ArticleJournal of molecular and cellular cardiology2016
Mechanisms of pro-arrhythmic abnormalities in ventricular repolarisation and anti-arrhythmic therapies in human hypertrophic cardiomyopathy.
Article in Journal of molecular and cellular cardiology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 71 papers.
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Who cites it
71 citing papers in PubMed, 124 citations in OpenAlex.
- Atrial electrophysiology in hypertrophic cardiomyopathy: current insights and knowledge gaps.Journal of interventional cardiac electrophysiology : an international journal of arrhythmias and pacing · 2026Review
- Insights from electromechanical simulations to assess omecamtiv mecarbil efficacy in heart failure.The Journal of physiology · 2026Article
- Can in silico models predict drug-induced cardiac risk in vulnerable populations?Toxicology reports · 2026Article
- Interplay between variability in intrinsic cellular properties and heart failure-associated remodeling in a simulated population with human heart failure.Journal of molecular and cellular cardiology · 2026Article
- An Electromechanical Model-Based Study on the Dosage Effects of Ranolazine in Treating Failing HCM Cardiomyocyte.Cellular and molecular bioengineering · 2025Article
- Sex differences in cardiac dynamics during myocardial ischemia using a single cell approach.Scientific reports · 2025Article
- A large population of cell-specific action potential models replicating fluorescence recordings of voltage in rabbit ventricular myocytes.Royal Society open science · 2025Article
- Accelerating virtual patient generation with a Bayesian optimization and machine learning surrogate model.CPT: pharmacometrics & systems pharmacology · 2025Article
- Quantitative assessment of the usability of electromechanical human-based modelling and simulation to replace Langendorff isolated rabbit heart experiments in the preclinical setting.Frontiers in pharmacology · 2025Article
- Fast and accurate prediction of drug induced proarrhythmic risk with sex specific cardiac emulators.NPJ digital medicine · 2024Article
- Mechanisms of ischaemia-induced arrhythmias in hypertrophic cardiomyopathy: a large-scale computational study.Cardiovascular research · 2024Article
- Computational modeling of cardiac electrophysiology and arrhythmogenesis: toward clinical translation.Physiological reviews · 2024Review
- Electrophysiological mechanisms underlying T wave pseudonormalisation on stress ECGs in hypertrophic cardiomyopathy.Computers in biology and medicine · 2024Article
- Effects of ranolazine on the arrhythmic substrate in hypertrophic cardiomyopathy.Frontiers in pharmacology · 2024Article
- HPC Framework for Performing in Silico Trials Using a 3D Virtual Human Cardiac Population as Means to Assess Drug-Induced Arrhythmic Risk.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Revisiting Diagnosis and Treatment of Hypertrophic Cardiomyopathy: Current Practice and Novel Perspectives.Journal of clinical medicine · 2023Review
- Lysosomal calcium loading promotes spontaneous calcium release by potentiating ryanodine receptors.Biophysical journal · 2023Article
- Mavacamten, a precision medicine for hypertrophic cardiomyopathy: From a motor protein to patients.Science advances · 2023Review
- The Impact of Standard Ablation Strategies for Atrial Fibrillation on Cardiovascular Performance in a Four-Chamber Heart Model.Cardiovascular engineering and technology · 2023Article
- Slower Calcium Handling Balances Faster Cross-Bridge Cycling in HumanCirculation research · 2023Article
11 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
introductionHypertrophic cardiomyopathy (HCM) is a cause of sudden arrhythmic death, but the understanding of its pro-arrhythmic mechanisms and an effective pharmacological treatment are lacking. HCM electrophysiological remodelling includes both increased inward and reduced outward currents, but their role in promoting repolarisation abnormalities remains unknown. The goal of this study is to identify key ionic mechanisms driving repolarisation abnormalities in human HCM, and to evaluate anti-arrhythmic effects of single and multichannel inward current blocks.
methodsExperimental ionic current, action potential (AP) and Ca(2+)-transient (CaT) recordings were used to construct populations of human non-diseased and HCM AP models (n=9118), accounting for inter-subject variability. Simulations were conducted for several degrees of selective and combined inward current block.
resultsSimulated HCM cardiomyocytes exhibited prolonged AP and CaT, diastolic Ca(2+) overload and decreased CaT amplitude, in agreement with experiments. Repolarisation abnormalities in HCM models were consistently driven by L-type Ca(2+) current (ICaL) re-activation, and ICaL block was the most effective intervention to normalise repolarisation and diastolic Ca(2+), but compromised CaT amplitude. Late Na(+) current (INaL) block partially abolished repolarisation abnormalities, with small impact on CaT. Na(+)/Ca(2+) exchanger (INCX) block effectively restored repolarisation and CaT amplitude, but increased Ca(2+) overload. Multichannel block increased efficacy in normalising repolarisation, AP biomarkers and CaT amplitude compared to selective block.
conclusionsExperimentally-calibrated populations of human AP models identify ICaL re-activation as the key mechanism for repolarisation abnormalities in HCM, and combined INCX, INaL and ICaL block as effective anti-arrhythmic therapies also able to partially reverse the HCM electrophysiological phenotype.
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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.