Low osmolarity transforms ventricular fibrillation from complex to highly organized, with a dominant high-frequency source

Background

An osmotic challenge activates volume-regulated chloride currents (I_Cl,vol), resulting in depolarization of the resting membrane potential and shortening of action potential duration (APD). I_Cl,vol is activated in ischemia/reperfusion, but the effects of osmotic challenges and I_Cl,vol on ventricular fibrillation (VF) are unknown.

Objectives

The purpose of this study was to investigate the influence of hypo-osmotic and hypotonic stress and I_Cl,vol activation on VF dynamics.

Methods

Guinea pig hearts were isolated, stained with di-4 ANEPPS to optically map action potentials (APs) from epicardium using a photodiode array, and perfused with iso-osmotic (low NaCl Ringer plus 45 mM mannitol) or hypo-osmotic (low NaCl Ringer) solution.

Results

Hypo-osmotic solution shortened APDs (143 ± 5 ms → 115 ± 10 ms) and increased APD gradients between right and left ventricles (21 ± 7 ms → 41 ± 10 ms, n = 4). In VF induced by burst stimulation, switching to hypo-osmotic solution increased VF frequencies (15.3 ± 1.2 Hz to 28.9 ± 3.6 Hz, n = 11), transforming complex fast Fourier transformation spectra to a single dominant high frequency on the left but not the right ventricle. Perfusion with the I_Cl,vol blocker indanyloxyacetic acid-94 (10 μM) reversed organized VF to complex VF with lower (13.5 ± 3.7 Hz in left ventricle) frequencies (n = 8), indicating that I_Cl,vol underlies the changes in VF dynamics. Consistent with this interpretation, the levels of ClC-3 channel protein were 27% greater on left than right ventricles (n = 10), and computer simulations showed that insertion of I_Cl,vol transformed complex VF to a stable spiral.

Conclusion

Activation of I_Cl,vol by decreasing osmolarity (45 mOsm) has a major impact on VF dynamics by transforming random multiple wavelets to a highly organized VF with a single dominant frequency.

Keywords:  I_Cl,vol swelling-activated chloride current , Ventricular fibrillation , Osmolarity , Time-frequency domain analysis , Multiple wavebreaks , Dominant frequency