Heart failure (HF) affects 2% of the EU population and is an unmet clinical need due to the limited treatment options. HF is associated with alterations of the immune system. Non-Alcoholic Fatty Liver Disease (NAFLD), an emerging health problem associated with metabolic diseases, such as obesity and type 2 diabetes (T2D), is an independent cardiovascular disease risk factor. When NAFLD progresses from simple steatosis to Non-Alcoholic SteatoHepatitis (NASH) with fibrosis, the risk to develop hepatic and cardiac complications increases. However, the mechanisms linking NASH and HF are not understood. Strikingly, monocytes (Mono) and macrophages (Macro) are important contributors to cardiovascular disease and these cells also plays a key role in NASH. Moreover, our preliminary results identify these immune cells as potential link between NAFLD and cardiac dysfunction. We thus hypothesize that NASH and its metabolic alterations impact on the immune compartment, which in turn functionally contributes to inappropriate cardiac remodelling (CR), leading to HF. We propose an ambitious project combining systems biology approaches, state-of-the-art molecular technologies, original preclinical models and human translational studies to: 1. Define the role of NASH in (the aggravation of) CR in mice; 2. Characterize the immune cell alterations in NASH-induced CR with a focus on Mono and Macro; 3. Determine the functional role of thus identified immune cells in CR; 4. Translate our findings to the human pathology by analyzing the impact of NAFLD on cardiac complications (atrial fibrillation and HF) in patients undergoing aortic valve stenosis surgery. The unique combination of expertise in immunology, metabolism and cardiology within our consortium is critical to decipher how immune system alterations link liver pathology to heart disease. Our results will improve our understanding of HF pathophysiology allowing the identification of novel patient management approaches.