The link between abnormal calcium handling and electrical instability in acquired long QT syndrome – does calcium precipitate arrhythmic storms?

摘要

Release of Ca²⁺ 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 Ca²⁺ between SR and cytoplasm in individual myocytes, and organ-level synchronization of this process by means of electrical coupling among ventricular myocytes. Abnormal Ca²⁺ release from SR causes arrhythmias in the setting of CPVT (catecholaminergic polymorphic ventricular tachycardia) and digoxin toxicity.Recent optical mapping data indicate that abnormal Ca²⁺ handling causes arrhythmias in models of both repolarization impairment and profound bradycardia. The mechanisms involve dynamic spatial heterogeneity of myocardial Ca²⁺ handling preceding arrhythmia onset, cell-synchronous systolic secondary Ca²⁺ elevation (SSCE), as well as more complex abnormalities of intracellular Ca²⁺ handling detected by subcellular optical mapping in Langendorff-perfused hearts. The regional heterogeneities in Ca²⁺ handling cause action potential (AP) heterogeneities through sodium-calcium exchange (NCX) activation and eventually overwhelm electrical coupling of the tissue.Divergent Ca²⁺ 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 Ca²⁺ dynamics causing specific arrhythmias such as Torsade de Pointes (TdP).