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BACKGROUND: In patients with coronary artery disease who are being evaluated for percutaneous coronary intervention (PCI), procedures can be guided by fractional flow reserve (FFR) or intravascular ultrasonography (IVUS) for decision making regarding revascularization and stent implantation. However, the differences in clinical outcomes when only one method is used for both purposes are unclear. METHODS: We randomly assigned 1682 patients who were being evaluated for PCI for the treatment of intermediate stenosis (40 to 70% occlusion by visual estimation on coronary angiography) in a 1:1 ratio to undergo either an FFR-guided or IVUS-guided procedure. FFR or IVUS was to be used to determine whether to perform PCI and to assess PCI success. In the FFR group, PCI was to be performed if the FFR was 0.80 or less. In the IVUS group, the criteria for PCI were a minimal lumen area measuring either 3 mm2 or less or measuring 3 to 4 mm2 with a plaque burden of more than 70%. The primary outcome was a composite of death, myocardial infarction, or revascularization at 24 months after randomization. We tested the noninferiority of the FFR group as compared with the IVUS group (noninferiority margin, 2.5 percentage points). RESULTS: The frequency of PCI was 44.4% among patients in the FFR group and 65.3% among those in the IVUS group. At 24 months, a primary-outcome event had occurred in 8.1% of the patients in the FFR group and in 8.5% of those in the IVUS group (absolute difference, -0.4 percentage points; upper boundary of the one-sided 97.5% confidence interval, 2.2 percentage points; P = 0.01 for noninferiority). Patient-reported outcomes as reported on the Seattle Angina Questionnaire were similar in the two groups. CONCLUSIONS: In patients with intermediate stenosis who were being evaluated for PCI, FFR guidance was noninferior to IVUS guidance with respect to the composite primary outcome of death, myocardial infarction, or revascularization at 24 months. (Funded by Boston Scientific; FLAVOUR ClinicalTrials.gov number, NCT02673424.).
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Doença da Artéria Coronariana , Reserva Fracionada de Fluxo Miocárdico , Infarto do Miocárdio , Intervenção Coronária Percutânea , Ultrassonografia de Intervenção , Constrição Patológica , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/fisiopatologia , Doença da Artéria Coronariana/terapia , Humanos , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/terapia , Intervenção Coronária Percutânea/métodos , Resultado do Tratamento , Ultrassonografia de Intervenção/métodosRESUMO
Phthalates are common endocrine disruptors. The placental barrier can be crossed by phthalates and may have a negative impact on the health of the fetus. However, the association between prenatal exposure to phthalates and birth size is still debatable. Here, we performed this meta-analysis to assess the relationship between prenatal phthalates exposure and birth size. Eighteen studies were finally included by searching PubMed, Embase, Scopus, Ovid, and Web of Science databases and standardized regression coefficients and standard errors were used to pool effect size. Our results showed that prenatal exposure to MMP (=-0.04, 95%CI: -0.08, -0.01) and MEP (=-0.01, 95%CI: -0.01, -0.002) was significantly associated with birth weight. However, no significant associations were identified for phthalate exposure with birth length, head circumference and chest circumference. Because the limiting of studies, more high-quality case-control studies or cohort studies are urgently needed to draw the best conclusions.
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The activity of a gene newly integrated into a chromosome depends on the genomic context of the integration site. This "position effect" has been widely reported, although the other side of the coin, that is, how integration affects the local chromosomal environment, has remained largely unexplored, as have the mechanism and phenotypic consequences of this "externality" of the position effect. Here, we examined the transcriptome profiles of approximately 250 Saccharomyces cerevisiae strains, each with GFP integrated into a different locus of the wild-type strain. We found that in genomic regions enriched in essential genes, GFP expression tended to be lower, and the genes near the integration site tended to show greater expression reduction. Further joint analysis with public genome-wide histone modification profiles indicated that this effect was associated with H3K4me2. More importantly, we found that changes in the expression of neighboring genes, but not GFP expression, significantly altered the cellular growth rate. As a result, genomic loci that showed high GFP expression immediately after integration were associated with growth disadvantages caused by elevated expression of neighboring genes, ultimately leading to a low total yield of GFP in the long run. Our results were consistent with competition for transcriptional resources among neighboring genes and revealed a previously unappreciated facet of position effects. This study highlights the impact of position effects on the fate of exogenous gene integration and has significant implications for biological engineering and the pathology of viral integration into the host genome.
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Efeitos da Posição Cromossômica , Mutagênese Insercional , Transcriptoma , Aptidão Genética , Código das Histonas , Saccharomyces cerevisiaeRESUMO
BACKGROUND: Fractional flow reserve (FFR) is a widely used gold standard to evaluate ischemia-causing lesions. A new method of non-invasive approach, termed as AccuFFRct, for calculating FFR based on coronary computed tomography angiography (CCTA) and computational fluid dynamics (CFD) has been proposed. However, its diagnostic accuracy has not been validated. OBJECTIVES: This study sought to present a novel approach for non-invasive computation of FFR and evaluate its diagnostic performance in patients with coronary stenosis. METHODS: A total of 54 consecutive patients with 78 vessels from a single center who underwent CCTA and invasive FFR measurement were retrospectively analyzed. The CT-derived FFR values were computed using a novel CFD-based model (AccuFFRct, ArteryFlow Technology Co., Ltd., Hangzhou, China). Diagnostic performance of AccuFFRct and CCTA in detecting hemodynamically significant coronary artery disease (CAD) was evaluated using the invasive FFR as a reference standard. RESULTS: Diagnostic accuracy, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for AccuFFRct in detecting FFR ≤ 0.8 on per-patient basis were 90.7, 89.5, 91.4, 85.0 and 94.1%, respectively, while those of CCTA were 38.9, 100.0, 5.71, 36.5 and 100.0%, respectively. The correlation between AccuFFRct and FFR was good (r = 0.76 and r = 0.65 on per-patient and per-vessel basis, respectively, both p < 0.0001). Area under the curve (AUC) values of AccuFFRct for identifying ischemia per-patient and per-vessel basis were 0.945 and 0.925, respectively. There was much higher accuracy, specificity and AUC for AccuFFRct compared with CCTA. CONCLUSIONS: AccuFFRct computed from CCTA images alone demonstrated high diagnostic performance for detecting lesion-specific ischemia, it showed superior diagnostic power than CCTA and eliminated the risk of invasive tests, which could be an accurate and time-efficient computational tool for diagnosing ischemia and assisting clinical decision-making.
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Doença da Artéria Coronariana , Estenose Coronária , Reserva Fracionada de Fluxo Miocárdico , Angiografia por Tomografia Computadorizada , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Estenose Coronária/diagnóstico por imagem , Humanos , Valor Preditivo dos Testes , Estudos Retrospectivos , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Intravascular ultrasound (IVUS) is the golden standard in accessing the coronary lesions, stenosis, and atherosclerosis plaques. In this paper, a fully automatic approach by an 8-layer U-Net is developed to segment the coronary artery lumen and the area bounded by external elastic membrane (EEM), i.e., cross-sectional area (EEM-CSA). The database comprises single-vendor and single-frequency IVUS data. Particularly, the proposed data augmentation of MeshGrid combined with flip and rotation operations is implemented, improving the model performance without pre- or post-processing of the raw IVUS images. RESULTS: The mean intersection of union (MIoU) of 0.937 and 0.804 for the lumen and EEM-CSA, respectively, were achieved, which exceeded the manual labeling accuracy of the clinician. CONCLUSION: The accuracy shown by the proposed method is sufficient for subsequent reconstruction of 3D-IVUS images, which is essential for doctors' diagnosis in the tissue characterization of coronary artery walls and plaque compositions, qualitatively and quantitatively.
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Vasos Coronários/diagnóstico por imagem , Elasticidade , Processamento de Imagem Assistida por Computador/métodos , Automação , Feminino , Humanos , Masculino , Membranas/diagnóstico por imagem , Pessoa de Meia-Idade , UltrassonografiaRESUMO
The nature of the pairing symmetry of the first heavy fermion superconductor CeCu2Si2 has recently become the subject of controversy. While CeCu2Si2 was generally believed to be a d-wave superconductor, recent low-temperature specific heat measurements showed evidence for fully gapped superconductivity, contrary to the nodal behavior inferred from earlier results. Here, we report London penetration depth measurements, which also reveal fully gapped behavior at very low temperatures. To explain these seemingly conflicting results, we propose a fully gapped [Formula: see text] band-mixing pairing state for CeCu2Si2, which yields very good fits to both the superfluid density and specific heat, as well as accounting for a sign change of the superconducting order parameter, as previously concluded from inelastic neutron scattering results.
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The excessive proliferation and migration of vascular smooth muscle cells (VSMCs) are mainly responsible for vascular occlusion diseases, such as pulmonary arterial hypertension and restenosis. Our previous study demonstrated thymoquinone (TQ) attenuated monocrotaline-induced pulmonary arterial hypertension. The aim of the present study is to systematically examine inhibitory effects of TQ on platelet-derived growth factor-BB (PDGF-BB)-induced proliferation and migration of VSMCs in vitro and neointimal formation in vivo and elucidate the potential mechanisms. Vascular smooth muscle cells were isolated from the aorta in rats. Cell viability and proliferation were measured in VSMCs using the MTT assay. Cell migration was detected by wound healing assay and Transwell assay. Alpha-smooth muscle actin (α-SMA) and Ki-67-positive cells were examined by immunofluorescence staining. Reactive oxygen species (ROS) generation and apoptosis were measured by flow cytometry and terminal deoxyribonucleotide transferase-mediated dUTP nick end labelling (TUNEL) staining, respectively. Molecules including the mitochondria-dependent apoptosis factors, matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9), PTEN/AKT and mitogen-activated protein kinases (MAPKs) were determined by Western blot. Neointimal formation was induced by ligation in male Sprague Dawley rats and evaluated by HE staining. Thymoquinone inhibited PDGF-BB-induced VSMC proliferation and the increase in α-SMA and Ki-67-positive cells. Thymoquinone also induced apoptosis via mitochondria-dependent apoptosis pathway and p38MAPK. Thymoquinone blocked VSMC migration by inhibiting MMP2. Finally, TQ reversed neointimal formation induced by ligation in rats. Thus, TQ is a potential candidate for the prevention and treatment of occlusive vascular diseases.
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Becaplermina/farmacologia , Benzoquinonas/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Neointima/prevenção & controle , Actinas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Antígeno Ki-67/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/metabolismo , Neointima/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
PURPOSE: Subclinical atrial fibrillation (AF) was found in a large number of pacemaker patients. It is not certain whether there is a similar risk/benefit ratio for oral anticoagulation in patients with subclinical AF compared to patients with similar risk profiles and clinically diagnosed AF. Given the weakness of clinical evidence for oral anticoagulation in patients with device-detected subclinical AF, specific recommendations in most guidelines for this population are scarce and rarely similar. METHODS: ART-CAF trial was primarily designed to evaluate the efficacy and safety of oral anticoagulant agent use in patients with device-detected subclinical AF at the approved dosage to prevent stroke and systemic arterial embolism. It is an open-label, registry-based, prospective, multicenter, cohort study, recruiting patients with subclinical AF first detected by a pacemaker, implantable cardioverter-defibrillator, or insertable cardiac monitor after device implantation for more than 3 months. The primary outcome is a composite of ischemic stroke and systemic arterial embolism. The primary safety outcome is the occurrence of clinically overt major bleeding. Approximately 750 patients will be needed to be enrolled to the two treatment groups in a 1:1 ratio until 66 primary efficacy outcomes are observed. The anticipated follow-up period is approximately 70 months from the enrollment of the first patient. CONCLUSIONS: ART-CAF evaluates the feasibility of selecting high-risk patients suitable for anticoagulation by AF burden combined with CHA2DS2-VASc score after pacemaker implantation and aims to select patients who could benefit from anticoagulation. TRIAL REGISTRATION: http://www.chictr.org.cn/index.aspx ChiCTR1800016221.
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Anticoagulantes/administração & dosagem , Fibrilação Atrial/tratamento farmacológico , Marca-Passo Artificial , Acidente Vascular Cerebral/prevenção & controle , Tromboembolia/prevenção & controle , Administração Oral , Anticoagulantes/efeitos adversos , Doenças Assintomáticas , Fibrilação Atrial/complicações , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/fisiopatologia , Estimulação Cardíaca Artificial , China , Tomada de Decisão Clínica , Técnicas de Apoio para a Decisão , Estudos de Viabilidade , Humanos , Estudos Multicêntricos como Assunto , Valor Preditivo dos Testes , Estudos Prospectivos , Sistema de Registros , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/etiologia , Tromboembolia/diagnóstico , Tromboembolia/etiologia , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Free fatty acids (FFAs) predicted the risk of heart failure (HF) and were elevated in HF with very low left ventricular ejection fraction (LVEF) compared to healthy subjects. The aim of this study was to investigate whether total levels of FFA in plasma differed in patients with HF with preserved (HFpEF), mid-range (HFmrEF), and reduced ejection fraction (HFrEF) and the association with the three categories. METHODS: One hundred thirty-nine patients with HFpEF, HFmrEF and HFrEF were investigated in this study. Plasma FFA levels were measured using commercially available assay kits, and LVEF was calculated by echocardiography with the Simpson biplane method. Dyspnea ranked by New York Heart Association (NYHA) was also identified. RESULTS: FFA concentrations were higher in HFrEF than in HFmrEF and HFpEF, respectively (689 ± 321.5 µmol/L vs. 537.9 ± 221.6 µmol/L, p = 0.036; 689 ± 321.5 µmol/L vs. 527.5 ± 185.5 µmol/L, p = 0.008). No significant differences in FFA levels were found between HFmrEF and HFpEF (537.9 ± 221.6 µmol/L vs. 527.5 ± 185.5 µmol/L, p = 0.619). In addition, we found a negative correlation between FFA levels and LVEF (regression coefficient: - 0.229, p = 0.004) and a positive correlation between FFAs and NYHA class (regression coefficient: 0.214, p = 0.014) after adjustment for clinical characteristic, medical history and therapies. ROC analysis revealed that FFAs predicted HFrEF across the three categories (AUC: 0.644, p = 0.005) and the optimal cut-off level to predict HFrEF was FFA levels above 575 µmol/L. CONCLUSIONS: FFA levels differed across the three categories, which suggests that energy metabolism differs between HFpEF, HFmrEF and HFrEF.
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Metabolismo Energético , Ácidos Graxos não Esterificados/sangue , Insuficiência Cardíaca/sangue , Volume Sistólico , Função Ventricular Esquerda , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Pressão Sanguínea , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertensão/sangue , Hipertensão/fisiopatologia , Masculino , Projetos Piloto , Regulação para CimaRESUMO
Statins have beneficial pleiotropic effects beyond lipid lowering on the cardiovascular system. These cardio-protective effects are mediated through inhibition of the intracellular mevalonate pathway, by decreasing isoprenoid intermediate synthesis and the subsequent post-translational modification of small GTPases, such as Ras, Rho, and Rac. Impaired intracellular calcium handling is considered an important pathophysiologic mechanism responsible for cardiac dysfunction. Our study aimed at investigating the influence of mevalonate pathway, including its downstream small GTPases (Ras, RhoA, and Rac1) on anoxia-mediated alterations of calcium handling in H9c2 cardiomyocytes. Cultured H9c2 cardiomyocytes were exposed to acute anoxia after pretreatment with different drugs that specifically antagonize five key components in the mevalonate pathway, including 3-hydroxy-3-methylglutaryl-CoA reductase, farnesyl pyrophosphate synthase, Rho-kinase, Rac1 and Ras farnesyltransferase. Thereafter, we evaluated the effects of the mevalonate pathway on anoxia-induced cell death, expression of the sarcoplasmic reticulum calcium release channel (ryanodine receptor 2) and its regulator FK506-binding protein 12.6, as well as functional calcium release from intracellular calcium stores. Our experiments confirmed the role of prenylated proteins in regulating cardiomyocyte dysfunction, especially via RhoA- and Ras-related signaling pathways. Furthermore, our data demonstrated that inhibition of the mevalonate pathway could ameliorate anoxia-mediated calcium handling dysfunction with the up-regulated expression of FK506-binding protein 12.6 and consequently provided evidence for FK506-binding protein 12.6 as a "stabilizer" of ryanodine receptor 2.
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Cálcio/metabolismo , Hipóxia/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , Ácido Mevalônico/metabolismo , Proteínas de Ligação a Tacrolimo/metabolismo , Animais , Sinalização do Cálcio/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo , Regulação da Expressão Gênica/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipóxia/genética , Espaço Intracelular/metabolismo , Mioblastos Cardíacos/efeitos dos fármacos , Mioblastos Cardíacos/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Ratos , Proteínas de Ligação a Tacrolimo/genéticaRESUMO
BACKGROUND: The early secreted antigenic target 6-kDa protein (ESAT-6) of Mycobacterium tuberculosis (Mtb) not only acts as a key player for virulence but also exhibits a strong immunotherapeutic potential against Mtb. However, little is known about the molecular basis for its potential in immunotherapy. The present study was designed to unravel the role of miRNA-155 in ESAT-6-mediated enhancement of host immunity and apoptosis in macrophages. METHODS: Lentivirus-mediated miR-155 sponge and miR-155 and SOCS1 overexpression vectors were developed in macrophages. TLR2- or p65-specific siRNA knockdown was employed to silence TLR2 or p65. Quantitative polymerase chain reaction and western blotting analyses were performed to determine mRNA and protein expression levels, respectively. Macrophage apoptosis was analyzed by flow cytometry. RESULTS: ESAT-6 significantly increased miR-155 expression, which was dependent on TLR2/NF-κB activation in macrophages. Induced expression of miRNA-155 was required for the ESAT-6-mediated protective immune response and macrophage apoptosis. ESAT-6 promoted macrophage apoptosis by targeting the miR-155-SOCS1 pathway. The differential expression levels of TLR2, BIC, and SOCS1 were involved in regulating the immune response in human peripheral blood mononuclear cells of patients with active tuberculosis (TB) and latent TB (LTB). CONCLUSION: ESAT-6 promotes apoptosis of macrophages via targeting the miRNA155-SOCS1 interaction.
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Antígenos de Bactérias/farmacologia , Apoptose/efeitos dos fármacos , MicroRNAs/metabolismo , Mycobacterium tuberculosis/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Tuberculose/patologia , Animais , Antígenos de Bactérias/genética , Antígenos de Bactérias/metabolismo , Linhagem Celular , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Leucócitos Mononucleares/metabolismo , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Interferência de RNA , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacologia , Proteínas Supressoras da Sinalização de Citocina/genética , Receptor 2 Toll-Like/antagonistas & inibidores , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismo , Fator de Transcrição RelA/antagonistas & inibidores , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Tuberculose/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Retinoblastoma (RB) is the most common intraocular malignancy in childhood. The causal variants in RB are mostly characterized by previously used short-read sequencing (SRS) analysis, which has technical limitations in identifying structural variants (SVs) and phasing information. Long-read sequencing (LRS) technology has advantages over SRS in detecting SVs, phased genetic variants, and methylation. In this study, we comprehensively characterized the genetic landscape of RB using combinatorial LRS and SRS of 16 RB tumors and 16 matched blood samples. We detected a total of 232 somatic SVs, with an average of 14.5 SVs per sample across the whole genome in our cohort. We identified 20 distinct pathogenic variants disrupting RB1 gene, including three novel small variants and five somatic SVs. We found more somatic SVs were detected from LRS than SRS (140 vs. 122) in RB samples with WGS data, particularly the insertions (18 vs. 1). Furthermore, our analysis shows that, with the exception of one sample who lacked the methylation data, all samples presented biallelic inactivation of RB1 in various forms, including two cases with the biallelic hypermethylated promoter and four cases with compound heterozygous mutations which were missing in SRS analysis. By inferring relative timing of somatic events, we reveal the genetic progression that RB1 disruption early and followed by copy number changes, including amplifications of Chr2p and deletions of Chr16q, during RB tumorigenesis. Altogether, we characterize the comprehensive genetic landscape of RB, providing novel insights into the genetic alterations and mechanisms contributing to RB initiation and development. Our work also establishes a framework to analyze genomic landscape of cancers based on LRS data.
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Metilação de DNA , Neoplasias da Retina , Proteínas de Ligação a Retinoblastoma , Retinoblastoma , Humanos , Retinoblastoma/genética , Retinoblastoma/patologia , Proteínas de Ligação a Retinoblastoma/genética , Neoplasias da Retina/genética , Neoplasias da Retina/patologia , Masculino , Feminino , Mutação , Ubiquitina-Proteína Ligases/genética , Pré-Escolar , Criança , Lactente , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento Completo do Genoma/métodosRESUMO
Atrial fibrillation (AF) is a significant precursor to cerebral embolism. Our study sought to unearth new diagnostic biomarkers for atrial fibrillation-related cerebral embolism (AF-CE) by meticulously examining multiple GEO datasets and meta-analysis. The gene expression omnibus (GEO) database provided RNA sequencing data associated with AF and stroke. We began by pinpointing genes with varied expressions in AF-CE patient blood samples. A meta-analysis was subsequently undertaken using several RNA sequencing datasets to verify these genes. LASSO regression discerned key genes for AF-CE, with their diagnostic prowess verified through ROC curve examination. Active signaling pathways within stroke patients were discerned via GO and KEGG enrichment, with PPI interactions detailing gene interplay. Differential gene analysis revealed an upregulation of sixteen genes and a downregulation of four in stroke patient blood samples. Eight genes showcased varied expression in the meta-analysis. LASSO regression zeroed in on five of these, culminating in HIST1H2BH's identification as a characteristic gene. HIST1H2BH's prowess in predicting AF-CE was confirmed through ROC. Integrin signaling, platelet activation, ECM interactions, and the PI3K-Akt pathway were found active in stroke victims. HIST1H2BH's interaction with the notably upregulated ITGA2B was spotlighted by PPI. Additionally, HIST1H2BH exhibited links with NK cells and eosinophils. HIST1H2BH emerges as an insightful diagnostic beacon for AF-CE. Its presence, post AF, potentially modulates pathways, accentuating platelet activation and consequent thrombus generation, leading to cerebral embolism.
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Our previous study has indicated that tetrandrine (TET) can target miR-202-5p to repress the activation of transient receptor potential vanilloid type 2 (TRPV2), eventually ameliorating the progression of myocardial ischemia/reperfusion injury (MI/RI). This study is aimed to further ascertain the detailed mechanisms between TET and TRPV2 in MI/RI pathogenesis. Here, a myocardial I/R injury rat model and a hypoxia-reoxygenation (H/R) model in rat myocardial cell line (H9C2 cells) were established. We reported that pronounced upregulation of TRPV2 was observed in I/R rats and H/R-induced H9C2 cells. Silencing of TRPV2 could improve cardiac function and myocardial injury, reduced infarction size, and promoted cardiomyocyte proliferation in I/R rats. In I/R rats or H/R-induced H9C2 cells, cardiomyocyte apoptosis was inhibited by knocking-down TRPV2. Meanwhile, the silenced TRPV2 or TET treatment ameliorated the damaged mitochondrial structure, mitigated ROS generation, restored the impaired ΔΨM, inhibited mPTP opening and alleviated Ca2+ overload in H/R-induced H9C2 cells. The results obtained from the overexpression of TRPV2 were contrary to those depicted above. Moreover, TET could downregulate TRPV2 expression, while the overexpression of TRPV2 could reverse the above protective effects of TET in H/R-induced H9C2 cells. The results indicated that TET may function as a TRPV2 blocking agent, thereby attenuating the progression of MI/RI through modulation of cardiomyocyte apoptosis, calcium homeostasis and mitochondrial function. These findings offer a theoretical foundation for potential clinical application of TET therapy in patients with MI/RI.
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Benzilisoquinolinas , MicroRNAs , Traumatismo por Reperfusão Miocárdica , Ratos , Humanos , Animais , Miócitos Cardíacos , Traumatismo por Reperfusão Miocárdica/metabolismo , Cálcio/metabolismo , Apoptose , Mitocôndrias , Hipóxia/metabolismo , Homeostase , MicroRNAs/metabolismo , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismoRESUMO
Ocular neurodegenerative diseases like glaucoma lead to progressive retinal ganglion cell (RGC) loss, causing irreversible vision impairment. Neuroprotection is needed to preserve RGCs across debilitating conditions. Nerve growth factor (NGF) protein therapy shows efficacy, but struggles with limited bioavailability and a short half-life. Here we explore a novel approach to address this deficiency by utilizing circular RNA (circRNA)-based therapy. We show that circRNAs exhibit an exceptional capacity for prolonged protein expression and circRNA-expressed NGF protects cells from glucose deprivation. In a mouse optic nerve crush model, lipid nanoparticle (LNP)-formulated circNGF administered intravitreally protects RGCs and axons from injury-induced degeneration. It also significantly outperforms NGF protein therapy without detectable retinal toxicity. Furthermore, single-cell transcriptomics revealed LNP-circNGF's multifaceted therapeutic effects, enhancing genes related to visual perception while reducing trauma-associated changes. This study signifies the promise of circRNA-based therapies for treating ocular neurodegenerative diseases and provides an innovative intervention platform for other ocular diseases.
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BACKGROUND: ArteryFlow Technology (AccuFFRct) is a novel noninvasive method for calculating fractional flow reserve (FFR) from coronary computed tomography angiography (CCTA). The accuracy of AccuFFRct has not been adequately assessed. OBJECTIVES: This study sought to evaluate the diagnostic performance of AccuFFRct in detecting lesion-specific ischemia. METHODS: This prospective study enrolled 339 patients with 404 vessels. CCTA-derived FFR was calculated using an on-site computational fluid dynamics-based method and compared with invasive FFR. The performance of AccuFFRct was comprehensively analyzed in all lesions and subgroups, including "gray zone" lesions, various lesion classifications, clinical presentations, stenosis severities, and lesion locations. RESULTS: Using FFR ≤0.80 as a reference standard, the overall diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value for AccuFFRct were 90.6% (95% CI: 87.3%-93.3%), 90.9% (95% CI: 85.1%-94.9%), 90.4% (95% CI: 86.1%-93.8%), 85.3% (95% CI: 79.8%-89.5%), and 94.2% (95% CI: 90.8%-96.4%), respectively. Good correlation and agreement were found between the computed AccuFFRct and measured FFR. AccuFFRct showed superior discrimination ability to CCTA (AUC: 0.93 [95% CI: 0.89-0.95] vs 0.77 [95% CI: 0.72-0.81]; P < 0.001) and quantitative coronary angiography (AUC: 0.93 [95% CI: 0.89-0.95] vs 0.89 [95% CI: 0.85-0.92]; P = 0.048) for identifying functionally significant stenosis. Notably, AccuFFRct maintained high diagnostic accuracy across the spectrum of lesion classifications, clinical presentations, stenosis severities, lesion locations, and in the gray zone. Furthermore, in the cohort with ≥70% stenosis, AccuFFRct could significantly reduce the rate of un-necessary invasive tests (33.1% vs 6.6%; P < 0.001). CONCLUSIONS: The study confirms the potential of AccuFFRct as a noninvasive alternative to invasive FFR for detecting ischemia in coronary artery disease and to risk stratify patients. The results highlight AccuFFRct's robust diagnostic ability across a wide range of lesion classifications, clinical presentations, stenosis severities, lesion locations, and in the gray zone. (Diagnostic Performance of Fractional Flow Reserve Derived From Coronary CT Angiography [ACCURATE-CT]; NCT04426396).
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BACKGROUND: Quantitative flow ratio (QFR) is a method for evaluating fractional flow reserve without the use of an invasive coronary pressure wire or pharmacological hyperemic agent. OBJECTIVES: The aim of this study was to investigate the prognostic implications of QFR and plaque characteristics in patients who underwent intravascular ultrasound (IVUS)-guided treatment for intermediate lesions. METHODS: Among the IVUS-guided strategy group in the FLAVOUR (Fractional Flow Reserve and Intravascular Ultrasound for Clinical Outcomes in Patients with Intermediate Stenosis) trial, vessels suitable for QFR analysis were included in this study. High-risk features were defined as low QFR (≤0.90), quantitative high-risk plaque characteristics (qn-HRPCs) (minimal lumen area ≤3.5 mm2, or plaque burden ≥70%), and qualitative high-risk plaque characteristics (ql-HRPCs) (attenuated plaque, positive remodeling, or plaque rupture) assessed using IVUS. The primary clinical endpoint was target vessel failure (TVF), defined as a composite of cardiac death, target vessel myocardial infarction, and target vessel revascularization. RESULTS: A total of 415 (46.1%) vessels could be analyzable for QFR. The numbers of qn-HRPCs and ql-HRPCs increased with decreasing QFR. Among deferred vessels, those with 3 high-risk features exhibits a significantly higher risk of TVF compared with those with ≤2 high-risk features (12.0% vs 2.7%; HR: 4.54; 95% CI: 1.02-20.29). CONCLUSIONS: Among the IVUS-guided deferred group, vessels with qn-HRPC and ql-HRPC with low QFR (≤0.90) exhibited a significantly higher risk for TVF compared with those with ≤2 features. Integrative assessment of angiography-derived fractional flow reserve and anatomical and morphological plaque characteristics is recommended to improve clinical outcomes in patients undergoing IVUS-guided deferred treatment.
Assuntos
Doença da Artéria Coronariana , Estenose Coronária , Reserva Fracionada de Fluxo Miocárdico , Placa Aterosclerótica , Humanos , Prognóstico , Angiografia Coronária , Resultado do Tratamento , Vasos Coronários/diagnóstico por imagem , Ultrassonografia de Intervenção/métodos , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/terapia , Valor Preditivo dos Testes , Estenose Coronária/diagnóstico por imagem , Estenose Coronária/terapiaRESUMO
BACKGROUND AND OBJECTIVES: Angiographic assessment of coronary stenosis severity using quantitative coronary angiography (QCA) is often inconsistent with that based on fractional flow reserve (FFR) or intravascular ultrasound (IVUS). We investigated the incidence of discrepancies between QCA and FFR or IVUS, and the outcomes of FFR- and IVUS-guided strategies in discordant coronary lesions. METHODS: This study was a post-hoc analysis of the FLAVOUR study. We used a QCA-derived diameter stenosis (DS) of 60% or greater, the highest tertile, to classify coronary lesions as concordant or discordant with FFR or IVUS criteria for percutaneous coronary intervention (PCI). The patient-oriented composite outcome (POCO) was defined as a composite of death, myocardial infarction, or revascularization at 24 months. RESULTS: The discordance rate between QCA and FFR or IVUS was 30.2% (n=551). The QCA-FFR discordance rate was numerically lower than the QCA-IVUS discordance rate (28.2% vs. 32.4%, p=0.050). In 200 patients with ≥60% DS, PCI was deferred according to negative FFR (n=141) and negative IVUS (n=59) (15.3% vs. 6.5%, p<0.001). The POCO incidence was comparable between the FFR- and IVUS-guided deferral strategies (5.9% vs. 3.4%, p=0.479). Conversely, 351 patients with DS <60% underwent PCI according to positive FFR (n=118) and positive IVUS (n=233) (12.8% vs. 25.9%, p<0.001). FFR- and IVUS-guided PCI did not differ in the incidence of POCO (9.5% vs. 6.5%, p=0.294). CONCLUSIONS: The proportion of QCA-FFR or IVUS discordance was approximately one third for intermediate coronary lesions. FFR- or IVUS-guided strategies for these lesions were comparable with respect to POCO at 24 months. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02673424.
RESUMO
Importance: Treatment strategies for intermediate coronary lesions guided by fractional flow reserve (FFR) and intravascular ultrasonography (IVUS) have shown comparable outcomes. Identifying low-risk deferred vessels to ensure the safe deferral of percutaneous coronary intervention (PCI) and high-risk revascularized vessels that necessitate thorough follow-up can help determine optimal treatment strategies. Objectives: To investigate outcomes according to treatment types and FFR and IVUS parameters after FFR- or IVUS-guided treatment. Design, Setting, and Participants: This cohort study included patients with intermediate coronary stenosis from the Fractional Flow Reserve and Intravascular Ultrasound-Guided Intervention Strategy for Clinical Outcomes in Patients With Intermediate Stenosis (FLAVOUR) trial, an investigator-initiated, prospective, open-label, multicenter randomized clinical trial that assigned patients into an IVUS-guided strategy (which recommended PCI for minimum lumen area [MLA] ≤3 mm2 or 3 mm2 to 4 mm2 with plaque burden [PB] ≥70%) or an FFR-guided strategy (which recommended PCI for FFR ≤0.80). Data were analyzed from November to December 2022. Exposures: FFR or IVUS parameters within the deferred and revascularized vessels. Main Outcomes and Measures: The primary outcome was target vessel failure (TVF), a composite of cardiac death, target vessel myocardial infarction, and revascularization at 2 years. Results: A total of 1619 patients (mean [SD] age, 65.1 [9.6] years; 1137 [70.2%] male) with 1753 vessels were included in analysis. In 950 vessels for which revascularization was deferred, incidence of TVF was comparable between IVUS and FFR groups (3.8% vs 4.1%; P = .72). Vessels with FFR greater than 0.92 in the FFR group and MLA greater than 4.5 mm2 or PB of 58% or less in the IVUS group were identified as low-risk deferred vessels, with a decreased risk of TVF (hazard ratio [HR], 0.25 [95% CI, 0.09-0.71]; P = .009). In 803 revascularized vessels, the incidence of TVF was comparable between IVUS and FFR groups (3.6% vs 3.7%; P = .95), which was similar in the revascularized vessels undergoing PCI optimization (4.2% vs 2.5%; P = .31). Vessels with post-PCI FFR of 0.80 or less in the FFR group or minimum stent area of 6.0 mm2 or less or with PB at stent edge greater than 58% in the IVUS group had an increased risk for TVF (HR, 7.20 [95% CI, 3.20-16.21]; P < .001). Conclusions and Relevance: In this cohort study of patients with intermediate coronary stenosis, FFR- and IVUS-guided strategies showed comparable outcomes in both deferred and revascularized vessels. Binary FFR and IVUS parameters could further define low-risk deferred vessels and high-risk revascularized vessels.
Assuntos
Estenose Coronária , Reserva Fracionada de Fluxo Miocárdico , Intervenção Coronária Percutânea , Placa Aterosclerótica , Idoso , Feminino , Humanos , Masculino , Estudos de Coortes , Angiografia Coronária , Estenose Coronária/diagnóstico por imagem , Estenose Coronária/terapia , Estudos Prospectivos , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Mitral regurgitation is a serious complication of post-myocardial infarction, with increasing mortality. Surgery as the primary treatment carries a high risk. MitraClip is a new therapeutic to treat post-myocardial infarction mitral regurgitation. In this case, a 62-year-old male patient suffered from severe heart failure symptoms after emergency coronary intervention and extracorporeal membrane oxygenation support. Based on cardiac echocardiography, severe mitral regurgitation was monitored in this patient. After MitraClip treatment, the patient's condition was gradually improved and discharged successfully. This case highlights that MitraClip is a safe and effective strategy for post-myocardial infarction mitral regurgitation.