Contents

📒 Ellinwood 2017

In Silico Assessment of Efficacy and Safety of IKur Inhibitors in Chronic Atrial Fibrillation: Role of Kinetics and State-Dependence of Drug Binding1

Sciwheel

Introduction

  • Atrial fibrillation (AF) is characterized by rapid, irregular heart contractions following fast, disorganized electrical signals in the atria
  • most common cardiac arrhythmia (1-2%)
  • Pharmacological therapy against AF is limited by low efficacy and substantial adverse side effects including an increased risk of lethal ventricular tachyarrhythmias. radiofrequency ablation is the most effective treatment.
  • Genetic mutations causing both loss- and gain-of-function of IKur have been associated with atrial arrhythmias in human

Methods

Atrial AP Model and Simulationss

  • Grandi et al. model
  • IKur gating was described by a 6-state Markov type model
  • The cycle length (CL) was allowed to vary randomly following a uniform distribution between 285.7 and 400 ms, corresponding to a minimum pacing frequency of 2.5 Hz and a maximum pacing frequency of 3.5 Hz
  • The model code is available for download at the following webpages: https://somapp.ucdmc.ucdavis.edu/Pharmacology/bers/ and http://elegrandi.wixsite.com/grandilab/downloads (e-mail required)
  • Parameter sensitivity analysis was performed with the population-based approach described in Sobie (2009), Morotti et al. (2017), and Morotti and Grandi (2017)

KV1.5 Drug-Binding Model

https://www.frontiersin.org/files/Articles/301424/fphar-08-00799-HTML/image_m/fphar-08-00799-g002.jpg

  • dissociation constants (Kd) for our drug scenarios were calculated as koff/kon, and affinity constants were calculated as kon/koff

Results

Role of IKur in nSR and cAF Atrial Electrophysiology

https://www.frontiersin.org/files/Articles/301424/fphar-08-00799-HTML/image_m/fphar-08-00799-g001.jpg

  • 900 variations of our nSR (normal sinus rhythm) and cAF (chronic AF) human atrial cardiomyocyte models
  • At 3-Hz pacing, GKur impacts AP and ERP prolongation more in cAF vs. nSR despite the fact that GKur is smaller in cAF conditions.
  • This points to IKur inhibition as a promising approach to counteract the abbreviated APD and ERP in cAF

Effect of Conformational State Specificity and Binding/Unbinding Kinetics on Human Atrial Cardiomyocyte APD at Normal and Fast Pacing Rates in cAF Conditions

https://www.frontiersin.org/files/Articles/301424/fphar-08-00799-HTML/image_m/fphar-08-00799-g002.jpg

  • both types of inhibitors display a biphasic relationship between APD and drug-binding kinetics at 1- and 3-Hz pacing
  • Significant APD prolongation is only seen for intermediate drug-binding kinetics (0.3–30 s−1 for the open state blocker and 1–30 s−1 for the open and inactivated state blocker)
  • At 3-Hz pacing, the two types of inhibitors cause stronger relative prolongation as compared to 1-Hz pacing

https://www.frontiersin.org/files/Articles/301424/fphar-08-00799-HTML/image_m/fphar-08-00799-g003.jpg

  • Results in drug-free conditions and for an O & I blocker (modeled as in Figure 2F, black) with kon = koff (Kd = 1 ΞM) in Figure 3 again demonstrate a biphasic relationship between drug-binding kinetics and average APD90

Effect of Conformational State Specificity and Binding/Unbinding Kinetics on Human Atrial Cardiomyocyte ERP at Normal and Fast Pacing Rates in cAF Conditions

https://www.frontiersin.org/files/Articles/301424/fphar-08-00799-HTML/image_m/fphar-08-00799-g004.jpg

  • The desired effect of IKur inhibitors is prolongation of atrial ERP (effective refractory peroid)
  • Simulations reveal a similar biphasic relationship between ERP and drug-binding kinetics
  • At 1-Hz pacing, IKur inhibitors cause minimal ERP prolongation at slow drug-binding rates (â‰Ī0.3 Hz) and fast drug-binding rates (100 Hz)
  • ERP prolongation remains ~62 ms lower than the ERP in nSR given no block of IKur for both inhibitors
  • At 3-Hz pacing, however, IKur inhibitors appear to be more effective at extending ERP than APD => favorable drug property

Effects of Drug Binding/Unbinding Kinetics with Variable Kd on APD, ERP, and Ca2+ Handling

https://www.frontiersin.org/files/Articles/301424/fphar-08-00799-HTML/image_m/fphar-08-00799-g005.jpg

  • Previous figure are for k_on = k_off (Kd = 1)
  • Here we simulated all permutations of the nine different rates of drug binding (0.01 to 100 s−1), yielding 81 different combinations of kon and koff for the O & I state inhibitors
  • Except for the drugs with the largest Kd values (koff » kon), when kon is held constant, APD, ERP, and Ca2+ handling are not very sensitive to changes in koff. the effects of IKur inhibitors on atrial electrophysiology and Ca2+ handling are largely driven by kon rates as compared to koff rates.
  • In cAF conditions, ideal IKur inhibitors exhibiting AF-selectivity will prolong atrial refractoriness (ERP prolongation at 3-Hz pacing), have limited toxicity (minimal to no APD prolongation at 1-Hz pacing), and have a positive inotropic effect (an increase in CaTamp at 1-Hz pacing)

Effect of Relative State-Specific Drug Binding

https://www.frontiersin.org/files/Articles/301424/fphar-08-00799-HTML/image_m/fphar-08-00799-g006.jpg

Discussion

  • we sought to determine if IKur is a suitable anti-AF target despite it being downregulated in cAF patients
  • we implemented an in silico assessment of IKur inhibitors in cAF atrial cardiomyocyte models, and identified metrics for delineating ideal KV1.5 blockers against AF

https://www.frontiersin.org/files/Articles/301424/fphar-08-00799-HTML/image_m/fphar-08-00799-g007.jpg
Summary of main findings

  • Our simulations suggest that electrophysiological properties in cAF cardiomyocytes, such as shorter AP and more depolarized plateau potential, both might act to increase efficacy and dampen cardiotoxicity of potential KV1.5-targeting drugs as compared to nSR

IKur Role in APD and ERP Regulation Is Preserved Despite Its Downregulation in cAF

  • the consequences of IKur inhibition, including the extent of AP and ERP prolongation, depend not only on IKur magnitude (i.e., maximal conductance), but also on other fluxes affected by AF-induced remodeling
  • APD90 and ERP are more sensitive to changes in GKur at fast vs. slow pacing rates
  • GKur impacted the duration of AP repolarization and refractoriness more in cAF vs. nSR
  • Enhanced Efficacy and Safety of IKur Inhibitors in cAF vs. nSR

  1. Ellinwood N, Dobrev D, Morotti S, Grandi E. In Silico Assessment of Efficacy and Safety of IKur Inhibitors in Chronic Atrial Fibrillation: Role of Kinetics and State-Dependence of Drug Binding. Front Pharmacol. 2017 Nov 7;8:799. PMC5681918 ↩︎