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DOI: 10.1055/a-2239-1741
Sex Differences in the Histopathology of Acute Type A Aortic Dissections
Abstract
Background Although sex-related differences in cardiovascular surgery outcomes have increasingly garnered attention in the past decades, knowledge about sex disparities in the pathophysiology of acute type A aortic dissections (ATAADs) remains sparse. In this study, we evaluate the histopathologic and atherosclerotic lesions in female and male ATAAD patients.
Methods A total of 68 patients were studied: 51 ATAAD patients (mean age: 62.5 ± 10.8 years; 49% women) and 17 control patients (mean age: 63 ± 5.5 years; 53% women). Cardiovascular risk factors were assessed clinically. Intimal and medial histopathological features were systematically evaluated in all.
Results Compared to the control group, all ATAAD patients showed significantly more elastic fiber pathology, mucoid extracellular matrix accumulation, smooth muscle cell nuclei loss, and overall medial degeneration (p < 0.0001). The tunica intima was significantly thinner in the ATAAD patients than in the control group (p < 0.023), with the latter exhibiting significantly more progressive atherosclerotic lesions than the former. No difference in medial vessel wall pathology was seen between female and male patients. As compared to male ATAAD patients, atherosclerotic lesions were more severe in female ATAAD patients, independent of age and the cardiovascular risk factor hypertension.
Conclusion All ATAAD patients had a significantly thinner tunica intima and significantly diseased tunica media compared to the control patients. Our results suggest that the severity of medial aortic pathology is not sex specific in ATAAD patients. Intimal differences between females and males could, however, be considered a potential risk factor for the development of an aortic dissection.
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Introduction
An acute type A aortic dissection (ATAAD) occurs when an injury to the intima allows blood to flow between the vessel wall layers forcing the innermost layer to split from the media. An ATAAD has an incidence of 2.1 to 16.4 per 100,000 person-years,[1] making it a more common medical emergency than a ruptured abdominal aortic aneurysm.[2] An acute dissection is highly lethal if not recognized and treated aggressively. Mortality in an ATAAD is as high as 94 to 100% without treatment, with an estimated 1% per hour in the acute setting.[3] Despite advances in diagnostics and treatment strategies, mortality and morbidity of treated patients have failed to decrease in recent years. Vigorous prevention strategies are therefore urgently required. To date, the only way to prevent an acute aortic syndrome is with prophylactic aortic replacement based on screening of the aortic diameter.[4] [5] At present, the guidelines do not advice sex-specific strategies in the risk stratification or treatment of an aortic aneurysms, even though women are three times more vulnerable to an acute aortic complication as compared to men and have a worse clinical outcome.[6] Moreover, most acute aortopathy occurs at a smaller aneurysm size in females than in males, even after correcting for aneurysm size to body size.[6] [7]
To comprehend the higher risk of aortopathy in female patients, there is a critical need to understand sex disparities in ATAAD behavior and biology. Although sex-related differences in cardiovascular surgery have in general been investigated in the past decades, knowledge about the impact of sex on the histopathological differences in the dissected aorta is poor. This study aims to identify the impact of sex differences on the histopathology of an ATAAD, which could aid in sex-specific strategies for aneurysm surveillance and treatment. We systematically describe the histopathological features of the ascending aortic wall in female and male ATAAD patients.
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Material and Methods
Ethical Statement
Approval for the study was granted by the Medial Ethical Committee of Leiden University Medical Center (LUMC), Leiden-Den Haag-Delft (METC-LDD, ref: B21.051/MS/ms) and was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all ATAAD patients.
All control specimens were obtained postmortem. Obduction and tissue collection have been performed according to the guidelines and protocols for secondary tissue use of the department of pathology of the LUMC.
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Patients and Tissue Samples
Residual ascending aortic specimen was obtained in 51 ATAAD patients undergoing an emergency aortic replacement at the LUMC in Leiden, the Netherlands. Age less than 18 years, a proven genetic disorder, or other etiologies (i.e., inflammatory, infective, congenital, trauma, and pregnancy) were considered the exclusion criteria for the study.
Control aortic specimens were obtained from diseased donors (n = 17); none of the donors had a cardiac cause of death. Causes of death were cancer in 6 patients, sepsis in 4 patients, pulmonary embolism in 3 patients, bowel perforation in 2 patients, pancreatitis in 1 patient, and cardiac arrest in 1 patient, without signs of coronary artery disease on coronary angiography.
Collection of circular ascending aortic wall tissue was uniformly performed at the aortotomy site in the ATAAD and control patients.
After retrieval, aortic tissue was fixed with 4% formalin (1 day) and embedded in paraffin. Transverse sections (4 μm thick) were mounted on precoated StarFrost slides (Klinipath BV, Duiven, the Netherlands). To avoid sampling error of the aortic tissue, the complete circular specimen was sectioned and studied.
Successive sections were stained with hematoxylin and eosin (H&E), resorcin-fuchsin (RF), and Movat's pentachrome. Additional immunofluorescence staining with alpha smooth muscle actin (αSMA) was performed to identify smooth muscle cell nuclei loss. The sectioning and staining protocols have been described previously.[8]
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Histological Classification of the Lesions
H&E, RF, and Movat stained sections were examined for the histopathological evaluation of all samples of each circular aortic specimen. Histomorphological grading of the sections was performed according to the consensus classification for degenerative aorta pathology.[8] [9] Elastic fiber fragmentation/loss, elastic fiber thinning, elastic fiber disorganization, mucoid extracellular matrix accumulation, smooth muscle cell nuclei loss, and overall medial degeneration were described as none (0), mild (1), moderate (2), or severe (3). The tunica intima thickness was measured, defined as the distance between the endothelial cell layer and the internal elastic lamina, excluding atherosclerotic lesions.
Atherosclerotic lesions were further individually classified in each section according to the modified American Heart Association classification of atherosclerosis.[10] Across the circular ascending aortic wall tissue, the atherosclerotic lesion with the most advanced grade of atherosclerosis was called the “dominant lesion” and was analyzed for this study.
All the specimens were scored blinded to the clinical characteristics of the aortic specimen and reevaluated by an independent, experienced histopathologist, which confirmed the findings.
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Statistical Analysis
All numerical data are presented as mean ± standard deviation. Statistical differences were evaluated with the Mann–Whitney U test for comparison between the groups. One-, two-, and three-way analysis of covariance (ANCOVA), binary logistic regression, and linear regression analysis were performed to correct for age and hypertension. Significance was assumed when p < 0.05. SPSS 28.0 (IBM SPSS Statistics, Version 28.0; IBM Corp, Armonk, NY) was used for the statistical analyses.
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Results
Study Population and Clinical Characteristics
Patient characteristics of the 51 included ATAAD patients are presented in [Table 1]. The ATAAD group consisted of 49% females, with no significant age difference between female and male patients (mean age of female patients: 61.3 ± 9.8 years; mean age of male patients: 63.4 ± 11.9 years; p = 0.493).
Abbreviations: BAV, bicuspid aortic valve; BMI, body mass index; CI, confidence interval; COPD, chronic obstructive pulmonary disease; OR, odds ratio; PAOD, peripheral arterial occlusive disease.
Note: Data are presented as n (%), mean ± SD (standard deviation), or median (interquartile range).
The control group (n = 17) consisted of 53% female patients, with no significant age difference between female and male patients (mean age of female patients: 60.4 ± 6.1 years; mean age of male patients: 63.2 ± 5.4 years; p = 0.73).
All included patients had a tricuspid aortic valve, and no underlying aortic genetic disease was identified after genetic screening by the institutional geneticist ([Table 1]).
The mean body mass index (BMI) of all ATAAD patients was 26 kg/m2; 19 patients (37%) were considered overweight (BMI > 25 kg/m2), with no significant differences in BMI between female and male patients ([Table 1]). The majority of ATAAD patients had a history of hypertension (59%), defined as antihypertensive medication or systolic blood pressure greater than 140 mm Hg and diastolic blood pressure greater than 90 mm Hg in the period. Incidence of hypertension was significantly higher in female than in male ATAAD patients (p < 0.005). None of the ATAAD patients had a history of diabetes or peripheral arterial disease. The smoking status was not known for most patients.
In control patients, data on cardiovascular risk factors could not be retrieved for all.
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Ascending Aortic Wall Pathology
[Fig. 1] shows an overview of the normal ascending aortic wall. The tunica intima was significantly thinner in all ATAAD patients as compared to the control specimen (143 ± 126.5 vs. 193 ± 132 μm, p < 0.023; [Fig. 2]; [Table 2]). No difference in intimal thickness was noted between female and male ATAAD patients (p = 0.669; [Fig. 2D, E]; [Table 2]). No significant difference in intimal thickness was further observed when corrected for age or in the presence of (a history of) hypertension (age vs. intimal thickness; p = 0.406; hypertension vs. intimal thickness; odds ratio [OR]: 1.00 [95% confidence interval (CI): 1.00–1.00], p = 0.860).
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Abbreviations: ATAAD, acute type A aortic dissection; CI, confidence interval; elastic fiber degeneration; EFD, elastic fiber degeneration; EFF/L, elastic fiber fragmentation/loss; EFT, elastic fiber thinning; EMD, Overall medial degeneration; MEMA, mucoid extracellular matrix accumulation; OR, odds ratio; SMCNL, smooth muscle cell nuclei loss.
Medial layer pathology was significantly more profound in all ATAAD patients as compared to the control group ([Fig. 3]; [Table 2]): mucoid extracellular matrix accumulation (p > 0.0001; [Fig. 3A, D]; [Table 2]); elastic fiber fragmentation and loss (p > 0.0001; [Table 2]; [Fig. 3B, E]); elastic fiber thinning (p > 0.0001; [Table 2]; [Fig. 3B, F]); elastic fiber disorganization (p > 0.0001; [Fig. 3B, G]; [Table 2]); smooth muscle cell nuclei loss (p > 0.0001; [Fig. 3C, H, I–L]; [Table 2]); and overall medial degeneration (p > 0.0001; [Fig. 3C, M]; [Table 2]). Loss of smooth muscle cell nuclei is seen in the aortic media ([Fig. 3C, H, I–L]). The medial layer pathology of the female and male ATAAD specimens was similar ([Figs. 3] and [4]; [Table 2]).
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Intimal Atherosclerotic Lesions
Atherosclerotic lesions in the intima were scored according to the modified American Heart Association classification of atherosclerosis.[10] The classification categories and characterizations are provided in [Table 3].
Abbreviations: AHA, American Heart Association; ATAAD, acute type A aortic dissection; CI, confidence interval; OR, odds ratio.
Seven ATAAD patients had a normal intima, 43% of which were females ([Fig. 5A], [Table 3]). Twenty-two type A aortic dissection patients demonstrated adaptive intimal thickening ([Fig. 5B], [Table 3]). In these patients, the intimal thickening consisted mainly of smooth muscle cells with an increase in proteoglycan-rich matrix. Of the patients with adaptive intimal thickening, 64% were females.
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As soon as macrophage-derived foam cells become evident in the intima, the lesions are referred to as intimal xanthoma ([Fig. 5C], [Table 3]). These lesions were seen in 14 patients, of which 14% were females.
Progressive atherosclerotic lesions were seen in seven ATAAD patients ([Fi. 5D–G], [Table 3]), 86% of which were seen in female patients. Four of these seven patients demonstrated pathological intimal thickening, all of which were females ([Fig. 5D], [Table 3]). From the most severe atherosclerotic lesions, early fibroatheroma ([Fig. 5E]) and late fibroatheroma ([Fig. 5F]) were seen in female patients. Thin cap fibroatheroma was seen in a male ATAAD patient ([Fig. 5G]).
The severity of the atherosclerotic lesions was independent of age and the cardiovascular risk factor hypertension (age vs. atherosclerosis classification; p = 0.976; hypertension vs. atherosclerosis classification; OR: 1.14 [95%CI: 0.72–1.78]; p = 0.587).
In the control group, patients predominantly exhibited progressive atherosclerotic lesions. Nonprogressive atherosclerotic lesions (intimal xanthoma) were seen in only three patients. Three patients showed pathological intimal thickening, 2 had early fibroatheroma, 6 demonstrated late fibroatheroma, 1 had a healed rupture, and 2 had a fibrotic calcified plaque. Sex was randomly distributed across the nonprogressive and progressive atherosclerotic lesions in the control group.
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Discussion
A type A aortic dissection is a life-threatening condition that may be fatal if not detected and treated promptly. Current guidelines suggest prophylactic surgical aortic replacement based on a size cutoff, for both female and male individuals. However, the guidelines do not advice sex-specific strategies in the risk stratification or treatment, even though the clinical consequences are worse in women,[11] with a poorer surgical outcome and a higher mortality.[6] [12] [13] Despite evident clinical differences, little is known about the histopathological sex differences in ATAAD patients. Therefore, this study investigated the role of sex on the histopathology of a dissected ascending aorta in female and male patients.
Medial histopathological features were significantly distinct between the ATAAD patients and the control group, whereas the female and male ATAAD aorta did not exhibit any difference in elastic fiber pathology, mucoid extracellular matrix accumulation, medial degeneration, or smooth muscle cell nuclei loss.
Differences in intimal atherosclerosis were observed between female and male patients. Unlike abdominal aortopathy, thoracic aortopathy has not been associated with progressive aortic atherosclerosis in previous studies.[14] However, findings in earlier works might have been influenced by a male predominance in the ATAAD (study) population, with an underrepresentation of the female aortic pathology. In the current study, we sought to investigate the prevalence of atherosclerotic lesions in female and male patients according to the modified classification of the American Heart Association.[10] As both female and male patients were evenly distributed in our population with no significant difference in age, these factors could be eliminated as possible confounders of our histopathological findings. Eighty-four percent of the ATAAD group had a normal intima or exhibited nonprogressive atherosclerotic lesions. Notably, a large majority of the individuals who did develop progressive atherosclerotic lesions were females (86%, N = 6). To the best of our knowledge, this is the first study to demonstrate significant histopathological differences between male and female ATAAD patients, independent of age and cardiovascular risk factors such as hypertension. Even though medial pathological findings described in this study are not different between female and male ATAAD patients, the intimal differences could be considered as a potential risk factor for the development of an aortic dissection. As the prevalence of ascending aortic atherosclerosis in ATAADs is low, it should be highlighted that a larger study is needed to investigate the role of atherosclerosis as a potential risk stratification factor for future aortic complications in female patients. Improvement of personalized risk stratification is key to tailor treatment strategies of a life-threatening ATAAD.
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Study Limitations
Our study compared the histopathological features in the ascending aortic wall of patients with a type A aortic dissection and control specimen. Our approach is limited due to the absence of frozen tissue samples to confirm our semi-quantitively analyzed immunohistochemistry data. Our study is further limited by the relatively low number of control patients as compared to the dissected specimen. Genetic screening is performed in the patients to exclude an aortic genetic disease; however, unknown genetic mutations associated with sporadic type A dissections can be missed.
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Conflict of Interest
None declared.
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References
- 1 Wundram M, Falk V, Eulert-Grehn JJ. et al. Incidence of acute type A aortic dissection in emergency departments. Sci Rep 2020; 10 (01) 7434
- 2 Hallett JW, Mills JL, Earnshaw JJ, Reekers JA, Rooke TW. eds. Comprehensive Vascular and Endovascular Surgery. 2nd ed. Philadelphia, PA: Mosby; 2009
- 3 Johansson G, Markström U, Swedenborg J. Ruptured thoracic aortic aneurysms: a study of incidence and mortality rates. J Vasc Surg 1995; 21 (06) 985-988
- 4 Isselbacher EM, Preventza O, Hamilton Black Iii J. et al; Writing Committee Members. 2022 ACC/AHA guideline for the diagnosis and management of aortic disease: a report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol 2022; 80 (24) e223-e393
- 5 Erbel R, Aboyans V, Boileau C. et al; ESC Committee for Practice Guidelines, ; The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC). 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases: document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. Eur Heart J 2014; 35 (41) 2873-2926
- 6 Nienaber CA, Fattori R, Mehta RH. et al; International Registry of Acute Aortic Dissection. Gender-related differences in acute aortic dissection. Circulation 2004; 109 (24) 3014-3021
- 7 Pape LA, Tsai TT, Isselbacher EM. et al; International Registry of Acute Aortic Dissection (IRAD) Investigators. Aortic diameter >or = 5.5 cm is not a good predictor of type A aortic dissection: observations from the International Registry of Acute Aortic Dissection (IRAD). Circulation 2007; 116 (10) 1120-1127
- 8 Grewal N, Girdauskas E, Idhrees M. et al. Structural abnormalities in the non-dilated ascending aortic wall of bicuspid aortic valve patients. Cardiovasc Pathol 2023; 62: 107478
- 9 Halushka MK, Angelini A, Bartoloni G. et al. Consensus statement on surgical pathology of the aorta from the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology: II. Noninflammatory degenerative diseases: nomenclature and diagnostic criteria. Cardiovasc Pathol 2016; 25 (03) 247-257
- 10 Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000; 20 (05) 1262-1275
- 11 Boczar KE, Coutinho T. Sex considerations in aneurysm formation, progression, and outcomes. Can J Cardiol 2018; 34 (04) 362-370
- 12 Beller CJ, Farag M, Wannaku S. et al. Gender-specific differences in outcome of ascending aortic aneurysm surgery. PLoS One 2015; 10 (04) e0124461
- 13 Cheung K, Boodhwani M, Chan KL, Beauchesne L, Dick A, Coutinho T. Thoracic aortic aneurysm growth: role of sex and aneurysm etiology. J Am Heart Assoc 2017; 6 (02) 6
- 14 Dolmaci OB, El Mathari S, Driessen AHG. et al. Are thoracic aortic aneurysm patients at increased risk for cardiovascular diseases?. J Clin Med 2022; 12 (01) 12
Address for correspondence
Publikationsverlauf
Eingereicht: 28. Juni 2023
Angenommen: 03. Januar 2024
Accepted Manuscript online:
05. Januar 2024
Artikel online veröffentlicht:
12. Februar 2024
© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
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References
- 1 Wundram M, Falk V, Eulert-Grehn JJ. et al. Incidence of acute type A aortic dissection in emergency departments. Sci Rep 2020; 10 (01) 7434
- 2 Hallett JW, Mills JL, Earnshaw JJ, Reekers JA, Rooke TW. eds. Comprehensive Vascular and Endovascular Surgery. 2nd ed. Philadelphia, PA: Mosby; 2009
- 3 Johansson G, Markström U, Swedenborg J. Ruptured thoracic aortic aneurysms: a study of incidence and mortality rates. J Vasc Surg 1995; 21 (06) 985-988
- 4 Isselbacher EM, Preventza O, Hamilton Black Iii J. et al; Writing Committee Members. 2022 ACC/AHA guideline for the diagnosis and management of aortic disease: a report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol 2022; 80 (24) e223-e393
- 5 Erbel R, Aboyans V, Boileau C. et al; ESC Committee for Practice Guidelines, ; The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC). 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases: document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. Eur Heart J 2014; 35 (41) 2873-2926
- 6 Nienaber CA, Fattori R, Mehta RH. et al; International Registry of Acute Aortic Dissection. Gender-related differences in acute aortic dissection. Circulation 2004; 109 (24) 3014-3021
- 7 Pape LA, Tsai TT, Isselbacher EM. et al; International Registry of Acute Aortic Dissection (IRAD) Investigators. Aortic diameter >or = 5.5 cm is not a good predictor of type A aortic dissection: observations from the International Registry of Acute Aortic Dissection (IRAD). Circulation 2007; 116 (10) 1120-1127
- 8 Grewal N, Girdauskas E, Idhrees M. et al. Structural abnormalities in the non-dilated ascending aortic wall of bicuspid aortic valve patients. Cardiovasc Pathol 2023; 62: 107478
- 9 Halushka MK, Angelini A, Bartoloni G. et al. Consensus statement on surgical pathology of the aorta from the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology: II. Noninflammatory degenerative diseases: nomenclature and diagnostic criteria. Cardiovasc Pathol 2016; 25 (03) 247-257
- 10 Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000; 20 (05) 1262-1275
- 11 Boczar KE, Coutinho T. Sex considerations in aneurysm formation, progression, and outcomes. Can J Cardiol 2018; 34 (04) 362-370
- 12 Beller CJ, Farag M, Wannaku S. et al. Gender-specific differences in outcome of ascending aortic aneurysm surgery. PLoS One 2015; 10 (04) e0124461
- 13 Cheung K, Boodhwani M, Chan KL, Beauchesne L, Dick A, Coutinho T. Thoracic aortic aneurysm growth: role of sex and aneurysm etiology. J Am Heart Assoc 2017; 6 (02) 6
- 14 Dolmaci OB, El Mathari S, Driessen AHG. et al. Are thoracic aortic aneurysm patients at increased risk for cardiovascular diseases?. J Clin Med 2022; 12 (01) 12
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