Discordant Ca 2+ release in cardiac myocytes: characterization and susceptibility to pharmacological RyR2 modulation

Pflugers Arch. 2022 Jun;474(6):625-636. doi: 10.1007/s00424-022-02678-8. Epub 2022 Mar 2.

Abstract

Systolic Ca2+ transients are shaped by the concerted summation of Ca2+ sparks across cardiomyocytes. At high pacing rates, alterations of excitation-contraction coupling manifest as pro-arrhythmic Ca2+ alternans that can be classified as concordant or discordant. Discordance is ascribed to out-of-phase alternation of local Ca2+ release across the cell, although the triggers and consequences of this phenomenon remain unclear. Rat ventricular cardiomyocytes were paced at increasing rates. A discordance index (SD of local alternans ratios) was developed to quantify discordance in confocal recordings of Ca2+ transients. Index values were significantly increased by rapid pacing, and negatively correlated with Ca2+ transient amplitude change, indicating that discordance is an important contributor to the negative Ca2+ transient-frequency relationship. In addition, the largest local calcium transient in two consecutive transients was measured to build a potential "best release" profile, which quantitatively confirmed discordance-induced Ca2+ release impairment (DICRI). Diastolic Ca2+ homeostasis was also observed to be disrupted by discordance, as late Ca2+ release events elicited instability of resting Ca2+ levels. Finally, the effects of two RyR2 inhibitors (VK-II-86 and dantrolene) were tested. While both compounds inhibited Ca2+ wave generation, only VK-II-86 augmented subcellular discordance. Discordant Ca2+ release is a quantifiable phenomenon, sensitive to pacing frequency, and impairs both systolic and diastolic Ca2+ homeostasis. Interestingly, RyR2 inhibition can induce discordance, which should be considered when evaluating pharmacological RyR2 modulators for clinical use.

Keywords: Alternans; Dantrolene; Discordance; RyR2; VK-II-86.

MeSH terms

  • Animals
  • Arrhythmias, Cardiac / metabolism
  • Calcium / metabolism
  • Calcium Signaling
  • Excitation Contraction Coupling
  • Myocytes, Cardiac* / metabolism
  • Rats
  • Ryanodine Receptor Calcium Release Channel* / metabolism
  • Sarcoplasmic Reticulum

Substances

  • RyR2 protein, rat
  • Ryanodine Receptor Calcium Release Channel
  • Calcium