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Mechanism and treatment of cardiac arrhythmias

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Titel Mechanism and treatment of cardiac arrhythmias
Looptijd 01 / 2006 - onbekend
Status Afgesloten
Onderzoeknummer OND1332281
Leverancier gegevens Website AMC

Samenvatting (EN)

1) Arrhythmogenic characteristics of sodium channelopathies were studied in patients with Brugada syndrome and in a computer model of cardiac propagation. Catheter mapping in patients revealed impaired and asynchronous conduction in the right ventricle. Computer simulations showed that sodium channel reduction alone cannot explain the special ECG features of Brugada syndrome. 2) A number of cardiac diseases like Brugada syndrome and ARVC preferentially affect the right ventricle, despite the fact that the disease affects the entire heart. We previously showed that in mice with reduced cell-cell coupling (90% connexin43 reduction) or reduced excitability (50% reduction of sodium current) arrhythmias preferentially occurred in the right ventricle. Preferential arrhythmogeneity of the right ventricle was also observed in aged mice and related to differences in age related fibrotic patches between the left and right ventricle. 3) In mice with long standing pressure overload (aortic constriction) as a model for heart failure we showed that induced polymorphic tachycardias were based on transmural heterogeneity of cell-cell coupling. 4) The electrophysiological characteristics of differentiated cardiac progenitor cells derived from foetal human hearts were studied. Differentiated cells express the three major connexins types of the heart and the full content of cardiac ion channels resulting in rather negative resting membrane potentials and relatively mature action potential formats. 5) Development of a biological pacemaker using lentiviral constructs containing HCN4. Constructs were used to transfect monolayers of neonatal rat cardiomyocytes, which showed increased spontaneous activity compared to controls.

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