Jean-Sebastien Hulot

• MD PhD
• Group Leader at Hôpital Européen Georges-Pompidou (Hôpitaux Universitaires Paris-Ouest)

Obesity and heart failure (HF) represent two growing pandemics. In the general population, obesity affects one in eight adults and is linked with an increased risk for HF. Obesity is even more common in patients with HF, where it complicates the diagnosis of HF and is linked with worse symptoms and impaired exercise capacity. Over the past few year...

Background and aims There is conflicting evidence as to whether patients with pre-existing heart failure (HF) are at increased risk of developing cancer, especially because of common risk factors. We aimed to assess the incidence of cancer in patients with pre-existing HF compared with patients without known HF. Methods The French National Adminis...

Background and aim Developmental disorders caused by activating mutations in the RAS-MAPK pathway account for nearly 20% of hypertrophic cardiomyopathy (HCM) cases in paediatric patients. Compared to sarcomeric HCM, RAS-HCM presents a higher risk of obstruction and hospitalisation. The myosin inhibitor mavacamten has been approved in the European U...

BACKGROUND Primary aldosteronism is the most common form of secondary hypertension. The most frequent genetic cause of aldosterone-producing adenomas is somatic mutations in the potassium channel KCNJ5. They affect the ion selectivity of the channel, with sodium influx leading to cell membrane depolarization and activation of calcium signaling, the...

Background Mutations in LMNA gene, which encodes lamins A/C, cause a variety of diseases, called laminopathies. Some mutations are particularly associated with the occurrence of dilated cardiomyopathy. The pathological mechanisms are still unclear limiting the development of specific therapies. Purpose Here, we focused on a mutation in the LMNA ge...

BACKGROUND Genome-wide association studies implicate common genetic variations in the LRP1 (low-density lipoprotein receptor-related protein 1) locus at risk for multiple vascular diseases and traits. However, the underlying biological mechanisms are unknown. METHODS Fine mapping analyses included Bayesian colocalization to identify the most likel...

Adult cardiomyocytes are embedded within a highly organized myocardial microenvironment that imposes critical geometric cues es- sential for the alignment and distribution of organelles and the shaping of their unique, rectangular cellular morphology. Despite the association of cardiomyocyte disarray with human heart disease, the functional consequ...

The development of the human immune system lasts for several years after birth. The impact of this maturation phase on the quality of adaptive immunity and the acquisition of immunological memory after infection at a young age remains incompletely defined. Here, using an antigen-reactive T cell (ARTE) assay and multidimensional flow cytometry, we p...

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer great potential for drug screening and disease modeling. However, hiPSC-CMs remain immature compared to the adult cardiac cells. Cardiomyocytes isolated from adult human hearts have a typical rod-shaped morphology. Here, we sought to develop a simple method to improve the...

Background: Mutations in the LMNA gene, which encodes lamin A/C, cause a variety of diseases known as laminopathies. Some mutations are particularly associated with the occurrence of dilated cardiomyopathy and heart failure, but the genotype-phenotype relationship and underlying mechanisms are unclear. Here, we used induced pluripotent stem cells (...

Introduction: Aspirin and anti-P2Y12 are widely prescribed in cardiovascular patients, often in combination with proton pump inhibitors (PPIs) to limit the risk of upper gastrointestinal bleedings. The potential interaction between PPIs and antiplatelet agents has been widely discussed, but doubts remain as to whether PPIs may reduce the cardiovas...

Background Limited data are available on long-term respiratory disabilities in patients following acute COVID-19. Patients and Methods This prospective, monocentric, observational cohort study included patients admitted to our hospital with acute COVID-19 between March 3 and April 24, 2020. Clinical, functional, and radiological data were collecte...

Primary aldosteronism (PA) is the most common form of secondary hypertension. Major advances have been made in our understanding of PA with the identification of germline and somatic mutations in ion pumps and channels. These mutations lead to the activation of calcium signalling, the major trigger of aldosterone biosynthesis. To elucidate the mole...

BACKGROUND Drug-induced QT prolongation (diLQT) is a feared side effect that could expose susceptible individuals to fatal arrhythmias. The occurrence of diLQT is primarily attributed to unintended drug interactions with cardiac ion channels, notably the hERG (human ether-a-go-go-related gene) channels that generate the delayed-rectifier potassium...

We developed a 96-well plate assay which allows fast, reproducible, and high-throughput generation of 3D cardiac rings around a deformable optically transparent hydrogel (polyethylene glycol [PEG]) pillar of known stiffness. Human induced pluripotent stem cell-derived cardiomyocytes, mixed with normal human adult dermal fibroblasts in an optimized...

Purpose To investigate whether the peak early filling rate normalized to the filling volume (PEFR/FV) estimated from four-dimensional (4D) flow cardiac MRI may be used to assess impaired left ventricular (LV) filling and predict clinical outcomes in individuals with hypertrophic cardiomyopathy (HCM). Materials and Methods Cardiac MRI with a 4D flow...

We developed a 96-well plate assay which allows fast, reproducible and high-throughput generation of 3D cardiac rings around a deformable optically transparent hydrogel (PEG) pillar of known stiffness. Human induced pluripotent stem cell-derived cardiomyocytes, mixed with normal human adult dermal fibroblasts in an optimized 3:1 ratio, self-organiz...

Les peptides natriurétiques sont des outils pour le diagnostic, le pronostic, le suivi et le dépistage précoce de l'insuffisance cardiaque, en particulier dans les populations à risque : les dosages des BNP et NT-proBNP jouent un rôle essentiel en raison de leur spécificité et de leur reproductibilité. Des seuils spécifiques sont recommandés, ajust...

The impairment of left ventricular (LV) diastolic function with an inadequate increase in myocardial relaxation velocity directly results in lower LV compliance, increased LV filling pressures, and heart failure symptoms. The development of agents facilitating the relaxation of human cardiomyocytes requires a better understanding of the underlying...

In the last decade, clinical studies have investigated the clinical relevance of circulating cell-free-DNA (ccfDNA) as a diagnostic and prognosis tool in various diseases including cancers. However, limited knowledge on ccfDNA biology restrains its full development in the clinical practice. To improve our understanding, we evaluated the impact of t...

We developed a 96-well plate assay which allows fast, reproducible and high-throughput generation of 3D cardiac rings around a deformable optically transparent hydrogel (PEG) pillar of known stiffness. Human induced pluripotent stem cell-derived cardiomyocytes, mixed with normal human adult dermal fibroblasts in an optimized 3:1 ratio, self-organiz...

We developed a 96-well plate assay which allows fast, reproducible and high-throughput generation of 3D cardiac rings around a deformable optically transparent hydrogel (PEG) pillar of known stiffness. Human induced pluripotent stem cell-derived cardiomyocytes, mixed with normal human adult dermal fibroblasts in an optimized 3:1 ratio, self-organiz...

We developed a 96-well plate assay which allows fast, reproducible and high-throughput generation of 3D cardiac rings around a deformable optically transparent hydrogel (PEG) pillar of known stiffness. Human induced pluripotent stem cell-derived cardiomyocytes, mixed with normal human adult dermal fibroblasts in an optimized 3:1 ratio, self-organiz...

Purpose Following a severe COVID-19 infection, a proportion of individuals develop prolonged symptoms. We investigated the immunological dysfunction that underlies the persistence of symptoms months after the resolution of acute COVID-19. Methods We analyzed cytokines, cell phenotypes, SARS-CoV-2 spike-specific and neutralizing antibodies, and who...

Background: Drug-induced QT prolongation (diLQT) is a feared side-effect as exposing susceptible individuals to fatal arrhythmias. The occurrence of diLQT is primarily attributed to unintended drug interactions with cardiac ion channels, notably the hERG channels that generate the repolarizing current (IKr) and thereby regulate the late repolarizat...

Background: Vascular smooth muscle cells (SMCs) plasticity is a central mechanism in cardiovascular health and disease. We aimed at providing cellular phenotyping, epigenomic and proteomic depiction of SMCs derived from induced pluripotent stem cells and evaluating their potential as cellular models in the context of complex diseases. Methods: H...

Mutations in the lamin A/C gene ( LMNA ) cause dilated cardiomyopathy associated with increased activity of ERK1/2 in the heart. We recently showed that ERK1/2 phosphorylates cofilin-1 on threonine 25 (phospho(T25)-cofilin-1) that in turn disassembles the actin cytoskeleton. Here, we show that in muscle cells carrying a cardiomyopathy-causing LMNA...

Background: Myocardial infarction (MI) induces a repair response that ultimately generates a stable fibrotic scar. Although the scar prevents cardiac rupture, an excessive profibrotic response impairs optimal recovery by promoting the development of noncontractile fibrotic areas. The mechanisms that lead to cardiac fibrosis are diverse and incompl...

Aims: Heart failure (HF) in young adults is uncommon, and changes in its incidence and prognosis in recent years are poorly described. Methods and results: The incidence and prognosis of HF in young adults (18-50 years) were characterized using nationwide medico-administrative data from the French National Hospitalization Database (period 2013-2...

Background Integrins are surface receptors that bind to extracellular matrix ligands and regulate cellular function through mechanical stress-initiated signal transduction. Integrin alpha V (or CD51) is implicated in myocardial fibrosis and anti-CD51 therapy improves cardiac function and cardiac fibrotic remodeling following myocardial infarction....

Background The composition of the digestive microbiota may be associated with outcome and infections in patients admitted to the intensive care unit (ICU). The dominance by opportunistic pathogens (such as Enterococcus ) has been associated with death. However, whether this association remains all throughout the hospitalization are lacking. Method...

L’hyperaldostéronsime primaire (HAP), forme la plus fréquente d’hypertension artérielle secondaire, est due à la présence d’un adénome produisant de l’aldostérone (APA) ou d’une hyperplasie bilatérale des surrénales. Des mutations somatiques dans des gènes codants pour des canaux ioniques et des ATPases ont été identifiées dans la majorité des APA....

The prevalence of Heart failure (HF) is increasing with the aging of the population but it is estimated that 10% of HF patients are younger than 50 years-old. HF development in this population is characterized with a fast-growing prevalence, and important disparities according to underlying etiologies or gender. These observations highlight the nee...

The epicardium is a reservoir of progenitors that give rise to coronary vasculature and stroma during development and mediates cardiac vascular repair. However, its role as a source of progenitors in the adult mammalian heart remains unclear due to lack of clear lineage markers and single-cell culture systems to elucidate epicardial progeny cell fa...

Objective: Primary aldosteronism (PA) is the most frequent form of secondary hypertension. The identification of germline or somatic mutations in different genes coding for ion channels (KCNJ5, CACNA1D, CACNA1H and CLCN2) and ATPases (ATP1A1 and ATP2B3) defines PA as a channelopathy. These mutations promote activation of calcium signaling, the mai...

Introduction Myocardial fibrosis is involved in most forms of heart diseases, progressively leading to adverse cardiac remodeling and heart failure. We previously identified a population of cardiac stromal cells that contribute to fibrosis development through a CD51 (alpha v integrin) dependent activation of pro-fibrotic pathways in a murine model...

Introduction Primary aldosteronism (PA) is the most frequent form of secondary hypertension. The identification of germline or somatic mutations in different genes coding for ion channels and defines PA as a channelopathy. These mutations promote activation of calcium signaling, the main trigger for aldosterone biosynthesis. Objective The objectiv...

Introduction Smooth muscle cells (SMCs) capacity to switch between proliferative (synthetic) and quiescent (contractile) phenotypes is a widely studied mechanism in cardiovascular disease. Primary SMCs tend to lose many physiological features in culture, which makes the study of their contractile function challenging. Recently, an optimized protoco...

Introduction Cardiomyocytes derived from human-induced pluripotent stem cells (iPS-CMs) have numerous advantages for drug screening and disease modeling but present with structural and functional immaturity features. Experiments in cardiomyocytes isolated from adult human or animal hearts are conditioned by their typical rod-shaped morphology. Obj...

Introduction Cardiomyopathy caused by A-type lamins gene (LMNA) mutations is associated with an early development of heart failure and a poor prognosis. Gene editing is a promising approach to cure these monogenic disorders. CRISPR/Cas9-based strategies have recently allowed an in vivo correction of mutations leading to Duchenne muscular dystrophy....

Background Vascular smooth muscle cells (VSMCs) plasticity is a central mechanism in cardiovascular health and disease. We aimed at providing deep cellular phenotyping, epigenomic and proteomic depiction of SMCs derived from induced pluripotent stem cells (iPSCs) and evaluating their potential as cellular models in the context of complex genetic ar...

Ces vingt dernières années, l’intérêt pour les intégrines n’a cessé de grandir et les découvertes ont ouvert de nouvelles perspectives thérapeutiques, notamment dans le cadre de la fibrose, particulièrement pour les intégrines de la famille aV. Après les revers de la thérapie anti-angiogénique utilisée contre le cancer, de nouvelles molécules inhib...

Background/Introduction: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of myocardial infarction in young and middle-aged women. A common genetic variant, rs11172113, located in LRP1 ( low density lipoprotein receptor-related protein 1) first intron, was associated with several vascular diseases, including SCAD, c...

Purpose AMG 986 is a novel apelin receptor (APJ) agonist that improves cardiac contractility in animal models without adversely impacting hemodynamics. This phase 1b study evaluated the safety/tolerability, pharmacokinetics, and pharmacodynamics of AMG 986 in healthy subjects and patients with heart failure (HF). Methods Healthy adults (Parts A/B)...

Introduction et but de l’étude L’obésité constitue un facteur de risque pour le développement d’une insuffisance cardiaque (IC) difficile à diagnostiquer compte tenu de la prévalence de la dyspnée dans cette population. De plus le BNP est décrit comme plus bas en moyenne chez les patients avec obésité. L’objectif de l’étude OLECOEUR était d’évaluer...

Background In the last decade, clinical studies have investigated the clinical relevance of circulating cell-free-DNA (ccfDNA) as a diagnostic and prognosis tool in various diseases including cancers. However, limited knowledge on ccfDNA biology restrains its full development in the clinical practice. To improve our understanding, we evaluated the...

CYP2C19 catalyzes the bioactivation of the antiplatelet prodrug clopidogrel, and CYP2C19 genotype impacts clopidogrel active metabolite formation. CYP2C19 intermediate and poor metabolizers who receive clopidogrel experience reduced platelet inhibition and increased risk for major adverse cardiovascular and cerebrovascular events. This guideline is...

Cardiovascular diseases represent a major cause of morbidity and mortality, necessitating research to improve diagnostics, and to discover and test novel preventive and curative therapies. All of which warrant experimental models that recapitulate human disease. The translation of basic science results to clinical practice is a challenging task. In...

Arrhythmias are a critical health burden, responsible for a significant proportion of sudden cardiac death. They arise from inherited or acquired abnormalities in cardiac ion channels or their associated regulatory proteins functioning within cardiomyocytes. In opposite with the classical in vitro models, human induced pluripotent stem cells–derive...

Genetic cardiomyopathies are disorders of the cardiac muscle, most often explained by pathogenic mutations in genes encoding sarcomere, cytoskeleton or ion channel proteins. Clinical phenotypes such as heart failure and arrhythmia are classically treated with generic drugs, but aetiology-specific and targeted treatments are lacking. As a result, ca...

Clinical pharmacology is the study of drugs in humans, from first-in-human studies to randomized controlled trials (RCTs) and benefit-risk ratio assessment in large populations. The objective of this review is to present the recent innovations that may revolutionize the development of drugs in the future. On behalf of the French Society of Pharmaco...

During the transition from a healthy state to cardiometabolic disease, patients become heavily medicated, which leads to an increasingly aberrant gut microbiome and serum metabolome, and complicates biomarker discovery1,2,3,4,5. Here, through integrated multi-omics analyses of 2,173 European residents from the MetaCardis cohort, we show that the ex...

Aims Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome with various causes that may influence prognosis. Methods and results We extracted the electronic medical records for 2180 consecutive patients hospitalized between 2016 and 2019 for decompensated heart failure. Using a text mining algorithm looking for a left...

Introduction: The epicardium is a source of the coronary vasculature and stroma during heart development. Although quiescent in the physiological adult heart, increasing evidences indicate the potential epicardium activation and differentiation into its progeny after cardiac injury; however, this remains debated. Hypothesis: We hypothesize that in...

Introduction: Myocardial infarction (MI) induces a repair response that ultimately generates a stable fibrotic scar. Although the scar prevents cardiac rupture, an excessive profibrotic response impairs optimal recovery. Hypothesis: To explore the regulation of fibroblasts proliferation through a paracrine action of cardiac stromal cells post-MI Me...

The epicardium is a reservoir of progenitors that give rise to coronary vasculature and stroma during development and mediates cardiac vascular repair in lower vertebrates. However, its role as a source of progenitors in the adult mammalian heart remains unclear due to lack of clear lineage markers and single-cell culture systems to elucidate epica...

Background: Persistent physical symptoms are common after a coronavirus disease 2019 (COVID-19) episode, but their pathophysiological mechanisms remain poorly understood. In this study, we aimed to explore the association between anxiety and depression at 1-month after acute infection and the presence of fatigue, dyspnea, and pain complaints at 3-m...

Background/Introduction Alterations in cellular bioenergetic events owing to metabolic dysfunctions are well demonstrated in heart failure (HF). Cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) have the potential to model metabolic alterations as observed in the human failing hearts, which however requires precise arrang...

We aimed to compare the influence of cardiometabolic disorders on the incidence of severe COVID-19 vs. non-COVID pneumonia. We included all consecutive patients admitted with SARS-CoV-2-positive pneumonia between 12 March 2020 and 1 April 2020 and compared them to patients with influenza pneumonia hospitalized between December 2017 and December 201...

The epicardium is a reservoir of progenitors that give rise to coronary vasculature and stroma during development and mediates cardiac vascular repair in lower vertebrates. However, its role as a source of progenitors in the adult mammalian heart remains unclear due to lack of clear lineage markers and single-cell culture systems to elucidate epica...

Skeletal muscle injury results in a disruption of the muscle bed vascular network. A local source of vascular progenitors during muscle regeneration has not been clearly identified. Fibroadipogenic progenitors (FAPs) are required for proper regeneration, however they can also directly contribute to fibrotic and fatty infiltration in response to chr...

Background: Cognitive complaints are frequent after COVID-19 but their clinical determinants are poorly understood. This study aimed to explore the associations of objective cognitive performances and psychological distress with cognitive complaints in COVID-19 survivors. Materials and Methods: Patients previously hospitalized for COVID-19 in a uni...

SARS-CoV-2 infection leads to a highly variable clinical evolution, ranging from asymptomatic to severe disease with acute respiratory distress syndrome, requiring intensive care units (ICU) admission. The optimal management of hospitalized patients has become a worldwide concern and identification of immune biomarkers predictive of the clinical ou...

Purpose The purpose of this study was to evaluate the association between coronary artery calcium (CAC) visual score and 6-month mortality in patients with coronavirus disease 2019 (COVID-19). Material and methods A single-center prospective observational cohort was conducted in 169 COVID-19 consecutive hospitalized patients between March 13 and A...

The pandemic of Coronavirus disease (COVID)-19 is a global threat, causing high mortality, especially in the elderly. The main symptoms and the primary cause of death are related to interstitial pneumonia. Viral entry also into myocardial cells mainly via the angiotensin converting enzyme type 2 (ACE2) receptor and excessive production of pro-infla...

Introduction The significant morbidity and mortality in patients with heart failure (HF), notably in the most advanced forms of the disease, justify the need for novel therapeutic options. In the last year, the soluble guanylate cyclase (sGC) stimulator, vericiguat, has drawn the attention of the medical community following the report of reduced cl...

Background: Myocardial infarction (MI) induces a repair response that ultimately generates a stable fibrotic scar. Although the scar prevents cardiac rupture, an excessive profibrotic response impairs optimal recovery. Objective: To explore the regulation of fibroblasts proliferation through a paracrine action of cardiac stromal cells post-MI Metho...

To investigate the mechanisms underlying the SARS-CoV-2 infection severity observed in patients with obesity, we performed a prospective study of 51 patients evaluating the impact of multiple immune parameters during 2 weeks after admission, on vital organs’ functions according to body mass index (BMI) categories. High-dimensional flow cytometric c...

Cardiac tissue engineering aims at creating contractile structures that can optimally reproduce the features of human cardiac tissue. These constructs are becoming valuable tools to model some of the cardiac functions, to set preclinical platforms for drug testing, or to alternatively be used as therapies for cardiac repair approaches. Most of the...

Objectives Chest CT has been widely used to screen and to evaluate the severity of COVID-19 disease in the early stages of infection without severe acute respiratory syndrome, but no prospective data are available to study the relationship between extent of lung damage and short-term mortality. The objective was to evaluate association between stan...

Background: Humoral response to SARS-CoV-2 occurs within the first weeks after COVID-19. Those antibodies exert a neutralizing activity against SARS-CoV-2, whose evolution overtime after COVID-19 as well as efficiency against novel variants are however poorly characterized. Methods: In this prospective study, sera of 107 patients hospitalized wi...

Aims The role of renin‐angiotensin‐aldosterone system (RAAS) blockers on the course of coronavirus disease 2019 (COVID‐19) is debated. We assessed the association between chronic use of RAAS blockers and mortality among inpatients with COVID‐19, and explored reasons for discrepancies in the literature. Methods and results We included adult hyperte...

Aims Myocardial injury is frequently observed in patients hospitalized with coronavirus disease 2019 (COVID‐19) pneumonia. Different cardiac abnormalities have been reported during the acute COVID‐19 phase, ranging from infra‐clinic elevations of myocardial necrosis biomarkers to acute cardiac dysfunction and myocarditis. There is limited informati...

Acute myocardial infarction is a common condition responsible for heart failure and sudden death. Here, we show that following acute myocardial infarction in mice, CD8⁺ T lymphocytes are recruited and activated in the ischemic heart tissue and release Granzyme B, leading to cardiomyocyte apoptosis, adverse ventricular remodeling and deterioration o...

Background and objectives Kidney involvement is frequent among patients with coronavirus disease 2019 (COVID-19), and occurrence of AKI is associated with higher mortality in this population. The objective of this study was to describe occurrence and significance of proteinuria in this setting. Design, setting, participants & measurements We cond...

MYH7 is a major gene responsible for hypertrophic cardiomyopathy (HCM). From patient’s skin fibroblasts, we derived an iPSC line (CDGEN1.16) harboring the heterozygous MYH7 R403L mutation, a hot-spot codon in HCM. We subsequently corrected the mutated codon using CRISPR/Cas9 editing and obtained the isogenic control line (CDGEN1.16.40.5) preserving...