Na⁺ channel distribution and electrophysiological heterogeneities in guinea pig ventricular wall

Abstract

We sought to explore the distribution pattern of Na(+) channels across ventricular wall, and to determine its functional correlates, in the guinea pig heart. Voltage-dependent Na(+) channel (Na(v)) protein expression levels were measured in transmural samples of ventricular tissue by Western blotting. Isolated, perfused heart preparations were used to record monophasic action potentials and volume-conducted ECG, and to measure effective refractory periods (ERPs) and pacing thresholds, in order to assess excitability, electrical restitution kinetics, and susceptibility to stimulation-evoked tachyarrhythmias at epicardial and endocardial stimulation sites. In both ventricular chambers, Na(v) protein expression was higher at endocardium than epicardium, with midmyocardial layers showing intermediate expression levels. Endocardial stimulation sites showed higher excitability, as evidenced by lower pacing thresholds during regular stimulation and downward displacement of the strength-interval curve reconstructed after extrasystolic stimulation compared with epicardium. ERP restitution assessed over a wide range of pacing rates showed greater maximal slope and faster kinetics at endocardial than epicardial stimulation sites. Flecainide, a Na(+) channel blocker, reduced the maximal ERP restitution slope, slowed restitution kinetics, and eliminated epicardial-to-endocardial difference in dynamics of electrical restitution. Greater excitability and steeper electrical restitution have been associated with greater arrhythmic susceptibility of endocardium than epicardium, as assessed by measuring ventricular fibrillation threshold, inducibility of tachyarrhythmias by rapid cardiac pacing, and the magnitude of stimulation-evoked repolarization alternans. In conclusion, higher Na(+) channel expression levels may contribute to greater excitability, steeper electrical restitution slopes and faster restitution kinetics, and greater susceptibility to stimulation-evoked tachyarrhythmias at endocardium than epicardium in the guinea pig heart.

Role of abnormal repolarization in the mechanism of cardiac arrhythmia

“…In perfused guinea‐pig hearts, the inducibility of APD alternans and tachyarrhythmia is higher when electrical stimulations are applied at endocardium compared to epicardium, in both RV and LV chamber . Endocardial stimulations also require lower threshold current strength to induce VF.…”

“…The epicardial‐to‐endocardial difference in arrhythmic susceptibility is partly accounted for by transmural heterogeneities in the distribution of Na + channels. The expression levels of Na v 1.5 and/or I Na current density are greater at the endocardium than the epicardium in guinea‐pig, rat, and mouse, as well as in non‐diseased human hearts . Consequently, tissue excitability is higher at the endocardium, as evidenced by the lower ventricular capture thresholds compared to the epicardium .…”

Low Density Lipoproteins Promote Unstable Calcium Handling Accompanied by Reduced SERCA2 and Connexin-40 Expression in Cardiomyocytes

“…This observation is likely due to the concomitant LDL-mediated reduction in RyR2 and IP3R expression, which together with a reduced SERCA level is expected to cause a reduction in calcium cycling on a beat-to-beat basis. Additionally, LDL dose-dependently impaired propagation of the calcium transient across the myocyte culture at short pacing intervals, suggesting a reduction in excitability[25] and/or a reduction in the communication between the cultured cardiomyocytes[26], [27].…”

Impact of Hypokalemia on Electromechanical Window, Excitation Wavelength and Repolarization Gradients in Guinea-Pig and Rabbit Hearts

“…The experiments on isolated, perfused hearts were performed as described previously [20]–[21]. The guinea-pigs were anesthetized with sodium pentobarbital (50 mg/kg i.p.…”