Evangelia G Sigala ¹ Christina Chrysohoou ² Fotios Barkas ³ Evangelos Liberopoulos ⁴ Petros P Sfikakis ⁴ Antigoni Faka ⁵ Costas Tsioufis ² Christos Pitsavos ² Demosthenes Panagiotakos ^1*

• ¹ Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece
• ² First Cardiology Clinic, National and Kapodistrian University of Athens, Athens, Greece
• ³ Department of Internal Medicine, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
• ⁴ First Department of Propaedeutic and Internal Medicine, School of Health Sciences, National and Kapodistrian University of Athens, Athens, Greece
• ⁵ Department of Geography, School of Environmental Sciences and Economics, Harokopio University, Athens, Greece

Background and aim: This study aims to investigate the role of the built environment in terms of urban-rural disparities in cardiovascular disease (CVD) epidemiology, focusing on middle-and longterm CVD risk assessment. Moreover, this study seeks to explore sex-specific differences in urban and rural settings. Methods: The ATTICA Study is a prospective study conducted from 2002 onwards. At baseline, a random sample of 3,042 CVD-free adults (49.8% men) were randomly drawn from the population of the Attica region, in Greece, with 78% dwelling in urban and 22% in rural municipalities. Follow-up examinations were performed in 2006, 2012, and 2022. Of the total participants, 1,988 had complete data for CVD assessment in the 20-year follow-up. Results: The 10-year and 20-year CVD incidence was 11.8%, 28.0% in rural municipalities and 16.8%, 38.7% in urban municipalities, respectively (ps< 0.05). Unadjusted data analyses revealed significant differences in clinical, laboratory, and lifestyle-related CVD risk factors between urban and rural residents (ps< 0.05). Additionally, sex-based discrepancies in clinical, anthropometric, circulating, and lifestyle risk factors were observed in stratified analyses of urban and rural settings. Multivariate analyses, including generalized structural equation modeling (GSEM), revealed that the impact of the urban built environment on the long-term (20-year) CVD risk is mediated by lifestyle-related risk factors. Conclusion: Urban inhabitants exhibit a higher long-term CVD incidence compared to their rural counterparts, which was partially explained by their lifestyle behaviors. Targeted strategic city planning efforts promoting healthier lifestyle-related behaviors at the micro-environment level could potentially mitigate built-environment impacts on CVD health. Urban-rural settings, ref: rural areas 0.17 (-0.03, 0.37) Physical activity (2002), ref.: sedentary Urban-rural settings, ref: rural areas 0.04 (-0.14, 0.21) *** p-value < 0.001, ** p-value < 0.01, * p-value < 0.05.