RESUMO
BACKGROUND: Studies in humans and mice using the expression of an X-linked gene or lineage tracing, respectively, have suggested that clones of smooth muscle cells (SMCs) exist in human atherosclerotic lesions but are limited by either spatial resolution or translatability of the model. METHODS: Phenotypic clonality can be detected by X-chromosome inactivation patterns. We investigated whether clones of SMCs exist in unstable human atheroma using RNA in situ hybridization (BaseScope) to identify a naturally occurring 24-nucleotide deletion in the 3'UTR of the X-linked BGN (biglycan) gene, a proteoglycan highly expressed by SMCs. BGN-specific BaseScope probes were designed to target the wild-type or deletion mRNA. Three different coronary artery plaque types (erosion, rupture, and adaptive intimal thickening) were selected from heterozygous females for the deletion BGN. Hybridization of target RNA-specific probes was used to visualize the spatial distribution of mutants. A clonality index was calculated from the percentage of each probe in each region of interest. Spatial transcriptomics were used to identify differentially expressed transcripts within clonal and nonclonal regions. RESULTS: Less than one-half of regions of interest in the intimal plaque were considered clonal with the mean percent regions of interest with clonality higher in the intimal plaque than in the media. This was consistent for all plaque types. The relationship of the dominant clone in the intimal plaque and media showed significant concordance. In comparison with the nonclonal lesions, the regions with SMC clonality had lower expression of genes encoding cell growth suppressors such as CD74, SERF-2 (small EDRK-rich factor 2), CTSB (cathepsin B), and HLA-DPA1 (major histocompatibility complex, class II, DP alpha 1), among others. CONCLUSIONS: Our novel approach to examine clonality suggests atherosclerosis is primarily a disease of polyclonally and to a lesser extent clonally expanded SMCs and may have implications for the development of antiatherosclerotic therapies.
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Aterosclerose , Placa Aterosclerótica , Feminino , Humanos , Camundongos , Animais , Músculo Liso Vascular/metabolismo , Aterosclerose/patologia , Placa Aterosclerótica/patologia , Células Clonais/patologia , Proliferação de Células , Miócitos de Músculo Liso/metabolismo , RNARESUMO
BACKGROUND: During cardiomyocyte maturation, the centrosome, which functions as a microtubule organizing center in cardiomyocytes, undergoes dramatic structural reorganization where its components reorganize from being localized at the centriole to the nuclear envelope. This developmentally programmed process, referred to as centrosome reduction, has been previously associated with cell cycle exit. However, understanding of how this process influences cardiomyocyte cell biology, and whether its disruption results in human cardiac disease, remains unknown. We studied this phenomenon in an infant with a rare case of infantile dilated cardiomyopathy (iDCM) who presented with left ventricular ejection fraction of 18% and disrupted sarcomere and mitochondria structure. METHODS: We performed an analysis beginning with an infant who presented with a rare case of iDCM. We derived induced pluripotent stem cells from the patient to model iDCM in vitro. We performed whole exome sequencing on the patient and his parents for causal gene analysis. CRISPR/Cas9-mediated gene knockout and correction in vitro were used to confirm whole exome sequencing results. Zebrafish and Drosophila models were used for in vivo validation of the causal gene. Matrigel mattress technology and single-cell RNA sequencing were used to characterize iDCM cardiomyocytes further. RESULTS: Whole exome sequencing and CRISPR/Cas9 gene knockout/correction identified RTTN, the gene encoding the centrosomal protein RTTN (rotatin), as the causal gene underlying the patient's condition, representing the first time a centrosome defect has been implicated in a nonsyndromic dilated cardiomyopathy. Genetic knockdowns in zebrafish and Drosophila confirmed an evolutionarily conserved requirement of RTTN for cardiac structure and function. Single-cell RNA sequencing of iDCM cardiomyocytes showed impaired maturation of iDCM cardiomyocytes, which underlie the observed cardiomyocyte structural and functional deficits. We also observed persistent localization of the centrosome at the centriole, contrasting with expected programmed perinuclear reorganization, which led to subsequent global microtubule network defects. In addition, we identified a small molecule that restored centrosome reorganization and improved the structure and contractility of iDCM cardiomyocytes. CONCLUSIONS: This study is the first to demonstrate a case of human disease caused by a defect in centrosome reduction. We also uncovered a novel role for RTTN in perinatal cardiac development and identified a potential therapeutic strategy for centrosome-related iDCM. Future study aimed at identifying variants in centrosome components may uncover additional contributors to human cardiac disease.
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Cardiomiopatia Dilatada , Feminino , Gravidez , Animais , Humanos , Cardiomiopatia Dilatada/genética , Peixe-Zebra , Volume Sistólico , Função Ventricular Esquerda , Centrossomo/metabolismo , Miócitos CardíacosRESUMO
Vascular calcification (VC) is concomitant with atherosclerosis, yet it remains uncertain why rupture-prone high-risk plaques do not typically show extensive calcification. Intraplaque hemorrhage (IPH) deposits erythrocyte-derived cholesterol, enlarging the necrotic core and promoting high-risk plaque development. Pro-atherogenic CD163+ alternative macrophages engulf hemoglobin:haptoglobin (HH) complexes at IPH sites. However, their role in VC has never been examined to our knowledge. Here we show, in human arteries, the distribution of CD163+ macrophages correlated inversely with VC. In vitro experiments using vascular smooth muscle cells (VSMCs) cultured with HH-exposed human macrophage - M(Hb) - supernatant reduced calcification, while arteries from ApoE-/- CD163-/- mice showed greater VC. M(Hb) supernatant-exposed VSMCs showed activated NF-κB, while blocking NF-κB attenuated the anticalcific effect of M(Hb) on VSMCs. CD163+ macrophages altered VC through NF-κB-induced transcription of hyaluronan synthase (HAS), an enzyme that catalyzes the formation of the extracellular matrix glycosaminoglycan, hyaluronan, within VSMCs. M(Hb) supernatants enhanced HAS production in VSMCs, while knocking down HAS attenuated its anticalcific effect. NF-κB blockade in ApoE-/- mice reduced hyaluronan and increased VC. In human arteries, hyaluronan and HAS were increased in areas of CD163+ macrophage presence. Our findings highlight an important mechanism by which CD163+ macrophages inhibit VC through NF-κB-induced HAS augmentation and thus promote the high-risk plaque development.
Assuntos
Aterosclerose , Placa Aterosclerótica , Calcificação Vascular , Camundongos , Humanos , Animais , NF-kappa B , Ácido Hialurônico , Camundongos Knockout para ApoE , Macrófagos , Aterosclerose/complicações , Apolipoproteínas E/genéticaRESUMO
Importance: Unexplained sudden cardiac death (SCD) describes SCD with no cause identified. Genetic testing helps to diagnose inherited cardiac diseases in unexplained SCD; however, the associations between pathogenic or likely pathogenic (P/LP) variants of inherited cardiomyopathies (CMs) and arrhythmia syndromes and the risk of unexplained SCD in both White and African American adults living the United States has never been systematically examined. Objective: To investigate cases of unexplained SCD to determine the frequency of P/LP genetic variants of inherited CMs and arrhythmia syndromes. Design, Setting, and Participants: This genetic association study included 683 African American and White adults who died of unexplained SCD and were included in an autopsy registry. Overall, 413 individuals had DNA of acceptable quality for genetic sequencing. Data were collected from January 1995 to December 2015. A total of 30 CM genes and 38 arrhythmia genes were sequenced, and variants in these genes, curated as P/LP, were examined to study their frequency. Data analysis was performed from June 2018 to March 2021. Main Outcomes and Measures: The frequency of P/LP variants for CM or arrhythmia in individuals with unexplained SCD. Results: The median (interquartile range) age at death of the 413 included individuals was 41 (29-48) years, 259 (62.7%) were men, and 208 (50.4%) were African American adults. A total of 76 patients (18.4%) with unexplained SCD carried variants considered P/LP for CM and arrhythmia genes. In total, 52 patients (12.6%) had 49 P/LP variants for CM, 22 (5.3%) carried 23 P/LP variants for arrhythmia, and 2 (0.5%) had P/LP variants for both CM and arrhythmia. Overall, 41 P/LP variants for hypertrophic CM were found in 45 patients (10.9%), 9 P/LP variants for dilated CM were found in 11 patients (2.7%), and 10 P/LP variants for long QT syndrome were found in 11 patients (2.7%). No significant difference was found in clinical and heart characteristics between individuals with or without P/LP variants. African American and White patients were equally likely to harbor P/LP variants. Conclusions and Relevance: In this large genetic association study of community cases of unexplained SCD, nearly 20% of patients carried P/LP variants, suggesting that genetics may contribute to a significant number of cases of unexplained SCD. Our findings regarding both the association of unexplained SCD with CM genes and race-specific genetic variants suggest new avenues of study for this poorly understood entity.
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Negro ou Afro-Americano , Morte Súbita Cardíaca/patologia , Estudos de Associação Genética/métodos , Cardiopatias/complicações , Sistema de Registros , População Branca , Adulto , Autopsia , Morte Súbita Cardíaca/etnologia , Morte Súbita Cardíaca/etiologia , Feminino , Seguimentos , Testes Genéticos , Cardiopatias/etnologia , Cardiopatias/genética , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estados Unidos/epidemiologiaRESUMO
[Figure: see text].
Assuntos
Apolipoproteína L1/genética , Negro ou Afro-Americano/genética , Doença da Artéria Coronariana/genética , Trombose Coronária/genética , Variação Genética , Placa Aterosclerótica , Adulto , Autopsia , Causas de Morte , Doença da Artéria Coronariana/etnologia , Doença da Artéria Coronariana/mortalidade , Doença da Artéria Coronariana/patologia , Trombose Coronária/etnologia , Trombose Coronária/mortalidade , Trombose Coronária/patologia , Morte Súbita Cardíaca/etnologia , Morte Súbita Cardíaca/patologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , Maryland/epidemiologia , Pessoa de Meia-Idade , Necrose , Fenótipo , Sistema de Registros , Medição de Risco , Fatores de Risco , Ruptura EspontâneaRESUMO
PURPOSE: To compare the long-term vascular healing responses of healthy swine iliofemoral arteries treated with a polymer-free paclitaxel-eluting stent (Z-PES, Zilver PTX) or a fluoropolymer-based paclitaxel-eluting stent (FP-PES, Eluvia). MATERIALS AND METHODS: Bilateral iliofemoral arteries in 20 swine were treated with a Z-PES (n = 16) or a FP-PES (n = 24) and were examined histologically at 1, 3, 6, and 12 months. RESULTS: Morphometric analysis revealed larger external and internal elastic lamina, stent expansion, and lumen area in the FP-PES than in the Z-PES at all timepoints. Luminal narrowing was similar in the 2 groups at 1 month; however, greater stenosis was observed in the Z-PES group at 3 months, with significant regression thereafter, resulting in equivalent stenosis at 6 and 12 months. Greater drug effect and less complete vessel healing were found in the FP-PES group at all timepoints, including greater numbers of malapposed struts with excessive fibrin deposition at 1 and 3 months, than in the Z-PES group. Three of 12 FP-PESs from the 6- and 12-month cohorts also showed circumferential medial disruption with peri-strut inflammation, whereas no abnormal findings were observed in contralateral Z-PESs. CONCLUSIONS: Prolonged paclitaxel release with the presence of a permanent polymer may contribute to the differential vascular responses seen for the Z-PES and FP-PES groups, including medial layer disruption and aneurysmal vessel degeneration that was sometimes observed in the FP-PES group. These distinct features should be confirmed by pathology and in vivo imaging of human superficial femoral arteries to determine their clinical significance.
Assuntos
Fármacos Cardiovasculares/administração & dosagem , Stents Farmacológicos , Procedimentos Endovasculares/instrumentação , Artéria Femoral/efeitos dos fármacos , Paclitaxel/administração & dosagem , Polímeros , Animais , Fármacos Cardiovasculares/efeitos adversos , Procedimentos Endovasculares/efeitos adversos , Artéria Femoral/diagnóstico por imagem , Artéria Femoral/patologia , Neointima , Paclitaxel/efeitos adversos , Desenho de Prótese , Suínos , Porco Miniatura , Fatores de Tempo , Remodelação Vascular/efeitos dos fármacos , Cicatrização/efeitos dos fármacosRESUMO
Persons with HIV are at increased risk for diabetes mellitus compared with individuals without HIV. Adipose tissue is an important regulator of glucose and lipid metabolism, and adipose tissue T cells modulate local inflammatory responses and, by extension, adipocyte function. Persons with HIV and diabetes have a high proportion of CX3CR1+ GPR56+ CD57+ (C-G-C+) CD4+ T cells in adipose tissue, a subset of which are cytomegalovirus specific, whereas individuals with diabetes but without HIV have predominantly CD69+ CD4+ T cells. Adipose tissue CD69+ and C-G-C+ CD4+ T cell subsets demonstrate higher receptor clonality compared with the same cells in blood, potentially reflecting antigen-driven expansion, but C-G-C+ CD4+ T cells have a more inflammatory and cytotoxic RNA transcriptome. Future studies will explore whether viral antigens have a role in recruitment and proliferation of pro-inflammatory C-G-C+ CD4+ T cells in adipose tissue of persons with HIV.
Assuntos
Tecido Adiposo/imunologia , Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/imunologia , Análise de Célula Única , Linfócitos T CD8-Positivos/imunologia , Citomegalovirus/imunologia , Infecções por Citomegalovirus/imunologia , Diabetes Mellitus/metabolismo , Humanos , Análise de Célula Única/métodos , Subpopulações de Linfócitos T/imunologiaRESUMO
Introduction: In-stent restenosis (ISR) has been one of the biggest limitations to the success of percutaneous coronary intervention for the treatment of coronary artery disease (CAD). The introduction of drug-eluting stent (DES) was a revolution in the treatment of CAD because these devices drastically reduced ISR to very low levels (<5%). Subsequently, newer generation DES treatments have overcome the drawbacks of first-generation DES, i.e. delayed endothelialization, and late stent thrombosis. However, the issue of late ISR, including neoatherosclerosis after DES implantation especially in high-risk patients and complex lesions, still exists as a challenge to be overcome.Areas covered: We discuss the mechanisms of ISR development including neoatherosclerosis, past and current clinical status of ISR, and methods to predict and overcome this issue from pathological and clinical points of view.Expert opinion: The initial drawbacks of first-generation DES, such as delayed endothelial healing and subsequent risk of late stent thrombosis, have been improved upon by the current generation DES. To achieve better long-term clinical outcomes, further titration of drug-release and polymer degradation profile, strut thickness as well as material innovation are needed.
Assuntos
Doença da Artéria Coronariana , Reestenose Coronária , Stents Farmacológicos , Intervenção Coronária Percutânea , Angiografia Coronária , Reestenose Coronária/epidemiologia , Reestenose Coronária/etiologia , Stents Farmacológicos/efeitos adversos , Humanos , Intervenção Coronária Percutânea/efeitos adversos , Fatores de Risco , Stents , Resultado do TratamentoRESUMO
RATIONALE AND OBJECTIVES: Develop a deep learning-based algorithm using the U-Net architecture to measure abdominal fat on computed tomography (CT) images. MATERIALS AND METHODS: Sequential CT images spanning the abdominal region of seven subjects were manually segmented to calculate subcutaneous fat (SAT) and visceral fat (VAT). The resulting segmentation maps of SAT and VAT were augmented using a template-based data augmentation approach to create a large dataset for neural network training. Neural network performance was evaluated on both sequential CT slices from three subjects and randomly selected CT images from the upper, central, and lower abdominal regions of 100 subjects. RESULTS: Both subcutaneous and abdominal cavity segmentation images created by the two methods were highly comparable with an overall Dice similarity coefficient of 0.94. Pearson's correlation coefficients between the subcutaneous and visceral fat volumes quantified using the two methods were 0.99 and 0.99 and the overall percent residual squared error were 5.5% and 8.5%. Manual segmentation of SAT and VAT on the 555 CT slices used for testing took approximately 46 hours while automated segmentation took approximately 1 minute. CONCLUSION: Our data demonstrates that deep learning methods utilizing a template-based data augmentation strategy can be employed to accurately and rapidly quantify total abdominal SAT and VAT with a small number of training images.
Assuntos
Aprendizado Profundo , Gordura Intra-Abdominal , Gordura Abdominal , Humanos , Gordura Intra-Abdominal/diagnóstico por imagem , Gordura Subcutânea/diagnóstico por imagem , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVE: To co-register conventional computed tomography angiography (CTA), with ex vivo micro-computed tomography (microCT) and histology of popliteal atherosclerotic plaques. Improving the non-invasive imaging capabilities may be valuable to advance patient care with peripheral arterial obstructive disease towards lesion and individual based treatment. METHODS: In this prospective observational study, 12 popliteal arteries from 11 symptomatic patients who had undergone transfemoral amputations for chronic limb threatening ischaemia and who had pre-operative CTA, were analysed ex vivo by microCT and histology. A total of 353 histological cross sections were co-registered with microCT and CTA, and classified as: lipid rich (LP, n = 26), fibrous (FP, n = 80), or calcific (CP, n = 247) plaques. CTA and microCT plaque density was calculated in 791 regions of interest as Hounsfield units (HU). RESULTS: CTA and microCT could identify plaque components that were confirmed by histology such as fibrous tissue (FP), lipid pool/core (LP), and calcification (CP). MicroCT densities were 77.8 HU for FP (IQR 52.8, 129.5 HU), -28.4 HU for LP (IQR -87.1, 13.2 HU), and 3826.0 HU for CP (IQR 2989.0, 4501.0 HU). CTA densities of the three components of the plaque were: 78.0 HU for FP (IQR 59.5, 119.8 HU), 32.5 HU for LP (IQR 15.0, 42 HU), and 641.5 HU for CP (IQR 425.8, 1135 HU). The differences were statistically significant between the HU densitometric characteristics among the three groups (p < .0001) for both imaging modalities. Overall, microCT performed better diagnostically than conventional CTA for the three types of plaques: areas under the receiving operator characteristics curve were greater for microCT than CTA for FP (0.97 vs. 0.90), for LP (0.88 vs. 0.67), and for CP (0.97 vs. 0.90). CONCLUSION: CTA and microCT can be used to identify histological atherosclerotic plaque components, with better diagnostic performance for microCT. This study demonstrates the feasibility of using microCT to assess plaque morphology lesions in a manner that approaches histology thus becoming a useful tool for ex vivo assessment of atherosclerosis and towards lesion based treatment.
Assuntos
Angiografia por Tomografia Computadorizada , Isquemia/diagnóstico por imagem , Doença Arterial Periférica/diagnóstico por imagem , Placa Aterosclerótica/diagnóstico por imagem , Microtomografia por Raio-X , Idoso , Idoso de 80 Anos ou mais , Doença Crônica , Angiografia por Tomografia Computadorizada/métodos , Feminino , Humanos , Isquemia/patologia , Perna (Membro)/irrigação sanguínea , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/patologia , Placa Aterosclerótica/patologia , Artéria Poplítea/diagnóstico por imagem , Artéria Poplítea/patologia , Estudos Prospectivos , Microtomografia por Raio-X/métodosRESUMO
RATIONALE: Coronary artery disease (CAD) is a major cause of morbidity and mortality worldwide. Recent genome-wide association studies revealed 163 loci associated with CAD. However, the precise molecular mechanisms by which the majority of these loci increase CAD risk are not known. Vascular smooth muscle cells (VSMCs) are critical in the development of CAD. They can play either beneficial or detrimental roles in lesion pathogenesis, depending on the nature of their phenotypic changes. OBJECTIVE: To identify genetic variants associated with atherosclerosis-relevant phenotypes in VSMCs. METHODS AND RESULTS: We quantified 12 atherosclerosis-relevant phenotypes related to calcification, proliferation, and migration in VSMCs isolated from 151 multiethnic heart transplant donors. After genotyping and imputation, we performed association mapping using 6.3 million genetic variants. We demonstrated significant variations in calcification, proliferation, and migration. These phenotypes were not correlated with each other. We performed genome-wide association studies for 12 atherosclerosis-relevant phenotypes and identified 4 genome-wide significant loci associated with at least one VSMC phenotype. We overlapped the previously identified CAD loci with our data set and found nominally significant associations at 79 loci. One of them was the chromosome 1q41 locus, which harbors MIA3. The G allele of the lead risk single nucleotide polymorphism (SNP) rs67180937 was associated with lower VSMC MIA3 expression and lower proliferation. Lentivirus-mediated silencing of MIA3 (melanoma inhibitory activity protein 3) in VSMCs resulted in lower proliferation, consistent with human genetics findings. Furthermore, we observed a significant reduction of MIA3 protein in VSMCs in thin fibrous caps of late-stage atherosclerotic plaques compared to early fibroatheroma with thick and protective fibrous caps in mice and humans. CONCLUSIONS: Our data demonstrate that genetic variants have significant influences on VSMC function relevant to the development of atherosclerosis. Furthermore, high MIA3 expression may promote atheroprotective VSMC phenotypic transitions, including increased proliferation, which is essential in the formation or maintenance of a protective fibrous cap.
Assuntos
Aterosclerose/genética , Aterosclerose/patologia , Variação Genética , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Placa Aterosclerótica , Animais , Translocador Nuclear Receptor Aril Hidrocarboneto/genética , Translocador Nuclear Receptor Aril Hidrocarboneto/metabolismo , Aterosclerose/metabolismo , Movimento Celular , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , Feminino , Fibrose , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Camundongos Knockout para ApoE , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Fenótipo , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Despite advances in lipid-lowering therapies, people with diabetes continue to experience more limited cardiovascular benefits. In diabetes, hyperglycemia sustains inflammation and preempts vascular repair. We tested the hypothesis that the receptor for advanced glycation end-products (RAGE) contributes to these maladaptive processes. We report that transplantation of aortic arches from diabetic, Western diet-fed Ldlr-/- mice into diabetic Ager-/- (Ager, the gene encoding RAGE) versus WT diabetic recipient mice accelerated regression of atherosclerosis. RNA-sequencing experiments traced RAGE-dependent mechanisms principally to the recipient macrophages and linked RAGE to interferon signaling. Specifically, deletion of Ager in the regressing diabetic plaques downregulated interferon regulatory factor 7 (Irf7) in macrophages. Immunohistochemistry studies colocalized IRF7 and macrophages in both murine and human atherosclerotic plaques. In bone marrow-derived macrophages (BMDMs), RAGE ligands upregulated expression of Irf7, and in BMDMs immersed in a cholesterol-rich environment, knockdown of Irf7 triggered a switch from pro- to antiinflammatory gene expression and regulated a host of genes linked to cholesterol efflux and homeostasis. Collectively, this work adds a new dimension to the immunometabolic sphere of perturbations that impair regression of established diabetic atherosclerosis and suggests that targeting RAGE and IRF7 may facilitate vascular repair in diabetes.
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Aterosclerose/metabolismo , Colesterol/metabolismo , Inflamação/metabolismo , Fator Regulador 7 de Interferon/metabolismo , Macrófagos/metabolismo , Animais , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor para Produtos Finais de Glicação Avançada/genética , Receptor para Produtos Finais de Glicação Avançada/metabolismoRESUMO
Mammalian target of rapamycin (mTOR) inhibitors have been applied to vascular coronary devices to avoid neointimal growth and have become the predominant pharmacological agents used to prevent restenosis. mTOR inhibitors can affect not only proliferating vascular smooth muscle cells but also endothelial cells and therefore can result in delayed healing of the vessel including endothelialization. Emerging evidence suggests accelerated atherosclerosis due to the downstream negative effects on endothelial barrier functional recovery. The development of neoatherosclerosis within the neointima of drug-eluting stents can result in late thrombotic events. This type of problematic healing response may open the way for specific mTOR kinase inhibitors, such as ATP-competitive mTOR inhibitors. These inhibitors demonstrate a better healing profile than traditional limus-based drug-eluting stent and their clinical efficacy remains unknown.
Assuntos
Doença da Artéria Coronariana/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Aterosclerose/tratamento farmacológico , Humanos , Inibidores de Proteínas Quinases/química , Serina-Treonina Quinases TOR/metabolismoRESUMO
The data presented here are related to the research article, entitled Genetic linkage of oxidative stress with cardiometabolic traits in an intercross derived from hyperlipidemic mouse strains, published in Atherosclerosis 2019 Dec 3;293:1-10 (D. Fuller, A.T. Grainger, A. Manichaikul, W. Shi). The supporting materials include original genotypic and phenotypic data obtained from 266 female F2 mice derived from an intercross between C57BL/6 (B6) and BALB/cJ (BALB) Apoe-/- mice. F2 mice were fed 12 weeks of Western diet, starting at 6 weeks of age. Plasma levels of HDL, LDL cholesterol, triglycerides, glucose and malondialdehyde (MDA) and atherosclerosis in the aortic root and the left carotid artery were measured. 127 microsatellite markers across the entire genome were genotyped. The data is provided in the format ready for QTL analysis with J/qtl and MapManager QTX.
RESUMO
Introduction: Coronary bifurcation lesions are involved in up to 20% of all percutaneous coronary interventions (PCI). However, bifurcation lesion intervention is associated with a high complication rate, and optimal treatment of coronary bifurcation is an ongoing debate.Areas covered: Both different stenting techniques and a variety of devices have been suggested for bifurcation treatment, including the use of conventional coronary stents, bioresorbable vascular scaffolds (BVS), drug-eluting balloons (DEB), and stents dedicated to bifurcations. This review will summarize different therapeutic approaches with their advantages and shortcomings, with special emphasis on histopathologic and physiologic effects of each treatment strategy.Expert opinion: Histopathology and clinical data have shown that a more simple treatment strategy is beneficial in bifurcation lesions, achieving superior results. Bifurcation interventions through balloon angioplasty or placement of stents can importantly alter the bifurcation's geometry and accordingly modify local flow conditions. Computational fluid dynamics (CFD) studies have shown that the outcome of bifurcation interventions is governed by local hemodynamic shear conditions. Minimizing detrimental flow conditions as much as possible should be the ultimate strategy to achieve long-term success of bifurcation interventions.
Assuntos
Stents/tendências , Aterosclerose/terapia , Humanos , Alicerces Teciduais/química , Resultado do TratamentoRESUMO
BACKGROUND AND AIMS: Oxidative stress is associated with cardiometabolic traits in observational studies, yet the underlying causal relationship remains unclear. Apolipoprotein E-deficient (Apoe-/-) mice develop significant hyperlipidemia and hyperglycemia on a Western diet. Here we conducted linkage analysis to investigate genetic connections between cardiometabolic traits and oxidative stress. METHODS: 266 female F2 mice were generated from an intercross between C57BL/6 (B6) and BALB/c (BALB) Apoe-/- mice and fed 12 weeks of Western diet. Plasma levels of HDL, LDL cholesterol, triglycerides, glucose and malondialdehyde (MDA) and atherosclerosis in aortic root and left carotid artery were measured. 127 microsatellite markers across the genome were genotyped. RESULTS: One significant locus at 78.3 cM on chromosome (Chr) 1 (LOD score: 3.85), named Mda1, and two suggestive loci near 60.3 cM on Chr1 (LOD score: 2.32, named Mda2 due to replication in a separate cross) and 19.6 cM on Chr4 (LOD score: 2.34) were identified for MDA levels. Mda1 coincided precisely with loci for LDL, triglyceride, glucose, and body weight and overlapped with a locus for atherosclerosis in the aortic root. Plasma LDL, triglyceride, and glucose explained 25.5, 19.2, and 24.2% of the variation in MDA levels of F2 mice, respectively. After correction for triglyceride or LDL, QTLs for MDA on Chr1 and Chr4 disappeared. QTLs on Chr1 disappeared, remained on Chr4, and additional QTLs on Chr12 and Chr13 were detected after correction for glucose. The QTL on Chr12, named Mda3, had a significant LOD score of 8.034 and peaked 62.22 at cM. CONCLUSIONS: We demonstrated a causative role for cardiometabolic traits in oxidative stress and identified hyperlipidemia and hyperglycemia as a major driver of oxidative stress.
Assuntos
Apolipoproteínas E/genética , LDL-Colesterol/genética , Hiperlipidemias/genética , Estresse Oxidativo , Triglicerídeos/genética , Animais , LDL-Colesterol/sangue , Cruzamentos Genéticos , Modelos Animais de Doenças , Feminino , Ligação Genética , Genótipo , Hiperlipidemias/sangue , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Triglicerídeos/sangueRESUMO
The presence of macrophages within the plaque is a defining hallmark of atherosclerosis. Macrophages are exposed to various microenvironments such as oxidized lipids and cytokines which effect their phenotypic differentiation and activation. Classically, macrophages have been divided into two groups: M1 and M2 macrophages induced by T-helper 1 and T-helper 2 cytokines, respectively. However, for a decade, greater phenotypic heterogeneity and plasticity of these cells have since been reported in various models. In addition to M1 and M2 macrophage phenotypes, the concept of additional macrophage phenotypes such as M (Hb), Mox, and M4 has emerged. Understanding the mechanisms and functions of distinct phenotype of macrophages can lead to determination of their potential role in atherosclerotic plaque pathogenesis. However, there are still many unresolved controversies regarding their phenotype and function with respect to atherosclerosis. Here, we summarize and focus on the differential subtypes of macrophages in atherosclerotic plaques and their differing functional roles based upon microenvironments such as lipid, intraplaque hemorrhage, and plaque regression.