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(Circulation. 2004;109:3014-3021.)
© 2004 American Heart Association, Inc.

Clinical Investigation and Reports

Gender-Related Differences in Acute Aortic Dissection

Christoph A. Nienaber, MD^*; Rossella Fattori, MD^*; Rajendra H. Mehta, MD, MS; Barbara M. Richartz, MD; Arturo Evangelista, MD; Michael Petzsch, MD; Jeanna V. Cooper, MS; James L. Januzzi, MD; Hüseyin Ince, MD; Udo Sechtem, MD; Eduardo Bossone, MD; Jianming Fang, MD; Dean E. Smith, PhD; Eric M. Isselbacher, MD; Linda A. Pape, MD; Kim A. Eagle, MD, on Behalf of the International Registry of Acute Aortic Dissection

From the University Hospital Rostock (C.A.N., B.M.R., M.P., H.I.), Rostock School of Medicine, Rostock, Germany; University Hospital S. Orsola (R.F.), Bologna, Italy; University of Michigan (R.H.M., J.V.C., J.F., D.E.S., K.A.E.), Ann Arbor, Mich; Hospital General Universitari Vall d’Hebron (A.E.), Barcelona, Spain; Massachusetts General Hospital (J.L.J., E.M.I.), Boston, Mass; Robert-Bosch-Krankenhaus (U.S.), Stuttgart, Germany; National Research Council (E.B.), Southern Italy, Brindisi, Italy; and University of Massachusetts Hospital (L.A.P.), Worcester, Mass.

Correspondence to Christoph A. Nienaber, MD, FACC, Division of Cardiology, University Hospital Rostock, Rostock School of Medicine, Ernst-Heydemann-Straße 6, 18057 Rostock, Germany. E-mail christoph.nienaber{at}med.uni-rostock.de

Received June 24, 2003; de novo received October 20, 2003; revision received February 24, 2004; accepted March 4, 2004.

	Abstract

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Background— Few data exist on gender-related differences in clinical presentation, diagnostic findings, management, and outcomes in acute aortic dissection (AAD).

Methods and Results— Accordingly, we evaluated 1078 patients enrolled in the International Registry of Acute Aortic Dissection (IRAD) to assess differences in clinical features, management, and in-hospital outcomes between men and women. Of the patients enrolled in IRAD (32.1%) with AAD, 346 were women. Although less frequently affected by AAD (32.1% of AAD), women were significantly older and had more often presented later than men (P=0.008); symptoms of coma/altered mental status were more common, whereas pulse deficit was less common. Diagnostic imaging suggestive of rupture, ie, periaortic hematoma, and pleural or pericardial effusion were more commonly observed in women. In-hospital complications of hypotension and tamponade occurred with greater frequency in women, resulting in higher in-hospital mortality compared with men. After adjustment for age and hypertension, women with aortic dissection die more frequently than men (OR, 1.4, P=0.04), predominantly in the 66- to 75-year age group. Moreover, surgical outcome was worse in women than men (P=0.013); type A dissection in women was associated with a higher surgical mortality of 32% versus 22% in men despite similar delay, surgical technique, and hemodynamics.

Conclusions— Our analysis provides insights into gender-related differences in AAD with regard to clinical characteristics, management, and outcomes; important diagnostic and therapeutic implications may help shed light on aortic dissection in women to improve their outcomes.

Key Words: aneurysm • aorta • registries • sex • imaging

	Introduction

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Acute aortic dissection is a highly lethal cardiovascular emergency with an incidence of 2000 new cases per year in the United States and 3000 in Europe.^1–3 Although aortic dissection was first described in the 18th century,¹ interest in this disorder has heightened recently because of major diagnostic and therapeutic advances.^4–15 These developments have resulted in earlier recognition; more accurate diagnosis in an emergency situation; refined surgical, interventional, and medical treatment; and as a consequence, improved outcomes.¹⁶

Despite mounting interest in acute aortic dissection, few data exist on gender-related differences in clinical presentation, diagnostic imaging, management, and outcomes in a large unselected cohort. Accordingly, the purpose of this investigation was to evaluate differences between men and women using individuals with acute aortic dissection enrolled in the International Registry of Acute Aortic Dissection (IRAD).^1,2 We anticipated that this analysis would provide useful information distinguishing clinical features and influence management and outcomes in both genders.

	Methods

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Study Population
We examined data on all patients with acute aortic dissection in IRAD enrolled from January 1, 1996, to November 19, 2001 (n=1078). Both the rationale and methodology of IRAD have been published previously.^1,2 Acute type A dissection was defined as any dissection that involved the ascending aorta and/or aortic arch and acute type B as that involving the descending aorta (without any tear in or involvement of the ascending aorta) presenting within 14 days of symptom onset.^1,2,17,18 Patients were categorized on the basis of gender: men and women. The study protocol was approved by the institutional review boards for research at all IRAD sites.

Data Collection
Data were collected on standardized forms that included information on patient demographics, history, clinical presentation, imaging findings, management, and clinical events, including mortality. Completed data forms were forwarded to the IRAD coordinating center and entered into an Access database; data from prehospital community death certificates were not used.

Statistical Analysis
Summary statistics of both groups (men and women) were presented as frequencies and percentages, mean±SD. In all cases, missing data were not defaulted to negative, and denominators reflect only cases reported. Univariate associations between the 2 groups for nominal variables were compared using the Pearson ² test or 2-sided Fisher’s exact test, whereas the 2-tailed Student’s t test was used for continuous variables. Iterative logistic regression modeling was performed to derive adjusted estimates for odds ratios of in-hospital mortality, women versus men, using likelihood ratio tests. Initial modeling used variables marginally suggestive of unadjusted association to in-hospital death (P<0.20). Both SAS Version 8.02 (SAS Institute) and SPSS Version 11.0 (SPSS Inc) were used for the analyses.

	Results

Top Abstract Introduction Methods Results Discussion Appendix References

 
Gender-Related Differences in Demographics and Clinical Characteristics
Of 1078 patients with acute aortic dissection in the IRAD registry, 32.1% were women, and two thirds were men; there was no evidence of potential differences in mortality from dissection without a premortem diagnosis. Women were older than men; whereas 28.6% of men with dissection were 70 years of age or older, 49.7% of women were in this age group (P<0.001) (Figure 1). The ratio of type A versus type B dissection was approximately 2:1 in both genders, with 61.0% type A dissection in men and 65.9% in women. Although a history of hypertension was more frequent in women, previous cardiac surgery was more prevalent in men; other causes or risk constellations were similar in both genders. Relatively few women in IRAD (2 of 346) had dissection during pregnancy (Table 1).

View larger version (22K): [in this window] [in a new window]   Figure 1. Proportion of men vs women in different age groups; *P<0.001. Absolute numbers of patients are given at bottom of each column.

View this table: [in this window] [in a new window]   TABLE 1. Demographics and History of Patients by Gender

Although the interval from symptom onset to presentation at initial hospitalization, with 16.8±43.6 hours in men and 21.5±51.4 in women, revealed a trend (P=0.2) in favor of men, the mean absolute difference of 4.7 hours is likely to negatively affect outcomes in women. Although 27.5% of men and 26.0% of women were diagnosed early (within 4 hours) relatively fewer women were diagnosed in the time window between 4 and 24 hours (P=0.031); in the bracket after 24 hours of symptom onset, however, the percentage of women (with late premortem diagnosis) was higher than men (39.6% versus 30.2%; P=0.008). Although there may be observational suspicion of delayed diagnosis in women, no evidence was found for any disproportionately low incidence of premortem diagnosis of dissection. Moreover, classic presentation with chest or back pain was similar, although women were less likely to evidence abrupt onset of pain than men (P=0.004). Congestive heart failure and coma/altered mental status on presentation were more common in women. The mean presenting systolic and diastolic blood pressures did not differ between groups, whereas pulse deficit(s) was less frequent in women. ECG evidence of new myocardial ischemia or infarction, low voltage, and nonspecific ST-T changes at admission were similar.

Diagnostic imaging studies were used similarly, with no gender-related differences of number, type or order (Table 2). Tomographic findings suggestive of severe clinical/anatomic presentation or impending rupture, such as evidence of coronary artery compromise, pleural effusion, periaortic hematoma, and pericardial effusion, were more frequent among women, whereas lack of false lumen thrombosis was more frequent in men (P=0.007).

View this table: [in this window] [in a new window]   TABLE 2. Clinical Presentations, Signs, and Diagnostic Imaging Results of Patients by Gender

Gender Differences in Hospital Management and Complications
Proportionately more women were managed medically rather than with surgery; the surgical techniques, however, did not differ between groups. Among those managed medically, women were less likely to be given immediate treatment with intravenous ß-blockers (Table 3). As shown in Table 4, in-hospital complications of hypotension and cardiac tamponade occurred more commonly among women, who also showed a trend toward greater frequency of coma/altered mental status. In contrast, limb ischemia was observed less frequently in women. Mortality was higher among women than men (30.1% versus 21.0%, P=0.001). Figure 2 shows survival of women versus men stratified by the type of dissection, indicating lower survival in women than in men with type A dissection (log rank P=0.01) but not with type B dissection (log rank P=0.47). Adjustment for age, type of dissection, and history of hypertension by multivariate logistic regression analysis suggested a higher death rate in women than men (OR, 1.4; 95% CI, 1.0 to 1.9; P=0.04). However, higher female mortality was primarily due to a difference in outcomes of type A dissection as opposed to type B dissection, with 21.0% overall mortality in men and 30.1% in women (P=0.001, Table 4); in particular, the greatest gender-related difference was found in type A aortic dissection submitted to surgery (31.9% mortality in women versus 21.9% in men, P=0.013). The impact of additional comorbidities, eg, congestive heart failure, hypotension, tamponade, or renal failure, on postsurgical outcomes stratified by gender is summarized in Table 5. Whereas mortality was doubled in "high-risk" patients of either gender, both among high-risk and "non-high-risk" patients, mortality was higher in women; the disadvantage had a stronger trend in high-risk women (41.9% versus 30.9% in men) compared with the non-high-risk group (22.4% versus 17.7% in men). Interestingly, more women than men with type A dissection and advanced age were not subjected to surgery but rather managed by medical treatment (31.4% versus 14.0%; P=0.04). Conversely, no significant gender-related difference was found in mortality for type A dissection treated medically. Considering different age groups (age <50, 50 to 65, 66 to 75, and >75 years), major differences in death rate between women and men were present in the 66- to 75-year age group (36% versus 16%; P<0.001), whereas others revealed no differences in gender-specific mortality (Figure 3).

View this table: [in this window] [in a new window]   TABLE 3. In-Hospital Treatments and Surgical Data by Gender

View this table: [in this window] [in a new window]   TABLE 4. In-Hospital Complications and Mortality by Gender

View larger version (22K): [in this window] [in a new window]   Figure 2. Kaplan-Meier survival curves for men and women with acute aortic dissection stratified by type of dissection (type A and type B). Log rank test P=0.014 for type A dissection in men vs women and log rank P=0.47 for type B dissection in the 2 genders.

View this table: [in this window] [in a new window]   TABLE 5. Outcomes of Type A Surgery in Relation to Preoperative Condition

View larger version (21K): [in this window] [in a new window]   Figure 3. In-hospital mortality for women and men with acute aortic dissection in different age groups; *P<0.001. Absolute numbers of patients are given at bottom of each column.

	Discussion

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With the recognition of cardiovascular disease as the leading cause of mortality among women in the world, considerable interest has been directed toward gender-related differences in presentation, management, and outcomes.¹⁹ Although gender-related difference outcomes of acute coronary syndromes are well documented,^20–22 such information is not available in patients with acute aortic dissection. Thus, we believe that our study is the first to provide useful insights into gender-related differences in incidence, pathogenesis, clinical features, management, and in-hospital outcomes of unselected patients with acute aortic dissection presenting at multiple centers around the world.

Our analysis lends credence to the notion that diagnosis of aortic dissection is more often delayed (not diagnosed in a timely manner, within 4 hours) in women than in men (Table 2); although there was no difference in the proportion of patients with type A or B dissection, outcome of women operated on for aortic dissection was worse than that for men, possibly as a result of later diagnosis and critical preoperative condition. Similar to such other cardiovascular diseases as symptomatic coronary artery disease, aortic dissection occurs in women on average 6 or 7 years later; in fact, 50% of women with aortic dissection were 70 years of age or older. The older age and the higher proportion of women with history of high blood pressure support the notion that hypertension, the incidence of which increases with age, may play the most important role in the pathogenesis of dissection. Marfan’s syndrome-related dissections were equally common in both genders and in keeping with a lack of gender preponderance in this autosomal dominant genetic disease.²³ Interestingly, the prevalence of bicuspid aortic valves was greater in women, suggesting a higher risk of dissection for women than men affected by bicuspid aortic valves.²⁴

In contrast, pregnancy-related dissection^25–28 accounted for only 2 patients among 346 women in IRAD. This suggests that aortic dissection is an extremely rare complication of pregnancy as long as the patient is not affected by any connective tissue disease. The putative association of pregnancy and acute dissection may be largely an artifact of selective reporting. Pregnancy is a common condition, and coincidental occurrence is expected only with concomitant existence of other risk factors, such as hypertension and Marfan’s syndrome. Furthermore, our data indicate that in female patients with Marfan’s syndrome, dissection occurs outside the setting of pregnancy, and they corroborate previous findings suggesting that pregnancy in Marfan’s syndrome is generally well tolerated and not associated with aortic tears, unless the aortic root size exceeds 40 mm.²⁹ IRAD identifies a low incidence of pregnancy-related dissection, which contrasts with other reports that have derived from isolated case reports rather than studies involving larger cohorts of patients. Optimal treatment of hypertension in women may be an important strategy in preventing dissection, whereas pregnancy with Marfan’s syndrome and an aortic root diameter <40 mm at the time of conception is safer than previously thought.^28,29 Nevertheless, because of the autosomal dominant mode of inheritance, the risk of 50% to transmit the disease to the fetus should be recognized; appropriate counseling and amniocentesis may allow diagnosis at the fetal stage.

With this first systematic registry analysis on a large series of patients with acute aortic dissection, important gender-specific characteristics became apparent. Women with type A dissection had a higher death rate, including a 9% higher all cause in-hospital mortality, than men (Table 4; 30.1% versus 21.0%, P=0.001). This observation may be only partly explained by older age at onset of dissection. An intriguing observation is the delayed presentation with less typical pain in women. Fewer women than men present within 6 hours of symptom onset, and 40% of women wait more than 24 hours before first medical contact (Table 2), which may possibly be explained by less typical or less severe perception of pain with less frequent abrupt onset and more frequently observed alterations in consciousness; women seem likely to experience gradual onset of chest or back pain, possibly partly accounting for the longer delay to hospital presentation and less use of intravenous ß-blockers as seen in IRAD. Other aspects of symptomatology in aortic dissection seem to be more severe in women, such as a higher incidence of coma/altered mental status and congestive heart failure, both possibly related to delayed hospitalization and older age. Although imaging findings such as pleural, pericardial, and/or periaortic hematoma suggestive of impending rupture were more often seen in women, urgent surgery was twice as frequently refused by women as by men (31.6% versus 14.0%; P=0.04), potentially in consideration of advanced age/comorbid condition. Similarly, our notion of lower frequency but worse outcome of aortic diseases in elderly women is supported by the quadrupled risk of aortic rupture in women affected by abdominal aortic aneurysms.³⁰ Although a theoretical possibility of more women dying before hospital admission may not be fully excluded (reflecting an inherent limitation of incomplete access to death statistics in a registry), no evidence was produced for any disproportion in premortem diagnosis of dissection in women; the proportion of women presenting after 24 hours of symptoms with (more adverse) proximal dissection was even higher (P>0.008).

Coronary artery involvement was also more common in women, indicative of more proximal dissection(s) than men. Despite proximal involvement and higher incidence of bicuspid aortic valve in women, aortic regurgitation requiring aortic valve surgery occurs less frequently, suggesting that aortic valves may be more often spared by aortic dissection in women than in men. Moreover, women were less likely to be transferred to an aortic center of excellence and more likely to be treated medically than by surgery (Table 3). It is unclear whether older age or an inherent gender-related preferential management contributes to this bias. Even with surgery, however, the mortality of type A dissection is 10% higher in women than in men (P=0.013). Mortality in patients with type A dissection treated medically was high^1,2,17,18 and not different between genders, eg, 58.6% in men and 53.8% in women (Table 4).

Not surprisingly, in-hospital mortality was more common in women, considering that they presented later and were more frequently operated on under high-risk conditions, such as shock and tamponade, known to be associated with type A rather than type B dissection, and with worse outcomes.^2,31 The higher overall mortality in women with type A dissection is therefore related primarily to outcomes under high-risk conditions of tamponade, shock, and coma rather than to differences among medically treated patients (Table 5). Because we observed no significant variation in surgical technique, delay, or hemodynamics at surgery between genders, the differential result in postsurgical outcomes of women appears to be both real and possibly explained by older age and inherently higher risk at surgery. Postsurgical mortality was statistically higher in the advanced age bracket of 66 to 75 years (mortality of 36% in women versus 16% of men, Figure 3), most likely because of unfavorable comorbidity in elderly women. Although confounding hypertension and diabetes, both of which affect the microvasculature, were more prevalent in women, previous cardiac or aortic surgery was more often documented in men (Table 1); diabetes and associated microvascular pathology are known to coincide with greater risk for cardiac mortality in women.³² Increased mortality in type A dissection reminds us of the findings of increased mortality for women treated invasively with either percutaneous coronary intervention^33,34 or bypass surgery^35–37 for acute coronary syndromes.

Again, similar to acute coronary syndrome, clinical features of aortic dissection should be reconsidered in women because they may not be classic, underlining the relevance of neurological symptoms, state of consciousness, and atypical or less pronounced pain perception in women. With such gender-specific differences in mind, the spectrum of suggestive symptoms should be broadened, and female patients at risk (with aortic aneurysms, severe hypertension, and/or known connective tissue disease) should qualify for undelayed confirmatory imaging at a lower threshold.

In summary, this analysis highlights important differences in clinical characteristics, pathogenesis, presenting features, management, and outcomes between women and men with acute aortic dissection. Women with acute aortic dissections have different clinical features, which may explain temporal delay from symptom onset to diagnosis; increased mortality is confined to women with type A dissection treated surgically, a finding that is magnified in patients classified as at high risk. Therefore, physicians should have a heightened index of suspicion of acute aortic dissection in women, and its attendant morbidity and mortality. The development of strategies to identify and treat high-risk female patients with acute aortic syndrome may improve clinical outcomes.

	Appendix

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The International Registry of Acute Aortic Dissection (IRAD) Investigators
Co-Principal Investigators
Kim A. Eagle, MD, University of Michigan, Ann Arbor, Mich; Eric M. Isselbacher, MD, Massachusetts General Hospital, Boston, Mass; Christoph A. Nienaber, MD, University of Rostock, Rostock, Germany.

Co-Investigators
Eduardo Bossone, MD, National Research Council, Southern Italy, Brindisi, Italy; Arturo Evangelista, MD, Hospital General Universitari Vall d’Hebron, Barcelona, Spain; Rossella Fattori, MD, University Hospital S. Orsola, Bologna, Italy; Dan Gilon, MD, Hadassah University Hospital, Jerusalem, Israel; Steve Goldstein, MD, Washington Heart Center, Washington, DC; Stuart Hutchison, MD, St Michael’s Hospital, Toronto, Ontario, Canada; James L. Januzzi, MD, Massachusetts General Hospital, Boston, Mass; Alfredo Llovet, MD, Hospital Universitario 12 de Octubre, Madrid, Spain; Rajendra H. Mehta, MD, MS, University of Michigan, Ann Arbor, Mich; Truls Myrmel, MD, Tromsø University Hospital, Tromsø, Norway; Patrick O’Gara, MD, and Joshua Beckman, MD, Brigham and Women’s Hospital, Boston, Mass; Jae K. Oh, MD, Mayo Clinic, Rochester, Minn; Linda A. Pape, MD, University of Massachusetts Hospital, Worcester, Mass; Marc Penn, MD, Cleveland Clinic Foundation, Cleveland, Ohio; Udo Sechtem, MD, Robert-Bosch Krankenhaus, Stuttgart, Germany; Toru Suzuki, MD, University of Tokyo, Tokyo, Japan.

Data Management and Biostatistical Support
Jeanna V. Cooper, MS, Jianming Fang, MD, and Dean E. Smith, PhD, University of Michigan, Ann Arbor, Mich.

	Acknowledgments

 
This study was supported by the Faculty Group Practice of the University of Michigan Health System and the Varbedian Fund for Aortic Research. The authors thank Leonard G.M. Richartz, who joined the local team on June 22, 2003, for his stimulating and motivating impact.

	Footnotes

 
*Both authors contributed equally to this study.

See Appendix for list of contributors to the International Registry of Acute Aortic Dissection.

	References

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