A5001770484- Cardiac electrophysiology and arrhythmias
- Ion channel regulation and function
- Atrial Fibrillation Management and Outcomes
- Receptor Mechanisms and Signaling
- Neuroscience and Neural Engineering
- ECG Monitoring and Analysis
- Cardiac Arrhythmias and Treatments
- Neuroscience and Neuropharmacology Research
- Electrochemical Analysis and Applications
- Cardiac pacing and defibrillation studies
- Cardiomyopathy and Myosin Studies
- Cardiovascular Effects of Exercise
- Heart Rate Variability and Autonomic Control
- Cardiovascular Function and Risk Factors
- Computational Drug Discovery Methods
- Nitric Oxide and Endothelin Effects
- Caveolin-1 and cellular processes
- Pluripotent Stem Cells Research
- Gene Regulatory Network Analysis
- Cardiac Fibrosis and Remodeling
- Pharmacological Effects and Toxicity Studies
- Ion Transport and Channel Regulation
- Phosphodiesterase function and regulation
- Cardiac Ischemia and Reperfusion
- Congenital heart defects research
University of California, Davis
2016-2025
Johns Hopkins University
2022-2023
Robert Bosch (Germany)
2023
University of Wisconsin–Madison
2018
California State University, Northridge
2015
Simula Research Laboratory
2014
University of California, San Diego
2014
Columbia University
2013
Rockefeller University
2013
Cornell University
2013
Rationale: Understanding atrial fibrillation (AF) requires integrated understanding of ionic currents and Ca 2+ transport in remodeled human atrium, but appropriate models are limited. Objective: To study AF, we developed a new action potential (AP) model, derived from experimental results our ventricular myocyte model. Methods Results: Atria versus ventricles have lower I K1 , resulting more depolarized resting membrane (≈7 mV). We used higher to,fast density removed to,slow included an...
Rationale: In heart failure Ca/calmodulin kinase (CaMK)II expression and reactive oxygen species (ROS) are increased. Both ROS CaMKII can increase late I Na leading to intracellular accumulation arrhythmias. It has been shown that activate via oxidation. Objective: We tested whether CaMKIIδ is required for ROS-dependent regulation ROS-induced Ca released from the sarcoplasmic reticulum (SR) involved. Methods Results: 40 μmol/L H 2 O significantly increased oxidation autophosphorylation in...
Compartmentalized cAMP/PKA signalling is now recognized as important for physiology and pathophysiology, yet a detailed understanding of the properties, regulation function local signals lacking. Here we present fluorescence resonance energy transfer (FRET)-based sensor, CUTie, which detects compartmentalized cAMP with unprecedented accuracy. targeted to specific multiprotein complexes at discrete plasmalemmal, sarcoplasmic reticular myofilament sites, reveals differential kinetics...
Potassium currents contribute to action potential duration (APD) and arrhythmogenesis. In heart failure, Ca/calmodulin-dependent protein kinase II (CaMKII) is upregulated can alter ion channel regulation expression.We examine the influence of overexpressing cytoplasmic CaMKIIdelta(C), both acutely in rabbit ventricular myocytes (24-hour adenoviral gene transfer) chronically CaMKIIdelta(C)-transgenic mice, on transient outward potassium current (I(to)), inward rectifying (I(K1)). Acute...
Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) capture patient-specific genotype-phenotype relationships, as well cell-to-cell variability of cardiac electrical activity Computational modelling and simulation provide a high throughput approach to reconcile multiple datasets describing physiological variability, also identify vulnerable parameter regimes We have developed whole-cell model iPSC-CMs, composed single exponential voltage-dependent gating variable rate constants,...
Hypercontractility of arterial myocytes and enhanced vascular tone during diabetes are, in part, attributed to the effects increased glucose (hyperglycemia) on L-type CaV1.2 channels. In murine myocytes, kinase-dependent mechanisms mediate increase activity response extracellular glucose. We identified a subpopulation channel pore-forming subunit (α1C) within nanometer proximity protein kinase A (PKA) at sarcolemma human myocytes. This arrangement depended upon scaffolding PKA by an A-kinase...
This white paper presents principles for validating proarrhythmia risk prediction models regulatory use as discussed at the In Silico Breakout Session of a Cardiac Safety Research Consortium/Health and Environmental Sciences Institute/US Food Drug Administration–sponsored Think Tank Meeting on May 22, 2018. The meeting was convened to evaluate progress in development new cardiac safety paradigm, Comprehensive Vitro Proarrhythmia Assay (CiPA). opinions regarding these reflect collective views...
Small-conductance Ca2+-activated K+ (SK)-channel inhibitors have antiarrhythmic effects in animal models of atrial fibrillation (AF), presenting a potential novel option. However, the regulation SK-channels human cardiomyocytes and its modification patients with AF are poorly understood were object this study. Apamin-sensitive SK-channel current (ISK) action potentials recorded right-atrial from sinus rhythm control (Ctl) or (long-standing persistent) chronic (cAF). ISK was significantly...
Background . Although sudden death is one of the most frequent causes in haemodialysis (HD) patients, problem cardiac arrhythmias, major cause these outcomes, has been little discussed.
The reverse rate dependence (RRD) of actions I(Kr)-blocking drugs to increase the action potential duration (APD) and beat-to-beat variability repolarization (BVR) APD is proarrhythmic. We determined whether inhibition endogenous, physiological late Na(+) current (late I(Na)) attenuates RRD proarrhythmic effect I(Kr) inhibition.Duration monophasic (MAPD) was measured from female rabbit hearts paced at cycle lengths 400 2000 milliseconds, BVR calculated. In absence a drug, 90% completion...
Key points Intracellular [Na + ] ([Na i ) is elevated in heart failure (HF) and causes arrhythmogenic cellular [Ca 2+ loading. In HF, hyperactivity of Ca –calmodulin‐dependent protein kinase II (CaMKII), a key mediator electrical mechanical dysfunction myocytes, . We developed computational model mouse ventricular myocyte electrophysiology including CaMKII signalling quantitatively confirmed evidence suggesting that not only does cause , but this additional also promotes further activation...
The antianginal ranolazine blocks the human ether-a-go-go-related gene-based current IKr at therapeutic concentrations and causes QT interval prolongation. Thus, is contraindicated for patients with preexisting long-QT those repolarization abnormalities. However, its preferential targeting of late INa (INaL), disease resulting from increased INaL inherited defects (eg, syndrome type 3 or disease-induced electric remodeling ischemic heart failure) might be exactly ones to benefit most...
Graphical abstractAbstractPopulation-based computational approaches have been developed in recent years and helped to gain insight into arrhythmia mechanisms, intra- inter-patient variability (e.g., drug responses). Here, we illustrate the use of multivariable logistic regression analyze factors that enhance or reduce susceptibility cellular arrhythmogenic events. As an example, generate 1000 model variants by randomly modifying ionic conductances maximal rates ion transports our atrial...