title: Arrhythmogenic mechano-electric heterogeneity in the long-QT syndrome.
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 afterdepolarizations 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 aftercontractions 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.
authors: Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands.
authors: Rachel M A
authors: RM
authors: ter Bekke
authors: Paul G A
authors: PG
authors: Volders
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D055724:Electrophysiological Phenomena; D006801:Humans; D008133:Long QT Syndrome / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D055595:Mechanical Phenomena; D008564:Membrane Potentials; D013564:Sympathetic Nervous System / Q000503:physiopathology
chemical_list: D002118:Calcium