scholarly journals Multiscale Modelling of β-Adrenergic Stimulation in Cardiac Electromechanical Function

Mathematics ◽  
2021 ◽  
Vol 9 (15) ◽  
pp. 1785
Author(s):  
Ruben Doste ◽  
Alfonso Bueno-Orovio
Keyword(s):  
Cardiac Electrophysiology ◽  
Mechanical Response ◽  
Physiological Mechanism ◽  
Calcium Handling ◽  
Patient Specific ◽  
Clinical Environment ◽  
Adrenergic Stimulation ◽  
Cellular Models ◽  
Phosphorylation Cascade ◽  
Fight Or Flight Response

β-adrenergic receptor stimulation (β-ARS) is a physiological mechanism that regulates cardiovascular function under stress conditions or physical exercise. Triggered during the so-called “fight-or-flight” response, the activation of the β-adrenergic receptors located on the cardiomyocyte membrane initiates a phosphorylation cascade of multiple ion channel targets that regulate both cellular excitability and recovery and of different proteins involved in intracellular calcium handling. As a result, β-ARS impacts both the electrophysiological and the mechanical response of the cardiomyocyte. β-ARS also plays a crucial role in several cardiac pathologies, greatly modifying cardiac output and potentially causing arrhythmogenic events. Mathematical patient-specific models are nowadays envisioned as an important tool for the personalised study of cardiac disease, the design of tailored treatments, or to inform risk assessment. Despite that, only a reduced number of computational studies of heart disease have incorporated β-ARS modelling. In this review, we describe the main existing multiscale frameworks to equip cellular models of cardiac electrophysiology with a β-ARS response. We also outline various applications of these multiscale frameworks in the study of cardiac pathology. We end with a discussion of the main current limitations and the future steps that need to be taken to adapt these models to a clinical environment and to incorporate them in organ-level simulations.

scholarly journals Patient-specific iPSC-derived cellular models of LGMDR1

2021 ◽  
pp. 102333
Author(s):  
A.J. Mateos-Aierdi ◽  
M. Dehesa-Etxebeste ◽  
M. Goicoechea ◽  
A. Aiastui-Pujana ◽  
Y. Richaud-Patin ◽  
...  
Keyword(s):  
Patient Specific ◽  
Cellular Models

scholarly journals Spontaneous calcium release in tissue from the failing canine heart

2009 ◽  
Vol 297 (4) ◽  
pp. H1235-H1242 ◽  
Author(s):  
Gregory S. Hoeker ◽  
Rodolphe P. Katra ◽  
Lance D. Wilson ◽  
Bradley N. Plummer ◽  
Kenneth R. Laurita
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Calcium Release ◽  
Tissue Level ◽  
Calcium Handling ◽  
Canine Heart ◽  
Myocardial Cells ◽  
Spontaneous Release ◽  
Adrenergic Stimulation ◽  
Electrical Instability ◽  
Delayed Afterdepolarization

Abnormalities in calcium handling have been implicated as a significant source of electrical instability in heart failure (HF). While these abnormalities have been investigated extensively in isolated myocytes, how they manifest at the tissue level and trigger arrhythmias is not clear. We hypothesize that in HF, triggered activity (TA) is due to spontaneous calcium release from the sarcoplasmic reticulum that occurs in an aggregate of myocardial cells (an SRC) and that peak SCR amplitude is what determines whether TA will occur. Calcium and voltage optical mapping was performed in ventricular wedge preparations from canines with and without tachycardia-induced HF. In HF, steady-state calcium transients have reduced amplitude [135 vs. 170 ratiometric units (RU), P < 0.05] and increased duration (252 vs. 229 s, P < 0.05) compared with those of normal. Under control conditions and during β-adrenergic stimulation, TA was more frequent in HF (53% and 93%, respectively) compared with normal (0% and 55%, respectively, P < 0.025). The mechanism of arrhythmias was SCRs, leading to delayed afterdepolarization-mediated triggered beats. Interestingly, the rate of SCR rise was greater for events that triggered a beat (0.41 RU/ms) compared with those that did not (0.18 RU/ms, P < 0.001). In contrast, there was no difference in SCR amplitude between the two groups. In conclusion, TA in HF tissue is associated with abnormal calcium regulation and mediated by the spontaneous release of calcium from the sarcoplasmic reticulum in aggregates of myocardial cells (i.e., an SCR), but importantly, it is the rate of SCR rise rather than amplitude that was associated with TA.

A Proof of Concept Study of the Mechanical Behavior of Lattice Structures Used to Design a Shoulder Hemi-Prosthesis

2021 ◽  
Author(s):  
Marinela Peto ◽  
Oscar Aguilar-Rosas ◽  
Erick Erick Ramirez-Cedillo ◽  
Moises Jimenez ◽  
Adriana Hernandez ◽  
...  
Keyword(s):  
Mechanical Behavior ◽  
Mechanical Response ◽  
Mechanical Performance ◽  
Cell Attachment ◽  
Lattice Structure ◽  
Material Model ◽  
Patient Specific ◽  
Hexagonal Prism ◽  
Lattice Structures ◽  
Proof Of Concept

Abstract Lattice structures offer great benefits when employed in medical implants for cell attachment and growth (osseointegration), minimization of stress shielding phenomena, and weight reduction. This study is focused on a proof of concept for developing a generic shoulder hemi-prosthesis, from a patient-specific case of a 46 years old male with a tumor on the upper part of his humerus. A personalized biomodel was designed and a lattice structure was integrated in its middle portion, to lighten weight without affecting humerus’ mechanical response. To select the most appropriate lattice structure, three different configurations were initially tested: Tetrahedral Vertex Centroid (TVC), Hexagonal Prism Vertex Centroid (HPVC), and Cubic Diamond (CD). They were fabricated in resin by digital light processing and its mechanical behavior was studied via compression testing and finite element modeling (FEM). The selected structure according to the results was the HPVC, which was integrated in a digital twin of the biomodel to validate its mechanical performance through FEM but substituting the bone material model with a biocompatible titanium alloy (Ti6Al4V) suitable for prostheses fabrication. Results of the simulation showed acceptable levels of Von Mises stresses (325 MPa max.), below the elastic limit of the titanium alloys, and a better response (52 MPa max.) in a model with equivalent elastic properties, with stress performance in the same order of magnitude than the showed in bone’s material model.

scholarly journals Adrenergic supersensitivity and impaired neural control of cardiac electrophysiology following regional cardiac sympathetic nerve loss

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Srinivas Tapa ◽  
Lianguo Wang ◽  
Samantha D. Francis Stuart ◽  
Zhen Wang ◽  
Yanyan Jiang ◽  
...  
Keyword(s):  
Sympathetic Nerve ◽  
Cardiac Electrophysiology ◽  
Neural Control ◽  
Left Ventricular ◽  
Adrenergic Stimulation ◽  
Sympathetic Nerve Stimulation ◽  
Post Surgery ◽  
Dopamine Beta Hydroxylase ◽  
Perfused Hearts ◽  
Insight Into

Abstract Myocardial infarction (MI) can result in sympathetic nerve loss in the infarct region. However, the contribution of hypo-innervation to electrophysiological remodeling, independent from MI-induced ischemia and fibrosis, has not been comprehensively investigated. We present a novel mouse model of regional cardiac sympathetic hypo-innervation utilizing a targeted-toxin (dopamine beta-hydroxylase antibody conjugated to saporin, DBH-Sap), and measure resulting electrophysiological and Ca2+ handling dynamics. Five days post-surgery, sympathetic nerve density was reduced in the anterior left ventricular epicardium of DBH-Sap hearts compared to control. In Langendorff-perfused hearts, there were no differences in mean action potential duration (APD80) between groups; however, isoproterenol (ISO) significantly shortened APD80 in DBH-Sap but not control hearts, resulting in a significant increase in APD80 dispersion in the DBH-Sap group. ISO also produced spontaneous diastolic Ca2+ elevation in DBH-Sap but not control hearts. In innervated hearts, sympathetic nerve stimulation (SNS) increased heart rate to a lesser degree in DBH-Sap hearts compared to control. Additionally, SNS produced APD80 prolongation in the apex of control but not DBH-Sap hearts. These results suggest that hypo-innervated hearts have regional super-sensitivity to circulating adrenergic stimulation (ISO), while having blunted responses to SNS, providing important insight into the mechanisms of arrhythmogenesis following sympathetic nerve loss.

scholarly journals Three-dimensional technologies used for patient specific applications in orthopedics

2021 ◽  
Vol 67 (2) ◽  
pp. 77-85
Author(s):  
Flaviu Moldovan ◽  
Tiberiu Bataga
Keyword(s):  
Orthopedic Surgery ◽  
Three Dimensional ◽  
Medical Application ◽  
Surgical Instruments ◽  
Patient Specific ◽  
Innovative Technology ◽  
Clinical Environment ◽  
Clinical Practices ◽  
Content Description ◽  
Almost All

Abstract Background: Three-dimensional (3D) technologies have numerous medical applications and have gained a lot of interest in medical world. After the advent of three-dimensional printing technology, and especially in last decade, orthopedic surgeons began to apply this innovative technology in almost all areas of orthopedic traumatic surgery. Objective: The aim of this paper is to give an overview of 3D technologies current usage in orthopedic surgery for patient specific applications. Methods: Two major databases PubMed and Web of Science were explored for content description and applications of 3D technologies in orthopedic surgery. It was considered papers presenting controlled studies and series of cases that include descriptions of 3D technologies compatible with applications to human medical purposes. Results: First it is presented the available three-dimensional technologies that can be used in orthopedic surgery as well as methods of integration in order to achieve the desired medical application for patient specific orthopedics. Technology starts with medical images acquisition, followed by design, numerical simulation, and printing. Then it is described the state of the art clinical applications of 3D technologies in orthopedics, by selecting the latest reported articles in medical literature. It is focused on preoperative visualization and planning, trauma, injuries, elective orthopedic surgery, guides and customized surgical instrumentation, implants, orthopedic fixators, orthoses and prostheses. Conclusion: The new 3D digital technologies are revolutionizing orthopedic clinical practices. The vast potential of 3D technologies is increasingly used in clinical practice. These technologies provide useful tools for clinical environment: accurate preoperative planning for cases of complex trauma and elective cases, personalized surgical instruments and personalized implants. There is a need to further explore the vast potential of 3D technologies in many other areas of orthopedics and to accommodate healthcare professionals with these technologies, as well as to study their effectiveness compared to conventional methods.

scholarly journals Age-dependent changes in electrophysiology and calcium handling – implications for pediatric cardiac research

2019 ◽  
Author(s):  
Luther M. Swift ◽  
Morgan Burke ◽  
Devon Guerrelli ◽  
Manelle Ramadan ◽  
Marissa Reilly ◽  
...  
Keyword(s):  
Postnatal Development ◽  
Cardiac Electrophysiology ◽  
Calcium Handling ◽  
Cell Coupling ◽  
Altered Expression ◽  
Expression Of Genes ◽  
Age Dependent ◽  
Genes Encoding ◽  
Cardiac Maturation

ABSTRACTRationaleThe heart continues to develop and mature after birth and into adolescence. Accordingly, cardiac maturation is likely to include a progressive refinement in both organ morphology and function during the postnatal period. Yet, age-dependent changes in cardiac electrophysiology and calcium handling have not yet been fully characterized.ObjectiveThe objective of this study, was to examine the relationship between cardiac maturation, electrophysiology, and calcium handling throughout postnatal development in a rat model.MethodsPostnatal rat cardiac maturation was determined by measuring the expression of genes involved in cell-cell coupling, electrophysiology, and calcium handling. In vivo electrocardiograms were recorded from neonatal, juvenile, and adult animals. Simultaneous dual optical mapping of transmembrane voltage and calcium transients was performed on isolated, Langendorff-perfused rat hearts (postnatal day 0–3, 4-7, 8-14, adult).ResultsYounger, immature hearts displayed slowed electrical conduction, prolonged action potential duration and increased ventricular refractoriness. Slowed calcium handling in the immature heart increased the propensity for calcium transient alternans which corresponded to alterations in the expression of genes encoding calcium handling proteins. Developmental changes in cardiac electrophysiology were associated with the altered expression of genes encoding potassium channels and intercalated disc proteins.ConclusionUsing an intact whole heart model, this study highlights chronological changes in cardiac electrophysiology and calcium handling throughout postnatal development. Results of this study can serve as a comprehensive baseline for future studies focused on pediatric cardiac research, safety assessment and/or preclinical testing using rodent models.

HUMAN iPSC ENGINEERED CARDIAC TISSUE PLATFORM FAITHFULLY MODELS IMPORTANT CARDIAC PHYSIOLOGY

2021 ◽  
Author(s):  
Willem J. de Lange ◽  
Emily T. Farrell ◽  
Caroline R. Kreitzer ◽  
Derek R. Jacobs ◽  
Di Lang ◽  
...  
Keyword(s):  
Cardiac Tissue ◽  
Human Myocardium ◽  
Protein Isoforms ◽  
Calcium Handling ◽  
Unintended Effects ◽  
Cardiac Physiology ◽  
Adrenergic Stimulation ◽  
Cardiac Model ◽  
Short Period ◽  
Tubular System

Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CM) may provide an important bridge between animal models and intact human myocardium. Fulfilling this potential is hampered by their relative immaturity. hiPSC-CMs grown in monolayer culture lack a t-tubular system, have rudimentary intracellular calcium-handling systems, express predominantly embryonic sarcomeric protein isoforms, and preferentially use glucose as energy substrate. Culturing hiPSC-CM in a 3D environment and the addition of nutritional, pharmacologic and electromechanical stimuli have proven to be beneficial for maturation. We present an assessment of a model in which hiPSC-CMs and hiPSC-derived cardiac fibroblasts are co-cultured in a 3D fibrin matrix to form human engineered cardiac tissue constructs (hECT).The hECT respond to physiological stimuli, including stretch, frequency and β-adrenergic stimulation, develop a t-tubular system, and demonstrate calcium-handling and contractile kinetics that compare favorably with ventricular human myocardium. Transcript levels of genes involved in calcium-handling and contraction are increased. These markers of maturation become more robust over a short period of time in culture (6 weeks vs. 2 weeks in hECT). A comparison of the hECT molecular and performance variables with those of human cardiac tissue and other available engineered tissue platforms is provided to highlight strengths and weaknesses of these preparations. Important and noteworthy aspects of this human cardiac model system are its reliance on 'off-the-shelf' equipment, ability to provide detailed physiological performance data, and the ability to achieve a relatively mature cardiac physiology without additional nutritional, pharmacological and electromechanical stimuli that may elicit unintended effects on function.

A Feature-Based Morphing Methodology for Biological Structures Applied to the Spatial Organization of Cardiomyocytes in the Left Atrium

2011 ◽  
Author(s):  
Alessandro Satriano ◽  
Edward J. Vigmond ◽  
Elena S. Di Martino
Keyword(s):  
Spatial Organization ◽  
Experimental Tests ◽  
Smooth Transition ◽  
Patient Specific ◽  
Clinical Environment ◽  
Individual Values ◽  
Tissue Properties ◽  
Biological Structures ◽  
Critical Issues ◽  
Parameter Values

When complex biological structures are modeled, one of the most critical issues is the assignment of geometrical, mechanical and electrical properties to the meshed surfaces. Properties of interest are commonly obtained from diagnostic imaging, experimental tests or anatomical observation. These parameters are usually lumped into individual values assigned to a specific region after subdividing the structure in sub-regions. This practice simplifies the problem avoiding the cumbersome assignment of parameter values to each element. However, sub-regions may not adequately represent the smooth transition between regions thus resulting in artificial discontinuities. In addition, some parameters, such as for example the organization of cardiomyocytes, which is the objective of our research, may be obtained through destructive tests or through sophisticated methods that can only be performed on a limited number of samples. Or else, data structure obtained for one animal species could be applied on a different species. Furthermore, in a clinical environment the need for fast turnout of patient-specific models would benefit from the assignment of tissue properties in a semi-automatic manner.

scholarly journals Biomechanical simulations and 3D printing for endovascular device testing

2020 ◽  
Author(s):  
Michele Conti ◽  
Stefania Marconi ◽  
Ferdinando Auricchio
Keyword(s):  
3D Printing ◽  
Mechanical Response ◽  
Ex Vivo ◽  
Invasive Procedure ◽  
Patient Specific ◽  
Human Aorta ◽  
In Vitro Tests ◽  
Aortic Diseases ◽  
Endovascular Device

Endovascular aortic repair is a minimally invasive procedure to treat aortic diseases such as aneurysms and dissections. Thanks to technological advancements, such procedure has steadily shifted from the abdominal aorta towards the ascending part, i.e., near the heart, calling for an extensive and comprehensive benchmarking of (novel) endografts. Given such considerations, we have exploited porcine aorta with a pulse duplicator to analyse the mechanical interaction between the endovascular device and the native tissue. Our results have implications for using the porcine aorta as a model for human aorta in research. Particularly, the combination of in vitro tests performed using ex-vivo tissue, integrated validated patient-specific numerical simulations, mock arteries manufactured by 3D printing, can offer important insight on biomechanical impact of endograft design on post-operative aortic mechanical response.

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