Emerging misunderstood presentations of cardiovascular disease in young women

Background Cardiovascular disease (CVD) remains the leading cause of death for females in the United States accounting for over 412 000 female deaths in 2016. CVD mortality in young women <55 years old remains significantly high and greater than that in men. Hypothesis There is a void with regards to awareness of CVD in women. Many traditional CVD risk estimate tools fail to identify the “at risk” female and is true for the young female patient. There needs to be a shift in focus from looking for the vulnerable plaque to looking for the “at risk” patient. Methods This review outlines the emerging misunderstood presentations of CVD in young women which include certain categories of myocardial infarction (MI) with non‐obstructive coronary arteries (MINOCA), such as spontaneous coronary artery dissection (SCAD), as well as the more stable myocardial ischemia with non‐obstructive coronary arteries (INOCA) category focusing on mental stress‐induced myocardial ischemia (MSIMI). Results The prevalence of MINOCA in patients presenting with MI is greater in women. In younger women with CVD, SCAD is an emerging misunderstood presentation in this group of patients with type 2 SCAD being the most common form. MSIMI, a form of INOCA, is more common in women with CVD. Conclusions There are emerging misunderstood factors that are prevalent in young women, such as SCAD and MSIMI. It is important to recognize their presentations in young women to prevent misdiagnosis, missed diagnosis as well as mismanagement of these patients to improve their clinical outcomes.


| INTRODUCTION AND SIGNIFICANCE
Cardiovascular disease (CVD) remains the leading cause of death for females in the United States, accounting for over 412 000 female deaths in 2016. 1 CVD is not just a man's disease, an equal number of women and men die from CVD each year in the United States (US) 1 ).
Until recently, there was a higher CVD mortality in women compared to men. Despite this, there is still a need to increase awareness of CVD in women since only approximately half of women in the United States recognize heart disease as the leading cause of death in women and is greater than that of all cancers combined. 1 Furthermore, CVD mortality in young women (<55 years of age) remains significantly high and remains greater than that in men. 2 The latest heart disease and stroke statistics-2019 update indicates that while there has been a decline in CVD related mortality in older female patients, there has been relative stagnation in coronary heart disease (CHD) mortality in young women over the last decade. 1 In addition, the atherosclerotic cardiovascular disease (ASCVD) risk burden is greater in young women compared to men and the hospitalization rate for young women with ASCVD disease is lower than that in similar-aged men. 2 This higher mortality rate with lower hospitalization rate for young women with CVD suggests that many of these women die prior to reaching the hospital. In addition, even after treatment of their initial cardiac event, the rehospitalization rate for women with CVD disease after acute myocardial infarction (MI) is higher than that in men. 3 There is a significant void with regards to awareness of CVD in women for both the public and also the medical profession. The presence of this void was showed by a survey performed by the Women's Heart Alliance in 2017. 4 This study showed that only 45% of women are aware of CVD being the leading cause of death. In addition, only 22% of primary care providers and only 42% of cardiologists felt well prepared to assess the CVD risk of their female patients. There is therefore a need to educate physicians in the assessment of CVD risk in women, particularly in young women as CVD mortality in this group remains high. 4 In addition, many of the traditional ASCVD risk estimate tools fail to identify the "at risk" female 5 and this is particularly true for the young female patient. There needs to be a shift in focus from looking for the vulnerable plaque to looking for the "at risk" patient. In addition, there have been emerging misunderstood presentations of CVD in young women which include certain categories of MI with nonobstructive coronary arteries (MINOCA), such as spontaneous coronary artery dissection (SCAD), as well as certain categories of ischemia with non-obstructive coronary arteries (INOCA), such as mental stress-induced myocardial ischemia (MSIMI) which will be outlined in this article.  12 In view of this, myocarditis will be briefly discussed.
However, in younger women with CVD, SCAD has become an emerging presentation in this group of patients and is still a somewhat misunderstood form of MINOCA and will therefore be focused on in this review. Although half of these patients will have resolution of their presentation in a 2-4 week period, up to 25% of these patients will acutely decompensate to fulminant heart failure. This is particularly true for giant cell myocarditis. Cardiac magnetic resonance imaging (CMR) should be one of the initial tests performed in cases of suspected myocarditis. CMR has been reported to be able to detect 79% of endomyocardial biopsy (EMB) proven myocarditis. 13 The value of EMB is that it allows the underlying cause of myocarditis to be determined. Treatment of myocarditis particularly patients with ventricular dysfunction includes the use of beta blockers and angiotensinconverting enzyme inhibitors (ACE-I). 14 Immunosuppression is useful in the treatment of EMB has proven infection negative autoimmune  women accounting for 24% of MI. 16 Several other series have reported that SCAD is more prevalent with SCAD being the etiology for as much as 35% of ACS cases in young women aged <50 years of age. 17 SCAD is also the most common cause of pregnancy-associated MI accounting for as much as 43% of these cases. These findings highlight the fact that many cases of SCAD are either missed or misdiagnosed. These patients are therefore oftentimes mismanaged leading to worse outcomes. The average age of affected women ranges from 45 to 53 years of age and occurs predominantly in Caucasian women compared to other ethnic groups. 17 There are three types of SCAD: Type 1 SCAD has the pathognomonic contrast dye staining of the arterial wall with multiple radiolucent lumen with or without the presence of dye hang-up or decreased contrast clearing from the lumen. Type 2 SCAD is diffuse and usually involves a long segment of the vessel typically greater than 20 mm in length and usually has a smooth narrowing that can vary in severity from an inconspicuous mild stenosis to complete occlusion. There is an appreciable oftentimes subtle but abrupt decrease in arterial caliber with a demarcation from normal diameter to diffuse narrowing in which either of the following is present:  18 Although the pathognomonic contrast dye staining of the coronary artery seen in type 1 SCAD is the main perceived association with SCAD, this is not the most common form of SCAD as this type accounts for only a third of SCAD cases. 15 In fact, type 2 SCAD is the most common form and accounts for approximately 63% of SCAD cases. 15 The most common coronary artery involved is the left anterior descending (LAD) and diagonal branches (45%-61%), followed by the left circumflex and obtuse marginal branches (15%-45%), then the right coronary artery (10%-39%) with rare involvement of the left main coronary artery (4%). 17 SCAD usually involves the mid and distal segment rather than the proximal segment which occurs in <10% of SCAD cases. 17 The clinical features that should raise the suspicion for SCAD include the presence of particular demographic factors, predisposing  Table 2. 15,19,20 Women with SCAD present with ACS with the majority presenting as ST elevation MI (STEMI) or non-ST elevation MI (NSTEMI), but 2% to 5% present in cardiogenic shock. 17 An early invasive strategy with invasive coronary angiography is the recommended strategy for SCAD patients. There should be a high index of suspicion for SCAD in young women presenting with ACS as oftentimes if this diagnosis is missed and therefore mis-managed with a non-invasive strategy outcomes in these women are poor. Once coronary angiography is performed, if type 2 or type 3 SCAD is suspected OCT or IVUS should be performed to better define the intracoronary true/false lumen, intramural hematoma, and the site of intimal tear. 21 OCT has a better resolution at 10 to 20 μm vs IVUS with a lower resolution of (150-200 μm). 22 However, IVUS has better penetration with visualization of the full vessel extent of the hematoma vs OCT with poorer penetration which limits the visualization of this full extent. 22 Therefore, combined use of OCT and IVUS is recommended. 17,22 For cases of type 2 SCAD, intracoronary nitroglycerin should be administered to rule out vasospasm. 21 Unlike atherosclerotic CAD, the optimal management of SCAD is undetermined because of lack of randomized trials comparing medical therapies and revascularization strategies. In addition, guideline-directed medical therapies used for ACS have not been studied specifically in SCAD. Therefore, the current suggestions for the manage- stents may also be considered as a temporary scaffold to avoid long-  CTA of the head and neck is also recommended to screen for cerebrovascular FMD and intracranial aneurysms which is seen in 14% to 25% of SCAD patients. 21 Ongoing management of SCAD patients is important to decrease the risk of recurrence. Medical therapy includes adequate blood pressure control, use of a beta-blocker could also be considered. . 21 ACE-I/ARB, DAPT, aspirin, and statins may be considered in cases where these are recommended for non-SCAD-related indications as discussed previously. Nitrates have not shown any beneficial effect in SCAD patients. 17 However, it may be useful as an antianginal agent for patients with chest pain in whom coronary artery obstruction has been ruled out. 23 Enrollment in cardiac rehabilitation is important with supervised graded exercise that avoids lifting weights greater than 20 lbs. To reduce arterial shear stress, target exercise heart rate (HR) to 50% to 70% of HR reserve on the basis of the entrance exercise treadmill test and systolic BP during exercise is limited to <130 mm Hg during this exercise program. 26 Cardiac rehab has been associated with lower long-term major adverse cardiac events (MACE) events. 21 Psychosocial support is also important with counseling and peer group support. 16 Recurrent pregnancy should be avoided in those where this occurred during pregnancy. 21 Long-term systemic estrogen and/or progesterone contraceptives or hormone replacement therapy should be avoided. 17 Coronary CTA is not recommended as a first-line imaging test for SCAD because of the lower spatial resolution. However, it may be useful as an alternative to invasive angiography to reassess the large proximal to mid-arteries with SCAD to assess for arterial healing.

| Mental stress-induced myocardial ischemia
There is a significant interplay between emotional stress and CVD, this interplay is most predominant in young women (<50 years of age) with CVD. [29][30][31] MSIMI is more common in women with CVD (obstructive and non-obstructive). 29,30 In addition, compared to men with CVD, women with CVD are more likely to have MSIMI and the presence of MSIMI confers a worse outcome in this group of women compared to their male counterparts with a 2-fold higher risk of future cardiac events independent of physical stress-induced ischemia in patient with stable CVD. 29 It has also been shown that MSIMI post-MI is more common in women 50 years or younger compared with similarly aged men. 32,33 However, these sex differences are not observed in post-MI patients older than 50 years of age. 32 Microvascular dysfunction and peripheral vasoconstriction occurring with mental stress are thought to be the underlying cause of MSIMI among women but not in men. 29 This is possibly associated with women's propensity towards having ischemia because of underlying microcirculation abnormalities 29 Figure 2.  35 It has been more recently shown through the use of a novel mental stress protocol (Figure 3) that myocardial ischemia induced by mental stress occurs through a different mechanism of action when compared to ischemia induced by exercise or vasodilatory pharmacologic stress testing. Therefore, standard exercise or pharmacologic stress testing may not adequately assess the likelihood of occurrence or severity of MSIMI. 31,36 It has also been shown that MSIMI is more likely to occur in a single coronary artery territory distribution on SPECT imaging compared with exercise or pharmacologic stress-induced ischemia. 36 MSIMI is often missed on exercise or pharmacologic myocardial perfusion stress testing and often requires a mental stress test to be performed to illicit ischemia on myocardial perfusion imaging. 31,37 The degree of microvascular constriction is directly associated with the FIGURE 2 Pathophysiology of mental stress-induced myocardial ischemia. Diagram outlining the underlying mechanism of mental stress-induced myocardial ischemia FIGURE 3 Mental stress test protocol-public speaking task. At rest the patient is initially rested in a dark and quiet room for 30 minutes while their heart rate (HR) and blood pressure are measured every 5 minutes using an electrocardiographic (ECG) monitor and automatic oscillometric device, respectively. Mental stress is induced through public speaking task on an assigned topic describing a stressful real life event. The speech is performed in front of a small audience, and the patient is given 2 minutes to prepare their speech and 3 minutes to speak. The patients are also told that their speech would be videotaped and later rated for content, quality and duration. Hemodynamic measurements are obtained at 1 minute intervals during the preparation and during the speech periods. Technetium-99 m (Tc-99 m) radiotracer injection (20-30 mCi) is administered at 1 minute into the speech, which is 3 minutes into the stress period. Hemodynamic measurements were obtained at 1, 3, 5, and 10 minutes into the recovery period. Systolic blood pressure (SBP) and HR are used to calculate the double product (DP) value (DP = SBP × HR). Stress test is performed as a 2 day stress-rest study. Post-stress images acquired 30 to 60 minutes post-radiotracer injection. The rest images is obtained within 1 week of the stress test degree of MSIMI and this is independent of the angiographic burden of CAD. 31 This concept of mental stress testing has also been studied in echocardiography. Impaired resting myocardial annular velocities on echocardiography have been found to be independently associated with mental-stress-induced ischemia in patients with coronary heart disease. 38 In view of these findings of MSIMI in women with CVD, it is important that women with CVD are given the psychosocial support necessary to minimize life stressors. They should also be taught coping mechanisms so that they can change their reaction to these stressors as well. With regards to diagnostic testing, the studies outlined above suggest that mental stress testing is an underutilized resource. This underutilization may be as a result of lack of awareness and knowledge of mental stress testing protocols. The mental stress test protocol with a public speaking task outlined by Hassan et al. 36 Figure 3 appears to be a reproducible protocol that could be adopted in labs in an effort to make the diagnosis of MSIMI. This should especially be considered in young women (<50 years of age) with ASCVD and angina in whom exercise or pharmacologic stress testing have been normal and new obstructive epicardial CAD has been ruled out.

| CONCLUSION
CVD remains the leading cause of death among women in the United States and the mortality is particularly higher in younger women with this disease. There are several misunderstood emerging factors that are prevalent in young women, such as SCAD and MSIMI. It is important to recognize the presentations of these disease entities in young women to prevent misdiagnosis, missed diagnosis as well as mismanagement of these patients to improve their clinical outcomes.