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Pei Chi Yang

Bio: Pei Chi Yang is an academic researcher from University of California, Davis. The author has contributed to research in topics: hERG & QT interval. The author has an hindex of 18, co-authored 36 publications receiving 969 citations. Previous affiliations of Pei Chi Yang include University of California, Berkeley & George Mason University.

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TL;DR: The ability of this sophisticated model of living cardiac tissue to replicate the clinical adverse effects of lidocaine and flecainide is promising, but it will be necessary to validate its performance with other drugs to understand how to deploy it most effectively.
Abstract: A long-sought, and thus far elusive, goal has been to develop drugs to manage diseases of excitability. One such disease that affects millions each year is cardiac arrhythmia, which occurs when electrical impulses in the heart become disordered, sometimes causing sudden death. Pharmacological management of cardiac arrhythmia has failed because it is not possible to predict how drugs that target cardiac ion channels, and have intrinsically complex dynamic interactions with ion channels, will alter the emergent electrical behavior generated in the heart. Here, we applied a computational model, which was informed and validated by experimental data, that defined key measurable parameters necessary to simulate the interaction kinetics of the anti-arrhythmic drugs flecainide and lidocaine with cardiac sodium channels. We then used the model to predict the effects of these drugs on normal human ventricular cellular and tissue electrical activity in the setting of a common arrhythmia trigger, spontaneous ventricular ectopy. The model forecasts the clinically relevant concentrations at which flecainide and lidocaine exacerbate, rather than ameliorate, arrhythmia. Experiments in rabbit hearts and simulations in human ventricles based on magnetic resonance images validated the model predictions. This computational framework initiates the first steps toward development of a virtual drug-screening system that models drug-channel interactions and predicts the effects of drugs on emergent electrical activity in the heart.

192 citations

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TL;DR: The model predictions suggest that acute targeting of late INaL with ranolazine may be an effective therapeutic strategy in diverse arrhythmia-provoking situations that arise from a common pathway of increased pathological INal.
Abstract: Rationale: The antianginal ranolazine blocks the human ether-a-go-go–related gene–based current IKr at therapeutic concentrations and causes QT interval prolongation. Thus, ranolazine is contraindicated for patients with preexisting long-QT and those with repolarization abnormalities. However, with its preferential targeting of late INa (INaL), patients with disease resulting from increased INaL from inherited defects (eg, long-QT syndrome type 3 or disease-induced electric remodeling (eg, ischemic heart failure) might be exactly the ones to benefit most from the presumed antiarrhythmic properties of ranolazine. Objective: We developed a computational model to predict if therapeutic effects of pharmacological targeting of INaL by ranolazine prevailed over the off-target block of IKr in the setting of inherited long-QT syndrome type 3 and heart failure. Methods and Results: We developed computational models describing the kinetics and the interaction of ranolazine with cardiac Na+ channels in the setting of normal physiology, long-QT syndrome type 3–linked ΔKPQ mutation, and heart failure. We then simulated clinically relevant concentrations of ranolazine and predicted the combined effects of Na+ channel and IKr blockade by both the parent compound ranolazine and its active metabolites, which have shown potent blocking effects in the therapeutically relevant range. Our simulations suggest that ranolazine is effective at normalizing arrhythmia triggers in bradycardia-dependent arrhythmias in long-QT syndrome type 3 as well tachyarrhythmogenic triggers arising from heart failure–induced remodeling. Conclusions: Our model predictions suggest that acute targeting of INaL with ranolazine may be an effective therapeutic strategy in diverse arrhythmia-provoking situations that arise from a common pathway of increased pathological INaL. # Novelty and Significance {#article-title-75}

83 citations

Journal ArticleDOI
21 Apr 2014-PLOS ONE
TL;DR: Quantitative modeling was used to demonstrate that differences in adenylyl cyclase and phosphodiesterase activities are necessary but not sufficient to explain compartmentation of cAMP associated with different microdomains of the plasma membrane.
Abstract: Spatially restricting cAMP production to discrete subcellular locations permits selective regulation of specific functional responses. But exactly where and how cAMP signaling is confined is not fully understood. Different receptors and adenylyl cyclase isoforms responsible for cAMP production are not uniformly distributed between lipid raft and non-lipid raft domains of the plasma membrane. We sought to determine the role that these membrane domains play in organizing cAMP responses in HEK293 cells. The freely diffusible FRET-based biosensor Epac2-camps was used to measure global cAMP responses, while versions of the probe targeted to lipid raft (Epac2-MyrPalm) and non-raft (Epac2-CAAX) domains were used to monitor local cAMP production near the plasma membrane. Disruption of lipid rafts by cholesterol depletion selectively altered cAMP responses produced by raft-associated receptors. The results indicate that receptors associated with lipid raft as well as non-lipid raft domains can contribute to global cAMP responses. In addition, basal cAMP activity was found to be significantly higher in non-raft domains. This was supported by the fact that pharmacologic inhibition of adenylyl cyclase activity reduced basal cAMP activity detected by Epac2-CAAX but not Epac2-MyrPalm or Epac2-camps. Responses detected by Epac2-CAAX were also more sensitive to direct stimulation of adenylyl cyclase activity, but less sensitive to inhibition of phosphodiesterase activity. Quantitative modeling was used to demonstrate that differences in adenylyl cyclase and phosphodiesterase activities are necessary but not sufficient to explain compartmentation of cAMP associated with different microdomains of the plasma membrane.

75 citations

Journal ArticleDOI
TL;DR: The latest advances and novel concepts in the field as they relate to understanding the complex interplay between electrical, mechanical, structural, and genetic mechanisms during arrhythmia development at the level of ion channels, cells, and tissues are reviewed.
Abstract: Cardiac rhythms arise from electrical activity generated by precisely timed opening and closing of ion channels in individual cardiac myocytes. These impulses spread throughout the cardiac muscle to manifest as electrical waves in the whole heart. Regularity of electrical waves is critically important since they signal the heart muscle to contract, driving the primary function of the heart to act as a pump and deliver blood to the brain and vital organs. When electrical activity goes awry during a cardiac arrhythmia, the pump does not function, the brain does not receive oxygenated blood, and death ensues. For more than 50 years, mathematically based models of cardiac electrical activity have been used to improve understanding of basic mechanisms of normal and abnormal cardiac electrical function. Computer-based modeling approaches to understand cardiac activity are uniquely helpful because they allow for distillation of complex emergent behaviors into the key contributing components underlying them. Here we review the latest advances and novel concepts in the field as they relate to understanding the complex interplay between electrical, mechanical, structural, and genetic mechanisms during arrhythmia development at the level of ion channels, cells, and tissues. We also discuss the latest computational approaches to guiding arrhythmia therapy.

71 citations

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TL;DR: Simulations predict the effects of sex steroid hormones on clinically observed QT intervals and reveal mechanisms of estrogen-mediated susceptibility to prolongation of QT interval, indicating that acute effects of estrogen are not alone sufficient to cause arrhythmia triggers and explain the increased risk of females to Torsades de Pointes.
Abstract: Acute effects of sex steroid hormones likely contribute to the observation that post-pubescent males have shorter QT intervals than females. However, the specific role for hormones in modulating cardiac electrophysiological parameters and arrhythmia vulnerability is unclear. Here we use a computational modeling approach to incorporate experimentally measured effects of physiological concentrations of testosterone, estrogen and progesterone on cardiac ion channel targets. We then study the hormone effects on ventricular cell and tissue dynamics comprised of Faber-Rudy computational models. The “female” model predicts changes in action potential duration (APD) at different stages of the menstrual cycle that are consistent with clinically observed QT interval fluctuations. The “male” model predicts shortening of APD and QT interval at physiological testosterone concentrations. The model suggests increased susceptibility to drug-induced arrhythmia when estradiol levels are high, while testosterone and progesterone are apparently protective. Simulations predict the effects of sex steroid hormones on clinically observed QT intervals and reveal mechanisms of estrogen-mediated susceptibility to prolongation of QT interval. The simulations also indicate that acute effects of estrogen are not alone sufficient to cause arrhythmia triggers and explain the increased risk of females to Torsades de Pointes. Our results suggest that acute effects of sex steroid hormones on cardiac ion channels are sufficient to account for some aspects of gender specific susceptibility to long-QT linked arrhythmias.

69 citations


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692 citations

Journal ArticleDOI
TL;DR: The key role of Ca2+ in normal cardiac function-in particular, excitation-contraction coupling and normal electric rhythms is reviewed, followed by various inherited arrhythmia syndromes caused by mutations in Ca2-handling proteins.
Abstract: There has been a significant progress in our understanding of the molecular mechanisms by which calcium (Ca 2+ ) ions mediate various types of cardiac arrhythmias. A growing list of inherited gene defects can cause potentially lethal cardiac arrhythmia syndromes, including catecholaminergic polymorphic ventricular tachycardia, congenital long QT syndrome, and hypertrophic cardiomyopathy. In addition, acquired deficits of multiple Ca 2+ -handling proteins can contribute to the pathogenesis of arrhythmias in patients with various types of heart disease. In this review article, we will first review the key role of Ca 2+ in normal cardiac function—in particular, excitation–contraction coupling and normal electric rhythms. The functional involvement of Ca 2+ in distinct arrhythmia mechanisms will be discussed, followed by various inherited arrhythmia syndromes caused by mutations in Ca 2+ -handling proteins. Finally, we will discuss how changes in the expression of regulation of Ca 2+ channels and transporters can cause acquired arrhythmias, and how these mechanisms might be targeted for therapeutic purposes.

342 citations

Journal ArticleDOI
TL;DR: Mechanistically based preclinical strategies for detecting drug-induced electrophysiological and structural cardiotoxicity using in vitro human ion channel assays, human-based in silico reconstructions and human stem cell-derived cardiomyocytes are discussed.
Abstract: The early and efficient assessment of cardiac safety liabilities is essential to confidently advance novel drug candidates. This article discusses evolving mechanistically based preclinical strategies for detecting drug-induced electrophysiological and structural cardiotoxicity using in vitro human ion channel assays, human-based in silico reconstructions and human stem cell-derived cardiomyocytes. These strategies represent a paradigm shift from current approaches, which rely on simplistic in vitro assays that measure blockade of the Kv11.1 current (also known as the hERG current or IKr) and on the use of non-human cells or tissues. These new strategies have the potential to improve sensitivity and specificity in the early detection of genuine cardiotoxicity risks, thereby reducing the likelihood of mistakenly discarding viable drug candidates and speeding the progression of worthy drugs into clinical trials.

317 citations