@inbook{4734e3a4c2b445e2a69bb0d4188a3cca,
title = "In Silico Mapping of the Omecamtiv Mecarbil Effects from the Sarcomere to the Whole-Heart and Back Again",
abstract = "Omecamtiv mecarbil (OM) is a cardiac myosin activator developed as a treatment of heart failure. OM acts on cross-bridge formation without disrupting intracellular calcium homeostasis. OM effects are extensively characterised both in vitro and in vivo yet how these mechanistically translate from the sarcomere to whole-heart function is not fully understood. We employed a 3D biventricular contraction model of a healthy rat heart that was fitted to anatomic, structural, and hemodynamic and volumetric functional data. The model incorporates pre-load, after-load, fibre orientation, passive material properties, anatomy, calcium transients, and thin and thick filament dynamics. We identified 4 sarcomere model parameters that reflect cross-bridge behavior. Gaussian process emulators (GPEs) were trained to map these parameters to pressure- and volume-based indexes of left ventricular (LV) function. We constrained the 4-parameter space using preclinical OM data, either (1) in vivo whole-heart hemodynamics data (using the Bayesian history matching technique), or (2) in vitro force-pCa measurements. The OM-compatible sarcomere parameter space from case (1) was used to directly calculate force-pCa curves, while the one resulting from case (2) was mapped to the LV indexes using the trained GPEs. We found that our mapping from LV features to force-pCa and vice versa was in agreement with experimental data. In addition, our simulations supported the latest evidence that OM indirectly alters thin filament calcium sensitivity. Our work demonstrates how quantitative mapping from cellular to whole-organ level can be used to improve our understanding of drug action mechanisms.",
keywords = "Gaussian process, Omecamtiv mecarbil",
author = "Stefano Longobardi and Anna Sher and Niederer, {Steven A.}",
note = "Publisher Copyright: {\textcopyright} 2021, Springer Nature Switzerland AG. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.; 11th International Conference on Functional Imaging and Modeling of the Heart, FIMH 2021 ; Conference date: 21-06-2021 Through 25-06-2021",
year = "2021",
doi = "10.1007/978-3-030-78710-3_39",
language = "English",
isbn = "9783030787097",
series = "Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics)",
publisher = "Springer Science and Business Media Deutschland GmbH",
pages = "406--415",
editor = "Ennis, {Daniel B.} and Perotti, {Luigi E.} and Wang, {Vicky Y.}",
booktitle = "Functional Imaging and Modeling of the Heart - 11th International Conference, FIMH 2021, Proceedings",
address = "Germany",
}