@article {27937,
	title = {A computational method for identifying an optimal combination of existing drugs to repair the action potentials of SQT1 ventricular myocytes},
	journal = {PLoS Computational Biology},
	volume = {17},
	number = {8},
	year = {2021},
	pages = {e1009233},
	publisher = {Public Library of Science},
	abstract = {Mutations are known to cause perturbations in essential functional features of integral membrane proteins, including ion channels. Even restricted or point mutations can result in substantially changed properties of ion currents. The additive effect of these alterations for a specific ion channel can result in significantly changed properties of the action potential (AP). Both AP shortening and AP prolongation can result from known mutations, and the consequences can be life-threatening. Here, we present a computational method for identifying new drugs utilizing combinations of existing drugs. Based on the knowledge of theoretical effects of existing drugs on individual ion currents, our aim is to compute optimal combinations that can {\textquoteleft}repair{\textquoteright} the mutant AP waveforms so that the baseline AP-properties are restored. More specifically, we compute optimal, combined, drug concentrations such that the waveforms of the transmembrane potential and the cytosolic calcium concentration of the mutant cardiomyocytes (CMs) becomes as similar as possible to their wild type coun- terparts after the drug has been applied. In order to demonstrate the utility of this method, we address the question of computing an optimal drug for the short QT syndrome type 1 (SQT1). For the SQT1 mutation N588K, there are available data sets that describe the effect of various drugs on the mutated K+ channel. These published findings are the basis for our computational analysis which can identify optimal compounds in the sense that the AP of the mutant CMs resembles essential biomarkers of the wild type CMs. Using recently developed insights regarding electrophysiological properties among myocytes from different species, we compute optimal drug combinations for hiPSC-CMs, rabbit ventricular CMs and adult human ventricular CMs with the SQT1 mutation. Since the {\textquoteleft}composition{\textquoteright} of ion channels that form the AP is different for the three types of myocytes under consideration, so is the composition of the optimal drug.},
	doi = {https://doi. org/10.1371/journal.pcbi.1009233},
	author = {Karoline Horgmo {J{\ae}ger} and Andrew G {Edwards} and Wayne R. {Giles} and Tveito, Aslak}
}
@article {28097,
	title = {From Millimeters to Micrometers; Re-introducing Myocytes in Models of Cardiac Electrophysiology},
	journal = {Frontiers in Physiology},
	volume = {12},
	year = {2021},
	pages = {763584},
	publisher = {Frontiers},
	abstract = {Computational modeling has contributed significantly to present understanding of cardiac electrophysiology including cardiac conduction, excitation-contraction coupling, and the effects and side-effects of drugs. However, the accuracy of\&nbsp;in silico\&nbsp;analysis of electrochemical wave dynamics in cardiac tissue is limited by the homogenization procedure (spatial averaging) intrinsic to standard continuum models of conduction. Averaged models cannot resolve the intricate dynamics in the vicinity of individual cardiomyocytes simply because the myocytes are not present in these models. Here we demonstrate how recently developed mathematical models based on representing every myocyte can significantly increase the accuracy, and thus the utility of modeling electrophysiological function and dysfunction in collections of coupled cardiomyocytes. The present gold standard of numerical simulation for cardiac electrophysiology is based on the bidomain model. In the bidomain model, the extracellular (E) space, the cell membrane (M) and the intracellular (I) space are all assumed to be present everywhere in the tissue. Consequently, it is impossible to study biophysical processes taking place close to individual myocytes. The bidomain model represents the tissue by averaging over several hundred myocytes and this inherently limits the accuracy of the model. In our alternative approach both E, M, and I are represented in the model which is therefore referred to as the EMI model. The EMI model approach allows for detailed analysis of the biophysical processes going on in functionally important spaces very close to individual myocytes, although at the cost of significantly increased CPU-requirements.},
	doi = {https://doi.org/10.3389/fphys.2021.763584},
	url = {https://www.frontiersin.org/articles/10.3389/fphys.2021.763584/full},
	author = {Karoline Horgmo {J{\ae}ger} and Andrew G {Edwards} and Wayne R. {Giles} and Tveito, Aslak}
}
@article {27367,
	title = {Computational translation of drug effects from animal experiments to human ventricular myocytes},
	journal = {Nature Scientific Reports },
	number = {10},
	year = {2020},
	pages = {10537},
	publisher = {Nature Publishing Group},
	abstract = {Using animal cells and tissues as precise measuring devices for developing new drugs presents a long- standing challenge for the pharmaceutical industry. Despite the very significant resources that continue to be dedicated to animal testing of new compounds, only qualitative results can be obtained. This often results in both false positives and false negatives. Here, we show how the effect of drugs applied to animal ventricular myocytes can be translated, quantitatively, to estimate a number of different effects of the same drug on human cardiomyocytes. We illustrate and validate our methodology by translating, from animal to human, the effect of dofetilide applied to dog cardiomyocytes, the effect\&nbsp;of E-4031 applied to zebrafish cardiomyocytes, and, finally, the effect of sotalol applied to rabbit cardiomyocytes. In all cases, the accuracy of our quantitative estimates are demonstrated. Our computations reveal that, in principle, electrophysiological data from testing using animal ventricular myocytes, can give precise, quantitative estimates of the effect of new compounds on human cardiomyocytes.},
	doi = {10.1038/s41598-018-35858-7},
	url = { https://rdcu.be/b5iBl},
	author = {Tveito, Aslak and Karoline Horgmo {J{\ae}ger} and Maleckar, Molly and Wayne R. {Giles} and Wall, Samuel}
}
@article {Simula.simula.2492,
	title = {Na+ Current Expression in Human Atrial Myofibroblasts: Its Identity and Functional Consequences},
	journal = {Frontiers in Physiology},
	volume = {5},
	number = {5},
	year = {2014},
	month = {August},
	pages = {275},
	publisher = { },
	abstract = {In the mammalian heart fibroblasts have important functions in both healthy and diseased states. During pathophysiological challenges, a closely related myofibroblast cell population can play distinct and significant roles. Recently, it has been reported that human atrial myofibroblasts can express a Na+ current, INa. Some of the biophysical properties and molecular features of the corresponding integral membrane protein suggest that this INa is due to expression of Nav 1.5. This is the same Na+ channel \alpha subunit that generates the predominant INa in myocytes from adult mammalian heart. In principle, expression of Nav 1.5 could give rise to regenerative action potentials in the fibroblasts/myofibroblasts. If so, this would suggest an active as opposed to passive role for fibroblasts/myofibroblasts in both the {{\textquoteleft}}trigger\&$\#$39; and the {{\textquoteleft}}substrate\&$\#$39; components of cardiac rhythm disturbances. Our goals were: (i) to confirm and extend the electrophysiological and biophysical characterization of INa in a human atrial fibroblast/myofibroblast cell population maintained in tissue culture; (ii) to identify the molecular features of the \alpha and \beta subunits of the Na+ channel(s) that are expressed in these myofibroblasts; (iii) to define the biophysical and pharmacological properties of this Na+ current; (iv) to integrate the available multi-disciplinary data, and illustrate its functional consequences, using a mathematical model in which the human atrial myocyte is coupled to fibroblasts/myofibroblasts in a syncytial structure. Our experimental findings confirm that a significant fraction (\~50\%) of human atrial myofibroblasts express INa and address the previous finding that Nav 1.5 is the predominant Na+ channel \alpha subunit isoform. These electrophysiological and molecular findings, when complemented with our mathematical modeling, provide a basis for re-evaluating pharmacological approaches for the management of supraventricular rhythm disorders, e.g. persistent atrial fibrillation.},
	author = {Koivum{\"a}ki, Jussi and Clark, RB and Belke, Darrell and Kondo, C. and Fedak, P. and Maleckar, Molly and Wayne R. {Giles}}
}
@article {Simula.simula.1790,
	title = {Ca(2+) Entry Through TRP-C Channels Regulates Fibroblast Biology in Chronic Atrial Fibrillation},
	journal = {Circulation},
	volume = {126},
	number = {17},
	year = {2012},
	pages = {2039-2041},
	author = {Robert A. {Rose} and Belke, Darrell and Maleckar, Molly and Wayne R. {Giles}}
}
@article {Simula.SC.448,
	title = {Electrotonic Coupling Between Human Atrial Myocytes and Fibroblasts Alters Excitability and Repolarization},
	journal = {Biophysical Journal},
	volume = {97},
	number = {8},
	year = {2009},
	month = {October},
	pages = {2179-2190},
	abstract = {Atrial fibrosis has been implicated in the development and maintenance of atrial arrhythmias, and is characterized by expansion of the extracellular matrix and an increased number of fibroblasts (Fbs). Electrotonic coupling between atrial myocytes and Fbs may contribute to the formation of an arrhythmogenic substrate. However, the role of these cell-cell interactions in the function of both normal and diseased atria remains poorly understood. The goal of this study was to gain mechanistic insight into the role of electrotonic Fb-myocyte coupling on myocyte excitability and repolarization. To represent the system, a human atrial myocyte (hAM) coupled to a variable number of Fbs, we employed a new ionic model of the hAM, and a variety of membrane representations for atrial Fbs. Simulations elucidated the effects of altering the intercellular coupling conductance, electrophysiological Fb properties, and stimulation rate on the myocyte action potential. The results demonstrate that the myocyte resting potential and action potential waveform are modulated strongly by the properties and number of coupled Fbs, the degree of coupling, and the pacing frequency. Our model provides mechanistic insight into the consequences of heterologous cell coupling on hAM electrophysiology, and can be extended to evaluate these implications at both tissue and organ levels.},
	author = {Maleckar, Molly and Joseph L. {Greenstein} and Wayne R. {Giles} and Natalia A. {Trayanova}}
}
@article {Simula.SC.450,
	title = {K+ Current Changes Account for the Rate Dependence of the Action Potential in the Human Atrial Myocyte},
	journal = {American Journal of Physiology - Heart and Circulatory Physiology},
	volume = {297},
	number = {4},
	year = {2009},
	note = {Should be listed in 2010 Annual Report},
	month = {October},
	pages = {1398-1410},
	abstract = {Ongoing investigation of the electrophysiology and pathophysiology of the human atria requires an accurate representation of the membrane dynamics of the human atrial myocyte. However, existing models of the human atrial myocyte action potential do not accurately reproduce experimental observations with respect to the kinetics of key repolarizing currents or rate dependence of the action potential and fail to properly enforce charge conservation, an essential characteristic in any model of the cardiac membrane. In addition, recent advances in experimental methods have resulted in new data regarding the kinetics of repolarizing currents in the human atria. The goal of this study was to develop a new model of the human atrial action potential, based on the Nygren et al. model of the human atrial myocyte and newly available experimental data, that ensures an accurate representation of repolarization processes and reproduction of action potential rate dependence and enforces charge conservation. Specifically, the transient outward K(+) current (I(t)) and ultrarapid rectifier K(+) current (I(Kur)) were newly formulated. The inwardly recitifying K(+) current (I(K1)) was also reanalyzed and implemented appropriately. Simulations of the human atrial myocyte action potential with this new model demonstrated that early repolarization is dependent on the relative conductances of I(t) and I(Kur), whereas densities of both I(Kur) and I(K1) underlie later repolarization. In addition, this model reproduces experimental measurements of rate dependence of I(t), I(Kur), and action potential duration. This new model constitutes an improved representation of excitability and repolarization reserve in the human atrial myocyte and, therefore, provides a useful computational tool for future studies involving the human atrium in both health and disease.},
	author = {Maleckar, Molly and Joseph L. {Greenstein} and Wayne R. {Giles} and Natalia A. {Trayanova}}
}
@misc {Simula.SC.540,
	title = {Coupling of Human Atrial Myocytes and Myofibroblasts Can Lead to Conduction Disturbances},
	howpublished = {HRS Scientific Sessions 2008},
	year = {2008},
	month = {May},
	author = {Maleckar, Molly and Joseph L. {Greenstein} and Wayne R. {Giles} and Natalia A. {Trayanova}}
}
@article {Simula.SC.452,
	title = {Mathematical Simulations of Ligand-Gated and Specific Cell-Type Effects in the Human Atrium},
	journal = {Progress in Biophysics and Molecular Biology},
	volume = {98},
	number = {2-3},
	year = {2008},
	pages = {161-70},
	author = {Maleckar, Molly and Joseph L. {Greenstein} and Natalia A. {Trayanova} and Wayne R. {Giles}}
}
@article {Simula.sc.1208,
	title = {Arrhythmogenic Consequences of Na+ Channel Mutations in the Transmurally Heterogeneous Mammalian Left Ventricle: Analysis of the I1768V SCN5A Mutation},
	journal = {Heart Rhythm},
	volume = {4},
	number = {6},
	year = {2007},
	pages = {768-778},
	author = {S. N. {Flaim} and Wayne R. {Giles} and Andrew D. {McCulloch}}
}
