Difference of Coronary Artery Disease in Women and Men in Recent T rials

Pathophysiology and risk factors

Men are more likely to have obstructive CAD characterized by large calcified plaque formation in coronary arteries. Women, on the other hand, more frequently experience non-obstructive CAD, such as microvascular dysfunction and coronary artery spasms, which can lead to ischemia without significant plaque buildup, spontaneous coronary artery dissection and Takotsubo cardiomyopathy. In men, plaques are typically more calcified and larger, with a greater likelihood of causing severe blockages and acute coronary events like heart attacks. Women’s plaques are often smaller and more lipid-rich, and their vessel walls can be more prone to erosion rather than rupture [Figure 1]. Women exhibit more intense inflammatory responses, with higher levels of inflammatory markers like C-reactive protein. This can contribute to increased vascular damage and plaque instability.^[3,4] The women’s ischemia syndrome evaluation study is a landmark investigation initiated by the national heart, lung, and blood institute emphasized the importance of evaluating ischemia in women beyond obstructive CAD, challenging the assumption that non-obstructive CAD is benign.^[5]

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Figure 1:

Gender difference in pathology of atherosclerotic plaque

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The study “Sex differences in the genetic and molecular mechanisms of CAD” by Sakkers et al. explores how genetic and molecular factors contribute to differences in CAD between men and women. It highlights that women may have distinct genetic risk factors and molecular pathways influencing CAD progression.^[6]

Sex-specific risk factors have also been identified. Testosterone, prevalent in men, has complex effects. While some studies suggest it may have protective roles in heart health, it is also associated with higher Low-density lipoprotein (bad cholesterol) levels, which contribute to plaque formation. Pre-menopausal women have higher estrogen levels, which are thought to provide a protective effect by maintaining the flexibility and function of the endothelial cells (cells lining blood vessels) and enhancing vasodilation. After menopause, when estrogen levels drop, women become more vulnerable to CAD.^[7,8] The heart and estrogen/progestin replacement study (HERS) was a pivotal randomized controlled trial concluded that Hormone replacement therapy (HRT) with estrogen and progestin did not provide cardiovascular benefits for secondary prevention in postmenopausal women with CAD and posed significant risks of thromboembolic events.^[9] The HERS study, along with subsequent trials like the Women’s Health Initiative (WHI),^[10] has been instrumental in reshaping recommendations for HRT, highlighting the importance of weighing risks versus benefits.

A meta-analysis revealed that women with a history of preeclampsia face a twofold increase in cardiovascular disease risk, including CAD, even decades after pregnancy. Similarly, women with Gestational diaabetes mellitus (GDM) have a heightened risk of CAD and other cardiovascular complications later in life, with risk persisting up to 25 years postpartum.^[8,11-13]

An editorial in frontiers in cardiovascular medicine (2023) discussed how chronic psychosocial stress can differentially affect men and women, contributing to CAD pathophysiology.^[1] Studies have highlighted several psychosocial stressors that uniquely affect women, including job strain, stressful life events, and social strain. For example, the WHI observational study found that high-stress life events, such as the loss of a spouse or experiences of abuse, were linked to a 12% increased risk of developing CAD. Similarly, social strain was associated with a 9% higher risk, and a combination of job and social strain led to a 21% increased risk of CAD in women.^[14,15]

Clinical presentation

Men typically present with “classic” symptoms of CAD, such as chest pain, while women often have atypical symptoms, including fatigue, shortness of breath, and nausea. Stress and emotional factors might impact women with CAD more profoundly, potentially triggering symptoms.^[16,17] This can lead to symptom underreporting, as symptoms might be misinterpreted as stress or anxiety rather than CAD. As a result, CAD in women is more frequently misdiagnosed or diagnosed later in the disease process.^[18-21]

The American College of Cardiology (2021) reviewed the clinical implications of these sex differences, noting that while men typically have obstructive CAD with larger plaque burdens, women often have non-obstructive disease, which can complicate diagnosis and treatment.

The Motivational Interviewing to Support Oral Anticoagulation in Atrial Fibrillation (MISOAC-AF) sub-study investigates sex-related differences in clinical outcomes in patients with atrial fibrillation and CAD. It reveals that women experience worse outcomes, particularly in thromboembolic events and cardiovascular mortality, compared to men.^[22]

The study “Sex Differences in CAD: Insights From the KoRean wOmen’s chest pain rEgistry” explores sex-based disparities in CAD. It highlights that postmenopausal women experience a sharp increase in cardiovascular risk, primarily due to the decline in estrogen, which protects against cardiovascular issues. Women with CAD are typically older and have more cardiovascular risk factors than men. The study also notes that women are diagnosed later, as their symptoms tend to be more atypical. Furthermore, while inhospital outcomes may be similar between sexes, women face more frequent bleeding complications after procedures like percutaneous coronary interventions (PCIs).^[23]

Diagnostic and imaging tools

A study by Awesat et al. highlights the unique challenges in diagnosing and managing acute coronary syndromes in women. These include delays in diagnosis, under-recognition of symptoms, and gender biases in treatment protocols.^[24] Recent trials have shown that women are less likely to undergo invasive diagnostic procedures such as coronary angiography.^[21,25,26] There is also a considerable delay in arriving at a diagnosis due to atypical symptoms.^[27] Non-invasive imaging techniques, like coronary computed tomography angiography (CCTA) and stress echocardiography, are becoming more popular, especially for detecting microvascular disease and non-obstructive CAD in women. Women may have a higher rate of false negatives in exercise stress tests due to smaller heart size and differences in cardiac response.^[28]

The prospective multicenter imaging study for evaluation of chest Pain trial that investigated the effectiveness of anatomical testing using CCTA versus functional testing methods like exercise electrocardiography and nuclear stress testing indicated that women had distinct demographic and clinical characteristics.^[29]

Treatment

Recent studies have highlighted the differences in response to pharmacotherapy, such as statins and antiplatelet therapy. Women may have a lower response to certain doses of statins and may experience more side effects, leading to lower adherence. On the other hand, both genders benefit from Angiotension converting enzyme (ACE) inhibitors and beta-blockers, though women may require dose adjustments based on body weight and kidney function.^[30] A subgroup analysis of Ticagrelor With aspIrin or aLone In hiGH risk patients after coronary inTervention (TWILIGT) trial, also established that women had higher bleeding risk compared to men on continuing ticagrelor with aspiring post PCI, hence suggests early withdrawal of aspirin post procedure.^[31]

Studies also highlight that women tend to have worse outcomes after certain interventions, such as PCI^[32] and coronary artery bypass grafting (CABG). Women undergoing CABG generally experience higher mortality rates and complications compared to men, especially in the early postoperative period. This may be due to smaller vessel size, greater prevalence of comorbidities like diabetes and hypertension, and delayed diagnosis. However, long-term survival rates for women after CABG can be similar to men, particularly when advanced surgical techniques, such as off-pump CABG, are utilized.^[33,34] Another study by Kim et al. (2024) investigates the impact of body mass index (BMI) on CAD and post PCI outcomes, focusing on sex differences in a Korean population. It found that BMI influenced CAD outcomes differently in men and women, with women showing a more complex relationship involving other metabolic and hormonal factors. High visceral fat was particularly associated with worse outcomes in women.^[35] Women undergoing revascularization may have worse short-term outcomes (e.g., higher risk of bleeding, complications) but similar long-term mortality benefits compared to men. A recent study by in Kang et al., highlighted that even post-menopausal women may experience worse outcomes.^[36]

In contrast, men often benefit more from traditional therapies like stents or medication due to their more prevalent obstructive disease patterns.

Women are under-referred to cardiac rehabilitation and less likely to complete programs, which may be linked to caregiving roles or underestimation of their cardiac risk. Studies highlight the need for tailored rehabilitation programs for women, addressing psychosocial factors and specific health concerns like anxiety and depression, which are more common in women post-CAD.^[37]

Increased awareness and education

Educating healthcare providers about the gender-specific presentation of CAD is crucial. Training clinicians to recognize these differences can lead to earlier diagnosis and intervention.^[38] The European society of cardiology has called for increased public awareness campaigns specifically targeting women’s cardiovascular health. Efforts to increase adherence to treatment and improve illness perception through tools like the illness perception questionnaire have also been beneficial in enhancing women’s engagement with their own cardiovascular health.^[37]

Gender-specific diagnostic tools

Since women are more likely to experience non-obstructive CAD and microvascular dysfunction, the American college of cardiology advocates diagnostic tools like coronary flow reserve assessment, cardiac magnetic resonance imaging, and CCTA which offers more accurate detection of CAD in women without the risk of certain diagnostic artifacts that can affect women’s imaging results.^[39]

Inclusion of women in clinical trials

Women have been often underrepresented in cardiovascular research, which limits the generalizability of trial outcomes to female patients. Globally, women comprise only around 34% of participants in CAD-related trials, which is notably below their proportion in the affected population. Factors contributing to this disparity include stringent enrollment criteria, gender bias in referrals, and the perception of CAD as a primarily male disease. These barriers lead to lower screening rates and enrollment for women compared to men. Encouraging greater participation of women in clinical trials helps ensure that the data reflects sex-specific responses to treatments and interventions. This will improve the development of tailored therapies for women.^[40]

Personalized treatment approaches

Given the differences in CAD pathophysiology between men and women, treatment strategies should be personalized. For example, women may benefit more from therapies targeting microvascular dysfunction, while men typically respond better to therapies for obstructive disease. Efforts to address women’s unique CAD experiences have led to studies like the WARRIOR trial, which aims to find effective treatments for non-obstructive CAD.^[41]

Public health campaigns and screening programs

Raising public awareness about the risk of heart disease in women through health campaigns can help overcome misconceptions that CAD is primarily a male disease. Screening initiatives like the WISEWOMAN program have been pivotal. This program, managed by the CDC, focuses on screening underserved and low-income women and connecting participants to community resources for lifestyle support, which has demonstrated improved health outcomes for women at elevated risk of CAD. India is tackling CAD in women through initiatives like the population-based screening program under Ayushman Bharat. Healthcare workers, especially Accredited social health activist (ASHAs), are trained to support rural and low-income women. Awareness campaigns, often in partnership with WHO, educate women on unique CAD risks and preventive measures tailored to South Asian lifestyles.^[42] Encouraging early screenings and regular heart health checkups for women, especially post-menopause, is essential in reducing gender disparities.

Improving access to care

Barriers to healthcare access, including socioeconomic factors and geographic disparities, disproportionately affect women. Ensuring equal access to high-quality cardiovascular care, particularly for underserved populations, can improve outcomes by promoting earlier diagnosis and appropriate treatments.