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Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection can lead to life-threatening clinical manifestations. Patients with cardiovascular disease (CVD) are at higher risk for severe courses of COVID-19. So far, however, there are hardly any strategies for predicting the course of SARS-CoV-2 infection in CVD patients at hospital admission. Thus, we investigated whether this prediction is achievable by prospectively analysing the blood immunophenotype of 94 nonvaccinated participants, including uninfected and acutely SARS-CoV-2-infected CVD patients and healthy donors, using a 36-colour spectral flow cytometry panel. Unsupervised data analysis revealed little differences between healthy donors and CVD patients, whereas the distribution of the cell populations changed dramatically in SARS-CoV-2-infected CVD patients. The latter had more mature NK cells, activated monocyte subsets, central memory CD4+ T cells, and plasmablasts but fewer dendritic cells, CD16+ monocytes, innate lymphoid cells, and CD8+ T-cell subsets. Moreover, we identified an immune signature characterised by CD161+ T cells, intermediate effector CD8+ T cells, and natural killer T (NKT) cells that is predictive for CVD patients with a severe course of COVID-19. Thus, intensified immunophenotype analyses can help identify patients at risk of severe COVID-19 at hospital admission, improving clinical outcomes through specific treatment.
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BACKGROUND: Aortic stenosis (AS) is driven by progressive inflammatory and fibrocalcific processes regulated by circulating inflammatory and valve resident endothelial and interstitial cells. The impact of platelets, platelet-derived mediators, and platelet-monocyte interactions on the acceleration of local valvular inflammation and mineralization is presently unknown. METHODS: We prospectively enrolled 475 consecutive patients with severe symptomatic AS undergoing aortic valve replacement. Clinical workup included repetitive echocardiography, analysis of platelets, monocytes, chemokine profiling, aortic valve tissue samples for immunohistochemistry, and gene expression analysis. RESULTS: The patients were classified as fast-progressive AS by the median ∆Vmax of 0.45 m/s per year determined by echocardiography. Immunohistological aortic valve analysis revealed enhanced cellularity in fast-progressive AS (slow- versus fast-progressive AS; median [interquartile range], 247 [142.3-504] versus 717.5 [360.5-1234]; P<0.001) with less calcification (calcification area, mm2: 33.74 [27.82-41.86] versus 20.54 [13.52-33.41]; P<0.001). MIF (macrophage migration inhibitory factor)-associated gene expression was significantly enhanced in fast-progressive AS accompanied by significantly elevated MIF plasma levels (mean±SEM; 6877±379.1 versus 9959±749.1; P<0.001), increased platelet activation, and decreased intracellular MIF expression indicating enhanced MIF release upon platelet activation (CD62P, %: median [interquartile range], 16.8 [11.58-23.8] versus 20.55 [12.48-32.28], P=0.005; MIF, %: 4.85 [1.48-9.75] versus 2.3 [0.78-5.9], P<0.001). Regression analysis confirmed that MIF-associated biomarkers are strongly associated with an accelerated course of AS. CONCLUSIONS: Our findings suggest a key role for platelet-derived MIF and its interplay with circulating and valve resident monocytes/macrophages in local and systemic thromboinflammation during accelerated AS. MIF-based biomarkers predict an accelerated course of AS and represent a novel pharmacological target to attenuate progression of AS.
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Coronary artery disease (CAD) often leads to adverse events resulting in significant disease burdens. Underlying risk factors often remain inapparent prior to disease incidence and the cardiovascular (CV) risk is not exclusively explained by traditional risk factors. Platelets inherently promote atheroprogression and enhanced platelet functions and distinct platelet lipid species are associated with disease severity in patients with CAD. Lipidomics data were acquired using mass spectrometry and processed alongside clinical data applying machine learning to model estimates of an increased CV risk in a consecutive CAD cohort (n = 595). By training machine learning models on CV risk measurements, stratification of CAD patients resulted in a phenotyping of risk groups. We found that distinct platelet lipids are associated with an increased CV or bleeding risk and independently predict adverse events. Notably, the addition of platelet lipids to conventional risk factors resulted in an increased diagnostic accuracy of patients with adverse CV events. Thus, patients with aberrant platelet lipid signatures and platelet functions are at elevated risk to develop adverse CV events. Machine learning combining platelet lipidome data and common clinical parameters demonstrated an increased diagnostic value in patients with CAD and might improve early risk discrimination and classification for CV events.
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Carnitina/análogos & derivados , Doença da Artéria Coronariana , Humanos , Doença da Artéria Coronariana/diagnóstico , Hemorragia , Fatores de Risco , Aprendizado de Máquina , Lisofosfolipídeos , LipídeosRESUMO
Accumulation of free heme B in the plasma can be the result of severe hemolytic events, when the scavenger system for free hemoglobin and heme B is overwhelmed. Free heme B can be oxidized into toxic hemin, which has been proven to activate platelet degranulation and aggregation and promote thrombosis. In the present study we analyzed the effect of hemin on the activation-mediated lysosomal degranulation and CD63 surface expression on platelets using classic flow cytometry and fluorescence microscopy techniques. Classical platelet activators were used as control to distinguish the novel effects of hemin from known activation pathways. CD63 is a tetraspanin protein, also known as lysosomal-associated membrane protein 3 or LAMP-3. In resting platelets CD63 is located within the membrane of delta granules and lysosomes of platelet, from where it is integrated into the platelet outer membrane upon stimulation. We were able to show that hemin like the endogenous platelet activators ADP, collagen or thrombin does provoke CD63 re-localization. Interestingly, only hemin-induced CD63 externalization is dependent on the subtilisin-like pro-protein convertase furin as shown by inhibitor experiments. Furthermore, we were able to demonstrate that hemin induces lysosome secretion, a source of the hemin-mediated CD63 presentation. Again, only the hemin-induced lysosome degranulation is furin dependent. In summary we have shown that the pro-protein convertase furin plays an important role in hemin-mediated lysosomal degranulation and CD63 externalization.
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Furina , Hemina , Glicoproteínas da Membrana de Plaquetas , Tetraspanina 30 , Antígenos CD/metabolismo , Plaquetas/metabolismo , Furina/metabolismo , Hemina/metabolismo , Proteínas de Membrana Lisossomal , Ativação Plaquetária , Glicoproteínas da Membrana de Plaquetas/metabolismo , Tetraspanina 30/metabolismo , HumanosRESUMO
Spatial transcriptomics of histological sections have revolutionized research in life sciences and enabled unprecedented insights into genetic processes involved in tissue reorganization. However, in contrast to genomic analysis, the actual biomolecular composition of the sample has fallen behind, leaving a gap of potentially highly valuable information. Raman microspectroscopy provides untargeted spatiomolecular information at high resolution, capable of filling this gap. In this study we demonstrate spatially resolved Raman "spectromics" to reveal homogeneity, heterogeneity and dynamics of cell matrix on molecular levels by repurposing state-of-the-art bioinformatic analysis tools commonly used for transcriptomic analyses. By exploring sections of murine myocardial infarction and cardiac hypertrophy, we identify myocardial subclusters when spatially approaching the pathology, and define the surrounding metabolic and cellular (immune-) landscape. Our innovative, label-free, non-invasive "spectromics" approach could therefore open perspectives for a profound characterization of histological samples, while additionally allowing the combination with consecutive downstream analyses of the very same specimen.
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Disciplinas das Ciências Biológicas , Análise Espectral Raman , Animais , Camundongos , Genômica , Biologia Computacional , CitosolRESUMO
BACKGROUND: Intracoronary thrombus formation is a main cause of acute myocardial infarction triggered by platelet activation. However, there are no data on the impact of different treatment strategies with antiplatelet agents before percutaneous coronary intervention (PCI) on histological characteristics of thrombus formation. OBJECTIVE: In this study, we investigate the impact of preinterventional administration of the P2Y12-inhibitors clopidogrel and prasugrel on thrombus composition, highlighting significant changes associated with the antiplatelet pre-treatment. METHODS: We prospectively enrolled 104 consecutive patients with ST-segment elevation myocardial infarction (STEMI) undergoing immediate PCI and thrombus aspiration by immunohistochemical staining along with RNA-sequencing employing Nanostring analysis. Fifty-two patients were treated with either prasugrel loading (60 mg) or clopidogrel loading (600 mg) prior to PCI, respectively. RESULTS: In Patients with STEMI, intracoronary thrombus architecture was significantly altered between patients pre-treated with prasugrel when compared to clopidogrel. Fibrin content of thrombi was significantly decreased (41.8 % versus 66.7 %, p = 0.009) after pre-treatment with prasugrel compared to clopidogrel. Furthermore, levels of MPO positive cells in intracoronary thrombi were significantly decreased in patients with prasugrel pre-treatment (90.5 versus 201.1, p = 0.014) indicating an association of antiplatelet pre-treatment and the inflammatory responses during thrombus formation. Most strikingly, we observed significant differences among both pre-treatment groups regarding altered RNA expression and signaling pathways of thrombo-inflammatory processes within the thrombotic material, which were independently associated with antiplatelet strategies. CONCLUSIONS: Our study elucidates the impact of antiplatelet pre-treatment on thrombus remodeling and architecture, thereby lowering the risk of recurrent adverse cardiovascular events in prasugrel-treated patients.
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Infarto do Miocárdio , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Trombose , Humanos , Cloridrato de Prasugrel/farmacologia , Cloridrato de Prasugrel/uso terapêutico , Clopidogrel/uso terapêutico , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Infarto do Miocárdio com Supradesnível do Segmento ST/etiologia , Intervenção Coronária Percutânea/efeitos adversos , Resultado do Tratamento , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/etiologia , Inibidores da Agregação Plaquetária/efeitos adversos , Trombose/etiologia , RNARESUMO
We discuss a 38-year-old bodybuilder who had cardiogenic shock and multiorgan failure. The patient developed significant speech disorders resulting from thromboembolism of a huge, volatile left ventricular thrombus. Because of inoperability and the threat of severe ischemic stroke, the thrombus was removed with a snare and application of a cerebral embolic protection device. (Level of Difficulty: Advanced.).
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INTRODUCTION: Hemolysis results in release of free hemoglobin and hemin liberation from erythrocytes. Hemin has been described to induce platelet activation and to trigger thrombosis. METHODS: We evaluated the effect of hemin on platelet function and surface expression of the platelet collagen receptor glycoprotein VI (GPVI). Isolated platelets were stimulated with increasing concentrations of hemin. RESULTS: We found that hemin strongly enhanced platelet activation, aggregation, and aggregate formation on immobilized collagen under flow. In contrast, we found that surface expression of GPVI was significantly reduced upon hemin stimulation with high hemin concentrations indicating that hemin-induced loss of surface GPVI does not hinder platelet aggregation. Loss of hemin-induced surface expression of GPVI was caused by shedding of the ectodomain of GPVI as verified by immunoblotting and is independent of the GPVI or CLEC-2 mediated ITAM (immunoreceptor-tyrosine-based-activation-motif) signaling pathway as inhibitor studies revealed. Hemin-induced GPVI shedding was independent of metalloproteinases such as ADAM10 or ADAM17, which were previously described to regulate GPVI degradation. Similarly, concentration-dependent shedding of CD62P was also induced by hemin. Unexpectedly, we found that the subtilisin-like proprotein convertase furin controls hemin-dependent GPVI shedding as shown by inhibitor studies using the specific furin inhibitors SSM3 and Hexa-D-arginine. In the presence of SSM3 and Hexa-D-arginine, hemin-associated GPVI degradation was substantially reduced. Further, SSM3 inhibited hemin-induced but not CRP-XL-induced platelet aggregation and thrombus formation, indicating that furin controls specifically hemin-associated platelet functions. CONCLUSION: In summary, we describe a novel mechanism of hemin-dependent GPVI shedding and platelet function mediated by furin.
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Furina , Hemina , Humanos , Hemina/farmacologia , Hemina/metabolismo , Furina/metabolismo , Furina/farmacologia , Glicoproteínas da Membrana de Plaquetas/metabolismo , Plaquetas/metabolismo , Agregação Plaquetária , Ativação PlaquetáriaRESUMO
BACKGROUND: Risk stratification for transcatheter procedures in patients with severe mitral regurgitation is challenging. Deceleration capacity (DC) has already proven to be a reliable risk predictor in patients undergoing transcatheter aortic valve implantation. We hypothesized, that DC provides prognostic value in patients undergoing transcatheter edge-to-edge mitral valve repair (TEER). METHODS: We retrospectively analyzed electrocardiogram signals from 106 patients undergoing TEER at the University Hospital of Tübingen. All patients received continuous heart-rate monitoring to assess DC following the procedure. One-year all-cause mortality was defined as the primary end point. RESULTS: Sixteen patients (15.1%) died within 1 year. The DC in nonsurvivors was significantly reduced compared to survivors (5.1 ± 3.0 vs. 3.0 ± 1.6 ms, p = 0.002). A higher EuroSCORE II and impaired left ventricular function were furthermore associated with poor outcome. In Cox regression analyses, a DC < 4.5 ms was found a strong predictor of 1-year mortality (hazard ratio: 0.10, 95% confidence interval: 0.13-0.79, p = 0.029). Finally, a significant negative correlation was found between DC and residual mitral regurgitation after TEER (r = -0.41, p < 0.001). CONCLUSION: In patients with severe mitral regurgitation undergoing TEER, DC may serve as a new predictor of follow-up mortality.
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Implante de Prótese de Valva Cardíaca , Insuficiência da Valva Mitral , Humanos , Insuficiência da Valva Mitral/diagnóstico , Insuficiência da Valva Mitral/cirurgia , Valva Mitral/diagnóstico por imagem , Valva Mitral/cirurgia , Frequência Cardíaca , Implante de Prótese de Valva Cardíaca/métodos , Desaceleração , Estudos Retrospectivos , Resultado do Tratamento , Cateterismo Cardíaco/efeitos adversosRESUMO
We discuss the rare case of a myocardial abscess of the left ventricle in a 42-year-old man on immunosuppressive therapy after fulminant myocarditis. Multimodal imaging detected the myocardial abscess along with other septic emboli caused by infection with aspergillus fumigatus, which could be treated effectively with antimycotic strategies. (Level of Difficulty: Intermediate.).
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INTRODUCTION: Patients with cardiovascular disease (CVD) and acute SARS-CoV-2 infection might show an altered immune response during COVID-19. MATERIAL AND METHODS: Twenty-three patients with CVD and SARS-CoV-2 infection were prospectively enrolled and received a cardiological assessment at study entry and during follow-up visit. Inclusion criteria of our study were age older than 18 years, presence of CVD, and acute SARS-CoV-2 infection. The median age of the patient cohort was 69 (IQR 55-79) years. 12 (52.2%) patients were men. Peripheral monocytes and chemokine/cytokine profiles were analysed. RESULTS: Numbers of classical and non-classical monocytes were significantly decreased during acute SARS-CoV-2 infection compared to 3-month recovery. While classical monocytes reached the expected level in peripheral blood after 3 months, the number of non-classical monocytes remained significantly reduced. DISCUSSION: All three monocyte subsets exhibited changes of established adhesion and activation markers. Interestingly, they also expressed higher levels of pro-inflammatory cytokines like macrophage migration inhibitory factor (MIF) at the time of recovery, although MIF was only slightly increased during the acute phase. CONCLUSION: Changes of monocyte phenotypes and increased MIF expression after 3-month recovery from acute SARS-CoV-2 infection may indicate persistent, possibly long-lasting, pro-inflammatory monocyte function in CVD patients.
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COVID-19 , Humanos , SARS-CoV-2 , Monócitos , Citocinas , QuimiocinasRESUMO
BACKGROUND: Acute myocardial injury is associated with poor prognosis in respiratory tract infections. We aimed to highlight the differences in prevalence of myocardial injury and its impact on prognosis in patients with COVID-19 compared to those with seasonal influenza. METHODS: This was a single-center prospective cohort study with a historical control group. 300 age-/sex-matched SARS-CoV-2 and seasonal influenza positive patients were enrolled. Myocardial injury was assessed by electrocardiogram (ECG), transthoracic echocardiography and biomarkers including high-sensitivity troponin-I. All patients were followed-up for 30 days after enrollment for all-cause mortalitiy, admission to the intensive care unit (ICU) and mechanical ventilation. RESULTS: Right ventricular distress was more common in COVID-19 whereas pathological ECG findings and impaired left ventricular function were more prevalent among influenza patients. COVID-19 patients suffered from a higher percentage of hypertension and dyslipidaemia. Contrary to COVID-19, pericardial effusion at admission was associated with poor outcome in the influenza group. Severe course of disease and respiratory failure resulted in significantly higher rates of ICU treatment and mechanical ventilation in COVID-19 patients. Although distribution of myocardial injury was similar, significantly fewer cardiac catheterizations were performed in COVID-19 patients. However, number of cardiac catheterizations was low in both groups. Finally, 30-day mortality was significantly higher in COVID-19 compared to influenza patients. CONCLUSIONS: In adults requiring hospitalization due to COVID-19 or seasonal influenza, cardiovascular risk factors and signs of myocardial distress differ significantly. Furthermore, cardiovascular comorbidities may impair prognosis in COVID-19 patients to a higher degree than in their influenza counterparts.
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COVID-19 , Influenza Humana , Adulto , Humanos , Influenza Humana/complicações , Influenza Humana/epidemiologia , Prognóstico , Estudos Prospectivos , SARS-CoV-2 , Estações do AnoRESUMO
Platelets play a significant role in atherothrombosis. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is critically involved in the regulation of LDL metabolism and interacts with platelet function. The effect of PCSK9 in platelet function is poorly understood. The authors of this article sought to characterize platelets as a major source of PCSK9 and PCSK9's role in atherothrombosis. In a large cohort of patients with coronary artery disease (CAD), platelet count, platelet reactivity, and platelet-derived PCSK9 release were analyzed. The role of platelet PCSK9 on platelet and monocyte function was investigated in vitro. Platelet count and hyper-reactivity correlated with plasma LDL in CAD. The circulating platelets express on their surface and release substantial amounts of PCSK9. Release of PCSK9 augmented platelet-dependent thrombosis, monocyte migration, and differentiation into macrophages/foam cells. Platelets and PCSK9 accumulated in tissue derived from atherosclerotic carotid arteries in areas of macrophages. PCSK9 inhibition reduced platelet activation and platelet-dependent thrombo-inflammation. The authors identified platelets as a source of PCSK9 in CAD, which may have an impact on LDL metabolism. Furthermore, platelet-derived PCSK9 contributes to atherothrombosis, and inhibition of PCSK9 attenuates thrombo-inflammation, which may contribute to the reported beneficial clinical effects.
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Aterosclerose/metabolismo , Plaquetas/fisiologia , Doença da Artéria Coronariana/metabolismo , Lipoproteínas LDL/metabolismo , Pró-Proteína Convertase 9/fisiologia , Idoso , Idoso de 80 Anos ou mais , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ativação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Contagem de Plaquetas/estatística & dados numéricos , Trombose/metabolismoRESUMO
Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a severe adverse effect of ChAdOx1 nCoV-19 COVID-19 vaccine (Vaxzevria) and Janssen Ad26.COV2.S COVID-19 vaccine, and it is associated with unusual thrombosis. VITT is caused by anti-platelet factor 4 (PF4) antibodies activating platelets through their FcγRIIa receptors. Antibodies that activate platelets through FcγRIIa receptors have also been identified in patients with COVID-19. These findings raise concern that vaccination-induced antibodies against anti-SARS-CoV-2 spike protein cause thrombosis by cross-reacting with PF4. Immunogenic epitopes of PF4 and SARS-CoV-2 spike protein were compared using in silico prediction tools and 3D modeling. The SARS-CoV-2 spike protein and PF4 share at least 1 similar epitope. Reactivity of purified anti-PF4 antibodies from patients with VITT was tested against recombinant SARS-CoV-2 spike protein. However, none of the affinity-purified anti-PF4 antibodies from 14 patients with VITT cross-reacted with SARS-CoV-2 spike protein. Sera from 222 polymerase chain reaction-confirmed patients with COVID-19 from 5 European centers were tested by PF4-heparin enzyme-linked immunosorbent assays and PF4-dependent platelet activation assays. We found anti-PF4 antibodies in sera from 19 (8.6%) of 222 patients with COVID-19. However, only 4 showed weak to moderate platelet activation in the presence of PF4, and none of those patients developed thrombotic complications. Among 10 (4.5%) of 222 patients who had COVID-19 with thrombosis, none showed PF4-dependent platelet-activating antibodies. In conclusion, antibodies against PF4 induced by vaccination do not cross-react with the SARS-CoV-2 spike protein, indicating that the intended vaccine-induced immune response against SARS-CoV-2 spike protein is not the trigger of VITT. PF4-reactive antibodies found in patients with COVID-19 in this study were not associated with thrombotic complications.
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Anticorpos/efeitos adversos , Vacinas contra COVID-19/efeitos adversos , Reações Cruzadas/imunologia , Fator Plaquetário 4/imunologia , Púrpura Trombocitopênica Idiopática/etiologia , Púrpura Trombocitopênica Idiopática/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Plaquetas/imunologia , COVID-19/imunologia , Estudos de Coortes , Epitopos/imunologia , Feminino , Heparina/metabolismo , Humanos , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Ligação Proteica , Domínios Proteicos , Púrpura Trombocitopênica Idiopática/sangue , Glicoproteína da Espícula de Coronavírus/química , Adulto JovemRESUMO
[Figure: see text].
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Plaquetas/metabolismo , COVID-19/sangue , Doença da Artéria Coronariana/sangue , Furina/sangue , Ativação Plaquetária , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , COVID-19/diagnóstico , Estudos de Casos e Controles , Doença da Artéria Coronariana/diagnóstico , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Regulação para CimaRESUMO
Traditional antithrombotic agents commonly share a therapy-limiting side effect, as they increase the overall systemic bleeding risk. A novel approach for targeted antithrombotic therapy is nanoparticles. In other therapeutic fields, nanoparticles have enabled site-specific delivery with low levels of toxicity and side effects. Here, we paired nanotechnology with an established dimeric glycoprotein VI-Fc (GPVI-Fc) and a GPVI-CD39 fusion protein, thereby combining site-specific delivery and new antithrombotic drugs. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles, NP-BSA, NP-GPVI and NP-GPVI-CD39 were characterized through electron microscopy, atomic force measurements and flow cytometry. Light transmission aggregometry enabled analysis of platelet aggregation. Thrombus formation was observed through flow chamber experiments. NP-GPVI and NP-GPVI-CD39 displayed a characteristic surface coating pattern. Fluorescence properties were identical amongst all samples. NP-GPVI and NP-GPVI-CD39 significantly impaired platelet aggregation. Thrombus formation was significantly impaired by NP-GPVI and was particularly impaired by NP-GPVI-CD39. The receptor-coated nanoparticles NP-GPVI and the bifunctional molecule NP-GPVI-CD39 demonstrated significant inhibition of in vitro thrombus formation. Consequently, the nanoparticle-mediated antithrombotic effect of GPVI-Fc, as well as GPVI-CD39, and an additive impact of CD39 was confirmed. In conclusion, NP-GPVI and NP-GPVI-CD39 may serve as a promising foundation for a novel therapeutic approach regarding targeted antithrombotic therapy.
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Antígenos CD/metabolismo , Apirase/metabolismo , Fibrinolíticos/farmacologia , Fragmentos Fc das Imunoglobulinas/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Glicoproteínas da Membrana de Plaquetas/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Citometria de Fluxo , Humanos , Técnicas In Vitro , Microscopia Eletrônica , Modelos Biológicos , Nanopartículas , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/químicaRESUMO
AIMS: To elucidate the prognostic role of monocytes in the immune response of patients with coronary artery disease (CAD) at risk for life-threatening heart and lung injury as major complications of SARS-CoV-2 infection. METHODS AND RESULTS: From February to April 2020, we prospectively studied a cohort of 96 participants comprising 47 consecutive patients with CAD and acute SARS-CoV-2 infection (CAD + SARS-CoV-2), 19 CAD patients without infections, and 30 healthy controls. Clinical assessment included blood sampling, echocardiography, and electrocardiography within 12 h of admission. Respiratory failure was stratified by the Horovitz Index (HI) as moderately/severely impaired when HI ≤200 mmHg. The clinical endpoint (EP) was defined as HI ≤200 mmHg with subsequent mechanical ventilation within a follow-up of 30 days. The numbers of CD14dimCD16+ non-classical monocytes in peripheral blood were remarkably low in CAD + SARS-CoV-2 compared with CAD patients without infection and healthy controls (P < 0.0001). Moreover, these CD14dimCD16 monocytes showed decreased expression of established markers of adhesion, migration, and T-cell activation (CD54, CD62L, CX3CR1, CD80, and HLA-DR). Decreased numbers of CD14dimCD16+ monocytes were associated with the occurrence of EP. Kaplan-Meier curves illustrate that CAD + SARS-CoV-2 patients with numbers below the median of CD14dimCD16+ monocytes (median 1443 cells/mL) reached EP significantly more often compared to patients with numbers above the median (log-rank 5.03, P = 0.025). CONCLUSION: Decreased numbers of CD14dimCD16+ monocytes are associated with rapidly progressive respiratory failure in CAD + SARS-CoV-2 patients. Intensified risk assessments comprising monocyte sub- and phenotypes may help to identify patients at risk for respiratory failure.
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COVID-19/complicações , Doença da Artéria Coronariana/complicações , Receptores de Lipopolissacarídeos/análise , Monócitos/fisiologia , Receptores de IgG/análise , SARS-CoV-2 , Idoso , Idoso de 80 Anos ou mais , COVID-19/imunologia , Doença da Artéria Coronariana/imunologia , Feminino , Proteínas Ligadas por GPI/análise , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Fenótipo , Estudos RetrospectivosRESUMO
BACKGROUND: COVID-19 infection may cause severe respiratory distress and is associated with increased morbidity and mortality. Impaired cardiac function and/or pre-existing cardiovascular disease may be associated with poor prognosis. In the present study, we report a comprehensive cardiovascular characterization in the first consecutive collective of patients that was admitted and treated at the University Hospital of Tübingen, Germany. METHODS: 123 consecutive patients with COVID-19 were included. Routine blood sampling, transthoracic echocardiography and electrocardiography were performed at hospital admission. RESULTS: We found that impaired left-ventricular and right-ventricular function as well as tricuspid regurgitation > grade 1 were significantly associated with higher mortality. Furthermore, elevated levels of myocardial distress markers (troponin-I and NT pro-BNP) were associated with poor prognosis in this patient collective. CONCLUSION: Impaired cardiac function is associated with poor prognosis in COVID-19 positive patients. Consequently, treatment of these patients should include careful guideline-conform cardiovascular evaluation and treatment. Thus, formation of a competent Cardio-COVID-19 team may represent a major clinical measure to optimize therapy of cardiovascular patients during this pandemic.
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COVID-19/mortalidade , Insuficiência da Valva Tricúspide/mortalidade , Disfunção Ventricular Esquerda/mortalidade , Disfunção Ventricular Direita/mortalidade , Função Ventricular Esquerda , Função Ventricular Direita , Idoso , Idoso de 80 Anos ou mais , COVID-19/diagnóstico , COVID-19/fisiopatologia , COVID-19/terapia , Feminino , Alemanha , Mortalidade Hospitalar , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Insuficiência da Valva Tricúspide/diagnóstico , Insuficiência da Valva Tricúspide/fisiopatologia , Insuficiência da Valva Tricúspide/terapia , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Esquerda/terapia , Disfunção Ventricular Direita/diagnóstico , Disfunção Ventricular Direita/fisiopatologia , Disfunção Ventricular Direita/terapiaRESUMO
Frameshift mutations in the TTN gene encoding titin are a major cause for inherited forms of dilated cardiomyopathy (DCM), a heart disease characterized by ventricular dilatation, systolic dysfunction, and progressive heart failure. To date, there are no specific treatment options for DCM patients but heart transplantation. Here, we show the beneficial potential of reframing titin transcripts by antisense oligonucleotide (AON)-mediated exon skipping in human and murine models of DCM carrying a previously identified autosomal-dominant frameshift mutation in titin exon 326. Correction of TTN reading frame in patient-specific cardiomyocytes derived from induced pluripotent stem cells rescued defective myofibril assembly and stability and normalized the sarcomeric protein expression. AON treatment in Ttn knock-in mice improved sarcomere formation and contractile performance in homozygous embryos and prevented the development of the DCM phenotype in heterozygous animals. These results demonstrate that disruption of the titin reading frame due to a truncating DCM mutation can be restored by exon skipping in both patient cardiomyocytes in vitro and mouse heart in vivo, indicating RNA-based strategies as a potential treatment option for DCM.
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Cardiomiopatia Dilatada/fisiopatologia , Conectina/metabolismo , Éxons , Mutação da Fase de Leitura , Regulação da Expressão Gênica/efeitos dos fármacos , Oligonucleotídeos Antissenso/metabolismo , Animais , Cardiomiopatia Dilatada/terapia , Células Cultivadas , Conectina/genética , Técnicas Citológicas , Modelos Animais de Doenças , Terapia Genética/métodos , Humanos , Camundongos , Camundongos Transgênicos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Miofibrilas/metabolismo , Miofibrilas/fisiologia , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/uso terapêuticoRESUMO
Major causes of morbidity in intravenous drug users are infections. In infective endocarditis, the tricuspid valve is mainly involved. Masses can cause septic embolisms and, in rare cases, they are associated with mycotic aneurysms of pulmonary arteries that lead to severe haemorrhage. We report the case of a young woman with a history of intravenous drug abuse and prolonged infective tricuspid valve endocarditis. Initially, echocardiography showed large masses on the anterior leaflet of the tricuspid valve and severe tricuspid regurgitation; blood cultures revealed staphylococcus and streptococcus species. Eight months after initial diagnosis, she presented with severe haemoptysis and fever. CT revealed a ruptured mycotic aneurysm of the right pulmonary artery. Lobectomy was performed immediately. Postoperatively, the patient fully recovered. After continued antibiotic treatment, follow-up examinations showed negative echocardiographic findings and blood cultures results.