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BACKGROUND: PINNACLE FLX (Protection Against Embolism for Nonvalvular AF Patients: Investigational Device Evaluation of the WATCHMAN FLX LAA Closure Technology) demonstrated improved outcomes and low incidence of adverse events with the WATCHMAN FLX device in a controlled setting. The National Cardiovascular Disease Registry's Left Atrial Appendage Occlusion Registry was utilized to assess the safety and effectiveness of WATCHMAN FLX in contemporary clinical practice in the United States. METHODS: The WATCHMAN FLX Device Surveillance Post Approval Analysis Plan used data from the Left Atrial Appendage Occlusion registry to identify patients undergoing WATCHMAN FLX implantation between August 2020 and September 2022. The key safety end point was defined as all-cause death, ischemic stroke, systemic embolism, or device or procedure-related events requiring open cardiac surgery or major endovascular intervention between device implantation and hospital discharge. Major adverse events were reported at hospital discharge, 45 days, and 1 year. RESULTS: Among 97 185 patients in the Left Atrial Appendage Occlusion registry undergoing WATCHMAN FLX, successful implantation occurred in 97.5% (n=94 784) of patients. The key safety end point occurred in 0.45% of patients. At 45 days post-procedure, all-cause death occurred in 0.81% patients, ischemic stroke in 0.23%, major bleeding in 3.1%, pericardial effusion requiring intervention in 0.50%, device-related thrombus in 0.44%, and device embolism in 0.04% patients. No peri-device leak was observed in 83.1% of patients at 45 days. At 1 year, the rate of all-cause death was 8.2%, the rate of any stroke was 1.5% (ischemic stroke, 1.2%), and major bleeding occurred in 6.4% of patients. CONCLUSIONS: In a large contemporary cohort of patients with the WATCHMAN FLX device, the rates of implant success and clinical outcomes through 1 year were comparable with the PINNACLE FLX study, demonstrating that favorable outcomes achieved in the pivotal approval study can be replicated in routine clinical practice.
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AIMS: The FLXibility Post-Approval Study collected data on unselected patients implanted with a WATCHMAN FLX in a commercial clinical setting. METHODS AND RESULTS: Patients were implanted with a WATCHMAN FLX per local standard of care, with a subsequent first follow-up visit from 45 to 120 days post-implant and a final follow-up at 1-year post-procedure. A Clinical Event Committee adjudicated all major adverse events and TEE/CT imaging results were adjudicated by a core laboratory. Among 300 patients enrolled at 17 centres in Europe, the mean age was 74.6 ± 8.0 years, mean CHA2DS2-VASc score was 4.3 ± 1.6, and 62.1% were male. The device was successfully implanted in 99.0% (297/300) of patients. The post-implant medication regimen was DAPT for 87.3% (262/300). At first follow-up, core-lab adjudicated complete seal was 88.2% (149/169), 9.5% (16/169) had leak <3 mm, 2.4 (4/169) had leak ≥3 mm to ≤5 mm, and 0% had >5 mm leak. At 1 year, 93.3% (280/300) had final follow-up; 60.5% of patients were on a single antiplatelet medication, 21.4% were on DAPT, 5.6% were on direct oral anticoagulation, and 12.1% were not taking any antiplatelet/anticoagulation medication. Adverse event rates through 1 year were: all-cause death 10.8% (32/295); CV/unexplained death 5.1% (15/295); disabling and non-disabling stroke each 1.0% (3/295, all non-fatal); pericardial effusion requiring surgery or pericardiocentesis 1.0% (3/295); and device-related thrombus 2.4% (7/295). CONCLUSION: The WATCHMAN FLX device had excellent procedural success rates, high LAA seal rates, and low rates of thromboembolic events in everyday clinical practice.
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Apêndice Atrial , Fibrilação Atrial , Acidente Vascular Cerebral , Humanos , Masculino , Idoso , Idoso de 80 Anos ou mais , Feminino , Inibidores da Agregação Plaquetária/uso terapêutico , Apêndice Atrial/diagnóstico por imagem , Apêndice Atrial/cirurgia , Resultado do Tratamento , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/cirurgia , Fibrilação Atrial/complicações , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Anticoagulantes/efeitos adversos , Cateterismo Cardíaco/efeitos adversos , Ecocardiografia TransesofagianaRESUMO
Objectives: The PROGRESS PVL registry evaluated transcatheter aortic valve implantation (TAVI) in patients treated with ACURATE neo, a supra-annular self-expanding bioprosthetic aortic valve. Background: While clinical outcomes with TAVI are comparable with those achieved with surgery, residual aortic regurgitation (AR) and paravalvular leak (PVL) are common complications. The ACURATE neo valve has a pericardial sealing skirt designed to minimize PVL. Methods: The primary endpoint was the rate of total AR over time, as assessed by a core echocardiographic laboratory. The study enrolled 500 patients (mean age: 81.8 ± 5.1 years; 61% female; mean baseline STS score: 6.0 ± 4.5%) from 22 centers in Europe and Canada; 498 patients were treated with ACURATE neo. Results: The rate of ≥ moderate AR was 4.6% at discharge and 3.1% at 12 months; the rate of ≥ moderate PVL was 4.6% at discharge and 2.6% at 12 months. Paired analyses showed significant improvement in overall PVL between discharge and 12 months (P < 0.001); 64.6% of patients had no change in PVL grade, 24.9% improved, and 10.5% worsened. Patients also exhibited significant improvement in transvalvular gradient (P < 0.001) and effective orifice area (P=0.01). The mortality rate was 2.2% at 30 days and 11.3% at 12 months. The permanent pacemaker implantation (PPI) rate was 10.2% at 30 days and 12.2% at 12 months. Conclusions: Results from PROGRESS PVL support the sustained safety and performance of TAVI with the ACURATE neo valve, showing excellent valve hemodynamics, good clinical outcomes, and significant interindividual improvement in PVL from discharge to 12-month follow-up.
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Insuficiência da Valva Aórtica , Estenose da Valva Aórtica , Próteses Valvulares Cardíacas , Substituição da Valva Aórtica Transcateter , Idoso , Idoso de 80 Anos ou mais , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/cirurgia , Insuficiência da Valva Aórtica/etiologia , Insuficiência da Valva Aórtica/cirurgia , Estenose da Valva Aórtica/cirurgia , Feminino , Próteses Valvulares Cardíacas/efeitos adversos , Humanos , Masculino , Desenho de Prótese , Sistema de Registros , Substituição da Valva Aórtica Transcateter/métodos , Resultado do TratamentoRESUMO
The aim of this study was to determine the ability of multiparametric MRI to identify the early effects of individual treatment, during combined chemo-radiotherapy on brain tumours. Eighty male rats bearing 9L gliosarcomas were randomized into four groups: untreated, anti-angiogenic therapy (SORA group), microbeam radiation therapy (MRT group) and both treatments (MRT+SORA group). Multiparametric MRI (tumour volume, diffusion-weighted MR imaging (ADC), blood volume fraction (BVf), microvessel index (VSI), vessel wall integrity (AUC(P846)) and tissue oxygen saturation (StO2)) was performed 1 day before and 2, 5 and 8 days after treatment initiation. Unpaired t-tests and one-way ANOVA were used for statistical analyses. Each MR parameter measured in our protocol was revealed to be sensitive to tumour changes induced by any of the therapies used (individually or combined). When compared with untreated tumours, SORA induced a decrease in BVf, VSI, StO2 and AUC(P846), MRT generated an increase in ADC and AUC(P846) and combined therapies yielded mixed effects: an increase in ADC and AUC(P846) and a decrease in BVf, StO2 and AUC(P846). MRT and MRT+SORA significantly slowed tumour growth. Despite these two groups presenting with similar tumour sizes, the information yielded from MR multiparameter assessment indicated that, when used concomitantly, each therapy induced distinguishable and appreciable physiological changes in the tumour. Our results suggest that multiparametric MRI can monitor the effects of individual treatments, used concomitantly, on brain tumours. Such monitoring would be useful for the detection of tumour resistance to drug/radiotherapy in patients undergoing concomitant therapies.
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Neoplasias Encefálicas/terapia , Imageamento por Ressonância Magnética/métodos , Inibidores da Angiogênese/uso terapêutico , Animais , Biomarcadores , Neoplasias Encefálicas/patologia , Masculino , Medicina de Precisão , Ratos , Ratos Endogâmicos F344RESUMO
BACKGROUND: The TAXUS Liberté Post Approval Study (TL-PAS) contributed patients treated with TAXUS Liberté paclitaxel-eluting stent and prasugrel to the Dual Antiplatelet Therapy Study (DAPT) that compared 12 and 30 months thienopyridine plus aspirin therapy after drug-eluting stents. METHODS AND RESULTS: Outcomes for 2191 TL-PAS patients enrolled into DAPT were assessed. The DAPT coprimary composite end point (death, myocardial infarction [MI], or stroke) was lower with 30 compared with 12 months prasugrel treatment (3.7% versus 8.8%; hazard ratio [HR], 0.407; P<0.001). Rates of death and stroke were similar between groups, but MI was significantly reduced with prolonged prasugrel treatment (1.9% versus 7.1%; HR, 0.255; P<0.001). The DAPT coprimary end point, stent thrombosis, was also lower with longer therapy (0.2% versus 2.9%; HR, 0.063; P<0.001). MI related to stent thrombosis (0% versus 2.6%; P<0.001) and occurring spontaneously (1.9% versus 4.5%; HR, 0.407; P=0.007) were both reduced with prolonged prasugrel. MI rates increased within 90 days of prasugrel cessation after both 12 and 30 months treatment. Composite Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) moderate or severe bleeds were modestly increased (2.4% versus 1.7%; HR, 1.438; P=0.234) but severe bleeds were not more frequent (0.3% versus 0.5%; HR, 0.549; P=0.471) in the prolonged treatment group. CONCLUSIONS: Prasugrel and aspirin continued for 30 months reduced ischemic events for the TAXUS Liberté paclitaxel-eluting stent patient subset from DAPT through reductions in MI and stent thrombosis. Withdrawal of prasugrel was followed by an increase in MI after both 12 and 30 months therapy. The optimal duration of dual antiplatelet therapy with prasugrel after TAXUS Liberté paclitaxel-eluting stent remains unknown, but appears to be >30 months. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00997503.
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Aspirina/uso terapêutico , Doença das Coronárias/terapia , Stents Farmacológicos , Paclitaxel/uso terapêutico , Piperazinas/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Tiofenos/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Incidência , Internacionalidade , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Inibidores da Agregação Plaquetária/uso terapêutico , Cloridrato de Prasugrel , Piridinas/uso terapêutico , Fatores de Tempo , Resultado do TratamentoRESUMO
A quantitative estimate of cerebral blood oxygen saturation is of critical importance in the investigation of cerebrovascular disease. While positron emission tomography can map in vivo the oxygen level in blood, it has limited availability and requires ionizing radiation. Magnetic resonance imaging (MRI) offers an alternative through the blood oxygen level-dependent contrast. Here, we describe an in vivo and non-invasive approach to map brain tissue oxygen saturation (StO2) with high spatial resolution. StO2 obtained with MRI correlated well with results from blood gas analyses for various oxygen and hematocrit challenges. In a stroke model, the hypoxic areas delineated in vivo by MRI spatially matched those observed ex vivo by pimonidazole staining. In a model of diffuse traumatic brain injury, MRI was able to detect even a reduction in StO2 that was too small to be detected by histology. In a F98 glioma model, MRI was able to map oxygenation heterogeneity. Thus, the MRI technique may improve our understanding of the pathophysiology of several brain diseases involving impaired oxygenation.
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Lesões Encefálicas/diagnóstico por imagem , Lesões Encefálicas/metabolismo , Imageamento por Ressonância Magnética , Oxigênio/metabolismo , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/metabolismo , Animais , Gasometria/métodos , Modelos Animais de Doenças , Masculino , Radiografia , Ratos , Ratos Endogâmicos F344 , Ratos WistarRESUMO
PURPOSE: Synchrotron microbeam radiation therapy (MRT) is an innovative irradiation modality based on spatial fractionation of a high-dose X-ray beam into lattices of microbeams. The increase in lifespan of brain tumor-bearing rats is associated with vascular damage but the physiological consequences of MRT on blood vessels have not been described. In this manuscript, we evaluate the oxygenation changes induced by MRT in an intracerebral 9L gliosarcoma model. METHODS: Tissue responses to MRT (two orthogonal arrays (2 × 400Gy)) were studied using magnetic resonance-based measurements of local blood oxygen saturation (MR_SO2) and quantitative immunohistology of RECA-1, Type-IV collagen and GLUT-1, marker of hypoxia. RESULTS: In tumors, MR_SO2 decreased by a factor of 2 in tumor between day 8 and day 45 after MRT. This correlated with tumor vascular remodeling, i.e. decrease in vessel density, increases in half-vessel distances (×5) and GLUT-1 immunoreactivity. Conversely, MRT did not change normal brain MR_SO2, although vessel inter-distances increased slightly. CONCLUSION: We provide new evidence for the differential effect of MRT on tumor vasculature, an effect that leads to tumor hypoxia. As hypothesized formerly, the vasculature of the normal brain exposed to MRT remains sufficiently perfused to prevent any hypoxia.
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Neoplasias Encefálicas/radioterapia , Encéfalo/efeitos da radiação , Gliossarcoma/radioterapia , Oxigênio/sangue , Síncrotrons , Terapia por Raios X/métodos , Animais , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/metabolismo , Gliossarcoma/irrigação sanguínea , Gliossarcoma/metabolismo , Transportador de Glucose Tipo 1/análise , Imageamento por Ressonância Magnética , RatosRESUMO
BACKGROUND: Macrophages predominate among the inflammatory cells in rejecting allografts. These innate immune cells, in addition to allospecific T cells, can damage cardiomyocytes directly. METHODS AND RESULTS: We explored whether sensitive positron emission tomography-computed tomography (PET-CT) imaging of macrophages-avid nanoparticles detects rejection of heart allografts in mice. In addition, we used the imaging method to follow the immunomodulatory impact of angiotensin-converting enzyme inhibitor therapy on myeloid cells in allografts. Dextran nanoparticles were derivatized with the PET isotope copper-64 and imaged 7 days after transplantation. C57BL/6 recipients of BALB/c allografts displayed robust positron emission tomography signal (standard uptake value allograft, 2.8±0.3; isograft control, 1.7±0.2; P<0.05). Autoradiography and scintillation counting confirmed the in vivo findings. We then imaged the effects of angiotensin-converting enzyme inhibitor (5 mg/kg enalapril). Angiotensin-converting enzyme inhibitor significantly decreased nanoparticle signal (P<0.05). Histology and flow cytometry showed a reduced number of myeloid cells in the graft, blood, and lymph nodes and diminished antigen presentation (P<0.05 versus untreated allografts). Angiotensin-converting enzyme inhibitor also significantly prolonged allograft survival (12 versus 7 days; P<0.0001). CONCLUSIONS: Nanoparticle macrophage PET-CT detects heart transplant rejection and predicts organ survival by reporting on myeloid cells.
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Rejeição de Enxerto/diagnóstico por imagem , Rejeição de Enxerto/imunologia , Transplante de Coração/imunologia , Coração/diagnóstico por imagem , Imagem Multimodal , Miocárdio/imunologia , Nanomedicina/métodos , Nanopartículas , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Radioisótopos de Cobre , Enalapril/farmacologia , Feminino , Citometria de Fluxo , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Coração/efeitos dos fármacos , Transplante de Coração/efeitos adversos , Imunossupressores/farmacologia , Macrófagos/diagnóstico por imagem , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Valor Preditivo dos Testes , Compostos Radiofarmacêuticos , Fatores de TempoRESUMO
The quantification of bolus-tracking MRI techniques remains challenging. The acquisition usually relies on one contrast and the analysis on a simplified model of the various phenomena that arise within a voxel, leading to inaccurate perfusion estimates. To evaluate how simplifications in the interstitial model impact perfusion estimates, we propose a numerical tool to simulate the MR signal provided by a dynamic contrast enhanced (DCE) MRI experiment. Our model encompasses the intrinsic R1 and R2 relaxations, the magnetic field perturbations induced by susceptibility interfaces (vessels and cells), the diffusion of the water protons, the blood flow, the permeability of the vessel wall to the the contrast agent (CA) and the constrained diffusion of the CA within the voxel. The blood compartment is modeled as a uniform compartment. The different blocks of the simulation are validated and compared to classical models. The impact of the CA diffusivity on the permeability and blood volume estimates is evaluated. Simulations demonstrate that the CA diffusivity slightly impacts the permeability estimates (< 5% for classical blood flow and CA diffusion). The effect of long echo times is investigated. Simulations show that DCE-MRI performed with an echo time TE = 5 ms may already lead to significant underestimation of the blood volume (up to 30% lower for brain tumor permeability values). The potential and the versatility of the proposed implementation are evaluated by running the simulation with realistic vascular geometry obtained from two photons microscopy and with impermeable cells in the extravascular environment. In conclusion, the proposed simulation tool describes DCE-MRI experiments and may be used to evaluate and optimize acquisition and processing strategies.
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Simulação por Computador , Meios de Contraste , Aumento da Imagem/métodos , Imageamento por Ressonância Magnética/métodos , Algoritmos , Vasos Sanguíneos , Meios de Contraste/metabolismo , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Permeabilidade , Fluxo Sanguíneo Regional , Reprodutibilidade dos TestesRESUMO
The purpose of this study was to estimate magnetic resonance imaging-based brain perfusion parameters from combined multiecho spin-echo and gradient-echo acquisitions, to correct them for T1â, T2â, and T2â*-related contrast agent (CA) extravasation effects, and to simultaneously determine vascular permeability. Perfusion data were acquired using a combined multiecho spin- and gradient-echo (SAGE) echo-planar imaging sequence, which was corrected for CA extravasation effects using pharmacokinetic modeling. The presented method was validated in simulations and brain tumor patients, and compared with uncorrected single-echo and multiecho data. In the presence of CA extravasation, uncorrected single-echo data resulted in underestimated CA concentrations, leading to underestimated single-echo cerebral blood volume (CBV) and mean transit time (MTT). In contrast, uncorrected multiecho data resulted in overestimations of CA concentrations, CBV, and MTT. The correction of CA extravasation effects resulted in CBV and MTT estimates that were more consistent with the underlying tissue characteristics. Spin-echo perfusion data showed reduced large-vessel blooming effects, facilitating better distinction between increased CBV due to active tumor progression and elevated CBV due to the presence of cortical vessels in tumor proximity. Furthermore, extracted permeability parameters were in good agreement with elevated T1-weighted postcontrast signal values.
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Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/patologia , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Meios de Contraste , Angiografia por Ressonância Magnética/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Encéfalo/metabolismo , Neoplasias Encefálicas/metabolismo , Permeabilidade Capilar , Circulação Cerebrovascular , Meios de Contraste/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos BiológicosRESUMO
PURPOSE: To assess the reproducibility of the magnetic resonance (MR) estimate of blood oxygen saturation (sO(2)) in the rat brain, to evaluate the relationship between low MR estimate of sO(2) values and tissue hypoxia in a hypoxic and necrotic glioscarcoma model (9L gliosarcoma cells), and to evaluate the capability of the MR estimate of sO(2) parameter to help identify modifications induced by an antiangiogenic treatment (sorafenib) in 9L gliosarcoma tumors. MATERIALS AND METHODS: Experiments were performed with permits from the French Ministry of Agriculture. Forty-eight male rats bearing a 9L gliosarcoma were randomized in untreated and treated (sorafenib) groups. MR blood volume fraction and MR estimate of sO(2) parameters were estimated 1 day before and 1, 3, 5, and 8 days after the start of the treatment. The in vivo MR estimate of sO(2) measurement was correlated with the ex vivo hypoxia assessment by using pimonidazole staining. Paired and unpaired t tests, as well as parametric Pearson tests, were used for the statistical analyses. RESULTS: In healthy tissues, MR estimate of sO(2) measurements were comparable to literature values and were reproducible (mean across all animals, 68.0% ± 6.5 [standard deviation]). In untreated tumors, MR estimate of sO(2) and immunohistochemical analysis yielded correlated fractional hypoxic-necrotic areas (R(2) = 0.81). In tumors treated with antiangiogenic therapy, tumor MR estimate of sO(2) was decreased with respect to the healthy tissue (P< .001). CONCLUSION: Results of this study suggest that the MR estimate of sO(2) is a reproducible estimate that could be used as an in vivo probe of hypoxia in brain tumors and as a sensitive reporter of the hypoxic effects of antiangiogenic therapies.
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Inibidores da Angiogênese/farmacologia , Benzenossulfonatos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Gliossarcoma/tratamento farmacológico , Gliossarcoma/metabolismo , Imageamento por Ressonância Magnética/métodos , Oxigênio/sangue , Piridinas/farmacologia , Análise de Variância , Animais , Dextranos/administração & dosagem , Hipóxia Encefálica/metabolismo , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Modelos Lineares , Nanopartículas de Magnetita/administração & dosagem , Masculino , Niacinamida/análogos & derivados , Nitroimidazóis/administração & dosagem , Compostos de Fenilureia , Distribuição Aleatória , Ratos , Ratos Endogâmicos F344 , Reprodutibilidade dos Testes , SorafenibeRESUMO
Functional MRI (fMRI) brain studies performed in the presence of a steady-state or "blood pool" contrast agent yields activation maps that are weighted for cerebral blood volume (CBV). Previous animal experiments suggest significant contrast-to-noise ratio (CNR) improvements, but these studies have not yet been performed in humans due to the lack of availability of a suitable agent. Here we report the use of the USPIO ferumoxytol (AMAG Pharmaceuticals, Inc., Cambridge, MA) for functional brain activation in humans, termed contrast enhanced functional blood volume imaging (CE-fBVI). Four subjects were scanned during a unilateral finger tapping task with standard blood-oxygen level dependent (BOLD) imaging before contrast and CE-fBVI after contrast injection. The CE-fBVI response showed both a fast (5.8±1.3 s) and a slow (75.3±27.5 s) component of CBV response to stimuli. A significant CNR gain of approximately 2-3 was found for CE-fBVI compared to BOLD fMRI. Interestingly, less susceptibility-related signal dropouts were observed in the inferior frontal and temporal lobes with CE-fBVI. The combination of higher CNR and better spatial specificity, enabled by CE-fBVI using blood pool USPIO contrast agent opens the door to higher resolution brain mapping.
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Determinação do Volume Sanguíneo/métodos , Mapeamento Encefálico/métodos , Encéfalo/fisiologia , Meios de Contraste , Óxido Ferroso-Férrico , Imageamento por Ressonância Magnética/métodos , Adulto , Volume Sanguíneo/fisiologia , Humanos , Interpretação de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Desempenho Psicomotor/fisiologia , Razão Sinal-Ruído , Adulto JovemRESUMO
PURPOSE: To analyze the contribution of the transverse relaxation parameter (T2), macroscopic field inhomogeneities (B0), and blood volume fraction (BVf) to blood oxygen level-dependent (BOLD)-based magnetic resonance (MR) measurements of blood oxygen saturation (SO2) obtained in a brain tumor model. MATERIALS AND METHODS: This study was approved by the local committee for animal care and use. Experiments were performed in accordance with permit 380 820 from the French Ministry of Agriculture. The 9L gliosarcoma cells were implanted in the brain of eight rats. Fifteen days later, 4.7-T MR examinations were performed to estimate T2*, T2, BVf, and T2*ΔB0corrected in the tumor and contralateral regions. MR estimates of SO2 were derived by combining T2, BVf, and T2*ΔB0corrected according to a recently described quantitative BOLD approach. Scatterplots and linear regression analysis were used to identify correlation between parameters. Paired Student t tests were used to compare the tumor region with the contralateral region. RESULTS: No significant correlations were found between T2* and any parameter in either tumor tissue or healthy tissue. T2* in the tumor and T2* in the uninvolved contralateral brain were the same (36 msec±4 [standard deviation] vs 36 msec±5, respectively), which might suggest similar oxygenation. Adding T2 information (98 msec±7 vs 68 msec±2, respectively) alone yields results that suggest apparent hypo-oxygenation of the tumor, while incorporating BVf (5.3%±0.6 vs 2.6%±0.3, respectively) alone yields results that suggest apparent hyperoxygenation. MR estimates of SO2 obtained with a complete quantitative BOLD analysis, although not correlated with T2* values, suggest normal oxygenation (68%±3 vs 65%±4, respectively). MR estimates of SO2 obtained in the contralateral tissue agree with previously reported values. CONCLUSION: Additional measurements, such as BVf, T2, and B0, are needed to obtain reliable information on oxygenation with BOLD MR imaging. The proposed quantitative BOLD approach, which includes these measurements, appears to be a promising tool with which to map tumor oxygenation.
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Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/metabolismo , Glioblastoma/diagnóstico , Glioblastoma/metabolismo , Imageamento por Ressonância Magnética/métodos , Oximetria/métodos , Oxigênio/análise , Animais , Linhagem Celular Tumoral , Masculino , Ratos , Ratos Endogâmicos F344 , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Vessel size index (VSI), a parameter related to the distribution of vessel diameters, may be estimated using two MRI approaches: (i) dynamic susceptibility contrast (DSC) MRI following the injection of a bolus of Gd-chelate. This technique is routinely applied in the clinic to assess intracranial tissue perfusion in patients; (ii) steady-state susceptibility contrast with USPIO contrast agents, which is considered here as the standard method. Such agents are not available for human yet and the steady-state approach is currently limited to animal studies. The aim is to compare VSI estimates obtained with these two approaches on rats bearing C6 glioma (n = 7). In a first session, VSI was estimated from two consecutive injections of Gd-Chelate (Gd(1) and Gd(2)). In a second session (4 hours later), VSI was estimated using USPIO. Our findings indicate that both approaches yield comparable VSI estimates both in contralateral (VSI{USPIO} = 7.5 ± 2.0 µm, VSI{Gd(1)} = 6.5 ± 0.7 µm) and in brain tumour tissues (VSI{USPIO} = 19.4 ± 7.1 µm, VSI{Gd(1)} = 16.6 ± 4.5 µm). We also observed that, in the presence of BBB leakage (as it occurs typically in brain tumours), applying a preload of Gd-chelate improves the VSI estimate with the DSC approach both in contralateral (VSI{Gd(2)} = 7.1 ± 0.4 µm) and in brain tumour tissues (VSI{Gd(2)} = 18.5 ± 4.3 µm) but is not mandatory. VSI estimates do not appear to be sensitive to T(1) changes related to Gd extravasation. These results suggest that robust VSI estimates may be obtained in patients at 3 T or higher magnetic fields with the DSC approach.
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Vasos Sanguíneos/patologia , Neoplasias Encefálicas/irrigação sanguínea , Meios de Contraste , Dextranos , Gadolínio , Glioma/irrigação sanguínea , Imageamento por Ressonância Magnética/métodos , Nanopartículas de Magnetita , Animais , Linhagem Celular Tumoral , Difusão , Modelos Animais de Doenças , Humanos , Masculino , Transplante de Neoplasias , Tamanho do Órgão , Ratos , Ratos WistarRESUMO
OBJECTIVES: This study investigated the regulation of glucose uptake in cells that participate in atherogenesis by stimuli relevant to this process, to gain mechanistic insight into the origin of the (18)fluorine-labeled 2-deoxy-D-glucose (FdG) uptake signals observed clinically. BACKGROUND: Patient studies suggest that positron emission tomography (PET) using FdG can detect "active" atherosclerotic plaques, yet the mechanism giving rise to FdG signals remains unknown. METHODS: We exposed cells to conditions thought to operate in atheroma and determined rates of glucose uptake. RESULTS: Hypoxia, but not pro-inflammatory cytokines, potently stimulated glucose uptake in human macrophages and foam cells. Statins attenuated this process in vitro, suggesting that these agents have a direct effect on human macrophages. Immunohistochemical study of human plaques revealed abundant expression of proteins regulating glucose utilization, predominantly in macrophage-rich regions of the plaques-regions previously proved hypoxic. Smooth-muscle cells and endothelial cells markedly increased rates of glucose uptake when exposed to pro-inflammatory cytokines. CONCLUSIONS: Glucose uptake and, probably, FdG uptake signals in atheroma may reflect hypoxia-stimulated macrophages rather than mere inflammatory burden. Cytokine-activated smooth-muscle cells also may contribute to the FdG signal.
Assuntos
Aterosclerose/diagnóstico por imagem , Aterosclerose/terapia , Glucose/farmacocinética , Hipóxia , Inflamação , Macrófagos/efeitos dos fármacos , Aorta/patologia , Aterosclerose/patologia , Citocinas/metabolismo , Células Endoteliais/citologia , Fluordesoxiglucose F18/farmacologia , Células Espumosas/metabolismo , Glucose/metabolismo , Humanos , Hidrólise , Macrófagos/metabolismo , Monócitos/citologia , Miócitos de Músculo Liso/metabolismo , Tomografia por Emissão de Pósitrons/métodosRESUMO
Early imaging or blood biomarkers of tumor response is needed to customize anti-tumor therapy on an individual basis. This study evaluates the sensitivity and relevance of five potential MRI biomarkers. Sixty nude rats were implanted with human glioma cells (U-87 MG) and randomized into three groups: one group received an anti-angiogenic treatment (Sorafenib), a second a cytotoxic drug [1,3-bis(2-chloroethyl)-1-nitrosourea, BCNU (Carmustine)] and a third no treatment. The tumor volume, apparent diffusion coefficient (ADC) of water, blood volume fraction (BVf), microvessel diameter (vessel size index, VSI) and vessel wall integrity (contrast enhancement, CE) were monitored before and during treatment. Sorafenib reduced tumor CE as early as 1 day after treatment onset. By 4 days after treatment onset, tumor BVf was reduced and tumor VSI was increased. By 14 days after treatment onset, ADC was increased and the tumor growth rate was reduced. With BCNU, ADC was increased and the tumor growth rate was reduced 14 days after treatment onset. Thus, the estimated MRI parameters were sensitive to treatment at different times after treatment onset and in a treatment-dependent manner. This study suggests that multiparametric MR monitoring could allow the assessment of new anti-tumor drugs and the optimization of combined therapies.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Glioma/tratamento farmacológico , Glioma/patologia , Imageamento por Ressonância Magnética/métodos , Inibidores da Angiogênese/farmacologia , Animais , Benzenossulfonatos/farmacologia , Benzenossulfonatos/uso terapêutico , Volume Sanguíneo/efeitos dos fármacos , Carmustina/farmacologia , Carmustina/uso terapêutico , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Glioma/irrigação sanguínea , Humanos , Masculino , Microvasos/efeitos dos fármacos , Microvasos/patologia , Modelos Biológicos , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/farmacologia , Piridinas/uso terapêutico , Ratos , Ratos Nus , Sorafenibe , Coloração e Rotulagem , Análise de SobrevidaRESUMO
AIM: prostaglandin E(2), by ligation of its receptor EP4, suppresses the production of inflammatory cytokines and chemokines in macrophages in vitro. Thus, activation of EP4 may constitute an endogenous anti-inflammatory pathway. This study investigated the role of EP4 in atherosclerosis in vivo, and particularly its impact on inflammation. METHODS AND RESULTS: Ldlr(-/-) mice transplanted with EP4(+/+) or EP4(-/-) bone marrow consumed a high-fat diet for 5 or 10 weeks. Allogenic bone marrow transplantation promoted exacerbation of atherosclerosis irrespective of EP4 genotype, compatible with prior observations of exacerbated atherogenesis by allogenicity. EP4 deficiency had little effect on plaque size or morphology in early atherosclerosis, but at the later time point, mice deficient in EP4 displayed enhanced inflammation in their atherosclerotic plaques. Expression of monocyte chemoattractant protein-1 and interferon-γ inducible protein 10 increased, and there was a corresponding increase in macrophage and T-cell infiltration. These plaques also contained fewer smooth muscle cells. Despite these changes, mice deficient in EP4 in bone marrow-derived cells at an advanced stage had similar lesion size (in both aorta and aortic root) as mice with EP4. CONCLUSION: this study shows that in advanced atherosclerosis, EP4 deficiency did not alter atherosclerotic lesion size, but yielded plaques with exacerbated inflammation and altered lesion composition.
Assuntos
Células da Medula Óssea/metabolismo , Placa Aterosclerótica/metabolismo , Receptores de Prostaglandina E Subtipo EP4/deficiência , Animais , Apoptose , Células da Medula Óssea/patologia , Transplante de Medula Óssea , Quimiocina CCL2/genética , Quimiocina CXCL10/genética , Primers do DNA/genética , Feminino , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Knockout , Modelos Cardiovasculares , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologia , Receptores de LDL/deficiência , Receptores de LDL/genética , Receptores de Prostaglandina E Subtipo EP4/genética , Receptores de Prostaglandina E Subtipo EP4/metabolismoRESUMO
BACKGROUND: Low levels of plasma adiponectin, an adipocytokine that possesses anti-inflammatory and antiatherogenic properties, frequently observed among obese subjects correlate with higher prevalence of several cardiovascular diseases. This study investigated whether adiponectin modulates allograft rejection in major histocompatibility complex class II-mismatched cardiac transplants. METHODS: We heterotopically transplanted Bm12 allografts into adiponectin-deficient (APN-/-, C57BL/6 background) or wild-type (APN+/+) mice. Some APN-/- mice received adiponectin reconstitution by adenovirus. Histologic analyses assessed allograft rejection, and real-time reverse-transcriptase polymerase chain reaction evaluated the genes for cytokines/chemokines associated with the immune and inflammatory responses. In addition, we tested the effect of adiponectin on proliferation and cytokine/chemokine production in mouse T lymphocytes stimulated in vitro with anti-CD3 antibodies. RESULTS: Allografts transplanted to APN-/- mice showed severe acute rejection relative to transplants in APN+/+ hosts accompanied by increased accumulation of CD4- and CD8-positive T lymphocytes and Mac3-positive macrophages. Adiponectin provision by adenovirus in APN-/- mice reversed these exacerbated responses to allografting. The rejected allografts in APN-/- mice contained significantly higher levels of tumor necrosis factor-alpha, interferon-gamma, and regulated on activation normal t expressed and presumably secreted. Moreover, adiponectin significantly suppressed proliferation and production of tumor necrosis factor-alpha, interferon-gamma, regulated on activation normal t expressed and presumably secreted, monocyte chemotactic protein-1, and interferon-gamma inducible protein-10 in mouse T lymphocytes stimulated in vitro with anti-CD3 antibodies. CONCLUSIONS: These observations provide new mechanistic insight into immunoregulation in allograft recipients relative to obesity, an increasingly prevalent risk factor. Adiponectin may offer a new therapeutic target for allograft rejection after cardiac transplantation.
Assuntos
Adiponectina/uso terapêutico , Rejeição de Enxerto/patologia , Rejeição de Enxerto/prevenção & controle , Transplante de Coração/imunologia , Transplante Homólogo/patologia , Adiponectina/deficiência , Animais , Quimiocinas/genética , Citocinas/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Inflamação/genética , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Baço/efeitos dos fármacos , Baço/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
BACKGROUND: Clinical detection of transplant rejection by repeated endomyocardial biopsy requires catheterization and entails risks. Recently developed molecular and cellular imaging techniques that visualize macrophage host responses could provide a noninvasive alternative. Yet, which macrophage functions may provide useful markers for detecting parenchymal rejection remains uncertain. METHODS AND RESULTS: We transplanted isografts from B6 mice and allografts from Balb/c mice heterotopically into B6 recipients. In this allograft across major histocompatability barriers, the transplanted heart undergoes predictable progressive rejection, leading to graft failure after 1 week. During rejection, crucial macrophage functions, including phagocytosis and release of proteases, render these abundant innate immune cells attractive imaging targets. Two or 6 days after transplantation, we injected either a fluorescent protease sensor or a magnetofluorescent phagocytosis marker. Histological and flow cytometric analyses established that macrophages function as the major cellular signal source. In vivo, we obtained a 3-dimensional functional map of macrophages showing higher phagocytic uptake of magnetofluorescent nanoparticles during rejection using magnetic resonance imaging and higher protease activity in allografts than in isografts using tomographic fluorescence. We further assessed the sensitivity of imaging to detect the degree of rejection. In vivo imaging of macrophage response correlated closely with gradually increasing allograft rejection and attenuated rejection in recipients with a genetically impaired immune response resulting from a deficiency in recombinase-1 (RAG-1(-/-)). CONCLUSIONS: Molecular imaging reporters of either phagocytosis or protease activity can detect cardiac allograft rejection noninvasively, promise to enhance the search for novel tolerance-inducing strategies, and have translational potential.