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Een niet-belastende modaliteit voor de bepaling van pro-aritmische...

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Titel Een niet-belastende modaliteit voor de bepaling van pro-aritmische mechanismen bij primaire natrium-kanalopathie├źn
Looptijd 01 / 2005 - onbekend
Status Afgesloten
Onderzoeknummer OND1311605

Samenvatting (EN)

* BACKGROUND. The arrhythmogenic mechanism of primary ion channelopathies is often unclear because: 1) biophysical characteristics of the affected channel are not or not well known, 2) synergism with other ion channels is unclear, 3) sodium channel disorders may induce structural abnormalities. These different features of pro-arrhythmia have not yet been linked to specific electrocardiographic characteristics. Knowing the exact mechanism and contribution of the various channelopathy-related arrhythmogenic parameters in the individual patient is, however, important to optimize treatment. * HYPOTHESIS. We hypothesize that a computer model of the electrophysiology of the human heart in which biophysical characteristics of a mutant channel can be incorporated together with structural abnormalities due to altered gap junction and collagen expression, is able: 1) to delineate the mechanism of increased vulnerability for arrhythmias in the individual patient, 2) to link these mechanisms to specific electrocardiographic features. * OBJECTIVES. In this study we will investigate the effect of sodium channel disorders alone and in concert with concomitant structural abnormalities on conduction to delineate the mechanism of pro-arrhythmia and define the pro-arrhythmia related ECG characteristics in the individual patient. To vary parameters with great flexibility we will use a sophisticated, high resolution, computer model to simulate conduction of the electrical impulse in the human heart. Our final goal is to identify the mechanism of pro-arrhythmia from subtle features in electrocardiographic recordings. * METHODS. Patients who are carrier of an SCN5A mutation (Brugada, LQT3, Conduction Disease) will be included in the study. Body surface mapping and catheter mapping (CARTO-system) of the right ventricle will be performed. The model is based on a mathematical description of the cellular action potential and its underlying ionic currents and computes propagating action potentials by solving "bidomain equations" for a complete human heart at 50 million nodes. Realistic fiber orientations of the heart are incorporated in the model. MRI data are used to tailor the model anatomically for an individual patient. Structural abnormalities will be incorporated as estimated from the CARTO-mapping data (fractionation; activation delay). Cellular coupling can be varied with high spatial resolution to simulate structural (fibrosis and gap junctions) remodeling. The biophysical characteristics of the sodium channel will be adapted to the channelopathy of the individual patient. Spatial distribution and expression of ion channels will be based on existing experimental (human or animal) data. The model determines conduction and action potential characteristics, endocardial and epicardial electrograms and calculates surface ECGs. Body surface mapping data and electrophysiological parameters obtained by catheter mapping are used to validate results generated by the model. The effect of pharmacological interventions and selective ablation on conduction and ECG will be estimated with the model. * EXPECTED RESULTS. Simulating channelopathy in a patient-tailored model will allow assessment of the dominant arrhythmogenic parameter(s) in individual patients and select mechanism-specific ECG features. Knowledge of these mechanism related ECG characteristics will help to select strategies for antiarrhythmic treatment of the individual patient.

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Classificatie

A70000 Volksgezondheid en gezondheidszorg
D21100 Bioinformatica, biomathematica, biomechanica
D21200 Biofysica, klinische fysica
D23220 Inwendige geneeskunde

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