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

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

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 (I_Na,L) and contribute to arrhythmogenesis in hearts with reduced repolarization reserve.

Monophasic action potential durations at 90% completion of repolarization (MAPD₉₀) from isolated rabbit hearts, I_Na,L, and extra- (pH_o) and intracellular pH (pH_i) 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.

Increasing CO₂ levels from 5% to 10% and 20% and administration of 1 nM sea anemone toxin (ATX)-II increased I_Na,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 pH_o and pH_i 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 pH_o maintained at 7.4 produced smaller changes in pH_i (P <.05) but similar increases in I_Na,L, prolongation of MAPD₉₀, and incidence of ventricular tachycardias (n = 8). Inhibition of I_Na,L reversed the increase in I_Na,L, suppressed MAPD₉₀ prolongations, and ventricular tachycardias induced by 20% CO₂. Increased phospho-calmodulin-dependent protein kinase II-δ (CaMKIIδ) and phospho-Na_V1.5 protein levels in hearts treated with 20% CO₂ was attenuated by eleclazine.

Increased CO₂ levels enhance I_Na,L and are proarrhythmic factors in hearts with reduced repolarization reserve, possibly via mechanisms related to phosphorylation of CaMKIIδ and Na_V1.5.