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1.
Chemosphere ; 284: 131345, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34216924

RESUMO

As environmental pollution with plastic waste is increasing, numerous reports show the contamination of natural habitats, food and drinking water with plastic particles in the micro- and nanometer range. Since oral exposure to these particles is virtually unavoidable, health concerns towards the general population have been expressed and risk assessment regarding ingested plastic particles is of great interest. To study the intestinal effects of polymeric particles with a density of <1 g/cm³ in vitro, we spatially inverted a triple culture transwell model of the healthy and inflamed intestine (Caco-2/HT29-MTX-E12/THP-1), which allows contact between buoyant particles and cells. We validated the inverted model against the original model using the enterotoxic, non-steroidal anti-inflammatory drug diclofenac and subsequently assessed the cytotoxic and pro-inflammatory effects of polyethylene (PE) microparticles. The results show that the inverted model exhibits the same distinct features as the original model in terms of barrier development and inflammatory parameters. Treatment with 2 mM diclofenac causes severe cytotoxicity, DNA damage and complete barrier disruption in both models. PE particles induced cytotoxicity and pro-inflammatory effects in the inverted model, which would have remained undetected in conventional in vitro approaches, as no effect was observed in non-inverted control cultures.


Assuntos
Intestinos , Polietileno , Células CACO-2 , Humanos , Plásticos , Polietileno/toxicidade
2.
ESC Heart Fail ; 8(2): 953-961, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33560591

RESUMO

AIMS: The mortality in cardiogenic shock (CS) is high. The role of specific mechanical circulatory support (MCS) systems is unclear. We aimed to compare patients receiving Impella versus ECLS (extracorporal life support) with regard to baseline characteristics, feasibility, and outcomes in CS. METHODS AND RESULTS: This is a retrospective cohort study including CS patients over 18 years with a complete follow-up of the primary endpoint and available baseline lactate level, receiving haemodynamic support either by Impella 2.5 or ECLS from two European registries. The decision for device implementation was made at the discretion of the treating physician. The primary endpoint of this study was all-cause mortality at 30 days. A propensity score for the use of Impella was calculated, and multivariable logistic regression was used to obtain adjusted odds ratios (aOR). In total, 149 patients were included, receiving either Impella (n = 73) or ECLS (n = 76) for CS. The feasibility of device implantation was high (87%) and similar (aOR: 3.14; 95% CI: 0.18-56.50; P = 0.41) with both systems. The rates of vascular injuries (aOR: 0.95; 95% CI: 0.10-3.50; P = 0.56) and bleedings requiring transfusions (aOR: 0.44; 95% CI: 0.09-2.10; P = 0.29) were similar in ECLS patients and Impella patients. The use of Impella or ECLS was not associated with increased odds of mortality (aOR: 4.19; 95% CI: 0.53-33.25; P = 0.17), after correction for propensity score and baseline lactate level. Baseline lactate level was independently associated with increased odds of 30 day mortality (per mmol/L increase; OR: 1.29; 95% CI: 1.14-1.45; P < 0.001). CONCLUSIONS: In CS patients, the adjusted mortality rates of both ECLS and Impella were high and similar. The baseline lactate level was a potent predictor of mortality and could play a role in patient selection for therapy in future studies. In patients with profound CS, the type of device is likely to be less important compared with other parameters including non-cardiac and neurological factors.


Assuntos
Coração Auxiliar , Choque Cardiogênico , Humanos , Pontuação de Propensão , Estudos Retrospectivos , Choque Cardiogênico/terapia , Resultado do Tratamento
3.
Small ; 17(15): e2004223, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33458953

RESUMO

With the rising interest in the effects of orally ingested engineered nanomaterials (ENMs), much effort is undertaken to develop and advance intestinal in vitro models. The cytotoxic, proinflammatory, and DNA damaging properties of polyvinylpyrrolidone-capped silver (Ag-PVP) and titanium dioxide (TiO2 , P25) ENM in four in vitro models of increasing complexity-from proliferating Caco-2 and HT29-MTX-E12 monocultures to long-term transwell triple cultures including THP-1 macrophages to reproduce the human intestine in healthy versus inflamed-like state-are studied. Results are compared against in vivo effects of the same ENM through intestinal tissue analysis from 28-day oral exposure studies in mice. Adverse responses are only observed in monocultures and suggest toxic potential for both ENM, typically showing stronger effects for Ag-PVP than for TiO2 . By contrast, no adverse effects are observed in either the transwell cultures or the analyzed murine tissues. The data provide further support that monoculture models represent a cost and time efficient tool for early-phase hazard assessment. However, the observed similarities in morphology and ENM effects in murine intestinal tissue and the in vitro triple culture model suggest that advanced multifacetted research questions concerning oral ENM exposure are more adequately addressed by the more complex and time intensive models.


Assuntos
Nanoestruturas , Prata , Animais , Células CACO-2 , Humanos , Intestinos , Camundongos , Prata/toxicidade , Titânio/toxicidade
4.
Vascul Pharmacol ; 136: 106808, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33130016

RESUMO

BACKGROUND: The G-protein-coupled apelin receptor and its apelin ligand are an emerging regulatory system of the vascular homeostasis. To date, the implications of the apelin/apelin receptor system in athero-thrombosis are not completely clarified yet. This study determines the expression of the apelin receptor on human platelets, the effect of different apelin isoforms on platelet aggregation and the potential role of the apelin/apelin receptor system in acute myocardial infarction. METHODS: We applied immunofluorescence staining, Western Blot analysis, aggregometry, and flow cytometry to elucidate the role of the apelin receptor in activated platelets. Furthermore, in an observational pilot study, we assessed platelet apelin recpetor expression and apelin-17 plasma levels in patients with acute myocardial infarction (AMI, n = 27). RESULTS: Immunofluorescence staining indicates that the apelin receptor is located at the cell membrane in resting platelets and diminishes upon activation with a selective thrombin receptor-activating peptide (AP1, 3 to 100 µM). Western Blot analyses of AP1-activated platelets and their supernatants suggest that the apelin receptor is not predominantly internalized but is released from activated platelets. The isoform apelin-17 attenuated AP-1-induced platelet activation in-vitro, presumably via a NO-dependent mechanism. Furthermore, platelet apelin receptor expression was significantly reduced in patients with AMI (n = 27) compared to age-matched controls (n = 14; p < 0.05) and inversely correlated with troponin I plasma levels (r = -0.46; p = 0.03). Besides that, circulating apelin-17 was significantly reduced in MI patients compared to the control group. CONCLUSION: Taken together, our data support a crucial role of the platelet apelinergic system assuming an antithrombotic effect and therefore holding a potential diagnostic and therapeutic impact.


Assuntos
Receptores de Apelina/sangue , Plaquetas/metabolismo , Infarto do Miocárdio/sangue , Agregação Plaquetária , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Ligantes , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Projetos Piloto , Transdução de Sinais
5.
J Interv Card Electrophysiol ; 61(2): 339-348, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32661865

RESUMO

PURPOSE: Inappropriate implantable cardioverter-defibrillator (ICD) shocks are associated with greater healthcare resource utilization, poorer quality-of-life, and higher mortality. We aimed to investigate the performance of enhanced supraventricular tachycardia (SVT) discrimination algorithms (morphology discrimination, rate stability, and sudden or chamber onset) for reducing inappropriate ICD therapies in patients with ICD/cardiac resynchronization therapy devices. METHODS: This prospective, non-randomized, multicenter study (ReduceIT) study took place at 56 sites across Germany and Estonia. Adults at risk of sudden cardiac death undergoing St. Jude Medical™ ICD or CRT-D implantation were included. The primary endpoint was freedom from inappropriate ICD shock at 12 months and was analyzed in the intention to treat (ITT) and per-protocol population. RESULTS: Overall, 733 patients (65.9 ± 11.4 years) were included, of which 40.9% and 59.1% received a single- and dual-chamber detection device, respectively. During follow-up (median 11.9 [0-21.6] months), 96.3% of patients experienced no inappropriate therapy (ITT). The sensitivity, specificity, and accuracy for VT/VF were 91.9%, 95.5%, and 94.7%, respectively. In the per-protocol population (n = 620), the proportion of patients free from inappropriate shock at 12 months was 98.4% (n = 610; 95% CI 97.1-99.2%) and exceeded the expected value of 93% (p < 0.0001) which was derived from the rates in the SPICE, ATPonFastVT, and DECREASE studies. A total of 44 patients (6.0%) died during follow-up, 19 deaths were cardiac-related which is consistent with a meta-analysis of EMPIRIC, MADIT-RIT, ADVANCE III, and PROVIDE. Serious device and procedure-related adverse effects occurred in 9.8% of patients. CONCLUSIONS: In ICD/CRT-D devices with advanced SVT discriminators, device programming according to clinical setting and detection chamber significantly reduces the rate of inappropriate ICD shocks without compromising patient safety. The algorithms and settings described herein have particular clinical importance and their employment may be of benefit to ICD recipients.


Assuntos
Desfibriladores Implantáveis , Taquicardia Supraventricular , Taquicardia Ventricular , Adulto , Arritmias Cardíacas , Dispositivos de Terapia de Ressincronização Cardíaca , Humanos , Estudos Multicêntricos como Assunto , Estudos Prospectivos , Taquicardia Supraventricular/diagnóstico , Taquicardia Supraventricular/terapia , Taquicardia Ventricular/terapia
6.
Environ Res ; 193: 110536, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33253701

RESUMO

The continuous degradation of plastic waste in the environment leads to the generation of micro- and nanoplastic fragments and particles. Due to the ubiquitous presence of plastic particles in natural habitats as well as in food, beverages and tap water, oral exposure of the human population with plastic particles occurs worldwide. We investigated acute toxicological effects of polystyrene (PS) and polyvinyl chloride (PVC) micro- and nanoparticles in an advanced in vitro triple culture model (Caco-2/HT29-MTX-E12/THP-1) mimicking the healthy and inflamed human intestine to study the effect of inflammatory processes on plastic particle toxicity. We monitored barrier integrity, cytotoxicity, cell layer integrity, DNA damage, the release of pro-inflammatory cytokines (IL-1ß, IL-6, IL-8 and TNF-α) and mucus distribution after 24 h of particle exposure. In addition, we investigated cytotoxicity, DNA damage and IL-1ß release in monocultures of the three cell lines. Amine-modified polystyrene nanoparticles (PS-NH2) served as a positive control for particle-induced toxicity. No acute effects in the investigated endpoints were observed in the model of the healthy intestine after PS or PVC exposure. However, during active inflammatory processes, exposure to PVC particles was found to augment the release of IL-1ß and to cause a loss of epithelial cells. Our results suggest that prevalent intestinal inflammation might be an important factor to consider when assessing the hazard of ingested micro- and nanoplastic particles.


Assuntos
Nanopartículas , Poliestirenos , Células CACO-2 , Humanos , Intestinos , Microplásticos , Nanopartículas/toxicidade , Poliestirenos/toxicidade , Cloreto de Polivinila/toxicidade
7.
Chem Res Toxicol ; 33(5): 1163-1178, 2020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-32383381

RESUMO

There is growing concern about the potential adverse effects of oral exposure to engineered nanomaterials (ENM). Recent years have witnessed major developments in and advancement of intestinal in vitro models for nanosafety evaluation. The present paper reviews the key factors that should be considered for inclusion in nonanimal alternative testing approaches to reliably reflect the in vivo dynamics of the physicochemical properties of ENM as well the intestinal physiology and morphology. Currently available models range from simple cell line-based monocultures to advanced 3D systems and organoids. In addition, in vitro approaches exist to replicate the mucous barrier, digestive processes, luminal flow, peristalsis, and interactions of ENM with the intestinal microbiota. However, while the inclusion of a multitude of individual factors/components of particle (pre)treatment, exposure approach, and cell model approximates in vivo-like conditions, such increasing complexity inevitably affects the system's robustness and reproducibility. The selection of the individual modules to build the in vitro testing strategy should be driven and justified by the specific purpose of the study and, not least, the intended or actual application of the investigated ENM. Studies that address health hazards of ingested ENM likely require different approaches than research efforts to unravel the fundamental interactions or toxicity mechanisms of ENM in the intestine. Advanced reliable and robust in vitro models of the intestine, especially when combined in an integrated testing approach, offer great potential to further improve the field of nanosafety research.


Assuntos
Intestinos/efeitos dos fármacos , Modelos Biológicos , Nanoestruturas/toxicidade , Animais , Humanos , Nanoestruturas/efeitos adversos , Tamanho da Partícula , Testes de Toxicidade
8.
Medicines (Basel) ; 7(4)2020 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-32244404

RESUMO

Background: Gagging during transesophageal echocardiography examination (TEE) can be distressing and even dangerous for patients. The needling of acupuncture point CV24 was described to be effective in reducing the gag reflex during TEE in patients with ischemic stroke or transient ischemic attack. Methods: We describe a proposal for a prospective, randomized, patient, practitioner and assessor-blinded, single-center trial with two arms/groups; real acupuncture will be compared to placebo acupuncture. A total of 60 (30 per group) patients scheduled for elective TEE in order to exclude a cardiac embolic source, endocarditis or for valve failure evaluation will be recruited according to patients' selection criteria and receive either indwelling fixed intradermal needles at acupoints CV24 and bilateral PC6 or placebo needles at the same areas. Patients, the practitioners who will perform the TEE procedure, and the assessor of the outcome measures will be unaware of the group's (real or placebo) allocation. Results: The primary outcome is the intensity of gagging, measured using verbal rating scale (VRS-11) from 0 = no gagging to 10 = intolerable gagging. Secondary outcomes include the incidence of gagging, the use of rescue medication, patients' satisfaction with relief of unwanted side effects during TEE procedure, success of patients' blinding (patients' opinion to group allocation), heart rate and oxygen saturation measured by pulse oxymetry. Conclusions: To study the effects of acupuncture against gagging during TEE, we test the needling of acupoints CV24 and PC6 bilaterally. A placebo acupuncture is used for the control group. Trial registration number: NCT NCT0382142.

9.
Circ Arrhythm Electrophysiol ; 12(6): e007247, 2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-31693319

RESUMO

Background: The FIRE AND ICE trial assessed efficacy and safety of pulmonary vein (PV) isolation using cryoballoon versus radiofrequency current (RFC) ablation in patients with drug refractory, symptomatic, paroxysmal atrial fibrillation (AF). The purpose of the current study was to assess index lesion durability as well as reablation strategy and outcomes in trial patients undergoing a reablation procedure. Methods: Patients with reablation procedures during FIRE AND ICEwere retrospectively consented and enrolled at 13 trial centers. The first reablation for each patient was included in the analysis. Documented arrhythmias before reablation, number and location of reconnected PVs, lesions created during reablations, procedural characteristics, and acute as well as long-term outcomes were assessed. Results: Eighty-nine (36 cryoballoon and 53 RFC) patients were included in this study. Paroxysmal atrial fibrillation was the predominant recurrent arrhythmia (69%) before reablation. Reablations occurred at a median of 173 and 182 days (P=0.54) in the cryoballoon and RFC cohorts, respectively. The number of reconnected PVs was significantly higher in the RFC than the cryoballoon group (2.1±1.4 versus 1.4±1.1; P=0.010), which was driven by significantly more reconnected left superior PVs and markedly more reconnected right superior PVs. The number of (predominantly RFC) lesions applied during reablation was significantly greater in patients originally treated with RFC (3.3±1.3 versus 2.5±1.5; P=0.015) with no difference in overall acute success (P=0.70). After reablation, no differences in procedure-related rehospitalization or antiarrhythmic drug utilization were observed between cohorts. Conclusions: At reablation, patients originally treated with the cryoballoon had significantly fewer reconnected PVs, which may reflect RFC catheter instability in certain left atrial regions, and thus required fewer lesions for reablation success. Repeat ablations were predominantly performed with RFC and resulted in similar acute success, duration of hospitalization, and antiarrhythmic drug prescription between the study cohorts.


Assuntos
Fibrilação Atrial/cirurgia , Ablação por Cateter , Criocirurgia , Veias Pulmonares/cirurgia , Potenciais de Ação , Adolescente , Adulto , Idoso , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/fisiopatologia , Ablação por Cateter/efeitos adversos , Criocirurgia/efeitos adversos , Europa (Continente) , Feminino , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Veias Pulmonares/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Reoperação , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
10.
Pacing Clin Electrophysiol ; 42(7): 1038-1046, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31119745

RESUMO

INTRODUCTION: We conducted this study to show the safety and efficacy of a new implantable cardiac monitor (ICM), the BioMonitor 2 (Biotronik SE & Co. KG; Berlin, Germany), and to describe the arrhythmia detection performance. METHODS: The BioMonitor 2 has an extended sensing vector and is implanted close to the heart. It can transmit up to six subcutaneous electrocardiogram strips by Home Monitoring each day. We enrolled 92 patients with a standard device indication for an ICM in a single-arm, multicenter prospective trial. Patients were followed for 3 months, and 48-h Holter recordings were used to evaluate the arrhythmia detection performance. RESULTS: One patient withdrew consent and in one patient, the implantation failed. Two study device-related serious adverse events were reported, satisfying the primary safety hypothesis. Implantations took 7.4 ± 4.4 min from skin cut to suture. At 1 week, the R-wave amplitude was 0.75 ± 0.53 mV. In the 82 patients with completed Holter recordings, all patients with arrhythmias were correctly identified. False positive detections of arrhythmia were mostly irregular rhythms wrongly detected as atrial fibrillation (episode-based positive predictive value 72.5%). Daily Home Monitoring transmission was 94.9% successful. CONCLUSION: Safety and efficacy of the new device has been demonstrated. The detected R-wave amplitudes are large, leading to a low level of inappropriate detections due to over- or undersensing.


Assuntos
Arritmias Cardíacas/diagnóstico , Eletrocardiografia Ambulatorial/instrumentação , Desenho de Equipamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
11.
Heart Rhythm ; 16(9): 1314-1319, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30910708

RESUMO

BACKGROUND: Insulin-like growth factor 1 (IGF-1) and its main binding protein insulin-like growth factor binding protein 3 (IGFBP-3) have been related to several cardiovascular diseases. The relation with atrial fibrillation (AF) is largely unknown. OBJECTIVE: The objective of this study was to investigate the association of IGF-1 and IGFBP-3 levels with prevalent and incident AF in a large population-based study. METHODS: Data from the Study of Health in Pomerania (SHIP) were collected. At presentation, a medical examination, standardized electrocardiographic assessment, and measurements of serum IGF-1 and IGFBP-3 levels were performed. Incident AF was assessed in individuals without AF at baseline (SHIP-1) who developed AF during follow-up (SHIP-2; after a mean of 5.2 years). RESULTS: Of 3160 participants, 66 (2.1%) exhibited AF at baseline. IGF-1 levels and IGF-1/IGFBP-3 ratios were significantly lower in individuals with AF than in those without AF (IGF-1: 104.2 ± 41.6 ng/mL vs 142.9 ± 53.5 ng/mL, P < .001 and IGF-1/IGFBP-3: 0.031 ± (0.009 ng/mL vs 0.036 ± 0.010 ng/mL, P = .006, respectively). Multivariable-adjusted logistic regression models showed that a low IGF-1/IGFBP-3 ratio was associated with prevalent AF (odds ratios 0.67; 95% confidence interval 0.48-0.94; P = .021). Of 1817 individuals without AF at baseline, 27 (1.5%) developed AF during follow-up. In these participants, IGF-1 levels, but not IGF-1/IGFBP-3 ratios, were significantly lower (IGF-1: 113.3 ± 38.6 ng/mL vs 147.2 ± 51.6 ng/mL, P = .013 and IGF-1/IGFBP-3: 0.033 ± 0.008 ng/mL vs 0.036 ± 0.010 ng/mL, P = .176). CONCLUSION: Low IGF-1/IGFBP-3 ratios are associated with a higher prevalence of AF. There seems to be a similar impact in incident AF.


Assuntos
Fibrilação Atrial , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/análise , Fator de Crescimento Insulin-Like I/análise , Fibrilação Atrial/sangue , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Estudos de Coortes , Eletrocardiografia/métodos , Eletrocardiografia/estatística & dados numéricos , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Prevalência
12.
Circulation ; 139(10): 1249-1258, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30586755

RESUMO

BACKGROUND: Percutaneous mechanical circulatory support devices are increasingly used in acute myocardial infarction complicated by cardiogenic shock (AMI-CS), despite limited evidence for their effectiveness. The aim of this study was to evaluate outcomes associated with use of the Impella device compared with intra-aortic balloon pump (IABP) and medical treatment in patients with AMI-CS. METHODS: Data of patients with AMI-CS treated with the Impella device at European tertiary care hospitals were collected retrospectively. All patients underwent early revascularization and received optimal medical treatment. Using IABP-SHOCK II (Intraaortic Balloon Pump in Cardiogenic Shock II) trial inclusion and exclusion criteria, 372 patients were identified and included in this analysis. These patients were matched to 600 patients from the IABP-SHOCK II trial. The following baseline criteria were used as matching parameters: age, sex, mechanical ventilation, ejection fraction, prior cardiopulmonary resuscitation, and lactate. Primary end point was 30-day all-cause mortality. RESULTS: In total, 237 patients treated with an Impella could be matched to 237 patients from the IABP-SHOCK II trial. Baseline parameters were similarly distributed after matching. There was no significant difference in 30-day all-cause mortality (48.5% versus 46.4%, P=0.64). Severe or life-threatening bleeding (8.5% versus 3.0%, P<0.01) and peripheral vascular complications (9.8% versus 3.8%, P=0.01) occurred significantly more often in the Impella group. Limiting the analysis to IABP-treated patients as a control group did not change the results. CONCLUSIONS: In this retrospective analysis of patients with AMI-CS, the use of an Impella device was not associated with lower 30-day mortality compared with matched patients from the IABP-SHOCK II trial treated with an IABP or medical therapy. To further evaluate this, a large randomized trial is warranted to determine the effect of the Impella device on outcome in patients with AMI-CS. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03313687.


Assuntos
Fármacos Cardiovasculares/uso terapêutico , Coração Auxiliar , Balão Intra-Aórtico , Infarto do Miocárdio/terapia , Revascularização Miocárdica , Choque Cardiogênico/terapia , Idoso , Fármacos Cardiovasculares/efeitos adversos , Europa (Continente) , Feminino , Coração Auxiliar/efeitos adversos , Humanos , Balão Intra-Aórtico/efeitos adversos , Balão Intra-Aórtico/mortalidade , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/complicações , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/fisiopatologia , Revascularização Miocárdica/efeitos adversos , Revascularização Miocárdica/mortalidade , Desenho de Prótese , Recuperação de Função Fisiológica , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Choque Cardiogênico/etiologia , Choque Cardiogênico/mortalidade , Choque Cardiogênico/fisiopatologia , Fatores de Tempo , Resultado do Tratamento
13.
J Cell Physiol ; 233(8): 6250-6261, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29369349

RESUMO

The adaption of endothelial cells to local flow conditions is a multifunctional process which leads to distinct alterations in cell shape, the subcellular distribution of structural proteins, and cellular function. G-protein-coupled receptors (GPCRs) have been identified to be fundamentally involved in such processes. Recently, we and others have shown that the expression of the endothelial GPCR apelin receptor (APJ) is regulated by fluid flow and that activation of APJ participates in signaling pathways which are related to processes of mechanotransduction. The present study aims to illuminate these findings by further visualization of APJ function. We show that APJ is located to the cellular junctions and might thus be associated with platelet endothelial cell adhesion molecule-1 (PECAM-1) in human umbilical vein endothelial cells (HUVEC). Furthermore, siRNA-mediated silencing of APJ expression influences the shear-induced adaption of HUVEC in terms of cytoskeletal remodeling, cellular elasticity, cellular motility, attachment, and distribution of adhesion complexes. Taken together, our results demonstrate that APJ is crucial for complemented endothelial adaption to local flow conditions.


Assuntos
Receptores de Apelina/metabolismo , Apelina/metabolismo , Células Endoteliais/metabolismo , Linhagem Celular , Movimento Celular/fisiologia , Elasticidade/fisiologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Mecanotransdução Celular/fisiologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , RNA Interferente Pequeno/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais/fisiologia
14.
BMC Res Notes ; 10(1): 311, 2017 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-28854963

RESUMO

BACKGROUND: Vasculitides are commonly unrecognized causes of coronary stenosis and myocardial ischemia. We report on a 24-year old patient with Takayasu's arteritis who underwent urgent percutaneous coronary intervention, suffered from symptomatic restenosis of the left main coronary artery during standard immunosuppressive therapy. CASE PRESENTATION: A 24-year old woman was referred for coronary angiography because of typical progressive angina pectoris. On bicycle ergometry, there were both reproducible symptoms and deep ST segment depressions on precordial leads. Semi-selective angiography of the left coronary artery revealed high-grade ostial stenosis. Because of persistent angina pectoris and electrocardiographic signs of acute myocardial ischemia, immediate percutaneous coronary angioplasty with subsequent implantation of an everolimus-eluting stent was performed. This intervention was performed with excellent angiographic results. Because of several concomitant criteria including hypoechogenicity on postprocedural intravascular ultrasonography, the diagnosis of Takayasu's disease was made. The patient was treated with prednisolone and cyclophosphamide for 5 months. Because of recurrent angina pectoris, another coronary angiography was performed, which revealed high-grade in-stent-restenosis. Immunomodulatory therapy was switched to high-dose prednisolone and the anti-IL-6 receptor antagonist tocilizumab. The high-grade in-stent-restenosis persisted, and aortocoronary bypass graft surgery was performed with two saphenous vein grafts to the left anterior descending and circumflex artery. Since then, the patient has been doing well for 2 years. CONCLUSION: In cases of treatment refractoriness during standard immunosuppressive therapy, more recently developed biological compounds may offer an alternative strategy.


Assuntos
Revascularização Miocárdica/métodos , Arterite de Takayasu/diagnóstico , Arterite de Takayasu/cirurgia , Adulto , Feminino , Humanos , Imunossupressores/farmacologia , Recidiva , Arterite de Takayasu/tratamento farmacológico , Adulto Jovem
15.
Am J Cardiol ; 120(1): 92-97, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28495433

RESUMO

Early repolarization (ER) is a common electrocardiographic (ECG) finding that is associated with an increased risk of idiopathic ventricular fibrillation and sudden cardiac death. This study investigated whether the presence of ER is a predictor of ventricular and supraventricular ectopy as a marker for electrical instability. Standard 12-lead electrocardiograms of the first follow-up in the population-based Study of Health in Pomerania (SHIP-1) (n = 3,300, age 20 to 79 years) were analyzed to identify subjects with an ER pattern. Ventricular and supraventricular ectopy was assessed via portable tele-ECG cards recording 2 electrocardiograms daily over the course of 4 weeks. Data of 1,630 subjects (n = 83,833 ECG card recordings, average 51.4 per subject) were analyzed for ventricular and supraventricular ectopy using a standardized automated algorithm. Associations of ER and several forms of arrhythmias were assessed using a 2-sided Fisher's exact test or t test, where appropriate. Overall, prevalence of ER in the SHIP-1 population was 4.8%. Presence of ER was not associated with the occurrence of ventricular and supraventricular arrhythmias (p ≥0.05 for all analyses). Furthermore, subgroup analyzes for ER localization (inferior) and ST-segment morphology (horizontal/descending) did not show any association with arrhythmic events. In conclusion, presence of the ER pattern is not associated with an increased occurrence of ventricular or supraventricular arrhythmias as assessed by serial ECG card recordings in this large population-based sample.


Assuntos
Morte Súbita Cardíaca/epidemiologia , Eletrocardiografia , Sistema de Condução Cardíaco/fisiopatologia , Ventrículos do Coração/fisiopatologia , Fibrilação Ventricular/fisiopatologia , Adulto , Idoso , Estudos Transversais , Morte Súbita Cardíaca/etiologia , Feminino , Seguimentos , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Vigilância da População , Prevalência , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida/tendências , Fatores de Tempo , Fibrilação Ventricular/complicações , Fibrilação Ventricular/mortalidade , Adulto Jovem
16.
Artigo em Inglês | MEDLINE | ID: mdl-28440600

RESUMO

BACKGROUND: The clinical relevance of extended monitoring of AF in the general population is unclear. The study evaluated the detection of AF using transtelephonic electrocardiography and the clinical relevance of additional AF findings, especially with regard to stroke risk and mortality. METHODS: The data of 1678 volunteers participating in the tele-ECG-subproject of the Study of Health in Pomerania was evaluated. Occurrence of AF as revealed by tele-ECG and conventional ECG was evaluated. Associations with mortality, history of stroke, and other clinical parameters were analyzed. RESULTS: AF was detected in 21 subjects (1.3%) by conventional ECG (ECG-AF) and in 43 (2.6%) by tele-ECG. All individuals with AF revealed by conventional ECG were also diagnosed to have AF by tele-ECG; 22 were diagnosed by tele-ECG only (Tele-AF). During follow-up (median: 6.3 years) 42/1635, 1/22, and 5/21 participants died in the no-AF-, tele-AF-, and ECG-AF groups (p < .001). Whereas, in comparison to the no-AF group, the risk of death was higher in the ECG-AF group (HR 9.4; 3.7-23.8; p < .001), there was no significant increase in mortality in the tele-AF group (HR 1.9; 0.26-14.0; p = .52). Prevalence of stroke history was higher in the ECG-AF group (19%; 5.5-42%) than with the no-AF (1.9%; 1.3-2.7%; p = .001) and the tele-AF groups (0%; 0-15%; p = .05). CONCLUSIONS: Tele-ECG identifies significantly more AF cases in a population-based setting compared to conventional ECG. The impact of AF diagnosed only by extended monitoring differs from conventionally diagnosed AF. Additional studies are warranted, since this might have an impact on clinical management.


Assuntos
Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Eletrocardiografia/métodos , Acidente Vascular Cerebral/epidemiologia , Telemedicina/métodos , Idoso , Estudos de Coortes , Comorbidade , Feminino , Seguimentos , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Risco , Acidente Vascular Cerebral/diagnóstico
17.
Eur J Pharmacol ; 767: 1-9, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26407652

RESUMO

In cardiovascular diseases, reduced responsiveness of soluble guanylate cyclase (sGC) to nitric oxide (NO) upon long-term application has led to the development of NO-independent sGC stimulators (heme-dependent) and sGC activators (heme-independent). Any direct inotropic or lusitropic effects of these compounds on isolated cardiac myocytes, however, remain to be elucidated. Here, we analyzed the dose-dependent effects of clinical relevant concentrations (10(-10)-10(-5) M) of the sGC activator cinaciguat and the sGC stimulator riociguat on the contraction, relaxation, and calcium transients of isolated field-stimulated cardiac myocytes from healthy rats. For comparison, we used isoproterenol, which induced a dose-dependent significant increase in cell contractility, relaxation, and calcium transients, verapamil that significantly decreased these parameters (both at 10(-9)-10(-5) M) and 8-(4-Chlorophenylthio)-guanosine 3',5'-cyclic monophosphate (8-pCPT-cGMP) that induced a negative inotropic effect at 10(-5) M accompanied by a slight increase in relaxation. In contrast, neither cinaciguat nor riociguat significantly influenced any measured parameters. Furthermore, isoproterenol significantly increased intracellular cAMP levels that were not influenced by cinaciguat or riociguat (all at 10(-6) M). Otherwise, riociguat and cinaciguat (both at 10(-6) M) significantly enhanced intracellular cGMP generation. This accumulation was significantly augmented by cinaciguat in the presence of the sGC inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 25 µM), whereas ODQ blocked cGMP generation by riociguat. However, blocking of sGC did not influence cell contractility. Our results demonstrate that, in isolated cardiac myocytes from healthy rats, the increase in cGMP levels induced by cinaciguat and riociguat at clinical relevant concentrations is not associated with acute direct effects on cell contraction and relaxation.


Assuntos
Benzoatos/farmacologia , Relaxamento Muscular/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Pirazóis/farmacologia , Pirimidinas/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Animais , Benzoatos/agonistas , Cálcio/metabolismo , AMP Cíclico/metabolismo , GMP Cíclico/análogos & derivados , GMP Cíclico/metabolismo , GMP Cíclico/farmacologia , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Estimulação Elétrica , Feminino , Guanilato Ciclase , Isoproterenol/farmacologia , Miócitos Cardíacos/metabolismo , Oxidiazóis/farmacologia , Pirazóis/antagonistas & inibidores , Pirimidinas/antagonistas & inibidores , Quinoxalinas/farmacologia , Ratos , Guanilil Ciclase Solúvel , Tionucleotídeos/farmacologia , Verapamil/farmacologia
18.
Cell Signal ; 27(7): 1286-96, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25817266

RESUMO

Although the apelin/APJ system is abundantly expressed in vascular endothelial cells (EC), it has not yet been considered to be regulated by fluid flow. The aim of this study was to explore the influence of shear stress on the expression of apelin/APJ in human EC. Therefore, gene and protein expression were assessed after flow exposure; cell supernatants were collected for measurements of NO and apelin; APJ or apelin knockdown were performed using siRNA. Our data show that gene and protein expression of apelin and APJ are modulated by fluid flow depending on the magnitude of shear stress. Moreover, apelin-12 activated NO production via PI3K/Akt signaling in human EC. In contrast, apelin-13 additionally activated Erk1/2 phosphorylation and enhanced EC proliferation. Knockdown of APJ inhibited phosphorylation of PI3K and impaired flow-induced eNOS and PECAM-1 expression. Knockdown of apelin had no influence on flow-induced APJ and PECAM-1 expression, but derogated eNOS expression under static and flow conditions. The present study reveals a flow-mediated adjustment of the apelin/APJ system in human EC in which APJ expression is induced by shear stress independently of its ligand. Furthermore, apelin-12 signaling is an essential regulatory element in endothelial NO synthesis.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Apelina , Linhagem Celular , Ensaio de Imunoadsorção Enzimática , Células Endoteliais da Veia Umbilical Humana , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/análise , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Acoplados a Proteínas G/genética , Resistência ao Cisalhamento , Transdução de Sinais/efeitos dos fármacos
19.
Am J Cardiol ; 115(3): 367-73, 2015 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-25579886

RESUMO

Patient radiation exposure in invasive cardiology is considerable. We aimed to investigate, in a multicenter field study, the long-term efficacy of an educational 90-minute workshop in cardiac invasive techniques with reduced irradiation. Before and at a median period of 2.5 months and 2.0 years after the minicourse (periods I, II, and III, respectively) at 5 German cardiac centers, 18 interventionalists documented various radiation parameters for 10 coronary angiographies. The median patient dose area product (DAP) for periods I, II, and III amounted to 26.6, 12.2, and 9.6 Gy × cm(2), respectively. The short-term and long-term effects were related to shorter median fluoroscopy times (180, 138, and 114 seconds), fewer radiographic frames (745, 553, and 417) because of fewer (11, 11, and 10) and shorter (64, 52, and 44 frames/run) runs, consistent collimation, and restriction to an adequate image quality; both radiographic DAP/frame (27.7, 17.3, and 18.4 mGy × cm(2)) and fluoroscopic DAP/second (26.6, 12.9, and 14.9 mGy × cm(2)) decreased significantly. Multivariate analysis over time indicated increasing efficacy of the minicourse itself (-55% and -64%) and minor influence of interventionist experience (-4% and -3% per 1,000 coronary angiographies, performed lifelong until the minicourse and until period III). In conclusion, autonomous self-surveillance of various dose parameters and feedback on individual radiation safety efforts supported the efficacy of a 90-minute course program toward long-lasting and ongoing patient dose reduction.


Assuntos
Cateterismo Cardíaco/efeitos adversos , Cardiologia/educação , Angiografia Coronária/efeitos adversos , Educação Médica Continuada/métodos , Fluoroscopia/efeitos adversos , Lesões por Radiação/prevenção & controle , Proteção Radiológica/métodos , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Radiometria
20.
Circ J ; 78(7): 1693-700, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24899232

RESUMO

BACKGROUND: Ventricular dilation is known as a pivotal predictor in recent-onset cardiomyopathy (ROCM), but its pathophysiology is not fully understood. In the present study we investigated whether single-cell stiffness of right and left ventricular-derived fibroblasts has an effect on cardiac phenotype in patients with ROCM. METHODS AND RESULTS: Patients with endomyocardial biopsy-proven ROCM were included (n=10). Primary cardiac fibroblasts (CFBs) were cultured from left and right ventricular endomyocardial biopsies and their single-cell stiffness was analyzed by quantification of Young's modulus using colloidal probe atomic force microscopy. Cardiac fibrosis was analyzed by Masson's trichrome staining. CFBs from the left ventricle showed significantly decreased stiffness when compared with CFBs from the right ventricle, indexed by decreased stiffness (Young's modulus 3,374±389 vs. 4,837±690 Pa; P<0.05). Young's modulus of CFBs derived from the left ventricle correlated negatively with the left ventricular end-diastolic dimension derived from 2-dimensional echocardiography (R(2)=0.77; P<0.01). Neither left nor right ventricular fibrosis correlated with the respective ventricular dimensions. CONCLUSIONS: Our data suggest that a decrease in single-cell stiffness of left ventricular fibroblasts could trigger left ventricular dilation in patients with ROCM. This implies a new potential mechanism for the ventricular dilation with this disease.


Assuntos
Cardiomiopatia Dilatada , Módulo de Elasticidade , Fibroblastos , Ventrículos do Coração , Adulto , Idoso , Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/patologia , Cardiomiopatia Dilatada/fisiopatologia , Feminino , Fibroblastos/metabolismo , Fibroblastos/ultraestrutura , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Microscopia de Força Atômica , Pessoa de Meia-Idade
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