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1.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 2654-2657, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018552

RESUMO

Historically, cardiovascular computational models have been developed considering the case of a 70 Kg male patient. However, hemodynamic quantities differ widely due to sex, age, and weight. In this study, we developed a female-specific model of the blood circulation of a young (18-40 y.o.) woman with BSA of 1.6 m2. The lumped-parameter (0D) model, which includes the uterus, has been calibrated with female-specific parameters and validated with sex-specific literature data.


Assuntos
Hemodinâmica , Modelos Cardiovasculares , Feminino , Humanos
2.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 2804-2807, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018589

RESUMO

The advances in cardiovascular modelling over the past two decades have given the opportunity to create accurate three dimensional models of the coronary vasculature which, combined with advanced computational fluid dynamics algorithms can shed light to intriguing matters that concern clinicians. One of these issues is the presence of a stenosis near bifurcations in one of the major coronary vessels. In this work, we try to shed light on the aforementioned matter by creating a healthy arterial bifurcation reconstructed using the fusion of Optical Coherence Tomography and X-Ray angiography images. The healthy model was edited by adding an artificial stenosis of 50% diameter reduction into three different locations after the bifurcation, thus creating three diseased models. After performing the appropriate blood flow simulations, we observed that the location of the stenosis affects the Wall Shear Stress (WSS) distribution but it does not affect the functional significance of the stenosis itself.


Assuntos
Vasos Coronários , Modelos Cardiovasculares , Constrição Patológica , Vasos Coronários/diagnóstico por imagem , Hemodinâmica , Humanos , Estresse Mecânico
3.
PLoS One ; 15(10): e0235373, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33052908

RESUMO

The development of retinal blood vessels has extensively been used as a model to study vascular pattern formation. To date, various quantitative measurements, such as size distribution have been performed, but the relationship between pattern formation mechanisms and these measurements remains unclear. In the present study, we first focus on the islands (small regions subdivided by the capillary network). We quantitatively measured the island size distribution in the retinal vascular network and found that it tended to exhibit an exponential distribution. We were able to recapitulate this distribution pattern in a theoretical model by implementing the stochastic disappearance of vessel segments around arteries could reproduce the observed exponential distribution of islands. Second, we observed that the diameter distribution of the retinal artery segment obeyed a power law. We theoretically showed that an equal bifurcation branch pattern and Murray's law could reproduce this pattern. This study demonstrates the utility of examining size distribution for understanding the mechanisms of vascular pattern formation.


Assuntos
Modelos Cardiovasculares , Neovascularização Retiniana , Vasos Retinianos/anatomia & histologia , Vasos Retinianos/fisiologia , Animais , Velocidade do Fluxo Sanguíneo , Camundongos , Camundongos Endogâmicos C57BL
4.
Nat Commun ; 11(1): 5433, 2020 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-33116136

RESUMO

Scorpion envenomation is a leading cause of morbidity and mortality among accidents caused by venomous animals. Major clinical manifestations that precede death after scorpion envenomation include heart failure and pulmonary edema. Here, we demonstrate that cardiac dysfunction and fatal outcomes caused by lethal scorpion envenomation in mice are mediated by a neuro-immune interaction linking IL-1 receptor signaling, prostaglandin E2, and acetylcholine release. IL-1R deficiency, the treatment with a high dose of dexamethasone or blockage of parasympathetic signaling using atropine or vagotomy, abolished heart failure and mortality of envenomed mice. Therefore, we propose the use of dexamethasone administration very early after envenomation, even before antiserum, to inhibit the production of inflammatory mediators and acetylcholine release, and to reduce the risk of death.


Assuntos
Acetilcolina/metabolismo , Dinoprostona/biossíntese , Insuficiência Cardíaca/etiologia , Receptores Tipo I de Interleucina-1/metabolismo , Venenos de Escorpião/toxicidade , Animais , Antivenenos/administração & dosagem , Atropina/farmacologia , Dexametasona/administração & dosagem , Modelos Animais de Doenças , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Cardiovasculares , Neuroimunomodulação/efeitos dos fármacos , Receptores Tipo I de Interleucina-1/deficiência , Receptores Tipo I de Interleucina-1/genética , Picadas de Escorpião/complicações , Escorpiões , Transdução de Sinais , Vagotomia
5.
Nat Commun ; 11(1): 5319, 2020 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-33087700

RESUMO

Arterial networks enlarge in response to increase in tissue metabolism to facilitate flow and nutrient delivery. Typically, the transition of a growing artery with a small diameter into a large caliber artery with a sizeable diameter occurs upon the blood flow driven change in number and shape of endothelial cells lining the arterial lumen. Here, using zebrafish embryos and endothelial cell models, we describe an alternative, flow independent model, involving enlargement of arterial endothelial cells, which results in the formation of large diameter arteries. Endothelial enlargement requires the GEF1 domain of the guanine nucleotide exchange factor Trio and activation of Rho-GTPases Rac1 and RhoG in the cell periphery, inducing F-actin cytoskeleton remodeling, myosin based tension at junction regions and focal adhesions. Activation of Trio in developing arteries in vivo involves precise titration of the Vegf signaling strength in the arterial wall, which is controlled by the soluble Vegf receptor Flt1.


Assuntos
Células Endoteliais/citologia , Células Endoteliais/fisiologia , Fatores de Troca do Nucleotídeo Guanina/fisiologia , Fator A de Crescimento do Endotélio Vascular/fisiologia , Remodelação Vascular/fisiologia , Animais , Animais Geneticamente Modificados , Tamanho Celular , Células Cultivadas , Fatores de Troca do Nucleotídeo Guanina/genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Modelos Cardiovasculares , Fator de Crescimento Placentário/genética , Fator de Crescimento Placentário/fisiologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/fisiologia , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/fisiologia , Remodelação Vascular/genética , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Peixe-Zebra/fisiologia , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/fisiologia , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/fisiologia
6.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 918-922, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018134

RESUMO

Synthesis of accurate, personalize photoplethysmogram (PPG) signal is important to interpret, analyze and predict cardiovascular disease progression. Generative models like Generative Adversarial Networks (GANs) can be used for signal synthesis, however, they are difficult to map to the underlying pathophysiological conditions. Hence, we propose a PPG synthesis strategy that has been designed using a cardiovascular system, modeled through the hemodynamic principle. The modeled architecture is composed of a two-chambered heart along with the systemic-pulmonic blood circulation and a baroreflex auto-regulation mechanism to control the arterial blood pressure. The comprehensive PPG signal is synthesized from the cardiac pressure-flow dynamics. In order to tune the modeled cardiac parameters with respect to a measured PPG data, a novel feature extraction strategy has been employed along with the particle swarm optimization heuristics. Our results demonstrate that the synthesized PPG is accurately followed the morphological changes of the ground truth (GT) signal with an RMSE of 0.003 occurring due to the Coronary Artery Disease (CAD) which is caused by an obstruction in the artery.


Assuntos
Doenças Cardiovasculares , Modelos Cardiovasculares , Pressão Arterial , Doenças Cardiovasculares/diagnóstico , Humanos , Fotopletismografia , Processamento de Sinais Assistido por Computador
7.
Nat Commun ; 11(1): 4883, 2020 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-32985528

RESUMO

Early stages of the novel coronavirus disease (COVID-19) are associated with silent hypoxia and poor oxygenation despite relatively minor parenchymal involvement. Although speculated that such paradoxical findings may be explained by impaired hypoxic pulmonary vasoconstriction in infected lung regions, no studies have determined whether such extreme degrees of perfusion redistribution are physiologically plausible, and increasing attention is directed towards thrombotic microembolism as the underlying cause of hypoxemia. Herein, a mathematical model demonstrates that the large amount of pulmonary venous admixture observed in patients with early COVID-19 can be reasonably explained by a combination of pulmonary embolism, ventilation-perfusion mismatching in the noninjured lung, and normal perfusion of the relatively small fraction of injured lung. Although underlying perfusion heterogeneity exacerbates existing shunt and ventilation-perfusion mismatch in the model, the reported hypoxemia severity in early COVID-19 patients is not replicated without either extensive perfusion defects, severe ventilation-perfusion mismatch, or hyperperfusion of nonoxygenated regions.


Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Infecções por Coronavirus/fisiopatologia , Hipóxia/etiologia , Hipóxia/fisiopatologia , Pneumopatias/etiologia , Pneumopatias/fisiopatologia , Pulmão/irrigação sanguínea , Pulmão/fisiopatologia , Modelos Biológicos , Pneumonia Viral/complicações , Pneumonia Viral/fisiopatologia , Circulação Pulmonar/fisiologia , Simulação por Computador , Infecções por Coronavirus/epidemiologia , Humanos , Hipóxia/terapia , Pneumopatias/terapia , Conceitos Matemáticos , Modelos Cardiovasculares , Oxigenoterapia , Pandemias , Pneumonia Viral/epidemiologia , Fatores de Tempo , Vasoconstrição/fisiologia , Vasodilatação/fisiologia , Relação Ventilação-Perfusão/fisiologia
8.
J Vis Exp ; (162)2020 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-32894270

RESUMO

By replacing lost or dysfunctional myocardium, tissue regeneration is a promising approach to treat heart failure. However, the challenge of detecting bona fide heart regeneration limits the validation of potential regenerative factors. One method to detect new cardiomyocytes is multicolor lineage tracing with clonal analysis. Clonal analysis experiments can be difficult to undertake, because labeling conditions that are too sparse lack sensitivity for rare events such as cardiomyocyte proliferation, and diffuse labeling limits the ability to resolve clones. Presented here is a protocol to undertake clonal analysis of the neonatal mouse heart by using statistical modeling of nearest neighbor distributions to resolve cardiomyocyte clones. This approach enables resolution of clones over a range of labeling conditions and provides a robust analytical approach for quantifying cardiomyocyte proliferation and regeneration. This protocol can be adapted to other tissues and can be broadly used to study tissue regeneration.


Assuntos
Células Clonais/citologia , Modelos Cardiovasculares , Miócitos Cardíacos/citologia , Animais , Animais Recém-Nascidos , Proliferação de Células , Camundongos
10.
PLoS One ; 15(9): e0239447, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32991605

RESUMO

The paper deals with the impact of chosen geometric and material factors on maximal stresses in carotid atherosclerotic plaque calculated using patient-specific finite element models. These stresses are believed to be decisive for the plaque vulnerability but all applied models suffer from inaccuracy of input data, especially when obtained in vivo only. One hundred computational models based on ex vivo MRI are used to investigate the impact of wall thickness, MRI slice thickness, lipid core and fibrous tissue stiffness, and media anisotropy on the calculated peak plaque and peak cap stresses. The investigated factors are taken as continuous in the range based on published experimental results, only the impact of anisotropy is evaluated by comparison with a corresponding isotropic model. Design of Experiment concept is applied to assess the statistical significance of these investigated factors representing uncertainties in the input data of the model. The results show that consideration of realistic properties of arterial wall in the model is decisive for the stress evaluation; assignment of properties of fibrous tissue even to media and adventitia layers as done in some studies may induce up to eightfold overestimation of peak stress. The impact of MRI slice thickness may play a key role when local thin fibrous cap is present. Anisotropy of media layer is insignificant, and the stiffness of fibrous tissue and lipid core may become significant in some combinations.


Assuntos
Artérias Carótidas/patologia , Fenômenos Mecânicos , Modelagem Computacional Específica para o Paciente , Placa Aterosclerótica/patologia , Fenômenos Biomecânicos , Artérias Carótidas/diagnóstico por imagem , Análise de Elementos Finitos , Humanos , Imagem por Ressonância Magnética , Modelos Cardiovasculares , Placa Aterosclerótica/diagnóstico por imagem
11.
Asian Cardiovasc Thorac Ann ; 28(8): 520-532, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32878458

RESUMO

Computational fluid dynamics has become an important tool for studying blood flow dynamics. As an in-silico collection of methods, computational fluid dynamics is noninvasive and provides numerical values for the most important parameters of blood flow, such as velocity and pressure that are crucial in hemodynamic studies. In this primer, we briefly explain the basic theory and workflow of the two most commonly applied computational fluid dynamics techniques used in the congenital heart disease literature: the finite element method and the finite volume method. We define important terminology and include specific examples of how using these methods can answer important clinical questions in congenital cardiac surgery planning and perioperative patient management.


Assuntos
Cardiopatias Congênitas/diagnóstico por imagem , Hemodinâmica , Modelos Cardiovasculares , Modelagem Computacional Específica para o Paciente , Tomada de Decisão Clínica , Cardiopatias Congênitas/fisiopatologia , Cardiopatias Congênitas/terapia , Humanos , Hidrodinâmica , Valor Preditivo dos Testes
12.
Phys Rev Lett ; 125(5): 058102, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32794888

RESUMO

Animal hearts are soft shells that actively pump blood to oxygenate tissues. Here, we propose an allometric scaling law for the heart rate based on the idea of elastohydrodynamic resonance of a fluid-loaded soft active elastic shell that buckles and contracts axially when twisted periodically. We show that this picture is consistent with numerical simulations of soft cylindrical shells that twist-buckle while pumping a viscous fluid, yielding optimum ejection fractions of 35%-40% when driven resonantly. Our scaling law is consistent with experimental measurements of heart rates over 2 orders of magnitude, and provides a mechanistic basis for how metabolism scales with organism size. In addition to providing a physical rationale for the heart rate and metabolism of an organism, our results suggest a simple design principle for soft fluidic pumps.


Assuntos
Frequência Cardíaca/fisiologia , Coração/anatomia & histologia , Coração/fisiologia , Modelos Cardiovasculares , Animais , Simulação por Computador , Elasticidade , Ventrículos do Coração/anatomia & histologia , Hidrodinâmica , Função Ventricular
13.
PLoS Comput Biol ; 16(8): e1008161, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32834001

RESUMO

Arterial growth and remodeling at the tissue level is driven by mechanobiological processes at cellular and sub-cellular levels. Although it is widely accepted that cells seek to promote tissue homeostasis in response to biochemical and biomechanical cues-such as increased wall stress in hypertension-the ways by which these cues translate into tissue maintenance, adaptation, or maladaptation are far from understood. In this paper, we present a logic-based computational model for cell signaling within the arterial wall, aiming to predict changes in extracellular matrix turnover and cell phenotype in response to pressure-induced wall stress, flow-induced wall shear stress, and exogenous sources of angiotensin II, with particular interest in mouse models of hypertension. We simulate a number of experiments from the literature at both the cell and tissue level, involving single or combined inputs, and achieve high qualitative agreement in most cases. Additionally, we demonstrate the utility of this modeling approach for simulating alterations (in this case knockdowns) of individual nodes within the signaling network. Continued modeling of cellular signaling will enable improved mechanistic understanding of arterial growth and remodeling in health and disease, and will be crucial when considering potential pharmacological interventions.


Assuntos
Artérias/fisiologia , Modelos Cardiovasculares , Transdução de Sinais , Animais , Humanos , Camundongos
14.
Eur J Vasc Endovasc Surg ; 60(4): 539-547, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32741677

RESUMO

OBJECTIVE: The rupture of abdominal aortic aneurysms (AAAs) is associated with high mortality despite surgical developments. The determination of aneurysm diameter allows for follow up of aneurysm growth but fails in precisely predicting aneurysm rupture. In this study, time resolved three dimensional ultrasound (4D ultrasound) based wall motion indices (WMIs) are investigated to see if they are capable of distinguishing between uneven affected regions of the aneurysm wall. METHODS: In a prospective study, 56 patients with an AAA were examined using 4D ultrasound. Local longitudinal, circumferential, and shear strains were computed using custom methods. The deformation of the neck and sac of each aneurysm was characterised by statistical indices of the obtained distributions of local wall strains (WMIs): mean and peak strain, heterogeneity index, and local strain ratio. The locations of regions with highest local peak strain were determined. RESULTS: Compared with the aneurysm neck, the sac is characterised by low mean strain, but highly heterogeneous deformation, described by high local strain ratio and heterogeneity index. Differences were highly significant (p < .001) for all strain components. The regions with the highest circumferential peak strain were found more often in the posterior part of the aneurysm neck (p < .050) and sac (p < .001) regions, compared with other wall regions. No statistically significant correlation was found between the WMIs and maximum AAA diameter, except for longitudinal mean strain, which decreased with the increasing diameter (rho = -.42, p < .010). CONCLUSION: Characterisation of wall kinematics by 4D ultrasound based WMIs provides a new and independent criterion for the distinction of diseased tissue in the AAA sac and the less affected neck region. This is a promising step towards the establishment of new biomarkers to differentiate between the mechanical instability of the AAA and rupture risk.


Assuntos
Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador , Modelos Cardiovasculares , Modelagem Computacional Específica para o Paciente , Ultrassonografia , Idoso , Idoso de 80 Anos ou mais , Aorta Abdominal/fisiopatologia , Aneurisma da Aorta Abdominal/complicações , Aneurisma da Aorta Abdominal/fisiopatologia , Ruptura Aórtica/diagnóstico por imagem , Ruptura Aórtica/etiologia , Ruptura Aórtica/fisiopatologia , Fenômenos Biomecânicos , Feminino , Hemodinâmica , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Fatores de Risco , Estresse Mecânico
15.
Med Hypotheses ; 143: 110125, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32763657

RESUMO

The novel coronavirus (SARS-CoV-2) is primarily a respiratory pathogen and its clinical manifestations are dominated by respiratory symptoms, the most severe of which is acute respiratory distress syndrome (ARDS). However, COVID-19 is increasingly recognized to cause an overwhelming inflammatory response and cytokine storm leading to end organ damage. End organ damage to heart is one of the most severe complications of COVID-19 that increases the risk of death. We proposed a two-fold mechanism responsible for causing acute coronary events in patients with COVID-19 infection: Cytokine storm leading to rapid onset formation of new coronary plaques along with destabilization of pre-existing plaques and direct myocardial injury secondary to acute systemic viral infection. A well-coordinated immune response is the first line innate immunity against a viral infection. However, an uncoordinated response and hypersecretion of cytokines and chemokines lead to immune related damage to the human body. Human Coronavirus (HCoV) infection causes infiltration of inflammatory cells that cause excessive production of cytokines, proteases, coagulation factors, oxygen radicals and vasoactive molecules causing endothelial damage, disruption of fibrous cap and initiation of formation of thrombus. Systemic viral infections also cause vasoconstriction leading to narrowing of vascular lumen and stimulation of platelet activation via shear stress. The resultant cytokine storm causes secretion of hypercoagulable tissue factor without consequential increase in counter-regulatory pathways such as AT-III, activated protein C and plasminogen activator type 1. Lastly, influx of CD4+ T-cells in cardiac vasculature results in an increased production of cytokines that stimulate smooth muscle cells to migrate into the intima and generate collagen and other fibrous products leading to advancement of fatty streaks to advanced atherosclerotic lesions. Direct myocardial damage and cytokine storm leading to destabilization of pre-existing plaques and accelerated formation of new plaques are the two instigating mechanisms for acute coronary syndromes in COVID-19.


Assuntos
Síndrome Coronariana Aguda/etiologia , Betacoronavirus , Infecções por Coronavirus/complicações , Modelos Cardiovasculares , Pandemias , Pneumonia Viral/complicações , Síndrome Coronariana Aguda/fisiopatologia , Linfócitos T CD4-Positivos/imunologia , Quimiocinas/fisiologia , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/fisiopatologia , Vasos Coronários/metabolismo , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/fisiopatologia , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/fisiopatologia , Citocinas/fisiologia , Humanos , Imunidade Inata , Placa Aterosclerótica/etiologia , Placa Aterosclerótica/fisiopatologia , Ativação Plaquetária , Pneumonia Viral/imunologia , Pneumonia Viral/fisiopatologia , Vasoconstrição , Viroses/complicações , Viroses/imunologia
16.
PLoS One ; 15(8): e0236946, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764790

RESUMO

Hemodialysis catheters are used to support blood filtration, yet there are multiple fundamentally different approaches to catheter tip design with no clear optimal solution. Side-holes have been shown to increase flow rates and decrease recirculation but have been associated with clotting/increased infection rates. This study investigates the impact of changing the shape, size and number of side-holes on a simple symmetric tip catheter by evaluating the velocity, shear stress and shear rate of inflowing blood. A platelet model is used to examine the residence time and shear history of inflowing platelets. The results show that side-holes improve the theoretical performance of the catheters, reducing the maximum velocity and shear stress occurring at the tip compared to non-side-hole catheters. Increasing the side-hole area improved performance up to a point, past which not all inflow through the hole was captured, and instead a small fraction slowly 'washed-out' through the remainder of the tip resulting in greater residence times and increasing the likelihood of platelet adhesion. An oval shaped hole presents a lower chance of external fibrin formation compared to a circular hole, although this would also be influenced by the catheter material surface topology which is dependent on the manufacturing process. Overall, whilst side-holes may be associated with increased clotting and infection, this can be reduced when side-hole geometry is correctly implemented though; a sufficient area for body diameter (minimising residence time) and utilising angle-cut, oval shaped holes (reducing shear stress and chances of fibrin formation partially occluding holes).


Assuntos
Cateteres , Diálise Renal/instrumentação , Velocidade do Fluxo Sanguíneo , Plaquetas/citologia , Cateteres/estatística & dados numéricos , Biologia Computacional , Simulação por Computador , Desenho de Equipamento , Hemodinâmica , Humanos , Hidrodinâmica , Modelos Cardiovasculares , Adesividade Plaquetária
17.
AJR Am J Roentgenol ; 215(4): 795-799, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32809859

RESUMO

OBJECTIVE. The purpose of this study was to determine the capability of a newly developed antireflux valve for a multiuse contrast agent injection system. MATERIALS AND METHODS. Multiuse contrast agent injection systems require an antireflux valve to eliminate the risk of cross-patient blood contamination. An electrically actuated antireflux valve developed for this purpose can control risk of contamination because it is under forced control and surveillance. In this study, the injection system was connected to a pulsatile circulation system that reproduced an aortic flow environment in vitro. The transvalvular pressure difference was measured, and flow dynamics during valve opening and closing were visualized by high-speed flow visualization. A total of 30 injection conditions were tested, which included two catheters (6- and 2-French diameter), five contrast agent concentrations (100%, 90%, 50%, 10%, and 0%), and a wide range of flow rates (0.1-25.0 mL/s). RESULTS. The transvalvular pressure difference and flow dynamics during valve opening and closing were characterized. Just before valve opening, a minimum transvalvular pressure difference of 0.20 MPa (1500 mm Hg) was confirmed. The positive pressure difference prevented regurgitation during valve opening. During valve closing, the front of the backflow was monitored continuously, and we confirmed that the front failed to reach the valve before complete closure. CONCLUSION. This study provided proof of concept for an electrically actuated antireflux valve to be used in a multiuse contrast agent injection system.


Assuntos
Meios de Contraste/administração & dosagem , Contaminação de Equipamentos/prevenção & controle , Injeções/instrumentação , Pressão Sanguínea/fisiologia , Equipamentos e Provisões Elétricas , Desenho de Equipamento , Humanos , Modelos Cardiovasculares , Fluxo Pulsátil
18.
PLoS Comput Biol ; 16(8): e1008109, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32797034

RESUMO

In the last decade, there has been tremendous progress in identifying genetic anomalies linked to clinical disease. New experimental platforms have connected genetic variants to mechanisms underlying disruption of cellular and organ behavior and the emergence of proarrhythmic cardiac phenotypes. The development of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) signifies an important advance in the study of genetic disease in a patient-specific context. However, considerable limitations of iPSC-CM technologies have not been addressed: 1) phenotypic variability in apparently identical genotype perturbations, 2) low-throughput electrophysiological measurements, and 3) an immature phenotype which may impact translation to adult cardiac response. We have developed a computational approach intended to address these problems. We applied our recent iPSC-CM computational model to predict the proarrhythmic risk of 40 KCNQ1 genetic variants. An IKs computational model was fit to experimental data for each mutation, and the impact of each mutation was simulated in a population of iPSC-CM models. Using a test set of 15 KCNQ1 mutations with known clinical long QT phenotypes, we developed a method to stratify the effects of KCNQ1 mutations based on proarrhythmic markers. We utilized this method to predict the severity of the remaining 25 KCNQ1 mutations with unknown clinical significance. Tremendous phenotypic variability was observed in the iPSC-CM model population following mutant perturbations. A key novelty is our reporting of the impact of individual KCNQ1 mutant models on adult ventricular cardiomyocyte electrophysiology, allowing for prediction of mutant impact across the continuum of aging. This serves as a first step toward translating predicted response in the iPSC-CM model to predicted response of the adult ventricular myocyte given the same genetic mutation. As a whole, this study presents a new computational framework that serves as a high throughput method to evaluate risk of genetic mutations based-on proarrhythmic behavior in phenotypically variable populations.


Assuntos
Canal de Potássio KCNQ1/genética , Modelos Cardiovasculares , Mutação/genética , Miócitos Cardíacos , Arritmias Cardíacas/genética , Biologia Computacional , Predisposição Genética para Doença/genética , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Miócitos Cardíacos/classificação , Miócitos Cardíacos/citologia
19.
PLoS Comput Biol ; 16(8): e1008074, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32804929

RESUMO

Congestive heart failure is characterized by suppressed cardiac output and arterial filling pressure, leading to renal retention of salt and water, contributing to further volume overload. Mathematical modeling provides a means to investigate the integrated function and dysfunction of heart and kidney in heart failure. This study updates our previously reported integrated model of cardiac and renal functions to account for the fluid exchange between the blood and interstitium across the capillary membrane, allowing the simulation of edema. A state of heart failure with reduced ejection fraction (HF-rEF) was then produced by altering cardiac parameters reflecting cardiac injury and cardiovascular disease, including heart contractility, myocyte hypertrophy, arterial stiffness, and systemic resistance. After matching baseline characteristics of the SOLVD clinical study, parameters governing rates of cardiac remodeling were calibrated to describe the progression of cardiac hemodynamic variables observed over one year in the placebo arm of the SOLVD clinical study. The model was then validated by reproducing improvements in cardiac function in the enalapril arm of SOLVD. The model was then applied to prospectively predict the response to the sodium-glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin, which has been shown to reduce heart failure events in HF-rEF patients in the recent DAPAHF clinical trial by incompletely understood mechanisms. The simulations predict that dapagliflozin slows cardiac remodeling by reducing preload on the heart, and relieves congestion by clearing interstitial fluid without excessively reducing blood volume. This provides a quantitative mechanistic explanation for the observed benefits of SGLT2i in HF-rEF. The model also provides a tool for further investigation of heart failure drug therapies.


Assuntos
Insuficiência Cardíaca/fisiopatologia , Rim/fisiopatologia , Modelos Cardiovasculares , Volume Sistólico/fisiologia , Compostos Benzidrílicos/uso terapêutico , Cardiomegalia/fisiopatologia , Líquido Extracelular/fisiologia , Glucosídeos/uso terapêutico , Coração/fisiopatologia , Insuficiência Cardíaca/tratamento farmacológico , Hemodinâmica/fisiologia , Humanos , Miócitos Cardíacos/fisiologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
20.
PLoS Comput Biol ; 16(7): e1008048, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32658888

RESUMO

Heart failure (HF) is associated with an increased propensity for atrial fibrillation (AF), causing higher mortality than AF or HF alone. It is hypothesized that HF-induced remodelling of atrial cellular and tissue properties promotes the genesis of atrial action potential (AP) alternans and conduction alternans that perpetuate AF. However, the mechanism underlying the increased susceptibility to atrial alternans in HF remains incompletely elucidated. In this study, we investigated the effects of how HF-induced atrial cellular electrophysiological (with prolonged AP duration) and tissue structural (reduced cell-to-cell coupling caused by atrial fibrosis) remodelling can have an effect on the generation of atrial AP alternans and their conduction at the cellular and one-dimensional (1D) tissue levels. Simulation results showed that HF-induced atrial electrical remodelling prolonged AP duration, which was accompanied by an increased sarcoplasmic reticulum (SR) Ca2+ content and Ca2+ transient amplitude. Further analysis demonstrated that HF-induced atrial electrical remodelling increased susceptibility to atrial alternans mainly due to the increased sarcoplasmic reticulum Ca2+-ATPase (SERCA) Ca2+ reuptake, modulated by increased phospholamban (PLB) phosphorylation, and the decreased transient outward K+ current (Ito). The underlying mechanism has been suggested that the increased SR Ca2+ content and prolonged AP did not fully recover to their previous levels at the end of diastole, resulting in a smaller SR Ca2+ release and AP in the next beat. These produced Ca2+ transient alternans and AP alternans, and further caused AP alternans and Ca2+ transient alternans through Ca2+→AP coupling and AP→Ca2+ coupling, respectively. Simulation of a 1D tissue model showed that the combined action of HF-induced ion channel remodelling and a decrease in cell-to-cell coupling due to fibrosis increased the heart tissue's susceptibility to the formation of spatially discordant alternans, resulting in an increased functional AP propagation dispersion, which is pro-arrhythmic. These findings provide insights into how HF promotes atrial arrhythmia in association with atrial alternans.


Assuntos
Remodelamento Atrial , Insuficiência Cardíaca/fisiopatologia , Potenciais de Ação , Algoritmos , Animais , Fibrilação Atrial/fisiopatologia , Sinalização do Cálcio , Proteínas de Ligação ao Cálcio/metabolismo , Simulação por Computador , Cães , Condutividade Elétrica , Átrios do Coração/fisiopatologia , Ventrículos do Coração/fisiopatologia , Humanos , Camundongos , Modelos Cardiovasculares , Contração Miocárdica , Miócitos Cardíacos/patologia , Fosforilação , Retículo Sarcoplasmático/metabolismo
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