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2.
Circulation ; 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32160764

RESUMO

Background: Immune checkpoint inhibitor (ICI) therapy is often accompanied by immune-related pathology, with an increasing occurrence of high-risk ICI-related myocarditis. Understanding the mechanisms involved in this side effect could enable the development of management strategies. In mouse models, immune checkpoints, such as PD-1, control the threshold of self-antigen responses directed against cardiac troponin I (TnI). Here, we aimed at identifying how the immunoproteasome, the main proteolytic machinery in immune cells harboring three distinct protease activities in the LMP2, LMP7 and MECL1 subunit, affects TnI-directed autoimmune pathology of the heart. Methods: TnI-directed autoimmune myocarditis (TnI-AM), a CD4+ T cell-mediated disease, was induced in mice lacking all three immunoproteasome subunits, triple-ip-/-, or lacking either the LMP2 or LMP7 gene, by immunization with a cardiac TnI peptide. Alternatively, prior to induction of TnI-AM or after establishment of AM, mice were treated with the immunoproteasome inhibitor ONX 0914. Immune parameters defining heart-specific autoimmunity were investigated in both experimental TnI-AM and in two cases of ICI-related myocarditis. Results: All immunoproteasome-deficient strains showed mitigated autoimmune-related cardiac pathology with less inflammation, lower pro-inflammatory and chemotactic cytokines, less IL-17 production, and reduced fibrosis formation. Protection from TnI-directed autoimmune heart pathology with improved cardiac function in LMP7-/- mice involved a changed balance between effector and regulatory CD4+ T cells in the spleen, with CD4+ T cells from LMP7-/- mice showing a higher expression of inhibitory PD-1 molecules. Blocked immunoproteasome proteolysis, by treatment of TLR2 and TLR7/8-engaged CD14+ monocytes with ONX 0914, diminished pro-inflammatory cytokine responses, thereby reducing the boost for the expansion of self-reactive CD4+ T cells. Correspondingly, in mice, ONX 0914 treatment reversed cardiac autoimmune pathology, preventing both the induction and progression of TnI-AM, when self-reactive CD4+ T cells were primed. The autoimmune signature during experimental TnI-AM, with high immunoproteasome expression, immunoglobulinG deposition, IL-17 production in heart tissue and TnI-directed humoral autoimmune responses, was also present in two cases of ICI-related myocarditis, thus demonstrating the activation of heart-specific autoimmune reactions by ICI therapy. Conclusions: By reversing heart-specific autoimmune responses, immunoproteasome inhibitors applied to a mouse model demonstrate their potential to aid in the management of autoimmune myocarditis in humans, possibly including cases with ICI-related heart-specific autoimmunity.

3.
Herz ; 2020 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-32170340

RESUMO

BACKGROUND: Postcardiac injury syndrome (PCIS) is an inflammatory complication that derives from injury to the epicardium, myocardium, or endocardium. It occurs after trauma, myocardial infarction, percutaneous coronary intervention, cardiac surgery, intracardiac ablation, and implantation of cardiac implantable electronic device (CIED). In this study we assessed the incidence of PCIS after CIED implantation and its possible risk factors. MATERIAL AND METHODS: All patients who received CIED implantation at Heidelberg University Hospital between 2000 and 2014 were evaluated (n = 4989 patients). Clinical data including age, sex, underlying cardiac disease, type of implanted CIED, location of electrode implantation, clinical symptoms, time of symptom onset of PCIS, therapy, and outcome were extracted and analyzed. RESULTS: We identified 19 cases of PCIS in 4989 patients, yielding an incidence of 0.38%. The age of patients with PCIS ranged from 39 to 86 years. Dilated cardiomyopathy (DCM) as underlying cardiac disease and right atrial (RA) lead implantation had a significant association with occurrence of PCIS (p = 0.045 in DCM and p < 0.001 in RA lead implantation). Dyspnea, chest pain, dry cough, and fever were the most frequently reported symptoms in patients with PCIS. Pericardial and pleura effusion as well as elevated C­reactive protein (CRP), increased erythrocyte sedimentation rate (ESR), and leukocytosis were the most common findings. CONCLUSION: To the best of our knowledge, this is the largest cohort evaluating the incidence of PCIS after CIED implantation. The data show that PCIS is a rare complication after CIED implantation and occurs more frequently in patients with DCM and those with RA lead implantation. Although rare and mostly benign, PCIS can lead to potentially lethal complications and physicians must be aware of its symptoms.

4.
JAMA Oncol ; 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32134442

RESUMO

Importance: The overall low survival rate of patients with lung cancer calls for improved detection tools to enable better treatment options and improved patient outcomes. Multivariable molecular signatures, such as blood-borne microRNA (miRNA) signatures, may have high rates of sensitivity and specificity but require additional studies with large cohorts and standardized measurements to confirm the generalizability of miRNA signatures. Objective: To investigate the use of blood-borne miRNAs as potential circulating markers for detecting lung cancer in an extended cohort of symptomatic patients and control participants. Design, Setting, and Participants: This multicenter, cohort study included patients from case-control and cohort studies (TREND and COSYCONET) with 3102 patients being enrolled by convenience sampling between March 3, 2009, and March 19, 2018. For the cohort study TREND, population sampling was performed. Clinical diagnoses were obtained for 3046 patients (606 patients with non-small cell and small cell lung cancer, 593 patients with nontumor lung diseases, 883 patients with diseases not affecting the lung, and 964 unaffected control participants). No samples were removed because of experimental issues. The collected data were analyzed between April 2018 and November 2019. Main Outcomes and Measures: Sensitivity and specificity of liquid biopsy using miRNA signatures for detection of lung cancer. Results: A total of 3102 patients with a mean (SD) age of 61.1 (16.2) years were enrolled. Data on the sex of the participants were available for 2856 participants; 1727 (60.5%) were men. Genome-wide miRNA profiles of blood samples from 3046 individuals were evaluated by machine-learning methods. Three classification scenarios were investigated by splitting the samples equally into training and validation sets. First, a 15-miRNA signature from the training set was used to distinguish patients diagnosed with lung cancer from all other individuals in the validation set with an accuracy of 91.4% (95% CI, 91.0%-91.9%), a sensitivity of 82.8% (95% CI, 81.5%-84.1%), and a specificity of 93.5% (95% CI, 93.2%-93.8%). Second, a 14-miRNA signature from the training set was used to distinguish patients with lung cancer from patients with nontumor lung diseases in the validation set with an accuracy of 92.5% (95% CI, 92.1%-92.9%), sensitivity of 96.4% (95% CI, 95.9%-96.9%), and specificity of 88.6% (95% CI, 88.1%-89.2%). Third, a 14-miRNA signature from the training set was used to distinguish patients with early-stage lung cancer from all individuals without lung cancer in the validation set with an accuracy of 95.9% (95% CI, 95.7%-96.2%), sensitivity of 76.3% (95% CI, 74.5%-78.0%), and specificity of 97.5% (95% CI, 97.2%-97.7%). Conclusions and Relevance: The findings of the study suggest that the identified patterns of miRNAs may be used as a component of a minimally invasive lung cancer test, complementing imaging, sputum cytology, and biopsy tests.

5.
ESC Heart Fail ; 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31802644

RESUMO

Cardiac sarcoidosis is a chronic inflammatory disease with a large spectrum of symptoms that can mimic diseases such as dilated, hypertrophic, or arrhythmogenic cardiomyopathies. It can be asymptomatic but can also present with ventricular arrhythmias, conduction disease, and heart failure (HF) or even sudden cardiac death (SCD). We present here the case of a patient transplanted due to end-stage arrhythmogenic right ventricular cardiomyopathy (ARVC), fulfilling the task force criteria. A few years after successful heart transplantation (HTX), the patient developed similar symptoms and morphofunctional changes of the heart, which led to critical re-evaluation of his primary diagnosis.

6.
Biochem Biophys Res Commun ; 519(1): 141-147, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31481236

RESUMO

Atrial fibrillation (AF) is the most frequent sustained arrhythmia and can lead to structural cardiac changes, known as tachycardia-induced cardiomyopathy (TIC). HCN4 is implicated in spontaneous excitation of the sinoatrial node, while channel dysfunction has been associated with sinus bradycardia, AF and structural heart disease. We here asked whether HCN4 mutations may contribute to the development of TIC, as well. Mutation scanning of HCN4 in 60 independent patients with AF and suspected TIC followed by panel sequencing in carriers of HCN4 variants identified the HCN4 variant P883R [minor allele frequency (MAF): 0,88%], together with the KCNE1 variant S38G (MAF: 65%) in three unrelated patients. Family histories revealed additional cases of AF, sudden cardiac death and cardiomyopathy. Patch-clamp recordings of HCN4-P883R channels expressed in HEK293 cells showed remarkable alterations of channel properties shifting the half-maximal activation voltage to more depolarized potentials, while channel deactivation was faster compared to wild-type (WT). Co-transfection of WT and mutant subunits, resembling the heterozygous cellular situation of our patients, revealed significantly higher current densities compared to WT. In conclusion HCN4-P883R may increase ectopic trigger and maintenance of AF by shifting the activation voltage of If to more positive potentials and producing higher current density. Together with the common KCNE1 variant S38G, previously proposed as a genetic modifier of AF, HCN4-P883R may provide a substrate for the development of AF and TIC.

7.
Acta Cardiol ; : 1-8, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311434

RESUMO

Background: Reduced ejection fraction (EF) in chronic moderate aortic regurgitation (AR) could be either due to a late remodelling response after longstanding moderate AR, or could represent a specific phenotype of cardiomyopathy (CMP) with concomitant AR. The aim of this study was to analyse progression of left ventricular (LV) impairment in moderate AR. Methods: All patients in our echocardiography database between 2005 and 2016 were screened to identify pure chronic moderate AR, excluding significant coronary artery disease (CAD) or concomitant valve disease. Remaining 152 patients were divided into three groups: (a) preserved systolic LV function; (b) reduced LV EF and prediagnosed concomitant cardiomyopathy (CMP); (c) reduced LV EF without prediagnosed CMP. Results: The majority patients (group A = 66%) had preserved systolic LV function, remaining oligosymptomatic with stable LVEDD at follow-up. Non-CMP patients with reduced EF at baseline (group C = 18%) were significantly older (group C: 74 vs. group A: 61 years, p < .001) whereas left ventricular end-diastolic diameter (LVEDD) significantly increased over time (p = .046). Development of renal insufficiency, atrial fibrillation and NYHA > II were significant risk factors linked to the worsening of LV function in patients with moderate AR. Conclusion: Preserved LV EF and LVEDD remain stable over a long lasting period in the majority of patients. However, these data suggest that some patients develop reduced LV EF, even without progression of AR to severe, especially if renal insufficiency or atrial fibrillation are present.

8.
Biochem Biophys Res Commun ; 512(4): 845-851, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-30929919

RESUMO

Pathogenic long QT mutations often comprise high phenotypic variability and particularly variants in ANK2 (long QT syndrome 4) frequently lack QT prolongation. We sought to elucidate the genetic and functional background underlying the clinical diversity in a 3-generation family with different cardiac arrhythmias. Next-generation sequencing-based screening of patients with QT prolongation identified the index patient of the family carrying an ANK2-E1813K variant and a previously uncharacterized KCNH2-H562R mutation in a double heterozygous conformation. The patient presented with a severe clinical phenotype including a markedly prolonged QTc interval (544 ms), recurrent syncope due to Torsade de Pointes tachycardias, survived cardiopulmonary resuscitation, progressive cardiac conduction defect, and atrial fibrillation. Evaluation of other family members identified a sister and a niece solely carrying the ANK2-E1813K variant, who showed age-related conduction disease. An asymptomatic second sister solely carried the KCNH2-H562R mutation. Voltage-clamp recordings in Xenopus oocytes revealed that KCNH2-H562R subunits were non-functional but did not exert dominant-negative effects on wild-type subunits. Expression of KCNH2-H562R in HEK293 cells showed a trafficking deficiency. Co-expression of the C-terminal regulatory domain of ANK2 in Xenopus oocytes revealed that ANK2-E1813K diminished currents mediated by the combination of wild-type and H562R KCNH2 subunits. Our data suggest that ANK2 functionally interacts with KCNH2 leading to a stronger current suppression and marked aggravation of long QT syndrome in the patient carrying variants in both proteins.

9.
Clin Res Cardiol ; 108(11): 1297-1308, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30980206

RESUMO

BACKGROUND: Left ventricular non-compaction has been increasingly diagnosed in recent years. However, it is still debated whether non-compaction is a pathological condition or a physiological trait. In this meta-analysis and systematic review, we compare studies, which investigated these two different perspectives. Furthermore, we provide a comprehensive overview on the clinical outcome as well as genetic background of left ventricular non-compaction cardiomyopathy in adult patients. METHODS AND RESULTS: We retrieved PubMed/Medline literatures in English language from 2000 to 19/09/2018 on clinical outcome and genotype of patients with non-compaction. We summarized and extensively reviewed all studies that passed selection criteria and performed a meta-analysis on key phenotypic parameters. Altogether, 35 studies with 2271 non-compaction patients were included in our meta-analysis. The mean age at diagnosis was the mid of their fifth decade. Two-thirds of patients were male. Congenital heart diseases including atrial or ventricular septum defect or Ebstein anomaly were reported in 7% of patients. Twenty-four percent presented with family history of cardiomyopathy. The mean frequency of neuromuscular diseases was 5%. Heart rhythm abnormalities were reported frequently: conduction disease in 26%, supraventricular tachycardia in 17%, and sustained or non-sustained ventricular tachycardia in 18% of patients. Three important outcome measures were reported including systemic thromboembolic events with a mean frequency of 9%, heart transplantation with 4%, and adequate ICD therapy with 15%. Nine studies investigated the genetics of non-compaction cardiomyopathy. The most frequently mutated gene was TTN with a pooled frequency of 11%. The average frequency of MYH7 mutations was 9%, for MYBPC3 mutations 5%, and for CASQ2 and LDB3 3% each. TPM1, MIB1, ACTC1, and LMNA mutations had an average frequency of 2% each. Mutations in PLN, HCN4, TAZ, DTNA, TNNT2, and RBM20 were reported with a frequency of 1% each. We also summarized the results of eight studies investigating the non-compaction in altogether 5327 athletes, pregnant women, patients with sickle cell disease, as well as individuals from population-based cohorts, in which the presence of left ventricular hypertrabeculation ranged from 1.3 to 37%. CONCLUSION: The summarized data indicate that non-compaction may lead to unfavorable outcome in different cardiomyopathy entities. The presence of key features in a multimodal diagnostic approach could distinguish between benign morphological trait and manifest cardiomyopathy.

10.
Dtsch Med Wochenschr ; 144(7): 447-451, 2019 04.
Artigo em Alemão | MEDLINE | ID: mdl-30925598

RESUMO

The increase in life expectancy and Healthy Life Years in Europe is largely attributable to the success of cardiovascular medicine. Technical developments enable ever more detailed insights into disease processes and enable a precise, multimodal diagnosis of even complex diseases using digital imaging, cardiac biomarkers and genomic information. The rapid availability of this data, often in real time, allows optimized planning and performing of tailored interventional, surgical, or pharmacotherapies. But there are also completely new challenges due to the growing flood of data, the integration of which can no longer be achieved by the individual doctor. The active involvement and participation of the patient also requires new digital concepts and should include decision-making, treatment planning, (long-term) history, and feedback on success and adverse drug reactions. By using artificial intelligence, digital communication and decision support systems, economic benefits, quality improvements and acceleration of outpatient and inpatient treatment become possible.The DGK supports these developments in its own activities, both in project planning, communication with specialist groups, and in training and education. In this article you will find excerpts from current developments of digital cardiology.


Assuntos
Cardiologia , Sistemas de Apoio a Decisões Clínicas , Informática Médica , Telemedicina , Humanos
11.
Sci Rep ; 9(1): 3866, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30846742

RESUMO

Recordings of aortic root movement represent one of the first accomplishments of ultrasound in medicine and mark the beginning of functional cardiac imaging. However, the underlying mechanism is not completely understood. Since the aortic root is directly connected to the cardiac skeleton we hypothesize, that the amplitude of systolic aortic root motion (SARM) may be mainly caused by displacement of the cardiac base towards the apex and might therefore be used as measure of left ventricular longitudinal function (LV-LF). One hundred and eighty patients with dilated cardiomyopathy and 180 healthy controls were prospectively included into this study. SARM was lower in patients compared to controls (9 ± 3 mm vs. 12 ± 2 mm, p < 0.001) and lowest in patients with cardiovascular events (9 ± 3 mm vs. 7 ± 3 mm, p < 0.001). During a median follow-up time of 38 months, the combined end-point of cardiovascular death or hospitalization for heart failure was reached by 25 patients (13.9%). Reduced SARM had significant prognostic impact on outcome (hazard ratio 0.74, 95% confidence interval 0.63-0.88, p < 0.001) and remained an independent predictor in the multivariate analysis. Compared to parameters with potential influence on its mechanism, SARM correlated best (r = 0.75, p < 0.001) with global longitudinal strain (GLS). SARM may therefore represent an alternative echocardiographic parameter for the assessment of LV-LF, particularly when GLS is not feasible or apical views are not available.

12.
Circ Heart Fail ; 12(3): e005371, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30871351

RESUMO

Background Variants in the cardiomyocyte-specific RNA splicing factor RBM20 have been linked to familial cardiomyopathy, but the causative genetic architecture and clinical consequences of this disease are incompletely defined. Methods and Results To define the genetic architecture of RBM20 cardiomyopathy, we first established a database of RBM20 variants associated with cardiomyopathy and compared these to variants observed in the general population with respect to their location in the RBM20 coding transcript. We identified 2 regions significantly enriched for cardiomyopathy-associated variants in exons 9 and 11. We then assembled a registry of 74 patients with RBM20 variants from 8 institutions across the world (44 index cases and 30 from cascade testing). This RBM20 patient registry revealed highly prevalent family history of sudden cardiac death (51%) and cardiomyopathy (72%) among index cases and a high prevalence of composite arrhythmias (including atrial fibrillation, nonsustained ventricular tachycardia, implantable cardiac defibrillator discharge, and sudden cardiac arrest, 43%). Patients harboring variants in cardiomyopathy-enriched regions identified by our variant database analysis were enriched for these findings. Further, these characteristics were more prevalent in the RBM20 registry than in large cohorts of patients with dilated cardiomyopathy and TTNtv cardiomyopathy and not significantly different from a cohort of patients with LMNA-associated cardiomyopathy. Conclusions Our data establish RBM20 cardiomyopathy as a highly penetrant and arrhythmogenic cardiomyopathy. These findings underline the importance of arrhythmia surveillance and family screening in this disease and represent the first step in defining the genetic architecture of RBM20 disease causality on a population level.


Assuntos
Arritmias Cardíacas/genética , Cardiomiopatias/genética , Proteínas de Ligação a RNA/genética , Morte Súbita Cardíaca/etiologia , Humanos , Mutação , Sistema de Registros
13.
Cardiovasc Res ; 115(13): 1886-1906, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30924864

RESUMO

AIMS: Inflammation is a key driver of atherosclerosis and myocardial infarction (MI), and beyond proteins and microRNAs (miRs), long noncoding RNAs (lncRNAs) have been implicated in inflammation control. To obtain further information on the possible role of lncRNAs in the context of atherosclerosis, we obtained comprehensive transcriptome maps of circulating immune cells (peripheral blood mononuclear cells, PBMCs) of early onset MI patients. One lncRNA significantly suppressed in post-MI patients was further investigated in a murine knockout model. METHODS AND RESULTS: Individual RNA-sequencing (RNA-seq) was conducted on PBMCs from 28 post-MI patients with a history of MI at age ≤50 years and stable disease ≥3 months before study participation, and from 31 healthy individuals without manifest cardiovascular disease or family history of MI as controls. RNA-seq revealed deregulated protein-coding transcripts and lncRNAs in post-MI PBMCs, among which nuclear enriched abundant transcript (NEAT1) was the most highly expressed lncRNA, and the only one significantly suppressed in patients. Multivariate statistical analysis of validation cohorts of 106 post-MI patients and 85 controls indicated that the PBMC NEAT1 levels were influenced (P = 0.001) by post-MI status independent of statin intake, left ventricular ejection fraction, low-density lipoprotein or high-density lipoprotein cholesterol, or age. We investigated NEAT1-/- mice as a model of NEAT1 deficiency to evaluate if NEAT1 depletion may directly and causally alter immune regulation. RNA-seq of NEAT1-/- splenocytes identified disturbed expression and regulation of chemokines/receptors, innate immunity genes, tumour necrosis factor (TNF) and caspases, and increased production of reactive oxygen species (ROS) under baseline conditions. NEAT1-/- spleen displayed anomalous Treg and TH cell differentiation. NEAT1-/- bone marrow-derived macrophages (BMDMs) displayed altered transcriptomes with disturbed chemokine/chemokine receptor expression, increased baseline phagocytosis (P < 0.0001), and attenuated proliferation (P = 0.0013). NEAT1-/- BMDMs responded to LPS with increased (P < 0.0001) ROS production and disturbed phagocytic activity (P = 0.0318). Monocyte-macrophage differentiation was deregulated in NEAT1-/- bone marrow and blood. NEAT1-/- mice displayed aortic wall CD68+ cell infiltration, and there was evidence of myocardial inflammation which could lead to severe and potentially life-threatening structural damage in some of these animals. CONCLUSION: The study indicates distinctive alterations of lncRNA expression in post-MI patient PBMCs. Regarding the monocyte-enriched NEAT1 suppressed in post-MI patients, the data from NEAT1-/- mice identify NEAT1 as a novel lncRNA-type immunoregulator affecting monocyte-macrophage functions and T cell differentiation. NEAT1 is part of a molecular circuit also involving several chemokines and interleukins persistently deregulated post-MI. Individual profiling of this circuit may contribute to identify high-risk patients likely to benefit from immunomodulatory therapies. It also appears reasonable to look for new therapeutic targets within this circuit.

14.
Cardiovasc Res ; 115(2): 302-314, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30101304

RESUMO

Aims: The immune system is considered a key driver of atherosclerosis, and beyond proteins and microRNAs (miRs), long non-coding RNAs (lncRNAs) are implicated in immune control. We previously described that lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is involved in cardiac innate immunity in a myocarditis model. Here, we investigated the impact of MALAT1 deficiency upon atherosclerosis development. Methods and results: Heterozygous MALAT1-deficient ApoE-/- mice displayed massive immune system dysregulation and atherosclerosis within 2 months even when kept on normal diet. Aortic plaque area (P < 0.05) and aortic root plaque size (P < 0.001) were increased in MALAT1-deficient vs. MALAT1-wildtype ApoE-/- mice. Serum levels of interferon-γ (IFN-γ), tumour necrosis factor (TNF), and interleukin 6 (IL6) were elevated (P < 0.001) in MALAT1-deficient animals. MALAT1-deficient bone marrow-derived macrophages showed enhanced expression of TNF (P = 0.001) and inducible NO synthase (NOS2) (P = 0.002), suppressed MMP9 (P < 0.001), and impaired phagocytic activity (P < 0.001) upon lipopolysaccharide stimulation. RNA-sequencing revealed grossly altered transcriptomes of MALAT1-deficient splenocytes already at baseline, with massive induction of IFN- γ, TNF, NOS2, and granzyme B; CC and CXC chemokines and CCR8; and innate immunity genes interferon-induced protein with tetratricopeptide repeats (IFIT)1/3, interferon-induced transmembrane protein (IFITM)1/3, ISG15. Multiple miRs were up to 45-fold upregulated. Further, selective ablation of the cytosolic part of the MALAT1 system only, the enzymatically MALAT1-derived mascRNA, resulted in massive induction of TNF (P = 0.004) and IL6 (P = 0.028) in macrophages. Northern analysis of post-myocardial infarction patient vs. control peripheral blood mononuclear cells showed reduced (P = 0.005) mascRNA in the patients. CHART-enriched RNA-sequencing reads at the genomic loci of MALAT1 and neighbouring nuclear enriched abundant transcript (NEAT1) documented direct interaction between these lncRNA transcripts. Conclusion: The data suggest a molecular circuit involving the MALAT1-mascRNA system, interactions between MALAT1 and NEAT1, and key immune effector molecules, cumulatively impacting upon the development of atherosclerosis. It appears reasonable to look for therapeutic targets in this circuit and to screen for anomalies in the NEAT1-MALAT1 region in humans, too, as possible novel disease risk factors.

15.
J Mol Cell Cardiol ; 126: 13-22, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30445017

RESUMO

AIMS: Circulating immune cells have a significant impact on progression and outcome of heart failure. Long non-coding RNAs (lncRNAs) comprise novel epigenetic regulators which control cardiovascular diseases and inflammatory disorders. We aimed to identify lncRNAs regulated in circulating immune cells of the blood of heart failure patients. METHODS AND RESULTS: Next-generation sequencing revealed 110 potentially non-coding RNA transcripts differentially expressed in peripheral blood mononuclear cells of heart failure patients with reduced ejection fraction. The up-regulated lncRNA Heat2 was further functionally characterized. Heat2 expression was detected in whole blood, PBMNCs, eosinophil and basophil granulocytes. Heat2 regulates cell division, invasion, transmigration and immune cell adhesion on endothelial cells. CONCLUSION: Heat2 is an immune cell enriched lncRNA that is elevated in the blood of heart failure patients and controls cellular functions.


Assuntos
Regulação da Expressão Gênica , Insuficiência Cardíaca/genética , RNA Longo não Codificante/genética , Adulto , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Eosinófilos/metabolismo , Feminino , Insuficiência Cardíaca/sangue , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
16.
J Interv Cardiol ; 31(6): 885-890, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30397939

RESUMO

BACKGROUND: To date, there are no guidelines recommending a specific prophylactic antibiotic treatment in transcatheter aortic valve replacement (TAVR). The aim of this study is to evaluate clinical data after TAVR with different periprocedural antibiotic regimens. METHODS: In May 2015 the institutional rules for periprocedural antibiotic prophylaxis were changed from 3 days to 1 day. Thus, a total of 450 consecutive TAVR patients between February 2014 and June 2016 were classified into two intention-to-treat groups: patients receiving a 1-day Cefuroxime prophylaxis (N = 225); patients receiving a 3-day Cefuroxime prophylaxis (N = 225). RESULTS: One-day Cefuroxime regimen was not associated with shorter hospitalization (3-day Cefuroxime 9 ± 4.7 vs 1-day Cefuroxime 8.9 ± 4.0; P = 0.87). Incidence of diarrhea (26.2% vs 18.2%; P = 0.04) and Clostridium difficile infections (4% vs 0.4%; P = 0.01) were significantly higher in the 3-day group. No endocarditis was registered after 1 year follow-up. There was no difference in 30-day overall mortality rate, major vascular complications, bleeding complications, pacemaker-implantation rate, paravalvular regurgitation, or acute kidney injury between patients groups. CONCLUSION: Three-day Cefuroxime prophylaxis does not seem to be advantageous compared to a shorter 1-day regimen, but even shows a significantly higher incidence of diarrhea and Clostridium difficile infection.


Assuntos
Antibacterianos/administração & dosagem , Antibioticoprofilaxia/métodos , Cefuroxima/administração & dosagem , Substituição da Valva Aórtica Transcateter/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/efeitos adversos , Antibioticoprofilaxia/efeitos adversos , Valva Aórtica/cirurgia , Estenose da Valva Aórtica/cirurgia , Cefuroxima/efeitos adversos , Feminino , Mortalidade Hospitalar , Humanos , Análise de Intenção de Tratamento , Tempo de Internação/estatística & dados numéricos , Masculino , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
17.
Front Immunol ; 9: 2303, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30349538

RESUMO

Myocarditis is an inflammatory disease of the heart muscle most commonly caused by viral infection and often maintained by autoimmunity. Virus-induced tissue damage triggers chemokine production and, subsequently, immune cell infiltration with pro-inflammatory and pro-fibrotic cytokine production follows. In patients, the overall inflammatory burden determines the disease outcome. Following the aim to define specific molecules that drive both immunopathology and/or autoimmunity in inflammatory heart disease, here we report on increased expression of colony stimulating factor 1 (CSF-1) in patients with myocarditis. CSF-1 controls monocytes originating from hematopoietic stem cells and subsequent progenitor stages. Both, monocytes and macrophages are centrally involved in mediating tissue damage and fibrotic scarring in the heart. CSF-1 influences monocytes via engagement of CSF-1 receptor, and it is also produced by cells of the mononuclear phagocyte system themselves. Based on this, we sought to modulate the virus-triggered inflammatory response in an experimental model of Coxsackievirus B3-induced myocarditis by silencing the CSF-1 axis in myeloid cells using nanoparticle-encapsulated siRNA. siCSF-1 inverted virus-mediated immunopathology as reflected by lower troponin T levels, a reduction of accumulating myeloid cells in heart tissue and improved cardiac function. Importantly, pathogen control was maintained and the virus was efficiently cleared from heart tissue. Since viral heart disease triggers heart-directed autoimmunity, in a second approach we investigated the influence of CSF-1 upon manifestation of heart tissue inflammation during experimental autoimmune myocarditis (EAM). EAM was induced in Balb/c mice by immunization with a myocarditogenic myosin-heavy chain-derived peptide dissolved in complete Freund's adjuvant. siCSF-1 treatment initiated upon established disease inhibited monocyte infiltration into heart tissue and this suppressed cardiac injury as reflected by diminished cardiac fibrosis and improved cardiac function at later states. Mechanistically, we found that suppression of CSF-1 production arrested both differentiation and maturation of monocytes and their precursors in the bone marrow. In conclusion, during viral and autoimmune myocarditis silencing of the myeloid CSF-1 axis by nanoparticle-encapsulated siRNA is beneficial for preventing inflammatory tissue damage in the heart and preserving cardiac function without compromising innate immunity's critical defense mechanisms.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Infecções por Coxsackievirus/tratamento farmacológico , Enterovirus Humano B , Fator Estimulador de Colônias de Macrófagos/genética , Miocardite/tratamento farmacológico , RNA Interferente Pequeno/uso terapêutico , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/patologia , Infecções por Coxsackievirus/genética , Infecções por Coxsackievirus/patologia , Modelos Animais de Doenças , Regulação para Baixo , Inativação Gênica , Humanos , Inflamação/prevenção & controle , Masculino , Camundongos Endogâmicos BALB C , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Miocardite/genética , Miocardite/patologia , Miocardite/virologia , Miocárdio/metabolismo , Miocárdio/patologia , Nanopartículas , RNA Interferente Pequeno/administração & dosagem
18.
Cardiovasc Res ; 114(10): 1287-1303, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29800419

RESUMO

Dilated cardiomyopathy (DCM) frequently affects relatively young, economically, and socially active adults, and is an important cause of heart failure and transplantation. DCM is a complex disease and its pathological architecture encounters many genetic determinants interacting with environmental factors. The old perspective that every pathogenic gene mutation would lead to a diseased heart, is now being replaced by the novel observation that the phenotype depends not only on the penetrance-malignancy of the mutated gene-but also on epigenetics, age, toxic factors, pregnancy, and a diversity of acquired diseases. This review discusses how gene mutations will result in mutation-specific molecular alterations in the heart including increased mitochondrial oxidation (sarcomeric gene e.g. TTN), decreased calcium sensitivity (sarcomeric genes), fibrosis (e.g. LMNA and TTN), or inflammation. Therefore, getting a complete picture of the DCM patient will include genomic data, molecular assessment by preference from cardiac samples, stratification according to co-morbidities, and phenotypic description. Those data will help to better guide the heart failure and anti-arrhythmic treatment, predict response to therapy, develop novel siRNA-based gene silencing for malignant gene mutations, or intervene with mutation-specific altered gene pathways in the heart.This article is part of the Mini Review Series from the Varenna 2017 meeting of the Working Group of Myocardial Function of the European Society of Cardiology.


Assuntos
Cardiomiopatia Dilatada/genética , Mutação , Contração Miocárdica/genética , Sarcômeros/genética , Função Ventricular/genética , Animais , Cardiomiopatia Dilatada/epidemiologia , Cardiomiopatia Dilatada/patologia , Cardiomiopatia Dilatada/fisiopatologia , Interação Gene-Ambiente , Predisposição Genética para Doença , Humanos , Miocárdio/patologia , Fenótipo , Prognóstico , Fatores de Risco , Sarcômeros/patologia
19.
Circ Genom Precis Med ; 11(3): e001901, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29540468

RESUMO

BACKGROUND: Inhibition of PKC-α (protein kinase C-α) enhances contractility and cardioprotection in animal models, but effects in humans are unknown. Genotypes at rs9912468 strongly associate with PRKCA expression in the left ventricle, enabling genetic approaches to measure effects of reduced PKC-α in human populations. METHODS AND RESULTS: We analyzed the cis expression quantitative trait locus for PRKCA marked by rs9912468 using 313 left ventricular specimens from European Ancestry patients. The forward strand minor allele (G) at rs9912468 is associated with reduced PKC-α transcript abundance (1.7-fold reduction in minor allele homozygotes, P=1×10-41). This association was cardiac specific in expression quantitative trait locus data sets that span 16 human tissues. Cardiac epigenomic data revealed a predicted enhancer in complete (R2=1.0) linkage disequilibrium with rs9912468 within intron 2 of PRKCA. We cloned this region and used reporter constructs to verify cardiac-specific enhancer activity in vitro in cardiac and noncardiac cells and in vivo in zebrafish. The PRKCA enhancer contains 2 common genetic variants and 4 haplotypes; the haplotype correlated with the rs9912468 PKC-α-lowering allele (G) showed lowest activity. In contrast to previous reports in animal models, the PKC-α-lowering allele is associated with adverse left ventricular remodeling (higher mass, larger diastolic dimension), reduced fractional shortening, and higher risk of dilated cardiomyopathy in human populations. CONCLUSIONS: These findings support PKC-α as a regulator of the human heart but suggest that PKC-α inhibition may adversely affect the left ventricle depending on timing and duration. Pharmacological studies in human subjects are required to discern potential benefits and harms of PKC-α inhibitors as an approach to treat heart disease.


Assuntos
Ventrículos do Coração/metabolismo , Proteína Quinase C-alfa/genética , Remodelação Ventricular/genética , Adulto , Idoso , Alelos , Animais , Feminino , Genes Reporter , Predisposição Genética para Doença , Genótipo , Haplótipos , Homozigoto , Humanos , Íntrons , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Proteína Quinase C-alfa/metabolismo , Locos de Características Quantitativas , Peixe-Zebra
20.
Cell Death Differ ; 25(12): 2053-2070, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29515255

RESUMO

The prognosis of advanced stage neuroblastoma patients remains poor and, despite intensive therapy, the 5-year survival rate remains less than 50%. We previously identified histone deacetylase (HDAC) 8 as an indicator of poor clinical outcome and a selective drug target for differentiation therapy in vitro and in vivo. Here, we performed kinome-wide RNAi screening to identify genes that are synthetically lethal with HDAC8 inhibitors. These experiments identified the neuroblastoma predisposition gene ALK as a candidate gene. Accordingly, the combination of the ALK/MET inhibitor crizotinib and selective HDAC8 inhibitors (3-6 µM PCI-34051 or 10 µM 20a) efficiently killed neuroblastoma cell lines carrying wildtype ALK (SK-N-BE(2)-C, IMR5/75), amplified ALK (NB-1), and those carrying the activating ALK F1174L mutation (Kelly), and, in cells carrying the activating R1275Q mutation (LAN-5), combination treatment decreased viable cell count. The effective dose of crizotinib in neuroblastoma cell lines ranged from 0.05 µM (ALK-amplified) to 0.8 µM (wildtype ALK). The combinatorial inhibition of ALK and HDAC8 also decreased tumor growth in an in vivo zebrafish xenograft model. Bioinformatic analyses revealed that the mRNA expression level of HDAC8 was significantly correlated with that of ALK in two independent patient cohorts, the Academic Medical Center cohort (n = 88) and the German Neuroblastoma Trial cohort (n = 649), and co-expression of both target genes identified patients with very poor outcome. Mechanistically, HDAC8 and ALK converge at the level of receptor tyrosine kinase (RTK) signaling and their downstream survival pathways, such as ERK signaling. Combination treatment of HDAC8 inhibitor with crizotinib efficiently blocked the activation of growth receptor survival signaling and shifted the cell cycle arrest and differentiation phenotype toward effective cell death of neuroblastoma cell lines, including sensitization of resistant models, but not of normal cells. These findings reveal combined targeting of ALK and HDAC8 as a novel strategy for the treatment of neuroblastoma.


Assuntos
Quinase do Linfoma Anaplásico/genética , Antineoplásicos/farmacologia , Neuroblastoma/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Interferência de RNA , Proteínas Repressoras/antagonistas & inibidores , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Quinase do Linfoma Anaplásico/metabolismo , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Crizotinibe/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacologia , Indóis/farmacologia , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Células Tumorais Cultivadas , Peixe-Zebra
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