Abstract
Since the first linkage of the long-QT syndrome to the Harvey ras-1 gene in 1991 ample research has been performed to decipher the molecular-biophysical basis of congenital repolarization defects and the electrophysiological mechanisms of torsades-de-pointes arrhythmias in this condition. Mechanistic knowledge is mostly derived from cellular experiments (cardiac myocytes, cultured cells), ventricular tissue (including arterially-perfused wedge) preparations and Langendorff-perfused hearts, with relatively little information from in-vivo animal models, and even more scant intact human-heart investigations. Until now, much emphasis has been put on purely membrane-related pathways of arrhythmia initiation with a prominent role for spatiotemporal dispersion of repolarization, early after-depolarizations and reentrant excitation. Here, we review additional factors that influence the onset of torsades de pointes, notably myocardial Ca2+ (over) loading and spontaneous SR Ca2+ release, occurring particularly during intense sympathetic nervous stimulation and dynamic cycle-length changes. Recent tissue and in-vivo data suggest that spontaneous SR Ca2+ release, underlying aftercontractions in the isolated myocyte, may organize to local myocardial Ca2+ waves and after contractions in the intact heart. In the setting of prolonged repolarization and a negative electromechanical window, these spontaneous [Ca2+](cyt)-based events (which often arise during early diastole) may exaggerate repolarization instability via [Ca2+](cyt)-activated inward membrane currents and, as we postulate, via mechano-sensitive ion currents. Future long-QT research should focus on the intact beating heart with preserved autonomic input to examine these arrhythmogenic mechanisms.
Original language | English |
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Pages (from-to) | 347-358 |
Journal | Progress in Biophysics & Molecular Biology |
Volume | 110 |
Issue number | 2-3 |
DOIs | |
Publication status | Published - 2012 |
Keywords
- Long-QT syndrome
- Electromechanical window
- Calcium
- Aftercontractions
- Torsades de pointes
- Ventricular arrhythmia