Biological heart and brain ageing in subjects with cardiovascular diseases

Elizabeth McAvoy^1,2,3*Matthias Wilms^1,3,4,5,6Nils Daniel Forkert^1,3,4,7

• ¹Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
• ²Department of Biomedical Engineering, Schulich School of Engineering, University of Calgary, Calgary, Alberta, Canada
• ³Department of Radiology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
• ⁴Alberta Children's Hospital Research Institute (ACHRI), Calgary, Alberta, Canada
• ⁵Department of Pediatrics, Cumming School fo Medicine, University of Calgary, Calgary, Alberta, Canada
• ⁶Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
• ⁷Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

The heart-brain axis hypothesis suggests a bidirectional connection between the brain and the heart with relevant implications in health and disease. Cardiovascular diseases have been empirically linked to an increased risk of neurological diseases. However, it remains unclear to what extent different cardiovascular diseases affect brain health quantitatively across subjects and if that is associated with the extent the heart is affected by a disease. Therefore, this study aims to explore how cardiovascular diseases affect biological ageing of the brain and heart by quantifying the brain age gap (BAG) and the heart age gap (HAG) and relating the two to each other. This study used data from UK Biobank participants with available T1-weighted brain magnetic resonance imaging (MRI) scans, cardiac MRI-derived features, as well as pulse wave analysis cardiac measurements. This dataset included 7500 healthy females and 6684 healthy males. The data from healthy subjects was used to train biological brain age prediction machine learning models. For BAG computation, a convolutional neural network was trained based on the MRI data, while a CatBoost model was trained for HAG analyses based on the tabulated cardiac features. Individuals with cardiovascular diseases (F=2304, M=2925) in the UK Biobank were categorized using Phecodes and split based on sex and used to calculate the HAG and BAG for further analyses. In 36 sex-specific cardiovascular disease groups, 24 showed significant differences from healthy subjects in the BAG and HAG distributions, whereas no strong correlations between the BAG and HAG distributions within disease groups were found. However, some diseases, such as hypotension and cardiac conduction disorders, showed sex-specific differences. This study demonstrates that the combined use of HAG and BAG biomarkers provides a more comprehensive understanding of the interplay between cardiovascular and neurological ageing. The significant differences observed in disease groups, while lacking a strong correlation between the BAG and HAG, questions the generalizability of the heart-brain axis theory with respect to age gap biomarkers, suggesting potentially heterogeneous aging processes of the two systems that warrant further investigation in future work.