title: The link between abnormal calcium handling and electrical instability in acquired long QT syndrome--Does calcium precipitate arrhythmic storms?
abstract: Release of Ca(2+) ions from sarcoplasmic reticulum (SR) into myocyte cytoplasm and their binding to troponin C is the final signal form myocardial contraction. Synchronous contraction of ventricular myocytes is necessary for efficient cardiac pumping function. This requires both shuttling of Ca(2+) between SR and cytoplasm in individual myocytes, and organ-level synchronization of this process by means of electrical coupling among ventricular myocytes. Abnormal Ca(2+) release from SR causes arrhythmias in the setting of CPVT (catecholaminergic polymorphic ventricular tachycardia) and digoxin toxicity. Recent optical mapping data indicate that abnormal Ca(2+) handling causes arrhythmias in models of both repolarization impairment and profound bradycardia. The mechanisms involve dynamic spatial heterogeneity of myocardial Ca(2+) handling preceding arrhythmia onset, cell-synchronous systolic secondary Ca(2+) elevation (SSCE), as well as more complex abnormalities of intracellular Ca(2+) handling detected by subcellular optical mapping in Langendorff-perfused hearts. The regional heterogeneities in Ca(2+) handling cause action potential (AP) heterogeneities through sodium-calcium exchange (NCX) activation and eventually overwhelm electrical coupling of the tissue. Divergent Ca(2+) dynamics among different myocardial regions leads to temporal instability of AP duration and - on the patient level - in T wave lability. Although T-wave alternans has been linked to cardiac arrhythmias, non-alternans lability is observed in pre-clinical models of the long QT syndrome (LQTS) and CPVT, and in LQTS patients. Analysis of T wave lability may provide a real-time window on the abnormal Ca(2+) dynamics causing specific arrhythmias such as Torsade de Pointes (TdP).
authors.affiliation: Department of Medicine, Heart and Vascular Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Němec
authors.affiliation: Department of Medicine, Heart and Vascular Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Jong J
authors.initials: JJ
authors.lastname: Kim
authors.affiliation: Department of Medicine, Heart and Vascular Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA. Electronic address: gsalama@pitt.edu.
authors.forename: Guy
authors.initials: G
authors.lastname: Salama
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D055724:Electrophysiological Phenomena; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008133:Long QT Syndrome / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D012727:Sex Characteristics
chemical_list: D002118:Calcium
keywords: AP duration, APD; Action potential, AP; Delayed afterdepolarization, DAD; Early afterdepolarization, EAD; Long QT syndrome, LQTS; Long QT type 2, LQT2; Simultaneous mapping of voltage and intracellular free Ca(2+); Subcellular voltage and Ca(2+) imaging; Systolic secondary Ca(2+) release, SSCR; Triggered activity, TA