Browsing by Author "Olcese, Riccardo"

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    Perspective: a dynamics-based classification of ventricular arrhythmias
    (Elsevier, 2015-05) Weiss, James N.; Garfinkel, Alan; Karagueuzian, Hrayr S.; Nguyen, Thao P.; Olcese, Riccardo; Chen, Peng-Sheng; Qu, Zhilin; Department of Medicine, IU School of Medicine
    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.
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    Small-conductance Ca2+-activated K+ channels promote J-wave syndrome and phase-2 reentry
    (Elsevier, 2020-09) Landaw, Julian; Zhang, Zhaoyang; Song, Zhen; Liu, Michael B.; Olcese, Riccardo; Chen, Peng-Sheng; Weiss, James N.; Qu, Zhilin; Medicine, School of Medicine
    Background: Small-conductance Ca2+-activated potassium (SK) channels play complex roles in cardiac arrhythmogenesis. SK channels colocalize with L-type Ca2+ channels, yet how this colocalization affects cardiac arrhythmogenesis is unknown. Objective: The purpose of this study was to investigate the role of colocalization of SK channels with L-type Ca2+ channels in promoting J-wave syndrome and ventricular arrhythmias. Methods: We carried out computer simulations of single-cell and tissue models. SK channels in the model were assigned to preferentially sense Ca2+ in the bulk cytosol, subsarcolemmal space, or junctional cleft. Results: When SK channels sense Ca2+ in the bulk cytosol, the SK current (ISK) rises and decays slowly during an action potential, the action potential duration (APD) decreases as the maximum conductance increases, no complex APD dynamics and phase 2 reentry can be induced by ISK. When SK channels sense Ca2+ in the subsarcolemmal space or junctional cleft, ISK can rise and decay rapidly during an action potential in a spike-like pattern because of spiky Ca2+ transients in these compartments, which can cause spike-and-dome action potential morphology, APD alternans, J-wave elevation, and phase 2 reentry. Our results can account for the experimental finding that activation of ISK induced J-wave syndrome and phase 2 reentry in rabbit hearts. Conclusion: Colocalization of SK channels with L-type Ca2+ channels so that they preferentially sense Ca2+ in the subsarcolemmal or junctional space may result in a spiky ISK, which can functionally play a similar role of the transient outward K+ current in promoting J-wave syndrome and ventricular arrhythmias.