ArticleAmerican journal of physiology. Heart and circulatory physiology2007
Pharmacogenetics and anti-arrhythmic drug therapy: a theoretical investigation.
Article in American journal of physiology. Heart and circulatory physiology, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 49 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
49 citing papers in PubMed, 96 citations in OpenAlex.
- Computational modeling of cardiac electrophysiology and arrhythmogenesis: toward clinical translation.Physiological reviews · 2024Review
- CYP3A4 gene expression discloses individual differences in postoperative pain susceptibility and drug treatment response in patients with lung cancer.International journal of clinical and experimental pathology · 2024Article
- Article
- The Antiarrhythmic Activity of Novel Pyrrolidin-2-one Derivative S-75 in Adrenaline-Induced Arrhythmia.Pharmaceuticals (Basel, Switzerland) · 2021Article
- A computational method for identifying an optimal combination of existing drugs to repair the action potentials of SQT1 ventricular myocytes.PLoS computational biology · 2021Article
- Computational prediction of drug response in short QT syndrome type 1 based on measurements of compound effect in stem cell-derived cardiomyocytes.PLoS computational biology · 2021Article
- A distinct molecular mechanism by which phenytoin rescues a novel long QT 3 variant.Journal of molecular and cellular cardiology · 2020Article
- Improved Computational Identification of Drug Response Using Optical Measurements of Human Stem Cell Derived Cardiomyocytes in Microphysiological Systems.Frontiers in pharmacology · 2019Article
- Inversion and computational maturation of drug response using human stem cell derived cardiomyocytes in microphysiological systems.Scientific reports · 2018Article
- Personalized Imaging and Modeling Strategies for Arrhythmia Prevention and Therapy.Current opinion in biomedical engineering · 2018Article
- A Heart for Diversity: Simulating Variability in Cardiac Arrhythmia Research.Frontiers in physiology · 2018Review
- Mexiletine rescues a mixed biophysical phenotype of the cardiac sodium channel arising from the SCN5A mutation, N406K, found in LQT3 patients.Channels (Austin, Tex.) · 2018Article
- Determinants of Isoform-Specific Gating Kinetics of hERG1 Channel: Combined Experimental and Simulation Study.Frontiers in physiology · 2018Article
- Protein-peptide association kinetics beyond the seconds timescale from atomistic simulations.Nature communications · 2017Article
- Revealing the Concealed Nature of Long-QT Type 3 Syndrome.Circulation. Arrhythmia and electrophysiology · 2017Article
- A mathematical model for active contraction in healthy and failing myocytes and left ventricles.PloS one · 2017Article
- Molecular Pathophysiology of Congenital Long QT Syndrome.Physiological reviews · 2017Review
- Dynamical characterization of inactivation path in voltage-gated Na(+) ion channel by non-equilibrium response spectroscopy.Channels (Austin, Tex.) · 2016Article
- Multiscale Modeling in the Clinic: Drug Design and Development.Annals of biomedical engineering · 2016Review
- The virtual heart as a platform for screening drug cardiotoxicity.British journal of pharmacology · 2015Review
Corrections and comments
- Erratum issued
Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
Pharmacological management of cardiac arrhythmias has been a long and widely sought goal. One of the difficulties in treating arrhythmia stems, in part, from incomplete understanding of the mechanisms of drug block and how intrinsic properties of channel gating affect drug access, binding affinity, and unblock. In the last decade, a plethora of genetic information has revealed that genetics may play a critical role in determining arrhythmia susceptibility and in efficacy of pharmacological therapy. In this context, we present a theoretical approach for investigating effects of drug-channel interaction. We use as an example open-channel or inactivated-channel block by the local anesthetics mexiletine and lidocaine, respectively, of normal and DeltaKPQ mutant Na(+) channels associated with the long-QT syndrome type 3. Results show how kinetic properties of channel gating, which are affected by mutations, are important determinants of drug efficacy. Investigations of Na(+) channel blockade are conducted at multiple scales (single channel and macroscopic current) and, importantly, during the cardiac action potential (AP). Our findings suggest that channel mean open time is a primary determinant of open state blocker efficacy. Channels that remain in the open state longer, such as the DeltaKPQ mutant channels in the abnormal burst mode, are blocked preferentially by low mexiletine concentrations. AP simulations confirm that a low dose of mexiletine can remove early afterdepolarizations and restore normal repolarization without affecting the AP upstroke. The simulations also suggest that inactivation state block by lidocaine is less effective in restoring normal repolarization and adversely suppresses peak Na(+) current.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.