title: Perspective: a dynamics-based classification of ventricular arrhythmias.
abstract: Despite key advances in the clinical management of life-threatening ventricular arrhythmias, culminating with the development of implantable cardioverter-defibrillators and catheter ablation techniques, pharmacologic/biologic therapeutics have lagged behind. The fundamental issue is that biological targets are molecular factors. Diseases, however, represent emergent properties at the scale of the organism that result from dynamic interactions between multiple constantly changing molecular factors. For a pharmacologic/biologic therapy to be effective, it must target the dynamic processes that underlie the disease. Here we propose a classification of ventricular arrhythmias that is based on our current understanding of the dynamics occurring at the subcellular, cellular, tissue and organism scales, which cause arrhythmias by simultaneously generating arrhythmia triggers and exacerbating tissue vulnerability. The goal is to create a framework that systematically links these key dynamic factors together with fixed factors (structural and electrophysiological heterogeneity) synergistically promoting electrical dispersion and increased arrhythmia risk to molecular factors that can serve as biological targets. We classify ventricular arrhythmias into three primary dynamic categories related generally to unstable Ca cycling, reduced repolarization, and excess repolarization, respectively. The clinical syndromes, arrhythmia mechanisms, dynamic factors and what is known about their molecular counterparts are discussed. Based on this framework, we propose a computational-experimental strategy for exploring the links between molecular factors, fixed factors and dynamic factors that underlie life-threatening ventricular arrhythmias. The ultimate objective is to facilitate drug development by creating an in silico platform to evaluate and predict comprehensively how molecular interventions affect not only a single targeted arrhythmia, but all primary arrhythmia dynamics categories as well as normal cardiac excitation-contraction coupling.
authors.affiliation: UCLA Cardiovascular Research Laboratory, Department of Medicine (Cardiology), UCLA and the David Geffen School of Medicine at UCLA, Los Angeles, CA, United States; Department of Physiology, UCLA and the David Geffen School of Medicine at UCLA, Los Angeles, CA, United States. Electronic address: jweiss@mednet.ucla.edu.
authors.forename: James N
authors.initials: JN
authors.lastname: Weiss
authors.affiliation: UCLA Cardiovascular Research Laboratory, Department of Medicine (Cardiology), UCLA and the David Geffen School of Medicine at UCLA, Los Angeles, CA, United States; Department of Integrative Biology and Physiology, UCLA and the David Geffen School of Medicine at UCLA, Los Angeles, CA, United States.
authors.forename: Alan
authors.initials: A
authors.lastname: Garfinkel
authors.affiliation: UCLA Cardiovascular Research Laboratory, Department of Medicine (Cardiology), UCLA and the David Geffen School of Medicine at UCLA, Los Angeles, CA, United States.
authors.forename: Hrayr S
authors.initials: HS
authors.lastname: Karagueuzian
authors.affiliation: UCLA Cardiovascular Research Laboratory, Department of Medicine (Cardiology), UCLA and the David Geffen School of Medicine at UCLA, Los Angeles, CA, United States.
authors.forename: Thao P
authors.initials: TP
authors.lastname: Nguyen
authors.affiliation: Department of Physiology, UCLA and the David Geffen School of Medicine at UCLA, Los Angeles, CA, United States; Department of Anesthesiology, UCLA and the David Geffen School of Medicine at UCLA, Los Angeles, CA, United States.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Olcese
authors.affiliation: Krannert Institute of Cardiology and Department of Medicine (Cardiology), Indiana University School of Medicine, Indianapolis, IN, United States.
authors.forename: Peng-Sheng
authors.initials: PS
authors.lastname: Chen
authors.affiliation: UCLA Cardiovascular Research Laboratory, Department of Medicine (Cardiology), UCLA and the David Geffen School of Medicine at UCLA, Los Angeles, CA, United States.
authors.forename: Zhilin
authors.initials: Z
authors.lastname: Qu
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000175:diagnosis* / Q000188:drug therapy / Q000209:etiology* / Q000503:physiopathology; D055808:Drug Discovery; D006801:Humans; D018754:Ventricular Dysfunction / Q000175:diagnosis* / Q000188:drug therapy / Q000209:etiology* / Q000503:physiopathology
chemical_list: D000889:Anti-Arrhythmia Agents
keywords: Ca signaling; Fibrillation; Nonlinear dynamics; Reentry; Repolarization reserve; Sudden cardiac death