Abnormal Intracellular Calcium Handling Underlying T-Wave Alternans and Its Hysteresis

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Aims: To investigate the mechanism underlying T-wave alternans (TWA) and its hysteresis under ischemia conditions. Methods: Transmembrane action potential (AP) from endocardial, M, and epicardial cells and monophasic AP (MAP) from four epicardial sites were recorded in ventricular wedge preparation and in isolated intact rabbit heart, respectively. The AP/MAP duration (APD/ MAPD), effective refractory period (ERP), activation time, and APD/MAPD restitution were determined under control and ischemia conditions. The effects of ryanodine (0.01 and 1 µmol·l^–1) on TWA, and the effects of low extracellular Ca²⁺ and 4-aminopyridine on its hysteresis were studied. Results: Ischemia shortened the APD/MAPD and effective refractory period of all recording sites symmetrically, except the APD of M cells, which shortened markedly. In the ischemia group, TWA was induced within a cycle length (CL) range from 160 to 250 ms, which corresponded to a diastolic interval region of 0–70 ms. In this diastolic interval region, the repolarization restitution curve was the steepest (slope > 1.0). All TWA were accompanied by repolarization alternations. Low concentration ryanodine (0.01 µmol·l^–1) facilitated TWA, high concentration (1 µmol·l^–1) abolished it. Alternans of calcium transient were observed in myocytes purfused with ischemia solution during rapid stimulation. Ryanodine (0.1 µmol·l^–1) abolished alternans of calcium transient, and ryanodine (0.01 µmol·l^–1) facilitated them. After 60 min pacing at a CL of 200 ms, TWA persisted until the initial several beats at a CL of 300 ms at which a TWA was exceptional. The suppression of hysteresis by low extracellular Ca²⁺ and 4-aminopyridine indicated an underlying role of the intracellular Ca²⁺ overload and transient outward current (I_to). Conclusion: TWA is principally due to repolarization alternans, which is secondary to steep APD/MAPD restitution, and relates to intracellular calcium cycling. Hysteresis relates to intracellular Ca²⁺ overload and I_to.