Increase in CO2 levels by upregulating late sodium current is proarrhythmic in the heart

Heart Rhythm. 2019 Jul;16(7):1098-1106. doi: 10.1016/j.hrthm.2019.01.029. Epub 2019 Jan 31.

Abstract

Background: Increased CO2 levels in the general circulation and/or in the myocardium are common under pathologic conditions.

Objective: The purpose of this study was to test the hypothesis that an increase in CO2 levels, and not just the subsequent extra- or intracellular acidosis, would augment late sodium current (INa,L) and contribute to arrhythmogenesis in hearts with reduced repolarization reserve.

Methods: Monophasic action potential durations at 90% completion of repolarization (MAPD90) from isolated rabbit hearts, INa,L, and extra- (pHo) and intracellular pH (pHi) values from cardiomyocytes using the whole-cell patch-clamp techniques and 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein, acetoxymethyl ester (BCECF-AM), respectively, were measured.

Results: Increasing CO2 levels from 5% to 10% and 20% and administration of 1 nM sea anemone toxin (ATX)-II increased INa,L and prolonged both epicardial and endocardial MAPD90 (n = 7 and 10, respectively) without causing arrhythmic activities. Compared to 5% CO2, 10% and 20% CO2 decreased pHo and pHi in hearts treated with 1 nM ATX-II, caused greater prolongation of MAPD90, and elicited ventricular tachycardias. Increasing CO2 levels from 5% to 10% and 20% with pHo maintained at 7.4 produced smaller changes in pHi (P <.05) but similar increases in INa,L, prolongation of MAPD90, and incidence of ventricular tachycardias (n = 8). Inhibition of INa,L reversed the increase in INa,L, suppressed MAPD90 prolongations, and ventricular tachycardias induced by 20% CO2. Increased phospho-calmodulin-dependent protein kinase II-δ (CaMKIIδ) and phospho-NaV1.5 protein levels in hearts treated with 20% CO2 was attenuated by eleclazine.

Conclusion: Increased CO2 levels enhance INa,L and are proarrhythmic factors in hearts with reduced repolarization reserve, possibly via mechanisms related to phosphorylation of CaMKIIδ and NaV1.5.

Keywords: Acidosis; CO(2); Cardiomyocyte; Eleclazine; Isolated heart; Late sodium current.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Animals
  • Arrhythmias, Cardiac / metabolism*
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Carbon Dioxide / metabolism*
  • Cnidarian Venoms
  • Hydrogen-Ion Concentration
  • Myocardium / metabolism*
  • Oxazepines
  • Patch-Clamp Techniques
  • Phosphorylation
  • Rabbits
  • Sodium Channels / metabolism*
  • Up-Regulation

Substances

  • Cnidarian Venoms
  • Oxazepines
  • Sodium Channels
  • eleclazine
  • Carbon Dioxide
  • toxin II (Anemonia sulcata)
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2