title: Insights and Challenges of Multi-Scale Modeling of Sarcomere Mechanics in cTn and Tm DCM Mutants-Genotype to Cellular Phenotype.
abstract: Dilated Cardiomyopathy (DCM) is a leading cause of sudden cardiac death characterized by impaired pump function and dilatation of cardiac ventricles. In this review we discuss variousin silicoapproaches to elucidating the mechanisms of genetic mutations leading to DCM. The approaches covered in this review focus on bridging the spatial and temporal gaps that exist between molecular and cellular processes. Mutations in sarcomeric regulatory thin filament proteins such as the troponin complex (cTn) and Tropomyosin (Tm) have been associated with DCM. Despite the experimentally-observed myofilament measures of contractility in the case of these mutations, the mechanisms by which the underlying molecular changes and protein interactions scale up to organ failure by these mutations remains elusive. The review highlights multi-scale modeling approaches and their applicability to study the effects of sarcomeric gene mutationsin-silico. We discuss some of the insights that can be gained from computational models of cardiac biomechanics when scaling from molecular states to cellular level.
authors.affiliation: Departments of Bioengineering and Medicine, University of California San Diego, La Jolla, CA, USA.
authors.forename: Sukriti
authors.initials: S
authors.lastname: Dewan
authors.affiliation: Departments of Bioengineering and Medicine, University of California San Diego, La Jolla, CA, USA.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: McCabe
authors.affiliation: Departments of Bioengineering and Medicine, University of Washington Seattle, WA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Regnier
authors.affiliation: Departments of Bioengineering and Medicine, University of California San Diego, La Jolla, CA, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: McCulloch
keywords: Markov; Tropomyosin; cross-bridge; dilated cardiomyopathy; mechanics; modeling; myofilament; troponin