Arterial hypertension (HT) represents one of the major risk factors for cardiovascular disease and a major public heaalth problem. Pathogenic mechanisms underlying HT are complex and include genetic and environmental, vascular and hormonal factors. Detection of secondary forms of HT is particularly important since it allows for the targeted management of the underlying disease. Primary aldosteronism (PAL) is the most common form of secondary hypertension, whose prevalence may reach 10% of cases referred to specialized centres, and its diagnosis is important since patients may be cured by surgical or medical treatment. The understanding of the pathogenic mechanisms underlying PAL is essential to allow for the development of new diagnostic tools and biomarkers and may allow to identify new therapeutic targets. In our research project (BeyondTASKs) we propose to identify new genes and signalling pathways involved in aldosterone biosynthesis in the normal adrenal cortex and in PAL through a strategy that integrates functional genomics, mouse models and studies in patients with PAL, taking advantage of the formidable model represented by Task mutant mice. Our project, which represents the continuation of our previous ANR GENOPAT HypertenTASK project, will be subdived into four tasks: 1) Management and coordination 2) Study of the transcriptional mechanisms regulating aldosterone production in the adrenal cortex 3) Investigation of mechanisms leading to hyperaldosteronism in the Task3-null mouse model 4) Investigation of the genetic and genomic determinants of PAL in humans We expect that the results produced by our project will considerably broaden our knowledge in the field of the regulation of aldosterone production in physiological and pathological conditions and discover new therapeutic targets.

The Valvosoft project aims to develop a revolutionary non-invasive ultrasound therapeutic strategy for the treatment of calcific aortic stenosis (CAS), a major public health issue. This valvular disease affects 2% of people over 65 and 12% of people over 75. The survival time is 2 to 5 years for patients with the most severe cases (1.3 million patients in Europe). Currently, the only medical answer is open heart surgery, a risky and extensive intervention which involves replacing the aortic valve. Morbidity and cost to the public health systems are very high. Moreover, many patients are not eligible for cardiac surgery. Percutaneous valve replacement has emerged as an effective solution to replace cardiac surgery but this technique is currently limited to only those who have a contraindication for traditional surgery and it comes at the cost of a high morbidity rate with vascular and hemorrhaging-related complications in over 20% of cases with a significant number of strokes. In Valvosoft, we propose a novel approach no longer based on valve replacement but rather on restoring the valve function through the application of an ultrasound beam precisely focused on the valve. This intense ultrasound beam enables a softening of the valve which in turn improves the valve opening and allows blood to reach vital organs. This innovative approach developed in Valvosoft fits perfectly into the current trend in heart surgery and interventional cardiology to be less and less invasive, safer for the patient and more cost-effective for public health systems. The objectives of this 30 months project are twofold: 1) enhance the existing technology with novel imaging capabilities for better targeting and monitoring in order to improve the efficacy and safety of the procedure and 2) perform the first proof of concept experiment on human patients. The first work package (WP1) is dedicated to the technological development of the novel imaging and monitoring tools to ensure the safety and the efficacy of the therapy. The second work package (WP2) aims to demonstrate the therapeutic efficacy and safety of the procedure on in vitro and in vivo preclinical models. The last work package (WP3) is the first in man pilot study of non-invasive calcified valve therapy. To achieve these objectives, the Valvosoft consortium combines the unique knowledge of two high-level academic research teams, highly specialized in imaging and ultrasound therapy (Inserm U979, Langevin Institute), in cardiovascular translational research and valve disease (HEGP) and an industrial partner, Cardiawave, an innovative young company created in 2014 to develop and commercialize a non-invasive therapeutic device for calcified aortic stenosis. This innovation will be a real breakthrough and is expected to have a strong impact on the quality of care (including reductions in mortality and morbidity rates, relief of pain), an impact on the cost of care (the resources used to develop it and provide it to patients, relative to those used for current practice), and an impact on the value of care (changes in quality relative to changes in cost).