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[Figure: see text].
Assuntos
Aorta/diagnóstico por imagem , Aneurisma Aórtico/diagnóstico por imagem , Dissecção Aórtica/diagnóstico por imagem , Ruptura Aórtica/diagnóstico por imagem , Aortografia , Angiografia por Tomografia Computadorizada , Meios de Contraste , Nanopartículas , Ácidos Tri-Iodobenzoicos , Microtomografia por Raio-X , Dissecção Aórtica/induzido quimicamente , Dissecção Aórtica/patologia , Angiotensina II , Animais , Aorta/patologia , Aneurisma Aórtico/induzido quimicamente , Aneurisma Aórtico/patologia , Ruptura Aórtica/induzido quimicamente , Ruptura Aórtica/patologia , Dieta Hiperlipídica , Dilatação Patológica , Modelos Animais de Doenças , Progressão da Doença , Diagnóstico Precoce , Masculino , Camundongos Endogâmicos C57BL , Valor Preditivo dos Testes , Fatores de TempoRESUMO
BACKGROUND: A declining amplitude of body temperature circadian rhythm (BTCR) predicts decompensation or death in cardiomyopathic hamsters. We tested the hypothesis that changes in BTCR amplitude accompany significant changes in left ventricular (LV) size and function. METHODS AND RESULTS: Using intraperitoneal transmitters, we continuously monitored the temperature of 30 male BIO TO-2 Syrian dilated cardiomyopathic hamsters. Cosinor analysis was used to detect significant changes--defined as changes >1 standard deviation from the baseline amplitude for 3 consecutive days--in BTCR amplitude over each hamster's lifespan. The Student t-test was used to compare BTCR variability and LV size and function (as assessed by 2D echocardiography) between baseline and the time that BTCR amplitude declined. All hamsters received 10 mg/kg furosemide daily. At the time of BTCR amplitude decline, functional parameters had changed significantly (P < .0001) from baseline: ejection fraction (0.31 ± 0.09% vs. 0.52 ± 0.08%), LV end-systolic volume (0.11 ± 0.03 vs. 0.05 ± 0.02 cm(3)), and LV end-diastolic volume (0.16 ± 0.04 vs. 0.10 ± 0.03 cm(3)). CONCLUSIONS: In decompensated cardiomyopathic hamsters, a decline in BTCR amplitude was associated with progression of heart failure and cardiac decompensation. Variation in BTCR warrants further investigation because of its potential implications for the diagnosis and treatment of cardiovascular disorders.
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Temperatura Corporal , Ritmo Circadiano/fisiologia , Insuficiência Cardíaca/patologia , Disfunção Ventricular Esquerda/patologia , Animais , Cricetinae , Modelos Animais de Doenças , Insuficiência Cardíaca/diagnóstico por imagem , Modelos Lineares , Masculino , Medição de Risco , Sístole , Ultrassonografia , Disfunção Ventricular Esquerda/diagnóstico por imagemRESUMO
BACKGROUND: Low body temperature is an independent predictor of poor prognosis in patients with congestive heart failure. The cardiomyopathic hamster develops progressive biventricular dysfunction, resulting in heart failure death at 9 months to 1 year of life. Our goal was to use cardiomyopathic hamsters to examine the relationship between body temperature and heart failure decompensation and death. METHODS AND RESULTS: To this end, we implanted temperature and activity transducers with telemetry into the peritoneal space of 46 male Bio-TO-2 Syrian cardiomyopathic hamsters. Multiple techniques, including computing mean temperature, frequency domain analysis, and nonlinear analysis, were used to determine the most useful method for predicting poor prognosis. Data from 44 hamsters were included in our final analysis. We detected a decline in core body temperature in 98% of the hamsters 8+/-4 days before death (P < .001). We examined the dominant frequency of temperature variation (ie, the circadian rhythm) by using cosinor analysis, which revealed a significant decrease in the amplitude of the body temperature circadian rhythm 8 weeks before death (0.28 degrees C; 95% CI, 0.26-0.31) compared to baseline (0.36 degrees C; 95% CI, 0.34-0.39; P=.005). The decline in the circadian temperature variation preceded all other evidence of decompensation. CONCLUSIONS: We conclude that a decrease in the amplitude of the body temperature circadian rhythm precedes fatal decompensation in cardiomyopathic hamsters. Continuous temperature monitoring may be useful in predicting preclinical decompensation in patients with heart failure and in identifying opportunities for therapeutic intervention.
Assuntos
Temperatura Corporal/fisiologia , Causas de Morte , Ritmo Circadiano , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Animais , Cardiomiopatias/mortalidade , Cardiomiopatias/fisiopatologia , Cricetinae , Modelos Animais de Doenças , Progressão da Doença , Masculino , Monitorização Fisiológica/métodos , Probabilidade , Sensibilidade e Especificidade , Análise de Sobrevida , Disfunção Ventricular Esquerda/mortalidade , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Direita/mortalidade , Disfunção Ventricular Direita/fisiopatologiaRESUMO
In these preclinical studies, we describe ADx-001, an Aß-targeted liposomal macrocyclic gadolinium (Gd) imaging agent, for MRI of amyloid plaques. The targeting moiety is a novel lipid-PEG conjugated styryl-pyrimidine. An MRI-based contrast agent such as ADx-001 is attractive because of the lack of radioactivity, ease of distribution, long shelf life, and the prevalence of MRI scanners. Dose-ranging efficacy studies were performed on a 1 T MRI scanner using a transgenic APP/PSEN1 mouse model of Alzheimer's disease. ADx-001 was tested at 0.10, 0.15, and 0.20 mmol Gd/kg. Gold standard post-mortem amyloid immunostaining was used for the determination of sensitivity and specificity. ADx-001 toxicity was evaluated in rats and monkeys at doses up to 0.30 mmol Gd/kg. ADx-001 pharmacokinetics were determined in monkeys and its tissue distribution was evaluated in rats. ADx-001-enhanced MRI demonstrated significantly higher (p < 0.05) brain signal enhancement in transgenic mice relative to wild type mice at all dose levels. ADx-001 demonstrated high sensitivity at 0.20 and 0.15 mmol Gd/kg and excellent specificity at all dose levels for in vivo imaging of ß amyloid plaques. ADx-001 was well tolerated in rats and monkeys and exhibited the slow clearance from circulation and tissue biodistribution typical of PEGylated nanoparticles.
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Doença de Alzheimer/diagnóstico por imagem , Amiloide/metabolismo , Meios de Contraste/administração & dosagem , Imageamento por Ressonância Magnética/métodos , Placa Amiloide/diagnóstico por imagem , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Meios de Contraste/farmacocinética , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Macaca fascicularis , Masculino , Camundongos , Camundongos Transgênicos , Fragmentos de Peptídeos/metabolismo , Placa Amiloide/genética , Placa Amiloide/metabolismo , Presenilina-1/genética , Ratos , Distribuição TecidualRESUMO
INTRODUCTION: Visualization of the retroplacental clear space (RPCS) may provide critical insight into the development of abnormally invasive placenta (AIP). In this pre-clinical study, we characterized the appearance of the RPCS on magnetic resonance imaging (MRI) during the second half of gestation using a liposomal gadolinium contrast agent (liposomal-Gd). MATERIALS AND METHODS: Studies were performed in fifteen pregnant C57BL/6 mice at 10, 12, 14, 16, and 18 days of gestation. MRI was performed on a 1T permanent magnet scanner. Pre-contrast and post-contrast images were acquired using T1-weighted gradient-recalled echo (T1w-GRE) and T2-weighted fast spin echo (T2w-FSE) sequences. Animals were euthanized after imaging and feto-placental units harvested for histological examination. Visualization of the RPCS was scored by a maternal-fetal radiologist and quantified by measuring the contrast-to-noise ratio (CNR) on T1w images. Feto-placental features were segmented for analysis of volumetric changes during gestation. RESULTS: Contrast-enhanced T1w images enabled the visualization of structural changes in placental development between days 10-18 of gestation. Although the placental margin on the fetal side was clearly visible at all time points, the RPCS was partially visible at day 10 of gestation, and clearly visible by day 12. Hematoxylin and eosin (H&E) staining of the placental tissue corroborated MRI findings of structural and morphological changes in the placenta. CONCLUSIONS: Contrast-enhanced MR imaging using liposomal-Gd enabled adequate visualization of the retroplacental clear space starting at day 12 of gestation. The agent also enabled characterization of placental structure and morphological changes through gestation.
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Imageamento por Ressonância Magnética/métodos , Placenta/diagnóstico por imagem , Animais , Meios de Contraste , Feminino , Gadolínio , Idade Gestacional , Lipossomos , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Placenta/anatomia & histologia , Placentação , GravidezRESUMO
Non-invasive methods for estimating placental fractional blood volume (FBV) are of great interest for characterization of vascular perfusion in placentae during pregnancy to identify placental insufficiency that may be indicative of local ischemia or fetal growth restriction (FGR). Nanoparticle contrast-enhanced magnetic resonance imaging (CE-MRI) may enable direct placental FBV estimation and may provide a reliable, 3D alternative to assess maternal-side placental perfusion. In this pre-clinical study, we investigated if placental FBV at 14, 16, and 18 days of gestation could be estimated through contrast-enhanced MRI using a long circulating blood-pool liposomal gadolinium contrast agent that does not penetrate the placental barrier. Placental FBV estimates of 0.47 ± 0.06 (E14.5), 0.50 ± 0.04 (E16.5), and 0.52 ± 0.04 (E18.5) were found through fitting pre-contrast and post-contrast T1 values in placental tissue using a variable flip angle method. MRI-derived placental FBV was validated against nanoparticle contrast-enhanced computed tomography (CE-CT) derived placental FBV, where signal is directly proportional to the concentration of iodine contrast agent. The results demonstrate successful estimation of the placental FBV, with values statistically indistinguishable from the CT derived values.
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Meios de Contraste/metabolismo , Placenta/irrigação sanguínea , Placenta/diagnóstico por imagem , Animais , Volume Sanguíneo , Feminino , Gadolínio , Lipossomos , Imageamento por Ressonância Magnética/métodos , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas , Placenta/metabolismo , GravidezRESUMO
Congestive heart failure has long been one of the most serious medical conditions in the United States; in fact, in the United States alone, heart failure accounts for 6.5 million days of hospitalization each year. One important goal of heart-failure therapy is to inhibit the progression of congestive heart failure through pharmacologic and device-based therapies. Therefore, there have been efforts to develop device-based therapies aimed at improving cardiac reserve and optimizing pump function to meet metabolic requirements. The course of congestive heart failure is often worsened by other conditions, including new-onset arrhythmias, ischemia and infarction, valvulopathy, decompensation, end-organ damage, and therapeutic refractoriness, that have an impact on outcomes. The onset of such conditions is sometimes heralded by subtle pathophysiologic changes, and the timely identification of these changes may promote the use of preventive measures. Consequently, device-based methods could in the future have an important role in the timely identification of the subtle pathophysiologic changes associated with congestive heart failure.
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Técnicas de Diagnóstico Cardiovascular/instrumentação , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/fisiopatologia , Desfibriladores Implantáveis , Insuficiência Cardíaca/diagnóstico , Humanos , Monitorização Fisiológica/instrumentação , Valor Preditivo dos TestesRESUMO
Inflammation drives the degradation of atherosclerotic plaque, yet there are no non-invasive techniques available for imaging overall inflammation in atherosclerotic plaques, especially in the coronary arteries. To address this, we have developed a clinically relevant system to image overall inflammatory cell burden in plaque. Here, we describe a targeted contrast agent (THI0567-targeted liposomal-Gd) that is suitable for magnetic resonance (MR) imaging and binds with high affinity and selectivity to the integrin α4ß1(very late antigen-4, VLA-4), a key integrin involved in recruiting inflammatory cells to atherosclerotic plaques. This liposomal contrast agent has a high T1 relaxivity (~2 × 105 mM-1s-1 on a particle basis) resulting in the ability to image liposomes at a clinically relevant MR field strength. We were able to visualize atherosclerotic plaques in various regions of the aorta in atherosclerosis-prone ApoE-/- mice on a 1 Tesla small animal MRI scanner. These enhanced signals corresponded to the accumulation of monocyte/macrophages in the subendothelial layer of atherosclerotic plaques in vivo, whereas non-targeted liposomal nanoparticles did not demonstrate comparable signal enhancement. An inflammatory cell-targeted method that has the specificity and sensitivity to measure the inflammatory burden of a plaque could be used to noninvasively identify patients at risk of an acute ischemic event.
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Integrina alfa4beta1/química , Integrina alfa4beta1/metabolismo , Imageamento por Ressonância Magnética , Placa Aterosclerótica/diagnóstico por imagem , Placa Aterosclerótica/metabolismo , Animais , Modelos Animais de Doenças , Integrina alfa4beta1/antagonistas & inibidores , Ligantes , Lipossomos , Imageamento por Ressonância Magnética/métodos , Camundongos , Camundongos Knockout , Modelos Moleculares , Conformação Molecular , Placa Aterosclerótica/patologia , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
Silent myocardial ischemia (SMI) is increasingly being recognized as part of the spectrum of ischemic heart disease. The spectrum of SMI ranges from asymptomatic coronary artery disease to critical illness necessitating intensive care. Although many diagnostic tools have been used to identify low- and high-risk subgroups, their use is limited by modest sensitivities and specificities. The present review identifies current concepts in the management of SMI in various clinical settings, as well as emerging technologies that may simplify the diagnosis and treatment of this condition.
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In a rat model of right free wall replacement, the transplantation of an engineered multilayered myocardial patch fabricated from a polycaprolactone membrane supporting a chitosan/heart matrix hydrogel induces significant muscular and vascular remodeling and results in a significantly higher right ventricular ejection fraction compared to use of a commercially available pericardium patch.