CAVD project: how to reconstitute in vitro mature contractile heart tissue?

The Arythmogenic Right Ventricular Cardiomyopathy (ARVC) is the cardiomyopathy that represents one of the leading causes of sudden death in young patients under the age of 40. It is characterized by a massive inflammation of the cardiac tissue accompanied by a progressive loss of muscle cells, the cardiomyocytes, which are replaced by fibro-fatty infiltrates leading to an increased risk of life-threatening ventricular arrhythmias.

Led by Dr. Pierre Bobin, the CAVD project aims to use artificial cardiac pseudo-tissues (EHT), derived from human induced pluripotent stem cells, as a translational research tool to test new approaches for the treatment of CAVD in the medium term.

What is the CAVD project?

The innovative and unique nature of the project

Sponsorship at the service of innovation

The actors involved in the project

Pictures ©Alkama.

MetaGenoPolis-INRAE and IHU ICAN accelerate research on microbiota and cardiovascular diseases in France

MetaGenoPolis -INRAE and the IHU ICAN, both of which are internationally recognized in the scientific community for their research work and are part of the MetaGenoPolis pre-industrial demonstrator, wish to join forces to accelerate knowledge of the link between microbiota and cardiometabolic diseases.

As part of the project Le French Gut, national contribution carried by INRAE in collaboration with the AP-HP which will collect gut microbiota from 100,000 adult volunteers residing in metropolitan France and associated nutritional and clinical data by 2027, the INRAE/ICAN collaboration will create synergies in ancillary projects to accelerate knowledge on the relationship between the gut microbiota and cardiometabolic diseases in France.

Indeed, several patient cohorts under the aegis of the IHU ICAN could join the French Gut in order to study this relationship.

Privileged links between MetaGenoPolis-INRAE and IHU ICAN already exist, notably through 2 international projects MetaHIT and Metacardis that have resulted in high impact factor publications, and more recently in joint discussions to propose offers for manufacturers wishing to explore the microbiota and its impact on health.

Who is MetaGenoPolis?

Since its creation in 2012, MetaGenoPolis has collaborated on 236 research projects, including 154 projects in partnership with industry.

MGP’s main missions are:

• To accelerate microbiota science in France and innovation in the field of health and food,

• To propose high-performance, high-throughput technologies to analyze the diversity of complex microbiota and the interactions between gut bacteria and human cells,
• To collaborate with industrial actors for the transformation of their discoveries into health-related products and services, to identify and fully process leads towards future industrial applications, to help design and lead scientific projects towards applications.

Heart failure: an increased risk for patients with type 2 diabetes?

Linked to 5 million deaths per year worldwide, type 2 diabetes (T2D) is a complex and heterogeneous clinical syndrome, as it represents an increased risk of deterioration of the various organs of the affected patient (heart, kidney, nervous system…).

Indeed, researchers have shown that patients with type 2 diabetes are at greater risk of developing heart failure (HF). To prevent this from happening, the ICAN UHI is setting up a multidisciplinary and personalized approach to patient care, which takes into account the causal relationships of all cardiometabolic diseases (diabetes, obesity, cardiovascular diseases…).

Heart failure: a high risk in type 2 diabetes

With more than 3.5 million French people affected, diabetes can be a silent disease diagnosed too late, at the onset of an acute episode that requires medical management of the patient.

In this case, diabetes has unfortunately already damaged other organs, resulting in an increased risk of developing other cardiometabolic diseases (cardiovascular accidents, heart failure, renal failure, peripheral neuropathies …).

Indeed, heart failure in patients with type 2 diabetes is associated with a significant risk of deterioration in quality of life, recurrent hospitalizations and death.

As a reminder, there are 4 warning signs to watch out for to diagnose the presence of heart failure and prevent its worsening:

• Unusual shortness of breath,
• Swollen feet and ankles (edema),
• Rapid weight gain,
• Excessive fatigue.

The MET-INF-T2D study: towards detection of metabolic heart failure associated with type 2 diabetes

How can cardiac metabolism be acutely affected by changes in blood glucose?

Indeed, the reduction of glucose levels in type 2 diabetes leads to major metabolic changes whose consequences for the heart are not known.

It is therefore essential today to set up a global and personalized management of patients, thanks to a sharing of knowledge between the different disciplines.

Led by Prof. Fabrizio Andreelli (Diabetologist APHP, Pitié-Salpêtrière, IHU ICAN), the MET-INF-T2D study aims to better predict the evolution of type 2 diabetes in order to develop new therapies and improve the management of patients.

The objective of this research project is to demonstrate that cardiac metabolic inflexibility is present in some patients with chronic hyperglycemia and revealed during the treatment of their diabetes by insulin therapy.

This project is supported by Entrepreneurs & Go as a sponsorship.

Heart failure: launch of the ICARD study, 1st patient included

More than 1 million French people are now affected by Heart Failure (HF), with 120,000 new cases diagnosed each year. This frequent and serious chronic disease occurs when the heart has difficulty pumping enough blood to oxygenate all the organs.

The IHU ICAN scientific research teams set up the ICARD study, which aims to analyze the mechanisms of dapagliflozin, a molecule that has demonstrated metabolic, cardiovascular and renal efficacy with a recognized place in the treatment of heart failure.

The study started in June 2022, with the inclusion of the 1^st patient! Find out more about the background and objectives of the ICARD study below.

Heart failure: 1 million French people concerned

The contraction of the heart of patients with Heart Failure (HF) is no longer effective in ensuring the blood flow necessary to supply the organs. shortness of breath, fatigue and/or edema and weight gain.

Heart failure can be the consequence of myocardial infarction, arterial hypertension, diabetes and arrhythmias such as atrial fibrillation, as well as diseases of the heart muscle (cardiomyopathies) often of genetic origin.

• In France, 2.3% of the adult population and 10% of people over 70 suffer from heart failure, i.e. more than 1 million people concerned,
• Each year, 165,000 patients are hospitalized and more than 70,000 deaths are associated with heart failure,
• More than 1 in 2 patients declare themselves to be in “poor” or “very poor” health.

Source: Public Health France, 2019

Dapagliflozin: an effective molecule in the treatment of heart failure

To deal with this disease, there are treatments that improve the symptoms, lighten the work of the heart, and reduce morbidity and mortality, but they are not effective for all patients.

Dapagliflozin is a molecule accessible since 2021 for patients with heart failure. It has given very recent results of complementary efficacy, the mechanisms of action of which deserve to be further investigated.

Today, understanding which mechanisms are activated will help to better identify patients who may have an increased benefit from the use of dapagliflozin compared to standard treatments for heart failure.

The objectives of the ICARD study conducted by the IHU ICAN

The ICARD study of the IHU ICAN therefore aims to understand how this molecule improves the energy metabolism of the heart and other organs (liver, kidney, abdominal fat), i.e. the flexibility of the use of different sources of energy (fats and sugar) that the heart needs to pump blood.

The 2 main objectives of the ICARD study are therefore:

• Understand, through MRI, the cardiovascular and metabolic effects of dapagliflozin, which benefit several types of patients,
• Analyze its role in reducing hospitalizations and mortality in patients with heart failure.

The scientific organization of the ICARD study

With the participation of AstraZeneca, this study with academic promotion is planned for a period of 2 years. ICARD will focus on 40 patients presenting with heart failure and followed in the Cardiology Department of the Pitié-Salpêtrière Hospital.

The study is taking place at Pitié-Salpêtrière, within the Heart Institute, in the nuclear medicine department and on the ICAN Clinical Investigation platform of the IHU ICAN.

It also involves the ICAN Imaging scientific platforms for MRI and ICAN Omics acquisitions, the biomedical imaging laboratory (LIB, INSERM 1146) as well as the support services of the IHU.

• Project leaders: Pr Richard Isnard, Pr Alban Redheuil, and Pr Fabrizio Andreelli
• Contact: Louise Meyfroit – Scientific operations officer – l.meyfroit@ihuican.org

Latest generation 1.5T cardiovascular MRI from the IHU ICAN

Phosphatidylserine improves the anti-inflammatory function of high density lipoproteins (HDL)

Chronic inflammatory diseases impact the lives of many people and represent a significant cost to our healthcare system today.

They can be treated using anti-inflammatory drugs of natural or synthetic origin. In the human body, a wide variety of molecules have anti-inflammatory properties that can help fight against these diseases.

Recent research conducted at IHU ICAN by Dr. Maryam Darabi and Dr. Anatol Kontush has demonstrated that the inclusion of phosphatidylserine significantly enhances the anti-inflammatory function of reconstituted high-density lipoprotein (rHDL).

How can this approach be used to treat certain chronic inflammatory diseases?

What are the objectives of this research?

Reconstituted HDL particles. In green, apolipoprotein A-I, the main protein of HDL. In yellow, phosphatidylcholine, the main lipid of HDL.

Present in the blood, human high-density lipoprotein (HDL) is a multimolecular complex with a strong capacity to reduce inflammation. It contains a set of lipid and protein molecules, a minority of which is phosphatidylserine (PS).

Using their major lipid and protein components, HDL (human high density lipoprotein) particles can be artificially reconstituted using apolipoprotein A-I (the major protein of HDL) and phosphatidylcholine (the major lipid of HDL) and thus used as therapeutic agents.

What are the results?

The results were obtained in vitro using the THP-1 human macrophage cell line, but also with primary human macrophages prepared from circulating monocytes.

• Research has shown that the inclusion of phosphatidylserine (PS) in reconstituted HDL improves its ability to reduce inflammation, with superior anti-inflammatory function to “standard” HDL without PS.
• In particular, HDL with PS helps to further reduce the secretion and expression of interleukin-6 (an inflammatory molecule) by macrophages.
• Finally, they also show superior anti-inflammatory properties in vivo in a mouse model of dyslipidemia and chronic inflammation.

HDL formulations were administered to dyslipidemic mice on a high-cholesterol diet to induce atherosclerosis and chronic inflammation.

Who are the actors involved?

The research work was mainly carried out within the UMRS 1166 (AP-HP, Inserm, Sorbonne University, IHU ICAN):

• By Dr. Maryam Darabi (Postdoctoral Researcher),
• Under the supervision of Dr. Anatol Kontush (Research Director),
• In collaboration with the ICAN Omics Lipidomics platform,
• And supported by SATT-Lutech, INSERM and Sorbonne University.

The results of this research were reported in the scientific article “Phosphatidylserine Enhances Anti-inflammatory Effects of Reconstituted HDL in Macrophages via Distinct Intracellular Pathways”, published in The Faseb Journal on April 13, 2022.

Carbohydrate-restricted diets:
what is the link with elevated cholesterol?

Following a carbohydrate-restricted diet is often indicated for weight loss and treatment of chronic diseases such as type 2 diabetes.

However, some studies have noted that this dietary change can lead to an increase in so-called “LDL” or “bad” cholesterol, which is an important risk factor in the development of cardiovascular disease.

Given the increasing popularity of carbohydrate-restricted dietand the high mortality from cardiovascular disease, there is a need to understand the mechanisms that impact LDL cholesterol levels and lipid metabolism in response to reduced carbohydrate intake.

What is the purpose of this study?

The study is based on self-collected data from 548 individuals following a carbohydrate-restricted diet, corresponding to less than 130 grams per day, with an average carbohydrate intake of 27 grams per day.

An initial analysis identified predictors of increased LDL cholesterol (LDL-C):

• The body mass index (BMI) of the individual,
• Metabolic markers of his health,
• The level of HDL cholesterol (HDL-C),
• Triglyceride (TG) levels before the diet.

The analysis revealed that lean people (thus having a low BMI) with a low TG/HDL-C ratio, and following a low-carbohydrate diet, were the most likely to experience increases in their LDL cholesterol levels.

This allowed us to isolate a subset of 100 “Lean Mass Hyper-responder” (LMHR) individuals with particularly large increases in both LDL and HDL cholesterol levels in the context of carbohydrate restriction, combined with low triglyceride levels. The mechanism was reversible with reintroduction of carbohydrates into the diet, and no significant genetic factors were revealed in testing.

What is Lipid Energy Model? (LEM) (LEM)

This increased dependence leads to increased hepatic secretion of VLDL and lipolysis of VLDL by lipoprotein lipase with high production of free fatty acids (FFA), which are an important source of energy for the body.

Then, the peripheral absorption of these acids increases, as does the accumulation in the circulation of LDL (which is the end product of VLDL lipolysis) and the level of LDL-C. In parallel, cholesterol-containing fragments of the VLDL surface are released and transferred to HDL, resulting in marked elevation of HDL-C. Finally, circulating triglyceride levels decrease as a result of lipolysis. According to the Lipid Energy Model (LEM), this pathway is particularly active in lean individuals with a low baseline TG/HDL-C ratio, because these individuals are characterized by particularly efficient VLDL lipolysis.

Know more about Lipid Energy Model (LEM) here.

What is the conclusion of this research work?

The research work carried out concludes that the Lipid Energy Model (LEM) could explain the inverse association observed between the individual’s BMI (Body Mass Index) and the change in his or her LDL cholesterol level in a context of carbohydrate consumption restriction. Indeed, high levels of LDL cholesterol are an important cardiovascular risk factor. This work therefore calls for further research to assess this risk in individuals on low-carbohydrate diets.

This model provides specific and testable predictions to be evaluated in future studies to better understand the mechanisms underlying the change in LDL cholesterol on low-carbohydrate diets. This will advance our knowledge of lipid and lipoprotein dynamics in human metabolism.

The excellence of the ICAN Omics lipidomics platform

The ICAN IHU has a “lipidomics” platform specialized in metabolic diseases (NASH, T2DM, atherosclerosis, hypercholesterolemia, cardiomyopathy…) which combines metabolomic and lipidomic approaches and bioinformatics tools. Thanks to cutting-edge technologies, it allows the identification of new biomarkers to improve the prediction of metabolic pathologies

Located at the Pitié-Salpêtrière Hospital in Paris, our platform has been awarded the IBiSA label(Infrastructures in Biology, Health and Agronomy) label in 2021.

The CT-AF study: imaging as a decision support in atrial ablation?

In heart disease, Atrial Fibrillation (AF) is the most common arrhythmia. It is responsible for almost 20% of ischemic strokes (obstruction of the cervical artery).

The standard treatment for Atrial Fibrillation includes anticoagulant therapy and antiarrhythmic therapy, and very often catheter ablation of foci of arrhythmias. This intervention consists, using catheters introduced into the heart via the blood vessels,to destroy the diseased area of ​​the heart muscle at the origin of the occurrence of the arrhythmia.

However, the predictive factors of the success of this practice remain insufficient whereas they are necessary for the selection of the patients who could derive the most benefit from this invasive procedure.

How to better assess the relevance of an ablation of AF foci?

Magnetic resonance imaging (MRI) is now capable of a detailed analysis of the atrial remodelingwhich makes the bed of Atrial Fibrillation (AF). In particular, MRI can visualize the abundance and texture of fat around the heart, which is known to contribute to the substrate of AF. Thus, this imaging has imposed itself in clinical practice before ablation of AF.

The CT-AF study, coordinated by Pr Estelle GANDJBAKHCH of the Institute of Cardiology, Rhythmology Unit of the Pitié-Salpêtrière Hospital in Paris, aims to to evaluate the value of multimodal imaging for the volume measurement of atrial intramyocardial fat in cardiac CT and the measurement of global atrial strain in MRI in patients who are candidates for a first AF ablation.

Four centers will include 130 patients in whom a first radiofrequency AF ablation procedure is scheduled in the next 6 months, with a follow-up over 18 months:

• The Pitié-Salpêtrière Hospital,
• Bordeaux University Hospital,
• The Northern Heart Center (CCN),
• The CHI of Poissy.

Each patient will have clinical examinations, blood tests (assay of biomarkers, serum library and plasma library) as well as scanner imaging, echocardiography, ECG and MRI examinations.

What is the role of the IHU ICAN in this study?

Several expertises of the IHU ICAN will be mobilized on this study:

• Imaging acquisition will be carried out within the ICAN Imaging platform, and the images will be analyzed at the end of the study within the CoreLab ICAN and of the Biomedical Imaging Laboratory(LIB) which has unique expertise in the modeling, instrumentation, signal and image processing and analysis,
• The CRB ICAN BioCollection, will ensure the storage and the plasma assays of the different samples,
• The ICAN Clinical Investigation Platform will receive patients included during follow-up visits.

How to support this study?