title: Electrophysiological and structural remodeling in heart failure modulate arrhythmogenesis. 1D simulation study.
abstract: BACKGROUND
  Heart failure is a final common pathway or descriptor for various cardiac pathologies. It is associated with sudden cardiac death, which is frequently caused by ventricular arrhythmias. Electrophysiological remodeling, intercellular uncoupling, fibrosis and autonomic imbalance have been identified as major arrhythmogenic factors in heart failure etiology and progression.
  
  
  OBJECTIVE
  In this study we investigate in silico the role of electrophysiological and structural heart failure remodeling on the modulation of key elements of the arrhythmogenic substrate, i.e., electrophysiological gradients and abnormal impulse propagation.
  
  
  METHODS
  Two different mathematical models of the human ventricular action potential were used to formulate models of the failing ventricular myocyte. This provided the basis for simulations of the electrical activity within a transmural ventricular strand. Our main goal was to elucidate the roles of electrophysiological and structural remodeling in setting the stage for malignant life-threatening arrhythmias.
  
  
  RESULTS
  Simulation results illustrate how the presence of M cells and heterogeneous electrophysiological remodeling in the human failing ventricle modulate the dispersion of action potential duration and repolarization time. Specifically, selective heterogeneous remodeling of expression levels for the Na+/Ca2+ exchanger and SERCA pump decrease these heterogeneities. In contrast, fibroblast proliferation and cellular uncoupling both strongly increase repolarization heterogeneities. Conduction velocity and the safety factor for conduction are also reduced by the progressive structural remodeling during heart failure.
  
  
  CONCLUSIONS
  An extensive literature now establishes that in human ventricle, as heart failure progresses, gradients for repolarization are changed significantly by protein specific electrophysiological remodeling (either homogeneous or heterogeneous). Our simulations illustrate and provide new insights into this. Furthermore, enhanced fibrosis in failing hearts, as well as reduced intercellular coupling, combine to increase electrophysiological gradients and reduce electrical propagation. In combination these changes set the stage for arrhythmias.
authors.affiliation: Instituto de Investigación en Ingeniería Biomédica, Universitat Politècnica de València, Valencia, Spain.
authors.forename: Juan F
authors.initials: JF
authors.lastname: Gomez
authors.affiliation: Instituto de Investigación en Ingeniería Biomédica, Universitat Politècnica de València, Valencia, Spain.
authors.forename: Karen
authors.initials: K
authors.lastname: Cardona
authors.affiliation: Instituto de Investigación en Ingeniería Biomédica, Universitat Politècnica de València, Valencia, Spain.
authors.forename: Lucia
authors.initials: L
authors.lastname: Romero
authors.affiliation: Instituto de Investigación en Ingeniería Biomédica, Universitat Politècnica de València, Valencia, Spain.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Ferrero
authors.affiliation: Instituto de Investigación en Ingeniería Biomédica, Universitat Politècnica de València, Valencia, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Trenor
mesh_terms: D000200:Action Potentials; D000465:Algorithms; D001145:Arrhythmias, Cardiac; D015415:Biomarkers; D002118:Calcium / Q000378:metabolism; D055724:Electrophysiological Phenomena; D005355:Fibrosis; D006333:Heart Failure / Q000473:pathology* / Q000503:physiopathology*; D006801:Humans; D008954:Models, Biological; D020257:Ventricular Remodeling
chemical_list: D015415:Biomarkers; D002118:Calcium