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1.
Heart ; 105(24): 1868-1875, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31422361

RESUMO

OBJECTIVES: Intraplaque angiogenesis and inflammation are key promoters of atherosclerosis and are mediated by the alpha-V beta-3 (αvß3) integrin pathway. We investigated the applicability of the αvß3-integrin receptor-selective positron emission tomography (PET) radiotracer 18F-fluciclatide in assessing human aortic atherosclerosis. METHODS: Vascular 18F-fluciclatide binding was evaluated using ex vivo analysis of carotid endarterectomy samples with autoradiography and immunohistochemistry, and in vivo kinetic modelling following radiotracer administration. Forty-six subjects with a spectrum of atherosclerotic disease categorised as stable (n=27) or unstable (n=19; recent myocardial infarction) underwent PET and CT imaging of the thorax after administration of 229 (IQR 217-237) MBq 18F-fluciclatide. Thoracic aortic 18F-fluciclatide uptake was quantified on fused PET-CT images and corrected for blood-pool activity using the maximum tissue-to-background ratio (TBRmax). Aortic atherosclerotic burden was quantified by CT wall thickness, plaque volume and calcium scoring. RESULTS: 18F-Fluciclatide uptake co-localised with regions of increased αvß3 integrin expression, and markers of inflammation and angiogenesis. 18F-Fluciclatide vascular uptake was confirmed in vivo using kinetic modelling, and on static imaging correlated with measures of aortic atherosclerotic burden: wall thickness (r=0.57, p=0.001), total plaque volume (r=0.56, p=0.001) and aortic CT calcium score (r=0.37, p=0.01). Patients with recent myocardial infarction had greater aortic 18F-fluciclatide uptake than those with stable disease (TBRmax 1.29 vs 1.21, p=0.02). CONCLUSIONS: In vivo expression of αvß3 integrin in human aortic atheroma is associated with plaque burden and is increased in patients with recent myocardial infarction. Quantification of αvß3 integrin expression with 18F-fluciclatide PET has potential to assess plaque vulnerability and disease activity in atherosclerosis.

2.
Eur Radiol ; 29(7): 3543-3552, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30919067

RESUMO

OBJECTIVES: Ferumoxytol is an alternative to gadolinium-based compounds as a vascular contrast agent for magnetic resonance angiography (MRA), particularly for patients with chronic kidney disease (CKD). However, dose-related efficacy data are lacking. We aimed to determine the optimal (minimum effective) dose of ferumoxytol for MRA in patients with CKD. METHODS: Ferumoxytol-enhanced MRA (FeMRA) was performed at 3.0 T in patients with CKD after dose increments up to a total of 4 mg/kg. Image quality was assessed by contrast-to-noise ratio (CNR) and signal-to-noise ratio (SNR) in the abdominal aorta and inferior vena cava. Quadratic regression analyses were performed to estimate the effects of dose increments on CNR and SNR. RESULTS: Twenty-three patients underwent FeMRA (mean age 60 [SD 13] years, 87% men, 48% had diabetic nephropathy) with cumulative doses of 0, 1, 2, 3 and 4 mg/kg of ferumoxytol. On regression analyses, a parabolic relationship was observed between ferumoxytol dose and signal with progressive signal loss using doses exceeding 4 mg/kg. A dose of 3 mg/kg achieved ≥ 75% of predicted peak CNR and SNR and images were deemed of excellent diagnostic quality. CONCLUSIONS: In patients with CKD undergoing FeMRA, a dose of 3 mg/kg provides excellent arterial and venous enhancement. The benefits of increasing the dose to a theoretically optimal value of 4 mg/kg appear to be negligible and likely of minimal, if any, diagnostic value. KEY POINTS: • Ferumoxytol is used off-label as an MRI contrast agent but dose-related data are lacking. • In patients with CKD requiring MR angiography, a dose of 3 mg/kg provides excellent vascular enhancement.


Assuntos
Óxido Ferroso-Férrico/administração & dosagem , Angiografia por Ressonância Magnética/métodos , Insuficiência Renal Crônica/diagnóstico , Relação Dose-Resposta a Droga , Feminino , Hematínicos/farmacologia , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
3.
Circ Cardiovasc Imaging ; 12(2): e008513, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30712363

RESUMO

BACKGROUND: Mitral annular calcification (MAC) is associated with cardiovascular events and mitral valve dysfunction. However, the underlying pathophysiology remains incompletely understood. In this prospective longitudinal study, we used a multimodality approach including positron emission tomography, computed tomography, and echocardiography to investigate the pathophysiology of MAC and assess factors associated with disease activity and progression. METHODS: A total of 104 patients (age 72±8 years, 30% women) with calcific aortic valve disease, therefore predisposed to MAC, underwent 18F-sodium fluoride (calcification activity) and 18F-Fluorodeoxyglucose (inflammation activity) positron emission tomography, computed tomography calcium scoring, and echocardiography. Sixty patients underwent repeat computed tomography and echocardiography after 2 years. RESULTS: MAC (mitral annular calcium score >0) was present in 35 (33.7%) patients who had increased 18F-fluoride (tissue-to-background ratio, 2.32 [95% CI, 1.81-3.27] versus 1.30 [1.22-1.49]; P<0.001) and 18F-Fluorodeoxyglucose activity (tissue-to-background ratio, 1.44 [1.37-1.58] versus 1.17 [1.12-1.24]; P<0.001) compared with patients without MAC. MAC activity (18F-fluoride uptake) was closely associated with the local calcium score and 18F-Fluorodeoxyglucose uptake, as well as female sex and renal function. Similarly, MAC progression was closely associated with local factors, in particular, baseline MAC. Traditional cardiovascular risk factors and calcification activity in bone or remote atherosclerotic areas were not associated with disease activity nor progression. CONCLUSIONS: MAC is characterized by increased local calcification activity and inflammation. Baseline MAC burden was associated with disease activity and the rate of subsequent progression. This suggests a self-perpetuating cycle of calcification and inflammation that may be the target of future therapeutic interventions.


Assuntos
Calcinose/diagnóstico por imagem , Doenças das Valvas Cardíacas/diagnóstico por imagem , Valva Mitral/diagnóstico por imagem , Imagem Multimodal/métodos , Idoso , Idoso de 80 Anos ou mais , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/patologia , Valva Aórtica/fisiopatologia , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/epidemiologia , Estenose da Valva Aórtica/fisiopatologia , Calcinose/epidemiologia , Calcinose/fisiopatologia , Angiografia por Tomografia Computadorizada , Angiografia Coronária/métodos , Progressão da Doença , Ecocardiografia , Feminino , Doenças das Valvas Cardíacas/epidemiologia , Doenças das Valvas Cardíacas/fisiopatologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Valva Mitral/fisiopatologia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Valor Preditivo dos Testes , Prevalência , Prognóstico , Fatores de Tempo
4.
J Am Coll Cardiol ; 71(5): 513-523, 2018 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-29406857

RESUMO

BACKGROUND: Fluorine-18-sodium fluoride (18F-NaF) uptake is a marker of active vascular calcification associated with high-risk atherosclerotic plaque. OBJECTIVES: In patients with abdominal aortic aneurysm (AAA), the authors assessed whether 18F-NaF positron emission tomography (PET) and computed tomography (CT) predicts AAA growth and clinical outcomes. METHODS: In prospective case-control (n = 20 per group) and longitudinal cohort (n = 72) studies, patients with AAA (aortic diameter >40 mm) and control subjects (aortic diameter <30 mm) underwent abdominal ultrasound, 18F-NaF PET-CT, CT angiography, and calcium scoring. Clinical endpoints were aneurysm expansion and the composite of AAA repair or rupture. RESULTS: Fluorine-18-NaF uptake was increased in AAA compared with nonaneurysmal regions within the same aorta (p = 0.004) and aortas of control subjects (p = 0.023). Histology and micro-PET-CT demonstrated that 18F-NaF uptake localized to areas of aneurysm disease and active calcification. In 72 patients within the longitudinal cohort study (mean age 73 ± 7 years, 85% men, baseline aneurysm diameter 48.8 ± 7.7 mm), there were 19 aneurysm repairs (26.4%) and 3 ruptures (4.2%) after 510 ± 196 days. Aneurysms in the highest tertile of 18F-NaF uptake expanded 2.5× more rapidly than those in the lowest tertile (3.10 [interquartile range (IQR): 2.34 to 5.92 mm/year] vs. 1.24 [IQR: 0.52 to 2.92 mm/year]; p = 0.008) and were nearly 3× as likely to experience AAA repair or rupture (15.3% vs. 5.6%; log-rank p = 0.043). CONCLUSIONS: Fluorine-18-NaF PET-CT is a novel and promising approach to the identification of disease activity in patients with AAA and is an additive predictor of aneurysm growth and future clinical events. (Sodium Fluoride Imaging of Abdominal Aortic Aneurysms [SoFIA3]; NCT02229006; Magnetic Resonance Imaging [MRI] for Abdominal Aortic Aneurysms to Predict Rupture or Surgery: The MA3RS Trial; ISRCTN76413758).


Assuntos
Aneurisma da Aorta Abdominal/diagnóstico por imagem , Radioisótopos de Flúor/farmacocinética , Fluoreto de Sódio/farmacocinética , Calcificação Vascular/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Aneurisma da Aorta Abdominal/complicações , Aneurisma da Aorta Abdominal/cirurgia , Ruptura Aórtica/etiologia , Estudos de Casos e Controles , Estudos de Coortes , Angiografia por Tomografia Computadorizada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Valor Preditivo dos Testes , Ultrassonografia
5.
Eur Radiol ; 28(1): 115-123, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28677065

RESUMO

OBJECTIVES: Traditional contrast-enhanced methods for scanning blood vessels using magnetic resonance imaging (MRI) or CT carry potential risks for patients with advanced kidney disease. Ferumoxytol is a superparamagnetic iron oxide nanoparticle preparation that has potential as an MRI contrast agent in assessing the vasculature. METHODS: Twenty patients with advanced kidney disease requiring aorto-iliac vascular imaging as part of pre-operative kidney transplant candidacy assessment underwent ferumoxytol-enhanced magnetic resonance angiography (FeMRA) between December 2015 and August 2016. All scans were performed for clinical indications where standard imaging techniques were deemed potentially harmful or inconclusive. Image quality was evaluated for both arterial and venous compartments. RESULTS: First-pass and steady-state FeMRA using incremental doses of up to 4 mg/kg body weight of ferumoxytol as intravenous contrast agent for vascular enhancement was performed. Good arterial and venous enhancements were achieved, and FeMRA was not limited by calcification in assessing the arterial lumen. The scans were diagnostic and all patients completed their studies without adverse events. CONCLUSIONS: Our preliminary experience supports the feasibility and utility of FeMRA for vascular imaging in patients with advanced kidney disease due for transplant listing, which has the advantages of obtaining both arteriography and venography using a single test without nephrotoxicity. KEY POINTS: • Evaluation of vascular disease is important in planning kidney transplantation. • Standard vascular imaging methods are often problematic in kidney disease patients. • FeMRA has the advantage of arteriography and venography in a single test. • FeMRA is safe and non-nephrotoxic. • FeMRA is not limited by arterial calcification.


Assuntos
Meios de Contraste , Óxido Ferroso-Férrico , Aumento da Imagem/métodos , Transplante de Rim , Rim/irrigação sanguínea , Angiografia por Ressonância Magnética/métodos , Seleção de Pacientes , Feminino , Humanos , Rim/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade
7.
J Cell Physiol ; 232(11): 2985-2995, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28369848

RESUMO

Patients with end-stage renal disease (ESRD) have elevated circulating calcium (Ca) and phosphate (Pi), and exhibit accelerated progression of calcific aortic valve disease (CAVD). We hypothesized that matrix vesicles (MVs) initiate the calcification process in CAVD. Ca induced rat valve interstitial cells (VICs) calcification at 4.5 mM (16.4-fold; p < 0.05) whereas Pi treatment alone had no effect. Ca (2.7 mM) and Pi (2.5 mM) synergistically induced calcium deposition (10.8-fold; p < 0.001) in VICs. Ca treatment increased the mRNA of the osteogenic markers Msx2, Runx2, and Alpl (p < 0.01). MVs were harvested by ultracentrifugation from VICs cultured with control or calcification media (containing 2.7 mM Ca and 2.5 mM Pi) for 16 hr. Proteomics analysis revealed the marked enrichment of exosomal proteins, including CD9, CD63, LAMP-1, and LAMP-2 and a concomitant up-regulation of the Annexin family of calcium-binding proteins. Of particular note Annexin VI was shown to be enriched in calcifying VIC-derived MVs (51.9-fold; p < 0.05). Through bioinformatic analysis using Ingenuity Pathway Analysis (IPA), the up-regulation of canonical signaling pathways relevant to cardiovascular function were identified in calcifying VIC-derived MVs, including aldosterone, Rho kinase, and metal binding. Further studies using human calcified valve tissue revealed the co-localization of Annexin VI with areas of MVs in the extracellular matrix by transmission electron microscopy (TEM). Together these findings highlight a critical role for VIC-derived MVs in CAVD. Furthermore, we identify calcium as a key driver of aortic valve calcification, which may directly underpin the increased susceptibility of ESRD patients to accelerated development of CAVD.


Assuntos
Anexina A6/metabolismo , Estenose da Valva Aórtica/metabolismo , Valva Aórtica/metabolismo , Valva Aórtica/patologia , Calcinose/metabolismo , Matriz Extracelular/metabolismo , Vesículas Extracelulares/metabolismo , Hipercalcemia/etiologia , Falência Renal Crônica/complicações , Idoso , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Animais , Valva Aórtica/ultraestrutura , Estenose da Valva Aórtica/etiologia , Estenose da Valva Aórtica/genética , Estenose da Valva Aórtica/patologia , Calcinose/etiologia , Calcinose/genética , Calcinose/patologia , Cálcio/metabolismo , Células Cultivadas , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Matriz Extracelular/ultraestrutura , Vesículas Extracelulares/ultraestrutura , Feminino , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Hipercalcemia/diagnóstico , Falência Renal Crônica/diagnóstico , Masculino , Microscopia Eletrônica de Transmissão , Mapas de Interação de Proteínas , Proteômica/métodos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Regulação para Cima
8.
ACS Nano ; 11(5): 4542-4552, 2017 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-28443337

RESUMO

The development of engineered nanomaterials is growing exponentially, despite concerns over their potential similarities to environmental nanoparticles that are associated with significant cardiorespiratory morbidity and mortality. The mechanisms through which inhalation of nanoparticles could trigger acute cardiovascular events are emerging, but a fundamental unanswered question remains: Do inhaled nanoparticles translocate from the lung in man and directly contribute to the pathogenesis of cardiovascular disease? In complementary clinical and experimental studies, we used gold nanoparticles to evaluate particle translocation, permitting detection by high-resolution inductively coupled mass spectrometry and Raman microscopy. Healthy volunteers were exposed to nanoparticles by acute inhalation, followed by repeated sampling of blood and urine. Gold was detected in the blood and urine within 15 min to 24 h after exposure, and was still present 3 months after exposure. Levels were greater following inhalation of 5 nm (primary diameter) particles compared to 30 nm particles. Studies in mice demonstrated the accumulation in the blood and liver following pulmonary exposure to a broader size range of gold nanoparticles (2-200 nm primary diameter), with translocation markedly greater for particles <10 nm diameter. Gold nanoparticles preferentially accumulated in inflammation-rich vascular lesions of fat-fed apolipoproteinE-deficient mice. Furthermore, following inhalation, gold particles could be detected in surgical specimens of carotid artery disease from patients at risk of stroke. Translocation of inhaled nanoparticles into the systemic circulation and accumulation at sites of vascular inflammation provides a direct mechanism that can explain the link between environmental nanoparticles and cardiovascular disease and has major implications for risk management in the use of engineered nanomaterials.


Assuntos
Nanopartículas Metálicas/administração & dosagem , Doenças Vasculares/metabolismo , Administração por Inalação , Adulto , Animais , Ouro , Voluntários Saudáveis , Humanos , Pulmão/patologia , Masculino , Camundongos , Nanopartículas , Nanoestruturas/análise , Tamanho da Partícula , Doenças Vasculares/terapia
9.
Circ Cardiovasc Imaging ; 10(3)2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28292859

RESUMO

BACKGROUND: Combined positron emission tomography (PET) and computed tomography (CT) can assess both anatomy and biology of carotid atherosclerosis. We sought to assess whether 18F-fluoride or 18F-fluorodeoxyglucose can identify culprit and high-risk carotid plaque. METHODS AND RESULTS: We performed 18F-fluoride and 18F-fluorodeoxyglucose PET/CT in 26 patients after recent transient ischemic attack or minor ischemic stroke: 18 patients with culprit carotid stenosis awaiting carotid endarterectomy and 8 controls without culprit carotid atheroma. We compared standardized uptake values in the clinically adjudicated culprit to the contralateral asymptomatic artery, and assessed the relationship between radiotracer uptake and plaque phenotype or predicted cardiovascular risk (ASSIGN score [Assessing Cardiovascular Risk Using SIGN Guidelines to Assign Preventive Treatment]). We also performed micro PET/CT and histological analysis of excised plaque. On histological and micro PET/CT analysis, 18F-fluoride selectively highlighted microcalcification. Carotid 18F-fluoride uptake was increased in clinically adjudicated culprit plaques compared with asymptomatic contralateral plaques (log10standardized uptake valuemean 0.29±0.10 versus 0.23±0.11, P=0.001) and compared with control patients (log10standardized uptake valuemean 0.29±0.10 versus 0.12±0.11, P=0.001). 18F-Fluoride uptake correlated with high-risk plaque features (remodeling index [r=0.53, P=0.003], plaque burden [r=0.51, P=0.004]), and predicted cardiovascular risk [r=0.65, P=0.002]). Carotid 18F-fluorodeoxyglucose uptake appeared to be increased in 7 of 16 culprit plaques, but no overall differences in uptake were observed in culprit versus contralateral plaques or control patients. However, 18F-fluorodeoxyglucose did correlate with predicted cardiovascular risk (r=0.53, P=0.019), but not with plaque phenotype. CONCLUSIONS: 18F-Fluoride PET/CT highlights culprit and phenotypically high-risk carotid plaque. This has the potential to improve risk stratification and selection of patients who may benefit from intervention.


Assuntos
Artéria Carótida Interna/diagnóstico por imagem , Estenose das Carótidas/diagnóstico por imagem , Fluoretos/administração & dosagem , Radioisótopos de Flúor/administração & dosagem , Fluordesoxiglucose F18/administração & dosagem , Ataque Isquêmico Transitório/etiologia , Placa Aterosclerótica , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/administração & dosagem , Acidente Vascular Cerebral/etiologia , Idoso , Idoso de 80 Anos ou mais , Artéria Carótida Interna/cirurgia , Estenose das Carótidas/complicações , Estenose das Carótidas/cirurgia , Estudos de Casos e Controles , Endarterectomia das Carótidas , Feminino , Humanos , Ataque Isquêmico Transitório/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Fenótipo , Projetos Piloto , Valor Preditivo dos Testes , Fatores de Risco , Índice de Gravidade de Doença , Acidente Vascular Cerebral/diagnóstico por imagem , Microtomografia por Raio-X
10.
Heart ; 103(8): 607-615, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27927700

RESUMO

OBJECTIVE: Maladaptive repair contributes towards the development of heart failure following myocardial infarction (MI). The αvß3 integrin receptor is a key mediator and determinant of cardiac repair. We aimed to establish whether αvß3 integrin expression determines myocardial recovery following MI. METHODS: 18F-Fluciclatide (a novel αvß3-selective radiotracer) positron emission tomography (PET) and CT imaging and gadolinium-enhanced MRI (CMR) were performed in 21 patients 2 weeks after ST-segment elevation MI (anterior, n=16; lateral, n=4; inferior, n=1). CMR was repeated 9 months after MI. 7 stable patients with chronic total occlusion (CTO) of a major coronary vessel and nine healthy volunteers underwent a single PET/CT and CMR. RESULTS: 18F-Fluciclatide uptake was increased at sites of acute infarction compared with remote myocardium (tissue-to-background ratio (TBRmean) 1.34±0.22 vs 0.85±0.17; p<0.001) and myocardium of healthy volunteers (TBRmean 1.34±0.22 vs 0.70±0.03; p<0.001). There was no 18F-fluciclatide uptake at sites of established prior infarction in patients with CTO, with activity similar to the myocardium of healthy volunteers (TBRmean 0.71±0.06 vs 0.70±0.03, p=0.83). 18F-Fluciclatide uptake occurred at sites of regional wall hypokinesia (wall motion index≥1 vs 0; TBRmean 0.93±0.31 vs 0.80±0.26 respectively, p<0.001) and subendocardial infarction. Importantly, although there was no correlation with infarct size (r=0.03, p=0.90) or inflammation (C reactive protein, r=-0.20, p=0.38), 18F-fluciclatide uptake was increased in segments displaying functional recovery (TBRmean 0.95±0.33 vs 0.81±0.27, p=0.002) and associated with increase in probability of regional recovery. CONCLUSION: 18F-Fluciclatide uptake is increased at sites of recent MI acting as a biomarker of cardiac repair and predicting regions of recovery. TRIAL REGISTRATION NUMBER: NCT01813045; Post-results.


Assuntos
Infarto Miocárdico de Parede Anterior/metabolismo , Infarto Miocárdico de Parede Inferior/metabolismo , Integrina alfaVbeta3/metabolismo , Miocárdio/metabolismo , Infarto do Miocárdio com Supradesnível do Segmento ST/metabolismo , Idoso , Infarto Miocárdico de Parede Anterior/diagnóstico por imagem , Infarto Miocárdico de Parede Anterior/patologia , Infarto Miocárdico de Parede Anterior/fisiopatologia , Biomarcadores/metabolismo , Estudos de Casos e Controles , Meios de Contraste/administração & dosagem , Feminino , Humanos , Infarto Miocárdico de Parede Inferior/diagnóstico por imagem , Infarto Miocárdico de Parede Inferior/patologia , Infarto Miocárdico de Parede Inferior/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Miocárdio/patologia , Peptídeos , Polietilenoglicóis , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Recuperação de Função Fisiológica , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Infarto do Miocárdio com Supradesnível do Segmento ST/patologia , Fatores de Tempo , Função Ventricular Esquerda , Remodelação Ventricular
11.
JACC Cardiovasc Imaging ; 10(11): 1320-1333, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28017384

RESUMO

OBJECTIVES: Cardiac magnetic resonance (CMR) was used to investigate the extracellular compartment and myocardial fibrosis in patients with aortic stenosis, as well as their association with other measures of left ventricular decompensation and mortality. BACKGROUND: Progressive myocardial fibrosis drives the transition from hypertrophy to heart failure in aortic stenosis. Diffuse fibrosis is associated with extracellular volume expansion that is detectable by T1 mapping, whereas late gadolinium enhancement (LGE) detects replacement fibrosis. METHODS: In a prospective observational cohort study, 203 subjects (166 with aortic stenosis [69 years; 69% male]; 37 healthy volunteers [68 years; 65% male]) underwent comprehensive phenotypic characterization with clinical imaging and biomarker evaluation. On CMR, we quantified the total extracellular volume of the myocardium indexed to body surface area (iECV). The iECV upper limit of normal from the control group (22.5 ml/m2) was used to define extracellular compartment expansion. Areas of replacement mid-wall LGE were also identified. All-cause mortality was determined during 2.9 ± 0.8 years of follow up. RESULTS: iECV demonstrated a good correlation with diffuse histological fibrosis on myocardial biopsies (r = 0.87; p < 0.001; n = 11) and was increased in patients with aortic stenosis (23.6 ± 7.2 ml/m2 vs. 16.1 ± 3.2 ml/m2 in control subjects; p < 0.001). iECV was used together with LGE to categorize patients with normal myocardium (iECV <22.5 ml/m2; 51% of patients), extracellular expansion (iECV ≥22.5 ml/m2; 22%), and replacement fibrosis (presence of mid-wall LGE, 27%). There was evidence of increasing hypertrophy, myocardial injury, diastolic dysfunction, and longitudinal systolic dysfunction consistent with progressive left ventricular decompensation (all p < 0.05) across these groups. Moreover, this categorization was of prognostic value with stepwise increases in unadjusted all-cause mortality (8 deaths/1,000 patient-years vs. 36 deaths/1,000 patient-years vs. 71 deaths/1,000 patient-years, respectively; p = 0.009). CONCLUSIONS: CMR detects ventricular decompensation in aortic stenosis through the identification of myocardial extracellular expansion and replacement fibrosis. This holds major promise in tracking myocardial health in valve disease and for optimizing the timing of valve replacement. (The Role of Myocardial Fibrosis in Patients With Aortic Stenosis; NCT01755936).


Assuntos
Estenose da Valva Aórtica/complicações , Cardiomiopatias/etiologia , Insuficiência Cardíaca/etiologia , Hipertrofia Ventricular Esquerda/etiologia , Miocárdio/patologia , Função Ventricular Esquerda , Remodelação Ventricular , Idoso , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/mortalidade , Estenose da Valva Aórtica/fisiopatologia , Biópsia , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/mortalidade , Cardiomiopatias/fisiopatologia , Estudos de Casos e Controles , Progressão da Doença , Ecocardiografia , Feminino , Fibrose , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/mortalidade , Hipertrofia Ventricular Esquerda/fisiopatologia , Estimativa de Kaplan-Meier , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo
12.
Circulation ; 133(21): 2050-65, 2016 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-27052414

RESUMO

BACKGROUND: Phenotypic switching of vascular smooth muscle cells from a contractile to a synthetic state is implicated in diverse vascular pathologies, including atherogenesis, plaque stabilization, and neointimal hyperplasia. However, very little is known about the role of long noncoding RNA (lncRNA) during this process. Here, we investigated a role for lncRNAs in vascular smooth muscle cell biology and pathology. METHODS AND RESULTS: Using RNA sequencing, we identified >300 lncRNAs whose expression was altered in human saphenous vein vascular smooth muscle cells following stimulation with interleukin-1α and platelet-derived growth factor. We focused on a novel lncRNA (Ensembl: RP11-94A24.1), which we termed smooth muscle-induced lncRNA enhances replication (SMILR). Following stimulation, SMILR expression was increased in both the nucleus and cytoplasm, and was detected in conditioned media. Furthermore, knockdown of SMILR markedly reduced cell proliferation. Mechanistically, we noted that expression of genes proximal to SMILR was also altered by interleukin-1α/platelet-derived growth factor treatment, and HAS2 expression was reduced by SMILR knockdown. In human samples, we observed increased expression of SMILR in unstable atherosclerotic plaques and detected increased levels in plasma from patients with high plasma C-reactive protein. CONCLUSIONS: These results identify SMILR as a driver of vascular smooth muscle cell proliferation and suggest that modulation of SMILR may be a novel therapeutic strategy to reduce vascular pathologies.


Assuntos
Proliferação de Células/fisiologia , Músculo Liso Vascular/fisiologia , Miócitos de Músculo Liso/fisiologia , RNA Longo não Codificante/fisiologia , Proteínas de Caenorhabditis elegans , Células Cultivadas , Técnicas de Silenciamento de Genes , Humanos , Músculo Liso Vascular/citologia , Veia Safena/citologia , Veia Safena/fisiologia
13.
Sci Rep ; 6: 24807, 2016 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-27095121

RESUMO

Vascular calcification powerfully predicts mortality and morbidity from cardiovascular disease. Men have a greater risk of cardiovascular disease, compared to women of a similar age. These gender disparities suggest an influence of sex hormones. Testosterone is the primary and most well-recognised androgen in men. Therefore, we addressed the hypothesis that exogenous androgen treatment induces vascular calcification. Immunohistochemical analysis revealed expression of androgen receptor (AR) in the calcified media of human femoral artery tissue and calcified human valves. Furthermore, in vitro studies revealed increased phosphate (Pi)-induced mouse vascular smooth muscle cell (VSMC) calcification following either testosterone or dihydrotestosterone (DHT) treatment for 9 days. Testosterone and DHT treatment increased tissue non-specific alkaline phosphatase (Alpl) mRNA expression. Testosterone-induced calcification was blunted in VSMC-specific AR-ablated (SM-ARKO) VSMCs compared to WT. Consistent with these data, SM-ARKO VSMCs showed a reduction in Osterix mRNA expression. However, intriguingly, a counter-intuitive increase in Alpl was observed. These novel data demonstrate that androgens play a role in inducing vascular calcification through the AR. Androgen signalling may represent a novel potential therapeutic target for clinical intervention.


Assuntos
Músculo Liso Vascular/metabolismo , Receptores Androgênicos/metabolismo , Testosterona/metabolismo , Calcificação Vascular/metabolismo , Calcificação Vascular/patologia , Animais , Apoptose/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Miócitos de Músculo Liso/metabolismo , Osteogênese/genética , Receptores Androgênicos/genética , Testosterona/farmacologia , Calcificação Vascular/genética
14.
JACC Cardiovasc Imaging ; 9(3): 306-16, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26965732

RESUMO

Cardiac magnetic resonance offers the promise of radiation-free imaging of the coronary arteries, providing information with respect to luminal stenosis, plaque burden, high-risk plaque characteristics, and disease activity. In combination, this would provide a comprehensive, individualized assessment of coronary atherosclerosis that could be used to improve patient risk stratification and to guide treatment. However, the technical challenges involved with delivering upon this promise are considerable, requiring sophisticated approaches to both data acquisition and post-processing. In this review, we describe the current status of this technology, its capabilities, its limitations, and what will be required in the future to translate this technology into routine clinical practice.


Assuntos
Angiografia Coronária/métodos , Doença da Artéria Coronariana/diagnóstico por imagem , Estenose Coronária/diagnóstico por imagem , Vasos Coronários/diagnóstico por imagem , Angiografia por Ressonância Magnética , Placa Aterosclerótica , Doença da Artéria Coronariana/terapia , Estenose Coronária/terapia , Humanos , Valor Preditivo dos Testes , Prognóstico , Índice de Gravidade de Doença
15.
Neuroimaging Clin N Am ; 26(1): 55-68, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26610660

RESUMO

By harnessing the versatility and soft tissue imaging capabilities of MR imaging alongside the unmatched sensitivity and biomolecular flexibility of PET, the potential to provide detailed multiparametric plaque characterization in the carotid arteries is clear. The ability to acquire simultaneous, and dynamic multimodal data is perhaps PET/MR's greatest strength that will be of major interest to researchers investigating carotid and coronary atherosclerosis alike. This review summarizes the current status of dedicated hybrid PET/MR imaging; to crystallize the rationale for and advantages of this technique with respect to carotid atherosclerosis; and to discuss current limitations, challenges, and future directions.


Assuntos
Algoritmos , Estenose das Carótidas/diagnóstico , Interpretação de Imagem Assistida por Computador/métodos , Angiografia por Ressonância Magnética/métodos , Imagem Multimodal/métodos , Tomografia por Emissão de Pósitrons/métodos , Humanos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
17.
J Am Heart Assoc ; 4(9): e001956, 2015 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-26316523

RESUMO

BACKGROUND: Preclinical data suggest that an acute inflammatory response following myocardial infarction (MI) accelerates systemic atherosclerosis. Using combined positron emission and computed tomography, we investigated whether this phenomenon occurs in humans. METHODS AND RESULTS: Overall, 40 patients with MI and 40 with stable angina underwent thoracic 18F-fluorodeoxyglucose combined positron emission and computed tomography scan. Radiotracer uptake was measured in aortic atheroma and nonvascular tissue (paraspinal muscle). In 1003 patients enrolled in the Global Registry of Acute Coronary Events, we assessed whether infarct size predicted early (≤30 days) and late (>30 days) recurrent coronary events. Compared with patients with stable angina, patients with MI had higher aortic 18F-fluorodeoxyglucose uptake (tissue-to-background ratio 2.15±0.30 versus 1.84±0.18, P<0.0001) and plasma C-reactive protein concentrations (6.50 [2.00 to 12.75] versus 2.00 [0.50 to 4.00] mg/dL, P=0.0005) despite having similar aortic (P=0.12) and less coronary (P=0.006) atherosclerotic burden and similar paraspinal muscular 18F-fluorodeoxyglucose uptake (P=0.52). Patients with ST-segment elevation MI had larger infarcts (peak plasma troponin 32 300 [10 200 to >50 000] versus 3800 [1000 to 9200] ng/L, P<0.0001) and greater aortic 18F-fluorodeoxyglucose uptake (2.24±0.32 versus 2.02±0.21, P=0.03) than those with non-ST-segment elevation MI. Peak plasma troponin concentrations correlated with aortic 18F-fluorodeoxyglucose uptake (r=0.43, P=0.01) and, on multivariate analysis, independently predicted early (tertile 3 versus tertile 1: relative risk 4.40 [95% CI 1.90 to 10.19], P=0.001), but not late, recurrent MI. CONCLUSIONS: The presence and extent of MI is associated with increased aortic atherosclerotic inflammation and early recurrent MI. This finding supports the hypothesis that acute MI exacerbates systemic atherosclerotic inflammation and remote plaque destabilization: MI begets MI. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01749254.


Assuntos
Aortite/diagnóstico , Aterosclerose/diagnóstico , Doença da Artéria Coronariana/diagnóstico , Infarto do Miocárdio/diagnóstico , Idoso , Aortite/sangue , Aortite/diagnóstico por imagem , Aterosclerose/sangue , Aterosclerose/diagnóstico por imagem , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Feminino , Fluordesoxiglucose F18 , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Imagem Multimodal/métodos , Análise Multivariada , Infarto do Miocárdio/sangue , Infarto do Miocárdio/diagnóstico por imagem , Placa Aterosclerótica , Tomografia por Emissão de Pósitrons , Valor Preditivo dos Testes , Estudos Prospectivos , Compostos Radiofarmacêuticos , Recidiva , Sistema de Registros , Fatores de Risco , Escócia , Fatores de Tempo , Tomografia Computadorizada por Raios X , Troponina/sangue
18.
Nat Commun ; 6: 7495, 2015 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-26151378

RESUMO

Vascular calcification is a complex biological process that is a hallmark of atherosclerosis. While macrocalcification confers plaque stability, microcalcification is a key feature of high-risk atheroma and is associated with increased morbidity and mortality. Positron emission tomography and X-ray computed tomography (PET/CT) imaging of atherosclerosis using (18)F-sodium fluoride ((18)F-NaF) has the potential to identify pathologically high-risk nascent microcalcification. However, the precise molecular mechanism of (18)F-NaF vascular uptake is still unknown. Here we use electron microscopy, autoradiography, histology and preclinical and clinical PET/CT to analyse (18)F-NaF binding. We show that (18)F-NaF adsorbs to calcified deposits within plaque with high affinity and is selective and specific. (18)F-NaF PET/CT imaging can distinguish between areas of macro- and microcalcification. This is the only currently available clinical imaging platform that can non-invasively detect microcalcification in active unstable atherosclerosis. The use of (18)F-NaF may foster new approaches to developing treatments for vascular calcification.


Assuntos
Aterosclerose/diagnóstico , Artérias Carótidas/patologia , Tomografia por Emissão de Pósitrons/métodos , Fluoreto de Sódio/química , Calcificação Vascular/diagnóstico , Idoso , Aterosclerose/patologia , Feminino , Radioisótopos de Flúor , Humanos , Masculino
19.
Cardiovasc Diagn Ther ; 5(2): 150-5, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25984456

RESUMO

Ischaemic vascular events occur in relation to an underlying vulnerable plaque. The pathological hallmarks of high-risk plaques are well described and include inflammation and microcalcification. To date, non-invasive imaging modalities have lacked the spatial resolution to detect these processes with the necessary precision to facilitate clinical utility. Positron emission tomography (PET) using targeted radiopharmaceuticals affords a highly sensitive tool for identifying features of interest and has been in use for several decades in oncological practice. Recent developments have created hybrid scanning platforms which add the detailed spatial resolution of computed tomography (CT) and, for the first time, made imaging of individual coronary plaques feasible. In this study we compared the utility of PET-CT using (18)F-fluoride and (18)F-fluorodeoxglucose ((18)F-FDG) to detect high-risk or ruptured atherosclerotic plaques in vivo. (18)F-fluoride localized to culprit and vulnerable plaques as determined by a combination of invasive imaging and histological tissue examination. In contradistinction, (18)F-FDG analysis was compromised by non-specific myocardial uptake that obscured the coronary arteries. We discuss the findings of this study, the limitations of the current approach of vulnerable plaque assessment and some on-going developments in cardiovascular imaging with (18)F-fluoride.

20.
Circ Cardiovasc Imaging ; 7(2): 371-8, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24508669

RESUMO

BACKGROUND: 18F-Sodium fluoride (18F-NaF) and 18F-fluorodeoxyglucose (18F-FDG) are promising novel biomarkers of disease activity in aortic stenosis. We compared 18F-NaF and 18F-FDG uptake with histological characterization of the aortic valve and assessed whether they predicted disease progression. METHODS AND RESULTS: Thirty patients with aortic stenosis underwent combined positron emission and computed tomography using 18F-NaF and 18F-FDG radiotracers. In 12 patients undergoing aortic valve replacement surgery (10 for each tracer), radiotracer uptake (mean tissue/ BACKGROUND: =0.65; P=0.04) and osteocalcin (r=0.68; P=0.03) immunohistochemistry. There was no significant correlation between 18F-FDG uptake and CD68 staining (r=-0.43; P=0.22). After 1 year, aortic valve calcification increased from 314 (193-540) to 365 (207-934) AU (P<0.01). Baseline 18F-NaF uptake correlated closely with the change in calcium score (r=0.66; P<0.01), and this improved further (r=0.75; P<0.01) when 18F-NaF uptake overlying computed tomography-defined macrocalcification was excluded. No significant correlation was noted between valvular 18F-FDG uptake and change in calcium score (r=-0.11; P=0.66). CONCLUSIONS: 18F-NaF uptake identifies active tissue calcification and predicts disease progression in patients with calcific aortic stenosis. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01358513.


Assuntos
Estenose da Valva Aórtica/diagnóstico por imagem , Calcinose/diagnóstico por imagem , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons/métodos , Fluoreto de Sódio , Idoso , Idoso de 80 Anos ou mais , Estenose da Valva Aórtica/complicações , Estenose da Valva Aórtica/metabolismo , Biomarcadores/metabolismo , Calcinose/etiologia , Calcinose/metabolismo , Progressão da Doença , Feminino , Radioisótopos de Flúor/farmacocinética , Fluordesoxiglucose F18/farmacocinética , Humanos , Masculino , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Fluoreto de Sódio/farmacocinética
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