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Sodium-Calcium Exchange Initiated by the Ca²⁺ Transient

An Arrhythmia Trigger Within Pulmonary Veins

Eugene Patterson, PhD^_*,_*, Ralph Lazzara, MD, FACC^_*, Bela Szabo, MD, PhD^_*, Hong Liu, PhD, David Tang, MS, Yu-Hua Li, PhD, Benjamin J. Scherlag, PhD, FACC^_* and Sunny S. Po, PhD, MD^_*

^_* University of Oklahoma Health Sciences Center and the DVA Medical Center, Oklahoma City, Oklahoma
University of Oklahoma, College of Engineering, School of Electrical and Computer Engineering, Norman, Oklahoma

View larger version (24K): [in a new window]   Figure 1 (A) The same action potential is shown during pacing at 1 Hz for 30 s (APD90 [an index for the magnitude of early afterdepolarization formation] = 173 ms) followed by a 2-s pause (APD90 = 253 ms) and during bigeminal pacing (800:200 ms intervals) for 30 s followed by a 2-s pause (APD90 = 410 ms). (B) An action potential and isometric force are shown for pacing at 1 Hz interrupted by a premature beat and for a 5-Hz pacing train (20 beats) followed by a 1,000-ms pause. Vertical lines mark peak force. (C) An action potential and isometric force are shown for pause intervals (350 and 2,000 ms) after a pacing train (5 Hz for five beats). Vertical calibration bars (B and C) designate 400 dynes.

View larger version (28K): [in a new window]   Figure 2 (A) Dose-response curves are shown for isoproterenol (left panel) and norepinephrine (right panel) for APD90 [an index for the magnitude of early afterdepolarization (EAD) formation] prolongation (EADs) at 1 Hz (closed circles) and for the first beat (post-pause) after a premature beat (open circles). (B) Isometric force is shown during 1.0-Hz pacing for control, norepinephrine, and norepinephrine + acetylcholine. (C) Action potentials are shown for the first post pacing beat (1.5-s pause) for control, acetylcholine, and acetylcholine + norepinephrine. Addition of norepinephrine resulted in a triggered extrasystole.

View larger version (42K): [in a new window]   Figure 3 (A) A microelectrode recording from a pulmonary vein (PV) cell shown in conjunction with three electrograms. With norepinephrine (3.2 x 10–8M) + acetylcholine (10–7M), a premature beat initiates non-sustained firing. After a 4,600-ms pause, the next paced beat initiated sustained firing. (B) A PV action potential is shown in conjunction with three electrograms. With norepinephrine (3.2 x 10–8M) + acetylcholine (10–7M), a single premature beat initiates non-sustained firing. After a 218-ms pause, a spontaneous (non-stimulated) beat (asterisk) initiates sustained firing. The timing of the spontaneous beat is similar to that observed at the same norepinephrine concentration, but at a lower acetylcholine (10–8M) concentration (C). Firing is rapid (sleeve) and conducts with variable block to other recording sites. Note that a stimulus (st) applied within atrium captures deep vein, microelectrode, and atrial recording sites (arrows) without capturing the arrhythmia focus (sleeve). Termination of a triggered rhythm (18 beats in duration) ending with an early afterdepolarization (EAD) (arrow) is shown (D).

View larger version (23K): [in a new window]   Figure 4 (A) Superimposed action potentials are shown for the first post-pause beat in normal Tyrode solution (NTyr), immediately after the resumption of normal Tyrode solution after superfusion for 15 min with 30 mM LiCl substituting for 30 mM NaCl, and immediately after a transient increase in [Ca2+]o from 1.35 to 5 mM. (B) Superimposed action potentials and force development are shown for 32°C to 38°C. With an increase in isometric force magnitude and duration, terminal repolarization is prolonged. (C) Action potentials are shown under control conditions and after norepinephrine, both before and after ryanodine. Recordings are shown both during pacing at 1 Hz (left panel) and for the first paced beats observed 1 s after a 10-beat pacing train (5 Hz) (right panel).

View larger version (47K): [in a new window]   Figure 5 (A) Focal firing is shown in a voltage-activation map during a rapid triggered rhythm during acetylcholine + norepinephrine. The focal firing originates within the pulmonary vein (PV) sleeve. Asterisks mark the advancing concentric circular wavefront. The origin marked by the circle is shown in (B), voltage recording from the earliest site of activation after a pacing-pause stimulation sequence. Arrow = 0 ms.

View larger version (21K): [in a new window]   Figure 6 A schematic illustration of the proposed arrhythmia mechanism is shown. Membrane voltage (Vm) is shown in black, and the calcium transient (Ca-T) is shown in orange. The Ca-T transient outlasts Vm even under control conditions. The difference between the Vm and the Ca-T is increased with action potential duration (APD) shortening observed after acetylcholine (ACH). The early afterdepolarization (EAD) formation is not observed because the Ca-T is also reduced in amplitude. With addition of norepinephrine (NE), the Ca-T is enhanced in amplitude while the APD remains abbreviated. The disparity between Vm and the Ca-T is increased, with inward sodium-calcium exchange (NCX) current producing an EAD. If even further enhancement of the Ca-T is observed after a tachycardia-pause interval, a second action potential is initiated. The Ca-T initiated by the first ectopic beat initiates the second ectopic beat, and so on, producing a repetitive rhythm.