title: Electrophysiology of Heart Failure Using a Rabbit Model: From the Failing Myocyte to Ventricular Fibrillation.
abstract: Heart failure is a leading cause of death, yet its underlying electrophysiological (EP) mechanisms are not well understood. In this study, we use a multiscale approach to analyze a model of heart failure and connect its results to features of the electrocardiogram (ECG). The heart failure model is derived by modifying a previously validated electrophysiology model for a healthy rabbit heart. Specifically, in accordance with the heart failure literature, we modified the cell EP by changing both membrane currents and calcium handling. At the tissue level, we modeled the increased gap junction lateralization and lower conduction velocity due to downregulation of Connexin 43. At the biventricular level, we reduced the apex-to-base and transmural gradients of action potential duration (APD). The failing cell model was first validated by reproducing the longer action potential, slower and lower calcium transient, and earlier alternans characteristic of heart failure EP. Subsequently, we compared the electrical wave propagation in one dimensional cables of healthy and failing cells. The validated cell model was then used to simulate the EP of heart failure in an anatomically accurate biventricular rabbit model. As pacing cycle length decreases, both the normal and failing heart develop T-wave alternans, but only the failing heart shows QRS alternans (although moderate) at rapid pacing. Moreover, T-wave alternans is significantly more pronounced in the failing heart. At rapid pacing, APD maps show areas of conduction block in the failing heart. Finally, accelerated pacing initiated wave reentry and breakup in the failing heart. Further, the onset of VF was not observed with an upregulation of SERCA, a potential drug therapy, using the same protocol. The changes introduced at the cell and tissue level have increased the failing heart's susceptibility to dynamic instabilities and arrhythmias under rapid pacing. However, the observed increase in arrhythmogenic potential is not due to a steepening of the restitution curve (not present in our model), but rather to a novel blocking mechanism.
authors.affiliation: Department of Mechanical and Aerospace Engineering, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Aditya V S
authors.initials: AV
authors.lastname: Ponnaluri
authors.affiliation: Department of Radiological Sciences and Department of Bioengineering, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Luigi E
authors.initials: LE
authors.lastname: Perotti
authors.affiliation: Department of Medicine - Division of Cardiology, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Medicine - Division of Cardiology, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Zhilin
authors.initials: Z
authors.lastname: Qu
authors.affiliation: Department of Medicine - Division of Cardiology, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: James N
authors.initials: JN
authors.lastname: Weiss
authors.affiliation: Department of Radiological Sciences and Department of Bioengineering, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Ennis
authors.affiliation: Department of Mechanical and Aerospace Engineering, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: William S
authors.initials: WS
authors.lastname: Klug
authors.affiliation: Department of Medicine - Division of Cardiology, University of California Los Angeles, Los Angeles, California, United States of America.|Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Alan
authors.initials: A
authors.lastname: Garfinkel
mesh_terms: D000818:Animals; D055724:Electrophysiological Phenomena / Q000502:physiology*; D006329:Heart Conduction System / Q000502:physiology; D006333:Heart Failure / Q000503:physiopathology*; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*; D011817:Rabbits; D014693:Ventricular Fibrillation / Q000503:physiopathology*