Coronary artery disease (CAD) is a significant health issue in the United States. Siddiqui and colleagues recently published a manuscript titled “Gender disparities in coronary artery disease: a review of factors influencing clinical outcomes,” which excellently describes the current state of affairs and outcomes of CAD between men and women [1]. It is important to recognize that while men and women share common cardiovascular risk factors such as diabetes, hyperlipidemia and obesity, each of these risk factors have more severe consequences in women compared to men [2]. However, the presence of estrogen is a critical turning point in cardiovascular disease. Estrogen plays a critical role in halting atherosclerotic progression. This hormone works by downregulating both the renin-angiotensin-aldosterone system (RAAS) and fibrinolytic pathways. Both pathways will eventually lead to hypertension and CAD if left unchecked [3]. In menopause, the sudden decrease in estrogen unleashes these harmful pathways, which not only catalyze the progression of CAD but also worsens weight gain and hyperlipidemia [3]. Ultimately, leading to worsening cardiovascular outcomes at earlier ages. Furthermore, estrogen has antioxidant characteristics that mitigate free radial damage to the endothelium [4]. The hormone also contributes to distribution of body fat, in menopause there is an increased risk of abdominal obesity which predisposes to insulin resistance and later DM [4,5]. In addition to estrogen, women also are predisposed to irregularities in sirtuin expression [6]. Sirtuins is a family of seven proteins involved in critical physiologic and aging functions such as cellular homeostasis, cellular metabolism, DNA damage, and senescence [6]. When expressed normally, Sirtuins are protective against cardiovascular disease [6]. Sirtuin1 is an important protein with anti-aging properties, cell circadian rhythm, and cell apoptosis [6,7]. There is a push to explore this protein thanks to its anti-aging characteristics [7]. It also plays a key part in nitric oxide homeostasis and epigenetic regulation. Sirtuin1 influences the expression of p53, immune regulation and glucose metabolism [7,8]. As such its dysregulation is linked to the development of diabetes, neurodegenerative disorders such as Parkinson’s Disease and Alzheimer’s Disease, non-alcoholic fatty liver disease, and autoimmune disorders [8]. However, especially in pregnancy, decreased expression of sirtuin1 is believed to contribute to the pathophysiology of preeclampsia as defects in sirtuin2, 3, and 4 are found to be present [6]. Following this discovery, sirtuin activating compounds and nicotinic adenine dinucleotide (NAD) boosters are being explored as potential therapeutic agents for the treatment of various cardiovascular diseases [6]. To date, the sirtuin activating agent resveratrol has shown promise in increasing sirtuin1 activity and preventing abnormal cardiac remodeling in those with hypertension [9]. Moreover, adverse pregnancy outcomes (APO) encompassing preeclampsia, gestational DM, and pre-term delivery are increasingly becoming acknowledged as perpetrators of CAD. While not evident in the short run, APOs were found to have contributed to downstream cardiovascular disease decades after the last pregnancy and delivery [10,11]. Siddiqui and colleges make an interesting point in highlighting non-traditional risk factors for cardiovascular disease. Among the not well recognized, depression and intimate partner violence are both significant risk factors for the development of CAD. While they do not directly cause cardiovascular disease, these conditions lead to chronic stress, which can manifest as somatic symptoms through autonomic dysregulation and predispose the victim to unhealthy and maladaptive lifestyle choices [12–14]. Expanding on this topic, post-traumatic stress disorder (PTSD) was shown to expedite the development of cardiovascular disease through autonomic dysregulation. The prevalence of PTSD is 10-12% in women and 5-6% in men [15]. Exposure to chronic stress alters the hypothalamic-pituitary-adrenal axis as well as the autonomic nervous system, leading to elevated levels of catecholamines, which in turn elevate basal heart rate and blood pressure [16]. Anxiety disorders were also studied in their association with cardiovascular disease. A meta-analysis conducted by Emdin et al. found that anxiety will increase the risk of CAD by 41% and stroke by 71% [17]. Overall, anxiety disorders in conjunction with depression ought to be better recognized as important risk factors for cardiovascular disease [18].

Furthermore, women are especially at higher risk of complications and death due to coronary artery disease. In acute coronary syndromes (ACS) such as MI manifesting as a ST-elevation MI (STEMI) or non-ST-elevation MI (NSTEMI), women were found to have non-conventional symptoms of ACS [19,20]. While chest pain and shortness of breath are both ubiquitous symptoms, women can have nausea, vomiting, fatigue, dizziness, and syncope [19,20]. Pain is often found in the jaw, interscapular region, or neck [19,20]. Due to the under recognition of atypical symptoms manifesting as MI, women are less likely to receive fibrinolytic therapy, percutaneous coronary intervention (PCI), or both compared to men [21]. Similarly, women are less likely to achieve a timely door-to-balloon time [22]. In the last two decades, trends in the incidence of myocardial infarction (MI) have remained similar for men; on the other hand, women were noted to have an increasing incidence of MI starting at earlier ages [23]. Compared to men, women were found to have more focal CAD compared to men [24]. With physiologic equivocal lesions based on fractional flow reserve (FFR), women reported frequent angina and worse quality of life compared to men [24]. Spontaneous coronary artery dissection (SCAD) is the separation of the intimal layers of the coronary artery without significant trauma or pre-existing atherosclerosis. Despite accounting for 1–4% of ACS events, 90% of the patients with SCAD are women [25]. SCAD does not have the traditional or atypical risk factors found in both sexes. Typically, SCAD is associated with emotional stressors, changes in hormone concentrations and connective tissue disease [25]. These differences are not unique to Western nations. In a Saudi Arabian study, unstable angina is more likely to be diagnosed in women and men had higher rates of STEMI compared to women. Women had less left anterior descending artery occlusion incidence compared to men [26]. Medical therapy was pursued more often in women and women also received less interventions. Elsewhere, women who present with STEMI had higher rates of stroke, in hospital and out of hospital mortality after undergoing percutaneous intervention (PCI) in a Singaporeon center [27].

Apart from ACS, women who present with chest pain should also be evaluated for non-obstructive CAD/coronary microvascular dysfunction (CMD). CMD is defined as anginal symptoms without significant coronary artery disease on angiography. As 50% of women who undergo coronary angiograms for angina symptoms will have normal findings, CMD is an important diagnosis to consider in this population [28]. Angina due to non-obstructive CAD is often attributed to coronary vasospasms, hypercoagulable state, and oxidative stress [28]. As a result, these patients with non-obstructive CAD can have symptoms at rest, not determined by their excursion. APOs, systemic inflammatory syndromes (such as autoimmune disorders), and prior chemotherapy for breast cancer are all unique risk factors for the development of CMD in women [28]. While the sex-difference of CMD is not well elucidated, experts postulate that the loss of estrogen catalyzes the loss of healthy endothelium [29]. Therefore, to better understand and risk-stratify women, it is imperative to have a comprehensive history and physical that thoroughly explores each unique risk factor women can have. Traditional stenosis-style approaches to risk stratification of CAD often lead to the underdiagnosis and delayed/poor treatment of these women [30]. Furthermore, risk stratification calculators such as the Framingham Risk Score fail to account for these unique risk factors [30].

Medical management of these diseases is the same as men, anti-anginal regimens consisting of beta-blockers, calcium channel blockers, and nicorandil. Additionally, risk factor-specific therapies such as angiotensin-converting enzyme inhibitors (ACEi) and statins are beneficial. However, studies have shown that women are less frequently prescribed statins, beta-blockers, and ACEi [31,32]. Once rejected, hormone replacement therapy (HRT) is now being re-evaluated for potential cardiovascular benefit. Recent studies demonstrate that the initiation of HRT within 10 years of menopause can mitigate the risk of cardiovascular disease [33]. Clear benefit was seen in those 50–59; however, experts warn that HRT can increase cardiovascular risk in those older than 70 and should be used with caution in women ages 60–69 [34].

As mentioned by Siddiqui and colleges, it is concerning that gender disparities exist in research. In the early clinical trials investigating ACS and CAD, women were underrepresented which hinders the generalizability of these trials [1]. Experts found that socioeconomic determinants of health including education, capital, and race are all contributing factors to this problem [1,2]. Even in the outpatient setting, women were found to delay seeking medical help [35]. They are less likely to be prescribed cardioprotective medications and undergo invasive interventions for the evaluation and treatment of CAD [2,35,36]. Black women, especially, suffer a higher cardiovascular disease burden compared to their white counterparts. To address these issues, one intervention being one within hospitals is the AHA’s Get With the Guidelines initiative (GWTG) [37]. This movement incorporates a multidisciplinary team to educate clinicians on better guideline-based practices to reduce variability amongst the treated populations [37]. Other interventions include sex-sensitive data gathering for clinical trials, all-female intervention teams and routine domestic violence screening [38]. However, policies aimed to directly intervene on gender disparities have been slow to implement. The difficulty of the creation and enforcement of these interventions are attributed to lack of political commitment, deep-seated gender norms, lack of awareness and lack of funding [38,39].

One limitation of this piece is there is a lack of recent research on the effectiveness of implementation programs or interventions designed to reduce gender disparities. While Siddiqui et al. mention programs to spread awareness, hormone replacement therapy and even the use of artificial intelligence (AI) as potential solutions, these interventions have little evidence supporting their efficacy. As such, discussion on solutions is limited, and for now remains theoretical.

Overall, the problem of reducing disparities between men and women remains an elusive challenge. Future research and efforts should focus on increasing female representation in clinical research and on incorporating female-specific risk factors, such as psychosocial history, menses, and socioeconomic status, into the risk stratification calculus. Therefore, a multidisciplinary approach (including both medical and political perspectives) is required not only to address this disparity but also to raise awareness of the problem among physicians.

None.