Computational Analysis of the Mode of Action of Disopyramide and Quinidine on hERG-Linked Short QT Syndrome in Human Ventricles

Whittaker, Dominic G.; Ni, Haibo; Benson, Alan P.; Hancox, Jules C.; Zhang, Henggui

doi:10.3389/fphys.2017.00759

Cited by 33 publications

(58 citation statements)

References 55 publications

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“…Further work is probably warranted to determine whether atrial-selective strategies, such as I Kur inhibition[126], might be viable against paroxysmal AF in different SQTS variants. Whilst, as considered in section 4, there is some evidence for modest contractile deficiency in some SQTS patients, as this is likely to be secondary to the We suggest that systematic in silico investigation of other SQTS variants would be beneficial incorporating both drug potency and the kind of binding kinetics that we have in SQT1 simulations[109], in order to establish clearly the target qualities that maximise effectiveness (and indeed limitations) of combined I Kr and I Na block in different SQTS variants. I Ks and/or I K1 inhibition at different potencies could then be systematically incorporated to establish clearly any additional benefit from synergistic I Kr and I Ks /I K1 block.It should be noted that other concomitant pharmacological actions have the potential to mitigate QT prolonging effects.…”

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confidence: 90%

Emerging therapeutic targets in the short QT syndrome

Hancox

Whittaker

Du³

et al. 2018

Expert Opinion on Therapeutic Targets

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Short QT Syndrome (SQTS) is a rare but dangerous condition characterised by abbreviated repolarisation, atrial and ventricular arrhythmias and risk of sudden death. Implantable cardioverter defibrillators (ICDs) are a first line protection against sudden death, but adjunct pharmacology is beneficial and desirable. Areas covered: The genetic basis for genotyped SQTS variants (SQT1-SQT8) and evidence for arrhythmia substrates from experimental and simulation studies are discussed. The main ion channel/transporter targets for antiarrhythmic pharmacology are considered in respect of potential genotype-specific and non-specific treatments for the syndrome. Expert opinion: Potassium channel blockade is valuable for restoring repolarisation and QT interval, though genotype-specific limitations exist in the use of some K channel inhibitors. A combination of K current inhibition during the action potential plateau, with sodium channel inhibition that collectively result in delaying repolarisation and post-repolarisation refractoriness is likely to be valuable in prolonging effective refractory period and wavelength for re-entry. Genotype-specific K channel inhibition is limited by a lack of targeted inhibitors in clinical use, though experimentally available selective inhibitors now exist. The relatively low proportion of successfully genotyped cases justifies an exome or genome sequencing approach, to reveal new mediators and targets, as demonstrated recently for SLC4A3 in SQT8.

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confidence: 90%

Emerging therapeutic targets in the short QT syndrome

Hancox

Whittaker

Du³

et al. 2018

Expert Opinion on Therapeutic Targets

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“…For the N558K mutation at least, simulation data suggest that the beneficial actions of quinidine on effective refractory period result from both I hERG / I Kr inhibition and the drug's Na channel inhibitory action (Whittaker et al. ). At present there are no patient data regarding effectiveness of quinidine in S631A hERG linked SQT1 (Akdis et al.…”

Section: Discussionmentioning

confidence: 99%

Action potential clamp characterization of the S631A hERG mutation associated with short QT syndrome

Butler¹,

Zhang²,

Stuart

et al. 2018

Physiol Rep

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The hERG potassium channel is critical to normal repolarization of cardiac action potentials (APs) and loss‐ and gain‐of‐function hERG mutations are associated, respectively, with long and short QT syndromes, pathological conditions that can lead to arrhythmias and sudden death. hERG current (I h ERG) exhibits uniquely fast inactivation involving conformational changes to the channel pore. The S631A hERG pore mutation was originally engineered to interrogate hERG channel inactivation, but has very recently been found in a family with short QT syndrome (SQTS). Accordingly, this study characterized the effects of the S631A mutation on I h ERG profile during ventricular, atrial, and Purkinje fiber (PF) AP waveforms, using patch clamp recording from hERG expressing HEK 293 cells at 37°C. Under conventional voltage clamp, the current–voltage (I–V) relation for I h ERG exhibited a marked right‐ward shift in the region of negative slope at positive membrane potentials. Under ventricular AP clamp, the S631A mutation resulted in augmented I h ERG, which also peaked much earlier during the AP plateau than did wild‐type (WT) I h ERG. Instantaneous I–V relations showed a marked positive shift in peak repolarizing current during the ventricular AP in the S631A setting, while the instantaneous conductance‐voltage relation showed an earlier and more sustained rise in S631A compared to WT I h ERG conductance during ventricular repolarization. Experiments with atrial and PF APs in each case also showed augmented and positively shifted I h ERG in the S631A setting, indicating that the S631A mutation is likely to accelerate repolarization in all three cardiac regions. Ventricular AP clamp experiments showed retained effectiveness of the class Ia antiarrhythmic drug quinidine (1 μmol/L) against S631A I h ERG. Quinidine is thus likely to be effective in reducing excessively fast repolarization in SQTS resulting from the S631A hERG mutation.

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“…The N588K mutation was found to increase greatly the current over the physiological range of membrane potentials due to impaired inactivation [43] causing increased maximal I hERG to occur earlier during a simulated human ventricular AP waveform [148]. These changes were integrated into a mathematical models of the human ventricular AP in which the N588K mutation was shown to shorten the action potential duration (APD) whilst increasing the transmural dispersion of repolarisation (TDR) across the ventricular wall [67,132]. At the tissue level this had the effect of shortening the QT interval whilst increasing the amplitude of the T wave, as has been observed clinically in SQTS patients.…”

Section: Synergy Between Clinical and Preclinical Studies In Understamentioning

confidence: 99%

“…When integrated into a human left ventricular wedge model with realistic geometry, the combined proarrhythmic substrate of shortened AP with increased heterogeneity of repolarisation due to the N588K-hERG mutation rendered ventricular tachycardia/fibrillation (VT/VF) inducible. Modified with permission from [132] Hancox et al Journal of Congenital Cardiology (2019) 3:3 fibrillation and flutter [15]. Further work is therefore required to uncover the basis for the difference in AF susceptibility between T618I and these other mutations.…”

Section: Synergy Between Clinical and Preclinical Studies In Understamentioning

confidence: 99%

“…Disopyramide, a second class Ia antiarrhythmic agent, also retains effectiveness against N588K and S631A channels [125,128,129] and has been tested successfully in SQT1 patients and a patient with unknown genotype [130,131]. Computational analysis of quinidine and disopyramide in the setting of N588K-linked SQT1 has demonstrated that normative effects on repolarization arise from the drug's I Kr blocking action, whilst ERP prolongation results from a combination of I Kr block and actions on I Na [132]. The fact that the N588 residue lies outside the hERG channel pore means that the N588K mutation provides a means of interrogating inactivation dependence of hERG blockade.…”

Section: Insights From Preclinical Sqts Studies Into Arrhythmia Substmentioning

confidence: 99%

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Learning from studying very rare cardiac conditions: the example of short QT syndrome

Hancox

Whittaker

Zhang

et al. 2019

J Congenit Heart Dis

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Background: Some congenital heart conditions are very rare. In a climate of limited resources, a viewpoint could be advanced that identifying diagnostic criteria for such conditions and, through empiricism, effective treatments should suffice and that extensive mechanistic research is unnecessary. Taking the rare but dangerous short QT syndrome (SQTS) as an example, this article makes the case for the imperative to study such rare conditions, highlighting that this yields substantial and sometimes unanticipated benefits. Genetic forms of SQTS are rare, but the condition may be under-diagnosed and carries a risk of sudden death. Genotyping of SQTS patients has led to identification of clear ion channel/transporter culprits in < 30% of cases, highlighting a role for as yet unidentified modulators of repolarization. For example, recent exome sequencing in SQTS has identified SLC4A3 as a novel modifier of ventricular repolarization. The need to distinguish "healthy" from "unhealthy" short QT intervals has led to a search for additional markers of arrhythmia risk. Some overlap may exist between SQTS, Brugada Syndrome, early repolarization and sinus bradycardia. Genotype-phenotype studies have led to identification of arrhythmia substrates and both realistic and theoretical pharmacological approaches for particular forms of SQTS. In turn this has increased understanding of underlying cardiac ion channels. In silico and pharmacological data have highlighted risks with abbreviation of refractoriness accompanied by local dispersion of repolarization, and this urges caution with the deployment of K + channel activation as a novel antiarrhythmic approach. The association between abbreviated QT c intervals and primary carnitine deficiency, particularly in patients with concomitant cardiomyopathy illustrates a link between metabolism and electrogenesis, in which the correct identification of causation could, in some cases, lead to dietary intervention that may obviate the need for antiarrhythmic or heart failure drugs. Conclusions: As illustrated here for the SQTS, the detailed study of rare disorders is both directly beneficial for the treatment/management of affected patients and for increasing the understanding of associated underlying cardiac physiology and pharmacology. The pursuit of underlying gene mutations can lead to unanticipated new links between particular genes and cardiac electrophysiology, opening new avenues for research and potential therapeutic intervention.

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Computational Analysis of the Mode of Action of Disopyramide and Quinidine on hERG-Linked Short QT Syndrome in Human Ventricles

Cited by 33 publications

References 55 publications

Emerging therapeutic targets in the short QT syndrome

Emerging therapeutic targets in the short QT syndrome

Action potential clamp characterization of the S631A hERG mutation associated with short QT syndrome

Learning from studying very rare cardiac conditions: the example of short QT syndrome

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