Introduction
Nowadays, cardiovascular diseases (CVDs) have become one of the most serious health-related problems in the world. Abnormalities of the inter-atrial septum, including atrial septal aneurysm (ASA), atrial septal defect, and patent foramen ovale (PFO), are common congenital diseases among adults. Non-congenital CVDs, including ischemic heart disease, arrhythmias, and aortic valve stenosis, are also common in adults. In studies conducted on ASA patients, it has been determined that ASA is associated with cerebral and cardiac events and can indirectly affect the mortality rate of patients. Although ASA can exist alone, it is often associated with other cardiac abnormalities such as mitral valve prolapse, ASD, PFO, and also with conduction disorders, especially right bundle branch block. Its association with congenital CVDs, increased pulmonary and systemic pressure, thrombosis, and thromboembolic strokes has also been reported. Based on results from some prospective studies, the prevalence of supraventricular arrhythmias in patients with ASA is estimated to be 30-40%. In studies conducted on patients with cerebral embolic events with unknown cause, it has been observed that in 40% of patients, the events were due to cardiac abnormalities. In cases where cardiac abnormalities, including PFO and ASA, are present, it has been proven that the risk of cerebral embolic events increases due to emboli sent from the heart to the cerebral vessels. Although the ASA is well-defined as a saccular deformity of the atrial wall, there is still limited information about its clinical significance. In the present study, we aimed to examine the association of congenital and non-congenital CVDs simultaneously with ASA using the transthoracic echocardiography (TTE) in patients referred to a specialized heart center in Guilan province, north of Iran.

Methods
In this study, 250 patients referred to the echo department of Dr. Heshmat Heart Hospital in Guilan province were selected and divided into two groups with and without ASA. Abnormalities of the inter-atrial septum as well as the history of congenital and non-congenital CVDs were determined and analyzed at the 95% confidence level. All cardiovascular examinations and TTE were performed by an echocardiography fellow. The data of patients regarding clinical events related to systemic embolism, history of arrhythmia, and any known disease in other body systems were examined using the medical records. Additionally, the presence or absence of electrocardiographic disorders, including arrhythmias, was examined. The diagnosis of ASA was done based on the criteria specified by Handley et al. (i.e. the deviation of the inter-atrial septum greater than 10-15 mm to the left or right side), confirmed by TTE. In the color Doppler imaging, PFO was diagnosed as an inter-atrial shunt from left to right at the site of the ovale fossa or an interatrial shunt from right to left by injecting 10 mL of agitated saline through the cubital vein in the resting state and during provocative maneuvers (cough or Valsalva maneuver). For the diagnosis of atrial septal and ventricular septal defects, the 2D echocardiography, as well as the color Doppler and contrast echocardiography, if necessary, were used. Aortic stenosis was diagnosed by examining the maximum velocity obtained from continuous Doppler exceeding 2.5 m/s. The ischemic heart disease was diagnosed when there was a stenosis of more than 50% in at least one of the three main coronary arteries. Moreover, left bundle branch block in the electrocardiogram was diagnosed when there was a delay or block in the conduction of electrical impulses to the left heart.
Qualitative variables were reported using frequency and percentage, and quantitative variables were reported using mean and standard deviation. The data were analyzed using the chi-squared test and Fisher’s exact test. To determine the predictors of ASA and to assess the role of demographic and disease-related variables, the logistic regression analysis was used, and the odds ratios (ORs) were calculated.

Results
The percentage of congenital CVDs in patients with ASA was 20% (95% CI; 10.8%, 32.6%). In patients without ASA, it was only 6% (95% CI; 3.3%, 9.9%), which was statistically significant based on Fisher’s exact test (P=0.004). The OR of congenital CVDs in the development of ASA in univariate analysis was 3.9 (95% CI; 1.59%, 9.69%). The percentage of non-congenital CVDs in patients with ASA was 17.5% ( 95% CI; 12.7%, 23.2%). In patients without ASA, it was 28% (95% CI; 17.0%, 41.4%). This difference was not statistically significant based on the chi-square test (P=0.094).
According to the results, 6% of patients with ASA and 1.5% of patients without ASA had a history of stroke, but the difference was not statistically significant (P=0.096). However, regarding the history of transient ischemic attack, the difference was significant (P=0.001). The percentage of transient ischemic attack in patients without ASA was 0.5%, while in patients with ASA, this rate was 10%. In the final logistic regression model, history of transient ischemic attack (P=0.002, OR=32.2), history of stroke (P=0.031, OR=6.3), history of congenital CVDs (P<0.001, OR=5.5), and history of non-congenital CVDs (P=0.029, OR=2.4) were found as the most important predictors of ASA.

Conclusion
The most important predictors of ASA are history of transient ischemic attack, stroke, and congenital and non-congenital CVDs. Therefore, it can be said that, in addition to the history of stroke and transient ischemic attack, ASA is significantly associated with congenital and non-congenital CVDs. 

Ethical Considerations

Compliance with ethical guidelines
This study was approved by the Ethics Committee of Guilan University of Medical Science, Rasht, Iran (Code: IR.GUMS.REC.1397.110). All procedures were in accordance with ethical guidelines. No additional cost was imposed on the participants. Written informed consent was obtained from all participants. 

Funding
This research was funded by Guilan University of Medical Science, Rasht, Iran (Grant No: 97022907). 

Authors contributions
Conceptualization and study design: Mohammad Reza Aghajankhah; Data collection and data analysis: Mohammad Reza Aghajankhah, Mahshid Ehteshami, Ehsan Kazemnezhad Leyli, and Hassan Moladoust; preparing the initial draft: Mahshid Ehteshami and Golshan Ghasemzadeh; editing & review: Mohammad Reza Aghajankhah, Hassan Moladoust, Golshan Ghasemzadeh; Statistical analysis: Ehsan Kazemnezhad Leyli and Hassan Moladoust; Funding acquisition: Mohammad Reza Aghajankhah and Mahshid Ehteshami; Supervision: Mohammad Reza Aghajankhah, Ehsan Kazemnezhad Leyli, and Hassan Moladoust.

Conflicts of interest
The authors declare no conflict of interest.

Acknowledgements
The authors would like to thank the Vice-Chancellor for Research and Technology of Guilan University of Medical Sciences for the financial support and all participants and the staff of Dr. Hashemat Heart Hospital for their cooperation in this research.

 

 

1. Nasrabadi T, Goodarzi Zadeh N, Shahrjerdi AR, Hamta A. [The effect of education on life style among patients suffering from ischemic heart disease (Persian)]. Journal of Mazandaran University of Medical Sciences. 2010; 20(79):72-9. [Link]
2. Khosravi A, Ebrahimi H. [Investigation of the possibility of one-year survival and its effective factors in patients with myocardial infarction (Persian)]. Shahroud Journal of Medical Sciences. 2008; 3(1):9-15. [Link]
3. Bakalli A, Koçinaj D, Georgievska-Ismail L, Bekteshi T, Pllana E, Sejdiu B. Right bundle branch block as a marker for interatrial septal abnormalities. Cardiology in the Young. 2012; 22(1):18-25. [DOI:10.1017/S1047951111000795] [PMID] 
4. Brida M, Chessa M, Celermajer D, Li W, Geva T, Khairy P, et al. Atrial septal defect in adulthood: A new paradigm for congenital heart disease. European Heart Journal. 2022; 43(28):2660-71. [DOI:10.1093/eurheartj/ehab646] [PMID] 
5. Yetkin E, Atalay H, Ileri M. Atrial septal aneurysm: Prevalence and covariates in adults. International Journal of Cardiology. 2016; 223:656-9. [DOI:10.1016/j.ijcard.2016.08.220] [PMID] 
6. Snijder RJ, Luermans JG, de Heij AH, Thijs V, Schonewille WJ, Van De Bruaene A, et al. Patent foramen ovale with atrial septal aneurysm is strongly associated with migraine with aura: A large observational study. Journal of the American Heart Association. 2016; 5(12):e003771. [DOI:10.1161/JAHA.116.003771] [PMID] [PMCID] 
7. Rigatelli G, Zuin M, Bilato C. Atrial septal aneurysm contribution to the risk of cryptogenic stroke in patients with patent foramen ovale: A brief updated systematic review and meta-analysis. Trends in Cardiovascular Medicine. 2023; 33(6):329-33. [DOI:10.1016/j.tcm.2022.02.006] [PMID] 
8. Waqas S, Dawes S, Brar J, Abid W, Kanitkar A. Atrial septal aneurysm leading to ischemic stroke: A case report and literature review. Cureus. 2024; 16(5):e60955. [DOI:10.7759/cureus.60955] 
9. Mügge A, Daniel WG, Angermann C, Spes C, Khandheria BK, Kronzon I, et al. Atrial septal aneurysm in adult patients: a multicenter study using transthoracic and transesophageal echocardiography. Circulation. 1995; 91(11):2785-92. [DOI:10.1161/01.CIR.91.11.2785] [PMID] 
10. Brand A, Keren A, Branski D, Abrahamov A, Stern S. Natural course of atrial septal aneurysm in children and the potential for spontaneous closure of associated septal defect. The American Journal of Cardiology; 64(16):996-1001. [DOI:10.1016/0002-9149(89)90797-2] [PMID] 
11. Ozcelik N, Atalay S, Tutar E, Ekici F. Prevalence of interatrial septal aneurysm in newborns and their natural course. Pediatric Cardiology. 2006; 27(3):343-6. [DOI:10.1007/s00246-005-1224-9] [PMID] 
12. Jatav RK, Kumbhare MB, Surender T, Rachan C, Krishna TV. Atrial septal aneurysm in adult patients: Spectrum of clinical, echocardiographic presentation and to propose a new classification on the basis of trans-thoracic-two-dimensional echocardiography. International Journal of Research in Medical Sciences. 2017; 2(2):708-17. [DOI:10.5455/2320-6012.ijrms20140564] 
13. Hanley PC, Tajik AJ, Hynes JK, Edwards WD, Reeder GS, Hagler DJ, et al. Diagnosis and classification of atrial septal aneurysm by two-dimensional echocardiography: Report of 80 consecutive cases.  Journal of the American College of Cardiology. 1985; 6(6):1370-82. [DOI:10.1016/S0735-1097(85)80228-X] [PMID] 
14. Nozary Y, Kaliji BA. [Frequency of atrial septal anomalies in patients with cerebral embolic events with unknown origin by transthoracic and transesophageal echocardiography (Persian)]. Tehran University of Medical Sciences Journal. 2003; 61(3):238-44. [Link]
15. Russo V, Rago A, Di Meo F, Papa AA, Ciardiello C, Cristiano A, et al. Atrial septal aneurysms and supraventricular arrhythmias: The role of atrial electromechanical delay. Echocardiography. 2015; 32(10):1504-14. [DOI:10.1111/echo.12908] [PMID] 
16. Bakalli A, Pllana E, Koçinaj D, Bekteshi T, Dragusha G, Gashi M, et al. Association of interatrial septal abnormalities with cardiac impulse conduction disorders in adult patients: Experience from a tertiary center in Kosovo. Heart International. 2011; 6(1):e4. [DOI:10.4081/hi.2011.e4] [PMID] [PMCID] 
17. Mattioli A, Aquilina M, Oldani A, Longhini C, Mattioli G. Atrial septal aneurysm as a cardioembolic source in adult patients with stroke and normal carotid arteries. A multicentre study. European Heart Journal. 2001; 22(3):261-8. [DOI:10.1053/euhj.2001.2293] [PMID] 
18. Bassareo PP, Fanos V, Puddu M, Cadeddu C, Cadeddu F, Saba L, et al. High prevalence of interatrial septal aneurysm in young adults who were born preterm. The Journal of Maternal-Fetal & Neonatal Medicine. 2014; 27(11):1123-8. [DOI:10.3109/14767058.2013.850667] [PMID] 
19. Zeng H, Lan B, Liu X, Xie H, Li B, Xue X, et al. Clinical implications and procedural complications in patients with patent foramen ovale concomitant with atrial septal aneurysm.Cardiovascular Innovations and Applications. 2024; 9(1):943. [DOI:10.15212/CVIA.2024.0038] 
20. Atak R, Ileri M, Ozturk S, Korkmaz A, Yetkin E. Echocardiographic findings in patients with atrial septal aneurysm: A prospective case-control study. Cardiology Research and Practice. 2019; 2019(1):3215765. [DOI:10.1155/2019/3215765] [PMID] [PMCID]