Cardiovascular diseases (CVD) such as myocardial infarction and stroke constitute the main cause of morbidity and mortality worldwide, accounting for 3.9 million deaths in Europe (45% of all deaths) and 17.9 deaths globally per year. Traditional risk factors-comorbidities of CVD have been obesity, diabetes and hypertension, promoting disease development and severity. Yet, it has been known for decades that an intimate relationship between CVD and depression also exists. Several studies have demonstrated, that one in three patients with CVD suffer from depression, and depression increases the likelihood for cardiac morbidity and mortality in these patients by 2-3-fold, independently of traditional risk factors or gender. This relationship is also bidirectional as people suffering from depression but do not have CVD have a greater risk of developing heart disease and having a heart attack.
While very strong, the link between depression and CVD is complex and remains poorly understood. Thus, it is not clear whether that involves physiologic and/or behavioural effects of depression, what comes first, depression or CVD, and whether medications for depression increase heart disease risk. Moreover, the causality behind the effects of depression on CVD, and vice versa, remains unknown. This becomes even more complex when metabolic and other mental diseases, which co-exist in these patients, are also considered.
Unknown drug-drug interactions of polypharmacy, targeting metabolic, inflammatory and psychiatric aspects of the disease can further complicate their management. This leads to dramatically reduced quality of life, higher mortality, higher rates of adverse drug events, and increased use of health care resources, largely because healthcare systems are configured for individual diseases rather than multimorbidity. There is therefore an urgent to unravel the common causative mechanisms driving comorbid or multimorbid manifestation of CVD-depression and other metabolic or mental disorders in order to advance prevention, diagnosis, prognosis, therapy and management of these highly prevalent and devastating conditions.
TO_AITION will address the overarching 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 multimorbidities.
Central to the ΤΟ_ΑΙΤΙΟΝ’s approach are unique longitudinal cohorts (with >15 years of follow-up) and biobanks, containing clinical, demographic, biochemical and biological information, as well as extensive genomic, epigenomic, transcriptomic, proteomic, lipidomic, metabolomics and microbiomic data.
These will be explored with systems biology approaches and artificial intelligence methodologies to uncover novel factors and pathways linked to immunemetabolic dysregulation and development of co/multimorbid disease and shed light into the pathophysiological mechanisms involved.
Causality will be evaluated in experimental animal models and cell systems where the role of myeloid progenitor cell reprogramming in this process will also be determined. Through the analysis of TO_AITION’s cohorts, the trajectory of multimorbid disease development will further be characterized, new biomarkers identified, and a new diagnostic test, in the form of a lab-on-chip, and a risk prediction tool will be developed.
OBJ 1 | To build maps of immune cell-specific genomic, epigenomic, transcriptomic and proteomic
characteristics from healthy individuals and patients.
OBJ 2 | To characterize CVD-depression multimorbidity phenotypes, imune-metabolic profiles and pathobiological states linked to clinical phenotypes through systems biology and artificial intelligence approaches
OBJ 3 | To identify common mechanisms, risk and susceptibility factors driving co/multimorbidities through hypothesis and data-driven high dimensional approaches, and causal inference studies
OBJ 4 | Evaluation of causality of novel factors and pathways identified in purpose-built human cellbased and animal models
OBJ 5 | To identify novel biomarkers for the diagnosis, prognosis and monitoring of CVD-depression multimorbidities
OBJ 6 | To develop a novel lab-on-chip test for the diagnosis, prognosis and monitoring of CVDdepression multimorbidities in patients
OBJ 7 | To develop a new multiscale risk model to identify high versus low risk states to assist the diagnosis
and management of CVD-depression multimorbidities
OBJ 8 | To plan medical professionals and patients-focused awareness programs and
educational activities for CVD-depression multimorbidities
The project is divided into 9 work packages covering the scientific and technical aspects of the project, exploitation and dissemination of results and project management. Each work package is managed by a work package leader who is responsible for the timely delivery of deliverables to the Coordinator, who represents the Consortium to the European Commission.
The main ideas behind the project are shown in the following schematic.