RESUMO
BACKGROUND: Cell phenotype switching is increasingly being recognized in atherosclerosis. However, our understanding of the exact stimuli for such cellular transformations and their significance for human atherosclerosis is still evolving. Intraplaque hemorrhage is thought to be a major contributor to plaque progression in part by stimulating the influx of CD163+ macrophages. Here, we explored the hypothesis that CD163+ macrophages cause plaque progression through the induction of proapoptotic endothelial-to-mesenchymal transition (EndMT) within the fibrous cap. METHODS: Human coronary artery sections from CVPath's autopsy registry were selected for pathological analysis. Athero-prone ApoE-/- and ApoE-/-/CD163-/- mice were used for in vivo studies. Human peripheral blood mononuclear cell-induced macrophages and human aortic endothelial cells were used for in vitro experiments. RESULTS: In 107 lesions with acute coronary plaque rupture, 55% had pathological evidence of intraplaque hemorrhage in nonculprit vessels/lesions. Thinner fibrous cap, greater CD163+ macrophage accumulation, and a larger number of CD31/FSP-1 (fibroblast specific protein-1) double-positive cells and TUNEL (terminal deoxynucleotidyl transferase-dUTP nick end labeling) positive cells in the fibrous cap were observed in nonculprit intraplaque hemorrhage lesions, as well as in culprit rupture sections versus nonculprit fibroatheroma sections. Human aortic endothelial cells cultured with supernatants from hemoglobin/haptoglobin-exposed macrophages showed that increased mesenchymal marker proteins (transgelin and FSP-1) while endothelial markers (VE-cadherin and CD31) were reduced, suggesting EndMT induction. Activation of NF-κB (nuclear factor kappa ß) signaling by proinflammatory cytokines released from CD163+ macrophages directly regulated the expression of Snail, a critical transcription factor during EndMT induction. Western blot analysis for cleaved caspase-3 and microarray analysis of human aortic endothelial cells indicated that apoptosis was stimulated during CD163+ macrophage-induced EndMT. Additionally, CD163 deletion in athero-prone mice suggested that CD163 is required for EndMT and plaque progression. Using single-cell RNA sequencing from human carotid endarterectomy lesions, a population of EndMT was detected, which demonstrated significant upregulation of apoptosis-related genes. CONCLUSIONS: CD163+ macrophages provoke EndMT, which may promote plaque progression through fibrous cap thinning.
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Antígenos CD , Antígenos de Diferenciação Mielomonocítica , Macrófagos , Placa Aterosclerótica , Receptores de Superfície Celular , Humanos , Antígenos de Diferenciação Mielomonocítica/metabolismo , Antígenos de Diferenciação Mielomonocítica/genética , Animais , Antígenos CD/metabolismo , Antígenos CD/genética , Macrófagos/metabolismo , Macrófagos/patologia , Placa Aterosclerótica/patologia , Placa Aterosclerótica/metabolismo , Receptores de Superfície Celular/metabolismo , Receptores de Superfície Celular/genética , Camundongos , Células Cultivadas , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Masculino , Camundongos Knockout para ApoE , Camundongos Endogâmicos C57BL , Apoptose , Feminino , Transição Epitelial-Mesenquimal , Vasos Coronários/patologia , Vasos Coronários/metabolismoRESUMO
While coronary artery disease remains a major cause of death, it is preventable. Therefore, the focus needs to shift to the early detection and prevention of atherosclerosis. Asymptomatic atherosclerosis is widely termed subclinical atherosclerosis, which is an early indicator of atherosclerotic burden, and understanding this disease is important because timely intervention could prevent future cardiovascular morbidity and mortality. We histologically recognize the earliest lesion of atherosclerosis as pathological intimal thickening, which is characterized by the presence of lipid pools. The difference between clinical atherosclerosis and subclinical atherosclerosis is whether the presence of atherosclerosis results in the clinical symptoms of ischemia, such as stroke, myocardial infarction, or chronic limb-threatening ischemia. In the absence of thrombosis, there are various types of histological plaque that encompass subclinical atherosclerosis: pathological intimal thickening, fibroatheroma, thin-cap fibroatheroma, plaque rupture, healed plaque ruptures, and fibrocalcific plaque. Plaque morphology that is most frequently responsible for acute coronary thrombosis is plaque rupture. Calcification of coronary arteries is the hallmark of atherosclerosis and is a predictor of future coronary events. Atherosclerosis occurs in other vascular beds and is most frequent in arteries of the lower extremity, followed by carotid, aorta, and coronary arteries, and the mechanisms leading to clinical symptoms are unique for each location.
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Aterosclerose , Doença da Artéria Coronariana , Trombose Coronária , Placa Aterosclerótica , Humanos , Placa Aterosclerótica/patologia , Aterosclerose/patologia , Doença da Artéria Coronariana/patologia , Fatores de RiscoRESUMO
BACKGROUND: Smooth muscle cells (SMCs), which make up the medial layer of arteries, are key cell types involved in cardiovascular disease, the leading cause of mortality and morbidity worldwide. In response to microenvironment alterations, SMCs dedifferentiate from a contractile to a synthetic phenotype characterized by an increased proliferation, migration, production of ECM (extracellular matrix) components, and decreased expression of SMC-specific contractile markers. These phenotypic changes result in vascular remodeling and contribute to the pathogenesis of cardiovascular disease, including coronary artery disease, stroke, hypertension, and aortic aneurysms. Here, we aim to identify the genetic variants that regulate ECM secretion in SMCs and predict the causal proteins associated with vascular disease-related loci identified in genome-wide association studies. METHODS: Using human aortic SMCs from 123 multiancestry healthy heart transplant donors, we collected the serum-free media in which the cells were cultured for 24 hours and conducted liquid chromatography-tandem mass spectrometry-based proteomic analysis of the conditioned media. RESULTS: We measured the abundance of 270 ECM and related proteins. Next, we performed protein quantitative trait locus mapping and identified 20 loci associated with secreted protein abundance in SMCs. We functionally annotated these loci using a colocalization approach. This approach prioritized the genetic variant rs6739323-A at the 2p22.3 locus, which is associated with lower expression of LTBP1 (latent-transforming growth factor beta-binding protein 1) in SMCs and atherosclerosis-prone areas of the aorta, and increased risk for SMC calcification. We found that LTBP1 expression is abundant in SMCs, and its expression at mRNA and protein levels was reduced in unstable and advanced atherosclerotic plaque lesions. CONCLUSIONS: Our results unravel the SMC proteome signature associated with vascular disorders, which may help identify potential therapeutic targets to accelerate the pathway to translation.
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Aterosclerose , Doenças Cardiovasculares , Humanos , Doenças Cardiovasculares/metabolismo , Estudo de Associação Genômica Ampla , Proteômica , Músculo Liso Vascular/metabolismo , Aorta/metabolismo , Aterosclerose/patologia , Miócitos de Músculo Liso/metabolismo , Células CultivadasRESUMO
BACKGROUND: Polygenic risk scores (PRSs) for coronary artery disease (CAD) potentially improve cardiovascular risk prediction. However, their relationship with histopathologic features of CAD has never been examined systematically. METHODS: From 4327 subjects referred to CVPath by the State of Maryland Office Chief Medical Examiner for sudden death between 1994 and 2015, 2455 cases were randomly selected for genotyping. We generated PRS from 291 known CAD risk loci. Detailed histopathologic examination of the coronary arteries was performed in all subjects. The primary study outcome measurements were histopathologic plaque features determining severity of atherosclerosis, including %stenosis, calcification, thin-cap fibroatheromas, and thrombotic CAD. RESULTS: After exclusion of cases with insufficient DNA sample quality or with missing data, 954 cases (mean age, 48.8±14.7 years; 75.7% men) remained in the final study cohort. Subjects in the highest PRS quintile exhibited more severe atherosclerosis compared with subjects in the lowest quintile, with greater %stenosis (80.3%±27.0% versus 50.4%±38.7%; adjusted P<0.001) and a higher frequency of calcification (69.6% versus 35.8%; adjusted P=0.004) and thin-cap fibroatheroma (26.7% versus 9.5%; adjusted P=0.007). Even after adjustment for traditional CAD risk factors, subjects within the highest PRS quintile had higher odds of severe atherosclerosis (ie, ≥75% stenosis; adjusted odds ratio, 3.77 [95% CI, 2.10-6.78]; P<0.001) and plaque rupture (adjusted odds ratio, 4.05 [95% CI, 2.26-7.24]; P<0.001). Moreover, subjects within the highest quintile had higher odds of CAD-associated cause of death, especially among those aged ≤50 years (adjusted odds ratio, 4.08 [95% CI, 2.01-8.30]; P<0.001). No statistically significant associations were observed with plaque erosion after adjusting for covariates. CONCLUSIONS: This is the first autopsy study investigating associations between PRS and atherosclerosis severity at the histopathologic level in subjects with sudden death. Our pathological analysis suggests PRS correlates with plaque burden and features of advanced atherosclerosis and may be useful as a method for CAD risk stratification, especially in younger subjects.
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Aterosclerose , Doença da Artéria Coronariana , Placa Aterosclerótica , Masculino , Humanos , Adulto , Pessoa de Meia-Idade , Feminino , Estratificação de Risco Genético , Constrição Patológica , Fatores de Risco , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/patologia , Morte Súbita , AutopsiaRESUMO
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
BACKGROUND: During the transition from dual antiplatelet therapy (DAPT) to single antiplatelet therapy (SAPT), previous studies have raised concerns about a rebound effect. We compared platelet and inflammatory cell adhesion on different types of stents in the setting of clopidogrel presence and withdrawal. METHODS: In Experiment 1, three pigs were administered with DAPT, that is, clopidogrel and acetylsalicylic acid (ASA), for 7 days. Each animal underwent an extracorporeal carotid arteriovenous shunt model implanted with fluoropolymer-coated everolimus-eluting stent (FP-EES), biodegradable-polymer sirolimus-eluting stent (BP-SES), and biodegradable-polymer everolimus-eluting stents (BP-EES). In Experiment 2, two pigs were administered DAPT, clopidogrel was then withdrawn at day 7, and SAPT with ASA was continued for next 21 days. Then flow-loop experiments with the drawn blood from each time point were performed for FP-EES, BioLinx-polymer zotarolimus-eluting stents (BL-ZES), and BP-EES. The rebound effect was defined as the statistical increase of inflammation and platelet adhesion assessed with immunohistochemistry on the stent-strut level basis from baseline to day-14 or 28. RESULTS: Both experiments showed platelet adhesion value was highest in BP-EES, while the least in FP-EES during DAPT therapy. There was no increase in platelet or inflammatory cell adhesion above baseline values (i.e., no therapy) due to the cessation of clopidogrel on the stent-strut level. Monocyte adhesion was the least for FP-EES with the same trend observed for neutrophil adhesion. CONCLUSIONS: No evidence of rebound effect was seen after the transition from DAPT to SAPT. FP-EES demonstrated the most favorable antithrombotic and anti-inflammatory profile regardless of the different experimental designs.
Assuntos
Aspirina , Clopidogrel , Stents Farmacológicos , Terapia Antiplaquetária Dupla , Everolimo , Adesividade Plaquetária , Inibidores da Agregação Plaquetária , Desenho de Prótese , Sirolimo , Trombose , Animais , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/farmacologia , Inibidores da Agregação Plaquetária/efeitos adversos , Clopidogrel/administração & dosagem , Clopidogrel/farmacologia , Fatores de Tempo , Sirolimo/análogos & derivados , Sirolimo/administração & dosagem , Sirolimo/farmacologia , Everolimo/administração & dosagem , Everolimo/farmacologia , Trombose/prevenção & controle , Trombose/etiologia , Aspirina/administração & dosagem , Adesividade Plaquetária/efeitos dos fármacos , Derivação Arteriovenosa Cirúrgica/efeitos adversos , Sus scrofa , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Esquema de Medicação , Modelos Animais de DoençasRESUMO
BACKGROUND: Ethylene diamine tetra-acetic acid (EDTA) is a chelating agent used to dissolve calcium deposits but evidence in decalcifying atherosclerotic lesions is limited. AIMS: We assessed the feasibility and efficacy of EDTA delivered via porous balloon to target calcified lesions in cadaveric below-the-knee (BTK) arteries. METHODS: Using porcine carotid arteries, EDTA concentration was measured in the arterial wall and outside the artery at the 0-, 0.5-, 4-, and 24-h circulation after the injection through a porous balloon. In cadaver BTK samples, the proximal and distal anterior tibial artery (ATA) and distal posterior tibial artery (PTA) were studied. EDTA-2Na/H2O or EDTA-3Na/H2O were administrated using a porous balloon, then circulated for 6 h for EDTA-3Na/H2O and 24 h for EDTA-2Na/H2O and EDTA-3Na/H2O. Micro-CT imaging of the artery segments before and after the circulation and cross-sectional analyses were performed to evaluate calcium burden. RESULTS: In the porcine carotid study, EDTA was delivered through a porous balloon present in the arterial wall and was retained there for 24 h. In BTK arteries, cross-sectional analyses of micro-CT revealed a significant decrease in the calcium area in the distal ATA segment under 24-h circulation with EDTA-2Na/H2O and in the distal ATA segment under 24-h circulation with EDTA-3Na/H2O. The proximal ATA segment under 6-h circulation with EDTA-3Na/H2O showed no significant change in any parameters of calcium CONCLUSION: EDTA-3Na/H2O or EDTA-2Na/H2O with longer circulation times resulted in greater calcium reduction in atherosclerotic lesion. EDTA may have a potential therapeutic option for the treatment of atherosclerotic calcified lesions.
Assuntos
Angioplastia com Balão , Ácido Edético , Estudos de Viabilidade , Calcificação Vascular , Animais , Ácido Edético/farmacologia , Angioplastia com Balão/instrumentação , Porosidade , Calcificação Vascular/diagnóstico por imagem , Calcificação Vascular/terapia , Cadáver , Artérias da Tíbia/diagnóstico por imagem , Quelantes de Cálcio/farmacologia , Fatores de Tempo , Microtomografia por Raio-X , Humanos , Dispositivos de Acesso Vascular , Desenho de Equipamento , Sus scrofa , Doença Arterial Periférica/terapia , Doença Arterial Periférica/diagnóstico por imagem , Doença Arterial Periférica/metabolismo , Placa Aterosclerótica , SuínosRESUMO
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
The clinical implications of hypertension in addition to a high prevalence of both uncontrolled blood pressure and medication nonadherence promote interest in developing device-based approaches to hypertension treatment. The expansion of device-based therapies and ongoing clinical trials underscores the need for consistency in trial design, conduct, and definitions of clinical study elements to permit trial comparability and data poolability. Standardizing methods of blood pressure assessment, effectiveness measures beyond blood pressure alone, and safety outcomes are paramount. The Hypertension Academic Research Consortium (HARC) document represents an integration of evolving evidence and consensus opinion among leading experts in cardiovascular medicine and hypertension research with regulatory perspectives on clinical trial design and methodology. The HARC document integrates the collective information among device-based therapies for hypertension to better address existing challenges and identify unmet needs for technologies proposed to treat the world's leading cause of death and disability. Consistent with the Academic Research Consortium charter, this document proposes pragmatic consensus clinical design principles and outcomes definitions for studies aimed at evaluating device-based hypertension therapies.
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Hipertensão , Ensaios Clínicos como Assunto , Consenso , Humanos , Hipertensão/diagnóstico , Hipertensão/terapiaRESUMO
BACKGROUND: Neighborhood disadvantage is associated with a higher risk of sudden cardiac death. However, autopsy findings have never been investigated in this context. Here, we sought to explore associations between neighborhood disadvantage and cardiovascular findings at autopsy in cases of sudden death in the State of Maryland. METHODS: State of Maryland investigation reports from 2,278 subjects within the CVPath Sudden Death Registry were screened for street addresses and 9-digit zip codes. Area deprivation index (ADI), used as metric for neighborhood disadvantage, was available for 1,464 subjects; 650 of whom self-identified as Black and 814 as White. The primary study outcome measurements were causes of death and gross and histopathologic findings of the heart. RESULTS: Subjects from most disadvantaged neighborhoods (i.e., ADI ≥ 8; n = 607) died at younger age compared with subjects from less disadvantaged neighborhoods (i.e., ADI ≤ 7; n = 857; 46.07 ± 14.10 vs 47.78 ± 13.86 years; P = 0.02) and were more likely Black or women. They were less likely to die from cardiac causes of death (61.8% vs 67.7%; P = 0.02) and had less severe atherosclerotic plaque features, including plaque burden, calcification, intraplaque hemorrhage, and thin-cap fibroatheromas. In addition, subjects from most disadvantaged neighborhoods had lower frequencies of plaque rupture (18.8% vs 25.1%, P = 0.004). However, these associations were omitted after adjustment for traditional risk factors and race. CONCLUSION: Neighborhood disadvantage did not associate with cause of death or coronary histopathology after adjustment for cardiovascular risk factors and race, implying that social determinants of health other than neighborhood disadvantage play a more prominent role in sudden cardiac death.
Assuntos
Placa Aterosclerótica , Características de Residência , Humanos , Feminino , Autopsia , Fatores de Risco , Morte Súbita Cardíaca/epidemiologia , Morte Súbita Cardíaca/etiologia , Características da Vizinhança , Fatores SocioeconômicosRESUMO
PURPOSE: To evaluate the incidence of distal embolism and local vascular responses after treatment with the Kanshas drug-coated balloon (DCB) in a preclinical model. MATERIALS AND METHODS: A total of 90 femoral arteries from 35 healthy swine were treated with a single-dose (×1) or triple-dose (×3) Kanshas DCB that applies the Unicoat technology with 3.2 µg/mm2 of paclitaxel. An uncoated Kanshas balloon was used as a control. The arterial wall, downstream skeletal muscle, and nontarget organs (kidneys, lungs, lymph nodes, liver, spleen, and heart) were histologically evaluated. For pharmacokinetic evaluation, a total of 40 healthy swine were treated with ×1 Kanshas DCB, and treated vessels were evaluated ex vivo with high-performance liquid chromatography-mass spectrometry. RESULTS: Arteries treated with the Kanshas DCB showed mild proteoglycan deposition accompanied by the loss of smooth muscle cells (SMCs). These changes increased in a dose-dependent manner (medial SMC loss at 28 days in the ×1 vs ×3 groups, in depth, 1 (0.75-1.38) vs 2 (1.63-2.44); P = .0008; in circumference, 0.83 (0.67-1) vs 1.5 (1.19-1.81); P = .0071). No evidence of distal embolization in skeletal muscles (0 of 210 histological sections) and nontarget organs (0 of 345 sections) was observed. The pharmacokinetic evaluation showed high paclitaxel concentration in the treated artery (912 ng/mg, peaking at 3 minutes), which remained detectable at up to 180 days (0.04 ng/mg). CONCLUSIONS: The Kanshas DCB showed a local drug effect in treated arteries up to 180 days with a high concentration of paclitaxel and no histological evidence of distal embolization.
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Artéria Femoral , Doença Arterial Periférica , Animais , Artéria Femoral/efeitos dos fármacos , Artéria Femoral/cirurgia , Doença Arterial Periférica/tratamento farmacológico , Paclitaxel/uso terapêutico , Fármacos Cardiovasculares/uso terapêutico , Suínos , Angioplastia com BalãoRESUMO
Radiation is associated with tissue damage and increased risk of atherosclerosis, but there are currently no treatments and a very limited mechanistic understanding of how radiation impacts tissue repair mechanisms. We uncovered that radiation significantly delayed temporal resolution programs that were associated with decreased efferocytosis in vivo. Resolvin D1 (RvD1), a known proresolving ligand, promoted swift resolution and restored efferocytosis in sublethally irradiated mice. Irradiated macrophages exhibited several features of senescence, including increased expression of p16INK4A and p21, heightened levels of SA-ß-gal, COX-2, several proinflammatory cytokines/chemokines, and oxidative stress (OS) in vitro, and when transferred to mice, they exacerbated inflammation in vivo. Mechanistically, heightened OS in senescent macrophages led to impairment in their ability to carry out efficient efferocytosis, and treatment with RvD1 reduced OS and improved efferocytosis. Sublethally irradiated Ldlr -/- mice exhibited increased plaque necrosis, p16INK4A cells, and decreased lesional collagen compared with nonirradiated controls, and treatment with RvD1 significantly reduced necrosis and increased lesional collagen. Removal of p16INK4A hematopoietic cells during advanced atherosclerosis with p16-3MR mice reduced plaque necrosis and increased production of key intraplaque-resolving mediators. Our results demonstrate that sublethal radiation drives macrophage senescence and efferocytosis defects and suggest that RvD1 may be a new therapeutic strategy to limit radiation-induced tissue damage.
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Aterosclerose/imunologia , Doenças Cardiovasculares/imunologia , Ácidos Docosa-Hexaenoicos/metabolismo , Células-Tronco Hematopoéticas/fisiologia , Macrófagos/imunologia , Lesões por Radiação/imunologia , Cicatrização/efeitos da radiação , Animais , Aterosclerose/genética , Células Cultivadas , Senescência Celular , Ciclo-Oxigenase 2/metabolismo , Genes p16 , Humanos , Inflamação , Camundongos , Camundongos Knockout , RadiaçãoRESUMO
Acute coronary syndromes due to atherosclerotic coronary artery disease are a leading cause of morbidity and mortality worldwide. Intra-plaque hemorrhage (IPH), caused by disruption of intra-plaque leaky microvessels, is one of the major contributors of plaque progression, causing a sudden increase in plaque volume and eventually plaque destabilization. IPH and its healing processes are highly complex biological events that involve interactions between multiple types of cells in the plaque, including erythrocyte, macrophages, vascular endothelial cells and vascular smooth muscle cells. Recent investigations have unveiled detailed molecular mechanisms by which IPH leads the development of high-risk "vulnerable" plaque. Current advances in clinical diagnostic imaging modalities, such as magnetic resonance image and intra-coronary optical coherence tomography, increasingly allow us to identify IPH in vivo. To date, retrospective and prospective clinical trials have revealed the significance of IPH as detected by various imaging modalities as a reliable prognostic indicator of high-risk plaque. In this review article, we discuss recent advances in our understanding for the significance of IPH on the development of high-risk plaque from basic to clinical points of view.
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Doença da Artéria Coronariana , Células Endoteliais , Humanos , Estudos Prospectivos , Estudos Retrospectivos , Doença da Artéria Coronariana/diagnóstico por imagem , Hemorragia/diagnóstico por imagem , Hemorragia/etiologia , Placa AmiloideRESUMO
BACKGROUND: Cardiac injury is common in patients who are hospitalized with coronavirus disease 2019 (COVID-19) and portends poorer prognosis. However, the mechanism and the type of myocardial damage associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain uncertain. METHODS: We conducted a systematic pathological analysis of 40 hearts from hospitalized patients dying of COVID-19 in Bergamo, Italy, to determine the pathological mechanisms of cardiac injury. We divided the hearts according to presence or absence of acute myocyte necrosis and then determined the underlying mechanisms of cardiac injury. RESULTS: Of the 40 hearts examined, 14 (35%) had evidence of myocyte necrosis, predominantly of the left ventricle. Compared with subjects without necrosis, subjects with necrosis tended to be female, have chronic kidney disease, and have shorter symptom onset to admission. The incidence of severe coronary artery disease (ie, >75% cross-sectional narrowing) was not significantly different between those with and without necrosis. Three of 14 (21.4%) subjects with myocyte necrosis showed evidence of acute myocardial infarction, defined as ≥1 cm2 area of necrosis, whereas 11 of 14 (78.6%) showed evidence of focal (>20 necrotic myocytes with an area of ≥0.05 mm2 but <1 cm2) myocyte necrosis. Cardiac thrombi were present in 11 of 14 (78.6%) cases with necrosis, with 2 of 14 (14.2%) having epicardial coronary artery thrombi, whereas 9 of 14 (64.3%) had microthrombi in myocardial capillaries, arterioles, and small muscular arteries. We compared cardiac microthrombi from COVID-19-positive autopsy cases to intramyocardial thromboemboli from COVID-19 cases as well as to aspirated thrombi obtained during primary percutaneous coronary intervention from uninfected and COVID-19-infected patients presenting with ST-segment-elevation myocardial infarction. Microthrombi had significantly greater fibrin and terminal complement C5b-9 immunostaining compared with intramyocardial thromboemboli from COVID-19-negative subjects and with aspirated thrombi. There were no significant differences between the constituents of thrombi aspirated from COVID-19-positive and -negative patients with ST-segment-elevation myocardial infarction. CONCLUSIONS: The most common pathological cause of myocyte necrosis was microthrombi. Microthrombi were different in composition from intramyocardial thromboemboli from COVID-19-negative subjects and from coronary thrombi retrieved from COVID-19-positive and -negative patients with ST-segment-elevation myocardial infarction. Tailored antithrombotic strategies may be useful to counteract the cardiac effects of COVID-19 infection.
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COVID-19/virologia , Trombose Coronária/etiologia , Infarto do Miocárdio , Miocárdio/patologia , Idoso , COVID-19/patologia , Trombose Coronária/patologia , Trombose Coronária/virologia , Vasos Coronários/patologia , Vasos Coronários/virologia , Feminino , Coração/virologia , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/patologia , Infarto do Miocárdio/virologia , SARS-CoV-2 , Infarto do Miocárdio com Supradesnível do Segmento ST/epidemiologia , Infarto do Miocárdio com Supradesnível do Segmento ST/virologiaRESUMO
Over the past 2 decades, chronic total occlusion (CTO) percutaneous coronary intervention has developed into its own subspecialty of interventional cardiology. Dedicated terminology, techniques, devices, courses, and training programs have enabled progressive advancements. However, only a few randomized trials have been performed to evaluate the safety and efficacy of CTO percutaneous coronary intervention. Moreover, several published observational studies have shown conflicting data. Part of the paucity of clinical data stems from the fact that prior studies have been suboptimally designed and performed. The absence of standardized end points and the discrepancy in definitions also prevent consistency and uniform interpretability of reported results in CTO intervention. To standardize the field, we therefore assembled a broad consortium comprising academicians, practicing physicians, researchers, medical society representatives, and regulators (US Food and Drug Administration) to develop methods, end points, biomarkers, parameters, data, materials, processes, procedures, evaluations, tools, and techniques for CTO interventions. This article summarizes the effort and is organized into 3 sections: key elements and procedural definitions, end point definitions, and clinical trial design principles. The Chronic Total Occlusion Academic Research Consortium is a first step toward improved comparability and interpretability of study results, supplying an increasingly growing body of CTO percutaneous coronary intervention evidence.
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Oclusão Coronária/terapia , Vasos Coronários/fisiologia , Ensaios Clínicos como Assunto , Feminino , Humanos , MasculinoRESUMO
PURPOSE OF REVIEW: The importance of cardiovascular disease (CVD) in women has long been underestimated. Therefore, we need to understand the impact of sex differences on CVD. RECENT FINDINGS: Traditional risk factors contribute to coronary artery disease (CAD) differently in women and men. There are female-specific risk factors and comorbid conditions that affect the risk of CAD. Plaque erosion is frequently seen in younger women who smoke, while plaque rupture is common in older women and men who have elevated blood cholesterol. Coronary artery calcification is also different in both sexes. Thus, coronary artery calcification score-based risk stratification in women is challenging. A deeper understanding of the sex differences in the risk factors and plaque morphology of coronary atherosclerosis may lead to improved outcomes of CVD in women.
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Doença da Artéria Coronariana , Placa Aterosclerótica , Idoso , Angiografia Coronária , Doença da Artéria Coronariana/epidemiologia , Feminino , Humanos , Masculino , Placa Aterosclerótica/diagnóstico por imagem , Fatores de Risco , Caracteres Sexuais , Fatores SexuaisRESUMO
INTRODUCTION: Sirolimus coated balloon (SCB) is a promising treatment option to prevent restenosis for peripheral arterial occlusive disease (PAOD). This is a pilot first-in-human study of MagicTouch percutaneous transluminal angioplasty (PTA) SCB for treatment of PAOD for both femoropopliteal and below the knee arteries (BTK). MATERIAL AND METHODS: Xtreme Touch-Neo [MagicTouch PTA] Sirolimus Coated Balloon (XTOSI) pilot study is a prospective, single-arm, open-label, single-center trial evaluating MagicTouch PTA SCB for symptomatic PAOD. Primary endpoint was defined as primary patency at 6 months (duplex ultrasound peak systolic velocity ratio ≤2.4). Secondary endpoints included clinically driven target lesion revascularization (CD-TLR), amputation free survival (AFS), all-cause mortality, and limb salvage success. RESULTS: Fifty patients were recruited. The mean age was 67 (n=31 [62%] males). SCB was applied to femoropopliteal in 20 patients (40%) and BTK in 30 patients (60%). Majority of treatments (94%) were performed for limb salvage indications (Rutherford scores 5 or 6). This was a high risk cohort, in which 90% had diabetes, 36% had coronary artery disease, 20% had end stage renal failure, and American Society of Anaesthesiologists (ASA) score was 3 or more in 80%. Mean lesion length treated was 227±81 mm, of which 36% were total occlusions. Technical and device success were both 100%. At 30 days, mortality was 2% and major limb amputation was also 2%. Six-month primary patency was 80% (88.2% for femoropopliteal; 74% for BTK). At 12 months, freedom from CD-TLR was 89.7% (94.1% for femoropopliteal; 86.3% for BTK), AFS was 81.6% (90.0% for femoropopliteal; 75.9% for BTK), all-cause mortality was 14.3% (10.0% for femoropopliteal; 17.2% for BTK), and limb salvage success was 92.9% (94.4% for femoropopliteal; 91.7% for BTK). There was a statistically significant increase between baseline and 6-month toe pressures for both femoropopliteal (57.3±23.3 mm Hg vs 82.5±37.8 mm Hg; p<.001) and BTK lesions (52.8±19.2 mm Hg vs 70.7±37 mm Hg; p<.037). At 12 months, wound healing rate was 33/39 (84.6%). CONCLUSIONS: MagicTouch PTA SCB in the XTOSI study showed promising 6-month primary patency and encouraging 12-month freedom from CD-TLR, AFS, and limb salvage rates. No early safety concerns were raised. Randomized trials are needed to investigate the safety and efficacy of SCB for treatment of PAOD.
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Angioplastia com Balão , Doença Arterial Periférica , Idoso , Materiais Revestidos Biocompatíveis , Feminino , Artéria Femoral/diagnóstico por imagem , Humanos , Masculino , Doença Arterial Periférica/diagnóstico por imagem , Doença Arterial Periférica/terapia , Projetos Piloto , Artéria Poplítea/diagnóstico por imagem , Artéria Poplítea/cirurgia , Estudos Prospectivos , Sirolimo/efeitos adversos , Resultado do Tratamento , Grau de Desobstrução VascularRESUMO
[Figure: see text].
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Lesões das Artérias Carótidas/enzimologia , Proteínas de Transporte/metabolismo , Movimento Celular , Proliferação de Células , Proteínas de Membrana/metabolismo , Músculo Liso Vascular/enzimologia , Miócitos de Músculo Liso/enzimologia , Neointima , Piruvato Quinase/metabolismo , Hormônios Tireóideos/metabolismo , Idoso , Animais , Lesões das Artérias Carótidas/genética , Lesões das Artérias Carótidas/patologia , Proteínas de Transporte/genética , Células Cultivadas , Modelos Animais de Doenças , Ativação Enzimática , Feminino , Glicólise , Humanos , Hiperplasia , Masculino , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Fenótipo , Piruvato Quinase/genética , Transdução de Sinais , Hormônios Tireóideos/genética , Proteínas de Ligação a Hormônio da TireoideRESUMO
OBJECTIVE: Healing processes, particularly reendothelialization, are essential for vascular homeostasis after plain old balloon angioplasty and stent implantation. Drug-eluting stents (DES) are commonly used for percutaneous coronary intervention because restenosis rates are reduced as compared with bare metal stents (BMS). However, in addition to understanding the nature of regenerated endothelial cells, concerns over incomplete stent healing persist, and the molecular effects of antiproliferative drug coatings on endothelium remain poorly understood. APPROACH AND RESULTS: We used the rabbit iliac artery model to analyze differences in stent endothelialization in BMS and DES. Histology and immunohistochemistry confirmed that stent coverage was significantly greater in BMS than in DES at 30 days after stent implantation. Single-cell RNA sequencing revealed a more immature transcriptomic signature of neointimal endothelial cell harvested from stented arteries in comparison with native and plain old balloon angioplasty treated arteries. Whereas the genetic signature of BMS was overall proangiogenic with enrichment of genes involved in endothelial proliferation, sprouting, and migration, as well as extracellular matrix assembly, DES-derived endothelial cell showed upregulation of genes associated with angiogenesis inhibition and endothelial activation. CONCLUSIONS: Single-cell RNA sequencing analysis identified unique transcriptional changes within regenerated endothelium after plain old balloon angioplasty and stent implantation. These data suggest unique endothelial transcriptional differences, which characterize the different response of the endothelium to vascular injury and may help explain why long-term responses in DES remain suboptimal.
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Stents Farmacológicos , Células Endoteliais/ultraestrutura , Procedimentos Endovasculares/instrumentação , Artéria Ilíaca/ultraestrutura , Neointima , Reepitelização , Análise de Célula Única , Animais , Proliferação de Células , Vasos Coronários/metabolismo , Vasos Coronários/patologia , Células Endoteliais/metabolismo , Procedimentos Endovasculares/efeitos adversos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/ultraestrutura , Humanos , Artéria Ilíaca/metabolismo , Masculino , Microscopia Confocal , Microscopia Eletrônica de Varredura , Modelos Animais , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/instrumentação , RNA-Seq , Coelhos , Fatores de Tempo , TranscriptomaRESUMO
[Figure: see text].