Vascular Disease in Women: An Overview of the Literature and Treatment Recommendations

By Caitlin Hicks and Linda Harris

Vascular Disease in Women highlights the epidemiology, natural history and treatment of vascular disease, specifically as it pertains to women. The book provides a thorough overview of what is known and waht is now known about vascular disease in women and highlights opportunities for further education and research on this topic. The book will serve as an essential reference for both clinicians and researchers, discussing the disease prevalence, treatment options, and treatment outcomes for vascular disease in women and explores the need for future research in vascular disease specifically as it pertains to women.

• Provides a comprehensive overview of vascular disease as it affects women
• Includes contributions from world-renowned vascular surgeons of both genders, who have a vested interest in women’s vascular health
• Covers what is known and not known about vascular disease in women, prompting further research in the area for what is still unknown

• Language: English
• Publisher: Academic Press
• Release date: Jul 16, 2021
• ISBN: 9780128231050

Book preview

Introduction

The majority of literature published about vascular disease focuses on men. However, we frequently hear at major meetings and through reading journal articles that women do worse with many vascular disease processes or interventions. Similarly, the majority of research studies throughout the years, whether basic science or clinical research, have also focused on men (or male animal models) as the subject of the investigation, making conclusions about women more difficult.

We have begun to realize that disease presentation, progression, outcomes with and without intervention, and disease processes may not be the same between the sexes. This book emanated out of a Women’s Vascular Health Summit that Dr. Harris originally organized in Buffalo, NY in the spring of 2018 to begin to address these issues. To effect change, we first need to determine what we currently do understand and where the gaps in knowledge remain.

The purpose of this book is to highlight the epidemiology, natural history, and treatment of various vascular diseases specifically because they pertain to women. Once we are able to understand the differences in the disease processes between sexes, we may be able to improve outcomes for women with vascular diseases in the future.

Section 1

Thoracic aortic disease

Chapter 1a: Thoracic aortic disease in women: Sex disparities in etiology, presentation, and outcomes

Dimitra Lotakisa; Kaspar Trochaa; Pallavi Manvar-Singhb    a Department of Surgery, New York Medical College at Metropolitan Hospital Center, Valhalla, NY, United States

b Division of Vascular and Endovascular Surgery, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States

Abstract

Multiple studies have observed statistically significant differences among men and women regarding thoracic aortic disease. Women presenting with acute aortic dissection present at an older age than men may present without typical onset of severe pain and are more likely to present with congestive heart failure and/or altered mental status. Women are also more likely to present for medical evaluation in a delayed fashion. In-hospital mortality, hemodynamic instability, and cardiac tamponade occur at higher frequency in women with aortic dissection. Female sex was also predictive for long-term death in chronic type B dissection. Female thoracic aortic aneurysm patients present at an older age with COPD, and the presence of concomitant thoracic and abdominal aortic aneurysms is observed more commonly in female patients. Women unequivocally present differently than men with thoracic aortic disease. These disparities must be studied to generate sex-specific screening and surveillance protocols for women.

Keywords

Sex bias; Sex disparity; Thoracic; Aorta; Female; Women; Dissection; Aneurysm

Chapter Outline

Introduction

Epidemiology

Thoracic aortic aneurysms

Aortic dissection

Natural history

Thoracic aortic aneurysms

Aortic dissection

Anatomic considerations

Sex disparities in aortic pathophysiology

Future considerations in screening and diagnosis

References

Introduction

The spectrum of aneurysmal diseases of the aorta includes thoracic aortic aneurysm (TAA), thoracoabdominal aortic aneurysm (TAAA), and abdominal aortic aneurysm (AAA). According to the Center for Disease Control, aortic aneurysms were the cause of 9928 deaths in 2017. About 60% of deaths due to aortic aneurysm or aortic dissection occur among men. Thus the US Preventative Task Force has provided recommendations for aortic screening in men [1]. Although multiple published studies demonstrate that female patients have a higher ratio of emergent aortic aneurysm repair, with higher mortality rates and longer length of stay after both elective and emergency repair, there are presently no evidence-based screening guidelines in place for women [2,3]. Historically, management guidelines, clinical research, and biomedical innovation have been largely based upon preceding studies that overlooked sex as a potential independent or confounding variable.

When considering disease prevalence after stratifying for sex, noteworthy differences are often uncovered between male and female subjects in a population. This sex disparity in research has drawn attention over the past three decades, causing the scientific community to acknowledge underrepresentation of women in published studies. The National Institutes of Health (NIH) Revitalization Act of 1993, titled Women and Minorities as Subjects in Clinical Research, mandated inclusion of women and minorities as subjects in research [4]. In 2009, Hoel et al. published a retrospective review of randomized controlled trials (RCTs) in vascular surgery from 1983 to 2007. The researchers concluded that minority, ethnicity, and female sex continue to remain underreported in vascular surgery RCTs [4]. Sex disparities must be critically examined because they directly affect the relative strength of clinical evidence and its application to the general population.

Initial understanding of cardiac and vascular diagnoses was predominantly based on data generated from male subject groups. Since then, multiple published studies have demonstrated statistically significant differences in outcomes among men and women regarding coronary, cardiovascular, and aortic diseases [5]. Because research efforts and sample sizes have grown, subsequent subgroup analyses revealed unequivocal sex-based disparities. For example, the presentation of acute coronary syndrome (ACS) is known to vary with the age of a patient, but female genetics and physiology likely contribute to atypical symptoms associated with ACS [6]. When considering the severity in presentation of women, it is not surprising that approximately 35% of all female mortalities are because of cardiovascular diseases (CVDs) [7]. An uncommon presentation of any disease, including cardiovascular or vascular, may result in a delay in diagnosis and treatment, which can ultimately lead to poor outcomes.

Our understanding of abdominal aortic aneurysmal disease dramatically improved throughout the end of the 20th century. However, to date, there has been little research regarding sex in thoracic aortic disease. Data regarding aneurysms of the abdominal aorta were initially extrapolated and used to guide management of thoracic aneurysmal disease. Certain thoracic aortic diseases are more prevalent in women, such as aortic dissection in Turner’s syndrome, aneurysms in Takayasu arteritis, and aneurysmal disease in Marfan syndrome. However, data obtained from these study groups are not broadly applicable to the female population at large [8–10]. Illustrating how women present differently than men may encourage future interest in creating evidence-based, sex-specific screening protocols for thoracic aortic diseases.

Epidemiology

Thoracic aortic aneurysms

Epidemiologic data and studies have consistently demonstrated that a greater proportion of men are afflicted with aortic disease when compared with women. While TAAs (Fig. 1) are more prevalent in men, a higher proportion of women are affected by TAAs compared with AAAs. Current studies indicate a male to female ratio of 1.7:1 in thoracic aneurysms, with an increasing incidence in the female population over time [11]. A much higher proportion of males are diagnosed with abdominal aneurysms, at a 5:1 ratio observed in published data [12]. Further analysis examining age at initial diagnosis suggest women present at a significantly later age than men. Clouse et al. demonstrated that women were diagnosed most commonly within the sixth to seventh decade of life. These data have since been supported in subsequent publications [13,14].

Fig. 1

Fig. 1 Thoracic aortic aneurysm in a 76-year-old female.

Despite having equal or decreased rates of hypertension, smoking, and chronic obstructive pulmonary disease (COPD), female subjects have a two- to threefold higher incidence of atherosclerotic aneurysmal disease versus chronic dissection [15–17]. A similar finding is not observed in the male population, in which the incidences between the two groups are nearly equal. Women are also more likely to be symptomatic at presentation with TAA and to have a nonelective procedure [18]. This sex bias gives rise to questions regarding the potential mechanisms in observed disease patterns. Advanced age at presentation and propensity for degenerative aneurysms in women is likely a result of decreased estrogen levels and its effect on the elastic properties of arterial walls. The precise mechanism remains poorly understood. Diagnosis at a later age may also be associated with a lack of aortic screening and surveillance protocols for women. What has been shown with consistency is that despite TAAs being more prevalent in men, its prognosis in women is worse. Therefore early detection, surveillance, and treatment are paramount to improving outcomes in women.

Additional observations of female-specific disease patterns are pertinent in the rate of concomitant thoracic and abdominal aneurysmal diseases. In a 2012 study published by Hultgren et al., 39% of women diagnosed with abdominal aneurysms were found to have concurrent thoracic aneurysms. This rate was far greater than the 16% of males with similar concomitant pathologies [14]. Since the study was published, additional research has substantiated these findings [19,20]. Currently, there are no evidence-based guidelines for screening of the thoracic aorta for women with a known AAA.

Aortic dissection

The Stanford classification divides aortic dissection into two groups: Type A and Type B. Type A involves the ascending aorta and aortic arch. (Fig. 2) Type B affects the descending aorta distal to the origin of the left subclavian artery. Published data from the early 21st century reported a consistent 2:1 ratio in Stanford Type A and Type B dissections, which remained significant even when stratified by sex [17]. More recent studies have documented an increased prevalence of thoracic dissections within the female population compared with past studies. Clouse et al. reported female sex as an independent risk factor for developing a dissection in the setting of thoracic aneurysmal disease [13]. In addition, symptoms present at the time of diagnosis, as well as advanced age at diagnosis, were documented as independent risk factors for dissection. Diagnosing thoracic aneurysms in women has advanced within the past decade, and similarly, diagnosis of thoracic aortic dissection has also improved.

Fig. 2

Fig. 2 Type A aortic dissection in a 92-year-old female.

Early research involving aortic dissection was conducted by examining patients with preexisting or concomitantly diagnosed degenerative aneurysmal disease. These efforts revealed uncontrolled hypertension and advanced age as the primary risk factors for developing acute dissections [21–23]. Continued efforts revealed the presence of aneurysmal disease as a significant contributor to overall risk of dissection [24]. Intimate associations between various inherited syndromes and aortic dissection have also been documented, such as Turner syndrome, Marfan syndrome, and bicuspid aortic valves, which will subsequently be discussed further. The increasing incidence of acute dissection in the female population highlights a critical need for research efforts and sex-specific recommendations.

Natural history

Thoracic aortic aneurysms

To fully understand the patterns and presentations of thoracic aortic aneurysmal disease, an understanding of its natural history must first be explained. Growth of AAAs progress at faster rates in females. Thoracic aortic aneurysm growth rates are also greater in women, notably with degenerative aneurysms [25]. Furthermore, factors that affect aneurysm anatomy and its susceptibility to rupture include aortic tortuosity, stiffness, and diameter to body surface area (BSA) ratio, and they are modified by age and sex [18,26]. Aortic tortuosity and stiffness increase with advancing age and decreasing estrogen levels. Aortic diameter to BSA ratio is a biologic factor determining aortic size and is lower in females compared with males [27]. Increased rupture rates in women may be attributed to these variable anatomic characteristics.

Clouse et al. documented a staggering 33% rupture rate at 5 years in women with degenerative thoracic aneurysmal disease, specifically without documented dissection, compared with only 9% in men. About 79% of all patients who experienced rupture were female, with female sex an independent predictor of rupture with relative risk (RR) 4.91. Symptoms at diagnosis (RR 3.25) and subsequent dissection (RR 15.75) were also independent predictors of rupture. These initial findings are supported by subsequent studies documenting a threefold increased rate of rupture in women [28]. The increased aneurysm growth rate found in female patients is important because it highlights the need for rigorous surveillance in these patients. Current surveillance guidelines, derived primarily for men, might not be applicable to the female population, and elective repair may be required at a smaller size in women. This would require further investigation. In addition, if female sex is an independent predictor of rupture, then this would support the need for revised future guidelines based on sex-specific studies.

Based on data examining the initial symptoms of women with AAAs, it is well understood that atypical presentations are far more common because symptoms are based on studies of men primarily. Women are also documented to have worse comorbid conditions at the time of diagnosis [17]. More recent publications were able to reproduce these findings in women with TAAs. These observations are likely secondary to differences in screening patterns as well as disease pathophysiology. In a 2010 study from Shah et al., women were more likely to be diagnosed at the time of rupture [29] and at an older age, with a higher incidence of severe COPD [15]. Research has also revealed significantly lower rates of earlier vascular and cardiac interventions in women before presenting with aneurysmal disease [30].

A substantial amount of data is available in the literature about overall morbidity and mortality, long-term survival, and rates of intervention in thoracic aortic disease. These studies have exposed an alarmingly high rate of overall mortality in the female population with TAAs. Overall prognosis is poor, and female sex has been documented as an independent risk factor for increased 30-day mortality and decreased long-term survival. An early study reported 5-year survival at only 56%, irrespective of sex. Further stratification revealed cause of death most likely secondary to aneurysm rupture (30%), followed by cardiac events (25%), and less likely pulmonary causes, cancer, and stroke (15%, 10%, 4%, respectively) [13]. Saeyeldin et al. reported up to 21% of female subjects experienced demise in their home and were unable to be transported to a care facility for treatment. A 40% risk of mortality was seen in the female population in a 2017 study by Cheung et al. In addition, women have been found to have decreased 5-year event-free survival [27].

Early research examining operative intervention for thoracic aneurysmal disease yielded striking outcomes. A 2004 study by Leurs et al. indicated a 28% mortality rate for emergent repairs of thoracic aneurysms, compared with 5% seen in elective procedures, irrespective of sex. Further investigation in the subsequent decade began to stratify based on sex. Initial reports from smaller studies showed increased hospital length of stay, transfusion rates, adverse events, vascular access complications, and utilization of iliac procedures in the female population [31,32]. Arnaoutakis et al. reproduced these relationships and reported an increased mortality rate in women versus men (6% versus 3%) in the setting of elective repair of nonruptured aneurysms [30]. One of the largest retrospective studies, using data from the Society for Vascular Surgery Vascular Quality Initiative (SVS-VQI), was published in 2017 by Deery et al., which again demonstrated increased transfusion rates and utilization of iliac procedures in women [18]. These data also supported the relationship between female sex and increased perioperative 30-day mortality (5.4% versus 3.3%), which increased with 1 year (9.8% versus 6.3%) [18].

Aortic dissection

While the incidence of aortic dissection diagnosed in women has increased in the past century, currently, less than 50% of total dissections occur in the women. Unfortunately, despite experiencing dissection less frequently, women suffer worse outcomes. In 2004 the International Registry of Acute Aortic Dissection (IRAD) study was published evaluating sex-related differences in acute aortic dissection (32% women). The study documented delayed time to diagnosis in female subjects, delayed presentation to the hospital, as well as increased time to diagnosis after presentation. A sex difference in presentation of an average of 5 h was noted, with men presenting earlier than women [17]. Further analysis revealed 26% of women were diagnosed within 4 h of presentation, similar to the male population. However, 40% of women were diagnosed over 24 h after presentation, whereas only 30% of men had delayed diagnosis. In the same study, women were older than men at presentation (49.7% of women >  70 years of age versus 28.6% of men, P < .001). Women were also less likely to present with abrupt onset of chest pain [17]. In addition, women with Type A dissection more commonly presented with congestive heart failure, coma, altered mental status, coronary artery dissection, pleural effusion, presence of periaortic hematoma, and pericardial effusions, which reflects their delay in seeking treatment. The 2004 IRAD study additionally demonstrated acute aortic dissections in women were more frequently managed with medical therapy alone compared with men, yet women were less likely to be given immediate intravenous beta-blocker therapy. These findings are significant because atypical symptoms may delay correct diagnosis and treatment, thereby negatively impacting patient outcomes.

Studies have consistently demonstrated worse outcomes in women diagnosed with thoracic aortic dissection, specifically citing female sex as a predictor of adverse events. Mortality rates have been reported at 40%, with an additional mortality rate of 1% per hour following initial diagnosis [5]. When stratified by sex, women suffer as high as 30% mortality compared with 21% in their male counterparts [17]. Liang et al. examined short-term outcomes of patients with acute Type B dissections and similar baseline characteristics to those patients included in the 2004 IRAD study (Table 1). While nonoperative management was the predominant treatment strategy for all comers (84.2%), subgroup analysis by sex revealed female patients as the majority within the nonoperative group (87.4% versus 81.8%) [16]. It is unclear whether advanced age, delay to presentation, other comorbid conditions, or an inherent sex-related bias in the management of aortic dissection contributes to an increased mortality of female patients.

Table 1

Despite overall mortality and rates of medical management being more prominent in the female population on aggregate data analysis, recent studies have demonstrated favorable outcomes in women who undergo operative intervention for aortic dissection. Fukui et al. specifically investigated outcomes in patients undergoing operative repair for Stanford Type A dissections and showed no significant difference in less than 30-day operative mortality and 5-year survival rates. These data demonstrated that female sex was not an independent predictor of early or long-term operative mortality [33]. More recent data have corroborated these findings documenting no significant difference in intraoperative mortality, 30-day mortality, and long-term overall survival [34,35]. When considering Stanford Type B dissections, Liang et al. established a higher rate of operative intervention in the male population (18.2% versus 12.6%) [16]. Further subgroup analysis showed no difference in mortality for men and women undergoing open repair. More compelling was the decreased overall mortality seen in the female patients undergoing endovascular repair (7.3% versus 11.4%) [16]. Additional research is necessary to understand why women underwent less operative intervention.

Anatomic considerations

The aorta is divided into five segments: root (includes aortic valve annulus, aortic valve cusps, and sinuses of Valsalva), arch, ascending aorta, descending aorta, and abdominal aorta. Normal aortic diameter is based on the modality of images being measured and the location of the measurements. Sex, age, BSA, and body mass index are known biologic factors that affect aortic size [36,37]. Current standardized aortic measurements were obtained by averaging aortic diameters based primarily on computerized tomography scans and were published in 1991 for reporting arterial aneurysms [37]. Variation in body habitus and aortic diameter indexed to body size have also emerged as important determinants for predicting aortic rupture, especially in women [38,39].

The ascending aorta originates from the left ventricle of the heart separated by a tricuspid aortic valve and is approximately 5 cm in length. Ascending in an anterior direction and to the right the ascending aorta also includes three orifices or coronary sinuses, which create the origin of the coronary arteries. The arch of the aorta then crosses the superior mediastinum and then descends to the left of the vertebral column to form the descending (thoracic) aorta. The descending aorta then turns midline and crosses through the diaphragmatic aortic hiatus (T12) to enter the abdomen in which the mediastinum is in direct communication with the retroperitoneum.

While aneurysm size is the most predictive variable pertaining to rupture risk, anatomic factors have also been proposed to contribute to the development of TAA, such as the presence of bicuspid aortic valve [40]. While the overall incidence is only 1%–2%, 9% of patients who succumb to dissections have a bicuspid valve [41–44]. The most important consideration is the fact that women have smaller average aortic diameters compared with males in relation to their body size. The assumption that the normal aortic diameters are smaller in women appears intuitive yet took years to substantiate. Data from the Framingham heart study revealed that the average descending aortic diameter based on CT measurements for men was 25.8 mm compared with 23.1 mm in women [45]. Infrarenal aortic size was 13% smaller, with measurements of 19.3 mm and 16.7 mm for men and women, respectively. The results of this cohort study are not applicable to the population as a whole because only caucasian patients were included. However, similar results were replicated in several other studies, and mean aortic size has been shown to be significantly smaller in women by 2–3 mm [46].

One of the most devastating complications following TAA repair is spinal cord ischemia, which can result in paresis/paralysis rates of 2%–10% when performed by endovascular techniques and up to 10% when performed open [47,48]. These rates can be affected by operative technique, patient comorbidities, operative volume, and aortic anatomy. Furthermore, successful endovascular repair of TAA depends on a long segment of healthy aorta as a landing zone. The branches of the thoracic aorta include pericardial, bronchial, esophageal/ mediastinal/ phrenic, and intercostal arteries. These nine pairs of intercostal arteries, which originate posterior from the thoracic aorta, form spinal branches that are most relevant to TAA repair. The artery of Adamkiewicz arises from the left posterior intercostal artery at T9–12 and supplies the lower third of the spinal cord. In a study published by Shah TR et al., it was noted that female patients undergoing endovascular repair of the thoracic aorta may have an increased risk of spinal cord ischemia postoperatively. The researchers concluded this was likely secondary to length of aortic coverage. Female patients were treated for larger aneurysms and more diffuse disease, necessitating longer length of aortic coverage with stent graft. This will require future investigation with follow-up studies to determine whether it is truly just length of coverage or other factors play a role in the worse outcomes for women following TAAA repair [29].

Sex disparities in aortic pathophysiology

While similarities exist regarding the biologic and biomechanical factors that contribute to aneurysm formation between various anatomic locations, particular differences exist. Specifically, TAAs are secondary to medial wall degeneration while AAAs are a result of atherosclerotic changes, which is now considered to be an inflammatory process. Moreover, while thoracic aneurysms are largely secondary to degenerative mechanisms, it is important to recount that 20% of TAAs are the consequence of chronic aortic dissections [49]. However, the questions that remain unanswered are: why do females have faster aneurysms growth rates and increased TAA rupture rates, and why is female sex an independent risk factor for increased 30-day mortality and decreased long-term survival?

Flow dynamics change rapidly throughout the ascending, descending, and distal abdominal aorta. Furthermore, aside from hemodynamics, complex genetic, epigenetic, and perivascular factors are responsible for different mechanisms of aortic aneurysms formation in different parts of the aorta. These differences that exist in different portions of the aorta are crucial to understand regarding presentation, treatment, and continued research efforts. Cystic medial necrosis was the term initially used to describe mechanisms involved in TAA formation; however, it is now known to be a misnomer because there is neither necrosis nor cyst formation, but rather it is a multifaceted degenerative process frequently superimposed with atherosclerosis [50,51]. Regulation of blood flow and pulse pressure is largely regulated by the media of the aorta, which consists of elastin fibers and smooth muscle cells (SMCs). When these fibers are disrupted and proteoglycans accumulate, degeneration of the media proceeds and dilation begins. Damage of elastin fibers, collagen, and accumulation of glycosaminoglycans results as a function of aging and increased mechanical stress such as hypertension [52–55]. In addition, an important pathologic mechanism to consider is the phenotypic change that occurs from a normal contractile quiescent SMC to a proliferative synthetic SMC, which increases matrix and, therefore, increases the stiffness of the aorta.

The aorta is a mechanical organ directly affected by chronotropy, blood pressure, contractility, and cardiac output. The ascending aorta has the highest percent of elastin, which makes it the most compliant segment [56]. This segment, which is an extension of the left ventricle, is continuously exposed to the aforementioned factors and plays an important role in biomechanics (mechanical stress) and aneurysmal pathophysiology. Recent work has highlighted that cells and proteins present in the extracellular matrix of the aorta have complex functions that sense hemodynamics changes and help maintain compliance. The decreased vascular compliance, increased pulse wave velocity, and increased systolic and central pressure are affected by the progression of aging and hypertension. This leads to increased hemodynamic load and loss of physiological homeostasis [57]. This ultimately can lead to aneurysm formation and possibly the most ominous complication of aortic dissection or rupture.

Aortic dissections and TAA can be classified as syndromic or nonsyndromic, which were first described by Tilson at Yale in 1984 [56]. While aging and hypertension are the principal risk factors for formation, 5% are secondary to patients with concomitant syndromes [57]. Syndromic TAA refers to Marfan, Loeys-Dietz, Ehlers-Danlos, arterial tortuosity, aneurysm-osteoarthritis, Turner, and cutis laxa syndromes that affect other organ systems as well as the vasculature, while nonsyndromic TAAs and TAADs are confined to the aorta [58]. Nonsyndromic disease can be further classified as familial or sporadic. This is important to consider when screening patients to treat before complications occur. Nonsyndromic familial patients are those that have had more than one family member with arterial aneurysms. This finding leads to pedigree analysis of families and ultimately the search for genes responsible for TAA [57]. These studies exemplify how directed research efforts delineated genes, which lead to increased screening and treatment, which can be applied to improve outcomes in female subjects with TAA.

The age of onset and progression of CVD varies between sexes. It was first observed in epidemiologic studies demonstrating the incidence of cardiovascular disease in premenopausal women was lower than age-matched men [58]. The finding revolutionized the basic science field of vascular diseases supported by the fact that postmenopausal women had comparable or even higher incidence of CVD. This suggests a protective effect of estrogen on the vasculature. The debate occurred when new data arose regarding postmenopausal women, who were randomized to receive hormone replacement therapy (estrogen/progesterone), were found to have increased risk of CVD, thromboembolic events, and gallbladder disease [59,60]. After years of dedicated advanced worldwide research efforts, there is no debate that estrogen has a protective modulatory effect on vasculature. Estradiol binds to estrogen receptors primarily on endothelial cells and SMC. These receptors belong to intracellular receptors canonically defined as nuclear ligand-activated transcription factors. Its protective effects are not simple but rather intricate and confer protection by directly altering molecular pathways on the perivasculature and more robustly on endothelial cells (ECs). ECs are the gatekeepers of the vessels and subendothelial space. They modulate vascular tone through a milieu of mechanisms but also present antiinflammatory and antithrombotic factors. This thorough understanding of the pathophysiologic difference seen in thoracic aortic disease in women helps guide further efforts to improve early diagnosis and treatment with the goal of improving outcomes.

Future considerations in screening and diagnosis

Although the knowledge of unique pathophysiologic mechanisms of thoracic aortic disease in women is limited, publications to date provide compelling evidence demonstrating a significant sex bias about the natural history of disease and outcomes. Owing to the retrospective nature of these studies, it remains unknown whether women truly have a lower burden of disease or are simply underdiagnosed because sex-specific data are underreported. Inadequate screening and failure to make an early diagnosis likely result in poor outcomes reported in female patients due to insufficient surveillance imaging and early intervention. Inferior outcomes when compared with men suggest a need for specific screening protocols and alternative diagnostic criteria for the female population. Unfortunately, the US Joint Task Force proposed guidelines published in 2010 based on data derived from previous studies and the consensus opinions of experts [1]. There remains a lack of level I evidence supporting the proposed screening guidelines. Current accepted recommendations do not account for sex disparities prevalent throughout retrospective data. Unbiased randomized controlled trials are critical to our future understanding of the relationship between sex and thoracic aortic disease.

Based on data reviewed thus far, there are several noteworthy distinctions between male and female cohorts with thoracic aortic disease. The presence of concomitant thoracic and abdominal aortic aneurysmal disease, delayed age at presentation, atypical clinical symptoms at presentation, and increased aneurysm growth rates observed in women all indicate a notable sex bias. It is expected that these disparities should drive changes in screening protocols to increase rates of early diagnosis. For example, female patients with known AAAs may benefit from a screening thoracic CT scan to identify a concomitant thoracic aneurysm early. Timely intervention can prevent aorta-related mortality. This might perhaps lower complication rates in women and is one example of how sex-specific screening and surveillance protocols are necessary to improve overall outcomes for women.

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Chapter 1b: Thoracic aortic aneurysm repair in women

Grace J. Wang    Division of Vascular Surgery and Endovascular Therapy, Hospital of the University of Pennsylvania, Philadelphia, PA, United States

Abstract

Thoracic endovascular aortic repair has become the preferred approach for treatment of thoracic aortic pathology since the approval of the first endograft device by the US Food and Drug Administration in 2005. This chapter discusses the indications for as well as conduct of the operation, highlighting sex differences where appropriate.

Keywords

Thoracic aortic aneurysm; Sex; Thoracic endovascular aortic repair

Chapter Outline

Introduction

Indications for repair

Anatomic considerations

Aortic arch

Access vessels

Intercostal arteries and spinal cord perfusion

Preoperative planning and landing zones

TEVAR devices

Conduct of the operation

Management of endoleak

Complications

Postoperative management/surveillance

Long-term surveillance

Conclusions

References

Introduction

Thoracic endovascular aortic repair (TEVAR) has become the preferred approach for treatment of thoracic aortic pathology since the approval of the first endograft device by the US Food and Drug Administration in 2005. Although there are no randomized controlled trials directly comparing TEVAR to open surgery, numerous studies have demonstrated that TEVAR is associated with decreased morbidity compared with open repair [1–5]. The benefits of the endovascular approach include avoidance of thoracotomy or sternotomy incision, avoidance of aortic cross-clamping, decreased blood loss, and decreased end-organ ischemia [6]. The indications for as well as conduct of the operation are discussed in this chapter, highlighting sex-based differences where appropriate.

Indications for repair

Indications for repair have typically used a threshold where the risk of repair is outweighed by the risk of rupture [7–9]. Patients with thoracic aortic aneurysms larger than 6 cm have a 14.1% annual risk of rupture, dissection, or death, when compared with a 6.5% risk for patients with aneurysms between 5 and 6 cm [10]. The diameter threshold for thoracic aortic aneurysm repair has recently been proposed to be 5.5–6 cm, according to the American Heart Association (AHA)/Society for Thoracic Surgery (STS) and European Society of Cardiology guidelines [11,12]. In the European Society for Vascular Surgery Guidelines for Management of Descending Thoracic Aortic Diseases, the diameter threshold for thoracic aortic aneurysm repair is 6 cm for the fit patient able to undergo open repair if they do not have amenable anatomy for endovascular repair. They recommend that a 5.5 cm cutoff be considered for endovascular repair, provided the patient has suitable anatomy for this treatment [13]. Similarly, the American College of Cardiology Foundation/AHA Task Force guidelines, also endorsed by the STS, uses a 5.5 cm threshold for recommending strong consideration of endovascular stent grafting when feasible [11]. They likewise recommend a 6 cm cut point for open repair of thoracic aortic aneurysms if endovascular options are limited. These thresholds for repair have been derived from detailed institutional series. Elefteriades’ group found in an institutional series of patients with thoracic aortic disease that female sex increased the odds of aortic dissection, rupture, or aortic-related death by 63% compared with male subjects, even after controlling for aortic diameter. Female subjects were well represented in this study and notably comprised 41% of this study population [14]. Owing to smaller body size and body surface area in women, the aortic size index (ASI) has been proposed as an alternative method for determining the appropriate threshold for thoracic aortic aneurysm repair [14,15]. Defined as aortic diameter/body surface area, it is thought to be a better predictor for rupture due to its ability to take into account body habitus and size. Elefteriades similarly contributed to the literature using this parameter, commenting that this measure is more accurate than aortic diameter in predicting rupture. Women were well represented in this study, making up 37.3% of the cohort [16]. Forbes’ group performed a retrospective review of all thoracic aortic aneurysms treated at a single institution and found that while aortic diameter did not differ between sexes, ASI was greater in female subjects. While this was also a small study, 15/40 of patients were female subjects and specifically described sex-specific dimensions regarding thoracic aortic disease, allowing for between sex comparisons for diameter and ASI [15]. While previous studies have demonstrated that ASI may have better modeling capability regarding predicting rupture, the relevance of this derived measurement remains unclear [14,17]. A study using the vascular quality initiative (VQI) dataset is underway to explore the relationship between diameter and ASI in a large cohort of men and women undergoing thoracic endovascular aortic aneurysm repair, in an attempt to better define the additive value of this measurement regarding intact versus ruptured status by sex. Thus, currently, the indications for repair for thoracic aortic aneurysm in women mimic the thresholds that have been set for both sexes.

Anatomic considerations

Aortic arch

The unique characteristics of the thoracic aorta, which are relevant for repair, are its relatively large diameter compared with the abdominal aorta and the anatomy of the aortic arch. There can be significant variability in the takeoff of the arch vessels, with either the normal three-vessel configuration or bovine anatomy where the left common carotid artery originates from the innominate artery or aberrant anatomy. Careful review of the preoperative computed tomography angiography (CTA) of the chest is important, and, at times, CTA of the neck is performed to better evaluate the origins and course of the vertebral arteries to assist in case planning. The degree of arch angulation should also be considered in the approach and may influence choice of endograft. Earlier generation stent grafts were characterized by failure of the proximal stent graft to conform to the aortic anatomy leading to bird beaking, increasing the risk of graft failure, migration, or collapse. Current generation devices are characterized by their improved flexibility, a design feature employed to allow for improved conformability to the aortic arch. Aortic arch debranching through ascending aortic to innominate and left common carotid artery bypass, carotid-carotid bypass, or left carotid to subclavian artery bypass may be required to obtain an adequate seal zone [18]. In addition, vertebral transposition may need to be performed if the left vertebral artery originates directly from the arch. Sex differences with regard to arch anatomy have been previously reported. A retrospective study of 2370 patients found that aortic arch branch anomalies are more prevalent in women [19]. Furthermore, in an anatomic and radiographic study evaluating the aortic arch, the total arch length, arch width, and assimilated curvature radius were smaller in women, indicating that women have tighter arch angulation [20].

Access vessels

Access vessel anatomy is also critical because the relatively large size of the thoracic endografts in turn require larger diameter delivery systems. The femoral and iliac systems should be carefully assessed to ensure that passage of the sheath will be possible and evaluated for small diameter or heavy, circumferential calcification. In a study reporting on outcomes from the TAG (W. L. Gore and Associates, Flagstaff, Arizona) thoracic stent graft trials, women were noted to have smaller external iliac artery diameters than men (7.1 mm versus 9.0 mm, P < .001), which led to a higher frequency of conduit use (24.4% versus 6.0%, P < .001) for device delivery, as well as local access site complications (14.1% versus 4.5%, P < .001) [21]. Current generations of stent graft devices have been marked by an attention to reducing delivery profiles to accommodate smaller access vessels [22]. If there is concern, alternative approaches may need to be considered, as highlighted further.

Intercostal arteries and spinal cord perfusion

Paired intercostal branches are derived from the descending thoracic aorta and provide collateral flow to the anterior spinal cord through the artery of Adamkiewicz and other radicular branches. Degree of coverage of these branches must be assessed during TEVAR because extensive coverage is a major risk factor for spinal cord ischemia and postoperative paraplegia. Consideration should also be given to previous EVAR or open aortic repair, or occluded or embolized internal iliac arteries, given that lumbar arteries and the internal iliac arteries provide collateral blood flow to spinal cord [23]. If extensive coverage of the thoracic aorta is required, and significant collateral network is also being sacrificed, consideration should be made for preemptive lumbar spinal drain, as well as preservation or revascularization of the left subclavian artery [24]. Because of small numbers in institutional series, no sex differences in spinal cord ischemia have been noted in center-based studies. However, the recent larger VQI study did show that women had a four times higher rate of spinal cord ischemia (4.0% versus 1.0%) following TEVAR compared to men, in addition to any postoperative major adverse event. Further research should be dedicated to understanding why women are more vulnerable to this neurologic complication when compared with men.

Preoperative planning and landing zones

Adequate preoperative measurements are critical for the correct sizing of thoracic endografts and are best facilitated by CTA, with three-dimensional reformatting. This provides information about seal zones, coverage length, and tortuosity and angulation of the aorta. CTA can also provide information about intraluminal thrombus or wall calcification, which may have implications for graft placement. The CTA should be obtained of the chest to include the abdomen and pelvis to allow assessment of the iliac arteries to ensure adequate diameter for passage of the endograft. If the femoral vessels are small in diameter, tortuous, or calcified, alternate access techniques may be required such as direct retroperitoneal iliac access, iliac bypass conduit, or use of an endoconduit with iliac angioplasty and stent placement [25,26]. Measurements from the CTA can then be used to accurately size the endograft, using oversizing recommendations per the device instructions for use. Magnetic resonance angiography (MRA) can also be used as a preoperative imaging study but does not show calcification as well as CTA due to signal dropout.

The commercially available thoracic stent grafts all require a 20-mm long proximal seal zone. It is critical to obtain good apposition throughout this segment to avoid endoleak or device migration. While compromised seal zones have been reported more frequently for abdominal aortic stent graft repair in women, there is no evidence that women have more difficult seal zones compared with men for the thoracic aorta [27]. Depending on the patient’s anatomy, it may be necessary to cover one or more of the arch branches to obtain adequate seal. Not infrequently, coverage of the left subclavian artery is required to obtain an adequate proximal seal, particularly in dissection or traumatic aortic transection cases. When this is necessary, consideration should be given to performing preemptive left carotid-subclavian bypass or subclavian transposition. TEVAR can then be completed as a second-stage procedure with embolization of the native subclavian artery to prevent type II endoleak. If the left carotid or innominate artery require coverage, then antegrade bypass from the ascending aorta [28–30] or extra-anatomic bypass through carotid-carotid bypass [31] is necessary. An endovascular approach to this anatomic problem has also been devised, which involves placement of a stent into the branch vessel parallel to the main endograft [32,33] and is referred to as the snorkel, periscope, or chimney technique. This can also be used as a bailout technique in the event of inadvertent branch coverage with the main endograft.

Branched and fenestrated devices are currently under investigation to provide an endovascular option and allow additional seal zone proximal to the left subclavian artery while maintaining perfusion to the arch vessels [34]. Single thoracic branched devices are in trial to preserve flow to the left subclavian or the innominate arteries (with left carotid and left subclavian debranching performed earlier) [35]. Dual-branched devices are also in trial preserving flow to the innominate and left carotid (with preemptive left subclavian revascularization performed earlier) [36]. Suffice to say, the evolving technology will allow for treatment of more complex anatomy through endovascular means.

The distal landing zone is also critical to avoid type Ib endoleak and also requires a 20-mm seal zone with the currently available devices. There are no sex-based differences observed regarding the distal seal zone in the literature. In patients with disadvantaged distal seal zones, where adequate seal can only be achieved with celiac artery coverage, selective arteriogram, and demonstration of an intact gastroduodenal artery, providing collateral flow from the superior mesenteric artery (SMA) is necessary before placement of TEVAR. Reports indicate that coverage of this vessel may have only a nominal rate of mesenteric ischemia of about 6% [31,37,38]. In instances where coverage is not safe or possible, a surgical debranching procedure or snorkel should be performed to preserve celiac artery flow.

TEVAR devices

The first stent graft approved by the Food and Drug Administration (FDA) for treatment of thoracic aortic aneurysms was the Gore TAG device (Flagstaff, Arizona), made of expanded polytetrafluoroethylene (ePTFE) with a nitinol exoskeleton. The initial trial leading to device approval had 42% women [39]. Gore has since introduced a new device called the conformable TAG (cTAG), which provides a wider range of diameters (21–45 mm), and was designed to improve treatment of small diameter, tortuous, and tapered aortic anatomy. This device was the first FDA approved stent graft for treatment of type B aortic dissection.

The Cook Zenith TX2 device (Bloomington, Indiana) is a two-piece system, with Dacron graft material and a stainless steel z-stent exoskeleton. The clinical trial leading to its approval included 28% women [40]. The proximal component has active fixation using steel barbs, and the distal component has bare metal stent component for fixation above the visceral vessels. This graft was modified with the addition of Pro-Form, which allows improved conformability to the arch and limits the bird-beak effect. The newer generation Cook Zenith Alpha Thoracic Endovascular Stent graft has a nitinol skeleton, is of lower profile, able to accommodate smaller access vessels, and had excellent 1-year outcomes [41].

The Medtronic initial thoracic aortic graft (Santa Rosa, California) was the Talent thoracic graft, which was then replaced by the next generation Valiant device. These were studied in the VALOR I and VALOR II trials, respectively, which demonstrated their efficacy and both of which included about 41% women [42,43]. The Valiant device is made of polyester graft with nitinol exoskeleton and has a modified proximal bare stent configuration. The longitudinal connecting bar of the Talent was also removed to improve flexibility. Modification of the Valiant with the addition of the Captivia delivery system allows tip capture and more controlled deployment. The most recent iteration, Valiant Navion, is also lower in profile and has shown excellent early outcomes [44].

The Bolton Relay (Terumo, Sunrise, Florida) is a polyester/nitinol graft, which also has a longitudinal nitinol bar for support and has both covered and bare metal proximal graft configurations. This device is approved for treatment of thoracic aortic aneurysmal disease and penetrating aortic ulcer. Its safety and efficacy have previously been demonstrated, and there were 47% women in the clinical trial leading up to device approval [45].

Relevant graft and access diameters are detailed in Table 1.

Table 1

Conduct of the operation

TEVAR is generally performed under general anesthesia, which allows respiratory control by the anesthesia team and permits more precise imaging. Consideration is given as to whether to place a lumbar drain preoperatively to mitigate the risk of spinal cord ischemia, and electroencephalography (EEG) and somatosensory evoked potentials (SSEP) or motor evoked potentials (MEP) are conducted as per the surgeon’s usual practice.

The operation is performed by gaining femoral access for placement of the sheath or device. This may be performed with a groin cutdown, percutaneously using the preclose technique [46], or through a retroperitoneal cutdown if needed due to small vessel size. Additional access can be obtained from either the arm or the contralateral groin to allow for angiography. Wire access is gained into the ascending aorta and exchanged for a stiff wire to allow tracking of the device. The c-arm is positioned in left anterior oblique position to maximally splay out the arch. Once the device is positioned, angiography is performed with power injection and respiratory arrest by anesthesia to allow for precise positioning. Additional techniques to minimize graft movement during deployment include induced hypotension, rapid pacing, and adenosine-induced cardiac arrest [47]. Once the graft is deployed, it may be ballooned at the seal zones and at any overlap zones to ensure full cooptation to the aortic wall. Completion angiogram is then performed to assess for endoleak, the sheath and device are removed, and the arteriotomy is closed.

Management of endoleak

Type I: Endoleak at the proximal or distal seal zones is usually managed by additional ballooning or by placement of an extension graft, anatomy permitting. Care must be taken with proximal ballooning to avoid causing retrograde dissection [48]. If proximal or distal seal zones are inadequate, arch or visceral artery debranching at a later time may be required to accomplish a hybrid approach. Open surgery and explant may ultimately be required if the above are not