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The large melting point depressions characterising deep eutectic solvents (DESs) are related to negative deviations from ideal mixing behaviour characterised by the excess Gibbs energy. Favourable excess Gibbs energies result from a balance between the excess entropy and enthalpy of mixing, which was experimentally determined for three choline chloride (ChCl) based mixtures using calorimetry. While the excess Gibbs energy of H2O + ChCl is enthalpy dominated, those of ethylene glycol (EG) + ChCl and 1,3-propanediol + ChCl are entropy dominated. Molecular dynamics simulations using polarisable force-fields show intermolecular hydrogen bonds between DES constituents for H2O + ChCl and EG + ChCl. Hence, inter-species hydrogen bonding does not guarantee enthalpy-dominated melting point depressions. We suggest future research to focus on tuning the entropy-enthalpy balance via the chemical nature of the DES constituents.
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Porous liquids are new materials that provide permanent porosity in the liquid phase through the dispersion of nanoporous solid particles in a bulky solvent. Herein, we aim at understanding how new sustainable solvents such as deep eutectic solvent (DES) can be used to form porous stable suspensions for the capture of gases of interest for sustainable chemistry. The properties of an ionic DES, methyltriphenylphosphonium bromide/glycerol in a 1:3 molar composition, and its behavior at the interface with a metal-organic framework (MOF), ZIF-8, are here investigated by polarizable molecular dynamics simulations. The structural and dynamic properties of the DES are analyzed in the bulk liquid and in the interfacial regions with the MOF, namely, in the accessible cavities exposed at the surface. The porosity of the suspension is maintained, and it is caused not only by the Coulomb cohesive energy between cations and anions, which prevents the small anions from entering the pores, but also by the glycerol molecules not penetrating the small aperture of the ZIF-8 structure. This was further verified by simulating a system composed of glycerol and ZIF-8. Simulations with CO2 show its partition between the DES and the MOF, with higher concentrations registered in the MOF cavities.
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This Perspective points toward pathways to prepare porous ionic liquids using easily accessible materials, aiming for reduced environmental impact. We demonstrate that suspensions of porous solids are stable in eutectic mixtures, underscoring their potential for the preparation of porous ionic liquids. Porous ionic liquids retain the wide electrochemical window observed in their precursor pure ionic liquids, rendering them well-suited for green electrochemical reactions, particularly those involving gases whose solubility is enhanced in the porous suspensions. Moreover, their capacity as gas-rich media points to sustainable biomedical and pharmaceutical applications, provided nontoxic, biocompatible ionic liquids and porous solids are utilized.
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Inhibitors of poly(ADP-ribose) polymerase (PARPi) are increasingly employed as salvage therapy in epithelial ovarian cancer (EOC), but cytotoxic drug exposure along with PARP inhibition may favor development of hematological disorders. In our study, of 182 women with EOC treated with PARPi, 16 (8.7%) developed therapy-related myeloid neoplasms (t-MNs), with 12 cases of myelodysplasia and 4 of acute myeloid leukemia. All experienced persistent cytopenia after PARPi discontinuation. Seven patients had del(5q)/-5 and/or del(7q)/-7, nine had a complex karyotype and TP53 mutations, recently reported as risk factor for t-MNs in EOC post-PARPi, were found in 12 out of 13 tested patients. Four patients had a rapid and fatal outcome, one had stable disease, eleven underwent induction therapy, followed by allogeneic hematopoietic cell transplantation in seven. Three of these 11 patients experienced refractory disease, and 8 had complete remission. During a 6.8 months (range 2.3-49) median observation time, 3 out of 16 patients were alive, with one surviving patient free of both solid and hematological tumors. Ten patients died because of leukemia, two because of transplant-related events, one from heart failure. Five more patients experienced persistent cell blood count abnormalities following PARPi discontinuation, without reaching MDS diagnostic criteria. A customized Myelo-panel showed clonal hematopoiesis in all five patients. These findings confirm the actual risk of t-MNs in EOC patients after chemotherapy and prolonged PARPi therapy. The management of these patients is complex and outcomes are extremely poor. Careful diagnostic procedures are strongly recommended whenever unusual cytopenias develop in patients receiving PARPi therapy.
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Segunda Neoplasia Primária , Neoplasias Ovarianas , Carcinoma Epitelial do Ovário/tratamento farmacológico , Análise Citogenética , Feminino , Humanos , Segunda Neoplasia Primária/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Poli(ADP-Ribose) Polimerases/uso terapêutico , Terapia de SalvaçãoRESUMO
Standard chemotherapies for diffuse large B-cell lymphoma (DLBCL), based on the induction of exogenous DNA damage and oxidative stress, are often less effective in the presence of increased MYC and BCL-2 levels, especially in the case of double hit (DH) lymphomas harboring rearrangements of the MYC and BCL-2 oncogenes, which enrich for a patient's population characterized by refractoriness to anthracycline-based chemotherapy. Here we hypothesized that adaptive mechanisms to MYC-induced replicative and oxidative stress, consisting in DNA damage response (DDR) activation and BCL-2 overexpression, could represent the biologic basis of the poor prognosis and chemoresistance observed in MYC/BCL-2-positive lymphoma. We first integrated targeted gene expression profiling (T-GEP), fluorescence in situ hybridization (FISH) analysis, and characterization of replicative and oxidative stress biomarkers in two independent DLBCL cohorts. The presence of oxidative DNA damage biomarkers identified a poor prognosis double expresser (DE)-DLBCL subset, characterized by relatively higher BCL-2 gene expression levels and enrichment for DH lymphomas. Based on these findings, we tested therapeutic strategies based on combined DDR and BCL-2 inhibition, confirming efficacy and synergistic interactions in in vitro and in vivo DH-DLBCL models. These data provide the rationale for precision-therapy strategies based on combined DDR and BCL-2 inhibition in DH or DE-DLBCL.
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Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Enzimas Reparadoras do DNA/antagonistas & inibidores , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Ureia/análogos & derivados , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Taxa de Sobrevida , Ureia/farmacologia , Adulto JovemRESUMO
Recent randomized trials focused on gene expression-based determination of the cell of origin in diffuse large B-cell lymphoma could not show significant improvements by adding novel agents to standard chemoimmunotherapy. The aim of this study was the identification of a gene signature able to refine current prognostication algorithms and applicable to clinical practice. Here we used a targeted gene expression profiling panel combining the Lymph2Cx signature for cell of origin classification with additional targets including MYC, BCL-2 and NFKBIA, in 186 patients from 2 randomized trials (discovery cohort) (NCT00355199 and NCT00499018). Data were validated in 3 independent series (2 large public datasets and a real-life cohort). By integrating the cell of origin, MYC/BCL-2 double expressor status and NFKBIA expression, we defined a 3-gene signature combining MYC, BCL-2 and NFKBIA (MBN-signature), which outperformed the MYC/BCL-2 double expressor status in multivariate analysis, and allowed further risk stratification within the germinal center B-cell/unclassified subset. The high-risk (MBN Sig-high) subgroup identified the vast majority of double hit cases and a significant fraction of Activated B-Cell-derived diffuse large B-cell lymphomas. These results were validated in 3 independent series including a cohort from the REMoDL-B trial, where, in an exploratory ad hoc analysis, the addition of bortezomib in the MBN Sig-high subgroup provided a progression free survival advantage compared with standard chemoimmunotherapy. These data indicate that a simple 3-gene signature based on MYC, BCL-2 and NFKBIA could refine the prognostic stratification in diffuse large B-cell lymphoma, and might be the basis for future precision-therapy approaches.
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Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma Difuso de Grandes Células B , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Perfilação da Expressão Gênica , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Inibidor de NF-kappaB alfa , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-myc/genética , Medição de RiscoRESUMO
We investigated the occurrence and management of therapy-related hematological disorders (tr-HDs) in women with epithelial ovarian cancer (EOC) exposed to poly-ADP-ribose polymerase inhibitors (PARPi), after previous chemotherapy. We analyzed 130 consecutive EOC patients treated with PARPi at the European Institute of Oncology, Milan. In line with the literature, overall survival of the entire population was 37% at 5.5 years (89% were advanced stages). Cell blood counts were collected prior to start PARPi, at each new cycle and at monthly intervals. Patients displaying persistent and/or marked hematological abnormalities underwent bone marrow evaluation, with cytogenetic and molecular analysis. Nine patients (6,9%) developed tr-HDs, after a median 22.8 months of PARPi exposure. Two patients died early and could not be treated. Two patients have no indication for active treatment and are presently under close hematological monitoring. Five patients underwent chemotherapy followed, in three cases, by allogeneic hematopoietic transplantation: three patients are in complete remission of their hematological and gynecological malignancies at 13, 19, and 25 months; the remaining two patients died due to progression of their hematological disease. We show the potential risk of hematological disorders in EOC patients treated with chemotherapy and prolonged PARPi therapy. In our series, tr-HDs incidence was higher compared to recent reports in large series. Our observations suggest careful monitoring in order to conclusively define, on large series and prolonged follow-up, the actual risk of tr-HDs in patients under PARPi. Notably, prompt diagnosis of hematological abnormalities and appropriate management allow achievement of remission from severe hematological complications, at least in most patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Epitelial do Ovário/tratamento farmacológico , Doenças Hematológicas/diagnóstico , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Adulto , Idoso , Contagem de Células Sanguíneas , Medula Óssea/patologia , Carcinoma Epitelial do Ovário/mortalidade , Feminino , Doenças Hematológicas/induzido quimicamente , Doenças Hematológicas/epidemiologia , Doenças Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Humanos , Incidência , Pessoa de Meia-Idade , Neoplasias Ovarianas/mortalidade , Estudos Retrospectivos , Transplante HomólogoRESUMO
Among metal ß-diketonates, nickel acetylacetonate (Ni(acac)2) has been widely employed as a precursor for many chemical structures, due to its catalytic properties. Here, we investigate, by means of density functional theory (DFT) calculations, the adsorption and dissociation of this complex: after an evaluation of the structural and electronic properties of Ni(acac)2, a comparison between different dissociation patterns reveals that the most favorable pattern for the complex adsorbed on iron is different from the one suggested by considering the strength of the bonds in the isolated complex and an attempt to generalize this dissociation model is made in this work. Moreover, the most favorable adsorption configurations turned out to be a long bridge positioning of the nickel atom along with an on top positioning of the oxygen atoms of Ni(acac)2, while a short bridge positioning is the most favorable for the central metallic unit alone.
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Superior cavopulmonary circulation (SCPC) can be achieved by either the Hemi-Fontan (hF) or Bidirectional Glenn (bG) connection. Debate remains as to which results in best hemodynamic results. Adopting patient-specific multiscale computational modeling, we examined both the local dynamics and global physiology to determine if surgical choice can lead to different hemodynamic outcomes. Six patients (age: 3-6 months) underwent cardiac magnetic resonance imaging and catheterization prior to SCPC surgery. For each patient: (1) a finite 3-dimensional (3D) volume model of the preoperative anatomy was constructed to include detailed definition of the distal branch pulmonary arteries, (2) virtual hF and bG operations were performed to create 2 SCPC 3D models, and (3) a specific lumped network representing each patient's entire cardiovascular circulation was developed from clinical data. Using a previously validated multiscale algorithm that couples the 3D models with lumped network, both local flow dynamics, that is, power loss, and global systemic physiology can be quantified. In 2 patients whose preoperative imaging demonstrated significant left pulmonary artery (LPA) stenosis, we performed virtual pulmonary arterioplasty to assess its effect. In one patient, the hF model showed higher power loss (107%) than the bG, while in 3, the power losses were higher in the bG models (18-35%). In the remaining 2 patients, the power loss differences were minor. Despite these variations, for all patients, there were no significant differences between the hF and bG models in hemodynamic or physiological outcomes, including cardiac output, superior vena cava pressure, right-left pulmonary flow distribution, and systemic oxygen delivery. In the 2 patients with LPA stenosis, arterioplasty led to better LPA flow (5-8%) while halving the power loss, but without important improvements in SVC pressure or cardiac output. Despite power loss differences, both hF and bG result in similar SCPC hemodynamics and physiology outcome. This suggests that for SCPC, the pre-existing patient-specific physiology and condition, such as pulmonary vascular resistance, are more deterministic in the hemodynamic performance than the type of surgical palliation. Multiscale modeling can be a decision-assist tool to assess whether an extensive LPA reconstruction is needed at the time of SCPC for LPA stenosis.
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Técnica de Fontan , Cardiopatias Congênitas , Criança , Pré-Escolar , Técnica de Fontan/efeitos adversos , Cardiopatias Congênitas/diagnóstico por imagem , Cardiopatias Congênitas/cirurgia , Hemodinâmica , Humanos , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/cirurgia , Circulação Pulmonar , Veia Cava Superior/diagnóstico por imagem , Veia Cava Superior/cirurgiaRESUMO
Breast implant-associated anaplastic large cell lymphoma (BI-ALCL) is a variant of anaplastic large cell lymphoma arising within seroma effusion associated with breast implants. BI-ALCL is a rare disease, recently recognized as a new provisional entity by the 2017 revised World Health Organization classification. All BI-ALCLs tested so far showed a "triple-negative" genetic profile-negative for ALK, DUSP22, and TP63 rearrangements-and were characterized by mutational and gene expression profiles consistent with aberrant activation of the JAK/STAT pathway. The active form of STAT3 (pSTAT3) is constantly expressed in BI-ALCLs and may favor tumor immune escape by triggering the transcription of PDL1 (CD274), a gene encoding the immune-checkpoint molecule programmed cell death ligand 1 (PDL1); immunohistochemical positivity for PDL1 has been recently described in 3 BI-ALCL cases, and one of them also harbored PDL1 gene amplification. We evaluated PDL1 and pSTAT expression by immunohistochemistry and PDL1 copy number alterations (CNAs) at chromosome 9p24.1 by fluorescent in situ hybridization in a cohort of 9 BI-ALCL cases; we also investigated the presence of tumor-infiltrating programmed cell death 1 (PD1)+ T cells (tumor-infiltrating lymphocytes, or TILs) and PDL1+ tumor-associated macrophages (TAMs) in BI-ALCL microenvironment. Tumor cells expressed PDL1 in 5 (56%) of 9 cases and harbored PDL1 CNAs in 3 (33%) of 9 cases; immunohistochemistry for pSTAT3 was positive in all 6 cases tested (100%), indicative of active JAK/STAT signaling. We observed PDL1 CNAs only among PDL1-positive cases, whereas PD1+ TILs and PDL1+ TAMs were present at variable levels in both PDL1-positive and PDL1-negative BI-ALCLs. We report frequent PDL1 expression and recurrent PDL1 CNAs in BI-ALCLs: our data suggest that 9p24.1 alterations represent a common mechanism of PDL1 overexpression in this disease, likely acting in synergy with constitutive pSTAT3 signaling. In PDL1-positive cases without chromosomal aberration, PDL1 expression may be induced by JAK/STAT signaling alone and/or others alternative pathways. BI-ALCL microenvironment hosts variable amounts of PD1+ TILs and PDL1+ TAMs, suggesting the presence of an active PD1/PDL1 axis. These findings may be of therapeutic value in advanced-stage patients who may benefit from a PD1/PDL1 blocking treatment.
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Antígeno B7-H1/genética , Implantes de Mama/efeitos adversos , Neoplasias da Mama/genética , Variações do Número de Cópias de DNA , Linfoma Anaplásico de Células Grandes/genética , Adulto , Idoso , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/genética , Neoplasias da Mama/etiologia , Neoplasias da Mama/patologia , Feminino , Humanos , Imuno-Histoquímica , Linfoma Anaplásico de Células Grandes/etiologia , Linfoma Anaplásico de Células Grandes/patologia , Pessoa de Meia-Idade , Fosforilação , Fator de Transcrição STAT3/metabolismoRESUMO
Initial palliation for univentricular hearts can be achieved via a systemic-to-pulmonary shunt (SPS). SPS configurations differ depending on the proximal anastomosis location, which might lead to dissimilar coronary and upper body perfusions. Mathematical modeling can be used to explore the local and global hemodynamic effects of the SPSs. In literature there are few patient-specific models of SPS that specifically address the influence of both the local and peripheral vasculature. In this study, multi-domain models of univentricular circulations were developed to investigate local hemodynamics and flow distribution in the presence of two shunt configurations. We also analyzed the relative impact of local and peripheral vascular resistances on coronary perfusion and flows through the upper aortic branches. A two-step approach was followed. First, two patient-specific models were based on clinical data collected from univentricular patients having different shunts and peripheral vasculatures. Each model coupled a three-dimensional representation of SPS, aortic arch (AA) and pulmonary arteries, with a lumped parameter model (LPM) of peripheral vasculature closing the circulatory loop. Then, two additional models of hypothetical subjects were created by coupling each customized LPM with the other patient's three-dimensional anatomy. Flow rates and pressures predicted by the patient-specific models revealed overall agreement with clinical data. Differences in the local hemodynamics were seen during diastole between the two models. Varying the three-dimensional models, while keeping an identical LPM, led to comparable flow distribution through the AA, suggesting that peripheral vasculatures have a dominant effect on local hemodynamics with respect to the shunt configuration.
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Aorta Torácica/fisiopatologia , Técnica de Fontan , Ventrículos do Coração/patologia , Hemodinâmica , Modelos Cardiovasculares , Artéria Pulmonar/fisiopatologia , Artéria Pulmonar/cirurgia , Circulação Coronária , Cardiopatias Congênitas/fisiopatologia , Cardiopatias Congênitas/cirurgia , Ventrículos do Coração/fisiopatologia , HumanosRESUMO
GOAL: This manuscript evaluates atrioventric-ular valve regurgitation (AVVR) in babies born with an already very challenging heart condition, i.e., with single ventricle physiology. Although the second surgery that single ventricle patients undergo is thought to decrease AVVR, there is much controversy in the clinical literature about AVVR treatment. METHODS: The effect of AVVR on Stage 1 haemodynamics and resulting acute changes from conversion to Stage 2 circulation in single ventricle patients are analyzed through lumped parameter models. Several degrees of AVVR severity are analyzed, for two types of valve regurgitation: incomplete leaflet closure and valve prolapse. RESULTS: The models show that increasing AVVR in Stage 1 induces the following effects: first, higher stroke volume and associated decrease in ventricular end-systolic volume; second, increase in atrial volumes with V-loop enlargement in pressure-volume curves; third, pulmonary venous hypertension. The Stage 2 surgery results in volume unloading of the ventricle, thereby, driving a decrease in AVVR. However, this effect is offset by an increase in ventricular pressures resulting in a net increase in regurgitation fraction (RF) of approximately 0.1 (for example, in severe AVVR, the preoperative RF increases from 60% to 70% postoperatively). Moreover, despite some improvements to sarcomere function early after Stage 2 surgery, it may deteriorate in cases of severe AVVR. CONCLUSION: In patients with moderate to severe AVVR, restoration of atrioventricular valve competence prior to, or at the time of, Stage 2 surgery would likely lead to improved haemodynamics and clinical outcome as the models suggest that uncorrected AVVR can worsen across Stage 2 surgery. This was found to be independent of the AVVR degree and mechanisms.
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Doenças das Valvas Cardíacas/fisiopatologia , Valvas Cardíacas/fisiopatologia , Síndrome do Coração Esquerdo Hipoplásico/fisiopatologia , Modelos Cardiovasculares , Hemodinâmica/fisiologia , Humanos , LactenteRESUMO
In this study, a mathematical model of the female circulation during pregnancy is presented in order to investigate the hemodynamic response to the cardiovascular changes associated with each trimester of pregnancy. First, a preliminary lumped parameter model of the circulation of a non-pregnant female was developed, including the heart, the systemic circulation with a specific block for the uterine district and the pulmonary circulation. The model was first tested at rest; then heart rate and vascular resistances were individually varied to verify the correct response to parameter alterations characterising pregnancy. In order to simulate hemodynamics during pregnancy at each trimester, the main changes applied to the model consisted in reducing vascular resistances, and simultaneously increasing heart rate and ventricular wall volumes. Overall, reasonable agreement was found between model outputs and in vivo data, with the trends of the cardiac hemodynamic quantities suggesting correct response of the heart model throughout pregnancy. Results were reported for uterine hemodynamics, with flow tracings resembling typical Doppler velocity waveforms at each stage, including pulsatility indexes. Such a model may be used to explore the changes that happen during pregnancy in female with cardiovascular diseases.
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Coração/fisiologia , Modelos Cardiovasculares , Circulação Placentária/fisiologia , Trimestres da Gravidez/fisiologia , Gravidez/fisiologia , Circulação Pulmonar/fisiologia , Artéria Uterina/fisiologia , Velocidade do Fluxo Sanguíneo/fisiologia , Pressão Sanguínea/fisiologia , Simulação por Computador , Feminino , Frequência Cardíaca/fisiologia , Humanos , Resistência Vascular/fisiologiaRESUMO
Inverse problems in cardiovascular modelling have become increasingly important to assess each patient individually. These problems entail estimation of patient-specific model parameters from uncertain measurements acquired in the clinic. In recent years, the method of data assimilation, especially the unscented Kalman filter, has gained popularity to address computational efficiency and uncertainty consideration in such problems. This work highlights and presents solutions to several challenges of this method pertinent to models of cardiovascular haemodynamics. These include methods to (i) avoid ill-conditioning of the covariance matrix, (ii) handle a variety of measurement types, (iii) include a variety of prior knowledge in the method, and (iv) incorporate measurements acquired at different heart rates, a common situation in the clinic where the patient state differs according to the clinical situation. Results are presented for two patient-specific cases of congenital heart disease. To illustrate and validate data assimilation with measurements at different heart rates, the results are presented on a synthetic dataset and on a patient-specific case with heart valve regurgitation. It is shown that the new method significantly improves the agreement between model predictions and measurements. The developed methods can be readily applied to other pathophysiologies and extended to dynamical systems which exhibit different responses under different sets of known parameters or different sets of inputs (such as forcing/excitation frequencies).
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Frequência Cardíaca/fisiologia , Hemodinâmica/fisiologia , Modelos Cardiovasculares , HumanosRESUMO
Surgical aortic valve replacement is the most common procedure of choice for the treatment of severe aortic stenosis. Bioprosthetic valves are traditionally sewed-in the aortic root by means of pledget-armed sutures during open-heart surgery. Recently, novel bioprostheses which include a stent-based anchoring system have been introduced to allow rapid implantation, therefore reducing the duration and invasiveness of the intervention. Different effects on the hemodynamics were clinically reported associated with the two technologies. The aim of this study was therefore to investigate whether the differences in hemodynamic performances are an effect of different anchoring systems. Two commercially available bio-prosthetic aortic valves, one sewed-in with pledget-armed sutures and one rapid-deployment, were thus tested in this study by means of a combined approach of experimental and computational tools. In vitro experiments were performed to evaluate the overall hydrodynamic performance under identical standard conditions; computational fluid dynamics analyses were set-up to explore local flow variations due to different design of the anchoring system. The results showed how the performance of cardiac valve substitutes is negatively affected by the presence of pledget-armed sutures. These are causing flow disturbances, which in turn increase the mean pressure gradient and decrease the effective orifice area. The combined approach of experiments and numerical simulations can be effectively used to quantify the detailed relationship between local fluid-dynamics and overall performances associated with different valve technologies.
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Valva Aórtica/cirurgia , Implante de Prótese de Valva Cardíaca/métodos , Próteses Valvulares Cardíacas , Modelos Cardiovasculares , Suturas/efeitos adversos , Implante de Prótese de Valva Cardíaca/efeitos adversos , Hemodinâmica , HumanosRESUMO
Subclavian arteries are a possible alternate location for left ventricular assist device (LVAD) outflow grafts due to easier surgical access and application in high risk patients. As vascular blood flow mechanics strongly influence the clinical outcome, insights into the hemodynamics during LVAD support can be used to evaluate different grafting locations. In this study, the feasibility of left and right subclavian artery (SA) grafting was investigated for the HeartWare HVAD with a numerical multiscale model. A 3-D CFD model of the aortic arch was coupled to a lumped parameter model of the cardiovascular system under LVAD support. Grafts in the left and right SA were placed at three different anastomoses angles (90°, 60° and 30°). Additionally, standard grafting of the ascending and descending aorta was modelled. Full support LVAD (5l/min) and partial support LVAD (3l/min) in co-pulsation and counter-pulsation mode were analysed. The grafting positions were investigated regarding coronary and cerebral perfusion. Furthermore, the influence of the anastomosis angle on wall shear stress (WSS) was evaluated. Grafting of left or right subclavian arteries has similar hemodynamic performance in comparison to standard cannula positions. Angularity change of the graft anastomosis from 90° to 30° slightly increases the coronary and cerebral blood flow by 6-9% while significantly reduces the WSS by 35%. Cannulation of the SA is a feasible anastomosis location for the HVAD in the investigated vessel geometry.
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Simulação por Computador , Coração Auxiliar , Hemodinâmica , Hidrodinâmica , Aorta/fisiologia , Aorta Torácica/fisiologia , Cateterismo , Modelos Cardiovasculares , Artéria Subclávia/fisiologiaRESUMO
A closed-loop lumped parameter model of blood circulation is considered for single-ventricle shunt physiology. Its parameters are estimated by an inverse problem based on patient-specific haemodynamics measurements. As opposed to a black-box approach, maximizing the number of parameters that are related to physically measurable quantities motivates the present model. Heart chambers are described by a single-fibre mechanics model, and valve function is modelled with smooth opening and closure. A model for valve prolapse leading to valve regurgitation is proposed. The method of data assimilation, in particular the unscented Kalman filter, is used to estimate the model parameters from time-varying clinical measurements. This method takes into account both the uncertainty in prior knowledge related to the parameters and the uncertainty associated with the clinical measurements. Two patient-specific cases - one without regurgitation and one with atrioventricular valve regurgitation - are presented. Pulmonary and systemic circulation parameters are successfully estimated, without assumptions on their relationships. Parameters governing the behaviour of heart chambers and valves are either fixed based on biomechanics, or estimated. Results of the inverse problem are validated qualitatively through clinical measurements or clinical estimates that were not included in the parameter estimation procedure. The model and the estimation method are shown to successfully capture patient-specific clinical observations, even with regurgitation, such as the double peaked nature of valvular flows and anomalies in electrocardiogram readings. Lastly, biomechanical implications of the results are discussed.
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Doenças das Valvas Cardíacas/fisiopatologia , Ventrículos do Coração/fisiopatologia , Função Ventricular , Humanos , Modelagem Computacional Específica para o PacienteRESUMO
Single ventricle heart defects involve pathologies in which the heart has only one functional pumping chamber. In these conditions, treatment consists of three staged procedures. At stage 1 pulmonary flow is provided through an artificial shunt from the systemic circulation. Representative hemodynamics models able to explore different virtual surgical options can be built based on pre-operative imaging and patient data. In this context, the specification of boundary conditions is necessary to compute pressure and flow in the entire domain. However, these boundary conditions are rarely the measured variables. Moreover, to take into account the rest of the circulation outside of the three-dimensional modeled domain, a number of reduced order models exist. A simplified method is presented to iteratively, but automatically, tune reduced model parameters from hemodynamic data clinically measured before stage 2 surgery. Patient-specific local hemodynamics around the distal systemic-to-pulmonary shunt anastomosis and the connected pulmonary arteries are also analyzed. Multi-scale models of pre-stage 2 single ventricle patients are developed, including a 3D model of shunt-pulmonary connection and a number of pulmonary arteries. For each pulmonary outlet a total downstream resistance is identified, consistent with measured flow split and pressures. Target pressures such as minimum, maximum or average over one or both lungs are considered, depending on the clinical measurement. When possible, both steady and pulsatile identifications are performed. The methodology is demonstrated with six patient-specific models: the clinical target data are well-matched, except for one case where clinical data were subsequently found inconsistent. Inhomogeneous pressure, swirling blood flow patterns and very high wall shear stress 3D maps highlight similarities and differences among patients. Steady and pulsatile tuning results are similar. This work demonstrates (1) how to use routine clinical data to define boundary conditions for patient-specific 3D models in pre-stage 2 single ventricle circulations and (2) how simulations can help to check the coherence of clinical data, or provide insights to clinicians that are otherwise difficult to measure, such as in the presence of kinks. Finally, the choice of steady vs. pulsatile tuning, limitations and possible extensions of this work are discussed.