Abstract
Cellular electrophysiology experiments, important for understanding cardiac arrhythmia mechanisms, are usually performed with channels expressed in non myocytes, or with non-human myocytes. Differences between cell types and species affect results. Thus, an accurate model for the undiseased human ventricular action potential (AP) which reproduces a broad range of physiological behaviors is needed. Such a model requires extensive experimental data, but essential elements have been unavailable. Here, we develop a human ventricular AP model using new undiseased human ventricular data: Ca2+ versus voltage dependent inactivation of L-type Ca2+ current (ICaL); kinetics for the transient outward, rapid delayed rectifier (IKr), Na+/Ca2+ exchange (INaCa), and inward rectifier currents; AP recordings at all physiological cycle lengths; and rate dependence and restitution of AP duration (APD) with and without a variety of specific channel blockers. Simulated APs reproduced the experimental AP morphology, APD rate dependence, and restitution. Using undiseased human mRNA and protein data, models for different transmural cell types were developed. Experiments for rate dependence of Ca2+ (including peak and decay) and intracellular sodium ([Na+]i) in undiseased human myocytes were quantitatively reproduced by the model. Early afterdepolarizations were induced by IKr block during slow pacing, and AP and Ca2+ alternans appeared at rates >200 bpm, as observed in the nonfailing human ventricle. Ca2+/calmodulin-dependent protein kinase II (CaMK) modulated rate dependence of Ca2+ cycling. INaCa linked Ca2+ alternation to AP alternans. CaMK suppression or SERCA upregulation eliminated alternans. Steady state APD rate dependence was caused primarily by changes in [Na+]i, via its modulation of the electrogenic Na+/K+ ATPase current. At fast pacing rates, late Na+ current and ICaL were also contributors. APD shortening during restitution was primarily dependent on reduced late Na+ and ICaL currents due to inactivation at short diastolic intervals, with additional contribution from elevated IKr due to incomplete deactivation.
Highlights
The first step toward preventing sudden cardiac death is understanding the basic mechanisms of ventricular arrhythmias at the level of ion channel currents and the single myocyte action potential (AP), using both experiments[1] and theoretical models[2]
Throughout, new undiseased human ventricle experimental data are represented by white circles or white squares for isolated myocyte or small tissue preparation measurements, respectively
Published nonfailing human ventricle experimental data are shown with black symbols
Summary
The first step toward preventing sudden cardiac death is understanding the basic mechanisms of ventricular arrhythmias at the level of ion channel currents and the single myocyte action potential (AP), using both experiments[1] and theoretical models[2]. These approaches have limitations, because functionally important accessory subunits and anchoring proteins native to ventricular myocytes[3] are absent in expression systems, and even among mammalian ventricular myocytes, ion channel kinetics[4,5,6] and arrhythmia mechanisms are strongly species dependent These issues limit the applicability of results from animal studies to human cardiac electrophysiology and clinical arrhythmia[7]. We obtained essential new measurements for the L-type Ca2+ current, K+ currents, and Na+/Ca2+ exchange current from undiseased human ventricle These previously unavailable data are critically important for correct formulation of mathematical models for simulation of electrophysiology and cellular arrhythmia mechanisms[8].
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