Repolarisation and arrhythmogenesis
Prof. Dr. Marc Vos
Delivering (oxygenated) blood to the body is the main task of the heart. For this, the heart has to be excited and the myocytes have to contract synchronously: the process of excitation-contraction. The ventricular impulse is generated in the sinus node and spreads rapidly (conduction). After contraction the heart has to restore its electrical and contractile parameters (repolarization). Ventricular arrhythmias can be based on 2 arrhythmogenic mechanisms: triggered activity and reentry. Their respective cause is disturbances in repolarization (triggered activity) and/or conduction (reentry).
When the repolarization reserve is decreased, a(n additional) challenge on repolarization may induce afterdepolarizations (triggered activity) that initiate ectopic beats. This process is started by instable prolongation of the ventricular action potential: an increase in beat-to-beat variability of repolarization. This increase can be detected in electrophysiological parameters and by that 1) identify patients at risk or 2) even prevent the arrhythmia from occurring when the parameter is coupled with an intervention algorithm. Perpetuation of the arrhythmia can be (a combination) of reentry and triggered activity.
Disturbed cardiac impulse propagation and arrhythmogenesis
Dr. Toon van Veen
Contraction of the heart depends on an orchestrated excitation of the individual cardiomyocytes that constitute the cardiac muscle. To achieve in this, the electrical impulse that spontaneously arises in the sino-atrial node propagates throughout the heart in a highly coordinated fashion. Three factors are most important to facilitate conduction: excitability of the cardiomyocytes depends on proper functioning of the sodium channels, cell-to-cell coupling is mediated by intercellular gap junction channels and third, homogeneous tissue architecture (cell size, cell orientation and extracellular matrix composition). On a microscale level, the intercalated disc (ID) which connects individual cardiomyocytes both electrically and mechanically plays a crucial role in this regard. At the ID large macromolecular protein complexes facilitate many important cellular processes. During pathological condition, either acquired (e.g. myocardial infarction or chronic hypertension) or inherited (e.g. mutations in ID proteins), the constitution and integrity of these complexes might alter in such a way that this can lead not only to contractile dysfunction, but also to arrhythmogenesis. A further deterioration of cardiac function during pathogenesis is triggered by enhanced deposition of extracellular matrix components (fibrosis), proliferation of fibroblasts and cell death (apoptosis). Ventricular arrhythmias often arise in the early (concealed) phase of cardiac disease and can be lethal if resuscitation isn’t achieved within minutes. Our research focusses on the mechanisms that trigger arrhythmogenesis and fibrosis formation. This is studied in several models of increasing complexity (cultured cardiomyocytes, fibroblasts, mouse models, patient material).
Ion channel trafficking
Dr. Marcel van der Heyden
A balanced expression of cardiac ion channels at the sarcolemma is of crucial importance for normal action potential formation and thus cardiac function. The cellular processes that transport channel proteins from the endoplasmic reticulum towards specified regions on the sarcolemmal membrane, and subsequently take them from the plasma membrane to the protein degradation machinery are commonly known as antegrade and retrograde transport, respectively. We recognize that aberrant channel trafficking stands at the basis of many congenital and acquired arrhythmias. At the department of Medical Physiology, we focus on trafficking of the repolarizing ion channels that underlie IKr and IK1. We are beginning to learn that ion channels traffic in channel-specific pathways using particular interacting proteins that target them to their destination membranes. We make use of a multidisciplinary approach that incorporates robust molecular and cell biology, state-of-the-art cellular imaging techniques and advanced electrophysiological readout methods and translates its findings to the clinic. We started initiatives to transit our cardiac ion channel trafficking research from ectopic cell expression systems, via isolated adult cardiomyocytes and tissue explants into in vivo approaches. This new knowledge will not only permit a more detailed understanding of pathophysiological mechanisms of cardiac arrhythmias but will also allow designing new therapeutic approaches and safer drugs.
Advanced methods in cellular electrophysiology
Dr. Teun de Boer
An important observation is that cells of an organ often replicate the primary function of the organ in which they reside; neurons integrate signals from their surroundings and heart muscle cells (cardiomyocytes) contract in response to an electrical stimulus. In our department we aim to study the cellular physiology of cardiomyocytes using conventional approaches that rely on isolated, single cardiomyocytes (such as patch clamp electrophysiology), but have also started work on novel methods that will help to increase our insight in the function of cardiomyocytes within the heart. For this we use optogenetic sensors that allow us to record e.g. intracellular calcium concentration or membrane potential of cardiomyocytes within the heart.
Another important aspect of our work is the development of real-time simulations of ion channels, the so-called dynamic clamp technique. The most important application is to simulate cardiac IK1channels that are missing from stem cell-derived cardiomyocytes (iPSC-CM). By combining the real-time simulated ion channels with human iPSC-CM, we can create a hybrid human cardiomyocyte model that is more similar to human adult cardiomyocytes. The main benefit of this approach is that it enables more specific in vitro testing of drugs that might negatively affect the human heart rhythm. Current focus is to enhance the throughput of this approach, which resulted in the establishment of a fully automated dynamic clamping system which is integrated with an automated patch clamping device developed by Nanion Technologies.