Key takeaways
- Cardiovascular disease (CVD) and depression are two of the world's leading health challenges, and their frequent coexistence dramatically worsens patient outcomes.
- These two conditions do not co-occur by chance; their comorbidity reflects deep biological and clinical connections that we urgently need to understand.
- Treating one disease in isolation is no longer enough: therapeutic strategies are needed that consider how cardiovascular treatments influence mental health, and how antidepressants may interact with cardiovascular risk.
- The multi-partner European Union funded TO_AITION project has generated knowledge that will enable earlier diagnosis of comorbidity, better prediction of high-risk patients and more effective, personalised treatment strategies.
Brussels 17 December 2025: The European Union-funded 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 over 3 million deaths every year including over 1.6 million deaths in females and 1.5 million deaths in males1. Depression affects over 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.2
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, unravelling patients' complexity and improving their diagnosis, monitoring and management.
The consortium, involving 14 partner organisations around Europe including the European Society of Cardiology (ESC), has harmonised and enriched large-scale human cohorts with proteomic, epigenetic and microbiome data, and used computer and statistical modelling 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, and biomarker discovery efforts 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 the TO_AITION cloud risk stratification platform during 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 published research in various peer-reviewed journals – 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 was submitted to MedRxiv (pre–peer review). This and further 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, personalised 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."
