title: Mechanisms of pro-arrhythmic abnormalities in ventricular repolarisation and anti-arrhythmic therapies in human hypertrophic cardiomyopathy.
abstract: Hypertrophic 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.
  
  
  
  Experimental 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.
  
  
  
  Simulated 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.
  
  
  
  Experimentally-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.
authors.affiliation: Department of Computer Science, University of Oxford, Oxford OX13QD, United Kingdom; Department of Electrical, Electronic and Information Engineering, University of Bologna, Cesena 47521, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Passini
authors.affiliation: Department of Computer Science, University of Oxford, Oxford OX13QD, United Kingdom.
authors.forename: Ana
authors.initials: A
authors.lastname: Mincholé
authors.affiliation: Department NEUROFARBA, University of Florence, Florence 50139, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Coppini
authors.affiliation: Department NEUROFARBA, University of Florence, Florence 50139, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Cerbai
authors.affiliation: Department of Computer Science, University of Oxford, Oxford OX13QD, United Kingdom.
authors.forename: Blanca
authors.initials: B
authors.lastname: Rodriguez
authors.affiliation: Department of Electrical, Electronic and Information Engineering, University of Bologna, Cesena 47521, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Severi
authors.affiliation: Department of Computer Science, University of Oxford, Oxford OX13QD, United Kingdom. Electronic address: alfonso.bueno@cs.ox.ac.uk.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Bueno-Orovio
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002312:Cardiomyopathy, Hypertrophic / Q000150:complications* / Q000378:metabolism*; D055724:Electrophysiological Phenomena / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology*; D006801:Humans; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism
chemical_list: D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D019831:Sodium-Calcium Exchanger; D002118:Calcium
keywords: Hypertrophic cardiomyopathy; In silico drug testing; Inter-subject variability; Pro-arrhythmic mechanisms; Repolarization reserve