it is no longer appropriate to label perfusion abnormalities in the setting of nonobstructive CAD as “false positives” in women if accompanied by objective signs of ischemia, such as chest pain, electrocardiographic abnormalities, or reduced functional capacity due to the elevated IHD risk (52,106)The use of 82Rb PET has several advantages in women including quantification of absolute values of regional and global myocardial blood flow to assess microvascular disease (flow reserve) and integrated attenuation correction along with improved image quality compared to SPECT. PET has notable advantages for obese women however there is limited prognostic data with no gender-specific reports (122-123). As based on recent estimates, effective radiation dose appears slightly higher for PET when compared to single-isotope rest-stress SPECT imaging (12.6-13.5 for 82Rb PET vs. 11.3-11.4 for rest-stress Tc-99m SPECT) (124).
Stress CMR imaging uniquely allows measurement of subendocardial perfusion. In an initial report in 19 symptomatic women with abnormal stress tests and normal coronaries, subendocardial ischemia was frequently observed (125). These findings have been validated in a larger cohort reporting a strong correlation between subendocardial ischemia and abnormal coronary reactivity testing (126); although population heterogeneity has resulted in varying results (127). Investigation into the prognostic implications of CMR subendocardial ischemia with regard to IHD events and its association with future chest pain frequency and stability is needed.
Coronary computed tomographic angiography (CCTA) is a noninvasive anatomic technique with a reported high diagnostic accuracy for obstructive CAD (128-129). In a series of 51 women and 52 men, diagnostic sensitivity and specificity was similar by gender at 85% and 99% (130); although a recent larger controlled trial demonstrated a lower specificity of 90% (131). An important limitation for CCTA, and all tests of ionizing radiation exposure, is that imaging should be used cautiously in younger women due to a heightened lifetime cancer risk. CCTA is associated with effective radiation doses that average 11.3 mSv for men and 12.7 mSv for women (124). Test protocols emphasizing reductions in radiation exposure, including ECG-controlled tube current modulation, prospective gating, minimization of scan length, and optimization of tube current and voltage, should be emphasized in women. Moreover, especially for younger women, caution should be applied to use of testing that involves ionizing radiation and, in some cases, use of stress echocardiography or magnetic resonance imaging techniques may be favorable, in particular for younger women.
Importantly, women with angina and confirmatory ischemia have an elevated IHD mortality (106). In a recent report from an ambulatory population (n=56,441 women and 34,885 men), the coronary standardized mortality ratio was ~2-fold higher for females 55-74 years and increased to 12-fold higher for those aged 45-54 years (132).
In summary, abnormalities in functional capacity and noninvasive imaging are valuable IHD risk predictors in symptomatic women. Further work is needed to integrate the use of existing and novel strategies to optimize IHD risk detection in women.
Women suffer disproportionately from a variety of generalized vascular disorders, including migraine headaches, Raynaud’s phenomenon, and autoimmune arteritis. These observations support the influence of lifelong, varying reproductive hormone levels related to ovarian cycling, pregnancy, peri-partum, and menopause are likely related to vascular function in health and disease (133). While knowledge regarding the role of coronary reactivity was historically confined to Prinzemetal’s angina, characterized by abnormal proximal epicardial coronary artery vasospasm modulated by smooth muscle dysfunction (134), it is now clear that intra-myocardial microvascular arteries (135) mediated by endothelial (136) and autonomic nervous system adrenergic pathways (137) are involved.
Recent data support a gender-specific role for coronary microvascular dysfunction in IHD pathophysiology. Autopsy data from sudden cardiac death victims suggest that women have a higher frequency of coronary plaque erosion and distal embolization compared to men (14-15,138-141). Retinal arterial narrowing, a measure of microvascular disease, is related to CVD events in women but not men (13). Additional important sex differences in the arterial remodeling/repair response to injury/atherosclerosis may prove etiologic for the development of microvascular dysfunction in women. Although the onset of atherosclerosis for women temporally lags behind that of men, evidence that the combination of smaller arterial size and more prominent positive remodeling (49,83,142) may lead to a greater role of microvascular dysfunction in IHD in women compared with men (143). Recently Han et al. (144), studied patients with obstructive CAD who underwent simultaneous intravascular ultrasound (IVUS) and coronary reactivity assessment and demonstrated that men have a greater atheroma burden and more diffuse epicardial endothelial dysfunction while women have more disease of the microcirculation. These factors may influence the higher rates of angina, ischemia, and ACS in the absence of obstructive CAD in women supporting coronary microvascular dysfunction as a prominent disorder in women compared to men (113,143).
Endothelial function (measured centrally in the coronary or distally in the peripheral circulation) contributes to IHD pathophysiology in women. Brachial artery flow-mediated dilation, a peripheral measure of endothelial function, is impaired in hyperlipidemic, hypertensive, smokers, and diabetics (145), and exacerbated post-menopausally (146). Abnormal flow mediated dilation in a large cohort of 2,264 post-menopausal women was associated with a 1.3- to 4.4-fold increased IHD risk (p<0.0001) (147). Whether endothelial dysfunction mechanistically is a precursor to the development of hypertension, a marker for subclinical atherosclerosis, a measure of obstructive CAD severity, or related to left ventricular remodeling and diastolic dysfunction is unknown (5,148-149).
In the coronary circulation, both endothelial-dependent epicardial (endothelial dysfunction) and endothelial-independent (microvascular dysfunction) dysfunction predict adverse IHD events in patients undergoing diagnostic angiography, single vessel percutaneous coronary angioplasty (PCI), or post ACS/MI (150-153). These results are important because restoration of endothelial function is associated with improved outcome. In a study of 400 hypertensive post-menopausal women, improved endothelial function was associated with a 7.3-fold lower rate of IHD events when compared to women with no improvement (154).
The role that coronary reactivity dysfunction plays in ischemia in women without obstructive CAD has only now been described and the relative importance of endothelial and microvascular dysfunction has been insufficiently explored. An integrated working understanding of the cascade of mechanisms and manifestations of ischemia impacting IHD risk in women is reviewed in Figure 1.
We propose that coronary microvascular dysfunction is more prevalent in women than men due to risk factor clustering and hormonal alterations and is etiologic for the observed paradoxical frequent (atypical) symptoms, evidence of ischemia, and adverse outcomes. We propose that symptoms occurring due to coronary microvascular dysfunction which result in myocardial ischemia should be called microvascular angina. A hypothetical model of microvascular angina in women is depicted in Figure 2. This model provides a rationale for why current approaches for detection of focal obstructive coronary lesions are less effective in women with a greater prevalence of nonobstructive CAD. Abnormal coronary reactivity occurs in the setting of underlying atheroma vulnerable to clinical instability and more progressive disease states. It is for this reason that identifying nonobstructive atheroma may provide greater risk stratification in women. An overarching working model of this proposed female-specific IHD pathophysiology is depicted in Figure 3. While the relationship between microvascular dysfunction and epicardial atherosclerosis is not fully understood, a leading hypothesis is that it is a single disease process, where response to intimal injury may vary related to sex differences in vascular remodeling and vascular reactivity.
A consistent pattern in the literature is a higher mortality in women compared to men with acute MI (155-157). In the Thrombolysis In Myocardial Infarction (TIMI)-II trial, significantly higher rates of death and re-infarction were observed in women compared to men at 6-weeks and 1-year, even following adjustment for age and comorbidity (158-159). The National Registry of Myocardial Infarction-2 analyzed data from 384,878 patients demonstrating that among younger patients (<50 years of age), adjusted mortality for women was more than twice that of men (105). The Primary Angioplasty in Myocardial Infarction (PAMI) trial demonstrating that primary PCI post-MI reduced the risk of intracranial bleeding resulting in comparable survival by gender; in contrast to patients treated with t-PA where in-hospital mortality from acute MI was 3.3-fold higher in women than men (160). Although absolute mortality reduction in MI patients treated with fibrinolytic therapy is similar by gender, there is a higher mortality following reperfusion with fibrinolytic therapy in women of all ages (161).
In women undergoing invasive coronary angiography, those with obstructive CAD have a 1.7 to 2.0-fold higher odds of in-hospital mortality as compared to nonobstructive CAD (p=0.013) (11). In-hospital mortality is highest for ACS women ranging from 22-38% for those with 1-3 vessel CAD (p<0.0001). The higher short-term mortality includes more frequent complications of reinfarction and higher procedural complications; with older age, more diabetes, and greater comorbidity contributory (5,103,113,162-163). In a recent post-infarction trial, there was a borderline increased risk of sudden cardiac arrest and resuscitated cardiac arrest occurring within the first week post-MI for women (p=0.08), suggesting a higher acute post-MI instability in women (164).
The prognosis with “normal” coronary arteries co-occurring with signs and symptoms of myocardial ischemia has historically been interpreted as benign (165-167). More recent prognostic data in patients with ACS and non-obstructive CAD does not appear to be consistent with these historical findings and notes a 2% risk of death and myocardial infarction at 30 days of follow-up (168). Notably, while a majority of these subjects were women, these datasets include men with nonobstructive CAD and comparative analyses by sex are needed. A recent investigation demonstrated that 30% of women with chest pain, “normal” angiograms, and endothelial dysfunction developed obstructive CAD during 10-year follow-up (169). A pooled analysis of women from recent, large randomized trials reveals that women with mild CAD have a worsening prognosis as compared to those with normal coronaries (170). Recently, Gulati and colleagues (96) reported 5-year CVD event rates of 16.0% for those with mild CAD (stenosis 1-49%), 7.9% for those with no coronary stenosis, and 2.4% in asymptomatic women (p≤0.002); following adjustment of cardiac risk factors. Despite these compelling findings, treatment for women with open coronary arteries remains often reassurance, sedative-hypnotic prescriptions, and/or repeated hospitalization and coronary angiography in response to refractory symptoms (97).
Given the sizeable gap in IHD prognosis between women and men, further research into sex-specific pathophysiology is needed. A model summarizing the factors known to contribute to the prognostic risk of IHD events in women with and without obstructive CAD is depicted in Figure 4.
For women with ACS, existing evidence-based guidelines support a stratified invasive vs. conservative strategy for high and low risk women (171). Data from a recent meta-analysis of 8 ACS trials (3,075 women and 7,075 men) compared risk reduction using an invasive compared to a conservative strategy (172). For both women and men, an invasive strategy resulted in an equivalent 19-27% relative risk reduction using a composite endpoint of death, MI, or repeat ACS. There were, however, important differences in risk reduction between biomarker-positive and -negative women. The invasive strategy was associated with a 33% lower risk of the composite endpoint in biomarker-positive women in contrast to a higher risk in biomarker-negative women, a difference that was not evident in men. Similarly, although women and men with ACS derive similar benefit from drug-eluting stents (174), women have an overall higher mortality with PCI for STEMI and non-STEMI (173).
Following fibrinolysis, the 30-day incidence of death or nonfatal MI was significantly lower in women compared to men in the enoxaparin group compared to unfractionated heparin (161), suggesting that sex differences may beneficially impact outcomes in women for specific therapies. For both women and men undergoing PCI, despite higher bleeding risk in women, the clinical benefit of glycoprotein IIb/IIIa platelet receptor blockade with abciximab for adverse events is similar (175). Overall, among patients with ACS treated with IIb/IIIa receptor blockade (not undergoing early coronary angiography), men experienced a benefit with an odds ratio (OR) of 0.81 (95% CI=0.75-0.89) compared to a suggestion of harm in women (OR=1.15, 95% CI=1.01-1.30); although high risk women with elevated troponins did derive a benefit (176). Prior studies document that women’s higher risk of bleeding is due in part to lack of dose adjustment to body size and renal function compared to men (177). A sex difference in bleeding risk was not observed when doses were adjusted for age and renal function (175). From a large international registry, women with ACS were generally treated less aggressively, including less acute heparin, angiotensin-converting enzyme inhibitors, and glycoprotein IIb/IIIa inhibitors and lower rates of discharge with aspirin, angiotensin-converting enzyme inhibitors, and statins as compared to men (104). Application of guideline-indicated therapy post-ACS is associated with abolishment of the adverse mortality gap in women (178).
As noted above, one factor contributing to relatively higher IHD risk in women is less intensive use of indicated medical therapy (aspirin, beta-blocker, statin, ACE, therapeutic lifestyle counseling) (179-183); despite specific guidelines noting their benefit (6). The Cooperative Cardiovascular Project (184) showed that women received less medical treatment post-MI, including 5% less aspirin at discharge; although they were 5% more likely than men to receive ACE inhibitor, perhaps due to hypertension. A more recent registry (104) indicates that this observation has not changed with women receiving less (indicated) discharge aspirin (87.5% vs. 90.4%), beta-blockers (80.5% vs. 82.7%), and statins (55.9% vs. 69.4%) compared to men.
Undertreatment of women has been attributed to the lower prevalence of obstructive CAD. Recent data from the Euro Heart Survey of Stable Angina reported that women with CAD less likely received coronary revascularization (OR=0.70 [95% CI=0.52-0.94], p=0.019) and were less often on lipid-lowering therapy at 1-year follow-up (76% vs. 81%, p=0.05), despite adjustment for an array of clinical factors (185). In contrast, the CRUSADE registry (104) revealed similar rates of PCI among women and men after accounting for the severity of angiographic CAD (adjusted OR=0.97, 95% CI=0.91-1.03). The GRACE study investigated women with obstructive CAD and demonstrated less use of aspirin (95% vs. 96%), beta-blockers (87% vs. 89%), and statins (75% vs. 77%) compared to men (186). The recent COURAGE trial demonstrated that women with CAD and chronic stable angina derive an equal benefit from intensive, long-term medical therapy and with no added benefit of PCI (187) (Figure 5).
Thus, the weight of the evidence indicates suboptimal treatment of women with proven obstructive CAD (188), despite evidence and guidelines supporting effective risk reduction when applying acute, revascularization and/or chronic medical therapies (6,189-191).
Much of the evidence of treatment in women with nonobstructive CAD has focused on improvement in symptoms or vascular function. Many anti-ischemic therapies have been evaluated including data that calcium antagonists reduce coronary flow reserve and fail to improve symptoms (192). Beta-blockers, however, are highly effective for improving chest pain symptoms (193). No controlled studies are available on the effects of nitrates on health status outcomes in women. Statins and ACE-inhibitors improve endothelial dysfunction (194-195) and may be of benefit in patients with nonobstructive CAD (194-196). Beneficial effects of statins on the coronary microcirculation have been documented in clinical studies (197). Combinations of drugs, specifically statins and ACE-inhibitors, may amplify these benefits (194). However, combination therapy to more fully attenuate the renin-angiotensin aldosterone system has not been explored; additional work is required to determine the translational value of this treatment. The proven benefit of exercise training in this population (198) suggests that mechanisms of adrenergic modulation play a role.
Novel therapies have been evaluated in women without obstructive CAD. Imipramine improves symptoms in patients with abnormal cardiac pain perception and normal coronary angiograms; possibly through a visceral analgesic effect. It also has anticholinergic and alpha antagonist effects demonstrated both in the coronary and peripheral circulation (199). Six-month supplementation of L-arginine improved endothelial function and symptoms in patients with nonobstructive CAD (200); although a recent post-MI trial demonstrated adverse effects of L-arginine questioning its safety (201). Menopausal hormone therapy may improve emotional well-being in postmenopausal women with angina and “normal” angiograms yet there is no symptom benefit for these patients (202).
No randomized trials comparing therapies for risk reduction and cost effectiveness in women with angina/ischemia and “normal” coronary arteries have been conducted. Future IHD research will need to specifically characterize patients as to the pathophysiological mechanism(s) of disease, with regard to the presence or absence of coronary microvascular dysfunction, in order to devise optimal clinical trials aimed at improved IHD risk and health status outcomes.
Given the relatively lower prevalence of obstructive CAD yet the notably higher prevalence of ischemia, symptom burden, and mortality relative to men, we propose use of the term IHD as more appropriate for symptomatic women in lieu of terms, CAD or CHD. Traditional risk factors contribute to accelerating risk for IHD events in women, and novel risk markers, including inflammatory markers and reproductive sex hormones, provide unique value for identifying at-risk women. More recent specific global risk scores for women, such as the Reynold’s risk score, and markers of subclinical atherosclerosis improve risk detection. Routinely available diagnostic testing can be used to accurately risk stratify women, however identification of compromised functional capacity and evidence of ischemia as markers of an adverse prognosis are particularly important. Given the frequent paradoxical findings of angina and ischemia in women without obstructive CAD, new data support the use of the term microvascular angina to reflect the occurrence of microvascular dysfunction in IHD pathophysiology in women; models linking these findings with symptoms, ischemia, and adverse outcomes should be tested. For ACS, new sex-specific guidelines indicate that conservative management is indicated for biomarker negative women however, interventional strategies are equally effective in biomarker positive women and men. Yet, the weight of evidence documents suboptimal use of evidence-based guideline therapies in women with IHD compared to men. Anti-anginal and anti-atherosclerotic strategies are effective for symptom and ischemia management in symptomatic women with evidence of ischemia and no obstructive CAD, however are infrequently used and need to be evaluated in large outcome trials. The evolving knowledge regarding sex differences in IHD appears to be at the precipice of our understanding; future investigation should identify tailored diagnostic and therapeutic strategies to optimize outcomes for women and men (203).
This work was supported by contracts from the National Heart, Lung and Blood Institutes, nos. N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164, R01 HL090957-01A1, R03 AG032631-01, a GCRC grant MO1-RR00425 from the National Center for Research Resources, and grants from the Gustavus and Louis Pfeiffer Research Foundation, Danville, New Jersey, the Women’s Guild of Cedars-Sinai Medical Center, Los Angeles, California, the Edythe L. Broad Women’s Heart Research Fellowship, Cedars-Sinai Medical Center, Los Angeles, California, and the Barbra Streisand Women’s Cardiovascular Research and Education Program, Cedars-Sinai Medical Center, Los Angeles.
Disclosure: Leslee J. Shaw: Grant support from GE Healthcare and Bracco Diagnostics
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Raffaelle Bugiardini: None
C. Noel Bairey Merz: Consulting for Novartis, Karolinska Institute, Strategy Group, University of Pittsburgh, Pfizer, BSP, Kendle Internation, Inc., NHLBI; Lecture Honorarium for Northwestern University, University of California-Davis, Abbott Labs, CV Therapeutics, Boehringer Ingelheim, American College of Physicians, ProMedica, Mayo Clinic, Merck; and Stock in Boston Scientific, Medtronic, Johnson and Johnson, and Teva Pharmaceuticals.