Atrial Fibrillation
Prof. Uli Schotten, MD, PhD
Who am I?
Throughout my career, I have contributed to the discovery of numerous fundamental pathophysiological mechanisms underlying AF including loss of atrial contractility, altered atrial Ca2+ homeostasis, activation of coagulation, fatty infiltration, cellular hypertrophy, and atrial fibrosis. I worked on basic electrophysiological mechanisms of AF by repeatedly expanding technology of invasive mapping of AF, like the first systematic comparisons between various high-density mapping technologies stressing the necessity of high-resolution recordings to understand electrophysiological AF mechanisms. My group was also the first to demonstrate dissociation of electrical activity between endocardial and epicardial atrial wall layers, indicating that unravelling AF mechanisms requires both high density and high coverage of electrical recordings. More recently, I embarked on a systems biology approach to AF including the first truly 3-dimensional computer model for AF and a European atrial tissue bank project that uniquely combines newest next-generation sequencing technology with automated morphological assessment of tissue characteristics. Finally, my group provided the first large and systematic studies on non-invasive classification of AF using extended ECG analysis, a technology with superior predictive power for rhythm outcome as compared to traditional clinical predictors. Artificial intelligence techniques such as deep learning approaches could further improve performance of our prediction models. My research has resulted in several patents on functional markers characterizing the complexity of AF or on biomarkers that are associated with AF. My research focus was recently enriched by adding studies identifying molecular pathways underlying atrial cardiomyopathy using a combination of large-scale omics in international tissue banks with mechanistic validation in immortalized cell lines or stem-cell-derived organoids.
My projects
Immune Targets for AF
Funding organization: Leducq Foundation
Funding period: 2025-2030
This newly assembled consortium merges, for the first time, world experts in the traditionally separated fields of electrophysiology and macrophage biology. Our team will collect synergistic data in cell systems, macrophage-specific knockout mice, AFib pigs treated with macrophage-targeted drug candidates and patients from diverse AFib cohorts. Our ultimate goal is to develop new therapeutic targets for AFib patients.
EmbRACE
Electro-Molecular Basis and theRapeutic management of Atrial Cardiomyopathy, fibrillation and
associated outcomEs
Funding organization: Dutch Heart Foundation
Funding Period: 2023-2028
The Dutch consortium EmbRACE brings together the Dutch scientific community working on AF and aims to unravel the diversity of molecular and cellular mechanisms underlying the atrial cardiomyopathy (AtCM), to identify simple diagnostic tools to identify them, and to develop a therapeutic approach to prevent AtCM progression. Early rhythm-control therapy is one promising intervention to potentially
interfere with AtCM progression next to CVR management. For a sustained impact we aim to develop care pathways to prevent AtCM and AF progression and MACCE. Our team co-coordinates this team
effort and will deliver input for better understanding of the molecular and cellular mechanisms of AtCM.
https://nhs-embrace.nl
https://www.hartstichting.nl/nieuws/verborgen-hartafwijkingen-voorspellen-boezemfibrilleren-en-beroerte
MAESTRIA
Machine learning and artificial intelligence for early detection of stroke and atrial fibrillation
Funding organization: EU
Funding period: 2021-2026
Medical care of cardiac diseases needs to integrate more and more multiple parameters: functional and structural properties of cardiac tissues, genotype, metabolism or lifestyle. Multiple fields of expertise must be involved such as omics, biophysics of electrical signal, clinical imaging. Heterogeneous knowledge and data supporting complex and appropriate decisions to be taken by cardiologist clinicians for patient’s treatments; this new paradigm will revolutionize medical approaches and will durably impact the healthcare industry workflows starting from future emerging treatments to medical devices.
The MAESTRIA project is an 18-partner Research and Innovation action that on digital diagnostics –
developing tools for supporting clinical decisions by integrating various diagnostic data. MAESTRIA is an acronym that stands for Machine Learning and Artificial intelligence for Early detection of Stroke and Atrial Fibrillation. The acronym is used by the MAESTRIA consortium as a metaphor for expressing the mastery that leads to complete control of personalised and early diagnosis of atrial fibrillation and
cardioembolic stroke, two major health problems.
https://maestria-h2020.com
REPAIR
Restoring cardiac mechaniscal function by polymeric artificial muscular tissue
Funding organization: EU
Funding period: 2021-2025
Current medical or surgical treatments cannot restore muscular contractility in heart failure and atrial fibrillation, the most common and serious cardiac diseases. A revolutionary approach would be to use smart materials to support or restore cardiac mechanical function. The EU-funded REPAIR project aims to explore and consolidate a new approach in cardiac contraction assistance. Researchers will develop biomimetic contractile units made from a liquid crystalline elastomer. The project prototypes will pave the way for new biomedical technologies that will lead to enhanced life quality and survival. The role of our team in this project is to test whether the biomimetic contractile units can restore atrial contractility in a large animal model of atrial fibrillation in goats.
https://cordis.europa.eu/project/id/952166
Personalize AF
Personalized Therapies for Atrial Fibrillation. A Translational Approach
Funding organization: EU
Funding period: 2020-2024
PersonalizeAF is an EU-Innovative Training Network that aims to change the paradigm of classification and diagnosis of AF delivering a precision medicine strategy based on the personalized characterization of each atrial substrate and disease manifestation. It creates an innovative multinational, multi-sectorial, multidisciplinary and excellent doctoral training network programme to train 15 Early Stage Researchers (ESRs) in cardiac genetics, cardiac ion channel mapping, stem cell experimentation, novel drug testing, signal and image processing, computer modelling and patient management. The role of our team is to supervise 3 ESRs in stem-cell work on atrial inflammation, Computer modeling and advanced signal analysis.
https://personalizeaf.net
RACE V
Reappraisal of Atrial Fibrillation: Interaction between hyperCoagulability, Electrical remodeling, and Vascular Destabilisation in the Progression of AF
Funding organization: Dutch Heart Foundation
Funding Period: 2018-2025
In this Dutch research consortium, we study how AF affects blood coagulation and vascular function, how hyper-coagulability and vascular alterations enhance atrial remodelling and AF, how common genetic variants affect atrial gene expression, and how they modify the effect of mechanisms on AF progression. Translation to patients is implemented in a registry of patients with early selfterminating AF. Furthermore, we will assess determinants of AF progression using continuous rhythm monitoring
combined with in-depth molecular-to-clinical phenotyping at the time of calamity (AF attack) and outside the time of calamity (sinus rhythm) including blood biomarkers of hypercoagulability, vascular disease, and fibrosis as well as electrocardiographic and imaging biomarkers. In this way, we aim to produce new diagnostic algorithms, electrical and biochemical biomarkers, and novel therapeutic modalities to
prevent AF progression and its complications.
https://professionals.hartstichting.nl/actualiteiten/landelijk-consortium-atriumfibrilleren
Bastiaan J Boukens Ph.D.
Every second, more than five people die from cardiovascular disease. In many cases due to sudden cardiac death. My goal is to understand why people die from sudden cardiac death caused by arrhythmias and to provide mechanistic insight that will create new treatment options.
Research interest
The Purkinje system in the heart, ensures the synchronised activation and subsequent contraction of the left and right ventricles. However, it is important to note that cells from the Purkinje system also be a potential source of arrhythmias. For instance, in patients who have survived acute myocardial infarction or in patients with a seemingly healthy heart but experience ventricular fibrillation. In such cases, arrhythmias may occur in the the outflow tract of the right ventricle (RVOT) and treatment targeted to Purkinje fibers appears to prevent ventricular fibrillation. As Dr. Phillipe Coumel proposed in 1987, cardiac arrhythmias may occur in the presence of an initiating factor and a substrate, both of which are modulated by the autonomic nervous system. The role of the autonomic nervous system in arrhythmias involving the Purkinje system is not yet fully understood. This central theme is the focus of my research.
Aside from my primary research focus, I have a broad interest in cardiac electrophysiology and am leading various projects involving evolutionary and developmental aspects of arrhythmias. I am also intrigued by the mechanisms underlying arrhythmias in the atrium, which are much more prevalent than ventricular arrhythmias. The research techniques used in our laboratory are selected based on the particular research question and typically include intact, beating hearts of small and large mammals and engineered heart tissues made from cardiomyocytes derived from induced pluripotent stem cells, as well as tissue slices from human cardiac tissues.
Overview of publications
Figure 1. A shows a Langendorff-perfused pig heart 2 months after ligation of the anterior descending coronary artery. B shows activation maps from the last stimulated beat (s4) and three spontaneous premature ventricular beats (VPB). The traces in C are local electrograms depicted from the locations indicated in the activation map of s4 in panel B. Traces b and c are from the infarcted myocardium. Note the fractionated potentials.
Figure 2. Electrophysiological characterization of human experimental models A. Photograph of an organoid derived from female human induced pluripotent stem cells derived cardiomyocytes The electron microscopic photograph (shows the brick shaped morphology and clear Z lines of the myocytes in the organoid, demonstrating the adult phenotype. Optical mapping show conduction (B) and action potential with an adult shape (C). D Fluorescent photograph of a slice 450 um) generated from the left atrial appendage of a patient with atrial fibrillation Optical mapping shows anisotropic conduction with a longitudinal conduction velocity of 42 cm/s (E) and action potentials with an adult atrial shape (F). G Photograph of an atrial cardiomyocyte, isolated from the left atrial appendage, during patch clamp enabling the recording of absolute transmembrane potentials (H) and underlying ion currents (I).
