MASLD is the condition of excessive accumulation of liver fat unrelated to alcohol intake, ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH). With a 25% prevalence in the general population, MASLD is currently the most common liver disease, and a major healthcare and economic burden. While hyperlipidaemia, obesity and insulin resistance are the major risk factors for MASLD and contribute to its rising prevalence, growing evidence suggests that exposure to endocrine-disrupting chemicals (EDCs) can initiate and/or cause progression of MASLD. EDC-MASLD will focus on investigating the impact of environmental exposure to EDCs on the internal exposome (metabolome, gut microbiome, epigenome, proteome, immunome) and degree of liver damage in MASLD in prospective study settings, with a focus on the period of transition to progressive stages of MASLD. EDC-MASLD is particularly focused on interactions between EDC exposure, sex, genotype, diet, socioeconomic and lifestyle factors, via the data and biosamples available in the unique European NAFLD Registry, comprising over 9,000 patients with histologically characterised MASLD. EDC exposure studies will be performed in murine models of MASLD, zebrafish models, and human 2D/3D in vitro models, with an aim to understand respective mechanisms-of-action and to develop novel EDC screening tools. The EDC-MASLD consortium has diverse and complementary expertise in the domains of hepatology, endocrinology, toxicology, exposome research, metabolomics, systems biology, environmental economics, and communications & technology research, with respective PIs being global leaders in their fields. Taken together, EDC-MASLD will significantly contribute to the actions centred on identification and mechanistic assessment of impact of EDCs, strategies to monitor and reduce exposure, and regulatory actions that could better protect human and environmental health.

GRIP on MASH will address the unmet public health need of reducing disease burden and comorbidities associated with Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD). Together with seven medical technology, pharmaceutical and biotechnology companies, we will devise a sustainable and scalable GRIP on MASH Platform that will enable access to at-risk patients developing or having MASLD through the early detection of this condition at the primary care level. This Platform will allow A) the early detection of patients with MASLD: distributed in 12 European Centers of Excellence (CoEs), 10,000 patients at high risk of MASLD - defined as patients with type-2 diabetes mellitus, metabolic syndrome, obesity or arterial hypertension - will be screened and characterized; B) better patients’ stratification: the Platform will comprise artificial intelligence-based decision support tools that will make use of existing and novel biomarkers/biomarker combinations. Their predictive accuracy will be tested at the primary care level; there we will perform multi-OMICs analysis (proteomics, lipidomics, metabolomics, genomics, metagenomics and fluxomics) in fasted blood samples and we will explore imaging biomarkers/organ-on-a-chip to find future non-invasive diagnostic alternatives for the current standard (liver biopsies); and C) personalized lifestyle advice, by exploring evidence-based lifestyle features and the effect of nutritional recommendations: among the cohorts at the CoEs, we will use validated questionnaires to assess physical activity, diet, sleep, smoking, alcohol consumption, and perception of stress. Integrating patients’ perspectives with the participation of two patient organizations, the trustworthiness and sustainability of our GRIP on MASH Platform will be assessed by investigating potential economic, ethical and regulatory barriers to its future adoption. GRIP on MASH will change healthcare practice in MASLD and reduce the disease burden for patients.

Dilated Cardiomyopathy (DCM) is a heart muscle disorder characterised by thinning and stretching of the heart ventricles, making it harder for the heart to pump blood (systolic dysfunction). This disorder, with an estimated prevalence of up to 1/250, predominantly affects younger adults. It is associated with significant morbidity and mortality, including heart failure and sudden cardiac death, with end-stage DCM being the leading indication for heart transplantation. The current disease burden in DCM is largely attributable to two important gaps in scientific knowledge: Firstly, our understanding of the aetiology and genetic architecture of DCM remains limited, hindering the utility of genetic testing in clinical patient management. Secondly, there are limited therapeutic options for DCM patients. Existing therapies are generic and target symptoms. No curative treatments exist, apart from invasive heart transplantation and there are no approved therapies targeting underlying molecular disease mechanisms. A fuller understanding of the genetic architecture of DCM and knowledge of the genes and genetic variants involved are critically needed to provide solutions for these unmet medical needs. The DCM-NEXT consortium combines world-leading interdisciplinary expertise and resources of 8 investigators in the fields of DCM, deep clinical phenotyping, cardiogenomics, cardiac transcriptomics, artificial intelligence, in silico drug target discovery and functional studies. They will uniquely leverage their unparalleled cohort of 11,750 DCM probands and relatives with extensive clinical and omics data. Through cutting-edge genomic and cardiac transcriptomic studies, the project aims to (1) revolutionise genetic testing and patient stratification for more precise prediction of disease onset, progression and risk of major adverse cardiac events; and (2) accelerate development of novel therapies by identifying and validating targets involved in pathogenesis of DCM.

Liver cirrhosis and liver cancer are common and responsible for high morbidity, impaired quality of life, major costs for healthcare systems, causing 300K deaths per year in Europe. Predominant etiological factors are obesity, type2 diabetes, and increased alcohol in-take, which are all on the rise. It is predicted that healthy life expectancy will decrease in Europe over the next 30 years because of deaths due to liver disease. Liver cirrhosis develops after a very long period of asymptomatic liver fibrosis, staying undetected until patients develop severe complications due to cirrhosis or liver cancer. Currently the only effective treatment available is liver transplantation which is not applicable to all patients. If fibrosis is detected early, to target the course of liver disease, then liver fibrosis is reversible. The LIVERAIM project concentrates a team of renowned clinical centres and Industrial partners, including SMEs, with great expertise in the field of Liver Disease, the aim being to design and validate a screening platform with biomarkers for population screening to use across Europe. The objective is to identify liver disease early and apply personalized therapeutic interventions. A large number of existing biomarkers will be tested for fibrosis prediction accuracy using biobank plasma samples from 40,000 subjects from previous H2020 EU-funded cohorts. LIVERAIM will develop a screening platform with biomarkers using AI for personalized early diagnosis of fibrosis to be validated in a RCT of 100K subjects from 6 representative EU countries. The platform will be linked to tailored, personalized therapeutic interventions to halt fibrosis progression. With LIVERAIM, early diagnosis and personalized intervention can stop liver disease progression, help decrease morbidity and mortality and the associated societal burdens both economic and health inequity.

The ARTEMIs project aims to consolidate existing computational mechanistic and machine-learning models at different scales to deliver ‘virtual twins’ embedded in a clinical decision support system (CDSS). The CDSS will provide clinically meaningful information to clinicians, for a more personalised management of the whole spectrum of Metabolic Associated Fatty Liver Disease (MAFLD). MAFLD, with an estimated prevalence of about 25%, goes from an undetected sleeping disease, to inflammation (hepatitis), to fibrosis development (cirrhosis) and/or hepatocellular carcinoma (HCC), decompensated cirrhosis and HCC being the final stages of the disease. However, many MAFLD patients do not die from the liver disease itself, but from cardiovascular comorbidities or complications. The ARTEMIs will contribute to the earlier management of MAFLD patients, by prognosing the development of more advanced forms of the disease and cardiovascular comorbidities, promoting active surveillance of patients at risk. The system will predict the impact of novel drug treatments or procedures, or simply better life habits. The system will therefore not only serve as a clinical decision aid tool, but also as an educational tool for patients, to promote better nutritional and lifestyle behaviors. In more advanced forms of the disease, therapeutic interventions include TIPPS to manage portal hypertension, partial hepatectomy, partial or complete liver transplant. ARTEMIs will contribute to predict per- or post-intervention heart failure, building on existing microcirculation hemodynamics models. The model developers will benefit from a large distributed patient cohort and data exploration environment to identify patterns in data, draw new theories on the liver-heart metabolic axis and validate the performance of their models. The project includes a proof-of-concept feasibility study assessing the utility of the integrated virtual twins and CDSS in the clinical context.