Increased Risk for Atrial Alternans in Rabbit Heart Failure: The Role of Ca2+/Calmodulin-Dependent Kinase II and Inositol-1,4,5-trisphosphate Signaling

Biomolecules. 2023 Dec 30;14(1):53. doi: 10.3390/biom14010053.


Heart failure (HF) increases the probability of cardiac arrhythmias, including atrial fibrillation (AF), but the mechanisms linking HF to AF are poorly understood. We investigated disturbances in Ca2+ signaling and electrophysiology in rabbit atrial myocytes from normal and failing hearts and identified mechanisms that contribute to the higher risk of atrial arrhythmias in HF. Ca2+ transient (CaT) alternans-beat-to-beat alternations in CaT amplitude-served as indicator of increased arrhythmogenicity. We demonstrate that HF atrial myocytes were more prone to alternans despite no change in action potentials duration and only moderate decrease of L-type Ca2+ current. Ca2+/calmodulin-dependent kinase II (CaMKII) inhibition suppressed CaT alternans. Activation of IP3 signaling by endothelin-1 (ET-1) and angiotensin II (Ang II) resulted in acute, but transient reduction of CaT amplitude and sarcoplasmic reticulum (SR) Ca2+ load, and lowered the alternans risk. However, prolonged exposure to ET-1 and Ang II enhanced SR Ca2+ release and increased the degree of alternans. Inhibition of IP3 receptors prevented the transient ET-1 and Ang II effects and by itself increased the degree of CaT alternans. Our data suggest that activation of CaMKII and IP3 signaling contribute to atrial arrhythmogenesis in HF.

Keywords: Ca2+/calmodulin-dependent kinase II; alternans; arrhythmia; atria; calcium; heart failure; inositol-trisphosphate.

MeSH terms

  • Angiotensin II / pharmacology
  • Animals
  • Atrial Fibrillation*
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2*
  • Calmodulin
  • Heart Atria
  • Heart Failure*
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism
  • Inositol 1,4,5-Trisphosphate* / metabolism
  • Peptide Hormones*
  • Rabbits


  • Angiotensin II
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calmodulin
  • Peptide Hormones
  • Inositol 1,4,5-Trisphosphate Receptors
  • Inositol 1,4,5-Trisphosphate