Arrhythmogenic consequences of intracellular calcium waves

Lai-Hua Xie, James N. Weiss

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Intracellular Ca2+ (Cai2+) 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, Cai2+ waves also have other consequences relevant to arrhythmogenesis, including subcellular spatially discordant alternans (SDA, in which the amplitude of the local Ca i2+ transient alternates out of phase in different regions of the same cell), sudden repolarization changes promoting the dispersion of refractoriness, and early afterdepolarizations (EADs). Cai 2+ was imaged using a charge-coupled device-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. Cai2+ waves were induced by Bay K 8644 (50 nM) + isoproterenol (100 nM), or low temperature. When pacing was initiated during a spontaneous Cai2+ wave, SDA occurred abruptly and persisted during pacing. Similarly, during rapid pacing, SDA typically arose suddenly from spatially concordant alternans, due to an abrupt phase reversal of the subcellular Cai2+ transient in a region of the myocyte. Cai2+ waves could be visualized interspersed with AP-triggered Cai2+ transients, producing a rich variety of subcellular Cai2+ transient patterns. With free-running APs, complex Cai2+ release patterns were associated with DADs, EADs, and sudden changes in AP duration. These findings link Cai2+ waves directly to a variety of arrhythmogenic phenomena relevant to the intact heart.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume297
Issue number3
DOIs
StatePublished - Sep 1 2009

Fingerprint

Calcium Signaling
Action Potentials
Muscle Cells
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester
Digitalis
Isoproterenol
Running
Cardiac Arrhythmias
Heart Diseases
Heart Failure
Rabbits
Equipment and Supplies
Temperature

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

Keywords

  • Calcium transient
  • Cardiac myocytes
  • Discordant alternans
  • Ryanodine receptor
  • Sarcoplasmic reticulum

Cite this

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Arrhythmogenic consequences of intracellular calcium waves. / Xie, Lai-Hua; Weiss, James N.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 297, No. 3, 01.09.2009.

Research output: Contribution to journalArticle

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AU - Weiss, James N.

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AB - Intracellular Ca2+ (Cai2+) 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, Cai2+ waves also have other consequences relevant to arrhythmogenesis, including subcellular spatially discordant alternans (SDA, in which the amplitude of the local Ca i2+ transient alternates out of phase in different regions of the same cell), sudden repolarization changes promoting the dispersion of refractoriness, and early afterdepolarizations (EADs). Cai 2+ was imaged using a charge-coupled device-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. Cai2+ waves were induced by Bay K 8644 (50 nM) + isoproterenol (100 nM), or low temperature. When pacing was initiated during a spontaneous Cai2+ wave, SDA occurred abruptly and persisted during pacing. Similarly, during rapid pacing, SDA typically arose suddenly from spatially concordant alternans, due to an abrupt phase reversal of the subcellular Cai2+ transient in a region of the myocyte. Cai2+ waves could be visualized interspersed with AP-triggered Cai2+ transients, producing a rich variety of subcellular Cai2+ transient patterns. With free-running APs, complex Cai2+ release patterns were associated with DADs, EADs, and sudden changes in AP duration. These findings link Cai2+ waves directly to a variety of arrhythmogenic phenomena relevant to the intact heart.

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