Complex network populational analysis of comorbidities in patients with ruptured cerebral aneurysms, taking into account sex differences

Background. The population characteristics of comorbidities in patients with subarachnoid hemorrhage (SAH) are insufficiently underlined in the literature.

Aim. To test the method of complex network analysis (NA) in studying sex differences in comorbidities among patients with SAH at the population level.

Materials and methods. CN analysis was conducted on a population-based «big data» sample, including 628,831 patients. Statistical networks of comorbidities were created for 873 patients with SAH caused by cerebral aneurysms rupture of various localizations. Comorbidities were defined as any additional diagnoses presenting in patients with a ruptured cerebral aneurysm both before and after the SAH event. At the final stage of the CN analysis, all associations of comorbidities with the index diagnosis and with each other were examined for statistical significance.

Results. The CN analysis revealed 336 statistically significant associations between diagnostic codes. The number of comorbidities in women was 1.7 times higher than in men. In cases of vertebrobasilar aneurysms, the difference reached 10 times. Arterial hypertension was statistically correlated with the development of SAH only in women.

Conclusion. The CN method is applicable for analyzing clinical data at the population level. The analysis revealed that women with SAH have a higher number of comorbidities, particularly in cases of vertebrobasilar aneurysms. Interpretation of the results should consider the limitations and advantages of the method.

1. Kivelev J., Saarenpää I., Karlsson A. et al. Complex networks approach to study comorbidities in patients with unruptured intracranial aneurysms. Sci Rep 2024;14(1):9175. DOI: 10.1038/s41598-024-59919-2

2. Van Gijn J., Kerr R.S., Rinkel G.J. Subarachnoid haemorrhage. Lancet 2007;369(9558):306–18. DOI: 10.1016/S0140-6736(07)60153-6

3. Etminan N., Brown R.D. Jr., Beseoglu K. et al. The unruptured intracranial aneurysm treatment score: a multidisciplinary consensus. Neurology 2015;85(10):881–9. DOI: 10.1212/WNL.0000000000001891

4. Suarez J.I., Tarr R.W., Selman W.R. Aneurysmal subarachnoid hemorrhage. N Engl J Med 2006;354(4):387–96. DOI: 10.1056/NEJMra052732

5. Lawton M.T., Vates G.E. Subarachnoid hemorrhage. N Engl J Med 2017;377(3):257–66. DOI: 10.1056/NEJMcp1605827

6. Peng C., Zhao Y., Li F. et al., Aneurysmal subarachnoid hemorrhage and sex differences: analysis of epidemiology, outcomes, and risk factors. Neurocrit Care 2024;41(1):119–28. DOI: 10.1007/s12028-023-01929-5

7. Rinkel G.J., Djibuti M., Algra A., van Gijn J. Prevalence and risk of rupture of intracranial aneurysms: a systematic review. Stroke 1998;29(1):251–6. DOI: 10.1161/01.str.29.1.251

8. Catapano J.S., Winkler E.A., Rudy R.F. et al. Sex differences in patients with and without high-risk factors associated with aneurysmal subarachnoid hemorrhage. Acta Neurochir (Wien) 2024;166(1):125. DOI: 10.1007/s00701-024-06021-1

9. Vlak M.H., Algra A., Brandenburg R., Rinkel G.J. Prevalence of unruptured intracranial aneurysms, with emphasis on sex, age, comorbidity, country, and time period: a systematic review and meta-analysis. Lancet Neurol 2011;10(7):626–36. DOI: 10.1016/S1474-4422(11)70109-0

10. Laukka D., Kivelev J., Rahi M. et al. Detection rates and trends of asymptomatic unruptured intracranial aneurysms from 2005 to 2019. Neurosurgery 2024;94(2):297–306. DOI: 10.1227/neu.0000000000002664

11. Kivelev J.V., Saarenpää I., Krivoshapkin A.L. Establishing of big data clinical dataset in brain vessel aneurysm research. Sibirski nauchnyi medicinskij jurnal = Sibirian Scientidic Medical Journal 2023;43(3):86–94. (In Russ.). DOI: 10.18699/SSMJ20230311

12. Barabási A.L. Network medicine – from obesity to the “diseasome”. New Engl J Med 2007;357(4):404–7. DOI: 10.1056/NEJMe078114

13. Tumminello M., Miccichè S., Lillo F. et al., Statistically validated networks in bipartite complex systems. PloS One 2011;6(3):e17994. DOI: 10.1371/journal.pone.0017994

14. Tabuchi S. Relationship between postmenopausal estrogen deficiency and aneurysmal subarachnoid hemorrhage. Behav Neurol 2015;2015:720141. DOI: 10.1155/2015/720141

15. Tada Y., Wada K., Shimada K. et al., Estrogen protects against intracranial aneurysm rupture in ovariectomized mice. Hypertension 2014;63(6):1339–44. DOI: 10.1161/HYPERTENSIONAHA.114.03300

16. Algra A.M., Klijn C.J., Helmerhorst F.M. et al. Female risk factors for subarachnoid hemorrhage: a systematic review. Neurology 2012;79(12):1230–6. DOI: 10.1212/WNL.0b013e31826aace6

17. Maekawa H., Tada Y., Yagi K. et al., Bazedoxifene, a selective estrogen receptor modulator, reduces cerebral aneurysm rupture in Ovariectomized rats. J Neuroinflammation 2017;14(1):197. DOI: 10.1186/s12974-017-0966-7

18. Jackson R.L., Greiwe J.S., Schwen R.J. Emerging evidence of the health benefits of S-equol, an estrogen receptor β agonist. Nutr Rev 2011;69(8):432–48. DOI: 10.1111/j.1753-4887.2011.00400.x

19. Mayo B., Vázquez L., Flórez A.B. Equol: a bacterial metabolite from the daidzein isoflavone and its presumed beneficial health effects. Nutrients 2019;11(9):2231. DOI: 10.3390/nu11092231

20. Setchell K.D., Clerici C., Lephart E.D. et al. S-equol, a potent ligand for estrogen receptor beta, is the exclusive enantiomeric form of the soy isoflavone metabolite produced by human intestinal bacterial flora. Am J Clin Nutr 2005;81(5):1072–9. DOI: 10.1093/ajcn/81.5.1072

21. Yokosuka K., Rutledge C., Kamio Y. et al. Roles of phytoestrogen in the pathophysiology of intracranial aneurysm. Stroke 2021;52(8):2661–70. DOI: 10.1161/STROKEAHA.120.032042

22. Kurmann L., Okoniewski M., Dubey R.K. Estradiol inhibits human brain vascular pericyte migration activity: a functional and transcriptomic analysis. Cells 2021;10(9):2314. DOI: 10.3390/cells10092314

23. Hasan D.M., Mahaney K.B., Brown R.D. Jr. et al., Aspirin as a promising agent for decreasing incidence of cerebral aneurysm rupture. Stroke 2011;42(11):3156–62. DOI: 10.1161/STROKEAHA.111.619411

24. Chalouhi N., Starke R.M., Correa T. et al. Differential sex response to aspirin in decreasing aneurysm rupture in humans and mice. Hypertension 2016;68(2):411–7. DOI: 10.1161/HYPERTENSIONAHA.116.07515

25. Woo D., Khoury J., Haverbusch M.M. et al., Smoking and family history and risk of aneurysmal subarachnoid hemorrhage. Neurology 2009;72(1):69–72. DOI: 10.1212/01.wnl.0000338567.90260.46

26. Cipolla M.J., Liebeskind D.S., Chan S.L. The importance of comorbidities in ischemic stroke: Impact of hypertension on the cerebral circulation. J Cereb Blood Flow Metab 2018;38(12): 2129–49. DOI: 10.1177/0271678X18800589

27. Baumbach G.L., Faraci F.M., Heistad D.D. Effects of local reduction in pressure on endothelium-dependent responses of cerebral arterioles. Stroke 1994;25(7):1456–61; discussion 1461–2. DOI: 10.1161/01.str.25.7.1456

28. Lindekleiv H.M., Valen-Sendstad K., Morgan M.K. et al. Sex differences in intracranial arterial bifurcations. Gend Med 2010;7(2):149–55. DOI: 10.1016/j.genm.2010.03.003

29. Cebral J.R., Castro M.A., Putman C.M., Alperin N. Flow-area relationship in internal carotid and vertebral arteries. Physiol Meas 2008;29(5):585–94. DOI: 10.1088/0967-3334/29/5/005