byEuropean Society of Cardiology

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The TO_AITION project, completed this month (December 2025), has been investigating the biological causes of inflammation linking cardiovascular diseases (CVD) and depression, and has used a wide range of biological and analytical techniques to identify the mechanisms, shared biological pathways and biomarkers that explain why cardiovascular diseases and depression can develop together.

"For too long, the biological links between heart disease and mental health have been underestimated and underexplored," explains Dr. Evangelos Andreakos, Director, Center for Clinical Research, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, and Coordinator of Horizon 2020 project TO_AITION. "Patients with CVD and depression are among the most vulnerable, yet their multimorbidity remains poorly understood. We are changing that."

CVD is the leading cause of death worldwide, with 10.2 million people falling ill with CVD every year across Europe. CVD has remained the most common cause of death across ESC member countries with more than 3 million deaths every year, including more than 1.6 million deaths in females and 1.5 million deaths in males. Depression affects more than 300 million people worldwide and increases CVD risk and mortality by 2–3 times: 1 in 3 CVD patients experiences depression; 1 in 2 develops it after major cardiac events.

TO_AITION addressed the hypothesis that immune-metabolic dysregulation, occurring as a result of genetic, lifestyle and environmental risk factors "training" innate immunity, drives low-grade systemic inflammation leading to the development of CVD-depression comorbidity. The project aimed to transform our current understanding of the causative mechanisms driving CVD-depression comorbidity, unraveling patients' complexity and improving their diagnosis, monitoring and management.

The consortium, involving 14 partner organizations around Europe including the European Society of Cardiology (ESC), has harmonized and enrichedlarge-scale human cohortswith proteomic, epigenetic and microbiome data, and used computer and statistical modeling to identify shared biological pathways. These analyses highlighted overlapping inflammatory and metabolic mechanisms, potential driver nodes of multimorbidity, and candidate biomarkers for diagnosis and prognosis.

Laboratory and preclinical studies also included in the project have also advanced our understanding of the CVD-depression comorbidity significantly, andbiomarker discoveryefforts have identified molecules including proteins, fats, messenger RNAs and epigenetic signatures associated with comorbid disease. The first versions of a lab-on-chip assay and a multiscale risk-prediction platform were also developed.

One of the successes of the project so far is the demonstration of theTO_AITION cloud risk stratification platformduring the ESC Congress 2025 (Madrid, August 2025), demonstrated by Dr. Antonis Sakellarios from partner institution, the University of Ioannina, Greece. It is a web-accessible risk stratification platform for diagnosis, prognosis, and treatment support of CVD/depression comorbidity. It is designed for use by caregivers, cardiologists, psychiatrists, mental health physicians, and industry partners.

The project has also led to publications including "Major depression and atherosclerotic disease: Linking shared genetics to pathways in blood, brain, heart, and atherosclerotic plaques." This work shows that "major depression and atherosclerotic diseases share genetic risk factors that may contribute to depression pathophysiology through gene expression in blood, brain, and heart tissues." The study waspostedto themedRxivpreprint server. This and future publications reflect the project's significant scientific output.

"Overall, the TO_AITION project concludes that systemic low-grade inflammation, potentially maintained by trained innate immunity, is a likely causal contributor to the development of CVD-depression multimorbidity," says Dr. Andreakos. "TO_AITION has generated an integrated mechanistic framework, identified actionable biomarkers, and produced early prototypes of diagnostic and risk-stratification tools that can improve patient monitoring and management."

He concludes, "The knowledge we are generating will enable earlier diagnosis of comorbidity, better prediction of high-risk patients and more effective, personalized treatment strategies. By clarifying how these diseases influence each other, we can design interventions that break the cycle of comorbidity rather than simply manage its consequences. Raising awareness of the strong links between cardiovascular and mental health is essential—through targeted outreach and dissemination, we aim to empower clinicians, patients and policymakers to act sooner and more effectively."

More information Emma Pruin et al, Major depression and atherosclerotic disease: Linking shared genetics to pathways in blood, brain, heart, and atherosclerotic plaques, medRxiv (2025). DOI: 10.1101/2025.07.11.25331336 Journal information: medRxiv

Provided by European Society of Cardiology