Disturbed Cardiac Impulse Propagation and Arrhythmogenesis
Disturbed Cardiac Impulse Propagation and Arrhythmogenesis
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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).
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