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BACKGROUND: Immunosuppressed individuals, including solid organ transplant recipients (SOTRs), are at high risk for severe COVID-19. METHODS: This open-label, phase 3b trial evaluated mRNA-1273 in 137 adult kidney and 77 liver SOTRs and 20 immunocompetent participants. In Part A, SOTRs received three 100-µg doses of mRNA-1273; immunocompetent participants received 2 doses. In Part B, an additional 100-µg dose was offered ≥4 months post-primary series. Here, we report interim trial results. RESULTS: mRNA-1273 was well-tolerated in SOTRs. Four serious adverse events were considered vaccine-related by the investigator in 3 SOTRs with pre-existing comorbidities. No vaccine-related biopsy-proven organ rejection events or deaths were reported. mRNA-1273 elicited modest neutralizing antibody (nAb) responses after dose 2 and improved responses after dose 3 in SOTRs. Post-dose 3 responses among liver SOTRs were comparable to post-dose 2 responses in immunocompetent participants. Post-additional dose responses were increased in SOTRs regardless of the primary series vaccination. In liver SOTRs, post-additional dose responses were â¼3-fold higher versus post-dose 2 but were lower than immunocompetent participant responses. Most kidney SOTRs received multiple immunosuppressants and had reduced antibody responses versus liver SOTRs. CONCLUSIONS: mRNA-1273 (100â µg) was well-tolerated and dose 3 and the additional dose improved antibody responses among SOTRs.
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BACKGROUND: Emotional stress is associated with increased risk of cardiovascular disease. We imaged the amygdala, a brain region involved in stress, to determine whether its resting metabolic activity predicts risk of subsequent cardiovascular events. METHODS: Individuals aged 30 years or older without known cardiovascular disease or active cancer disorders, who underwent 18F-fluorodexoyglucose PET/CT at Massachusetts General Hospital (Boston, MA, USA) between Jan 1, 2005, and Dec 31, 2008, were studied longitudinally. Amygdalar activity, bone-marrow activity, and arterial inflammation were assessed with validated methods. In a separate cross-sectional study we analysed the relation between perceived stress, amygdalar activity, arterial inflammation, and C-reactive protein. Image analyses and cardiovascular disease event adjudication were done by mutually blinded researchers. Relations between amygdalar activity and cardiovascular disease events were assessed with Cox models, log-rank tests, and mediation (path) analyses. FINDINGS: 293 patients (median age 55 years [IQR 45·0-65·5]) were included in the longitudinal study, 22 of whom had a cardiovascular disease event during median follow-up of 3·7 years (IQR 2·7-4·8). Amygdalar activity was associated with increased bone-marrow activity (r=0·47; p<0·0001), arterial inflammation (r=0·49; p<0·0001), and risk of cardiovascular disease events (standardised hazard ratio 1·59, 95% CI 1·27-1·98; p<0·0001), a finding that remained significant after multivariate adjustments. The association between amygdalar activity and cardiovascular disease events seemed to be mediated by increased bone-marrow activity and arterial inflammation in series. In the separate cross-sectional study of patients who underwent psychometric analysis (n=13), amygdalar activity was significantly associated with arterial inflammation (r=0·70; p=0·0083). Perceived stress was associated with amygdalar activity (r=0·56; p=0·0485), arterial inflammation (r=0·59; p=0·0345), and C-reactive protein (r=0·83; p=0·0210). INTERPRETATION: In this first study to link regional brain activity to subsequent cardiovascular disease, amygdalar activity independently and robustly predicted cardiovascular disease events. Amygdalar activity is involved partly via a path that includes increased bone-marrow activity and arterial inflammation. These findings provide novel insights into the mechanism through which emotional stressors can lead to cardiovascular disease in human beings. FUNDING: None.
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Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/metabolismo , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/psicologia , Estresse Psicológico/metabolismo , Idoso , Artérias/fisiopatologia , Aterosclerose/fisiopatologia , Medula Óssea/metabolismo , Doenças Cardiovasculares/diagnóstico por imagem , Estudos Transversais , Fluordesoxiglucose F18 , Hematopoese/fisiologia , Humanos , Inflamação/fisiopatologia , Estudos Longitudinais , Pessoa de Meia-Idade , Percepção , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Compostos Radiofarmacêuticos , Fatores de RiscoRESUMO
BACKGROUND: The objective of this study was to evaluate how different measures of adiposity are related to both arterial inflammation and the risk of subsequent cardiovascular events. METHODS AND RESULTS: We included individuals who underwent (18)F-fluorodeoxyglucose positron emission tomography/computed tomography imaging for oncological evaluation. Subcutaneous adipose tissue (SAT) volume, visceral adipose tissue (VAT) volume, and VAT/SAT ratio were determined. Additionally, body mass index, metabolic syndrome, and aortic (18)F-fluorodeoxyglucose uptake (a measure of arterial inflammation) were determined. Subsequent development of cardiovascular disease (CVD) events was adjudicated. The analysis included 415 patients with a median age of 55 (P25-P75: 45-65) and a median body mass index of 26.4 (P25-P75: 23.4-30.9) kg/m(2). VAT and SAT volume were significantly higher in obese individuals. VAT volume (r=0.290; P<0.001) and VAT/SAT ratio (r=0.208; P<0.001) were positively correlated with arterial inflammation. Thirty-two subjects experienced a CVD event during a median follow-up of 4 years. Cox proportional hazard models showed that VAT volume and VAT/SAT ratio were associated with CVD events (hazard ratio [95% confidence interval]: 1.15 [1.06-1.25]; P<0.001; 3.60 [1.88-6.92]; P<0.001, respectively). Body mass index, metabolic syndrome, and SAT were not predictive of CVD events. CONCLUSIONS: Measures of visceral fat are positively related to arterial inflammation and are independent predictors of subsequent CVD events. Individuals with higher measures of visceral fat as well as elevated arterial inflammation are at highest risk for subsequent CVD events. The findings suggest that arterial inflammation may explain some of the CVD risk associated with adiposity.
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Adiposidade , Arterite/diagnóstico por imagem , Doenças Cardiovasculares/diagnóstico por imagem , Imagem Multimodal , Idoso , Índice de Massa Corporal , Feminino , Fluordesoxiglucose F18 , Humanos , Masculino , Síndrome Metabólica/complicações , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Valor Preditivo dos Testes , Compostos Radiofarmacêuticos , Estudos Retrospectivos , Fatores de Risco , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVES: This study sought to determine whether splenic activation after acute coronary syndrome (ACS) is linked to leukocyte proinflammatory remodeling and whether splenic activity independently predicts the risk of cardiovascular disease (CVD) events. BACKGROUND: Pre-clinical data suggest the existence of a cardiosplenic axis, wherein activation of hematopoietic tissues (notably in the spleen) results in liberation of proinflammatory leukocytes and accelerated atherosclerotic inflammation. However, it is presently unknown whether a cardiosplenic axis exists in humans and whether splenic activation relates to CVD risk. METHODS: (18)F-fluorodeoxyglucose ((18)FDG)-positron emission tomography (PET) imaging was performed in 508 individuals across 2 studies. In the first study, we performed FDG-PET imaging in 22 patients with recent ACS and 22 control subjects. FDG uptake was measured in spleen and arterial wall, whereas proinflammatory gene expression of circulating leukocytes was assessed by quantitative real-time polymerase chain reaction. In a second study, we examined the relationship between splenic tissue FDG uptake with subsequent CVD events during follow-up (median 4 years) in 464 patients who previously had undergone FDG-PET imaging. RESULTS: Splenic activity increased after ACS and was significantly associated with multiple indices of inflammation: 1) up-regulated gene expression of proinflammatory leukocytes; 2) increased C-reactive protein; and 3) increased arterial wall inflammation (FDG uptake). Moreover, in the second study, splenic activity (greater than or equal to the median) was associated with an increased risk of CVD events (hazard ratio [HR]: 3.3; 95% confidence interval [CI]: 1.5 to 7.3; p = 0.003), which remained significant after adjustment for CVD risk factors (HR: 2.26; 95% CI: 1.01 to 5.06; p = 0.04) and for arterial FDG uptake (HR: 2.68; 95% CI: 1.5 to 7.4; p = 0.02). CONCLUSIONS: Our findings demonstrate increased splenic metabolic activity after ACS and its association with proinflammatory remodeling of circulating leukocytes. Moreover, we observed that metabolic activity of the spleen independently predicted risk of subsequent CVD events. Collectively, these findings provide evidence of a cardiosplenic axis in humans similar to that shown in pre-clinical studies.
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Proteína C-Reativa/metabolismo , Fluordesoxiglucose F18 , Imagem Multimodal/métodos , Medição de Risco/métodos , Baço/metabolismo , Adulto , Idoso , Arterite/diagnóstico por imagem , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/métodos , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Compostos Radiofarmacêuticos , Fatores de Risco , Fatores de Tempo , Calcificação Vascular/diagnóstico por imagemRESUMO
OBJECTIVES: Recent data shows a relationship between aortic valve (AV) inflammation and calcification. However, direct evidence linking early valve inflammation (prior to hemodynamic compromise) to subsequent calcium (Ca) deposition is lacking in humans. We sought to test the hypothesis whether local AV inflammation predisposes to subsequent AV Ca deposition. METHODS: We identified 111 individuals (age 60[49, 68], 50.5% male) without active cancer or aortic stenosis who underwent 2 PET/CT studies 1-5 years apart for cancer surveillance. AV inflammation was determined by measuring FDG uptake (maximum standardized uptake value, SUVmax) within the AV on baseline PET/CT. Subsequent deposition of AV Ca was determined by comparing baseline and follow-up CT scans, determined as an increase in AV Ca volume score (CaVS). Patients were classified as "non-progressors" or "progressors" based on Square Root difference in CaVS (using a pre-determined cut-off value of 2.5). CT and PET measurements were conducted by 2 mutually blinded laboratories. RESULTS: During follow-up, AV Ca increased in 23 patients (20.2%) classified as "progressors", of whom 9 (9.2%) demonstrated subsequent 'incident' AV Ca. The AV SUVmax (mean ± SD) was higher in progressors vs. non-progressors (2.03 ± 0.52 vs.1.74 ± 0.36, p = 0.02) and especially in patients with-vs. without-incident AV Ca (2.28 ± 0.42 vs. 1.73 ± 0.36, p < 0.001). Moreover, AV inflammation (AV SUVmax) independently predicted subsequent calcification after adjusting for cardiovascular risk factors [OR (95%CI): 4.99 (1.30-19.15), p = 0.02]. CONCLUSION: The findings suggest that early AV inflammation may predispose to AV sclerosis. The evaluation of valvular metabolic activity may prove useful for developing a better understanding of calcific valve disease.
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Estenose da Valva Aórtica/diagnóstico , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/patologia , Calcinose/diagnóstico , Fluordesoxiglucose F18 , Inflamação/diagnóstico , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Tomografia Computadorizada por Raios X , Idoso , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/epidemiologia , Boston/epidemiologia , Calcinose/diagnóstico por imagem , Calcinose/epidemiologia , Progressão da Doença , Feminino , Humanos , Incidência , Inflamação/diagnóstico por imagem , Inflamação/epidemiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Análise Multivariada , Razão de Chances , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Fatores de Risco , Fatores de TempoRESUMO
BACKGROUND: Patients with familial hypercholesterolemia (FH) are characterized by elevated atherogenic lipoprotein particles, predominantly low-density lipoprotein cholesterol (LDL-C), which is associated with accelerated atherogenesis and increased cardiovascular risk. OBJECTIVES: This study used (18)F-fluorodeoxyglucose positron emission tomography ((18)FDG-PET) to investigate whether arterial inflammation is higher in patients with FH and, moreover, whether lipoprotein apheresis attenuates arterial wall inflammation in FH patients. METHODS: In total, 38 subjects were recruited: 24 FH patients and 14 normolipidemic controls. All subjects underwent FDG-PET imaging at baseline. Twelve FH patients who met the criteria for lipoprotein apheresis underwent apheresis procedures followed by a second FDG-PET imaging 3 days (range 1 to 4 days) after apheresis. Subsequently, the target-to-background ratio (TBR) of FDG uptake within the arterial wall was assessed. RESULTS: In FH patients, the mean arterial TBR was higher compared with healthy controls (2.12 ± 0.27 vs. 1.92 ± 0.19; p = 0.03). A significant correlation was observed between baseline arterial TBR and LDL-C (R = 0.37; p = 0.03) that remained significant after adjusting for statin use (ß = 0.001; p = 0.02) and atherosclerosis risk factors (ß = 0.001; p = 0.03). LDL-C levels were significantly reduced after lipoprotein apheresis (284 ± 118 mg/dl vs. 127 ± 50 mg/dl; p < 0.001). There was a significant reduction of arterial inflammation after lipoprotein apheresis (TBR: 2.05 ± 0.31 vs. 1.91 ± 0.33; p < 0.02). CONCLUSIONS: The arterial wall of FH patients is characterized by increased inflammation, which is markedly reduced after lipoprotein apheresis. This lends support to a causal role of apoprotein B-containing lipoproteins in arterial wall inflammation and supports the concept that lipoprotein-lowering therapies may impart anti-inflammatory effects by reducing atherogenic lipoproteins.
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Artérias/patologia , Remoção de Componentes Sanguíneos/métodos , Hiperlipoproteinemia Tipo II/terapia , Inflamação/terapia , Idoso , Aterosclerose/sangue , Estudos de Casos e Controles , LDL-Colesterol/sangue , Estudos Transversais , Feminino , Fluordesoxiglucose F18/química , Humanos , Hiperlipoproteinemia Tipo II/complicações , Inflamação/complicações , Lipoproteínas/química , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Tomografia por Emissão de Pósitrons/métodos , Estudos Prospectivos , Fatores de Risco , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVES: This study sought to determine whether arterial inflammation measured by (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET) improves prediction of cardiovascular disease (CVD) beyond traditional risk factors. BACKGROUND: It is unknown whether arterial (18)F-FDG uptake measured with routine PET imaging provides incremental value for predicting CVD events beyond Framingham risk score (FRS). METHODS: We consecutively identified 513 individuals from 6,088 patients who underwent (18)F-FDG-PET and computed tomography (CT) imaging at Massachusetts General Hospital between 2005 and 2008 and who met additional inclusion criteria: ≥30 years of age, no prior CVD, and free of cancer. CVD events were independently adjudicated, while blinded to clinical data, using medical records to determine incident stroke, transient ischemic attack, acute coronary syndrome, revascularization, new-onset angina, peripheral arterial disease, heart failure, or CVD death. FDG uptake was measured in the ascending aorta (as target-to-background-ratio [TBR]), while blinded to clinical data. RESULTS: During follow-up (median 4.2 years), 44 participants developed CVD (2 per 100 person-years at risk). TBR strongly predicted subsequent CVD independent of traditional risk factors (hazard ratio: 4.71; 95% confidence interval [CI]: 1.98 to 11.2; p < 0.001) and (hazard ratio: 4.13; 95% CI: 1.59 to 10.76; p = 0.004) after further adjustment for coronary calcium score. Addition of arterial PET measurement to FRS scores improved the C-statistic (mean ± standard error 0.62 ± 0.03 vs. 0.66 ± 0.03). Further, incorporation of TBR into a model with FRS variables resulted in an integrated discrimination of 5% (95% CI: 0.36 to 9.87). Net reclassification improvements were 27.48% (95% CI: 16.27 to 39.92) and 22.3% (95% CI: 11.54 to 35.42) for the 10% and 6% intermediate-risk cut points, respectively. Moreover, TBR was inversely associated with the timing of CVD (beta -0.096; p < 0.0001). CONCLUSIONS: Arterial FDG uptake, measured from routinely obtained PET/CT images, substantially improved incident CVD prediction beyond FRS among individuals undergoing cancer surveillance and provided information on the potential timing of such events.