Sex, Racial, and Ethnic Disparities in Acute Coronary Syndrome: Novel Risk Factors and Recommendations for Earlier Diagnosis to Improve Outcomes.

The prevalence and impact of ACS risk factors differ between men and women. In the Global Registry of Acute Coronary Events of >7000 women and >19 000 men from 14 countries with ACS who underwent a coronary angiogram between 1999 and 2006, women with ACS were older (median age, 69 versus 62 years) and had higher rates of hypertension (70% versus 55%) and diabetes (29% versus 22%). 6 Diabetes is a stronger risk factor for ACS in women than in men. 9 In the INTERHEART global case-control study of 27 000 subjects from 52 countries, women with diabetes were 4.3× more likely to suffer an MI than non-diabetic women, compared with 2.7× higher MI risk in men with versus without diabetes. 17 Women presenting with ACS are often 8 to 10 years older than their male counterparts. 17 , 18 The risk of developing ACS increases sharply after menopause in women due to the loss of estrogen and its vascular endothelial protective properties, including antioxidative, vasodilatory (increased release of nitric oxide), prostaglandin regulatory, and smooth muscle proliferation inhibitory effects. 19 Taken together, these differences in risk factors for CVD may account for differences in outcome at percutaneous coronary intervention (PCI) for ACS (discussed later). Early data suggested that women with ACS were more likely to present with atypical symptoms in the absence of chest pain 20 ; however, more recent studies have shown that women present equally with chest pain compared with men. In the Global Registry of Acute Coronary Events study, men and women presented equally with chest pain; however, women were more likely to have additional symptoms of jaw pain (10% versus 4%) and nausea/vomiting (32% versus 23%). 6 Moreover, in a study of 1941 patients with suspected ACS in Edinburgh, Scotland between 2013 and 2017, chest pain was the prevailing symptom of presentation among men and women (91% versus 92%). 21 Typical symptoms were more common in women than in men with MI (77% [69/90] versus 59% [109/184], respectively; P =0.007); however, women were more likely to also have atypical symptoms as jaw and abdominal pain, nausea, and vomiting. Regardless of ACS presentation, women tend to present to the hospital later after the onset of symptoms. In the Acute Coronary Syndrome Quality Improvement in Kerala trial, women presented on average an hour later after the onset of chest pain compared with men (median symptoms-to-door time 300 versus 238 minutes). 18 These disparities in later presentations may translate into worse outcomes (see below). Several studies have shown that female patients with ACS are misdiagnosed and underinvestigated when compared with their male counterparts. 22 In a large pooled analysis of 2520 patients from 2 prospective cohorts from Germany, women presented with chest pain similar to men, but the women were more likely to have additional symptoms as dyspnea, nausea, and vomiting. The women with ACS were less likely to undergo coronary angiography when compared with men (73.8% versus 84.3%), potentially related to underdiagnosis based on troponin levels. 23 High-sensitivity troponin assays have revealed that the 99th centile reference limits are up to 2-fold higher in men than in women, possibly contributing to ACS underdiagnosis in women when a single range is used for both sexes. 24 Use of hs-cTnI (high-sensitivity cardiac troponin I) assays with sex-specific thresholds (>16 ng/L women, >34 ng/L men) reclassified 5% of men and 30% of women as having an ST-segment–elevation MI (STEMI), whereas the contemporary assay (threshold >50 ng/L) classified 16% of men but only 12% of women in the Scotland study. 21 One in 3 women with a diagnosis of STEMI were only identified using a hs-cTnI assay with sex-specific thresholds. Use of the hs-cTnI assay is now endorsed by the fourth universal definition of MI. 25 A study of 48 282 patients (47% female) found that using sex-specific thresholds for the hs-cTnI assay increased myocardial injury diagnosis by 42% in women and 6% in men. 26 However, despite use of the new hs-cTnI thresh-olds, women still had a lower likelihood of undergoing coronary revascularization compared with men (15% versus 34%) and outcomes were not improved. 21 Several studies have shown that women have a lower likelihood of receiving essential ACS treatments, including antiplatelets, beta-blockers, statins, and angiotensin-converting enzyme inhibitors, whether at admission or at discharge. 9 Similarly, women with ACS are prone to disparities in reperfusion therapy, including primary PCI and fibrinolysis, despite adjusting for clinical parameters. Using the National Inpatient Sample of 1.2 million STEMI hospital admissions between 2010 and 2016 (32% women), female sex was associated with significantly lower utilization of different perfusion strategies, including primary PCI even after adjustment for demographics, type of hospital, and patients’ characteristics (adjusted odds ratio [OR], 0.74 [95% CI, 0.72–0.75]; crude prevalence 66% versus 78%; Table 1 ). 27 Similar results were found in representative samples from India 18 and the Middle East ( Table 1 ). 28 Women have been reported to experience worse out-comes than men after PCI with drug-eluting stents. A recent multinational meta-analysis of 56 observational studies and >700 000 patients (31% female) showed that women presenting with STEMI had a higher in-hospital mortality (OR, 1.91 [95% CI, 1.84–1.99]), rein-farction (OR, 1.25 [95% CI, 1.00–1.56]), and major bleeding (OR, 1.82 [95% CI, 1.56–2.12]). 29 Another meta-analysis of 15 observational studies and >128 000 patients (25% females) reported that both unadjusted and adjusted in-hospital and 30-day mortality was higher for women presenting with STEMI (relative risk [RR], 1.73 [95% CI, 1.53–1.96]; P <0.001 and RR, 1.24 [95% CI, 1.11–1.38]; P <0.001, respectively) but not 1 year. 30 Women were older and had higher rates of hypertension and diabetes. In an international survey of primary PCI for STEMI in 2596 patients, women had a 2-fold higher (95% CI, 1.27–3.15) risk of 30-day mortality. 31 However, there was no difference when the door-to-balloon time was 120 minutes ( Table 2 ). In a randomized controlled trial of primary PCI with randomization to ticagrelor in the catheterization lab or ambulance for STEMI of 1862 patients, the adjusted hazard ratio (HR) for women was 2.08 (95% CI, 1.03–4.20) for 30-day mortality. Bleeding was 2-to 3-fold higher in women due to older age and comorbidities, all of which accounted for the higher mortality in women ( Table 2 ). 32 Because lower socioeconomic status has been shown to adversely affect outcome, 33 we examined out-comes in the United Kingdom, Sweden, Australia, and Italy where universal health insurance is available such that access to health care is not dependent on job status or income level. Of 2074 subjects undergoing primary PCI for STEMI between 2006 and 2016 in Italy, the propensity score–adjusted HR for women was 2.09 (95% CI, 1.45–3.01; P <0.001) for 30-day all-cause mortality compared with men ( Table 2 ). 34 In a retrospective analysis of PCI for ACS of 4776 patients in Australia between 2008 and 2015, PCI success was similar in women and men (97.7% versus 97.8%, respectively). Women had a higher unadjusted 1-year mortality of 6.4% versus 4%; P =0.0012, but after adjustment for the older age of women and their higher rates of hypertension, diabetes, and obesity, there was no difference in mortality ( Table 2 ). 35 Age >70 years, diabetes, presence of 3-vessel disease, and STEMI were independent predictors of mortality at 1 year, whereas sex was not. In the United Kingdom of 368 492 patients and of 89 769 patients in Sweden for PCI for stable angina, non–STEMI (NSTEMI), and STEMI between 2007 and 2011, female sex was an independent predictor of all-cause mortality at both 30 days and 1 year with age as the strongest predictor ( Table 3 ). 36 Of 13 451 patients at 30 centers in Australia, women had a higher in-hospital mortality compared with men for STEMI due to a longer symptom-to-door and door-to-balloon time ( Table 3 ). 37 The delay in symptomto-door was due to lack of awareness of symptoms of MI in women; therefore, Australia initiated an Invisible Me program to educate women on the symptoms of ACS. These reports suggest that despite advances in care and the presence of universal health insurance, the outcome remained worse for women than men for PCI for CAD. Several factors accounted for this—older age of women, higher prevalence of diabetes and hypertension as risk factors, and delay in presentation. A patient-level pooled analysis of 10 Thrombolysis in Myocardial Infarction trials and >68 000 patients with NSTEMI (29% female) showed that women had a higher crude risk of mortality compared with men after NSTEMI (HR, 1.12 [95% CI, 1.01–1.24]). 38 However, after adjustment for baseline risk factors, women with NSTEMI had a lower risk of mortality compared with men (adjusted HR, 0.84 [95% CI, 0.78–0.90]), suggesting that sex disparities in NSTEMI outcomes may be explained by older age and worse CVD risk profile in women. The Australia study also reported no sex difference in in-hospital or 30-day mortality with NSTEMI. 37 The gender of the attending physician has been shown to impact outcome after MI. To examine the impact of gender match between patient and physician during an MI, emergency department patients’ admittances (N=581 845) to Florida hospitals between 1991 and 2010 were examined. 39 The baseline mortality rate was 11.9%. Gender concordance reduced the probability of death by 5.4% relative to the baseline ( P <0.01). The effect was driven by increased mortality when male physicians treat female patients. However, the mortality rate was lower when a female physician treated a female patient. 39 The study is an example of patient gender disparities which demonstrate that female gender concordance increases a patient’s probability of survival.

Inherent anatomic, physiological, and pathological differences may mediate, at least in part, the sex disparities in ACS. Women presenting with acute MI are twice as likely to present with MI in nonobstructive CAD (MINOCA) as men are. 8 To diagnose MINOCA, there should be evidence of a rise and fall of cardiac troponin and evidence of infarction (symptoms of myocardial ischemia or imaging evidence of infarction) in the absence of obstructive coronary artery disease (CAD; 0.8–with abnormal <0.8). MINOCA encompasses a range of pathophysiological processes; these include plaque disruption with thrombosis and spontaneous thrombolysis, epicardial coronary vasospasm, coronary microvascular dysfunction, and spontaneous coronary artery dissection (SCAD). 8 Accounting for ≈40% of MINOCA cases, epicardial coronary vasospasm is a transient and reversible intense vasoconstriction of a major epicardial coronary artery. Coronary vasospasm may occur in response to drugs/toxins (eg, cocaine) or spontaneously. The sex predilection is supported by the higher prevalence of other vasoreactive disorders, such as Raynaud phenomenon and migraines, in women, where sex hormones and inflammatory mediators seem to be plausible modulators. Calcium channel blockers and nitrates are the mainstay treatment for coronary vasospasm. 8 , 9 SCAD occurs when the layers of the coronary arterial wall separate leading to the formation of an intramural hematoma that compresses the true lumen, compromising anterograde blood flow. Serial angiographic and intravascular imaging of SCAD cases have demonstrated that hematoma development in the tunica media, possibly due to disruption of transversing microvessels, precedes development of intimal dissection, and the absence of communication between true and false lumens. 10 SCAD contributes to 24% to 35% of all ACS cases in women ≤50 years of age. 11 Around 87% to 95% of SCAD cases occur in women with a mean presentation age between 44 and 53 years. 12 Women with SCAD are more frequently multiparous with history of preeclampsia, implicating sex hormones in disease development. 12 Pregnancy-associated SCAD is responsible for 5% to 17% of all SCAD cases and up to 43% of ACS cases in pregnancy. 12 SCAD during pregnancy tends to have more severe features of cardiogenic shock and left main/multivessel dissections. 12 Patients with SCAD tend to have fewer traditional CAD risk factors compared with patients with atherosclerotic ACS. 12 SCAD appears linked with connective tissue disorders and fibromuscular dysplasia. 13 Patients carrying the rs9349379-A variant in the locus PHACTR1/EDN1 (phosphatase and actin regulator 1/ endothelin 1) have a higher risk of both SCAD and fibromuscular dysplasia. 14 A genome-wide association study of the United Kingdom Biobank and Million Veteran Program identified rs12740679 at the chromosome 1q21.2 locus, chromosome 12q13.3 in LRP1 (LDL receptor-related protein 1), and in females-only, at chromosome 21q22.11 near LINC00310 (long intergenic nonprotein coding RNA 310) with an increased risk of SCAD. 15 In a genome-wide association study of Canadian patients with SCAD and 7 pQTL (protein quantitative trait loci) studies, single-nucleotide polymorphisms linked to SCAD in 1q21.2 showed a robust correlation with the levels of extracellular matrix protein 1 and 25 other circulating proteins involved in the regulation of peptidase activity and cellular protein metabolic processes. Additionally, SCAD-associated single-nucleotide polymorphisms were associated with levels of 42 circulating cytokines including IL (interleukin)-10, IL-12p70, IL-13, IL-7, vascular endothelial growth factor, and 85 metabolites including low-density lipoprotein cholesterol (LDL-C). 16 Men have greater epicardial atheroma burden and more diffuse epicardial endothelial dysfunction than women, possibly explaining the greater prevalence of ACS in men. 10 ACS may occur due to luminal thrombosis within the coronary arteries. The 3 main mechanisms that lead to thrombosis are plaque rupture, erosion, and calcified nodules. 10 Plaque erosion is defined as an acute thrombus that happens in direct contact with an intimal area of stripped endothelium. In an autopsy study that included 442 cases of ACS, plaque erosion was more common in women compared with men (58% versus 24%), whereas plaque rupture was found to be more common in men than women (71% versus 33%). 10 Endothelial dysfunction, leukocyte activation, and coronary spasm have been implicated in plaque erosion. 10

To diagnose subclinical atherosclerosis earlier, results of screening mammography, which most women aged >40 years undergo annually, may have potential utility for primary CVD prevention by providing important information on breast arterial calcification (BAC). In a cohort of 5059 women aged 60 to 79 undergoing screening mammography, 26% had presence of BAC. After a mean follow-up of 6.5 years, presence of BAC was significantly associated with increased hazard of ASCVD (HR, 1.51 [95% CI, 1.08–2.11]; P =0.02). 91 BAC status provided additional risk stratification to that of the pooled cohort equation. The overall net reclassification improvement was 0.12 (95% CI, 0.03–0.14; P =0.01) and the bias-corrected clinical-net reclassification improvement was 0.11 (95% CI, 0.01–0.22; P =0.04) after adding BAC status. 91 BAC and CAC have different causes and pathophysiology. Although CAC represents intimal arterial calcium deposits and is tied with traditional risk factors as smoking and hyperlipidemia, BAC involves medial calcium deposits leading to arterial stiffening and is more closely related to comorbidities such as diabetes and hypertension. 92 The addition of prognostic information by BAC to the pooled cohort equation implies that women with BAC who fall into the borderline or intermediate ASCVD risk categories may require more aggressive treatment. 91 Similarly, women with BAC who are already at high risk may need to have their therapy intensified. Therefore, BAC should be considered a risk-enhancing factor for ASCVD among women undergoing mammography and should be adopted more universally to fully assess CVD risk in women. LDL-C levels increase as women go through menopause and with age in both sexes. In primary prevention of CVD, an LDL-C level >190 mg/dL is an indication to start a statin drug. 87 With levels of 130 to 189, the pooled cohort equation is used, but it is known to overestimate risk in women. Four primary prevention trials of statin drugs have included women. In the Air Force/Texas Coronary Atherosclerosis Prevention Study and Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese trial, no significant difference was seen in the primary end point of cardiovascular events in women. 93 , 94 In Justification for the Use of Statins in Primary Prevention trial, women randomized to rosuvastatin 20 mg daily had a significant reduction in first major cardiovascular event (MI, stroke, hospitalization for unstable angina, arterial revascularization, cardiovascular death) compared with women on placebo. 95 Women in the trial were >60 years of age, had an LDL-C 2. The trial results can be applied to women with these characteristics but not to the general population of women. In the Heart Outcomes Evaluation Prevention 3 trial, of 5874 women randomized to rosuvastatin 10 mg or placebo, women had a nonsignificant 17% reduction compared with a significant 28% reduction in men. 96 The P value for heterogeneity between men and women was nonsignificant; therefore, the authors stated that the results can be applied equally to men and women. This is no longer considered acceptable to base recommendations for women. The US Preventive Service Task Force recently made recommendations for statin use in primary prevention but had no comment on women. 97 Due to the lack of data on LDL-C levels for primary prevention in women, CAC screening has been recommended for women at intermediate risk based on the pooled cohort equation and who have an LDL-C generally >140 and 0) was 36.1% in a 2016 meta-analysis of 6739 women from 5 large-scale population-based studies with ages ranging from 44.0 to 63.3 years, mean LDL-C ranging from 102.8 to 141.5 mg/dL, and a 10-year ASCVD risk <7.5% based on the pooled cohort equation (low to borderline risk). 98 Over a mean follow-up period of 7.0 to 11.6 years, a detectable CAC was associated with an increased risk of ASCVD (multivariableadjusted HR, 2.04 [95% CI, 1.44–2.90]). Moreover, the incorporation of CAC alongside traditional risk factors resulted in a continuous net reclassification improvement index of 0.20 (95% CI, 0.09–0.31), signifying that 20% of women were reclassified into more appropriate risk categories. 98 CAC screening may lead to improvements in CVD risk factors and therapeutic compliance (medication adherence in addition to lifestyle changes). Radiation exposure is less than a mammogram. When CAC is known, the MESA (Multi-Ethnic Study of Atherosclerosis) calculator, instead of the Pooled Cohort Equation, can be used to determine CVD risk ( https://www.mesa-nhlbi.org/MESACHDRisk/MesaRiskScore/RiskScore.aspx ).

Accumulating evidence indicates that women, particularly younger women, may represent a unique high-risk group that requires special attention. Different pathophysiological factors, baseline risk profiles, and symptomatology in women can invoke discrepant diagnostic and therapeutic practices, and inevitably, differential outcomes between men and women (see Graphic Abstract). The worse outcome for women compared with men with PCI for STEMI is due primarily to the older age of women, higher rates of hypertension, diabetes, and obesity, and higher rates of bleeding. Recognition of sex-related risk factors as hypertensive disorders of pregnancy, preeclampsia, and small-for-gestational-age infant and referral of women with these risk factors for cardiovascular screening and risk reduction is important. The differences in risk factors and their effect on outcomes after ACS must be considered when evaluating CVD manifestations because they affect management and prognosis of cardiovascular conditions in women. Earlier diagnosis of subclinical CAD with BAC and CAC could lead to earlier preventive strategies which may prevent development of clinical CAD. Education of women as to signs of CAD as the Australian Invisible Me program could potentially decrease symptom-to-door time and improve outcomes at PCI. This could ensure timely delivery of life-saving care for women with ACS. Prospective research should adopt a more sex, racial and ethnic–inclusive approach while designing CVD clinical trials that delve into the mechanistic aspects of ACS sex disparities, leading to a better understanding of differences in a larger perspective of biological, psychosocial, and environmental factors.

Between 1995 and 2014, the proportion of MI attributable to young patients (35–54 years) increased steadily among women (from 21% to 31%) but plateaued among their male counterparts (from 30% to 33%). 5 Young women with MI were more likely to have hypertension (71% versus 64%) and diabetes (39% versus 26%) and less likely to present with STEMI (16% versus 26%) when compared with young men. 5 In a study of 14 931 patients with ACS enrolled in the International Survey of Acute Coronary Syndromes in Transitional Countries registry, among young patients with ACS, female sex was associated with a striking 6-fold increase in risk of 30-day mortality (adjusted OR, 6.0 [95% CI, 2.1–17.5]). 40 Studies from the Arabian Gulf, 28 India, 41 and China 42 found similar trends in worse short- and long-term outcomes in young women with ACS compared with men ( Table 1 ). Although sex disparities in ACS care are universal, most of the studies addressing sex disparities are from developed countries. The magnitude of sex disparities in ACS care varies between regions due to inherent geographic, cultural, ethnic, and socioeconomic disparities specific to a certain region. The Prospective Urban Rural Epidemiological study enrolled >200 000 individuals from 27 countries from high-income countries and low- and middle-income countries between 2005 and 2019. 43 At a median follow-up of 9.5 years, women in low- and middle-income countries had higher age-standardized incidence rates of major CVD (4.5 versus 2.6 per 1000 person-years) and higher age-adjusted case fatality rates after a major CVD event (38% versus 5%) compared with women in high-income countries. 43 Moreover, women in all regions were less likely to receive secondary prevention medications and coronary revascularization therapies compared with men. 43 The South-East Asian Region nations of India, Pakistan, Bangladesh, Sri Lanka, and Nepal are home to about one-quarter of the world’s population with highest burden of CVD, especially among the young. 44 Data on ACS sex disparities in the region are mainly from India and Bangladesh. 44 Using data from the Acute Coronary Syndrome Quality Improvement in Kerala study, our group showed that South Indian women with ACS had higher risk of in-hospital (adjusted relative risk, 1.67 [95% CI, 1.42–1.97]) and 30-day (adjusted relative risk, 1.48 [95% CI, 1.29–1.70]) mortality compared with men. 18 Among young patients with ACS (age ≤55 years) in Bangladesh, women were more likely to experience short-term adverse events when compared with men (14.7% versus 6.3%). 45 Studies from China, 46 Thailand, 47 and Malaysia 48 did not show significant differences in ACS outcomes between men and women. The Eastern Mediterranean Region includes the Arabian Gulf, Levant area, North Africa, and Western Asia. Several large ACS registries from the Gulf region and Egypt looked at sex disparities; however, data remain scarce from the rest of North African countries. 44 A patient-level pooled analysis of 15 532 patients with STEMI (2033 women) from 7 ACS registries from the Arabian Gulf found a higher in-hospital and 1-year mortality among women, driven mainly by increased mortality among young women (adjusted OR for age group, 46–55 years 2.12 [95% CI, 1.3–3.6]; Table 1 ). 28 In a study of 1681 patients with ACS (25% women) across 11 governorates in Egypt, 43% of men were young (<55 years), and 67% of women were young (<65 years). 49 A total of 51% of men with STEMI underwent primary PCI compared with only 46% of women. Other studies from Egypt did not show sex differences in terms of utilization of diagnostic and therapeutic procedures or adverse outcomes ( Table 1 ). 50 , 51 In Tunisia between 1997 and 2003, the ACS mortality rates increased more rapidly in women compared with men (23.8% versus 11.8%), attributed to unfavorable lifestyle changes and westernization. 52 Additionally, women from Tunisia presented later after onset of symptoms compared with men (median of 3 versus 2 hours). 53 Despite the increasing rate of ACS in Sub-Saharan Africa, few small-scale studies are available with scarce data on sex disparity. 44 In a study of 1072 patients with ACS (33.2% women) from Nigeria between 2013 and 2018, <11.2% of men and women presented within 12 hours from symptom onset, reflecting the use of nonmedical transportation to reach hospitals. 54 In a retrospective study of 98 women presenting with ACS to one major hospital in Senegal, women were older (mean age, 69 years) with aggregation of classical risk factors, such as hypertension (63%), diabetes (53%), and obesity (34%). 55 Shockingly, the average delay before getting medical care was 54 hours. The authors reported 6 in-hospital deaths. No comparison was made to male counterparts. 55 A plethora of socioeconomic and structural determinants may accentuate the ACS sex gap in low- and middle-income countries. 56 In addition to limited resources and harder access to care in low- and middle-income countries, gendered behavioral norms redirect women’s duties toward caring for others and less for themselves, potentially contributing to delays in seeking care when ACS symptoms arise. 57 Additionally, women in low- and middle-income countries are more likely to face childhood abuse and domestic violence that may promote poor eating patterns, predisposing them to obesity, type 2 diabetes, and eventually CVD. 58 , 59 Lower socioeconomic status was independently associated with an increased risk of metabolic syndrome among women but not men in the United States. 57 Ethnic and racial factors have been implicated in ACS risk factors, prevalence, incidence, access to therapies, and outcomes in women. In general, Black women in the United States have a higher prevalence of traditional CVD risk factors including diabetes (31% versus 14.6%), hypertension (66.3% versus 41.7%), and current smoking status (15.4% versus 12.7%) compared with non-Hispanic White women. 60 CVD risk factor prevalence among Hispanic women in the United States is heterogeneous and is dependent on the ethnic background. 61 Puerto Rican women have the highest prevalence of obesity (51.4%), current tobacco smoking (31.7%), and hypercholesteremia (41.0%) compared with their Cuban, Dominican, Mexican, and Central American counterparts. 62 Obesity is more prevalent in racially and ethnically diverse women; in the 2001 to 2016 National Health and Nutrition Examination Survey, obesity was more prevalent among non-Hispanic Black (56.1%) and Hispanic (48.4%) women compared with White (38.8%) and Asian (13.6%) women. 63 Hyperlipidemia, however, is more common in White women. 3 Using the 2011 to 2019 Behavioral Risk Factor Surveillance System database, disparities in cardiovascular health status were assessed among childbearing women (18–49 years). 64 Women with 7 ideal metrics (blood pressure, glucose, total cholesterol, smoking, body mass index, physical activity, and diet) were classified to have ideal cardiovascular health. The group found that Black (OR, 0.42 [95% CI, 0.36–0.49]) and Hispanic (OR, 0.70 [95% CI, 0.62–0.78]) women were less likely to have ideal cardiovascular health compared with White women. 69 After adjustment for sociodemo-graphic factors, Black women continued to have lower odds of having ideal cardiovascular health (adjusted OR, 0.54 [95% CI, 0.46–0.63]) but not Hispanic women. 64 Compared with White women, Black women had poorer socioeconomic conditions; for example, 34.3% of Black women had a household annual income <$20 000 compared with 17.1% of White women. 60 In a prospective cohort of 24 443 participants with a mean follow-up of 4.2 years, the age-standardized ACS risk was higher in Black women compared with White women: 5.0 versus 3.4 per 1000 person-years. 60 However, after adjustment for baseline risk factors, the HR for incident ACS events was similar in both groups, highlighting the burden of CVD risk factors in mediating the disparities in ACS incidence. 60 , 65 Unfortunately, there is a paucity of data on CVD disparities among American Indian and Alaskan Native women. 66 In terms of ACS management and outcomes, existing sex disparities are amplified by racial and ethnic factors. Among 26 575 Medicare patients with MI who met the strict eligibility criteria for reperfusion therapies, Black women were less likely to receive reperfusion therapies compared with White women (44% versus 56%) even after adjustment for clinical and demographic characteristics. 67 However, using the Acute Coronary Treatment and Intervention Outcomes Network registry that included 289 322 patients with STEMI and NSTEMI between 2008 and 2011, Anstey et al 68 reported that the rates of in-hospital medication administration and catheterization for patients with STEMI were similar among Black and White women. However, Black women with NSTEMI were less likely to undergo coronary angiogram (adjusted OR, 0.87 [95% CI, 0.8–0.95]) and revascularization procedures (adjusted OR, 0.8 [95% CI, 0.74–0.87]) compared with White women. 68 Adjusted risks of death and major bleeding were similar between White and Black women. 68 Using data from the Heart and Estrogen/Progestin Replacement Study that included 2699 postmenopausal women with preexisting CAD with an average follow-up of 4 years, Jha et al 69 reported that rates of CVD events (composite of CVD death and nonfatal MI) were more common in Black women compared with White women (adjusted HR, 1.52 [95% CI, 1.04–2.21]), driven mainly by higher incidence of non-fatal MIs. 69 Studies on ACS disparities in ethnic women of non-White Hispanic, Asian, and Native American groups are largely lacking. 66 Although a good proportion of disparities in ACS incidence and outcomes may be attributed to worse risk profiles among ethnically diverse women, it is important to consider the racial inequalities in socioeconomic status. Environmental influences and socioeconomic struggles faced by Black women may lead to higher burden of risk factors and cardiovascular disease and poorer access to care. 70 However, even accounting for socioeconomic status, racial disparities in health outcomes often persist. A study published by Assari 71 showed that although health improves for both Black and White Americans as income increases, this protective effect against chronic medical conditions is much larger for White Americans compared with Black Americans. As African Americans gain higher incomes and more education, health disparities persist with studies suggesting that racism and diverse experiences of racial discrimination in health care play a large role in these disparities. 72 In their perspective article, South et al 73 elegantly linked Health Systems’ potential role to closing the racial wealth gap between Black and White Americans. Black Americans roughly make up 13% of the US population, however, hold only 3% of the country’s wealth; in 2019, the median net worth of a Black family was around $24 100 as compared with $188 200 for White families. South et al 73 connected wealth to health, demonstrating that wealth is an important tool for better housing, balanced nutrition, and dealing with unexpected emergencies which can help reduce stress. The article proposed that Health systems address the racial wealth gap and thereby reduce the racial health gap urging health care–providing institutions to adopt a combination of 3 approaches: reducing expenses, maximizing income, and decreasing debt while increasing savings. The issue of ethnic and racial disparities in ACS care among women is not specific to the United States and manifests in other multiethnic communities. In a multiethnic Singaporean study that included 16 320 ACS events (3407 women) between 1991 and 1999, age-adjusted 28-day case fatality was greatest in Malay women (62.8%) followed by Indian (49.9%) and Chinese (50.3%) women. 74 The 28-day ACS case fatality was similar between men of all ethnicities ranging from 37.3% to 39.0%. The underlying basis of these differences is multifactorial and involves an interconnected set of biological, cultural, socioeconomic, and behavioral factors. For instance, the rise in tertiary education rates over a decade was highest for Chinese and lowest for Malays in Singapore, which may have contributed indirectly to worse ACS outcomes among the latter ethnic group. 74 Although no studies were found from Africa on ethnic disparities, this issue requires urgent attention as Africa is a multiethnic and multicultural continent, dominated by mainly Whites in the North and part of the South, and mainly Black Africans in the rest of the continent. The diversity in race and socioeconomic outlook of Africa provides an opportunity for a more comprehensive approach to understanding the ACS disparities in the region which can improve outcomes.

To improve outcomes in women, it is important to recognize risk factors that may be specific to women. Besides traditional risk factors, women possess sex-specific risk factors that can significantly add to the sex disparities in ACS. A history of premature menopause (age<40 years), endometriosis, and polycystic ovary syndrome have been associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). 75 , 76 Women who experience pregnancy-related hypertension (OR, 1.7 [95% CI, 1.3–2.2]), preeclampsia (OR, 2.7 [95% CI, 2.5–3.0]), placental abruption (OR, 1.8 [95% CI, 1.4–2.3]), preterm birth (OR, 1.6 [95% CI, 1.4–1.9]), gestational diabetes (OR, 1.7 [95% CI, 1.1–2.5]), and stillbirth (OR, 1.5 [95% CI, 1.1–2.1]) are at increased risk of adverse cardiovascular outcomes. 77 Hypertensive disorders during pregnancy affect about 10% of pregnancies worldwide, are responsible for ≈14% of maternal deaths and are the second leading cause of maternal mortality globally and a major cause of neonatal morbidity. 78 , 79 In a population-based cross-sectional analysis of 10 528 women aged 50 to 65 years in Sweden undergoing screening coronary computed tomographic angiography, women who had a history of preeclampsia or gestational hypertension had a prevalence of atherosclerosis of 36.3% and 40.9%, respectively, compared with 28.3% and 28.3% in those without. 80 The adjusted OR for any coronary atherosclerosis or a stenosis >50% with preeclampsia was 1.31 (95% CI, 1.07–1.61) and 2.21 (95% CI, 1.42–3.44), respectively; 1.33 (95% CI, 1.01–1.74) and 1.83 (95% CI, 1.00–3.33), respectively, for gestational hypertension and 1.80 (95% CI, 1.13–2.87) for a stenosis >50% for a small-for-gestational-age infant. 80 Preeclampsia and gestational hypertension were linked to a greater prevalence of a stenosis > 50% with prevalence ratios of 3.15 (1.90–5.21) and 1.58 (0.59–4.24), respectively, and coronary artery calcium (CAC) >100 with prevalence ratios of 1.81 (1.21–2.72) and 2.74 (1.71–4.37), respectively. 80 No significant associations were found for preterm delivery and gestational diabetes. Endothelial dysfunction is impaired in women with a history of preeclampsia, gestational hypertension, or a small-for-gestational-age infant and is a potential mechanism underlying development of atherosclerosis. 81 , 82 Women with hypertensive disorders during pregnancy are at increased risk of cardiac remodeling 10 years postpartum due to a higher risk of hypertension. 83 Observational evidence suggests that women who experience hypertensive disorders during pregnancy have double the risk of future cardiovascular events compared with women with normotensive pregnancies. 84 , 85 A 2023 large genome-wide genetic association study in female patients predominantly of European ancestry using Mendelian Randomization studied the association between hypertensive disorder of pregnancy (HDPs) and long-term risk of CVD in 122 733 cases for CAD, 34 217 cases for ischemic stroke, 47 309 cases for heart failure, and 60 620 cases for atrial fibrillation. 86 Uncorrelated ( r 2 <0.001) single-nucleotide variants were selected as instrumental variants from the FinnGen consortium summary statistics for exposures of any HDP, gestational hypertension, and preeclampsia or eclampsia. Genetically predicted HDPs were associated with a higher risk of CAD (OR, 1.24 [95% CI, 1.08–1.43]; P=0 .002); this included an association for both gestational hypertension and preeclampsia/eclampsia with ORs of 1.08 (95% CI, 1.00–1.17; P= 0.04) and 1.06 (95% CI, 1.01–1.12; P= 0.03), respectively. 86 The effect estimates were partially reduced when adjusting for systolic blood pressure (total effect OR, 1.24 [95% CI, 1.08–1.43]; direct effect OR, 1.10 [95% CI, 1.02–1.18]; P= 0.02) and type 2 diabetes (total effect OR, 1.24; direct effect OR, 1.16 [95% CI, 1.04–1.29]; P= 0.008), suggesting that these 2 factors partially mediate the association between HDPs and CAD. 86 The findings of this study provide genetic evidence supporting an association between HDPs and higher risk of CAD and stroke, which is only partially mediated by hypertension and type 2 diabetes. Promptly treating those factors is a fundamental tactic for patients with a history of HDP. Clinicians should recognize these conditions as CVD risk enhancers and refer women with a history to preventive cardiology screening. To reduce ASCVD risk, interventions must include intensive lifestyle counseling and possible statin therapy when the anticipated benefits outweigh the risk of adverse events. 87 A recent study reported that merely 58% of women diagnosed with HDP had a follow-up visit with a continuity clinician postpartum. 86 , 88 In a register-based study of 1 157 666 women in Denmark with >1 pregnancy between 1978 and 2017, women who experienced recurrent preeclampsia had 3- and 2-fold higher rates of MI (HR range, 2.90–3.19) and ischemic stroke (HR range, 1.58–2.37), respectively, compared with those who did not experience preeclampsia. Therefore, this represents a high-risk subgroup that would benefit the most from risk assessment and clinical monitoring while still comparatively young. 89 Younger women may also be more likely to have systemic inflammatory disorder (SID), which confers a high risk of MI and cardiovascular mortality. Among 2097 patients aged ≤50 years (median, age 45 years) who experienced a STEMI, 53 (2.5%) possessed a diagnosis of SID distributed as follows: 64% psoriasis, 23% systemic lupus erythematosus, 9% rheumatoid arthritis, and 4% other SID. 90 Patients with SID were more likely to be female (36% versus 19%; P =0.004). Over a median follow-up of 11.2 years, patients with SID experienced a higher risk of all-cause mortality compared with patients without SID (adjusted HR, 1.86 [95% CI, 1.02–3.42]; P =0.044), or a matched cohort based on age, gender, and cardiovascular risk factors (HR, 2.41 [95% CI, 1.04–5.61]; P =0.041), and were less likely to be prescribed guideline-based secondary prevention with aspirin (88% versus 95%; P =0.049) or a statin (76% versus 89%; P =0.008) upon discharge. 90 These results underscore the importance of assessing cardiovascular risk and implementing more aggressive prevention strategies in young women with SID to mitigate the burden of adverse cardiovascular events.