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BACKGROUND: Thrombocytopenia has been consistently described in patients with extracorporeal membrane oxygenation (ECMO) and associated with poor outcome. However, the prevalence and underlying mechanisms remain largely unknown, and a device-related role of ECMO in thrombocytopenia has been hypothesized. This study aims to investigate the mechanisms underlying thrombocytopenia in ECMO patients. METHODS: In a prospective cohort of 107 ECMO patients, we investigated platelet count, functions, and glycoprotein shedding. In an ex vivo mock circulatory ECMO loop, we assessed platelet responses and VWF (von Willebrand factor)-GP Ibα (glycoprotein Ibα) interactions at low- and high-flow rates, in the presence or absence of red blood cells. The clearance of human platelets subjected or not to ex vivo perfusion was studied using an in vivo transfusion model in NOD/SCID (nonobese diabetic/severe combined Immunodeficient) mice. RESULTS: In ECMO patients, we observed a time-dependent decrease in platelet count starting 1 hour after device onset, with a mean drop of 7%, 35%, and 41% at 1, 24, and 48 hours post-ECMO initiation (P=0.00013, P<0.0001, and P<0.0001, respectively), regardless of the type of ECMO. This drop in platelet count was associated with a decrease in platelet GP Ibα expression (before: 47.8±9.1 versus 24 hours post-ECMO: 42.3±8.9 mean fluorescence intensity; P=0.002) and an increase in soluble GP Ibα plasma levels (before: 5.6±3.3 versus 24 hours post-ECMO: 10.8±4.1 µg/mL; P<0.0001). GP Ibα shedding was also observed ex vivo and was unaffected by (1) red blood cells, (2) the coagulation potential, (3) an antibody blocking VWF-GP Ibα interaction, (4) an antibody limiting VWF degradation, and (5) supraphysiological VWF plasma concentrations. In contrast, GP Ibα shedding was dependent on rheological conditions, with a 2.8-fold increase at high- versus low-flow rates. Platelets perfused at high-flow rates before being transfused to immunodeficient mice were eliminated faster in vivo with an accelerated clearance of GP Ibα-negative versus GP Ibα-positive platelets. CONCLUSIONS: ECMO-associated shear forces induce GP Ibα shedding and thrombocytopenia due to faster clearance of GP Ibα-negative platelets. Inhibiting GP Ibα shedding could represent an approach to reduce thrombocytopenia during ECMO.
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Trombocitopenia , Fator de von Willebrand , Humanos , Animais , Camundongos , Fator de von Willebrand/metabolismo , Estudos Prospectivos , Camundongos Endogâmicos NOD , Camundongos SCID , Plaquetas/metabolismo , Trombocitopenia/terapia , Trombocitopenia/metabolismoRESUMO
OBJECTIVE: The study's aim was to analyze the capacity of human valve interstitial cells (VICs) to participate in aortic valve angiogenesis. Approach and Results: VICs were isolated from human aortic valves obtained after surgery for calcific aortic valve disease and from normal aortic valves unsuitable for grafting (control VICs). We examined VIC in vitro and in vivo potential to differentiate in endothelial and perivascular lineages. VIC paracrine effect was also examined on human endothelial colony-forming cells. A pathological VIC (VICp) mesenchymal-like phenotype was confirmed by CD90+/CD73+/CD44+ expression and multipotent-like differentiation ability. When VICp were cocultured with endothelial colony-forming cells, they formed microvessels by differentiating into perivascular cells both in vivo and in vitro. VICp and control VIC conditioned media were compared using serial ELISA regarding quantification of endothelial and angiogenic factors. Higher expression of VEGF (vascular endothelial growth factor)-A was observed at the protein level in VICp-conditioned media and confirmed at the mRNA level in VICp compared with control VIC. Conditioned media from VICp induced in vitro a significant increase in endothelial colony-forming cell proliferation, migration, and sprouting compared with conditioned media from control VIC. These effects were inhibited by blocking VEGF-A with blocking antibody or siRNA approach, confirming VICp involvement in angiogenesis by a VEGF-A dependent mechanism. CONCLUSIONS: We provide here the first proof of an angiogenic potential of human VICs isolated from patients with calcific aortic valve disease. These results point to a novel function of VICp in valve vascularization during calcific aortic valve disease, with a perivascular differentiation ability and a VEGF-A paracrine effect. Targeting perivascular differentiation and VEGF-A to slow calcific aortic valve disease progression warrants further investigation.
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Estenose da Valva Aórtica/metabolismo , Valva Aórtica/metabolismo , Valva Aórtica/patologia , Calcinose/metabolismo , Diferenciação Celular , Linhagem da Célula , Células Progenitoras Endoteliais/metabolismo , Neovascularização Patológica , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Estenose da Valva Aórtica/patologia , Calcinose/patologia , Estudos de Casos e Controles , Células Cultivadas , Técnicas de Cocultura , Células Progenitoras Endoteliais/patologia , Células Progenitoras Endoteliais/transplante , Feminino , Humanos , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Osteogênese , Comunicação Parácrina , Fenótipo , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
[Figure: see text].
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COVID-19/complicações , COVID-19/patologia , Endotélio Vascular/patologia , Insuficiência de Múltiplos Órgãos/virologia , Trombose/virologia , Biomarcadores/sangue , COVID-19/imunologia , Ativação do Complemento , Cuidados Críticos , Citocinas/sangue , Feminino , Humanos , Falência Hepática Aguda/virologia , Masculino , Microcirculação , Pessoa de Meia-Idade , Nucleossomos/metabolismo , Insuficiência Respiratória/virologia , SARS-CoV-2RESUMO
Transcatheter aortic valve replacement (TAVR), as an alternative to open heart surgery, has revolutionized the treatment of severe aortic valve stenosis (AVS), the most common valvular disorder in the elderly. AVS is now considered a form of atherosclerosis and, like the latter, partly of inflammatory origin. Patients with high-grade AVS have a highly disturbed blood flow associated with high levels of shear stress. The immediate reopening of the valve during TAVR leads to a sudden restoration of a normal blood flow hemodynamic. Despite its good prognosis for patients, TAVR remains associated with bleeding or thrombotic postprocedural complications, involving mechanisms that are still poorly understood. Many studies report the close link between blood coagulation and inflammation, termed thromboinflammation, including monocytes as a major actor. The TAVR procedure represents a unique opportunity to study the influence of shear stress on human monocytes, key mediators of inflammation and hemostasis processes. The purpose of this study was to conduct a review of the literature to provide a comprehensive overview of the impact of TAVR on monocyte phenotype and subset repartition and the association of these parameters with the clinical outcomes of patients with severe AVS who underwent TAVR.
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Estenose da Valva Aórtica , Próteses Valvulares Cardíacas , Trombose , Substituição da Valva Aórtica Transcateter , Idoso , Estenose da Valva Aórtica/etiologia , Humanos , Inflamação/etiologia , Monócitos , Trombose/etiologia , Substituição da Valva Aórtica Transcateter/efeitos adversos , Substituição da Valva Aórtica Transcateter/métodosRESUMO
RATIONALE: Vascular calcification is a process similar to bone formation leading to an inappropriate deposition of calcium phosphate minerals in advanced atherosclerotic plaques. Monocyte-derived macrophages, located in atherosclerotic lesions and presenting heterogeneous phenotypes, from classical proinflammatory M1 to alternative anti-inflammatory M2 macrophages, could potentially display osteoclast-like functions. OBJECTIVE: To characterize the phenotype of macrophages located in areas surrounding the calcium deposits in human atherosclerotic plaques. METHODS AND RESULTS: Macrophages near calcium deposits display an alternative phenotype being both CD68 and mannose receptor-positive, expressing carbonic anhydrase type II, but relatively low levels of cathepsin K. In vitro interleukin-4-polarization of human primary monocytes into macrophages results in lower expression and activity of cathepsin K compared with resting unpolarized macrophages. Moreover, interleukin-4 polarization lowers expression levels of the osteoclast transcriptional activator nuclear factor of activated T cells type c-1, associated with increased gene promoter levels of the transcriptional repression mark H3K27me3 (histone 3 lysine 27 trimethylation). Despite higher expression of the receptor activator of nuclear factor κB receptor, receptor activator of nuclear factor κB ligand/macrophage colony-stimulating factor induction of nuclear factor of activated T cells type c-1 and cathepsin K expression is defective in these macrophages because of reduced Erk/c-fos-mediated downstream signaling resulting in impaired bone resorption capacity. CONCLUSIONS: These results indicate that macrophages surrounding calcium deposits in human atherosclerotic plaques are phenotypically defective being unable to resorb calcification.
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Reabsorção Óssea/metabolismo , Macrófagos/metabolismo , Osteoclastos/metabolismo , Placa Aterosclerótica/metabolismo , Ligante RANK/metabolismo , Calcificação Vascular/metabolismo , Reabsorção Óssea/patologia , Células Cultivadas , Humanos , Microdissecção e Captura a Laser/métodos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Macrófagos/patologia , Osteoclastos/patologia , Placa Aterosclerótica/patologia , Calcificação Vascular/patologiaRESUMO
BACKGROUND: Aortic valve stenosis involves inflammation, excess deposition of a collagen-rich extracellular matrix, and calcification. Recent studies have shown that M1 or inflammatory macrophages derived from infiltrating monocytes promote calcification of valvular interstitial cells, the most prevalent cell type of the aortic valve. We hypothesized that valvular interstitial cells could modulate inflammatory macrophages phenotype. METHODS: We first assessed macrophage phenotype in human aortic valve stenosis and control aortic valves from donors. Then, we examined profibrotic and inflammatory-related gene expression in valves and valvular interstitial cells. Finally, we investigated whether valvular interstitial cells can modify the phenotype of inflammatory macrophages. RESULTS: Circulating monocytes and plasma transforming growth factor beta-1 levels of patients with aortic valve stenosis were significantly higher compared with patients without aortic valve stenosis. Histologic analysis of thickened spongiosa of the aortic valve from patients with aortic valve stenosis showed a high macrophage infiltration but a low matrix metalloproteinase-9 expression compared with control aortic valves. On the other hand, valvular interstitial cell culture of aortic valve stenosis exhibited a profibrotic phenotype with a high expression of transforming growth factor beta-1 and transforming growth factor beta-1/transforming growth factor beta-3 ratio but a decreased expression of the peroxisome proliferator-activated receptor gamma nuclear receptor. Valvular interstitial cell-conditioned media of aortic valve stenosis led to a decrease in enzymatic activity of matrix metalloproteinase-9 and an increase in production of collagen in inflammatory macrophages compared with valvular interstitial cell-conditioned media from control aortic valve donors. CONCLUSIONS: These findings indicate that profibrotic valvular interstitial cells promote the imbalance of extracellular matrix remodeling by reducing matrix metalloproteinase-9 production on inflammatory macrophages that lead to excessive collagen deposition observed in aortic valve stenosis. Further investigation is needed to clarify the role of transforming growth factor beta-1/proliferator-activated receptor gamma nuclear receptor/matrix metalloproteinase-9 in aortic valve stenosis.
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Clonal hematopoiesis of indeterminate potential (CHIP) is considered as being a novel age-related risk factor for cardiovascular diseases. By capture-sequencing of a 67-gene panel, we established a large spectrum of CHIP in 258 patients with aortic valve stenosis undergoing transcatheter aortic valve replacement (TAVR) and assessed their association with long-term survival after TAVR. One or several CHIP variants in 35 genes were identified in 68% of the cohort, DNMT3A and TET2 being the 2 most frequently mutated genes. Patients carrying a TET2-CHIP-driver variant with low variant allele frequency (2%-10%) had a significant decrease in overall survival 5 years after TAVR.
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BACKGROUND: COVID-19 convalescent plasma (CCP) contains neutralising anti-SARS-CoV-2 antibodies that may be useful as COVID-19 passive immunotherapy in patients at risk of developing severe disease. Such plasma from convalescent patients may also have additional immune-modulatory properties when transfused to COVID-19 patients. METHODS: CCP (n = 766) was compared to non-convalescent control plasma (n = 166) for soluble inflammatory markers, ex-vivo inflammatory bioactivity on endothelial cells, neutralising auto-Abs to type I IFNs and reported adverse events in the recipients. FINDINGS: CCP exhibited a statistically significant increase in IL-6 and TNF-alpha levels (0.531 ± 0.04 vs 0.271 ± 0.04; (95% confidence interval [CI], 0.07371-0.4446; p = 0.0061) and 0.900 ± 0.07 vs 0.283 ± 0.07 pg/mL; (95% [CI], 0.3097-0.9202; p = 0.0000829) and lower IL-10 (0.731 ± 0.07 vs 1.22 ± 0.19 pg/mL; (95% [CI], -0.8180 to -0.1633; p = 0.0034) levels than control plasma. Neutralising auto-Abs against type I IFNs were detected in 14/766 (1.8%) CCPs and were not associated with reported adverse events when transfused. Inflammatory markers and bioactivity in CCP with or without auto-Abs, or in CCP whether or not linked to adverse events in transfused patients, did not differ to a statistically significant extent. INTERPRETATION: Overall, CCP exhibited moderately increased inflammatory markers compared to the control plasma with no discernible differences in ex-vivo bioactivity. Auto-Abs to type I IFNs detected in a small fraction of CCP were not associated with reported adverse events or differences in inflammatory markers. Additional studies, including careful clinical evaluation of patients treated with CCP, are required in order to further define the clinical relevance of these findings. FUNDING: French National Blood Service-EFS, the Association "Les Amis de Rémi" Savigneux, France, the "Fondation pour la Recherche Médicale (Medical Research Foundation)-REACTing 2020".
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COVID-19 , Humanos , Estudos de Coortes , Células Endoteliais , Soroterapia para COVID-19 , Imunização Passiva , Anticorpos AntiviraisRESUMO
Predictive scores assessing the risk of respiratory failure in COVID-19 mostly focused on the prediction of early intubation. A combined assessment of clinical parameters and biomarkers of endotheliopathy could allow to predict late worsening of acute respiratory failure (ARF), subsequently warranting intubation in COVID-19. Retrospective single-center derivation (n = 92 subjects) and validation cohorts (n = 59 subjects), including severe COVID-19 patients with non-invasive respiratory support, were assessed for at least 48 h following intensive care unit (ICU) admission. We used stepwise regression to construct the COVID endothelial and respiratory failure (CERES) score in a derivation cohort, and secondly assessed its accuracy for the prediction of late ARF worsening, requiring intubation within 15 days following ICU admission in an independent validation cohort. Platelet count, fraction of inspired oxygen, and endocan measured on ICU admission were identified as the top three predictive variables for late ARF worsening and subsequently included in the CERES score. The area under the ROC curve of the CERES score to predict late ARF worsening was calculated in the derivation and validation cohorts at 0.834 and 0.780, respectively. The CERES score is a simple tool with good performances to predict respiratory failure worsening, leading to secondary intubation, in COVID-19 patients.
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Genome-wide association studies for calcific aortic valve stenosis (CAVS) previously reported strong signal for noncoding variants at 1p21.2. Previous study using Mendelian randomization suggested that the locus controls the expression of PALMD encoding Palmdelphin (PALMD). However, the molecular regulation at the locus and the impact of PALMD on the biology of the aortic valve is presently unknown. 3D genetic mapping and CRISPR activation identified rs6702619 as being located in a distant-acting enhancer, which controls the expression of PALMD. DNA-binding assay showed that the risk variant modified the DNA shape, which prevented the recruitment of NFATC2 and lowered the expression of PALMD. In co-expression network analysis, a module encompassing PALMD was enriched in actin-based process. Mass spectrometry and functional assessment showed that PALMD is a regulator of actin polymerization. In turn, lower level of PALMD promoted the activation of myocardin-related transcription factor and fibrosis, a key pathobiological process underpinning CAVS.
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Background In calcific aortic valve disease on tricuspid aortic valves (TAVs), men have higher aortic valve calcification and less fibrosis than women. However, little is known in bicuspid aortic valves (BAV). We thus aimed to investigate the impact of age, sex, and valve phenotype (TAVs versus BAVs) on fibro-calcific remodeling in calcific aortic valve disease. Methods and Results We included 2 cohorts: 411 patients who underwent multidetector computed tomography (37% women) for aortic valve calcification density assessment and 138 explanted aortic valves (histological cohort; 50% women). The cohorts were divided in younger (<60 years old) or older patients with BAV (≥60 years old), and TAV patients. In each group, women and men were matched. Women presented less aortic valve calcification density than men in each group of the multidetector computed tomography cohort (all P≤0.01). Moreover, in women, younger patients with BAV had the lowest aortic valve calcification density (both P=0.02). In multivariate analysis, aortic valve calcification density correlated with age (ß estimate±standard error: 6.5±1.8; P=0.0004) and male sex (109.2±18.4; P<0.0001), and there was a trend with TAVs (41.5±23.0; P=0.07). Women presented a higher collagen content than men (77.8±10.8 versus 69.9±12.9%; P<0.001) in the entire cohort. In women, younger patients with BAV had denser connective tissue than TAV and older patients with BAV (both P≤0.05), while no difference was observed between men. Conclusions In calcific aortic valve disease, women had less calcification and more fibrotic remodeling than men, regardless of the phenotype of the valve or age of the patient. Moreover, younger women with BAVs had less valve calcification. Thus, mineralization/fibrosis of the aortic valve is likely to have sex/age-specific mechanisms and be influenced by the valve morphology.
Assuntos
Estenose da Valva Aórtica/patologia , Valva Aórtica/anormalidades , Valva Aórtica/patologia , Doença da Válvula Aórtica Bicúspide/patologia , Calcinose/patologia , Disparidades nos Níveis de Saúde , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Valva Aórtica/química , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/metabolismo , Valva Aórtica/fisiopatologia , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/fisiopatologia , Doença da Válvula Aórtica Bicúspide/diagnóstico por imagem , Doença da Válvula Aórtica Bicúspide/metabolismo , Doença da Válvula Aórtica Bicúspide/fisiopatologia , Calcinose/diagnóstico por imagem , Calcinose/metabolismo , Calcinose/fisiopatologia , Colágeno/análise , Feminino , Fibrose , Hemodinâmica , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Medição de Risco , Fatores de Risco , Fatores SexuaisRESUMO
Growing evidence suggests that inflammation is a significant contributor to different cardiovascular diseases (CVDs). Mendelian randomization (MR) was performed to assess the causal inference between plasma soluble IL6 receptor (sIL6R), a negative regulator of IL6 signaling, and different cardiovascular and immune-related disorders. Cis-MR with multiple instrumental variables showed an inverse association of sIL6R with rheumatoid arthritis, atrial fibrillation, stroke, coronary artery disease, and abdominal aortic aneurysm. However, genetically-determined sIL6R level was positively associated with atopic dermatitis and asthma. Also, sIL6R level was associated with longevity, as evaluated by parental age at death, a heritable trait. Gene-based association analysis with S-PrediXcan by using tissues from GTExV7 showed that IL6R tissue expression-disease pair associations were consistent with the directional effect of IL6 signaling identified in MR. Genetically-determined reduced IL6 signaling lowers the risk of multiple CVDs and is associated with increased longevity, but at the expense of higher atopic risk.
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For decades, numerous observations have shown an intimate relationship between von Willebrand factor (VWF) multimer profile and heart valve diseases (HVD). The current knowledge of the unique biophysical properties of VWF helps us to understand the longstanding observations concerning the bleeding complications in patients with severe HVD. Not only does the analysis of the VWF multimer profile provide an excellent evaluation of HVD severity, it is also a strong predictor of clinical events. Also of importance, VWF responds within minutes to any significant change in hemodynamic valve status, making it an accurate marker of the quality of surgical and transcatheter therapeutic interventions. The authors provide in this review a practical, comprehensive, and evidence-based framework of the concept of VWF as a biomarker in HVD, advocating for its implementation into the clinical decision-making process besides usual clinical and imaging evaluation. They also delineate critical knowledge gaps and research priorities to definitely validate this concept.
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Tomada de Decisão Clínica , Gerenciamento Clínico , Doenças das Valvas Cardíacas/sangue , Implante de Prótese de Valva Cardíaca/métodos , Fator de von Willebrand/metabolismo , Biomarcadores/sangue , Doenças das Valvas Cardíacas/cirurgia , Humanos , Índice de Gravidade de DoençaRESUMO
Aims: Calcific aortic valve disease (CAVD) is characterized by the osteogenic transition of valve interstitial cells (VICs). In CAVD, lysophosphatidic acid (LysoPA), a lipid mediator with potent osteogenic activity, is produced in the aortic valve (AV) and is degraded by membrane-associated phospholipid phosphatases (PLPPs). We thus hypothesized that a dysregulation of PLPPs could participate to the osteogenic reprograming of VICs during CAVD. Methods and results: The expression of PLPPs was examined in human control and mineralized AVs and comprehensive analyses were performed to document the gene regulation and impact of PLPPs on the osteogenic transition of VICs. We found that PLPP3 gene and enzymatic activity were downregulated in mineralized AVs. Multidimensional gene profiling in 21 human AVs showed that expression of PLPP3 was inversely correlated with the level of 5-methylcytosine (5meC) located in an intronic mammalian interspersed repeat (MIR) element. Bisulphite pyrosequencing in a larger series of 67 AVs confirmed that 5meC in intron 1 was increased by 2.2-fold in CAVD compared with control AVs. In isolated cells, epigenome editing with clustered regularly interspersed short palindromic repeats-Cas9 system containing a deficient Cas9 fused with DNA methyltransferase (dCas9-DNMT) was used to increase 5meC in the intronic enhancer and showed that it reduced significantly the expression of PLPP3. Knockdown experiments showed that lower expression of PLPP3 in VICs promotes an osteogenic programme. Conclusions: DNA methylation of a MIR-based enhancer downregulates the expression of PLPP3 and promotes the mineralization of the AV.
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Estenose da Valva Aórtica/genética , Valva Aórtica/enzimologia , Valva Aórtica/patologia , Calcinose/genética , Metilação de DNA , Elementos de DNA Transponíveis , Osteogênese/genética , Fosfatidato Fosfatase/genética , Regiões Promotoras Genéticas , 5-Metilcitosina/metabolismo , Idoso , Estenose da Valva Aórtica/enzimologia , Estenose da Valva Aórtica/patologia , Sistemas CRISPR-Cas , Calcinose/enzimologia , Calcinose/patologia , Cálcio/metabolismo , Estudos de Casos e Controles , Regulação para Baixo , Edição de Genes/métodos , Perfilação da Expressão Gênica/métodos , Células HEK293 , Humanos , Lisofosfolipídeos/metabolismo , Masculino , Pessoa de Meia-Idade , Fosfatidato Fosfatase/metabolismoRESUMO
Significant paravalvular regurgitation (PVR) remains a relatively frequent (4% to 9%) and deleterious complication of transcatheter aortic valve replacement (TAVR), even with the latest generation of bioprosthesis. Although mini-invasive TAVR without general anesthesia or transesophageal echocardiography (TEE) is progressively becoming the predominant approach, identification and grading of PVR in the catheterization laboratory remain an important and challenging clinical issue. The authors discuss how a recently reported blood biomarker reflecting the von Willebrand factor activity, that is, the closure time with adenosine diphosphate, can be successfully applied during the TAVR procedure to detect and monitor PVR in real time, with an excellent negative predictive value. This point-of-care testing performed directly in the catheterization laboratory may improve the diagnosis of PVR and rationalize the decision of whether or not to perform corrective measures. They further discuss how such a test could be a substitute for the multimodal approach combining TEE, hemodynamics, and cine-angiography, and help to secure the transition to the mini-invasive approach and facilitate the expanding indications of less invasive procedures to lower-risk patients without jeopardizing procedural and clinical outcomes.
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Insuficiência da Valva Aórtica/prevenção & controle , Estenose da Valva Aórtica/cirurgia , Valva Aórtica/cirurgia , Testes de Coagulação Sanguínea , Monitorização Intraoperatória/métodos , Substituição da Valva Aórtica Transcateter/efeitos adversos , Fator de von Willebrand/metabolismo , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/fisiopatologia , Insuficiência da Valva Aórtica/etiologia , Insuficiência da Valva Aórtica/mortalidade , Insuficiência da Valva Aórtica/fisiopatologia , Estenose da Valva Aórtica/diagnóstico , Estenose da Valva Aórtica/mortalidade , Estenose da Valva Aórtica/fisiopatologia , Biomarcadores/sangue , Hemodinâmica , Humanos , Fatores de Risco , Fatores de Tempo , Substituição da Valva Aórtica Transcateter/mortalidade , Resultado do TratamentoRESUMO
Calcific aortic valve stenosis (CAVS) is a common and life-threatening heart disease and the current treatment options cannot stop or delay its progression. A GWAS on 1009 cases and 1017 ethnically matched controls was combined with a large-scale eQTL mapping study of human aortic valve tissues (n = 233) to identify susceptibility genes for CAVS. Replication was performed in the UK Biobank, including 1391 cases and 352,195 controls. A transcriptome-wide association study (TWAS) reveals PALMD (palmdelphin) as significantly associated with CAVS. The CAVS risk alleles and increasing disease severity are both associated with decreased mRNA expression levels of PALMD in valve tissues. The top variant identified shows a similar effect and strong association with CAVS (P = 1.53 × 10-10) in UK Biobank. The identification of PALMD as a susceptibility gene for CAVS provides insights into the genetic nature of this disease, opens avenues to investigate its etiology and to develop much-needed therapeutic options.
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Estenose da Valva Aórtica/genética , Valva Aórtica/patologia , Calcinose/genética , Proteínas de Membrana/genética , Transcriptoma/genética , Estenose da Valva Aórtica/patologia , Calcinose/patologia , Progressão da Doença , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , HumanosRESUMO
BACKGROUND: The main risk factor for bleeding in patients with continuous-flow mechanical circulatory support (CF-MCS) is the acquired von Willebrand factor (VWF) defect related to the high shear-stress forces developed by these devices. Although a higher bleeding rate has been reported in CF-MCS recipients who had reduced pulsatility, the relation between pulsatility and the VWF defect has never been studied. OBJECTIVES: The purpose of this study was to investigate the relation between pulsatility and VWF under CF-MCS. METHODS: We assessed the effect of 2 CF-MCS on VWF multimer degradation in a mock circulatory loop (model 1). Using these devices, we investigated in a dose-effect model (model 2) 3 levels of pulsatility in 3 groups of swine. In a cross-over model (model 3), we studied the effects of sequential changes of pulsatility on VWF. We reported the evolution of VWF multimerization in a patient undergoing serial CF-MCS and/or pulsatile-MCS. RESULTS: We demonstrated the proteolytic degradation of VWF multimers by high shear CF-MCS in a circulatory loop without pulsatility. We observed both in swine models and in a patient that the magnitude of the VWF degradation is modulated by the pulsatility level in the high shear-stress level condition, and that the restoration of pulsatility is a trigger for the endothelial release of VWF. CONCLUSIONS: We demonstrated that the VWF defect reflects the balance between degradation induced by the shear stress and the endothelial release of new VWF triggered by the pulsatility. This modulation of VWF levels could explain the relationship between pulsatility and bleeding observed in CF-MCS recipients. Preservation of pulsatility may be a new target to improve clinical outcomes of patients.
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Pressão Arterial/fisiologia , Circulação Extracorpórea/tendências , Coração Auxiliar/tendências , Fluxo Pulsátil/fisiologia , Choque Cardiogênico/terapia , Fator de von Willebrand/metabolismo , Animais , Biomarcadores/sangue , Circulação Extracorpórea/efeitos adversos , Coração Auxiliar/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Choque Cardiogênico/sangue , Choque Cardiogênico/fisiopatologia , Estresse Mecânico , SuínosRESUMO
AIMS: Calcific aortic valve disease (CAVD) affects 2-6% of the population over 65 years, and age, gender, smoking, overweight, dyslipidemia, diabetes contribute to the development of this disease. CAVD results, in part, from the osteoblast differentiation of human valvular interstitial cells (VICs). This study aims to elucidate the effects of leptin on osteoblast phenotype of VICs and the signalling pathways involved. METHODS: Patients who underwent aortic valve replacement for CAVD (n = 43) were included in this study. Patients with coronary artery disease (CAD) without CAVD (n = 129) were used as controls. RESULTS: Patients with CAVD had higher serum leptin concentrations than CAD patients (p = 0.002). Leptin was found in calcific aortic valves, with higher concentrations in calcified versus non-calcified zones (p = 0.01). Chronic leptin stimulation of human VICs enhanced alkaline phosphatase (ALP) activity and ALP, BMP-2 and RUNX2 expression and decreased osteopontin expression. Moreover, inhibiting Akt or ERK during leptin stimulation lowered the expression of osteoblast markers in VIC. CONCLUSIONS: Taken together, these findings indicate that leptin plays a critical role in CAVD development by promoting osteoblast differentiation of human aortic VICs in an Akt- and ERK-dependent manner. This study highlights the role of leptin in CAVD development, and further studies are needed to determine whether reducing circulating leptin levels or blocking leptin actions on VICs is efficient to slow CAVD progression.
Assuntos
Valva Aórtica/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Transdiferenciação Celular/efeitos dos fármacos , Leptina/farmacologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/fisiologia , Idoso , Idoso de 80 Anos ou mais , Valva Aórtica/patologia , Estenose da Valva Aórtica/patologia , Doença da Válvula Aórtica Bicúspide , Biomarcadores/metabolismo , Calcinose/patologia , Estudos de Casos e Controles , Células Cultivadas , Feminino , Cardiopatias Congênitas/patologia , Doenças das Valvas Cardíacas/patologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Proteína Oncogênica v-akt/metabolismo , Fenótipo , Transdução de Sinais/efeitos dos fármacosRESUMO
The high coronary artery disease (CAD) prevalence in patients with abdominal aortic aneurysm (AAA) is well known. However, the inverse relation has been little explored. We present, based on a systematic review and meta-analysis of the published evidence, a critical appraisal of the issue of AAA prevalence and also AAA predictive risk factors in patients with CAD, comparing it with AAA prevalence in subjects without CAD. A total of 22 studies involving 13,388 patients with CAD met the inclusion criteria. Overall, AAA prevalence in patients with CAD was 8.4% (95% confidence interval [CI] 6.9 to 10.3), significantly higher than in subjects without CAD (odds ratio [OR] 2.42, 95% CI 2.08 to 2.81). Pooled analysis revealed that smoking, arterial hypertension, and concomitant carotid artery stenosis were significantly associated with AAA in patients with CAD (OR 1.72, 95% CI 1.14 to 2.61; OR 1.57, 95% CI 1.06 to 2.35; OR 2.14, 95% CI 1.20 to 3.79, respectively). In patients with CAD, AAA prevalence tended to be higher with concomitant peripheral artery disease (OR 2.66, 95% CI 0.82 to 8.61, p = 0.08). In conclusion, AAA prevalence was significantly higher in patients with CAD versus subjects without CAD.