This call for projects supports data challenges focusing on specific medical issues in the field of personalized medicine, based on the analysis of available data and the use of Artificial Intelligence (AI).

Sarcopenic Obesity is a muscular disease characterized by reduced muscle mass and function in obese patients.

Unfortunately, there are no standardized diagnostic criteria for assessing sarcopenic obesity. Estimates of its prevalence therefore vary widely, leading to under-diagnosis of the disease among affected patients.

Sarcopenia is also a major factor in the progression of many cardiometabolic diseases (diabetes, heart and vascular disease…).

ICAN researchers have developed an innovative diagnostic method for sarcopenic obesity using artificial intelligence (AI) processing of a large number of body composition data, in a cohort of 1427 subjects.

This work identified a group of subjects with high levels of adiposity and low levels of muscle mass.

The phenotype identified correlates with numerous cardiometabolic traits. The diagnostic index thus developed, taking gender into account, is proposed as a powerful diagnostic criterion for sarcopenic obesity. Its clinical correlation with other parameters (hepatological, cardiological, metabolic) is currently the subject of further studies.

The number of people suffering from obesity has tripled in the last 50 years.

IHU ICAN’s research teams are working on a number of areas (role of the microbiota, development of new treatments, etc.) in the fight against this pathology, with the aim of developing multidisciplinary, personalized care for each patient.

Your support is invaluable in furthering our understanding of this disease, a major public health issue of today and tomorrow.

Hypertrophic cardiomyopathy (HCM) is an inherited heart disease that is a major cause of sudden death and/or heart failure in young people <40).

• This relatively rare disease affects 1 in 500 people in the general population.
• It is defined by an increase in the thickness of the left ventricular paroid of the heart that is not explained by load conditions.
• Until now considered monogenic, researchers and doctors have long thought that this disease was linked to a mutation affecting a single gene in the patient.
• Despite improved knowledge and management of hypertrophic cardiomyopathy, the disease remains unexplained in more than 1 in 3 cases.

Due to its rarity, the various clinical and genetic data collected for this disease are heterogeneous, and often based on separate patient cohorts.

At present, cardiogeneticists at rare disease centers are all too often at a loss when faced with the results of genetic and cardiological tests prescribed as part of their disease assessment. In reality, the course of the disease is highly variable and difficult to predict.

This is particularly true of their patients’ relatives who, despite having a similar genetic mutation, sometimes have a completely different clinical picture and/or evolution.

In fact, they are currently using a sudden death risk calculation proposed by the European Society of Cardiology (ESC) in 2014. The relevance of these risk scores is modest, and the distinction between high-risk and low-risk patients is insufficient and remains controversial.

It aims to establish, as accurately as possible and for each patient, a polygenic risk score (PRS), un score de risque polygénique (PRS), and integrate it with cardiological data to better identify patients who will benefit from pro-active therapeutic management, in particular via implantation of a medical device (endocavitary or subcutaneous automatic defibrillator, for example).

Artificial Intelligence (AI) will provide new risk stratification with direct translational application to guide therapeutic decision-making. In fact, we want it to enable clinicians to know the risk to which their patients are exposed, in order to adapt their decision-making and the frequency of their follow-up.

The CardI-HACK project will be managed by the Prof. Philippe Charron, Head of the Reference Center for Hereditary and Rare Heart Diseases, supported by Aurélie Foucher, Project Manager in the ICAN IHU Innovation and Research Valorization team.

Anonymizing genomic data is a key issue for the CardI-HACK project. Combining the analysis of specialists in artificial intelligence methods from Centre de la Sorbonne pour l’intelligence artificielle (SCAI) with the regulatory expertise of IHU ICAN and its data protection delegate, with the help of the regulatory and legal teams from Health Data HubA methodology for anonymizing genomic data will be defined to meet the regulatory requirements of the RGPD and the scientific requirements of the CardI-HACK project, and submitted to the CNIL for approval.

This project has received funding from Bpifrance as part of the “Data Challenges in Healthcare” call for projects under the France 2030 plan.

Financing obtained: €199,934

The ICONIC project, supported by the Pr Alban Redheuil (Head of the Cardiovascular and Thoracic Imaging Unit at the Pitié-Salpêtrière Heart Institute) will be carried out on the ICAN Imaging platform of the ICAN IHU, in association with the INSERM CONSTANCES cohort, headed by Pr Marie Zins of Université Paris Cité.

In addition to the importance of population-based health data, these data will make it possible to a new understanding of the origins of disease and aging, their very early detection, the determination of new cardiovascular and metabolic risk profiles and individual setting up a multimodal imaging cohort reference for research into common and rare diseases.

Advances in imaging techniques have opened up new and highly innovative avenues of research. Imaging now plays a central role in our in vivo understanding of pathophysiological mechanisms, enabling us to detect diseases earlier, assess individual risk of developing a disease or a severe form, and thus improve patient care by developing personalized medicine.

However, there are a lack of cardiovascular and liver imaging data in the general population, and even more so in the 20-40 age group. People under 45 are very poorly represented in internationally comparable population studies.

The first objective of the ICONIC project will be to generate normative data by age and sex category from the analysis of MRI and echocardiographic images in the French population. These normative data could form the basis for validating new imaging biomarkers, and serve as controls for fundamental or clinical studies on human data.

New diagnostic and prognostic tools are destined to become multiparametric, integrating clinical, biological and imaging data.

It will be open to doctors and researchers, enabling French teams to collaborate on current and future international population imaging projects.

A veritable tool for epidemiological research, the Constances “generalist” epidemiological cohort is made up of a representative sample of 200,000 volunteers aged between 18 and 69, included between 2012 and 2019 and consulting Social Security Health Examination Centers (CES).

Hypertrophic cardiomyopathy (HCM) is a disease in which the heart muscle (myocardium) becomes abnormally thick, causing the left ventricular muscle to stiffen and lose its ability to relax and allow blood to fill.

This relatively rare disease limits the heart’s pumping function, leading to symptoms such as syncope or loss of consciousness, chest pain, shortness of breath or heart failure.

These symptoms appear mainly during exertion, particularly in patients with obstructive” form of the disease (CMHo). In some cases, the disease is complicated by atrial arrhythmia (with a risk of stroke) or ventricular arrhythmia (with a risk of sudden death).

Designed to reduce the hypercontractility underlying the pathophysiology of HCM, a cardiac myosin inhibitor called aficamten is being developed as a potential chronic oral therapy for HCM patients.

Led by Cytokinetics, SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM) is an international, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of aficamten in adult patients with symptomatic obstructive hypertrophic cardiomyopathy.

Around 270 patients will be included in the study at some 105 centers worldwide. The first patients to be included at the Pitié-Salpêtrière hospital are scheduled for autumn 2022.

• Prof. Charron (UMRS 1166/IHU ICAN) is the study’s principal investigator at the Pitié-Salpêtrière Hospital (Paris 13th). He is the coordinator of the reference center for hereditary or rare heart diseases,
• The ICAN Clinical Investigation platform, which assists academic and industrial sponsors with the implementation of their clinical projects and ensures that clinical trials run smoothly. Find out more about ICAN Clinical Investigation.
• ICAN Imaging, with its latest-generation 1.5 T cardiovascular MRI, offers a unique technology in the Paris region. Know more.

To date, there is no reliable model for studying the pathophysiology of parental imprinting diseases in humans, the first step in developing appropriate therapeutic strategies. Human induced pluripotent stem cells (hiPSCs) are a promising cellular approach for modeling human diseases and complex genetic disorders.

However, aberrant hypermethylation of Imprinting control regions (ICRs) may occur during the reprogramming process and subsequent culture of hiPSCs. Consequently, the research team tested different reprogramming and culture conditions for hiPSCs and carried out an in-depth analysis of methylation at imprinting control regions, with the aim of developing a cellular model for understanding parental imprinting diseases.

The researchers assessed methylation at seven imprinted loci in hiPSCs before differentiation, at different cell culture passages, and during chondrogenic differentiation. As already described in the literature, hypermethylation was identified at the 11p15 H19/IGF2:IG-DMR and 14q32 MEG3/DLK1:IG-DMR imprinted regions, irrespective of the reprogramming method and cells of origin.

Hypermethylation at these two loci led to loss of parental imprinting, with biallelic expression of imprinted genes IGF2 and DLK1, in regions 11p15 and 14q32 respectively. The development of epiPS™ culture medium combined with cell culture in hypoxia made it possible to correct hypermethylation in H19/IGF2:IG-DMR and MEG3/DLK1:IG-DMR and restore parental imprinting, while preserving the proliferative and pluripotent qualities of these stem cells.

Extensive quantitative analysis of the methylation of imprinting control regions revealed hypermethylation at certain ICRs (those methylated on the paternal allele), in hiPSCs associated with loss of imprinting in these regions.

The epiPS™ culture medium and hypoxia culture of hiPSCs restored balanced methylation at these loci in controls. The research team was also able to show that methylation was disrupted in hiPSCs derived from a patient, thus recapitulating the molecular anomaly responsible for his pathology.

This project is supported by:

• The IHU ICAN
• Sorbonne University
• Inserm

The actors and authors of this study:

• Prof. Irène Netchine, PU-PH and Head of the “IGF system and fetal and post-natal growth” team at Sorbonne Université/Inserm/AP-HP
• Dr Aurélie Pham, CCU-AH, PhD at Sorbonne Université/Inserm/AP-HP
• Céline Selenou, Inserm doctoral student
• Dr Eloïse Giabicani, MCU-PH at Sorbonne University/Inserm/AP-HP
• Dr Vincent Fontaine, PhD at IHU ICAN
• Sibylle Marteau, iPS Cell Culture Assistant Engineer at the ICAN IHU
• Dr Frédéric Brioude, MCU-PH at Sorbonne Université/Inserm/AP-HP
• Dr Laurent David, MCU-PH, University of Nantes
• Prof. Delphine Mitanchez, PU-PH Sorbonne Université/Inserm
• Dr Marie-Laure Sobrier, Inserm CR

Maintenance of methylation profile in imprinting control regions in human induced pluripotent stem cells. Pham A, Selenou C, Giabicani E, Fontaine V, Marteau S, Brioude F, David L, Mitanchez D, Sobrier ML, Netchine I. Clin Epigenetics. 2022 Dec 28;14(1):190. doi: 10.1186/s13148-022-01410-8.

At a very young age, Laetitia Rialland developed an interest in medicine and in jobs related to human beings and the understanding of life, with a curiosity for biology. Medical studies thus proved to be an obvious choice, and she joined the Faculty of Medicine in Nantes in 2018.

His encounter with the research community took place in 2^nd year of medical school, when it integrates theInserm School Liliane Bettencourt in 2020. This double curriculum allows him to follow a early research training, with the completion of a Master 2 during which she will do a 6-month internship (from January to July 2022) at theUniversity Hospital of Pitié Salpêtrièrein the Functional Unit of Cardiogenetics and Molecular and Cellular Myogenetics of Pascale Richard (MD, PhD). This immersion in the scientific world confirms his passion for science.

Since October 2022, Laetitia Rialland has chosen to pursue this exciting path by carrying out a thesis entitled “Transcriptional analysis of the genetic causes of human dilated cardiomyopathies” within team 1 of UMRS 1166 (IHU ICAN).

His research project, called the Calorr project, is based around the understanding of cardiomyopathies, which are diseases affecting the structure and function of the heart muscle. They most often begin in adolescents or young adults, and are the ^first indication for heart transplantation (71% of transplants in patients under 40).

Laetitia Rialland is studying an innovative strategy of mRNA-seq by 3rd generation sequencing (Long Read). The objective is to better understand the splicing alterations responsible for cardiomyopathies, in order to consider the definition of a new diagnostic panel by mRNA sequencing that would improve the diagnostic yield.

Various actors are involved in the progress of the project, including:

• Eric Villard (PhD supervisor) and Phillipe Charron (Team leader, UMRS 1166 / IHU ICAN),
• Pascale Richard for the part on the established diagnosis (Functional Unit of Cardiogenetics and Molecular and Cellular Myogenetics), with whom Laetitia also continues to work on her Master 2 research project,
• The UMRS 1166 team,
• The Pitié-Salpêtrière (P3S) post-genomic platform for sequencing,
• The ICAN I/O platform for bioinformatics analysis,
• Oxford Nanopore for the use of Long Read sequencing technology.

After obtaining her thesis, Laetitia wishes to resume her medical studies in 4^th year and to continue in parallel the research with the Inserm Liliane Bettencourt School. She aspires to a university hospital career in order to share her time between research and direct contact with patients.

Poor nutrition is an important risk factor in the development of obesity, diabetes and cardiovascular disease. The WHO recommends limiting energy intake from fat consumption by reducing consumption of saturated fats in favor of unsaturated fats.

Although the beneficial role of unsaturated fats in preventing metabolic disorders associated with obesity is widely accepted, the underlying mechanisms are less clear.

These are mainly based on the protective effects associated with omega-3 polyunsaturated fatty acids (PUFAs), particularly against the development of insulin resistance, type 2 diabetes and cardiovascular disease.

From a mechanistic point of view, omega-3 PUFAs would notably reduce inflammation of adipose tissue, the fatty acid storage organ, which is at the origin of the development of insulin resistance and type 2 diabetes during obesity. However, the precise mechanisms are not known.

The work of Dr. W. Le Goff’s team (INSERM UMR_S1166 – IHU ICAN) has identified an enzyme that modulates the omega-3 PUFA content of macrophages, the key cells that control inflammation in adipose tissue. Preliminary results indicate that expression of this enzyme mobilizes omega-3 PUFAs from macrophage membranes to reduce inflammation.

Within the IHU ICAN, the ICAN Omics platform will perform lipidomic analysis.

The support of the Carrefour Foundation will contribute to the financing of a researcher’s position on a doctoral contract, the isolation of macrophages from adipose tissue of obese patients by cell sorting and their transcriptomic analysis.

This research program is also funded by the French-speaking Diabetes Society, the Sorbonne University Alliance (Emergence Program) and the French National Research Agency (ANR).