Gender Differences in Acute Aortic Dissection

Cardiovascular disease (CVD) represents the most important cause of mortality and morbidity worldwide. There is heterogeneity in the epidemiology and management of CVD between male and female patients. In the specific case of acute aortic dissection (AAD), women, at the time of diagnosis, are older than men and complain less frequently of an abrupt onset of pain with delayed presentation to the emergency department. Furthermore, a history of hypertension and chronic obstructive pulmonary disease is more common among women. In type A AAD, women more often experience pleural effusion and coronary artery compromise, but experience less neurological and malperfusion symptoms. They undergo less frequent surgical treatment and have higher overall in-hospital mortality. Conversely, in type B AAD no significant differences were shown for in-hospital mortality between the two genders. However, it should be highlighted that further studies are needed in order to develop AAD gender specific preventive, diagnostic and therapeutic strategies.


Introduction
Cardiovascular disease (CVD) represents the most important cause of mortality and morbidity worldwide [1,2]. Interestingly, there is evidence of heterogeneity in the mechanism, risk factors, clinical characteristics, and the short-and long-term outcomes of CVD between women and men [3]. Furthermore, women are under-represented in cardiovascular clinical trials, which has reduced the elaboration of gender-specific approaches that could improve guideline recommendations and physicians' adherence [4]. The aim of the present report was to highlight gender differences in patients with acute aortic dissection (AAD), including risk factors, presenting clinical features, diagnosis, management and outcomes. Pregnancy-related AAD is also discussed.

AAD
AAD represents a life-threatening emergency, needing prompt diagnosis and appropriate therapeutic interventions ( Figure 1) [5,6]. The real incidence of AAD is arduous to define, due to pre-hospital mortality and/or missing diagnoses. Population-based studies show an incidence of 2.6 to 3.5 cases per 100,000 person-years (67% Type A; 33% Type B) [7,8].
Men are more affected than women (9.1 vs. 5.4 per 100,000 men and women, respectively; p < 0.001) [9,10]. Interestingly, women are aged more than men at the time of AAD onset [11]. Due to non-specific symptoms and signs, the diagnosis is often delayed [11]. Therefore, a high index of suspicion is crucial to make the diagnosis. In this regard a specific integrated diagnostic algorithm has been designed, including clinical risk assessment along with biomarkers (D-dimer) and imaging techniques (computed tomography being by far the most utilized) (Figures 2 and 3) [12,13]. Urgent surgery is recommended for type A AAD, while medical treatment is usual for uncomplicated Type B AAD [5,6,14]. Thoracic endovascular aortic repair (TEVAR) is generally indicated in the case of complicated type B AAD [5]. The International Registry of Acute Aortic Dissection (IRAD) highlighted that type A AAD, while medical treatment is usual for uncomplicated Type B AAD [5,6,14]. Thoracic endovascular aortic repair (TEVAR) is generally indicated in the case of complicated type B AAD [5]. The International Registry of Acute Aortic Dissection (IRAD) highlighted that in-hospital mortality for type A AAD has a downward trend from 31% to 22% (p < 0.001), over 17 years (December 1995to February 2013, principally related to decreased surgical mortality (25% to 18%; p < 0.003) [15]. However, no changes in-hospital mortality rates for type B AAD (12% to 14%) were observed ( Figure 4) [16,17]. Given that AAD is a life-long condition, involving the whole aortic system (holistic concept), patients should obtain optimal blood pressure (≤120/80 mmHg) and heart rate (≤60 bpm) control and imaging follow up (MRI or CT) in order to prevent aorta-related death and major complications [5,6,10,17].  [5,6], and the International Registry of Acute Aortic Dissection (IRAD) [11]. Modified by Bossone et al., Nat Rev Cardiol. 2021 May;18(5):331-348 [10].

AORTIC DISSECTION
Definition: disruption of the medial layer provoked by intramural bleeding, resulting in separation of the aortic wall layers and subsequent formation of a true lumen and a false lumen with or without communication.
localization of the intimal tear (according to the involvement of the ascending aorta).
the time from the symptoms onset to the presentation at the emergency department.

ESC (5) Days
Acute <14 type A AAD, while medical treatment is usual for uncomplicated Type B AAD [5,6,14]. Thoracic endovascular aortic repair (TEVAR) is generally indicated in the case of complicated type B AAD [5]. The International Registry of Acute Aortic Dissection (IRAD) highlighted that in-hospital mortality for type A AAD has a downward trend from 31% to 22% (p < 0.001), over 17 years (December 1995 to February 2013), principally related to decreased surgical mortality (25% to 18%; p < 0.003) [15]. However, no changes in-hospital mortality rates for type B AAD (12% to 14%) were observed ( Figure 4) [16,17]. Given that AAD is a life-long condition, involving the whole aortic system (holistic concept), patients should obtain optimal blood pressure (≤120/80 mmHg) and heart rate (≤60 bpm) control and imaging follow up (MRI or CT) in order to prevent aorta-related death and major complications [5,6,10,17].   Ascending aorta (red arrow) and descending aorta (yellow arrow) dissection; (B) dissection extending into the right subclavian artery (sagittal view). Reprinted/adapted with permission from Ref. [18]. Copyright year 2021, with permission from Elsevier.   Reprinted/adapted with permission from Ref. [12]. Copyright year 2020, with permission from Elsevier.
Tables 1 and 2 summarized clinical characteristics and outcomes of type B AAD of the major population based studied.

Insights into Gender Related AAD from the IRAD
The IRAD, established in 1996 at the University of Michigan, Ann Arbor, USA, is an observational registry involving 53 highly specialized aortic centers around the world, aiming to assess diagnoses, management, and outcomes of AAD [15,16,31].
According to IRAD data [11] (Table 3), AAD was more frequent in men but women were generally older (overall population n = 1078, 32% women; 49.7% of women were 70 years of age or older vs. 28.6% of men). The type A/B AAD ratio was approximately 2:1 in both genders [11]. Previous cardiac surgery was more common in men, while hypertension was more prevalent in women [11]. Other etiologies or risk factors (atherosclerosis, diabetes, Marfan syndrome, bicuspid aortic valve, cocaine abuse, iatrogenic dissection, previous aortic dissection, previous aortic aneurysm,) were similar between genders [11]. Table 3. AAD gender-related differences in epidemiological, clinical, treatment and outcomes from International Registry of Acute Aortic Dissection (IRAD) [11,32].   The presentation to hospital, after symptom onset, was significantly more delayed in women than in men (mean absolute difference of 4.7 h), negatively affecting outcomes [11]. Although typical presentation with chest pain was similar in women and men, women were less likely to report an abrupt onset of pain (p = 0.004) [11]. Congestive heart failure (p = 0.03) and coma/neurologic alterations (p = 0.05) were more common in women [11]. Electrocardiographic findings were similar in the two groups. CT was the most utilized imaging in both genders (>70%; 80.6% in men and 76.6% in women) [11]. Tomographic findings suggestive of periaortic hematoma (p = 0.03), pericardial effusion (38.8% vs. 28.6%; p = 0.001), pleural effusion (26.1% vs. 14.7%; p < 0.001) and coronary artery involvement (10.8% vs. 6.9%; p = 0.05), were more frequent among women [11]. Initial medical management with intravenous beta-blockers was less used in women than in men (62.1% in men vs. 55.6% in women; p = 0.05) [11].
There was no difference in surgical techniques for both type A and B AAD, however more women were medically treated than men (35% in men vs. 45.7% in women; p = 0.001) [11]. In-hospital complications, such as hypotension (0.001) and cardiac tamponade (p = 0.007) occurred more among women [11]. On the other hand, limb ischemia was more common in men (p = 0.04) [11].
Women showed higher overall in-hospital mortality (type A AAD + type B AAD) than men (p = 0.001) [11]. Women had lower survival than men for type A AAD (log rank p = 0.01) but not for type B AAD (log rank p = 0.47) [11]. Furthermore, women showed the greatest in-hospital mortality for surgically treated type A AAD (31.9% mortality in women vs. 21.9% in men, p = 0.013) [11].
No significant gender-related difference was shown for type A AAD medically treated mortality [11]. Interestingly, in the advanced age cohort (>75 years) women with type A AAD were treated more with only medical treatment than men (31.4% vs. 14.0%; p = 0.04). In the analysis stratified by age (age < 50, 50 to 65, 66 to 75, and >75 years), major differences in mortality between gender were shown in the 66-to 75-year age group (36% vs. 16%; p = 0.001) [11]. Older age and less typical symptoms at onset of AAD have been proposed as possible factors contributing to poorer outcomes in women.
A more recent analysis of an IRAD-Interventional Cohort (IVC) [32], consisting of more than 2823 type A AAD patients treated with endovascular, surgical, or hybrid procedures has partly confirmed the previous IRAD data about gender differences (Table 1). Of particular interest was the fact that, overall, in-hospital mortality was 16.7% in women (n = 162) and 13.8% in men (n = 256, p = 0.039). The frequency of postoperative complications was similar between genders, except for acute kidney injury, which was lower in women (17.7% vs. 21.2%, p = 0.029) [32].
In summary, data from IRAD highlighting women as compared to men show women to have the following: (a) older age, higher incidence of a history of hypertension and more delayed presentation to hospital; (b) more complications, such as periaortic hematoma, pericardial effusion, pleural effusion and coronary artery involvement; (c) higher overall and surgical type A AAD in-hospital mortality.
In The NHLBI National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC) [37], among 94 women with Marfan syndrome, 10 (10.6%) experienced aortic complications during or post pregnancy (4 type A and 3 type BAAD). Regarding postpartum, 5 of 7 AAD including all 3 type B, experienced complications. Only 5 of 8 women were conscious of their Marfan syndrome diagnosis [37].
In the Nationwide Inpatient Sample of more than 10 million pregnancies and 41,000 AADs from 1998 to 2008, 44 cases of AAD in pregnancy were described, representing 0.1% of all cases of AAD. Only 7 of the 44 cases had Marfan syndrome, with 2 other women having other congenital anomalies [38]. The in-hospital mortality was of 6.8% for AAD during pregnancy vs. 15.4% of all AAD [38].
Thus, AAD is a rare, but serious, complication of pregnancy [in the majority of cases type A AAD (57-80%)] [40][41][42][43]. There is no evidence of increased in-hospital mortality in pregnancy-related AAD. However, it should be underlined that the recognition of predisposing conditions (namely aortopathies, often not diagnosed until the acute event) and the monitoring of the aorta diameters throughout pregnancy and in post-partum, may reduce complication rates and improve outcomes.

Conclusions
A comprehensive understanding of gender differences in AAD is lacking. For both type A and B AAD, women, at the time of diagnosis, are older than men and complain less frequently about abrupt onset of pain, with delayed presentation to the emergency department. Furthermore, a history of hypertension and chronic obstructive pulmonary disease is more common among women. In type A AAD, women more often experience pleural effusion and coronary artery compromise but experience less neurological and malperfusion symptoms. They undergo less frequent surgical treatment and have higher overall in-hospital mortality. On the other hand, in type B AAD no significant differences are registered for in-hospital mortality between the two genders. A greater knowledge of gender differences in AAD risk factors, clinical presentation and treatment may improve diagnostic accuracy, along with short-and long-term prognosis. However, it should be highlighted that further studies are needed in order to develop AAD gender-tailored preventive, diagnostic and therapeutic strategies.

Conflicts of Interest:
The authors declare no conflict of interest.