The evolving role of coronary computed tomography in understanding sex differences in coronary atherosclerosis

Abstract

Our understanding of sex differences in subclinical atherosclerosis and plaque composition and characteristics have greatly improved with the use of coronary computed tomography (CCTA) over the past years. CCTA has emerged as an important frontline diagnostic test for women, especially as we continue to understand the impact of non-obstructive atherosclerosis as well as diffuse, high risk plaque as precursors of acute cardiac events in women.

Based on its ability to identify complex plaque morphology such as low attenuation plaque, high risk non calcified plaque, positive remodeling, fibrous cap, CCTA can be used to assess plaque characteristics. CCTA can avoid false positive of other imaging studies, if included earlier in assessment of ischemic symptoms. In the contemporary clinical setting, CCTA will prove useful in further understanding and managing cardiovascular disease in women and those without traditional obstructive coronary disease.

1. Introduction

Despite significant improvement in cardiovascular care over the last 3 decades, cardiovascular disease (CVD) remains the leading cause of death for both women and men in the United States.^1,2 Although awareness related to CVD risk factors for women in the past had been growing, in the last 10 years there has been a decline in the knowledge that CVD remains the leading cause of death in women.³ It is recognized that there are significant sex differences in the pathophysiology of coronary artery disease (CAD) between men and women.⁴ Specifically, women are more likely to have non-obstructive lesions, diffuse disease, lower coronary flow reserve (CFR), and increased arterial stiffness,⁵ demonstrating that heart disease in women is not limited to just the epicardial coronaries, but exists as a spectrum including microvascular dysfunction (MVD) and non-obstructive disease.⁵ These biological differences are noteworthy as CVD events lag approximately 10 years in women compared to men, with approximately 1 in 3 women presenting with CVD after the age of 65.⁶ Additionally, over the past 3 decades, studies have demonstrated that conventional CVD risk factors impact women differently (and generally more adversely) than men and have also identified sex specific risk factors that are unique to or predominant in women.^7–11

Recently there has been an emphasis on use of multimodal imaging to understand the sex differences in clinical manifestations of ischemic heart disease as well as differences in coronary calcium and plaque morphology. Here, we describe sex differences in CAD as we understand them in presentation, risk factors and pathophysiology and how CCTA may spearhead imaging paradigm shifts used for diagnosis and treatment for patients.

2. Clinical manifestation of coronary artery disease

Due to the differences in risks and presentations of CAD in women, their cardiovascular mortality is different from men of similar age. This may be due to many factors including recognition of disease, differing biology, bias, as well as failure of applications and adherence to guideline directed care.

The detailed etiologies, clinical presentations and outcomes of CAD in women are outside the purview of this manuscript; however, the pre-dominating etiologies are outlined in Table 1. The clinical manifestations of CAD in women are varied, and choosing the most appropriate clinical imaging modality in early diagnosis is key to improved management and outcomes.

Table 1.

Clinical etiologies of chest pain in women.

Clinical Etiologies	Clinical Characteristics
Acute Myocardial Infarction 12 Coronary Plaque Disruption Coronary Plaque Erosion	Historically, women have often been under-recognized as having coronary artery disease and classified under “atypical presentations”, thus, the need for recognition for obstructive coronary disease or acute coronary syndromes remains crucial, given the rising mortality in young women. When presenting with ischemic heart disease, chest pain is the most common presenting symptom regardless of gender. However, women presenting with angina are more likely to also present with shortness of breath, palpitations, and fatigue, and they are more likely to present with pulmonary and pedal edema.
Myocardial Infarction in Non-Obstructive Coronary Arteries (MINOCA)13 Coronary causes Spontaneous Coronary Artery Dissection (SCAD) Vasospastic Angina Non-Coronary Causes Takotsubo’s Cardiomyopathy Pulmonary Embolism Stroke Sepsis Myocarditis	MINOCA is found in 1–4% of acute MI cases cases and is more commonly found in women under the age of 50. Patients with MINOCA are more likely to be younger, women, with fewer traditional risk factors such as hyperlipidemia, hypertension, diabetes, smoking, obesity and family history.
Ischemia in Non-Obstructive Coronary Arteries (INOCA)14 Microvascular Dysfunction (MVD) Microvascular Angina Microvascular Spasm Coronary Slow Flow	INOCA encompasses diffuse nonobstructive disease, vasospasm and coronary microvascular dysfunction (CMD). Presence of coronary microvascular or endothelial coronary dysfunction predicts adverse outcomes, and approximately 60–75% of women undergoing coronary angiography for stable IHD have non-obstructive disease, compared to 30–45% of men.

SCAD-spontaneous coronary artery dissection, INOCA-ischemia in non-obstructive coronary arteries, MINOCA-myocardial infarction in non-obstructive coronary arteries, MVD-microvascular dysfunction.

In short, the phenotypes of ischemic chest pain symptoms and CAD in women include presentation of vasospastic angina, coronary endothelial dysfunction, microvascular dysfunction, acute myocardial infarction from plaque erosion or rupture, and the evolving etiologies of myocardial infarction with non-obstructive coronary arteries (MINOCA) as well as ischemia with no obstructive coronary arteries (INOCA).

Although not fully understood, the biological underpinnings that lead to these sex differences in clinical presentations has been hypothesized. Differences in epigenetics, sex chromosomes as well as their hormones and receptors have all been studied as potential explanations of the differences in cardiovascular disease amongst the sexes. Given the later age in presentation of women of MI, estrogen has been hypothesized to play a substantive role in the biological differences, and it has also been found that disruption of the estrogen receptor in men have earlier ischemic heart disease.¹⁵ In men and women extremely low levels of testosterone and estradiol, respectively, has been associated with high rates of ischemic strokes, with this effect terminating post menopause.¹⁶ These results however have been difficult to reproduce given large trials such as the Women’s Health study and the Copenhagen City Heart Study showed no association between estradiol levels with risk of CVD.¹⁷ Further, differential remodeling between men and women has been found and in tissue samples men have higher collagen I and III as well as MMP2 gene expression than women.¹⁸ Differences in the RAS system as well as NO modulate differences in risk factors for IHD such as hypertension in men and women, with women showing sustained EFs yet still demonstrate high risks of developing heart failure.¹⁸ Animal models have found small infarct sizes and improved contractility and compliance after re-perfusion, but have thus far been unable to elucidate that despite this, there remains worsened mortality in young women post MI as compared to men.¹⁸ While some of these biological differences correspond with the clinical findings in sexes, some contradict our clinic findings and thus further investigation of the biological underpinnings, related to chromosomal expression, epigenetics as well as phenotypic expression of these sex related differences is ongoing and needed to understand the mechanisms underlying the differences we will discuss in this paper.

3. Sex differences in risk factors for CAD

Traditional CAD risk factors include older age, smoking, hypertension, hyperlipidemia, obesity, insulin resistance, and a family history of premature atherosclerosis.¹⁹ These factors play important roles in the development of ischemic heart disease (IHD) in both women and men, although the prevalence of certain risk factors differ between the sexes, and some are stronger predictors of IHD in women.^7,10 Further, there are sex specific factors that are unique to women that further increase their risk of cardiac events (Fig. 1).^9,11 Importance of recognition of these risks is highlighted by the fact that 2 of 3 US women have at least 1 major coronary risk factor, and the proportion of women with CVD risk factors only increases with age.¹⁹

Fig. 1.

Traditional and sex-specific risk factors in ischemic heart disease.

3.1. Sex-specific risk factors

The impact of sex-specific risk factors and effects of hormonal changes on CVD in women remains a very complex and highly researched field and has helped lead to the identification of additional female-specific or female-predominant risk factors for CAD and ischemic symptoms: (1) hormonal dysregulation including polycystic ovarian syndrome (PCOS) and early menarche (2) adverse pregnancy outcomes (3) menopause and primary ovarian insufficiency (4) certain autoimmune and inflammatory disorders like lupus and rheumatoid arthritis (5) Female oncologic risk factors as with breast cancer and chemotherapy and (6) depression and stressors related to stress related cardiomyopathies.¹¹

1. Hormone dysregulation: These include early menarche and PCOS. Many studies suggest that age of menarche (both premature age <10 or delayed age >17) increase the relative risk of CHD.²⁰ Premature menopause has also been linked with CHD later in life.²¹ PCOS also has a heterogeneous risk profile and has higher associated rates of traditional risk factors such as hypertension, insulin resistance, dyslipidemia and metabolic syndromes, and some studies have also found higher rates of subclinical atherosclerosis.¹¹ A meta-analysis of 10 cohort studies comparing PCOS to non-PCOS women, showed that the pooled risk of CVD events in PCOS women was higher and so was the risk of myocardial infarction (OR: 2.57, 95% CI: 1.37–4.82), IHD (OR: 2.77, 95% CI: 2.12–3.61), and stroke (OR: 1.96, 95% CI: 1.56–2.47).²²

2. Adverse Pregnancy Outcomes: These are a group of interrelated disorders with common placental etiology caused by oxidative stress, incomplete placentation, and vascular dysfunction. They include hypertensive disorders of pregnancy including gestational hypertension and preeclampsia, gestational diabetes, pre-term delivery and small for gestational age birth.^9,23 These are increasingly been recognized as early indicators of future CVD risk.^9,23,24 Those women who develop hypertensive disorders of pregnancy are anywhere from 2 to 25 times more likely to develop chronic hypertension.²⁵ Whether these pregnancy outcomes are causal in the pathway to development of CVD is unclear and warrants future research.¹⁰

3. Depression: Emotional stress and psychosocial factors disproportionally are present in women and impact women’s ASCVD risk. Furthermore, the link between depression and recent cardiovascular events is well documented though whether it is a risk factor or risk marker remains difficult to assess^26, though in the INTERHEART study, depression was 9% of the attributable risk related to MI^27; Moreover, data from the YOUNG MI registry that explored the risk factors of acute myocardial infarction in young adults, demonstrates that depression is more prevalent in young women than in young men¹²

4. Chronic inflammatory disorders: Systemic lupus erythematosus (SLE), systemic psoriasis, and rheumatoid arthritis, that are more prevalent in women, confer a 2–3 fold increase in MI and CVD mortality which underscore the pathological role of inflammation in atherosclerosis.^28–30 In a meta-analysis of 9 studies, the pooled risk ratio of CAD in patients with SLE was 3.39 (95% CI: 2.15–5.35). An elevated risk of CAD was consistently observed in both sexes but higher in female and male SLE patients [pooled risk ratio: 3.27 (95% CI: 2.01–5.30) and 3.16 (95% CI: 2.02–4.94), respectively.³¹

5. Oncologic Risk factors:. Because of the high prevalence of breast cancer in women and the excellent survival with early stage breast cancer, this is an important CV risk in women. However, the adverse impact of cancer treatment is not limited to breast cancer or to women Traditional and emerging cancer therapies, including hormonal mediated therapies, and breast cancer itself portend increased CVD risks. Further, there is a clear association between both left breast radiation and traditional anthracycline based therapies in the development of cardiomyopathies.³² Additionally many of the risk factors for cancer overlap with traditional cardiac risk factors; thus, those women with cancer actively or previously treated are another target population for those at need for improved cardiovascular screening and care.

6. Premature Menopause and Primary Ovarian Insufficiency: Menopausal changes lead to adverse changes in the lipid profile in women including increased levels of total cholesterol, LDL-C, and triglycerides and decreased levels of high-density lipoprotein cholesterol (HDL-C). In a large cohort study, premature natural and surgical menopause (before age 40 years) were associated with a small but statistically significant increased risk for a composite of CVD among postmenopausal women, hazard ratios of 1.36 (95% CI, 1.19–1.56; P < 0.001) and 1.87 (95% CI, 1.36–2.58; P < 0.001), respectively, after adjustment for conventional cardiovascular disease risk factors and use of menopausal hormone therapy.³³

These sex specific factors remain under-recognized and must be taken into account, in addition to traditional risk factors, when clinicians evaluate and characterize women who may be at risk for cardiovascular events, and institute appropriate preventive therapies.

3.2. Sex differences in traditional risk factors

Traditional coronary artery disease risk factors include 1) smoking, (2) hypertension, (3) dyslipidemia, (4) obesity, (5) diabetes (6) family history of premature atherosclerosis.^19,34

1. Hypertension: Hypertension is more prevalent in women and is associated with two-fold higher mortality for women compared to men and is more strongly associated with MI.^10,35–37 Women generally achieve poorer control of hypertension; in women above the age of 75, almost 80% have hypertension but only 29% of them have adequate blood pressure controlled as compared to 41% of men.³⁸ These higher rates of mortality related to hypertension may be due to the finding that CVD risk is associated with elevations from lower SBP range in women than men, and may indicate a need for sex-specific BP goals to best prevent disease amongst women.³⁹

2. Smoking: Differences in smoking patterns between women and men have decreased, but smoking confers a 25% increased adjusted relative risk of major adverse cardiovascular events (MACE) in women versus men in a meta-analysis of 86 prospective trials encompassing 3.9 million participants.⁴⁰

3. Diabetes: Although the prevalence of diabetes mellitus is similar in women and men, there is a greater excess risk of IHD among women than men with diabetes. It increases the risk of CVD by 3–7 fold in women compared to the 2–3 fold in men; fatal IHD is 2.5 times more common in a diabetic woman than in nondiabetic woman, and is higher than in diabetic men.^41–45 Diabetes also appears to nullify any cardioprotective effects associated with younger age in women. The transition from normoglycemia to overt diabetes in women appears to accompany a greater decline in health than in men; women who develop diabetes have a larger burden of risk factors, including a higher BMI, than men with diabetes.⁴⁶

4. Obesity: Even factors such as obesity and exercise are different in their impact on women. Obesity increases risk for coronary artery disease and myocardial infarction more for women than it does for men (64% in women, compared with only 46% in men), and further, obesity is more prevalent in women in low-middle income nations.^47–49

5. Hyperlipidemia: As discussed previously, changes during menopause and aging in women contribute to the differences in lipid management related to women. Additionally, statins, while clearly reducing cardiovascular risk, when used as secondary prevention, may confer less benefits for women from a mortality stand-point than men.⁵⁰

4. Sex differences in atherosclerotic plaque composition and morphology

Our understanding of the sex differences in coronary atherosclerotic plaque has improved over time. It is recognized that despite having a lower prevalence and volume of coronary atherosclerosis, women tend to have greater symptom burden and a higher rate of functional disability and adverse events following a diagnosis of angiographically significant CAD.⁵¹ In part, understanding the sex differences in plaque morphology and composition may lead to greater understanding of CAD in women,.^52–54

Differences in plaque size and morphology may contribute to differential pathologic presentation of CAD as demonstrated by the finding that younger women presenting with acute MI have more plaque erosion and worse short-term and long-term outcomes than men, while women >65 years of age have increased frequency of plaque rupture and similar outcomes to those of age-matched men.^55,56 Additionally, autopsy studies of patients who died after coronary artery bypass grafting revealed that atherosclerotic plaque in women contained significantly more cellular fibrous tissue compared to men.⁵⁵

Historically, the use of optical coherence tomography (OCT) and intravascular ultrasound (IVUS) on invasive angiography has provided excellent two-dimensional imaging and also helped in plaque characterization by identifying specific plaque morphologies that are associated with increased risk of rupture. OCT analysis has shown that non-culprit coronary plaques in men contain larger lipid cores than those in women, who have a reduced lipid index, but more unstable plaque.^57–61 Women also tend to have fewer non-culprit lesions and smaller luminal area than men in angiography and intravascular ultrasound studies.⁶²

The use of IVUS in ST-segment elevation MI has also shown that women tend to have less extensive CAD, increased rate of plaque erosion as compared to plaque rupture, reduced necrotic core and calcified plaque, and smaller vessel and lumen sizes compared to males.⁶³ Additionally, the Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study, that sought to assess the extent and composition of atherosclerosis on multimodal imaging of culprit lesions contributing to acute coronary syndrome events, further validated that despite having more comorbid risk factors than men, women have less CAD by both angiographic and IVUS measures and have less plaque burden, less necrotic core and calcium, similar plaque burden and smaller lumens.^64,65 These findings are similar in asymptomatic patients with CAD seen on coronary computed tomography angiography (CCTA) during routine health evaluation; women tend to have a lower plaque burden, and more non-calcified plaque than men⁶⁶ while men had more mixed calcified plaque and calcified plaque than women.

Overall, invasive angiographic and non-invasive methods have shown that women have less plaque burden (yet smaller lumens), more plaque erosion especially at younger ages, lower lipid indices, and less calcium.

It is important to recognize the prognostic significance of these sex differences. Essentially, the presence of any plaque increases CVD risk in women more than men and increased plaque burden is associated with major cardiac events in women6.^5,67–69 Further understanding of these pathophysiological differences may lead to better interventions and use of appropriate guideline directed medical therapy aggressively in both sexes to improve their clinical outcomes.

5. Use of coronary CT and noninvasive imaging to evaluate sex differences

CCTA provides accurate non-invasive detection, characterization and quantification of whole-heart coronary atherosclerosis, including identification of high-risk plaque features associated with increased patient risk of future adverse coronary events.^70–72

It is interesting to note the critical role CCTA played in the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial, perhaps underlining its relevance in the evolving field of cardiology since this trial.⁷³ This trial confirmed that women, despite having less severe ischemia than men and less extensive CAD, still had more frequent angina⁷⁴ — findings that reflect inherent sex differences in the complex relationships between angina, atherosclerosis, and ischemia, that indicate the urgency in identifying improving methods to evaluate IHD.^71,72

Recent advances in CCTA imaging not only determine plaque burden but also plaque characteristics noninvasively. They are highlighted in Fig. 2.

Fig. 2. Use of Coronary Computed Tomography in Assessment of Plaque Composition and Characteristics⁷⁵.

CCTA-coronary computed tomography angiography; FFR - fractional flow reserve; MLA - minimal lumen area; Vsub - subtended myocardial mass.

5.1. Sex differences in coronary artery calcifications

Coronary artery calcification (CAC) is a great tool for understanding subclinical atherosclerosis and risk in both sexes.⁷⁶

While the presence of CAC is a risk factor for cardiac events and mortality, its presence and significance varies between sexes.⁵⁵ In multiple studies, women have been found at similar ages and risk factors to have lower CAC scores than men.^77,78 Data from the Multi-Ethnic Study of Atherosclerosis (MESA)(53% women) showed that women had lower scores CAC than men with comparable risk factor levels and ages; 62% of women had calcium scores of 0 as compared with 40% of men, this finding was also illustrated in studies from the CAC consortium^67,77; about 96% of women younger than 55 years of age had a CAC score <100, indicating a large gap in the extent of CAC between the two sexes and also likely reflects the age discrepancy at which women present with their first cardiovascular event.⁷⁷ The lower calcium scores in women is likely in part indicative of the finding that women have more non-calcified plaque than men, indicating that lower CAC scores may be correlated with higher risk plaque⁷⁹

Prognostic Power of CAC in Women:

Although women have lower CAC scores at similar ages, CAC is associated with greater prognostic power in women as compared to men; data from the CAC Consortium shows that the presence of any CAC in asymptomatic women is associated with a 1.3 times increased risk of cardiovascular mortality as compared to the risk in men^67. Additionally, cardiovascular mortality was higher among women with more extensive, numerous, or larger CAC lesions. The relative CVD mortality hazard for women and men was 8.2 vs. 5.1 for multivessel CAC, 8.6 vs. 5.9 for ≥5 CAC lesions, and 8.5 vs. 4.4 for a lesion size ≥15 mm3, respectively. Additional analyses revealed that women with larger sized and more numerous calcified lesions had 2.2-fold higher CVD mortality (P < 0.0001) as compared to men.⁶⁷

CAC can also be prognostic in those with symptomatic but non-obstructive CAD. The Coronary CT Angiography Evaluation For Clinical Outcomes: An International Multicenter (CONFIRM) registry in symptomatic patients showed a CAC ≥ 400 and non-obstructive CAD was associated with a 13-fold increased risk of death^71. In the CONFIRM registry, the presence of non-obstructive CAD on CCTA was associated with worsening mortality and a ~2-fold increased major CAD events, and women older than 60 had a higher risk compared to men in the setting of non-obstructive CAD.⁸⁰

In the Women’s Health Initiative (WHI) Estrogen Alone Trial, a study of post-menopausal women aged 50–59 years, women with any CAC (>0) had rates of myocardial infarction and CAD 2 times higher when compared to women with a CAC score of 0⁸¹. When adjusted for baseline randomization and risk factors, the hazard ratio (95% confidence interval) for CAC >100 (19%) vs CAC = 0? was 4.06 (95% CI 2.11, 7.80) for CVD and 2.70 (95% CI 1.26, 5.79) for mortality.⁸¹ Importantly, regardless of randomization to estrogen versus placebo, the presence of CAC was strongly related to CAD, CVD, and mortality.⁸¹ Thus, a, CAC score is an important precision tool in assessing subclinical atherosclerosis and prognosis and may lead to early risk stratification in both sexes with certain sex-specific risks in women portending worse prognosis in women, who may still be considered low risk for CVD by traditional tools.^78,82

5.2. Coronary CCTA to evaluate sex differences

CCTA can be an important imaging tool to understand differences in the progression in coronary plaque morphology between sexes and may lead to better understanding of CAD in women. The use of CCTA in finding high risk plaque (HRP) has been shown, such as in the Coronary Atherosclerosis in outlier subjects: Protective and novel Individual Risk factors Evaluation (CAPIRE) study, to identify patients at an increased risk of CVD events.⁸³ This study showed that high non-calcified plaque volume was the most ACS-predictive parameter in patients with extensive CAD.⁸⁴ Additionally, CCTA has emerged as a comprehensive evaluation of the location, severity, and characteristics of atherosclerotic plaques, and “vulnerable plaque” along with CAC evaluation.

CCTA can have a role in improving efficiency of systems based care and cost-effective care.⁸³ The Rule Out Myocardial Infarction/Ischemia Using Computer Assisted Tomography (ROMICAT II) trial found that women who undergo CCTA compared with standard cardiac evaluation had less hospital admissions, shorter length of hospital stay, and lower total radiation dose compared with the benefits of CTA in men.⁸⁵

Further, the use of CCTA in assessing total coronary plaque volume, percent atheroma volume (the proportion of total vessel wall volume occupied by atherosclerotic plaque) and/or plaque volume indexed to coronary or patient size provides improved diagnostic and prognostic information. CCTA studies indicate that percent plaque volume may be the more appropriate measure of overall plaque burden and cardiovascular risk in women as this measure considers the amount of plaque as well as the smaller vessel volume often seen in women.^86–88

CCTA has also provided insights into sex differences in plaque progression. Recently, sex differences in plaque composition and progression were explored via the Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging (PARADIGM) Registry and found a slower progression of CAD in women as compared to men with women having a 9-year delay in women developing coronary atherosclerotic burden, documented by reaching a total plaque volume of 100 mm³ being 63 versus 54 years of age, respectively.⁸⁹ In multivariate analysis, after adjusting for age, clinical risk factors, medication use, and total plaque at baseline, despite similar total plaque volume progression rates, female sex was associated with greater calcified plaque volume progression but slower non-calcified plaque progression and less development of high-risk plaques than in men. This study confirmed what is seen clinically and angiographically in both sexes.

In a recent analysis of the Scottish Computed Tomography of the HEART (SCOT-HEART) trial, CT was used to identify low-attenuation (<30 HU) plaque volume in patients with chest pain, which was found to be the strongest predictor of future myocardial infarction, independent of CAC, clinical risk factors, or stenosis severity.⁷⁰ A secondary analysis from the Prospective Multicenter Study of Evaluation of Chest Pain (PROMISE) trial in patients with chest pain symptoms, also showed that HRP features increased the predictive value of CVD events in women (hazard ratio: 2.4, 95% CI1.3–4.6) with a higher prevalence of plaque erosion in younger women and women over the age of 65⁸⁸. HRP was more predictive of future events in women than in men.

These CCTA studies have helped increase utilization of plaque quantification techniques such as total plaque volume and subtyping into non-calcified, calcified, partially calcified, fibrous, fibrofatty, and low attenuation plaque as well as leading machine learning techniques to identify CAD patients early.^62,90–94

5.2.1. Coronary CT and its benefits for non obstructive coronary disease

CCTA can have a role in the assessment and evaluation of non-plaque related CAD. There are 4 criteria needed for diagnosis of microvascular dysfunction (MVD), according to current society consensus documents: (1) symptoms of myocardial ischemia, (2) absence of obstructive CAD (<50% stenosis on catheterization or coronary CTA), (3) objective evidence of myocardial ischemia, and (4) evidence of impaired coronary microvascular function.^95,96 Of note, MVD can also occur simultaneously with obstructive and non-obstructive CAD and the ischemic symptoms in the absence of significant luminal stenosis (>50%) is INOCA. Diagnosis of these syndromes due to our reliance on conventional methods such as SPECT, stress echocardiography and ETT leads to underdiagnoses of INOCA and MVD in women.

The Women’s Ischemia Syndrome Evaluation (WISE) study highlighted the important relationship of non-obstructive CAD, which is more commonly found in women compared with men, perhaps further indicating that MVD may be more prevalent than previously recognized.⁹⁷ This phenomenon of MVD may partly explain why women have more favorable plaque characteristics, including reduced lumen in non-culprit lesions, but show worse clinical outcomes.^98,99 In the CIAO-Ischemia trial, patients who were excluded from the ISCHEMIA trial due to non obstructive coronary disease were enrolled and monitored for a year. The percentage of patients who had non obstructive disease were predominantly women, and compared to those in ISCHEMIA (with obstructive disease) were found to have more frequent angina.¹⁰⁰

CCTA is a central test in the diagnosis of coronary MVD based on its ability to accurately exclude obstructive coronary artery disease in patients with suspected INOCA. Studies have shown that a significantly higher proportion of women are sent for invasive coronary angiography based on abnormal functional test for ischemia, yet are found to have nonobstructive disease.¹⁰¹ As demonstrated in the Coronary Computed Tomographic Angiography for Selective Cardiac Catheterization (CONSERVE trial), coronary CTA is ideally suited to rule out obstructive CAD in women who may have INOCA, as well as identifying patients with prognostically-important non-obstructive CAD.¹⁰²

In the ongoing Women’s IschemiA TRial to Reduce Events In Non-ObstRuctive CAD (WARRIOR NCT03417388) trial, CCTA is an important test in enrollment as women with non-obstructive disease but symptoms concerning for ischemia are randomized to aggressive risk management versus usual care.^103,104

5.3. Sex differences in computed tomography derived fractional flow reserve (FFR-_CT)

Cardiac CT may further be utilized by using FFR_-CT in improving diagnosis. Whether FFR_CT improves sex-based patient management decisions compared to CCTA alone was explored recently.

A study by Fairburn et al. in the Assessing Diagnostic Value of Noninvasive FFR_CT in Coronary Care (ADVANCE) registry determine the management and clinical outcomes of patients investigated with FFR_CT according to sex, showed that FFR_CT differs between the sexes, as women have a higher FFR_CT for the same degree of stenosis.¹⁰⁵

Fairbairn et al. also evaluated coronary vessel volume (V), myocardial mass (M), and the ratio between these two values and showed that women have a higher V/M ratio (26.17 ± 7.58 mm3/g vs. 24.76 ± 7.22 mm3/g; p < 0.0001) as compared to men that is associated with higher FFR_CT independent of degree stenosis (p < 0.001) and lower rates of revascularization.¹⁰⁵ A novel finding of women having a lower myocardial mass and smaller coronary vessels with higher V/M ratio. Women had less obstructive CAD as compared to men (65.4% vs. 74.7%; p < 0.0001) at CCTA, higher FFR_CT (0.76 ± 0.10 vs. 0.73 ± 0.10; p < 0.0001), and lower likelihood of positive FFR_CT ≤ 0.80 for the same degree stenosis (p < 0.0001). Fairbairn et al. showed that the V/M ratio decreased with an increasing burden of coronary plaque and predicted FFR_CT <0.8; thus, considering the difference of V/M ratio may be secondary to a lower plaque burden.^106,107 This suggests that CAD and FFR_CT variations may need specific interpretation by sex as they affect therapeutic decision making and clinical outcomes.

As FFR_CT advances and becomes more widely validated and accepted in clinical practice, it may improve diagnostic accuracy and discrimination of ischemia between the sexes as compared to other noninvasive imaging strategies. However, current guidelines have no sex-specific guidance as to which imaging test is preferable and recommend a pre-test CVD likelihood stratification before deciding upon a test strategy.

Based on the extensive data published over the last decade, we have summarized the evolving role of CCTA in assessment of CAD and the various studies that have improved our understanding of these sex differences in Table 2.

Table 2.

Studies highlighting the sex differences in coronary calcium and plaque characteristics.

Study	Year	n=	Women (%)	Key Findings in Women Compared to Men
STUDIES OF CCTA IN ASYMPTOMATIC PATIENTS
Multi-Ethnic Study of Atherosclerosis (MESA) a 55	2006	6110	3251 (53%)	Lower CAC Scores (p < 0.0001) Different percentiles for the same CAC score i.e.90th percentile of CAC in Women = 1200 AU compared to 4000 AU in men 62% of women have calcium scores of 0, compared to 40% men
Coronary CT Angiography Evaluation For Clinical Outcomes: An International Multicenter Registry (CONFIRM) a 108	2014	7200	3795 (52.7%)a	Relative hazard ratio for all cause mortality was 3.33 (95% CI 2.07–5.35) for patients with luminal stenosis vs without stenosis Women >60 years higher risk compared to with non-obstructive CAD CAC ≥400 HU and non-obstructive CAD was associated with a 10x increased mortality (p < 0.0001) aHR for mortality with a CAC score ≥400HU was 2.14 (95% CI 2.06–8.10, P < 0.0001)
Coronary Artery Calcium (CAC) Consortium67 a	2018	63,215	20,508 (32.4%)	Women had lower CAC scores (p < 0.0001), greater lesion size (p < 0.0001) and higher plaque density (p = 0.013) Cardiovascular mortality was higher among women with more extensive, numerous, or larger CAC lesions.
STUDIES OF CCTA IN SYMPTOMATIC PATIENTS
Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) 64	2011	697	167 (24%)	Women more like to have MACE with nonculprit lesions 13.2% vs 11.8% (HR 1.17 [0.70, 1.95] p 0.55) Less CAD by angiography/IVUS Less plaque burden Less necrotic core and calcium
Rule Out Myocardial Infarction/Ischemia Using Computer Assisted Tomography (ROMICATII) 109	2012	1000	480 (48%)	CCTA was more effective at ruling out CAD (p < 0.0001) Less obstructive coronary disease by CCTA (5% versus 17%; p < 0.0001) CCTA led to shorter ER stay and lower admission rates
Prospective Multicenter Study of Evaluation of Chest Pain (PROMISE) a 88	2018a	4415a	2283a (51.7%a)	High-risk plaque was a stronger predictor of MACE (aHR, 2.41; 95% CI, 1.25–4.64 p < 0.001) High-risk plaque 10.9% for women vs 20.1% for men (P < 0.001)
Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging (PARADIGM)110	2020	1255	543 (42.3%)	Higher prevalence of plaque erosion in younger women and women over the age of 65 years Higher total cholesterol levels (195 ± 41 mg/dl vs. 187 ± 39 mg/dl; p = 0.002) Less total Plaque Volume (31.3 mm3 vs. 56.7 mm3 p = 0.005) 9-year delay in developing total plaque volume Prevalence of high-risk plaques was lesser (20% vs. 31%; p < 0.001) Greater calcified plaque volume progression (β = 2.83; p = 0.004)
Scottish Computed Tomography of the HEART (SCOT-HEART) a 111	2020a	1769a	772a (44%)a	Low-attenuation plaque volume is the strongest predictor of future MI (hazard ratio, 4.65; 95% CI, 2.06–10.5; P < 0.001) Low-attenuation plaque burden correlated strongly with coronary artery calcium score (r = 0.62; P < 0.001)
Assessing Diagnostic Value of Noninvasive FFRCT in Coronary Care (ADVANCE) 105	2020	4737	1603 (33.8%)	Less obstructive CAD (65.4% vs. 74.7%; p < 0.0001) Higher FFRCT for the same degree of stenosis (0.76 ± 0.10 vs. 0.73 ± 0.10; p < 0.0001) Lower likelihood of positive FFRCT for the same degree stenosis (p < 0.0001) Lower myocardial mass and smaller coronary vessels with higher Vessel Volume/Mass ratio (p < 0.0001)
International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) a 74	2020a	8518a	2262a (23%)a	More likely to have non obstructive CAD 34.4% vs 11.3% (p < 0.001) More angina at baseline (p < 0.001) Less severe ischemia on stress imaging 41.7% vs 45.9% (p < 0.001) Less extensive CAD on CCTA 36% vs 47% (p < 0.001) Independently associated with greater angina frequency (OR, 1.41; 95% CI, 1.13–1.76)

HU- Hounsfield Units, CCTA- Coronary Computed Tomography, CI- Confidence Intervals, HR- Hazard Ratio, Odds Ratio-OR, aHR- Adjusted Hazard Ratio.

^aSecondary Analysis.

5.4. Diagnosing myocardial ischemia with functional imaging

There remain many options of imaging modalities to appropriately diagnose and risk stratify women’s cardiovascular disease. We briefly discuss the benefits and limitations of other multimodality imaging.

Exercise testing is still the most cost-effective way to assess functional capacity; however, diagnostic accuracy of the exercise ECG for obstructive CAD was decidedly lower in women than men^112–114 with lower specificity in women compared to men^115. Further, women generally have worse functional capacity, engage less often in physical exercise programs, have more functional decline as compared to age-matched men and are at increased risk of a CVD event if they achieve <5METS.^113,116,117

Comparatively, stress echocardiography and myocardial perfusion single photon emission computed tomography (SPECT) have improved diagnostic and prognostic accuracy. Stress echocardiography is useful in evaluating wall motion abnormalities, in younger or low risk women capable of exercising, with a high diagnostic accuracy (sensitivity = 79% and specificity = 83%) in women.^115,118 Sensitivity and specificity for SPECT is comparable for women as compared to men,¹¹⁸ and women with a normal SPECT have a very low (0.6%/year) event rate in contrast to those with an abnormal SPECT (5%/year).^83,119,120 However, there are some limitations with reduced sensitivity and specificity in multivessel disease or microvascular disease, limited resolution due to a smaller heart, breast attenuation, and radiation exposure, which might make it a less utilized test in women given better diagnostic modalities.

Stress CMR is a high resolution technique without radiation for women with smaller hearts and breast attenuation on alternative studies, with a sensitivity and specificity of 84% and 88% for women.^121–123 Another meta-analysis of stress CMR myocardial perfusion with adenosine and dobutamine reported a sensitivity of 83% and specificity of 86% in both men and women with a higher sensitivity in women 88.7%.^123–125 A semi-qualitative approach of myocardial perfusion reserve index (MPRI) can be seen on CMR in patients with INOCA.^126–129

Novel CT therapies such as CT perfusion imaging (CTP), extracellular volume (ECV), LV mass quantification,¹³⁰ and CT LV strain¹³¹ may augment the information provided by CCTA alone with addition of physiological measure of the significance of a coronary artery stenosis, early myocardial dysfunction, and infiltration and fibrosis.¹³² Limited recent studies in CTP have shown that a combined CCTA-CTP strategy improved the specificity of CCTA alone from 61% to 81% with a diagnostic accuracy comparable to other stress imaging modalities.^133–135 A recent study showed a possible sex disparity with the discrimination of ischemia in women with the use of CTP (AUC, 0.92 for CCTA-CTP versus 0.83 for CCTA alone for women) (AUC, 0.92 for CCTA-CTP versus 0.83 for CCTA alone for women).¹³⁶ A combined CCTA-CTP approach is also associated with a higher rate of detection of CAD and those with a class I indication of revascularization.¹³⁷ The CRESCENT II trial demonstrated a combined approach to achieve a diagnosis faster and potentially remove the need for additional noninvasive testing.¹³⁸ Although additional clinical data including prognostic information is needed, in the era of personalized medicine approaches, these techniques represent another step forward in the evaluation of CAD.

Thus, due to anatomic differences, and differences in pathophysiology, it is important for clinicians to recognize limitations and potential future breakthroughs related to functional imaging in diagnostic IHD in women.

5.5. Comparison of CCTA with other modalities

Several recent trials have compared CCTA versus ETT showing similar CVD outcomes, leading one to conclude that CCTA may be a favorable option in determining prognosis in low to intermediate risk women.^139,140 In the Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) study, as compared to men, women were significantly more likely to have a positive functional study (predominately SPECT imaging) as compared to coronary CTA (11.5% versus 7.9%, respectively), yet disease severity on coronary CTA was significantly more predictive of adverse events as compared to an abnormal functional study in women, as compared to men.¹⁴¹ Further, the recent Computed TomogRaphic Evaluation of Atherosclerotic DEtermiNants of Myocardial IsChEmia (CREDENCE) Trial found that a comprehensive anatomic CCTA analysis that includes plaque volume and high risk plaque features was superior to nuclear stress MPI and FFR_CT for detection of invasive FFR ≤ 0.80¹⁴²

The sex differences in multimodal imaging is summarized in Fig. 3.

Fig. 3.

Characteristics of female sex in cardiac testing.

5.5.1. Functional testing includes FFR_CT

In summary, the strengths and limitations of the different modalities to assess ischemic heart disease are heighted in Table 3. Here we compare and ETT, stress echocardiography, SPECT, CCTA and FFR_CT, PET-CFR and Stress CMR.

Table 3.

Differences in Multimodality Imaging and their Assessment of Coronary Atherosclerosis.

	Exercise stress testing	Stress echocardiography	SPECT	Coronary CTA & FFRCT	PET-CFR	Stress CMR
Methodological strengths	Low cost Little post-processing analysis Relatively fast to perform	Real time and low cost assessment of functional and myocardial function Portable Velocity and M-mode No ionizing radiation Relatively fast to perform	Evaluate physiological functions-perfusion, metabolism, contractility	High Spatial resolution over SPECT Calcium evaluation Lumen evaluation Relatively fast to perform	Improved resolution spatial resolution over SPECT Attenuation correction algorithms Evaluate physiological functions-perfusion, metabolism, contractility Coronary Flow Reserve evaluation Calcium Score Evaluation	Improved Temporal resolution Assessment of Biventricular function Improved Tissue characterization with Late gadolinium enhancement and T1 and T2 mapping No ionizing radiation
Clinical strengths	Can assess Exercise capacity Arrhythmia evaluation	Evaluation of wall motion abnormalities Valve disease assessment Diastolic Heart Failure assessment Septal defects can be identified	Long-term prognostic data	High sensitivity for detection and quantification of coronary atherosclerosis and stenosis. Identifies non-obstructive CAD and high-risk plaque features. Evaluation of the pericardium and non-cardiac structures (lung fields, aorta).	Ischemia (epicardial and microvascular) Viability evaluation Evaluation of extra-cardiac pathology	Ischemia (epicardial and microvascular) Scar evaluation Extra-coronary evaluation including pericardium and infiltrative processes
Methodological limitations	Limited by patient’s physical capacity	Limited windows. Increased artifacts related to body habitus Poor windows in lung disease Limited tissue characterization given time constraint. Operator dependent	Breast attenuation Increased artifacts related to body habitus Ionizing radiation	Increased ionizing radiation Increased artifacts related to body habitus	Increased ionizing radiation Time consuming Expensive Limited Access to PET centers.	Time consuming Expensive Limited access to MRI centers. Claustrophobia Image quality in setting of arrhythmia or breath holding
Clinical weaknesses	Poor diagnostic accuracy Unable to evaluate coronary arteries	Limited evaluation of RV Unable to evaluate coronary arteries	Unable to evaluate coronary arteries	Limited use in advanced CKD due to iodinated contrast. Often requires medications to lower heart rate. Increased cost for performance of FFRCT	Unable to evaluate coronary artery plaque and lumen	Unable to evaluate plaque in coronary arteries Limited use in CKD

CAD-coronary artery disease, SPECT-single photon emission computed tomography, CTA-computed tomography angiography, CT-FFR-computed tomography fractional flow reserve, RV- right ventricle, PET-positron emission tomography, PET- CFR-positron emission tomography coronary flow reserve, CMR-cardiovascular magnetic resonance, MRI- magnetic resonance imaging, CKD-chronic kidney disease.

6. Conclusions

Despite the increased research on sex differences and several calls for more thorough examination of clinical detection and care gaps, there remains a paucity of understanding of cardiovascular disease in women.

There is still need for increased recognition of what drives heart disease in women including, traditional ischemic risk factors as well as sex specific risk factors. Despite the increasing recognition that ischemic heart disease is more than our traditional understanding of obstructive coronary disease, further understanding of these differences in coronary artery calcification, plaque morphology and plaque composition, may lead to better management of patients, specifically women.

The use of multi-modal imaging techniques can help in both understanding the differences in pathology, as well as diagnosis and treatment. CT as demonstrated in so many of the studies discussed here, presents itself as a very useful test in understanding the sex differences in plaque in women with symptoms of CAD based on its ability to identify low attenuation plaque, positive remodeling, fibrous cap and avoid false positive imaging studies considering the limitations of other imaging modalities. In the post-ISCHEMIA trial setting, as the field re-examines who is a candidate for revascularization, coronary CTA may prove to be a very useful non-invasive tool for the clinician.

Although at this time, it remains unclear if differences in plaque morphology should be treated differently, more research is needed in order to fully understand these differences and their clinical implications. Future research exploring the novel CT techniques such as shear stress, LV mass assessment and strain might further explain the sex differences in CVD.

Future guidelines should take into account sex differences and CT guided adjustments may improve management and prognostication for our patients. While research and guidelines continue to evolve, ongoing improved awareness of differential risks, pathologies, prognostic power of tests, and response to therapies is needed to better treat women and enhance our use of CT and multimodal imaging to better treat IHD.

Abbreviations

AHA

American Heart Association

ACC

American College of Cardiology

ASCVD

Atherosclerotic coronary vascular disease

CAC

Coronary Artery Calcium

CAD

Coronary Artery Disease

CCTA

Coronary computed tomographic angiography

CFR Coronary

Flow Reserve

CVD

Coronary Vascular Disease

CMR

Cardiac Magnetic Resonance

DTS

Duke Treadmill Score

ETT

Exercise Treadmill Testing

FFR

Fractional Flow Reserve

FFRct

Computed tomography fractional flow reserve

IHD

Ischemic heart disease

IVUS

Intravascular Ultrasound

MRI

Magnetic Resonance Imaging

MVD

Microvascular Dysfunction

OCT

Optical Coherence Tomography

SPECT

single photon emission computed tomography