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1.
Arterioscler Thromb Vasc Biol ; 44(4): 976-986, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38328935

RESUMO

BACKGROUND: Plaque composition and wall shear stress (WSS) magnitude act as well-established players in coronary plaque progression. However, WSS magnitude per se does not completely capture the mechanical stimulus to which the endothelium is subjected, since endothelial cells experience changes in the WSS spatiotemporal configuration on the luminal surface. This study explores WSS profile and lipid content signatures of plaque progression to identify novel biomarkers of coronary atherosclerosis. METHODS: Thirty-seven patients with acute coronary syndrome underwent coronary computed tomography angiography, near-infrared spectroscopy intravascular ultrasound, and optical coherence tomography of at least 1 nonculprit vessel at baseline and 1-year follow-up. Baseline coronary artery geometries were reconstructed from intravascular ultrasound and coronary computed tomography angiography and combined with flow information to perform computational fluid dynamics simulations to assess the time-averaged WSS magnitude (TAWSS) and the variability in the contraction/expansion action exerted by WSS on the endothelium, quantifiable in terms of topological shear variation index (TSVI). Plaque progression was measured as intravascular ultrasound-derived percentage plaque atheroma volume change at 1-year follow-up. Plaque composition information was extracted from near-infrared spectroscopy and optical coherence tomography. RESULTS: Exposure to high TSVI and low TAWSS was associated with higher plaque progression (4.00±0.69% and 3.60±0.62%, respectively). Plaque composition acted synergistically with TSVI or TAWSS, resulting in the highest plaque progression (≥5.90%) at locations where lipid-rich plaque is exposed to high TSVI or low TAWSS. CONCLUSIONS: Luminal exposure to high TSVI, solely or combined with a lipid-rich plaque phenotype, is associated with enhanced plaque progression at 1-year follow-up. Where plaque progression occurred, low TAWSS was also observed. These findings suggest TSVI, in addition to low TAWSS, as a potential biomechanical predictor for plaque progression, showing promise for clinical translation to improve patient prognosis.


Assuntos
Doença da Artéria Coronariana , Placa Aterosclerótica , Humanos , Vasos Coronários/diagnóstico por imagem , Células Endoteliais , Doença da Artéria Coronariana/diagnóstico por imagem , Angiografia por Tomografia Computadorizada , Lipídeos , Estresse Mecânico , Angiografia Coronária
2.
Artigo em Inglês | MEDLINE | ID: mdl-39354881

RESUMO

Over the last decade, several in vivo and computational investigations have significantly advanced our understanding of the pathophysiology of coronary bifurcations, contributing to the enhancement of their percutaneous revascularization. The carina of the coronary bifurcations plays a substantial role in generating their main hemodynamic features, including distinctive flow patterns with secondary flows and specific shear stress patterns. These factors play a pivotal role in determining the susceptibility, development, and progression of atherosclerosis. The underlying pathophysiological mechanisms of atherosclerosis in coronary bifurcations are complex and multifactorial. Understanding these mechanisms is fundamental to comprehending lesions at the bifurcation level and informing future treatment strategies. This review aims to present the currently available data regarding the pathophysiological and prognostic role of the carina in coronary bifurcations, offering an interpretation of these findings from the perspective of interventional cardiologists, providing valuable insights for their clinical practice.

3.
Circ Res ; 131(3): 239-257, 2022 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-35770662

RESUMO

BACKGROUND: Conversion of cardiac stromal cells into myofibroblasts is typically associated with hypoxia conditions, metabolic insults, and/or inflammation, all of which are predisposing factors to cardiac fibrosis and heart failure. We hypothesized that this conversion could be also mediated by response of these cells to mechanical cues through activation of the Hippo transcriptional pathway. The objective of the present study was to assess the role of cellular/nuclear straining forces acting in myofibroblast differentiation of cardiac stromal cells under the control of YAP (yes-associated protein) transcription factor and to validate this finding using a pharmacological agent that interferes with the interactions of the YAP/TAZ (transcriptional coactivator with PDZ-binding motif) complex with their cognate transcription factors TEADs (TEA domain transcription factors), under high-strain and profibrotic stimulation. METHODS: We employed high content imaging, 2-dimensional/3-dimensional culture, atomic force microscopy mapping, and molecular methods to prove the role of cell/nuclear straining in YAP-dependent fibrotic programming in a mouse model of ischemia-dependent cardiac fibrosis and in human-derived primitive cardiac stromal cells. We also tested treatment of cells with Verteporfin, a drug known to prevent the association of the YAP/TAZ complex with their cognate transcription factors TEADs. RESULTS: Our experiments suggested that pharmacologically targeting the YAP-dependent pathway overrides the profibrotic activation of cardiac stromal cells by mechanical cues in vitro, and that this occurs even in the presence of profibrotic signaling mediated by TGF-ß1 (transforming growth factor beta-1). In vivo administration of Verteporfin in mice with permanent cardiac ischemia reduced significantly fibrosis and morphometric remodeling but did not improve cardiac performance. CONCLUSIONS: Our study indicates that preventing molecular translation of mechanical cues in cardiac stromal cells reduces the impact of cardiac maladaptive remodeling with a positive effect on fibrosis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Fosfoproteínas , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Fibrose , Humanos , Camundongos , Fosfoproteínas/metabolismo , Transativadores/genética , Transativadores/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ativação Transcricional , Verteporfina , Proteínas de Sinalização YAP
4.
Ann Vasc Surg ; 104: 237-247, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38492732

RESUMO

BACKGROUND: Fenestrated (FEVAR) and chimney (ChEVAR) endovascular aortic repair have been applied in anatomically suitable complex aortic aneurysms. However, local hemodynamic changes may occur after repair. This study aimed to compare FEVAR's and ChEVAR's hemodynamic properties, focusing on visceral arteries. METHODS: Preoperative and postoperative computed tomography angiographies have been used to reconstruct patient-based models. Data of 3 patients, for each modality, were analyzed. Following geometric reconstruction, computational fluid dynamics simulations were used to extract near-wall and intravascular hemodynamic indicators, such as pressure drops, velocity, wall shear stress, time averaged wall shear stress, oscillatory shear index, relative residence time, and local normalized helicity. RESULTS: An overall improvement in hemodynamics was detected after repair, with either technique. Preoperatively, a disturbed prothrombotic wall shear stress profile was recorded in several zones of the sac. The local normalized helicity results showed a better organization of the helical structures at postoperative setting, decreasing thrombus formation, with both modalities. Similarly, time averaged wall shear stress increased and oscillatory shear index decreased postoperatively, signaling nondisturbed blood flow. The relative residence time was locally reduced. The flow in visceral arteries tended to be more streamlined in ChEVAR, compared to evident recirculation regions at renal and superior mesenteric artery fenestrations (P = 0.06). CONCLUSIONS: ChEVAR and FEVAR seem to improve hemodynamics toward normal values with a reduction of recirculation zones in the main graft and aortic branches. Visceral artery flow comparison revealed that ChEVAR tended to present lower recirculation regions at parallel grafts' entries while FEVAR showed less intense flow regurgitation in visceral stents.


Assuntos
Implante de Prótese Vascular , Prótese Vascular , Angiografia por Tomografia Computadorizada , Procedimentos Endovasculares , Hemodinâmica , Modelos Cardiovasculares , Modelagem Computacional Específica para o Paciente , Desenho de Prótese , Estresse Mecânico , Humanos , Procedimentos Endovasculares/instrumentação , Procedimentos Endovasculares/efeitos adversos , Implante de Prótese Vascular/instrumentação , Implante de Prótese Vascular/efeitos adversos , Resultado do Tratamento , Velocidade do Fluxo Sanguíneo , Fatores de Tempo , Aortografia , Fluxo Sanguíneo Regional , Aneurisma da Aorta Abdominal/cirurgia , Aneurisma da Aorta Abdominal/fisiopatologia , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Idoso , Masculino , Stents , Hidrodinâmica , Correção Endovascular de Aneurisma
5.
Lancet ; 397(10270): 199-207, 2021 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-33453782

RESUMO

BACKGROUND: The accuracy of current prediction tools for ischaemic and bleeding events after an acute coronary syndrome (ACS) remains insufficient for individualised patient management strategies. We developed a machine learning-based risk stratification model to predict all-cause death, recurrent acute myocardial infarction, and major bleeding after ACS. METHODS: Different machine learning models for the prediction of 1-year post-discharge all-cause death, myocardial infarction, and major bleeding (defined as Bleeding Academic Research Consortium type 3 or 5) were trained on a cohort of 19 826 adult patients with ACS (split into a training cohort [80%] and internal validation cohort [20%]) from the BleeMACS and RENAMI registries, which included patients across several continents. 25 clinical features routinely assessed at discharge were used to inform the models. The best-performing model for each study outcome (the PRAISE score) was tested in an external validation cohort of 3444 patients with ACS pooled from a randomised controlled trial and three prospective registries. Model performance was assessed according to a range of learning metrics including area under the receiver operating characteristic curve (AUC). FINDINGS: The PRAISE score showed an AUC of 0·82 (95% CI 0·78-0·85) in the internal validation cohort and 0·92 (0·90-0·93) in the external validation cohort for 1-year all-cause death; an AUC of 0·74 (0·70-0·78) in the internal validation cohort and 0·81 (0·76-0·85) in the external validation cohort for 1-year myocardial infarction; and an AUC of 0·70 (0·66-0·75) in the internal validation cohort and 0·86 (0·82-0·89) in the external validation cohort for 1-year major bleeding. INTERPRETATION: A machine learning-based approach for the identification of predictors of events after an ACS is feasible and effective. The PRAISE score showed accurate discriminative capabilities for the prediction of all-cause death, myocardial infarction, and major bleeding, and might be useful to guide clinical decision making. FUNDING: None.


Assuntos
Síndrome Coronariana Aguda/complicações , Conjuntos de Dados como Assunto , Aprendizado de Máquina , Mortalidade , Complicações Pós-Operatórias , Adulto , Tomada de Decisão Clínica , Feminino , Hemorragia/etiologia , Humanos , Masculino
6.
Rev Cardiovasc Med ; 23(11): 377, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39076179

RESUMO

Hemodynamics interacts with the cellular components of human vessels, influencing function and healthy status. Locally acting hemodynamic forces have been associated-by a steadily increasing amount of scientific evidence-with nucleation and evolution of atherosclerotic plaques in several vascular regions, resulting in the formulation of the 'hemodynamic risk hypothesis' of the atherogenesis. At the level of coronary arteries, however, the complexity of both anatomy and physiology made the study of this vascular region particularly difficult for researchers. Developments in computational fluid dynamics (CFD) have recently allowed an accurate modelling of the intracoronary hemodynamics, thus offering physicians a unique tool for the investigation of this crucial human system by means of advanced mathematical simulations. The present review of CFD applications in coronary artery disease was set to concisely offer the medical reader the theoretical foundations of quantitative intravascular hemodynamics-reasoned schematically in the text in its basic (i.e., pressure and velocity) and derived quantities (e.g., fractional flow reserve, wall shear stress and helicity)-along with its current implications in clinical research. Moreover, attention was paid in classifying computational modelling derived from invasive and non-invasive imaging modalities with unbiased remarks on the advantages and limitations of each procedure. Finally, an extensive description-aided by explanatory figures and cross references to recent clinical findings-was presented on the role of near-wall hemodynamics, in terms of shear stress, and of intravascular flow complexity, in terms of helical flow.

7.
J Biomech Eng ; 144(6)2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35015058

RESUMO

Despite the important advancements in the stent technology for the treatment of diseased coronary arteries, major complications still affect the postoperative long-term outcome. The stent-induced flow disturbances, and especially the altered wall shear stress (WSS) profile at the strut level, play an important role in the pathophysiological mechanisms leading to stent thrombosis (ST) and in-stent restenosis (ISR). In this context, the analysis of the WSS topological skeleton is gaining more and more interest by extending the current understanding of the association between local hemodynamics and vascular diseases. This study aims to analyze the impact that a deployed coronary stent has on the WSS topological skeleton. Computational fluid dynamics (CFD) simulations were performed in three stented human coronary artery geometries reconstructed from clinical images. The selected cases presented stents with different designs (i.e., two contemporary drug-eluting stents and one bioresorbable scaffold) and included regions with stent malapposition or overlapping. A recently proposed Eulerian-based approach was applied to analyze the WSS topological skeleton features. The results highlighted that the presence of single or multiple stents within a coronary artery markedly impacts the WSS topological skeleton. In particular, repetitive patterns of WSS divergence were observed at the luminal surface, highlighting a WSS contraction action exerted proximal to the stent struts and a WSS expansion action distal to the stent struts. This WSS action pattern was independent from the stent design. In conclusion, these findings could contribute to a deeper understanding of the hemodynamics-driven processes underlying ST and ISR.


Assuntos
Vasos Coronários , Modelos Cardiovasculares , Simulação por Computador , Vasos Coronários/fisiologia , Hemodinâmica/fisiologia , Humanos , Esqueleto , Stents , Estresse Mecânico
8.
Cardiovasc Drugs Ther ; 35(6): 1171-1182, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34224052

RESUMO

PURPOSE: Higher risk of bleeding with ticagrelor over clopidogrel in elderly patients with acute coronary syndrome (ACS) who underwent percutaneous coronary intervention (PCI) has been suggested. We assessed the incidence of major bleedings (MB), reinfarction (re-MI), and all-cause death to evaluate safety and efficacy of ticagrelor versus clopidogrel in such population. METHODS: Real-world registries RENAMI and BleeMACS were merged. The pooled cohort was divided into two groups, clopidogrel versus ticagrelor. Statistical analysis considered patients <75 versus ≥75 years old. Endpoints were BARC 3-5 MB, re-MI, and all-cause death at 1-year follow-up. The study included 16,653 patients (13,153 < 75 and 3500 ≥ 75 years). Ticagrelor was underused in elderly patients (16.3% versus 20.8%, P < 0.001). Using propensity score matching (PSM), two treatment groups of 1566 patients were included in the final analysis. RESULTS: Ticagrelor was able to prevent re-MI (hazard ratio [HR], 0.31; 95% confidence interval [CI], 0.2-0.6; P < 0.001) and all-cause death (HR, 0.60; 95% CI, 0.4-0.9; P = 0.026) irrespective of age. In patients ≥75 years, ticagrelor reduced all-cause death (HR, 0.32; 95% CI, 0.1-0.8; P = 0.012) and re-MI (HR, 0.25; 95% CI, 0.1-1.1, P = 0.072). Moreover, even with the limit of the low number of events, ticagrelor did not significantly increase the incidence of MB (HR, 1.49; 95% CI, 0.70-3.0; P = 0.257). At multiple Cox regression, age (HR, 1.03; 95% CI, 1.02-1.05; P < 0.001) resulted an independent risk factor for bleeding. CONCLUSION: In our study, reflecting the results from two large retrospective, real-world registries, Ticagrelor did not significantly increase MB compared with clopidogrel in elderly patients with ACS treated with PCI, while significantly improving 1-year survival. Further studies on elderly patients are suggested.


Assuntos
Síndrome Coronariana Aguda/terapia , Clopidogrel/uso terapêutico , Intervenção Coronária Percutânea/estatística & dados numéricos , Inibidores da Agregação Plaquetária/uso terapêutico , Ticagrelor/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Clopidogrel/administração & dosagem , Clopidogrel/efeitos adversos , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Infarto do Miocárdio/epidemiologia , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/efeitos adversos , Pontuação de Propensão , Sistema de Registros , Estudos Retrospectivos , Ticagrelor/administração & dosagem , Ticagrelor/efeitos adversos
9.
Artif Organs ; 45(7): 754-761, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33326636

RESUMO

Noninvasive continuous positive airway pressure (NIV-CPAP) is effective in patients with hypoxemic respiratory failure. Building evidence during the COVID-19 emergency reported that around 50% of patients in Italy treated with NIV-CPAP avoided the need for invasive mechanical ventilation. Standard NIV-CPAP systems operate at high gas flow rates responsible for noise generation and inadequate humidification. Furthermore, open-configuration systems require a high concentration of oxygen to deliver the desired FiO2 . Concerns outlined the risk for aerosolization in the ambient air and the possible pressure drop in hospital supply pipes. A new NIV-CPAP system is proposed that includes automatic control of patient respiratory parameters. The system operates as a closed-loop breathing circuit that can be assembled, combining a sleep apnea machine with existing commercially available components. Analytical simulation of a breathing patient and simulation with a healthy volunteer at different FiO2 were performed. Inspired and expired oxygen fraction and inspired and expired carbon dioxide pressure were recorded at different CPAP levels with different oxygen delivery. Among the main findings, we report (a) a significant (up to 30-fold) reduction in oxygen feeding compared to standard open high flow NIV-CPAP systems, to assure the same FiO2 levels, and (b) a negligible production of the noise generated in ventilatory systems, and consequent minimization of patients' discomfort. The proposed NIV-CPAP circuit, reshaped in closed-loop configuration with the blower outside of the circuit, has the advantages of minimizing aerosol generation, environmental contamination, oxygen consumption, and noise to the patient. The system is easily adaptable and can be implemented using standard CPAP components.


Assuntos
COVID-19/terapia , Pressão Positiva Contínua nas Vias Aéreas/instrumentação , Pulmão/virologia , Ruído/prevenção & controle , Ventilação não Invasiva/instrumentação , Oxigênio/administração & dosagem , SARS-CoV-2/patogenicidade , Ventiladores Mecânicos , Aerossóis , COVID-19/fisiopatologia , COVID-19/transmissão , COVID-19/virologia , Simulação por Computador , Pressão Positiva Contínua nas Vias Aéreas/efeitos adversos , Desenho de Equipamento , Filtração/instrumentação , Humanos , Pulmão/fisiopatologia , Ruído/efeitos adversos , Ventilação não Invasiva/efeitos adversos , Análise Numérica Assistida por Computador , Oxigênio/efeitos adversos
10.
Am Heart J ; 220: 108-115, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31809991

RESUMO

BACKGROUND: The risk of recurrent ischemia and bleeding after percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) may vary during the first year of follow-up according to clinical presentation, and medical and interventional strategies. METHODS: BleeMACS and RENAMI are 2 multicenter registries enrolling patients with ACS treated with PCI and clopidogrel, prasugrel, or ticagrelor. The average daily ischemic and bleeding risks (ADIR and ADBR) in the first year after PCI were the primary end points. The difference between ADBR and ADIR was calculated to estimate the potential excess of bleeding/ischemic events in a given period or specific subgroup. RESULTS: A total of 19,826 patients were included. Overall, in the first year after PCI, the ADBR was 0.008085%, whereas ADIR was 0.008017% (P = .886). In the first 2 weeks ADIR was higher than ADBR (P = .013), especially in patients with ST-segment elevation myocardial infarction or incomplete revascularization. ADIR continued to be, albeit non-significantly, greater than ADBR up to the third month, whereas ADBR became higher, although not significantly, afterward. Patients with incomplete revascularization had an excess in ischemic risk (P = .003), whereas non-ST-segment elevation ACS patients and those on ticagrelor had an excess of bleeding (P = .012 and P = .022, respectively). CONCLUSIONS: In unselected ACS patients, ADIR and ADBR occurred at similar rates within 1 year after PCI. ADIR was greater than ADBR in the first 2 weeks, especially in ST-segment elevation myocardial infarction patients and those with incomplete revascularization. In the first year, ADIR was higher than ADBR in patients with incomplete revascularization, whereas ADBR was higher in non-ST-segment elevation ACS patients and in those discharged on ticagrelor.


Assuntos
Síndrome Coronariana Aguda/terapia , Hemorragia/epidemiologia , Isquemia/epidemiologia , Intervenção Coronária Percutânea/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Idoso , Clopidogrel/uso terapêutico , Feminino , Hemorragia/etiologia , Humanos , Isquemia/etiologia , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/uso terapêutico , Complicações Pós-Operatórias/etiologia , Cloridrato de Prasugrel/uso terapêutico , Recidiva , Sistema de Registros , Infarto do Miocárdio com Supradesnível do Segmento ST/complicações , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Ticagrelor/efeitos adversos , Ticagrelor/uso terapêutico , Fatores de Tempo
11.
Catheter Cardiovasc Interv ; 96(7): 1417-1422, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-30980471

RESUMO

INTRODUCTION: In new generation drug eluting stents (DESs) era, the impact of stent geometry on freedom from recurrent events has been poorly explored. Impact of struts thickness and the number of crowns and connectors on clinical outcomes were evaluated in the present study. METHODS: Randomized controlled trials comparing last generation DESs were selected. The primary endpoint was the rate of target lesion revascularization (TLR), while secondary was definite stent thrombosis (ST). RESULTS: Fifty-three studies with 52,006 patients were included. A struts thickness ≤81 nm was associated with a lower incidence of TLR (2.9%: 2.4-3.4 vs. 3.6%: 3.0-4.3) and ST (0.8%: 0.6-1.1 vs. 1.3%: 0.9-1.8). A mean number of connectors >2.5 was also associated with a lower incidence of TLR (3.2%: 2.8-3.6 vs. 3.5%: 2.9-4.2) and ST (1.0%:0.8-1.3 vs. 1.3%: 0.9-1.7 vs. for ST). On the other hand, stents with average number of crowns <7.5 did not perform better than stents with higher average number of crowns. CONCLUSIONS: The findings of the study support that lower struts thickness and higher numbers of connectors have a positive clinical outcome reducing stent thrombosis and target lesion revascularizations, while the average number of stent crowns plays a secondary role.


Assuntos
Doença da Artéria Coronariana/terapia , Trombose Coronária/prevenção & controle , Stents Farmacológicos , Intervenção Coronária Percutânea/instrumentação , Idoso , Idoso de 80 Anos ou mais , Doença da Artéria Coronariana/diagnóstico por imagem , Trombose Coronária/diagnóstico por imagem , Trombose Coronária/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Desenho de Prótese , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
12.
Catheter Cardiovasc Interv ; 96(1): 1-9, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31860158

RESUMO

OBJECTIVES: To evaluate the independent clinical impact of stent structural features in a large cohort of patients undergoing unprotected left main (ULM) or coronary bifurcation percutaneous coronary intervention (PCI) with a range of very thin strut stents. BACKGROUND: Clinical impact of structural features of contemporary stents remains to be defined. METHODS: All consecutive patients enrolled in the veRy thin stents for patients with left mAIn or bifurcatioN in real life (RAIN) registry were included. The following stent structural features were studied: antiproliferative drugs (everolimus vs. sirolimus vs. zotarolimus), strut material (platinum-chromium vs. cobalt-chromium), polymer (bioresorbable vs. durable), number of crowns (<8 vs. ≥8) and number of connectors (<3 vs. ≥3). For small diameter stents (≤2.5 mm), struct thickness (74 vs. 80/81 µm) was also tested. Target lesion failure (TLF), a composite of target lesion revascularization and stent thrombosis, was the primary endpoint. Multivariate analysis was performed with Cox regression models. RESULTS: Out of 2,707 patients, 110 (4.1%) experienced a TLF event after 16 months (12-18). After adjustment for confounders, an increased number of connectors (adjusted hazard ratio [adj-HR] 0.62, 95% confidence interval (CI) 0.39-0.99, p = .04) reduced risk of TLF, driven by stents with ≥2.5 mm diameter (HR 0.54, 95% CI 0.32-0.93, p = .02). This independent relationship was lost for stents with diameter <2.5 mm, where only strut thickness appeared to impact. Conversely, no independent relationship of polymer type, number of crowns, and the specific limus-family eluted drug with outcomes was observed. CONCLUSIONS: Among a range of contemporary very thin stent models, an increased number of connectors improved device-related outcomes in this investigated high-risk procedural setting.


Assuntos
Doença da Artéria Coronariana/terapia , Stents Farmacológicos , Intervenção Coronária Percutânea/instrumentação , Idoso , Doença da Artéria Coronariana/diagnóstico por imagem , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Desenho de Prótese , Sistema de Registros , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
13.
Biophys J ; 114(2): 323-330, 2018 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-29401430

RESUMO

The AXH domain of protein Ataxin 1 is thought to play a key role in the misfolding and aggregation pathway responsible for Spinocerebellar ataxia 1. For this reason, a molecular level understanding of AXH oligomerization pathway is crucial to elucidate the aggregation mechanism, which is thought to trigger the disease. This study employs classical and enhanced molecular dynamics to identify the structural and energetic basis of AXH tetramer stability. Results of this work elucidate molecular mechanisms behind the destabilizing effect of protein mutations, which consequently affect the AXH tetramer assembly. Moreover, results of the study draw attention for the first time, to our knowledge, to the R638 protein residue, which is shown to play a key role in AXH tetramer stability. Therefore, R638 might be also implicated in the AXH oligomerization pathway and stands out as a target for future experimental studies focused on self-association mechanisms and fibril formation of full-length ATX1.


Assuntos
Ataxinas/química , Ataxinas/genética , Mutação , Agregados Proteicos/genética , Multimerização Proteica/genética , Ataxinas/metabolismo , Simulação de Dinâmica Molecular , Estabilidade Proteica , Estrutura Quaternária de Proteína , Termodinâmica
14.
J Biomech Eng ; 140(11)2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30029263

RESUMO

Endovascular aneurysm repair (EVAR) has disseminated rapidly as an alternative to open surgical repair for the treatment of abdominal aortic aneurysms (AAAs), because of its reduced invasiveness, low mortality, and morbidity rate. The effectiveness of the endovascular devices used in EVAR is always at question as postoperative adverse events can lead to re-intervention or to a possible fatal scenario for the circulatory system. Motivated by the assessment of the risks related to thrombus formation, here the impact of two different commercial endovascular grafts on local hemodynamics is explored through 20 image-based computational hemodynamic models of EVAR-treated patients (N = 10 per each endograft model). Hemodynamic features, susceptible to promote thrombus formation, such as flow separation and recirculation, are quantitatively assessed and compared with the local hemodynamics established in image-based infrarenal abdominal aortic models of healthy subjects (N = 10). Moreover, the durability of endovascular devices is investigated analyzing the displacement forces (DFs) acting on them. The hemodynamic analysis is complemented by a geometrical characterization of the EVAR-induced reshaping of the infrarenal abdominal aortic vascular region. The findings of this study indicate that (1) the clinically observed propensity to thrombus formation in devices used in EVAR strategies can be explained in terms of local hemodynamics by means of image-based computational hemodynamics approach; (2) reportedly prothrombotic hemodynamic structures are strongly associated with the geometry of the aortoiliac tract postoperatively; and (3) DFs are associated with cross-sectional area of the aortoiliac tract postoperatively. In perspective, our study suggests that future clinical followup studies could include a geometric analysis of the region of the implant, monitoring shape variations that can lead to hemodynamic disturbances of clinical significance.

15.
Int J Mol Sci ; 19(2)2018 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-29443891

RESUMO

Alzheimer's disease is the most fatal neurodegenerative disorder characterized by the aggregation and deposition of Amyloid ß (Aß) oligomers in the brain of patients. Two principal variants of Aß exist in humans: Aß1-40 and Aß1-42. The former is the most abundant in the plaques, while the latter is the most toxic species and forms fibrils more rapidly. Interestingly, fibrils of Aß1-40 peptides can only assume U-shaped conformations while Aß1-42 can also arrange as S-shaped three-stranded chains, as recently discovered. As alterations in protein conformational arrangement correlate with cell toxicity and speed of disease progression, it is important to characterize, at molecular level, the conformational dynamics of amyloid fibrils. In this work, Replica Exchange Molecular Dynamics simulations were carried out to compare the conformational dynamics of U-shaped and S-shaped Aß17-42 small fibrils. Our computational results provide support for the stability of the recently proposed S-shaped model due to the maximized interactions involving the C-terminal residues. On the other hand, the U-shaped motif is characterized by significant distortions resulting in a more disordered assembly. Outcomes of our work suggest that the molecular architecture of the protein aggregates might play a pivotal role in formation and conformational stability of the resulting fibrils.


Assuntos
Peptídeos beta-Amiloides/química , Simulação de Dinâmica Molecular , Humanos , Domínios Proteicos , Multimerização Proteica , Estabilidade Proteica
16.
PLoS Comput Biol ; 12(1): e1004699, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26745628

RESUMO

The Josephin Domain (JD), i.e. the N-terminal domain of Ataxin 3 (At3) protein, is an interesting example of competition between physiological function and aggregation risk. In fact, the fibrillogenesis of Ataxin 3, responsible for the spinocerebbellar ataxia 3, is strictly related to the JD thermodynamic stability. Whereas recent NMR studies have demonstrated that different JD conformations exist, the likelihood of JD achievable conformational states in solution is still an open issue. Marked differences in the available NMR models are located in the hairpin region, supporting the idea that JD has a flexible hairpin in dynamic equilibrium between open and closed states. In this work we have carried out an investigation on the JD conformational arrangement by means of both classical molecular dynamics (MD) and Metadynamics employing essential coordinates as collective variables. We provide a representation of the free energy landscape characterizing the transition pathway from a JD open-like structure to a closed-like conformation. Findings of our in silico study strongly point to the closed-like conformation as the most likely for a Josephin Domain in water.


Assuntos
Ataxina-3/química , Biologia Computacional/métodos , Simulação de Dinâmica Molecular , Estrutura Terciária de Proteína , Modelos Químicos , Análise de Componente Principal , Termodinâmica
17.
Molecules ; 22(8)2017 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-28813011

RESUMO

The transcription factor p53 is a potent tumor suppressor dubbed as the "guardian of the genome" because of its ability to orchestrate protective biological outputs in response to a variety of oncogenic stresses. Mutation and thus inactivation of p53 can be found in 50% of human tumors. The majority are missense mutations located in the DNA binding region. Among them, G245S is known to be a structural hotspot mutation. To understand the behaviors and differences between the wild-type and mutant, both a dimer of the wild type p53 (wt-p53) and its G245S mutant (G245S-mp53), complexed with DNA, were simulated using molecular dynamics for more than 1 µs. wt-p53 and G245S-mp53 apo monomers were simulated for 1 µs as well. Conformational analyses and binding energy evaluations performed underline important differences and therefore provide insights to understand the G245S-mp53 loss of function. Our results indicate that the G245S mutation destabilizes several structural regions in the protein that are crucial for DNA binding when found in its apo form and highlight differences in the mutant-DNA complex structure compared to the wt protein. These findings not only provide means that can be applied to other p53 mutants but also serve as structural basis for further studies aimed at the development of cancer therapies based on restoring the function of p53.


Assuntos
Proteínas de Ligação a DNA/química , DNA/química , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/química , Apoptose/genética , Linhagem Celular Tumoral , DNA/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Humanos , Simulação de Dinâmica Molecular , Mutação Puntual/genética , Ligação Proteica , Ativação Transcricional/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
18.
Proteins ; 84(1): 52-9, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26522012

RESUMO

In this paper, we report the results of molecular dynamics simulations of AXH monomer of Ataxin-1. The AXH domain plays a crucial role in Ataxin-1 aggregation, which accompanies the initiation and progression of Spinocerebellar ataxia type 1. Our simulations involving both classical and replica exchange molecular dynamics, followed by principal component analysis of the trajectories obtained, reveal substantial conformational fluctuations of the protein structure, especially in the N-terminal region. We show that these fluctuations can be generated by thermal noise since the free energy barriers between conformations are small enough for thermally stimulated transitions. In agreement with the previous experimental findings, our results can be considered as a basis for a future design of ataxin aggregation inhibitors that will require several key conformations identified in the present study as molecular targets for ligand binding.


Assuntos
Ataxina-1/química , Ataxina-1/metabolismo , Humanos , Simulação de Dinâmica Molecular , Agregados Proteicos , Estrutura Terciária de Proteína , Ataxias Espinocerebelares/metabolismo , Termodinâmica
19.
Proteins ; 84(5): 666-73, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26879337

RESUMO

Ataxin-1 is the protein responsible for the Spinocerebellar ataxia type 1, an incurable neurodegenerative disease caused by polyglutamine expansion. The AXH domain plays a pivotal role in physiological functions of Ataxin-1. In Spinocerebellar ataxia 1, the AXH domain is involved in the misfolding and aggregation pathway. Here molecular modeling is applied to investigate the protein-protein interactions contributing to the AXH dimer stability. Particular attention is focused on: (i) the characterization of AXH monomer-monomer interface; (ii) the molecular description of the AXH monomer-monomer interaction dynamics. Technically, an approach based on functional mode analysis, here applied to replica exchange molecular dynamics trajectories, was employed. The findings of this study are consistent with previous experimental results and elucidate the pivotal role of the I580 residue in mediating the AXH monomer-monomer interaction dynamics.


Assuntos
Ataxina-1/química , Ataxina-1/metabolismo , Humanos , Simulação de Dinâmica Molecular , Ligação Proteica , Domínios Proteicos , Estabilidade Proteica , Termodinâmica
20.
Magn Reson Med ; 75(2): 873-82, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25754538

RESUMO

PURPOSE: To propose and assess a new method that automatically extracts a three-dimensional (3D) geometric model of the thoracic aorta (TA) from 3D cine phase contrast MRI (PCMRI) acquisitions. METHODS: The proposed method is composed of two steps: segmentation of the TA and creation of the 3D geometric model. The segmentation algorithm, based on Level Set, was set and applied to healthy subjects acquired in three different modalities (with and without SENSE reduction factors). Accuracy was evaluated using standard quality indices. The 3D model is characterized by the vessel surface mesh and its centerline; the comparison of models obtained from the three different datasets was also carried out in terms of radius of curvature (RC) and average tortuosity (AT). RESULTS: In all datasets, the segmentation quality indices confirmed very good agreement between manual and automatic contours (average symmetric distance < 1.44 mm, DICE Similarity Coefficient > 0.88). The 3D models extracted from the three datasets were found to be comparable, with differences of less than 10% for RC and 11% for AT. CONCLUSION: Our method was found effective on PCMRI data to provide a 3D geometric model of the TA, to support morphometric and hemodynamic characterization of the aorta.


Assuntos
Aorta Torácica/anatomia & histologia , Imageamento Tridimensional/métodos , Imagem Cinética por Ressonância Magnética/métodos , Adulto , Algoritmos , Voluntários Saudáveis , Hemodinâmica , Humanos
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