Author + information
- Yu Juan
Acidosis is a pathological process in myocardial ischemia, heart failure and sepsis. Although lidocaine appeared to function exactly in arrhythmia, the Cardiac Arrhythmia Suppression Trial (CAST) paradoxically showed that it caused a two- to threefold increase in sudden cardiac death compared with placebo. It is still unclear why lidocaine is poor in acidosis up to now. The present study is to reveal the mechanism that lidocaine are weak in acidosis states.
Markov models of voltage dependent sodium current(INa), rapid delayed rectified potassium current (IKr) and L-type calcium current(ICaL) were formulated via numerical optimization from experimentally derived rate constants that formed the basis action potential(AP) in acidosis. The drug-channel model was incorporated into Roberts-Christini AP model of the guinea pig. 2D Spiral waves and 3D magnetic resonance imaging (MRI)-based Spiral scrolls were constructed in cardiac ventricles. Simulations were encoded in C++ and run on 3 nodes' server based on Pros 3.6 GHz 20-Core using OpenMP and MPI.
Firstly, INa, IKr, and ICaL were simulated with published data in acidosis(extracellular pH and intracellular pH both 6.5) and control(extracellular pH 7.4 and intracellular pH 7.2). Peak INa reduced 50%, peak IKr reduced 60%, and peak ICaL reduced 50% with AP duration delayed 20ms. Secondly, we studied the effects of lidocaine on single-cell upstroke velocity in acidosis. With 0, 5 and 20mM lidocaine, the upstroke velocity were ∼380, 315, and 285 V/s in control and 300, 285, and 255 V/s in acidosis, respectively. Pacing in 60, 80,120,160 bpm with 20 mM lidocaine, the upstroke velocity is ∼270, 255, 235,200 V/s in control, and 250, 235, 215, 195 V/s in acidosis respectively. Therefore, both dose-dependent and frequency-dependent effects of lidocaine on upstroke velocity were reduced in acidosis. Fourthly, we expanded to one-dimensional (1D) 100 cells cardiac tissue of 20 mM lidocaine at 120 BPM on conduction velocity (CV). CV was 50 cm/s in control and reduced to 40 cm/s in acidosis. Fifthly, we used the 1D predictions to guide 2D simulations with 20 mM lidocaine at 120 BPM in a 2D homogeneous 500 by 500 cells. the spiral wave of reentry was 1.1s in acidosis and 0.5s in control. Finally, we tested in a MRI-based, anatomically detailed 3D model of the rabbit ventricles and paced from the apex at a rate of 120 BPM with high-dose lidocaine (20 mM). An ectopic stimulus initiated a >2.2 s persistent reentrant wave in acidosis while <0.6 s in normal tissue.
This is the most detailed acidosis action potential model up to now as we know, it included INa,IKr markov model, dynamic intracellular and extracellular pH changes. Furthermore, our study interpreted why lidocaine takes weak effects on acidosis, which provide a novel thinking of anti-arrhythmia drugs on heart diseases.