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2.
Eur Heart J Case Rep ; 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31365055

RESUMO

BACKGROUND : The aetiology of dilated cardiomyopathy (DCM) is highly heterogeneous including genetic and/or acquired (infective, toxic, immune, endocrine, and nutritional) factors. The major part of acquired DCM in developed countries is caused by either viral or autoimmune myocarditis. It is believed that the activation of the T-lymphocyte cell system is the major pathomechanism underlying autoimmune myocarditis and inflammatory DCM (DCMi). However, in the hearts of a subset of patients, a significant number of CD20+ B-lymphocytes can be detected too. Limited information exists on the role of B-cell-dependent mechanisms in the progression of DCMi. Particularly CD20+ B-lymphocytes, which can be targeted by anti-CD20+ B-lymphocytes antibodies or inhibitors, might contribute to the pathogenesis of myocardial damage beyond antibody production. CASE SUMMARY : Here, we present a case series of six patients with subacute and chronic endomyocardial biopsy-proven CD20+ B-lymphocyte-associated DCMi, where symptomatic heart failure therapy, with or without combined immunosuppressive therapy with steroid-based treatment regime, was insufficient to improve cardiac function. Five patients improved clinically several weeks after a standard infusion protocol with rituximab, a chimeric monoclonal antibody against the pan-B-cell surface molecule CD20. DISCUSSION : Our case series shows that CD20+ B-lymphocyte persistence can play a pathophysiologic role in a subset of DCMi patients and highlights the potential of targeting CD20+ B cells in patients with prominent CD20+ B-lymphocyte persistence.

3.
JCI Insight ; 4(10)2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31092728

RESUMO

Although cardiovascular disease (CVD) is the leading cause of morbimortality worldwide, promising new drug candidates are lacking. We compared the arterial high-resolution proteome of patients with advanced versus early-stage CVD to predict, from a library of small bioactive molecules, drug candidates able to reverse this disease signature. Of the approximately 4000 identified proteins, 100 proteins were upregulated and 52 were downregulated in advanced-stage CVD. Arachidonyl trifluoromethyl ketone (AACOCF3), a cytosolic phospholipase A2 (cPLA2) inhibitor was predicted as the top drug able to reverse the advanced-stage CVD signature. Vascular cPLA2 expression was increased in patients with advanced-stage CVD. Treatment with AACOCF3 significantly reduced vascular calcification in a cholecalciferol-overload mouse model and inhibited osteoinductive signaling in vivo and in vitro in human aortic smooth muscle cells. In conclusion, using a systems biology approach, we have identified a potentially new compound that prevented typical vascular calcification in CVD in vivo. Apart from the clear effect of this approach in CVD, such strategy should also be able to generate novel drug candidates in other complex diseases.

4.
J Nanobiotechnology ; 17(1): 72, 2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-31133024

RESUMO

BACKGROUND: Nano-sized vesicles, so called extracellular vesicles (EVs), from regenerative cardiac cells represent a promising new therapeutic approach to treat cardiovascular diseases. However, it is not yet sufficiently understood how cardiac-derived EVs facilitate their protective effects. Therefore, we investigated the immune modulating capabilities of EVs from human cardiac-derived adherent proliferating (CardAP) cells, which are a unique cell type with proven cardioprotective features. RESULTS: Differential centrifugation was used to isolate EVs from conditioned medium of unstimulated or cytokine-stimulated (IFNγ, TNFα, IL-1ß) CardAP cells. The derived EVs exhibited typical EV-enriched proteins, such as tetraspanins, and diameters mostly of exosomes (< 100 nm). The cytokine stimulation caused CardAP cells to release smaller EVs with a lower integrin ß1 surface expression, while the concentration between both CardAP-EV variants was unaffected. An exposure of either CardAP-EV variant to unstimulated human peripheral blood mononuclear cells (PBMCs) did not induce any T cell proliferation, which indicates a general low immunogenicity. In order to evaluate immune modulating properties, PBMC cultures were stimulated with either Phytohemagglutin or anti-CD3. The treatment of those PBMC cultures with either CardAP-EV variant led to a significant reduction of T cell proliferation, pro-inflammatory cytokine release (IFNγ, TNFα) and increased levels of active TGFß. Further investigations identified CD14+ cells as major recipient cell subset of CardAP-EVs. This interaction caused a significant lower surface expression of HLA-DR, CD86, and increased expression levels of CD206 and PD-L1. Additionally, EV-primed CD14+ cells released significantly more IL-1RA. Notably, CardAP-EVs failed to modulate anti-CD3 triggered T cell proliferation and pro-inflammatory cytokine release in monocultures of purified CD3+ T cells. Subsequently, the immunosuppressive feature of CardAP-EVs was restored when anti-CD3 stimulated purified CD3+ T cells were co-cultured with EV-primed CD14+ cells. Beside attenuated T cell proliferation, those cultures also exhibited a significant increased proportion of regulatory T cells. CONCLUSIONS: CardAP-EVs have useful characteristics that could contribute to enhanced regeneration in damaged cardiac tissue by limiting unwanted inflammatory processes. It was shown that the priming of CD14+ immune cells by CardAP-EVs towards a regulatory type is an essential step to attenuate significantly T cell proliferation and pro-inflammatory cytokine release in vitro.


Assuntos
Doenças Cardiovasculares/terapia , Vesículas Extracelulares/imunologia , Monócitos/imunologia , Miócitos Cardíacos/imunologia , Doenças Cardiovasculares/imunologia , Linhagem Celular , Proliferação de Células , Técnicas de Cocultura , Citocinas/metabolismo , Vesículas Extracelulares/metabolismo , Humanos , Imunomodulação , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/imunologia , Monócitos/citologia , Miócitos Cardíacos/citologia , Regeneração , Linfócitos T/citologia , Linfócitos T/imunologia
5.
Circ Res ; 124(11): 1568-1583, 2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-31120823

RESUMO

Myocarditis is generally a mild and self-limited consequence of systemic infection of cardiotropic viruses. However, patients can develop a temporary or permanent impairment of cardiac function including acute cardiomyopathy with hemodynamic compromise or severe arrhythmias. In this setting, specific causes of inflammation are associated with variable risks of death and transplantation. Recent translational studies suggest that treatments tailored to specific causes of myocarditis may impact clinical outcomes when added to guideline-directed medical care. This review summarizes recent advances in translational research that influence the utility of endomyocardial biopsy for the management of inflammatory cardiomyopathies. Emerging therapies for myocarditis based on these mechanistic hypotheses are entering clinical trials and may add to the benefits of established heart failure treatment.

6.
Cardiovasc Ultrasound ; 17(1): 7, 2019 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-31010431

RESUMO

Echocardiography is the most commonly applied technique for non-invasive assessment of cardiac function in small animals. Manual tracing of endocardial borders is time consuming and varies with operator experience. Therefore, we aimed to evaluate a novel automated two-dimensional software algorithm (Auto2DE) for small animals and compare it to the standard use of manual 2D-echocardiographic assessment (2DE). We hypothesized that novel Auto2DE will provide rapid and robust data sets, which are in agreement with manually assessed data of animals.2DE and Auto2DE were carried out using a high-resolution imaging-system for small animals. First, validation cohorts of mouse and rat cine loops were used to compare Auto2DE against 2DE. These data were stratified for image quality by a blinded expert in small animal imaging. Second, we evaluated 2DE and Auto2DE in four mouse models and four rat models with different cardiac pathologies.Automated assessment of LV function by 2DE was faster than conventional 2DE analysis and independent of operator experience levels. The accuracy of Auto2DE-assessed data in healthy mice was dependent on cine loop quality, with excellent agreement between Auto2DE and 2DE in cine loops with adequate quality. Auto2DE allowed for valid detection of impaired cardiac function in animal models with pronounced cardiac phenotypes, but yielded poor performance in diabetic animal models independent of image quality.Auto2DE represents a novel automated analysis tool for rapid assessment of LV function, which is suitable for data acquisition in studies with good and very good echocardiographic image quality, but presents systematic problems in specific pathologies.

7.
J Mol Cell Cardiol ; 131: 53-65, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31005484

RESUMO

AIMS: Atrial contractile dysfunction is associated with increased mortality in heart failure (HF). We have shown previously that a metabolic syndrome-based model of HFpEF and a model of hypertensive heart disease (HHD) have impaired left atrial (LA) function in vivo (rat). In this study we postulate, that left atrial cardiomyocyte (CM) and cardiac fibroblast (CF) paracrine interaction related to the inositol 1,4,5-trisphosphate signalling cascade is pivotal for the manifestation of atrial mechanical dysfunction in HF and that quantitative atrial remodeling is highly disease-dependent. METHODS AND RESULTS: Differential remodeling was observed in HHD and HFpEF as indicated by an increase of atrial size in vivo (HFpEF), unchanged fibrosis (HHD and HFpEF) and a decrease of CM size (HHD). Baseline contractile performance of rat CM in vitro was enhanced in HFpEF. Upon treatment with conditioned medium from their respective stretched CF (CM-SF), CM (at 21 weeks) of WT showed increased Ca2+ transient (CaT) amplitudes related to the paracrine activity of the inotrope endothelin (ET-1) and inositol 1,4,5-trisphosphate induced Ca2+ release. Concentration of ET-1 was increased in CM-SF and atrial tissue from WT as compared to HHD and HFpEF. In HHD, CM-SF had no relevant effect on CaT kinetics. However, in HFpEF, CM-SF increased diastolic Ca2+ and slowed Ca2+ removal, potentially contributing to an in-vivo decompensation. During disease progression (i.e. at 27 weeks), HFpEF displayed dysfunctional excitation-contraction-coupling (ECC) due to lower sarcoplasmic-reticulum Ca2+ content unrelated to CF-CM interaction or ET-1, but associated with enhanced nuclear [Ca2+]. In human patients, tissue ET-1 was not related to the presence of arterial hypertension or obesity. CONCLUSIONS: Atrial remodeling is a complex entity that is highly disease and stage dependent. The activity of fibrosis related to paracrine interaction (e.g. ET-1) might contribute to in vitro and in vivo atrial dysfunction. However, during later stages of disease, ECC is impaired unrelated to CF.

8.
Eur Heart J ; 40(26): 2164-2169, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30891599

RESUMO

AIMS: Haemodynamic load induces cardiac remodelling via mechano-transduction pathways, which can further trigger inflammatory responses. We hypothesized that particularly in an inflammatory disorder such as myocarditis, a therapeutic strategy is required which, in addition to providing adequate circulatory support, unloads the left ventricle, decreases cardiac wall stress, and mitigates inflammatory responses. METHODS AND RESULTS: Axial flow pumps such as the Impella systems comply with these requirements. Here, we report a potential mode-of-action of prolonged Impella support (PROPELLA concept) in fulminant myocarditis, including a decrease in cardiac immune cell presence, and integrin α1, α5, α6, α10 and ß6 expression during unloading. CONCLUSION: PROPELLA may provide benefits beyond its primary function of mechanical circulatory support in the form of additional disease-altering effects, which may contribute to enhanced myocardial recovery/remission in patients with chronic fulminant myocarditis.

9.
Cardiovasc Res ; 115(3): 488-500, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30657875

RESUMO

Morbidity and mortality from ischaemic heart disease (IHD) and heart failure (HF) remain significant in Europe and are increasing worldwide. Patients with IHD or HF might benefit from novel therapeutic strategies, such as cell-based therapies. We recently discussed the therapeutic potential of cell-based therapies and provided recommendations on how to improve the therapeutic translation of these novel strategies for effective cardiac regeneration and repair. Despite major advances in optimizing these strategies with respect to cell source and delivery method, the clinical outcome of cell-based therapy remains unsatisfactory. Major obstacles are the low engraftment and survival rate of transplanted cells in the harmful microenvironment of the host tissue, and the paucity or even lack of endogenous cells with repair capacity. Therefore, new ways of delivering cells and their derivatives are required in order to empower cell-based cardiac repair and regeneration in patients with IHD or HF. Strategies using tissue engineering (TE) combine cells with matrix materials to enhance cell retention or cell delivery in the transplanted area, and have recently received much attention for this purpose. Here, we summarize knowledge on novel approaches emerging from the TE scenario. In particular, we will discuss how combinations of cell/bio-materials (e.g. hydrogels, cell sheets, prefabricated matrices, microspheres, and injectable matrices) combinations might enhance cell retention or cell delivery in the transplantation areas, thereby increase the success rate of cell therapies for IHD and HF. We will not focus on the use of classical engineering approaches, employing fully synthetic materials, because of their unsatisfactory material properties which render them not clinically applicable. The overall aim of this Position Paper from the ESC Working Group Cellular Biology of the Heart is to provide recommendations on how to proceed in research with these novel TE strategies combined with cell-based therapies to boost cardiac repair in the clinical settings of IHD and HF.

10.
J Am Heart Assoc ; 8(2): e008968, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30638108

RESUMO

Background Myocarditis is an important cause of acute and chronic heart failure. Men with myocarditis have worse recovery and an increased need for transplantation compared with women, but the reason for the sex difference remains unclear. Elevated sera soluble (s) ST2 predicts mortality from acute and chronic heart failure, but has not been studied in myocarditis patients. Methods and Results Adults with a diagnosis of clinically suspected myocarditis (n=303, 78% male) were identified according to the 2013 European Society of Cardiology position statement. Sera sST2 levels were examined by ELISA in humans and mice and correlated with heart function according to sex and age. Sera sST2 levels were higher in healthy men ( P=8×10-6) and men with myocarditis ( P=0.004) compared with women. sST2 levels were elevated in patients with myocarditis and New York Heart Association class III - IV heart failure ( P=0.002), predominantly in men ( P=0.0003). Sera sST2 levels were associated with New York Heart Association class in men with myocarditis who were ≤50 years old ( r=0.231, P=0.0006), but not in women ( r=0.172, P=0.57). Sera sST2 levels were also significantly higher in male mice with myocarditis ( P=0.005) where levels were associated with cardiac inflammation. Gonadectomy with hormone replacement showed that testosterone ( P<0.001), but not estradiol ( P=0.32), increased sera sST2 levels in male mice with myocarditis. Conclusions We show in a well-characterized subset of heart failure patients with clinically suspected and biopsy-confirmed myocarditis that elevated sera sST2 is associated with an increased risk of heart failure based on New York Heart Association class in men ≤50 years old.

11.
Eur J Heart Fail ; 2018 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-30485591

RESUMO

Heart failure (HF) is responsible for substantial morbidity and mortality and is increasing in prevalence. Although there has been remarkable progress in the treatment of HF with reduced ejection fraction (HFrEF), morbidity and mortality are still substantial. Cardiac contractility modulation (CCM) signals, consisting of biphasic high-voltage bipolar signals delivered to the right ventricular septum during the absolute refractory period, have been shown to improve symptoms, exercise tolerance and quality of life and reduce the rate of HF hospitalizations in patients with ejection fractions (EF) between 25% and 45%. CCM therapy is currently approved in the European Union, China, India, Australia and Brazil for use in symptomatic HFrEF patients with normal or slightly prolonged QRS duration. CCM is particularly beneficial in patients with baseline EF between 35% and 45%, which includes half the range of HF patients with mid-range EFs (HFmrEF). At the cellular level, CCM has been shown in HFrEF patients to improve calcium handling, to reverse the foetal myocyte gene programme associated with HF, and to facilitate reverse remodelling. This review highlights the preclinical and clinical literature related to CCM in HFrEF and HFmrEF and outlines the potential of CCM for HF with preserved EF, concluding that CCM may fill an important unmet need in the therapeutic approach to HF across the range of EFs.

12.
Eur J Heart Fail ; 2018 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-30328645

RESUMO

AIMS: Empagliflozin, a clinically used oral antidiabetic drug that inhibits the sodium-dependent glucose co-transporter 2, has recently been evaluated for its cardiovascular safety. Surprisingly, empagliflozin reduced mortality and hospitalization for heart failure (HF) compared to placebo. However, the underlying mechanisms remain unclear. Therefore, our study aims to investigate whether empagliflozin may cause direct pleiotropic effects on the myocardium. METHODS AND RESULTS: In order to assess possible direct myocardial effects of empagliflozin, we performed contractility experiments with in toto-isolated human systolic end-stage HF ventricular trabeculae. Empagliflozin significantly reduced diastolic tension, whereas systolic force was not changed. These results were confirmed in murine myocardium from diabetic and non-diabetic mice, suggesting independent effects from diabetic conditions. In human HF cardiomyocytes, empagliflozin did not influence calcium transient amplitude or diastolic calcium level. The mechanisms underlying the improved diastolic function were further elucidated by studying myocardial fibres from patients and rats with diastolic HF (HF with preserved ejection fraction, HFpEF). Empagliflozin beneficially reduced myofilament passive stiffness by enhancing phosphorylation levels of myofilament regulatory proteins. Intravenous injection of empagliflozin in anaesthetized HFpEF rats significantly improved diastolic function measured by echocardiography, while systolic contractility was unaffected. CONCLUSION: Empagliflozin causes direct pleiotropic effects on the myocardium by improving diastolic stiffness and hence diastolic function. These effects were independent of diabetic conditions. Since pharmacological therapy of diastolic dysfunction and HF is an unmet need, our results provide a rationale for new translational studies and might also contribute to the understanding of the EMPA-REG OUTCOME trial.

13.
Artigo em Inglês | MEDLINE | ID: mdl-30084076

RESUMO

Mechanical circulatory support (MCS) is often required to stabilize patients with acute fulminant myocarditis with cardiogenic shock. This review gives an overview of the successful use of left-sided Impella in the setting of fulminant myocarditis and cardiogenic shock as the sole means of MCS as well as in combination with right ventricular (RV) support devices including extracorporeal life support (ECLS) (ECMELLA) or an Impella RP (BI-PELLA). It further provides evidence from endomyocardial biopsies that in addition to giving adequate support, LV unloading by Impella exhibits disease-modifying effects important for myocardial recovery (i.e., bridge-to-recovery) achieved by this newly termed "prolonged Impella" (PROPELLA) concept in which LV-IMPELLA 5.0, implanted via an axillary approach, provides support in awake, mobilized patients for several weeks. Finally, this review addresses the question of how to define the appropriate time point for weaning strategies and for changing or discontinuing unloading in fulminant myocarditis.

14.
ESC Heart Fail ; 5(5): 818-829, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30099854

RESUMO

AIMS: Myocarditis is often associated with parvovirus B19 (B19V) persistence, which can induce vascular damage. Based on the antiviral and anti-inflammatory properties of telbivudine, we aimed to evaluate its efficacy to protect B19V-infected endothelial cells in vitro and to treat chronic lymphocytic myocarditis patients with B19V transcriptional activity. METHODS AND RESULTS: We evaluated the endothelial-protective potential of telbivudine in human microvascular endothelial cells-1, which were infected with B19V. Treatment with 10 ng/mL of telbivudine decreased the B19V-induced endothelial cell apoptosis and endothelial-to-mesenchymal transition. Along with this finding, telbivudine reduced the expression of transforming growth factor-ß1 and of tenascin-C. The endothelial-protective properties of telbivudine were also found in tumour necrosis factor-α-stressed human microvascular endothelial cells-1. In addition, oxidative stress in angiotensin II-stressed and transforming growth factor-ß1-stressed HL-1 cardiomyocytes and fibroblasts, respectively, was reduced upon telbivudine treatment, illustrating that telbivudine exerts multimodal protective effects. Based on these in vitro findings, four patients severely suffering from an endomyocardial biopsy-proven myocarditis associated with B19V transcriptional activity (VP1/VP2-mRNA positive) were treated with telbivudine (600 mg/dL) for 6 months in a single-patient-use approach. Follow-up biopsies 6 months after treatment showed that VP1/VP2-mRNA levels and CD3 cells decreased in all patients and were associated with an improvement in ejection fraction and New York Heart Association class. These findings were paralleled by a drop in tenascin-C expression as shown via matrix-assisted laser desorption ionization-imaging mass spectrometry. CONCLUSIONS: Telbivudine exerts endothelial-protective effects in B19V-infected endothelial cells and improves chronic myocarditis associated with B19V transcriptional activity. These findings will be further evaluated in the clinical exploratory trial: the PreTopic study.

15.
FASEB J ; : fj201701408R, 2018 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-29863913

RESUMO

Regulatory T (Treg) cells offer new therapeutic options for controlling undesired systemic and local immune responses. The aim of the current study was to determine the impact of therapeutic Treg administration on systemic and cardiac inflammation and remodeling in coxsackievirus B3 (CVB3) -induced myocarditis. Therefore, syngeneic Treg cells were applied intravenously in CVB3-infected mice 3 d after infection. Compared with CVB3 + PBS mice, CVB3 + Treg mice exhibited lower left ventricular (LV) chemokine expression, accompanied by reduced cardiac presence of proinflammatory Ly6ChighCCR2highCx3Cr1low monocytes and higher retention of proinflammatory Ly6CmidCCR2highCx3Cr1low monocytes in the spleen. In addition, splenic myelopoiesis was reduced in CVB3 + Treg compared with CVB3 + PBS mice. Coculture of Treg cells with splenocytes isolated from mice 3 d post-CVB3 infection further demonstrated the ability of Treg cells to modulate monocyte differentiation in favor of the anti-inflammatory Ly6ClowCCR2lowCx3Cr1high subset. Treg-mediated immunomodulation was paralleled by lower collagen 1 protein expression and decreased levels of soluble and insoluble collagen in LV of CVB3 + Treg compared with CVB3 + PBS mice. In agreement with these findings, LV systolic and diastolic function was improved in CVB3 + Treg mice compared with CVB3 + PBS mice. In summary, adoptive Treg transfer in the inflammatory phase of viral-induced myocarditis protects the heart against inflammatory damage and fibrosis via modulation of monocyte subsets.-Pappritz, K., Savvatis, K., Miteva, K., Kerim, B., Dong, F., Fechner, H., Müller, I., Brandt, C., Lopez, B., González, A., Ravassa, S., Klingel, K., Diez, J., Reinke, P., Volk, H.-D., Van Linthout, S., Tschöpe, C. Immunomodulation by adoptive regulatory T-cell transfer improves Coxsackievirus B3-induced myocarditis.

16.
Vascul Pharmacol ; 2018 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-29684642

RESUMO

Atherosclerosis is a chronic inflammatory disorder of the large and medium-size arteries characterized by the subendothelial accumulation of cholesterol, immune cells, and extracellular matrix. At the early onset of atherogenesis, endothelial dysfunction takes place. Atherogenesis is further triggered by the accumulation of cholesterol-carrying low-density lipoproteins, which acquire properties of damage-associated molecular patterns and thereby trigger an inflammatory response. Following activation of the innate immune response, mainly governed by monocytes and macrophages, the adaptive immune response is started which further promotes atherosclerotic plaque formation. In this review, an overview is given describing the role of damage-associated molecular patterns, NLRP3 inflammasome activation, and innate and adaptive immune cells in the atherogenesis process.

17.
Sci Rep ; 8(1): 5575, 2018 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-29615815

RESUMO

Cardiac fibroblasts play an important role in the regulation of the extracellular matrix and are newly recognized as inflammatory supporter cells. Interferon (IFN)-γ is known to counteract transforming growth factor (TGF)-ß1-induced myofibroblast differentiation. This study aims at investigating in vitro how IFN-γ affects TGF-ß1-induced monocyte attraction. Therefore, C4 fibroblasts and fibroblasts obtained by outgrowth culture from the left ventricle (LV) of male C57BL6/j mice were stimulated with TGF-ß1, IFN-γ and TGF-ß1 + IFN-γ. Confirming previous studies, IFN-γ decreased the TGF-ß1-induced myofibroblast differentiation, as obviated by lower collagen I, III, α-smooth muscle actin (α-SMA), lysyl oxidase (Lox)-1 and lysyl oxidase-like (LoxL)-2 levels in TGF-ß1 + IFN-γ- versus TGF-ß1-stimulated cardiac fibroblasts. TGF-ß1 + IFN-γ-stimulated C4 and cardiac fibroblasts displayed a higher CC-chemokine ligand (CCL) 2, CCL7 and chemokine C-X3-C motif ligand (Cx3CL1) release versus sole TGF-ß1-stimulated fibroblasts. Analysis of migrated monocyte subsets towards the different conditioned media further revealed that sole TGF-ß1- and IFN-γ-conditioned media particularly attracted Ly6Clow and Ly6Chigh monocytes, respectively, as compared to control media. In line with theses findings, TGF-ß1 + IFN-γ-conditioned media led to a lower Ly6Clow/Ly6Chigh monocyte migration ratio compared to sole TGF-ß1 treatment. These differences in monocyte migration reflect the complex interplay of pro-inflammatory cytokines and pro-fibrotic factors in cardiac remodelling and inflammation.

18.
Curr Opin Cardiol ; 33(3): 325-333, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29528906

RESUMO

PURPOSE OF REVIEW: Myocarditis is an inflammatory disease of the cardiac muscle mainly caused by viral infection. Due to the diverse clinical presentation of myocarditis, accurate diagnosis demands simultaneous histologic, immunohistochemical and molecular biological workup of endomyocardial biopsies (EMBs) as defined by the position statement of the Working Group on Myocardial and Pericardial Diseases of the European Society of Cardiology on myocarditis. RECENT FINDINGS: Endomyocardial biopsy-based analysis of viral transcriptional activity, mRNA expression, epigenetics and region-specific protein expression analysis via imaging mass spectrometry have led to the identification of novel potential diagnostic criteria, markers with prognostic value and therapeutic targets for the treatment of viral myocarditis, opening new avenues for novel therapies, including cell therapies, as well as the use of established treatment options, be it from other indications. SUMMARY: Under certain clinical scenarios EMB-based analysis is required to come to a tailored individualized therapy that improves symptoms and prognosis of patients with acute and chronic viral-driven cardiac inflammation.

19.
Vascul Pharmacol ; 2018 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-29548901

RESUMO

Vascular adaptations to either physiological or pathophysiological conditions commonly require gene expression modifications in the most represented cellular elements of the vessel wall, i.e. endothelial and smooth muscle cells. In addition to transcription factors, a number of mechanisms contribute to the regulation of gene expression in these cells including noncoding RNAs, histone and DNA modifications, collectively indicated as epigenetic modifications. Here, we summarize the state of art regarding the role of epigenetic changes in major vascular diseases, and discuss the potential diagnostic and therapeutic applications of epigenetic modulation in this context.

20.
Sci Rep ; 8(1): 2820, 2018 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-29434214

RESUMO

Inflammation in myocarditis induces cardiac injury and triggers disease progression to heart failure. NLRP3 inflammasome activation is a newly identified amplifying step in the pathogenesis of myocarditis. We previously have demonstrated that mesenchymal stromal cells (MSC) are cardioprotective in Coxsackievirus B3 (CVB3)-induced myocarditis. In this study, MSC markedly inhibited left ventricular (LV) NOD2, NLRP3, ASC, caspase-1, IL-1ß, and IL-18 mRNA expression in CVB3-infected mice. ASC protein expression, essential for NLRP3 inflammasome assembly, increased upon CVB3 infection and was abrogated in MSC-treated mice. Concomitantly, CVB3 infection in vitro induced NOD2 expression, NLRP3 inflammasome activation and IL-1ß secretion in HL-1 cells, which was abolished after MSC supplementation. The inhibitory effect of MSC on NLRP3 inflammasome activity in HL-1 cells was partly mediated via secretion of the anti-oxidative protein stanniocalcin-1. Furthermore, MSC application in CVB3-infected mice reduced the percentage of NOD2-, ASC-, p10- and/or IL-1ß-positive splenic macrophages, natural killer cells, and dendritic cells. The suppressive effect of MSC on inflammasome activation was associated with normalized expression of prominent regulators of myocardial contractility and fibrosis to levels comparable to control mice. In conclusion, MSC treatment in myocarditis could be a promising strategy limiting the adverse consequences of cardiac and systemic NLRP3 inflammasome activation.

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