Cardiac hypertrophy is an adaption of the heart to a change in cardiovascular loading conditions. The current understanding is that progression may be stress or strain driven, but the multi-scale nature of the cellular remodelling processes have yet to be uncovered. In this study, we develop a model of the contractile left ventricle, with the active cell tension described by a thermodynamically motivated cross-bridge cycling model. Simulation of the transient recruitment of myosin results in correct patterns of ventricular pressure predicted over a cardiac cycle. We investigate how changes in tissue loading and associated deviations in transient force generation can drive restructuring of cellular myofibrils in the heart wall. Our thermodynamic framework predicts in-series sarcomere addition (eccentric remodelling) in response to volume overload, and sarcomere addition in parallel (concentric remodelling) in response to valve and signalling disfunction. This framework provides a significant advance in the current understanding of the fundamental sub-sarcomere level biomechanisms underlying cardiac remodelling. Simulations reveal that pathological tissue loading conditions can significantly alter actin-myosin cross-bridge cycling over the course of the cardiac cycle. The resultant variation in sarcomere stress pushes an imbalance between the internal free energy of the myofibril and that of unbound contractile proteins, initiating remodelling. The link between cross-bridge thermodynamics and myofibril remodelling proposed in this study may significantly advance current understanding of cardiac disease onset.
{"title":"A thermodynamic transient cross-bridge model for prediction of contractility and remodelling of the ventricle.","authors":"Eóin McEvoy, W. Wijns, P. McGarry","doi":"10.31224/osf.io/zfrhq","DOIUrl":"https://doi.org/10.31224/osf.io/zfrhq","url":null,"abstract":"Cardiac hypertrophy is an adaption of the heart to a change in cardiovascular loading conditions. The current understanding is that progression may be stress or strain driven, but the multi-scale nature of the cellular remodelling processes have yet to be uncovered. In this study, we develop a model of the contractile left ventricle, with the active cell tension described by a thermodynamically motivated cross-bridge cycling model. Simulation of the transient recruitment of myosin results in correct patterns of ventricular pressure predicted over a cardiac cycle. We investigate how changes in tissue loading and associated deviations in transient force generation can drive restructuring of cellular myofibrils in the heart wall. Our thermodynamic framework predicts in-series sarcomere addition (eccentric remodelling) in response to volume overload, and sarcomere addition in parallel (concentric remodelling) in response to valve and signalling disfunction. This framework provides a significant advance in the current understanding of the fundamental sub-sarcomere level biomechanisms underlying cardiac remodelling. Simulations reveal that pathological tissue loading conditions can significantly alter actin-myosin cross-bridge cycling over the course of the cardiac cycle. The resultant variation in sarcomere stress pushes an imbalance between the internal free energy of the myofibril and that of unbound contractile proteins, initiating remodelling. The link between cross-bridge thermodynamics and myofibril remodelling proposed in this study may significantly advance current understanding of cardiac disease onset.","PeriodicalId":94117,"journal":{"name":"Journal of the mechanical behavior of biomedical materials","volume":"113 1","pages":"104074"},"PeriodicalIF":0.0,"publicationDate":"2020-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46624337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This tutorial paper provides a step-by-step guide to developing a comprehensive understanding of the different forms of the deformation gradient used in Abaqus, and outlines a number of key issues that must be considered when developing an Abaqus user defined material subroutine (UMAT) in which the Cauchy stress is computed from the deformation gradient. Firstly, we examine the "classical" forms of global and local deformation gradients. We then show that Abaqus/Standard does not use the classical form of the local deformation gradient when continuum elements are used, and we highlight the important implications for UMAT development. We outline the key steps that must be implemented in developing an anisotropic fibre-reinforced hyperelastic UMAT for use with continuum elements and local orientation systems. We also demonstrate that a classical local deformation gradient is provided by Abaqus/Standard if structural (shell and membrane) elements are used, and by Abaqus/Explicit for all element types. We emphasise, however, that the majority of biomechanical simulations rely on the use of continuum elements with a local coordinate system in Abaqus/Standard, and therefore the development of a hyperelastic UMAT requires an in-depth and precise understanding of the form of the non-classical deformation gradient provided as input by Abaqus. Several worked examples and case studies are provided for each section, so that the details and implications of the form of the deformation gradient can be fully understood. For each worked example in this tutorial paper the source files and code (Abaqus input files, UMATs, and Matlab script files) are provided, allowing the reader to efficiently explore the implications of the form of the deformation gradient in the development of a UMAT.
{"title":"Understanding the deformation gradient in Abaqus and key guidelines for anisotropic hyperelastic user material subroutines (UMATs).","authors":"David Nolan, C. Lally, Patrick McGarry","doi":"10.31224/osf.io/4ryu2","DOIUrl":"https://doi.org/10.31224/osf.io/4ryu2","url":null,"abstract":"This tutorial paper provides a step-by-step guide to developing a comprehensive understanding of the different forms of the deformation gradient used in Abaqus, and outlines a number of key issues that must be considered when developing an Abaqus user defined material subroutine (UMAT) in which the Cauchy stress is computed from the deformation gradient. Firstly, we examine the \"classical\" forms of global and local deformation gradients. We then show that Abaqus/Standard does not use the classical form of the local deformation gradient when continuum elements are used, and we highlight the important implications for UMAT development. We outline the key steps that must be implemented in developing an anisotropic fibre-reinforced hyperelastic UMAT for use with continuum elements and local orientation systems. We also demonstrate that a classical local deformation gradient is provided by Abaqus/Standard if structural (shell and membrane) elements are used, and by Abaqus/Explicit for all element types. We emphasise, however, that the majority of biomechanical simulations rely on the use of continuum elements with a local coordinate system in Abaqus/Standard, and therefore the development of a hyperelastic UMAT requires an in-depth and precise understanding of the form of the non-classical deformation gradient provided as input by Abaqus. Several worked examples and case studies are provided for each section, so that the details and implications of the form of the deformation gradient can be fully understood. For each worked example in this tutorial paper the source files and code (Abaqus input files, UMATs, and Matlab script files) are provided, allowing the reader to efficiently explore the implications of the form of the deformation gradient in the development of a UMAT.","PeriodicalId":94117,"journal":{"name":"Journal of the mechanical behavior of biomedical materials","volume":"126 1","pages":"104940"},"PeriodicalIF":0.0,"publicationDate":"2019-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47398870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ligament tension is an important factor that can affect the success of total knee arthroplasty (TKA) procedures. However, surgeons currently lack objective approaches for assessing tension in a particular ligament intraoperatively. The purpose of this study was to investigate the use of noninvasive shear wave tensiometry to characterize stress in medial and lateral collateral ligaments (MCLs and LCLs) ex vivo and evaluate the capacity of shear wave speed to predict axial load. Nine porcine MCL and LCL specimens were subjected to cyclic axial loading while shear wave speeds were measured using laser vibrometry. We found that squared shear wave speed increased linearly with stress in both the MCL (r2avg = 0.94) and LCL (r2avg = 0.98). Shear wave speeds were slightly lower in the MCL than the LCL when subjected to a comparable axial stress (p < 0.001). Specimen-specific calibrations predicted tension within 13.0 N, or 5.2% of the maximum load. A leave-one-out analysis was also performed and showed that calibrated relationships based on ligament type could predict axial tension within 15% of the maximum load. These observations suggest it may be feasible to use noninvasive shear wave speed measures as a proxy of ligament loading, which in the future might enhance decision making during orthopedic procedures such as TKA.
{"title":"Shear wave speeds track axial stress in porcine collateral ligaments.","authors":"Jonathon L. Blank, D. Thelen, J. Roth","doi":"10.31224/osf.io/ksg2p","DOIUrl":"https://doi.org/10.31224/osf.io/ksg2p","url":null,"abstract":"Ligament tension is an important factor that can affect the success of total knee arthroplasty (TKA) procedures. However, surgeons currently lack objective approaches for assessing tension in a particular ligament intraoperatively. The purpose of this study was to investigate the use of noninvasive shear wave tensiometry to characterize stress in medial and lateral collateral ligaments (MCLs and LCLs) ex vivo and evaluate the capacity of shear wave speed to predict axial load. Nine porcine MCL and LCL specimens were subjected to cyclic axial loading while shear wave speeds were measured using laser vibrometry. We found that squared shear wave speed increased linearly with stress in both the MCL (r2avg = 0.94) and LCL (r2avg = 0.98). Shear wave speeds were slightly lower in the MCL than the LCL when subjected to a comparable axial stress (p < 0.001). Specimen-specific calibrations predicted tension within 13.0 N, or 5.2% of the maximum load. A leave-one-out analysis was also performed and showed that calibrated relationships based on ligament type could predict axial tension within 15% of the maximum load. These observations suggest it may be feasible to use noninvasive shear wave speed measures as a proxy of ligament loading, which in the future might enhance decision making during orthopedic procedures such as TKA.","PeriodicalId":94117,"journal":{"name":"Journal of the mechanical behavior of biomedical materials","volume":"105 1","pages":"103704"},"PeriodicalIF":0.0,"publicationDate":"2019-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46450067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-01-01Epub Date: 2015-11-27DOI: 10.3109/07853890.2015.1068949
Philip N Hawkins, Yukio Ando, Angela Dispenzeri, Alejandra Gonzalez-Duarte, David Adams, Ole B Suhr
Transthyretin (TTR) amyloidosis (ATTR amyloidosis) is a multisystemic, multigenotypic disease resulting from deposition of insoluble ATTR amyloid fibrils in various organs and tissues. Although considered rare, the prevalence of this serious disease is likely underestimated because symptoms can be non-specific and diagnosis largely relies on amyloid detection in tissue biopsies. Treatment is guided by which tissues/organs are involved, although therapeutic options are limited for patients with late-stage disease. Indeed, enthusiasm for liver transplantation for familial ATTR amyloidosis with polyneuropathy was dampened by poor outcomes among patients with significant neurological deficits or cardiac involvement. Hence, there remains an unmet medical need for new therapies. The TTR stabilizers tafamidis and diflunisal slow disease progression in some patients with ATTR amyloidosis with polyneuropathy, and the postulated synergistic effect of doxycycline and tauroursodeoxycholic acid on dissolution of amyloid is under investigation. Another therapeutic approach is to reduce production of the amyloidogenic protein, TTR. Plasma TTR concentration can be significantly reduced with ISIS-TTR(Rx), an investigational antisense oligonucleotide-based drug, or with patisiran and revusiran, which are investigational RNA interference-based therapeutics that target the liver. The evolving treatment landscape for ATTR amyloidosis brings hope for further improvements in clinical outcomes for patients with this debilitating disease.
{"title":"Evolving landscape in the management of transthyretin amyloidosis.","authors":"Philip N Hawkins, Yukio Ando, Angela Dispenzeri, Alejandra Gonzalez-Duarte, David Adams, Ole B Suhr","doi":"10.3109/07853890.2015.1068949","DOIUrl":"10.3109/07853890.2015.1068949","url":null,"abstract":"<p><p>Transthyretin (TTR) amyloidosis (ATTR amyloidosis) is a multisystemic, multigenotypic disease resulting from deposition of insoluble ATTR amyloid fibrils in various organs and tissues. Although considered rare, the prevalence of this serious disease is likely underestimated because symptoms can be non-specific and diagnosis largely relies on amyloid detection in tissue biopsies. Treatment is guided by which tissues/organs are involved, although therapeutic options are limited for patients with late-stage disease. Indeed, enthusiasm for liver transplantation for familial ATTR amyloidosis with polyneuropathy was dampened by poor outcomes among patients with significant neurological deficits or cardiac involvement. Hence, there remains an unmet medical need for new therapies. The TTR stabilizers tafamidis and diflunisal slow disease progression in some patients with ATTR amyloidosis with polyneuropathy, and the postulated synergistic effect of doxycycline and tauroursodeoxycholic acid on dissolution of amyloid is under investigation. Another therapeutic approach is to reduce production of the amyloidogenic protein, TTR. Plasma TTR concentration can be significantly reduced with ISIS-TTR(Rx), an investigational antisense oligonucleotide-based drug, or with patisiran and revusiran, which are investigational RNA interference-based therapeutics that target the liver. The evolving treatment landscape for ATTR amyloidosis brings hope for further improvements in clinical outcomes for patients with this debilitating disease.</p>","PeriodicalId":94117,"journal":{"name":"Journal of the mechanical behavior of biomedical materials","volume":"1 1","pages":"625-38"},"PeriodicalIF":4.4,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720049/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90688969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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