RESUMO
Our current understanding of the spread and neurodegenerative effects of tau neurofibrillary tangles (NFTs) within the medial temporal lobe (MTL) during the early stages of Alzheimer's Disease (AD) is limited by the presence of confounding non-AD pathologies and the two-dimensional (2-D) nature of conventional histology studies. Here, we combine ex vivo MRI and serial histological imaging from 25 human MTL specimens to present a detailed, 3-D characterization of quantitative NFT burden measures in the space of a high-resolution, ex vivo atlas with cytoarchitecturally-defined subregion labels, that can be used to inform future in vivo neuroimaging studies. Average maps show a clear anterior to poster gradient in NFT distribution and a precise, spatial pattern with highest levels of NFTs found not just within the transentorhinal region but also the cornu ammonis (CA1) subfield. Additionally, we identify granular MTL regions where measures of neurodegeneration are likely to be linked to NFTs specifically, and thus potentially more sensitive as early AD biomarkers.
Assuntos
Doença de Alzheimer , Imageamento por Ressonância Magnética , Emaranhados Neurofibrilares , Lobo Temporal , Proteínas tau , Humanos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/metabolismo , Lobo Temporal/patologia , Proteínas tau/metabolismo , Masculino , Feminino , Idoso , Imageamento por Ressonância Magnética/métodos , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Idoso de 80 Anos ou mais , Autopsia , Neuroimagem/métodos , Pessoa de Meia-Idade , Imageamento post mortemRESUMO
Objective.The selective multiple quantum coherence (Sel-MQC) sequence is a magnetic resonance spectroscopy (MRS) technique used to detect lactate and suppress co-resonant lipid signalsin vivo. The coherence pathways of J-coupled lipids upon the sequence, however, have not been studied, hindering a logical design of the sequence to fully attenuate lipid signals. The objective of this study is to elucidate the coherence pathways of J-coupled lipids upon the Sel-MQC sequence and find a strategy to effectively suppress lipid signals from these pathways while keeping the lactate signal.Approach.The product operator formalism was used to express the evolutions of the J-coupled spins of lipids and lactate. The transformations of the product operators by the spectrally selective pulses of the sequence were calculated by using the off-resonance rotation matrices. The coherence pathways and the conversion rates of the individual pathways were derived from them. Experiments were performed on phantoms and two human subjects at 3 T.Main results.The coherence pathways contributing to the various lipid resonance signals by the Sel-MQC sequence depending on the gradient ratios and RF pulse lengths were identified. Theoretical calculations of the signals from the determined coherence pathways and signal attenuations by gradients matched the experimental data very well. Lipid signals from fatty tissues of the subjects were successfully suppressed to the noise level by using the gradient ratio -0.8:-1:2 or 1:0.8:2. The new gradient ratios kept the lactate signal the same as with the previously used gradient ratio 0:-1:2.Significance.The study has elucidated the coherence pathways of J-coupled lipids upon the Sel-MQC sequence and demonstrated how lipid signals can be effectively suppressed while keeping lactate signals by using information from the coherence pathway analysis. The findings enable applying the Sel-MQC sequence to lactate detection in an environment of high concentrations of lipids.
Assuntos
Ácido Láctico , Imageamento por Ressonância Magnética , Humanos , Ácido Láctico/análise , Ácido Láctico/química , Ácido Láctico/metabolismo , Lipídeos/química , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/métodos , Imagens de FantasmasRESUMO
Frontotemporal lobar degeneration (FTLD) is a heterogeneous spectrum of age-associated neurodegenerative diseases that include two main pathologic categories of tau (FTLD-Tau) and TDP-43 (FTLD-TDP) proteinopathies. These distinct proteinopathies are often clinically indistinguishable during life, posing a major obstacle for diagnosis and emerging therapeutic trials tailored to disease-specific mechanisms. Moreover, MRI-derived measures have had limited success to date discriminating between FTLD-Tau or FTLD-TDP. T2*-weighted (T2*w) ex vivo MRI has previously been shown to be sensitive to non-heme iron in healthy intracortical lamination and myelin, and to pathological iron deposits in amyloid-beta plaques and activated microglia in Alzheimer's disease neuropathologic change (ADNC). However, an integrated, ex vivo MRI and histopathology approach is understudied in FTLD. We apply joint, whole-hemisphere ex vivo MRI at 7 T and histopathology to the study autopsy-confirmed FTLD-Tau (n = 4) and FTLD-TDP (n = 3), relative to ADNC disease-control brains with antemortem clinical symptoms of frontotemporal dementia (n = 2), and an age-matched healthy control. We detect distinct laminar patterns of novel iron-laden glial pathology in both FTLD-Tau and FTLD-TDP brains. We find iron-positive ameboid and hypertrophic microglia and astrocytes largely in deeper GM and adjacent WM in FTLD-Tau. In contrast, FTLD-TDP presents prominent superficial cortical layer iron reactivity in astrocytic processes enveloping small blood vessels with limited involvement of adjacent WM, as well as more diffuse distribution of punctate iron-rich dystrophic microglial processes across all GM lamina. This integrated MRI/histopathology approach reveals ex vivo MRI features that are consistent with these pathological observations distinguishing FTLD-Tau and FTLD-TDP subtypes, including prominent irregular hypointense signal in deeper cortex in FTLD-Tau whereas FTLD-TDP showed upper cortical layer hypointense bands and diffuse cortical speckling. Moreover, differences in adjacent WM degeneration and iron-rich gliosis on histology between FTLD-Tau and FTLD-TDP were also readily apparent on MRI as hyperintense signal and irregular areas of hypointensity, respectively that were more prominent in FTLD-Tau compared to FTLD-TDP. These unique histopathological and radiographic features were distinct from healthy control and ADNC brains, suggesting that iron-sensitive T2*w MRI, adapted to in vivo application at sufficient resolution, may eventually offer an opportunity to improve antemortem diagnosis of FTLD proteinopathies using tissue-validated methods.
Assuntos
Demência Frontotemporal , Degeneração Lobar Frontotemporal , Proteínas de Ligação a DNA , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/patologia , Degeneração Lobar Frontotemporal/diagnóstico por imagem , Degeneração Lobar Frontotemporal/patologia , Humanos , Inflamação/diagnóstico por imagem , Ferro , Imageamento por Ressonância Magnética , Proteínas tauRESUMO
Tau neurofibrillary tangle (NFT) pathology in the medial temporal lobe (MTL) is closely linked to neurodegeneration, and is the early pathological change associated with Alzheimer's disease (AD). To elucidate patterns of structural change in the MTL specifically associated with tau pathology, we compared high-resolution ex vivo MRI scans of human postmortem MTL specimens with histology-based pathological assessments of the MTL. MTL specimens were obtained from twenty-nine brain donors, including patients with AD, other dementias, and individuals with no known history of neurological disease. Ex vivo MRI scans were combined using a customized groupwise diffeomorphic registration approach to construct a 3D probabilistic atlas that captures the anatomical variability of the MTL. Using serial histology imaging in eleven specimens, we labelled the MTL subregions in the atlas based on cytoarchitecture. Leveraging the atlas and neuropathological ratings of tau and TAR DNA-binding protein 43 (TDP-43) pathology severity, morphometric analysis was performed to correlate regional MTL thickness with the severity of tau pathology, after correcting for age and TDP-43 pathology. We found significant correlations between tau pathology and thickness in the entorhinal cortex (ERC) and stratum radiatum lacunosum moleculare (SRLM). When focusing on cases with low levels of TDP-43 pathology, we found strong associations between tau pathology and thickness in the ERC, SRLM and the subiculum/cornu ammonis 1 (CA1) subfields of the hippocampus, consistent with early Braak stages.
Assuntos
Imageamento Tridimensional/métodos , Emaranhados Neurofibrilares/patologia , Neuroimagem/métodos , Lobo Temporal/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Atlas como Assunto , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Lobo Temporal/patologia , Proteínas tauRESUMO
Tau protein neurofibrillary tangles are closely linked to neuronal/synaptic loss and cognitive decline in Alzheimer's disease and related dementias. Our knowledge of the pattern of neurofibrillary tangle progression in the human brain, critical to the development of imaging biomarkers and interpretation of in vivo imaging studies in Alzheimer's disease, is based on conventional two-dimensional histology studies that only sample the brain sparsely. To address this limitation, ex vivo MRI and dense serial histological imaging in 18 human medial temporal lobe specimens (age 75.3 ± 11.4 years, range 45 to 93) were used to construct three-dimensional quantitative maps of neurofibrillary tangle burden in the medial temporal lobe at individual and group levels. Group-level maps were obtained in the space of an in vivo brain template, and neurofibrillary tangles were measured in specific anatomical regions defined in this template. Three-dimensional maps of neurofibrillary tangle burden revealed significant variation along the anterior-posterior axis. While early neurofibrillary tangle pathology is thought to be confined to the transentorhinal region, we found similar levels of burden in this region and other medial temporal lobe subregions, including amygdala, temporopolar cortex, and subiculum/cornu ammonis 1 hippocampal subfields. Overall, the three-dimensional maps of neurofibrillary tangle burden presented here provide more complete information about the distribution of this neurodegenerative pathology in the region of the cortex where it first emerges in Alzheimer's disease, and may help inform the field about the patterns of pathology spread, as well as support development and validation of neuroimaging biomarkers.
Assuntos
Mapeamento Encefálico/métodos , Imageamento Tridimensional/métodos , Emaranhados Neurofibrilares/patologia , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/patologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: Fenofibrate has shown to reduce major cardiovascular events and slow angiographic progression of coronary atherosclerosis. The postulated mechanism of action is via the activation of peroxisomal proliferator-activated receptor-alpha (PPAR-alpha), a nuclear transcription factor that controls a variety of cellular functions. We investigated the anti-atherogenic effects of fenofibrate on previously established experimental atherosclerotic lesions. METHOD: Atherosclerotic lesions were induced in the abdominal aorta of New Zealand white (NZW) rabbits (n=19) by a combination of a double-balloon injury and a 9-month hypercholesterolemic diet. The rabbits were randomized into placebo or fenofibrate group. The corresponding treatments were added to the hypercholesterolemic diet. All rabbits underwent MRI examination at randomization and after 6 months of treatment, and were then sacrificed for histopathology. RESULTS: LDL-cholesterol was similarly elevated at randomization and follow-up, and was not significantly modified by fenofibrate therapy. HDL-cholesterol decreased (-27+/-10%, p=0.04) in the placebo and increased (+36.8+/-2%, p=0.04) in the fenofibrate group. MRI showed comparable vessel wall area (VWA) at randomization in both groups. At 15months, a significant increase in VWA was seen in the placebo group (15+/-4%, p=0.007), while fenofibrate treatment was associated with a regression (-11+/-4%, p=0.041) of previously established lesions. Fenofibrate also decreased macrophage and increased smooth muscle cell/collagen content of atherosclerotic lesions. CONCLUSION: MRI measurements can, in conjunction with in vitro histological measurements, contribute to the understanding of the actions of pharmacologic agents in experimental models of atherosclerosis. Fenofibrate significantly regresses atherosclerotic lesions and induced changes in plaque composition associated with a more "stable" phenotype (reduced macrophages and increased SMC). These observations support the potential anti-atherogenic effects of PPAR-alpha agonists.
Assuntos
Aterosclerose/tratamento farmacológico , Fenofibrato/farmacologia , Hipercolesterolemia/tratamento farmacológico , Hipolipemiantes/farmacologia , Imageamento por Ressonância Magnética/métodos , Animais , Aterosclerose/patologia , Hipercolesterolemia/patologia , Lipoproteínas/sangue , Masculino , Coelhos , Artéria Renal/patologiaRESUMO
PURPOSE: To compare two multislice turbo spin-echo (TSE) carotid artery wall imaging techniques at 1.5 T and 3.0 T, and to investigate the feasibility of higher spatial resolution carotid artery wall imaging at 3.0 T. MATERIALS AND METHODS: Multislice proton density-weighted (PDW), T2-weighted (T2W), and T1-weighted (T1W) inflow/outflow saturation band (IOSB) and rapid extended coverage double inversion-recovery (REX-DIR) TSE carotid artery wall imaging was performed on six healthy volunteers at 1.5 T and 3.0 T using time-, coverage-, and spatial resolution-matched (0.47 x 0.47 x 3 mm3) imaging protocols. To investigate whether improved signal-to-noise ratio (SNR) at 3.0 T could allow for improved spatial resolution, higher spatial resolution imaging (0.31 x 0.31 x 3 mm3) was performed at 3.0 T. Carotid artery wall SNR, carotid lumen SNR, and wall-lumen contrast-to-noise ratio (CNR) were measured. RESULTS: Signal gain at 3.0 T relative to 1.5 T was observed for carotid artery wall SNR (223%) and wall-lumen CNR (255%) in all acquisitions (P < 0.025). IOSB and REX-DIR images were found to have different levels of SNR and CNR (P < 0.05) with IOSB values observed to be larger. Normalized to a common imaging time, the higher spatial resolution imaging at 3.0 T and the lower spatial resolution imaging at 1.5 T provided similar levels of wall-lumen CNR (P = NS). CONCLUSION: Multislice carotid wall imaging at 3.0 T with IOSB and REX-DIR benefits from improved SNR and CNR relative to 1.5 T, and allows for higher spatial resolution carotid artery wall imaging.
Assuntos
Artérias Carótidas/anatomia & histologia , Aumento da Imagem/métodos , Imageamento por Ressonância Magnética/métodos , Magnetismo , Adulto , Sangue , Estudos de Viabilidade , Feminino , Humanos , Aumento da Imagem/instrumentação , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/instrumentação , Masculino , Valores de ReferênciaRESUMO
PURPOSE: To comparatively analyze two fast in vivo multislice black-blood carotid artery vessel wall imaging techniques with and without cardiac gating. MATERIALS AND METHODS: Eight subjects with carotid artery atherosclerosis, and four healthy subjects were studied using two black-blood multislice techniques: rapid extended coverage double inversion recovery (REX-DIR), and inflow/outflow saturation band (IOSB) rapid acquisition with relaxation enhancement (RARE) multislice acquisitions. Quantitative, qualitative, and morphometric analyses were performed on images. RESULTS: Gating produced significantly lower values for the REX-DIR sequence with respect to signal intensity in muscle and the carotid artery wall, whereas it had no effect on flow suppression compared to non-gated images. For the IOSB sequences, gating had no significant effect on signal intensity of muscle and the carotid artery wall, but worsened flow suppression. REX-DIR and IOSB sequences were statistically different with respect to signal intensity of muscle (with REX-DIR sequences having lower values), while no statistical significance was observed for flow suppression and wall delineation. A morphologic analysis of the vessel wall and lumen comparing REX-DIR gated, IOSB gated, REX-DIR non-gated, and IOSB non-gated sequences revealed no significant differences between the acquisition techniques tested. CONCLUSION: Non-gated sequences may be used instead of gated sequences in atherosclerotic vessel wall imaging without compromising image quality. This may shorten examination time and improve patient comfort.
Assuntos
Algoritmos , Artérias Carótidas/patologia , Doenças das Artérias Carótidas/diagnóstico , Eletrocardiografia/métodos , Interpretação de Imagem Assistida por Computador/métodos , Arteriosclerose Intracraniana/diagnóstico , Imageamento por Ressonância Magnética/métodos , Adolescente , Adulto , Anatomia Transversal/métodos , Humanos , Aumento da Imagem/métodos , Imageamento Tridimensional/métodos , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: Plaque rupture leading to thrombosis and occlusion is a major source of acute coronary syndromes. Methods for accurate detection of thrombosis in veins or arteries may expand our capacity to predict clinical complications and guide therapeutic decisions. We sought to demonstrate the feasibility of in vivo acute thrombus detection using a fibrin-targeted gadolinium based magnetic resonance contrast agent (EP-1242). METHODS: Carotid thrombosis was induced in 12 guinea pigs by external injury and blood stasis. MR images were obtained after thrombus formation pre- and post- EP-1242 injection, using a T1-weighted high-resolution fast spin-echo sequence. RESULTS: An occlusive fibrin-rich thrombus was achieved in all animals. Correlation for thrombus location was excellent between MRI and histology (R=0.94; P<0.001). Contrast-enhanced MRI significantly improved thrombus detection when compared to non contrast-enhanced MRI (100% versus 41.6%; p<0.001). In addition, thrombus signal intensity (SI) was significantly increased after injection (SI(30 min-post)=4.39+/-0.12 versus 1.0; p<0.001). Contrast-to-noise ratio (CNR) was 43.8+/-7.2, 30 min post-injection (P<0.001). No enhancement was seen in the uninjured control arteries. CONCLUSIONS: We demonstrate the feasibility of in vivo MRI for carotid thrombus detection using a novel fibrin-targeted contrast agent. This technique significantly improves detection of small size thrombi in an animal model of occlusive fibrin-rich thrombosis.
Assuntos
Trombose das Artérias Carótidas/diagnóstico , Meios de Contraste/farmacologia , Fibrina , Imageamento por Ressonância Magnética/métodos , Peptídeos Cíclicos/farmacologia , Doença Aguda , Animais , Meios de Contraste/química , Modelos Animais de Doenças , Cobaias , Peptídeos Cíclicos/químicaRESUMO
OBJECTIVES: This study sought to compare the effects of aggressive and conventional lipid lowering by two different dosages of the same statin on early human atherosclerotic lesions using serial noninvasive magnetic resonance imaging (MRI). BACKGROUND: Regression of atherosclerotic lesions by lipid-lowering therapy has been reported. METHODS: Using a double-blind design, newly diagnosed hypercholesterolemic patients (n = 51) with asymptomatic aortic and/or carotid atherosclerotic plaques were randomized to 20 mg/day (n = 29) or 80 mg/day (n = 22) simvastatin. Mean follow-up was 18.1 months. A total of 93 aortic and 57 carotid plaques were detected and sequentially followed up by MRI every six months after lipid-lowering initiation. The primary MRI end point was change in vessel wall area (VWA) as a surrogate for atherosclerotic burden. RESULTS: Both statin doses reduced significantly total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) versus baseline (p < 0.001). Total cholesterol decreased by 26% versus 33% and LDL-C by 36% versus 46% in the conventional (20 mg) versus aggressive (80 mg) simvastatin groups, respectively. Although the simvastatin 80-mg group had significantly higher baseline TC and LDL-C levels, both groups reached similar absolute values after treatment. A significant reduction in VWA was already observed by 12 months. No difference on vascular effects was detected between the randomized doses. Post-hoc analysis showed that patients reaching mean on-treatment LDL-C < or = 100 mg/dl had larger decreases in plaque size. CONCLUSIONS: Effective and protracted lipid-lowering therapy with simvastatin is associated with a significant regression of atherosclerotic lesions. No difference in vessel wall changes was seen between high and conventional doses of simvastatin. Changes in vessel wall parameters are more related to LDL-C reduction rather than to the dose of statin.
Assuntos
Arteriosclerose/tratamento farmacológico , Hipolipemiantes/administração & dosagem , Sinvastatina/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Aorta Torácica/patologia , Arteriosclerose/complicações , Arteriosclerose/patologia , Artérias Carótidas/patologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Hipercolesterolemia/complicações , Hipercolesterolemia/tratamento farmacológico , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de TempoRESUMO
A two-dimensional rapid extended coverage (REX) rapid acquisition with relaxation enhancement (RARE) pulse sequence for simultaneous multisection double inversion-recovery (DIR) black-blood vessel wall magnetic resonance (MR) imaging was developed. Aortic vessel wall MR imaging was performed in five healthy subjects (mean age, 33 years +/- 4 [SD]) and five patients with atherosclerotic disease (mean age, 67 years +/- 11.7). Shortening of blood inversion time and imaging of multiple sections after single DIR block resulted in simultaneous acquisition of up to 20 aortic wall sections in less than 1 minute (spatial resolution, 0.97 x 0.97 x 3 mm(3)). Higher signal-to-noise ratios per unit time per section (16.0 +/- 2.45 vs 7.5 +/- 1.10, P <.05), no significant changes in contrast-to-noise ratios (15.0 +/- 5.3 vs 20.1 +/- 3.9, P >.05), and 17-fold improvement in acquisition time compared with those at conventional single-section DIR RARE imaging was achieved. Use of the REX method significantly shortened aortic imaging acquisition times without degrading image quality.
Assuntos
Aorta/anatomia & histologia , Imageamento por Ressonância Magnética/métodos , Adulto , Idoso , Aorta/patologia , Doenças da Aorta/diagnóstico , Arteriosclerose/diagnóstico , Eletrocardiografia , Feminino , Humanos , MasculinoRESUMO
PURPOSE: To reduce long examination times of black-blood vessel wall imaging by acquiring multiple slices simultaneously and by using parallel acquisition techniques. MATERIALS AND METHODS: DIR-rapid acquisition with relaxation enhancement (RARE) techniques imaging up to 10 simultaneous slices per acquisition with single and multiple 180 degrees -reinversion pulses were developed. A slab-selective reinversion multislice DIR-RARE sequence incorporating generalized autocalibrating partially parallel acquisitions (GRAPPA) imaging was implemented. Four-channel and eight-channel carotid coils were built to test these sequences. A total of 11 subjects were studied. Contrast-to-noise ratio (CNR) and signal-to-noise ratio (SNR) efficiency factor (SEF, SNR/unit time/slice) were measured from aortic images of three healthy subjects to determine optimal MR parameters. The DIR-RARE-GRAPPA sequence was run on aortas and carotid arteries of the five remaining healthy subjects and three atherosclerotic patients with optimal parameters (acquisition times 12-21 seconds). RESULTS: SEFs of slab-selective protocols were significantly higher than those of slice-selective protocols, and SEFs of DIR-RARE-GRAPPA protocols were significantly higher than corresponding non-GRAPPA protocols (P < 0.05). CNR was not significantly different for all imaging protocols. The DIR-RARE-GRAPPA multislice sequence showed 8.35-fold time improvement vs. single-slice DIR-2RARE sequence. CONCLUSION: Future MRI atherosclerotic plaque studies can be performed in substantially shorter times using these methods.
Assuntos
Doenças da Aorta/diagnóstico , Arteriosclerose/diagnóstico , Doenças das Artérias Carótidas/diagnóstico , Imageamento por Ressonância Magnética/métodos , Adulto , Idoso , Aorta/anatomia & histologia , Aorta/patologia , Artérias Carótidas/anatomia & histologia , Artérias Carótidas/patologia , Humanos , Pessoa de Meia-Idade , Processamento de Sinais Assistido por ComputadorRESUMO
OBJECTIVES: We sought to investigate the anti-atherogenic effects of a selective peroxisomal proliferator-activated receptor-gamma (PPAR-gamma) agonist and simvastatin, as well as their combination, over time, in a rabbit model of experimental atherosclerosis. BACKGROUND: The PPARs are nuclear transcription factors that control a variety of cellular functions, with the potential effects required to induce plaque regression and stabilization. METHODS: Atherosclerosis was induced in rabbits (n = 37) by the combination of double-balloon injury and a nine-month high-cholesterol (HC) diet. The rabbits were randomized into a continued HC diet, a normal chow (NC) diet, NC plus simvastatin, NC plus PPAR-gamma agonist, and NC plus simvastatin plus PPAR-gamma agonist. All rabbits underwent magnetic resonance imaging (MRI) at randomization and after six months of treatment and were then sacrificed for histopathologic study. RESULTS: All groups had a similar vessel wall area by MRI (8.45 +/- 0.65 mm(2), p = NS between groups) at randomization. Significant progression was seen in the HC diet group (15 +/- 4%, p < 0.01). In the NC and NC plus PPAR-gamma agonist groups, progression was abolished (-2.5 +/- 3% and -4.5 +/- 5%, respectively; p = NS). The NC plus simvastatin and NC plus simvastatin plus PPAR-gamma agonist groups had significant plaque regression (-12 +/- 4% [p < 0.05] and -22 +/- 4% [p < 0.01], respectively). Regression was independent of plasma lipid levels. All NC groups had similar lipid profiles at the end of treatment. Histopathologic analysis of the NC groups showed a decreased macrophage content and matrix metalloproteinase activity and an increased smooth muscle cell/collagen content of lesions. CONCLUSIONS: Our data indicate that normalization of plasma lipid levels abolishes progression of atherosclerosis. Simvastatin elicits regression of atherosclerotic lesions, and the combination simvastatin plus PPAR-gamma agonist has additive regression effects on plaque. This is paralleled by structural alterations in plaque composition, which may increase plaque stability. These observations support the beneficial effects of statins on atherosclerosis and show additional anti-atherogenic benefits of combining a PPAR-gamma agonist with simvastatin.
Assuntos
Anti-Inflamatórios/uso terapêutico , Arteriosclerose/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Receptores Citoplasmáticos e Nucleares/agonistas , Sinvastatina/uso terapêutico , Fatores de Transcrição/agonistas , Animais , Arteriosclerose/diagnóstico , Sinergismo Farmacológico , Imageamento por Ressonância Magnética , Masculino , Modelos Animais , Coelhos , Indução de RemissãoRESUMO
BACKGROUND: Statins are widely used to treat hypercholesterolemia and atherosclerotic disease. Noninvasive MRI allows serial monitoring of atherosclerotic plaque size changes. Our aim was to investigate the effects of lipid lowering with simvastatin on atherosclerotic lesions. METHODS AND RESULTS: A total of 44 aortic and 32 carotid artery plaques were detected in 21 asymptomatic hypercholesterolemic patients at baseline. The effects of statin on these atherosclerotic lesions were evaluated as changes versus baseline in lumen area (LA), vessel wall thickness (VWT), and vessel wall area (VWA) by MRI. Maximal reduction of plasma total and LDL cholesterol by simvastatin (23% and 38% respectively; P<0.01 versus baseline) was achieved after approximately 6 weeks of therapy and maintained thereafter throughout the study. Significant (P<0.01) reductions in maximal VWT and VWA at 12 months (10% and 11% for aortic and 8% and 11% for carotid plaques, respectively), without changes in LA, have been reported. Further decreases in VWT and VWA ranging from 12% to 20% were observed at 18 and 24 months. A slight but significant increase (ranging from 4% to 6%) in LA was seen in both carotid and aortic lesions at these later time points. CONCLUSION: The present study demonstrates that maintained lipid-lowering therapy with simvastatin is associated with significant regression of established atherosclerotic lesions in humans. Our observations indicate that lipid-lowering therapy is associated with sustained vascular remodeling and emphasize the need for longer-term treatment.
Assuntos
Arteriosclerose/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Lipídeos/sangue , Sinvastatina/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Aorta Torácica/efeitos dos fármacos , Arteriosclerose/complicações , Arteriosclerose/diagnóstico , Artérias Carótidas/efeitos dos fármacos , Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Seguimentos , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/complicações , Hipolipemiantes/uso terapêutico , Angiografia por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Indução de Remissão , Tempo , Resultado do Tratamento , Grau de Desobstrução Vascular/efeitos dos fármacosRESUMO
OBJECTIVES: The purpose of this study was to evaluate the potential of magnetic resonance (MR) to detect arterial thrombotic obstruction and define thrombus age. BACKGROUND; Arterial thrombi underlie the clinical consequences of atherosclerosis and are not reliably detected by current noninvasive diagnostic techniques. METHODS: Carotid thrombi were induced in swine (n = 7) by arterial injury. Serial high-resolution in vivo MR images were obtained using black-blood T1-weighted (T1W) and T2-weighted (T2W) sequences in a clinical 1.5T MR system at 6 h, 1 day and at 1, 2, 3, 6 and 9 weeks. At each time point one animal was sacrificed and the occluded carotid artery processed for histopathology. Thrombus signal intensity (SI) was normalized to that of the adjacent muscle. Thrombus age was assessed based on MR appearance by two blinded independent observers. RESULTS: Thrombus appearance and relative SI revealed characteristic temporal changes in multicontrast-weighted MR images, reflecting histologic changes in the composition. Acute thrombus appeared very bright on the T2W images, facilitating the detection. Signal intensity was 197 +/- 25% at 6 h, peaking at 1 week (246 +/- 51%), reaching a plateau by 6 weeks (120 +/- 15%). At six weeks, complete thrombus organization was confirmed histologically. The T1W images had similar pattern with lower SI than T2W. Age definition using visual appearance was highly accurate (Pearson's chi-square with 4 df ranging from 96 to 132 and Cohen's kappa at 0.81 to 0.94). Agreement between observers was substantial (Pearson chi-square with 4 df = 91.5, kappa = 0.79). CONCLUSIONS: Magnetic resonance imaging is a promising tool to noninvasively detect arterial thrombosis. Measurement of SI and the characteristic visual appearance of the thrombus have the potential to define thrombus age.