|Authors||M. Maleckar, G. T. Lines, J. Koivumäki, J. M. Cordeiro and K. Calloe|
|Title||NS5806 Partially Restores Action Potential Duration But Fails to Ameliorate Calcium Transient Dysfunction in a Computational Model of Canine Heart Failure|
|Afilliation||Cardiac Modeling, Center for Biomedical Computing (SFF), Center for Cardiological Innovation (SFI), Scientific Computing|
|Publication Type||Journal Article|
|Year of Publication||2014|
Aims The study investigates how increased Ito, as mediated by the activator NS5806, affects excitation -contraction coupling in chronic heart failure (HF). We hypothesized that restoring spike-and-dome morphology of the action potential (AP) to a healthy phenotype would be insufficient to restore the intracellular Ca2+ transient (CaT), due to HF-induced remodelling of Ca2+ handling. Methods An existing mathematical model of the canine ventricular myocyte was modified to incorporate recent experimental data and results from healthy and failing myocytes, resulting in models of both healthy and HF epicardial, midmyocardial, and endocardial cell variants. Affects of NS5806 were also included in HF models through its direct interaction with Kv4.3 and Kv1.4. Single-cell simulations performed in all models (control, HF, and HF + drug) and variants (epi, mid, and endo) assessed AP morphology and underlying ionic processes with a focus on CaT, how these were altered in HF across the ventricular wall, and the subsequent effects of varying compound concentration in HF. Heart failure model variants recapitulated a characteristic increase in AP duration (APD) in the disease. The qualitative effects of application of half-maximal effective concentration (EC50) of NS5806 on APs and CaT are heterogeneous and non-linear. Deepening in the AP notch with drug is a direct effect of the activation of Ito; both Ito and consequent alteration of IK1 kinetics cause decrease in AP plateau. Decreased APD50 and APD90 are due to altered IK1. Analysis revealed that drug effects depend on transmurality. Ca2+ transient morphology changes-increased amplitude and shorter time to peak-are due to direct increase in ICa,L and indirect larger SR Ca2+ release subsequent to Ito activation. Conclusions Downstream effects of a compound acting exclusively on sarcolemmal ion channels are difficult to predict. Remediation of APD topre-failing state does not ameliorate dysfunction in CaT; however, restoration of notch depth appears to impart modest benefit and a likelihood of therapeutic value in modulating early repolarization.