Submitted on April 27, 2009
Revised on June 8, 2009
Accepted on June 24, 2009
Arrhythmogenic Consequences of Intracellular Calcium Waves
Lai-Hua Xie1* and James N. Weiss2
1 UMDNJ-NJ Medical School
2 University of California School of Medicine
* To whom correspondence should be addressed. E-mail: xiela{at}umdnj.edu.
Intracellular Ca (Cai) waves are known to cause delayed afterdepolarizations (DADs), which have been associated with arrhythmias in cardiac disease states such as heart failure, catecholaminergic polymorphic ventricular tachycardia and digitalis toxicity. Here we show that, in addition to DADs, Cai waves also have other consequences relevant to arrhythmogenesis, including subcellular spatially discordant alternans (SDA, in which the amplitude of local Cai transient alternates out-of-phase in different regions of the same cell), sudden repolarization changes promoting dispersion of refractoriness and early afterdepolarizations (EADs). Cai was imaged using a CCD-based system in fluo-4-AM loaded isolated rabbit ventricular myocytes paced at constant or incrementally increasing rates, using either field-stimulation, current-clamp or action-potential (AP) clamp. Cai waves were induced by Bay K8644 (50 nM) + Isoproterenol (100nM), elevated extracellular 1 or low temperature. When pacing was initiated during a spontaneous Cai wave, SDA occurred abruptly and persisted during pacing. Similarly, during rapid pacing, SDA typically arose suddenly from SCA, due to abrupt phase reversal of the subcellular Cai transient in a region of the myocyte. Cai waves could be visualized interspersed with AP-triggered Cai transients, producing a rich variety of subcellular Cai transient patterns. With free-running APs, complex Cai release patterns were associated with DADs, EADs and sudden changes in AP duration. These findings link Cai waves directly to a variety of arrhythmogenic phenomena relevant to the intact heart.
