Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 279
Filtrar
1.
J Am Heart Assoc ; 10(19): e021985, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34583520

RESUMO

Background PKARIα (protein kinase A type I-α regulatory subunit) is redox-active independent of its physiologic agonist cAMP. However, it is unknown whether this alternative mechanism of PKARIα activation may be of relevance to cardiac excitation-contraction coupling. Methods and Results We used a redox-dead transgenic mouse model with homozygous knock-in replacement of redox-sensitive cysteine 17 with serine within the regulatory subunits of PKARIα (KI). Reactive oxygen species were acutely evoked by exposure of isolated cardiac myocytes to AngII (angiotensin II, 1 µmol/L). The long-term relevance of oxidized PKARIα was investigated in KI mice and their wild-type (WT) littermates following transverse aortic constriction (TAC). AngII increased reactive oxygen species in both groups but with RIα dimer formation in WT only. AngII induced translocation of PKARI to the cell membrane and resulted in protein kinase A-dependent stimulation of ICa (L-type Ca current) in WT with no effect in KI myocytes. Consequently, Ca transients were reduced in KI myocytes as compared with WT cells following acute AngII exposure. Transverse aortic constriction-related reactive oxygen species formation resulted in RIα oxidation in WT but not in KI mice. Within 6 weeks after TAC, KI mice showed an enhanced deterioration of contractile function and impaired survival compared with WT. In accordance, compared with WT, ventricular myocytes from failing KI mice displayed significantly reduced Ca transient amplitudes and lack of ICa stimulation. Conversely, direct pharmacological stimulation of ICa using Bay K8644 rescued Ca transients in AngII-treated KI myocytes and contractile function in failing KI mice in vivo. Conclusions Oxidative activation of PKARIα with subsequent stimulation of ICa preserves cardiac function in the setting of acute and chronic oxidative stress.

2.
Heart Rhythm ; 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34517118

RESUMO

BACKGROUND: Patients with atrial fibrillation (AF) exhibit decreased atrial expression of connexin (Cx), which has been causally linked to a proarrhythmogenic substrate. Interestingly, patients with sleep-disordered breathing (SDB) are at increased risk of AF, but the mechanisms remain unclear. OBJECTIVE: We tested the hypothesis that patients with SDB have reduced atrial Cx expression independent of important comorbidities. METHODS: We analyzed right atrial appendage biopsies from 77 patients undergoing coronary artery bypass grafting. Patients were tested for SDB by polygraphy before surgery. Expression of Cx40 and Cx43 messenger RNA was quantified using real-time quantitative polymerase chain reaction and Western blot (Cx43). Structural atrial remodeling was investigated histologically and by quantitative polymerase chain reaction. Postoperative AF was assessed by 12-lead electrocardiography. RESULTS: Patients were stratified according to apnea-hypopnea index (SDB if apnea-hypopnea index ≥15 per hour, n = 32 vs n = 45). Patients with SDB had significantly lower atrial Cx43 expression, which was negatively correlated with apnea-hypopnea index and oxygen desaturation index. No significant increase in atrial fibrosis or expression of hypertrophy and inflammatory markers was observed. Interestingly, SDB remained the strongest independent predictor of decreased atrial Cx43 expression in a multivariate logistic regression model including age, sex, diabetes, and heart failure with reduced ejection fraction (odds ratio 7.58; 95% confidence interval 1.891-30.375; P = .004). Moreover, reduced atrial Cx43 expression was strongly associated with the occurrence of postoperative AF (odds ratio 15.749; 95% confidence interval 1.072-231.472; P = .044). CONCLUSION: Patients with SDB exhibited decreased atrial Cx43 expression, which correlated with the severity of SDB. This correlation was independent of several concomitant diseases and may be linked to an increased risk of AF after cardiac surgery.

3.
Int J Mol Sci ; 22(15)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34360742

RESUMO

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are emerging as a new treatment strategy for heart failure with reduced ejection fraction (HFrEF) and-depending on the wistfully awaited results of two clinical trials (DELIVER and EMPEROR-Preserved)-may be the first drug class to improve cardiovascular outcomes in patients suffering from heart failure with preserved ejection fraction (HFpEF). Proposed mechanisms of action of this class of drugs are diverse and include metabolic and hemodynamic effects as well as effects on inflammation, neurohumoral activation, and intracellular ion homeostasis. In this review we focus on the growing body of evidence for SGLT2i-mediated effects on cardiac intracellular Na+ as an upstream mechanism. Therefore, we will first give a short overview of physiological cardiomyocyte Na+ handling and its deterioration in heart failure. On this basis we discuss the salutary effects of SGLT2i on Na+ homeostasis by influencing NHE1 activity, late INa as well as CaMKII activity. Finally, we highlight the potential relevance of these effects for systolic and diastolic dysfunction as well as arrhythmogenesis.


Assuntos
Arritmias Cardíacas/tratamento farmacológico , Cardiotônicos/uso terapêutico , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Transportador 2 de Glucose-Sódio/metabolismo , Animais , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/patologia , Humanos , Miocárdio/patologia , Miócitos Cardíacos/patologia
4.
Dalton Trans ; 2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34378607

RESUMO

Acylgermanes are known as highly efficient photoinitiators. In this contribution, we present the synthesis of new diacylgermanes 4a-e via a multiple silyl abstraction methodology. The method outperforms the state-of-the-art approach (Corey-Seebach reaction) towards diacylgermanes in terms of group tolerance and toxicity of reagents. Moreover, these compounds are decorated with bulky mesityl groups in order to improve their storage stability. The isolated diacylgermanes were characterized by multinuclear NMR-, UV-Vis spectroscopy and X-ray crystallography, as well as photolysis experiments (photobleaching) and photo-DSC measurements (photopolymerization behavior). Upon irradiation with an LED emitting at 385 nm, all compounds except for 4a and 4c bleach efficiently with quantum yields above 0.6. Due to their broad absorption bands, the compounds can be also bleached with blue light (470 nm), where especially 4e bleaches more efficiently than Ivocerin®.

5.
ESC Heart Fail ; 8(5): 4055-4066, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34196135

RESUMO

AIMS: There is a lack of diagnostic and therapeutic options for patients with atrial cardiomyopathy and paroxysmal atrial fibrillation. Interestingly, an abnormal P-wave terminal force in electrocardiogram lead V1 (PTFV1 ) has been associated with atrial cardiomyopathy, but this association is poorly understood. We investigated PTFV1 as a marker for functional, electrical, and structural atrial remodelling. METHODS AND RESULTS: Fifty-six patients with acute myocardial infarction and 13 kidney donors as control cohort prospectively underwent cardiac magnetic resonance imaging to evaluate the association between PTFV1 and functional remodelling (atrial strain). To further investigate underlying pathomechanisms, right atrial appendage biopsies were collected from 32 patients undergoing elective coronary artery bypass grafting. PTFV1 was assessed as the product of negative P-wave amplitude and duration in lead V1 and defined as abnormal if ≥4000 ms*µV. Activity of cardiac Ca/calmodulin-dependent protein kinase II (CaMKII) was determined by a specific HDAC4 pull-down assay as a surrogate for electrical remodelling. Atrial fibrosis was quantified using Masson's trichrome staining as a measure for structural remodelling. Multivariate regression analyses were performed to account for potential confounders. A total of 16/56 (29%) of patients with acute myocardial infarction, 3/13 (23%) of kidney donors, and 15/32 (47%) of patients undergoing coronary artery bypass grafting showed an abnormal PTFV1 . In patients with acute myocardial infarction, left atrial (LA) strain was significantly reduced in the subgroup with an abnormal PTFV1 (LA reservoir strain: 32.28 ± 12.86% vs. 22.75 ± 13.94%, P = 0.018; LA conduit strain: 18.87 ± 10.34% vs. 10.17 ± 8.26%, P = 0.004). Abnormal PTFV1 showed a negative correlation with LA conduit strain independent from clinical covariates (coefficient B: -7.336, 95% confidence interval -13.577 to -1.095, P = 0.022). CaMKII activity was significantly increased from (normalized to CaMKII expression) 0.87 ± 0.17 to 1.46 ± 0.15 in patients with an abnormal PTFV1 (P = 0.047). This increase in patients with an abnormal PTFV1 was independent from clinical covariates (coefficient B: 0.542, 95% confidence interval 0.057 to 1.027, P = 0.031). Atrial fibrosis was significantly lower with 12.32 ± 1.63% in patients with an abnormal PTFV1 (vs. 20.50 ± 2.09%, P = 0.006), suggesting PTFV1 to be a marker for electrical but not structural remodelling. CONCLUSIONS: Abnormal PTFV1 is an independent predictor for impaired atrial function and for electrical but not for structural remodelling. PTFV1 may be a promising tool to evaluate patients for atrial cardiomyopathy and for risk of atrial fibrillation.

6.
Br Dent J ; 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34239058

RESUMO

Introduction Nursing home residents with cognitive and physical disabilities often depend on assistance from caregivers to perform personal hygiene tasks including toothbrushing. Only a minority receives the care needed and toothbrushing compliance levels are not registered.Aims To describe toothbrushing compliance levels in a nursing home setting and investigate the relevance and practicality of using telemonitoring-enabled powered toothbrushes for automated compliance tracking. Furthermore, to investigate changes in plaque and bleeding scores.Materials and methods Nursing home residents were provided with powered toothbrushes and telemonitoring gateways. Toothbrushing frequency and duration were automatically recorded by the telemonitoring gateways, and an email report was sent once a week to the nursing home manager. Plaque index and bleeding index were assessed by dentists at baseline, at the end of the intervention and at three months post-intervention.Results Data from 20 participants for 100 days (3,920 measurements) were collected and used to evaluate toothbrushing compliance. A minority of toothbrushings (5%) were in compliance with the two-minute toothbrushing duration recommendation, while around 30% achieved the one-minute toothbrushing minimum duration recommendation. Around 25% of participants would get only one toothbrushing per day, while 40% would get none. Both plaque and bleeding scores improved significantly during the project, but all progress was lost three months after the project's end.Conclusions It is relevant and practical to monitor toothbrushing compliance in the nursing home setting using telemonitoring-enabled powered toothbrushes. Despite finding limited compliance levels, a significant improvement in the plaque and bleeding index was found after the intervention, which was lost again three months after the telemonitoring gateways had been removed.

7.
PLoS One ; 16(6): e0252649, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34086773

RESUMO

Arrhythmogenic right ventricular cardiomyopathy is a hereditary, rare disease with an increased risk for sudden cardiac death. The disease-causing mutations are located within the desmosomal complex and the highest incidence is found in plakophilin2. However, there are other factors playing a role for the disease progression unrelated to the genotype such as inflammation or exercise. Competitive sports have been identified as risk factor, but the type and extend of physical activity as cofactor for arrhythmogenesis remains under debate. We thus studied the effect of light voluntary exercise on cardiac health in a mouse model. Mice with a heterozygous PKP2 loss-of-function mutation were given the option to exercise in a running wheel which was monitored 24 h/d. We analyzed structural and functional development in vivo by echocardiography which revealed that neither the genotype nor the exercise caused any significant structural changes. Ejection fraction and fractional shortening were not influenced by the genotype itself, but exercise did cause a drop in both parameters after 8 weeks, which returned to normal after 16 weeks of training. The electrophysiological analysis revealed that the arrhythmogenic potential was slightly higher in heterozygous animals (50% vs 18% in wt littermates) and that an additional stressor (isoprenaline) did not lead to an increase of arrhythmogenic events pre run or after 8 weeks of running but the vulnerability was increased after 16 weeks. Exercise-induced alterations in Ca handling and contractility of isolated myocytes were mostly abolished in heterozygous animals. No fibrofatty replacements or rearrangement of gap junctions could be observed. Taken together we could show that light voluntary exercise can cause a transient aggravation of the mutation-induced phenotype which is abolished after long term exercise indicating a beneficial effect of long term light exercise.

9.
J Gen Physiol ; 153(2)2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33410863

RESUMO

Phosphorylation of the voltage-gated Na+ (NaV) channel NaV1.5 regulates cardiac excitability, yet the phosphorylation sites regulating its function and the underlying mechanisms remain largely unknown. Using a systematic, quantitative phosphoproteomic approach, we analyzed NaV1.5 channel complexes purified from nonfailing and failing mouse left ventricles, and we identified 42 phosphorylation sites on NaV1.5. Most sites are clustered, and three of these clusters are highly phosphorylated. Analyses of phosphosilent and phosphomimetic NaV1.5 mutants revealed the roles of three phosphosites in regulating NaV1.5 channel expression and gating. The phosphorylated serines S664 and S667 regulate the voltage dependence of channel activation in a cumulative manner, whereas the nearby S671, the phosphorylation of which is increased in failing hearts, regulates cell surface NaV1.5 expression and peak Na+ current. No additional roles could be assigned to the other clusters of phosphosites. Taken together, our results demonstrate that ventricular NaV1.5 is highly phosphorylated and that the phosphorylation-dependent regulation of NaV1.5 channels is highly complex, site specific, and dynamic.

10.
Theranostics ; 11(5): 2020-2033, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33500706

RESUMO

Rationale: The heterogeneous nature of gliomas makes the development and application of novel treatments challenging. In particular, infiltrating myeloid cells play a role in tumor progression and therapy resistance. Hence, a detailed understanding of the dynamic interplay of tumor cells and immune cells in vivo is necessary. To investigate the complex interaction between tumor progression and therapy-induced changes in the myeloid immune component of the tumor microenvironment, we used a combination of [18F]FET (amino acid metabolism) and [18F]DPA-714 (TSPO, GAMMs, tumor cells, astrocytes, endothelial cells) PET/MRI together with immune-phenotyping. The aim of the study was to monitor temozolomide (TMZ) treatment response and therapy-induced changes in the inflammatory tumor microenvironment (TME). Methods: Eighteen NMRInu/nu mice orthotopically implanted with Gli36dEGFR cells underwent MRI and PET/CT scans before and after treatment with TMZ or DMSO (vehicle). Tumor-to-background (striatum) uptake ratios were calculated and areas of unique tracer uptake (FET vs. DPA) were determined using an atlas-based volumetric approach. Results: TMZ therapy significantly modified the spatial distribution and uptake of both tracers. [18F]FET uptake was significantly reduced after therapy (-53 ± 84%) accompanied by a significant decrease of tumor volume (-17 ± 6%). In contrast, a significant increase (61 ± 33%) of [18F]DPA-714 uptake was detected by TSPO imaging in specific areas of the tumor. Immunohistochemistry (IHC) validated the reduction in tumor volumes and further revealed the presence of reactive TSPO-expressing glioma-associated microglia/macrophages (GAMMs) in the TME. Conclusion: We confirm the efficiency of [18F]FET-PET for monitoring TMZ-treatment response and demonstrate that in vivo TSPO-PET performed with [18F]DPA-714 can be used to identify specific reactive areas of myeloid cell infiltration in the TME.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Neoplasias Encefálicas/patologia , Glioma/patologia , Processamento de Imagem Assistida por Computador/métodos , Temozolomida/farmacologia , Microambiente Tumoral , Animais , Apoptose , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Proliferação de Células , Feminino , Glioma/tratamento farmacológico , Glioma/metabolismo , Humanos , Camundongos , Tomografia por Emissão de Pósitrons , Carga Tumoral , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
11.
FEBS J ; 288(6): 1822-1838, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32710568

RESUMO

Head and neck squamous cell carcinoma (HNSCC) is an aggressive and difficult-to-treat cancer entity. Current therapies ultimately aim to activate the mitochondria-controlled (intrinsic) apoptosis pathway, but complex alterations in intracellular signaling cascades and the extracellular microenvironment hamper treatment response. On the one hand, proteins of the BCL-2 family set the threshold for cell death induction and prevent accidental cellular suicide. On the other hand, controlling a cell's readiness to die also determines whether malignant cells are sensitive or resistant to anticancer treatments. Here, we show that HNSCC cells upregulate the proapoptotic BH3-only protein NOXA in response to hyperosmotic stress. Induction of NOXA is sufficient to counteract the antiapoptotic properties of MCL-1 and switches HNSCC cells from dual BCL-XL/MCL-1 protection to exclusive BCL-XL addiction. Hypertonicity-induced functional loss of MCL-1 renders BCL-XL a synthetically lethal target in HNSCC, and inhibition of BCL-XL efficiently kills HNSCC cells that poorly respond to conventional therapies. We identify hypertonicity-induced upregulation of NOXA as link between osmotic pressure in the tumor environment and mitochondrial priming, which could perspectively be exploited to boost efficacy of anticancer drugs.

12.
ESC Heart Fail ; 8(1): 309-316, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33215884

RESUMO

AIMS: We aimed to assess whether expression of whole-blood RNA of sodium proton exchanger 1 (NHE1) and glucose transporter 1 (GLUT1) is associated with COVID-19 infection and outcome in patients presenting to the emergency department with respiratory infections. Furthermore, we investigated NHE1 and GLUT1 expression in the myocardium of deceased COVID-19 patients. METHODS AND RESULTS: Whole-blood quantitative assessment of NHE1 and GLUT1 RNA was performed using quantitative PCR in patients with respiratory infection upon first contact in the emergency department and subsequently stratified by SARS-CoV-2 infection status. Assessment of NHE1 and GLUT1 RNA using PCR was also performed in left ventricular myocardium of deceased COVID-19 patients. NHE1 expression is up-regulated in whole blood of patients with COVID-19 compared with other respiratory infections at first medical contact in the emergency department (control: 0.0021 ± 0.0002, COVID-19: 0.0031 ± 0.0003, P = 0.01). The ratio of GLUT1 to NHE1 is significantly decreased in the blood of COVID-19 patients who are subsequently intubated and/or die (severe disease) compared with patients with moderate disease (moderate disease: 0.497 ± 0.083 vs. severe disease: 0.294 ± 0.0336, P = 0.036). This ratio is even further decreased in the myocardium of patients who deceased from COVID-19 in comparison with the myocardium of non-infected donors. CONCLUSIONS: NHE1 and GLUT1 may be critically involved in the disease progression of SARS-CoV-2 infection. We show here that SARS-CoV-2 infection critically disturbs ion channel expression in the heart. A decreased ratio of GLUT1/NHE1 could potentially serve as a biomarker for disease severity in patients with COVID-19.


Assuntos
COVID-19/metabolismo , Transportador de Glucose Tipo 1/sangue , Trocador 1 de Sódio-Hidrogênio/sangue , COVID-19/sangue , COVID-19/diagnóstico , Estudos de Casos e Controles , Serviço Hospitalar de Emergência , Feminino , Transportador de Glucose Tipo 1/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Valor Preditivo dos Testes , Estudos Prospectivos , RNA Mensageiro/sangue , Índice de Gravidade de Doença , Trocador 1 de Sódio-Hidrogênio/metabolismo
13.
ChemMedChem ; 16(4): 640-645, 2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33205603

RESUMO

Herein we report the design and synthesis of a series of highly selective CCR2 antagonists as 18 F-labeled PET tracers. The derivatives were evaluated extensively for their off-target profile at 48 different targets. The most potent and selective candidate was applied in vivo in a biodistribution study, demonstrating a promising profile for further preclinical development. This compound represents the first potential nonpeptidic PET tracer for the imaging of CCR2 receptors.

14.
Chest ; 159(2): 798-809, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32798522

RESUMO

BACKGROUND: Postoperative major pulmonary complications (MPCs) continue to be leading causes of increased morbidity and death after cardiac surgery. Although various risk factors have been identified, reports on the association between sleep-disordered breathing (SDB) and postoperative MPCs remain inconclusive. RESEARCH QUESTION: What is the incidence of the composite end point postoperative MPCs? What are predictors for postoperative MPCs in patients without SDB, with OSA, and with central sleep apnea (CSA) who undergo cardiac surgery? STUDY DESIGN AND METHODS: In this subanalysis of the ongoing prospective observational study "Impact of Sleep-disordered breathing on Atrial Fibrillation and Perioperative complications in Patients undergoing Coronary Artery Bypass grafting Surgery (CONSIDER AF)," preoperative risk factors for postoperative MPCs were examined in 250 patients who underwent cardiac surgery. Postoperative MPCs (including respiratory failure, acute respiratory distress syndrome, pneumonia, or pulmonary embolism) were registered prospectively within the first seven postoperative days. Presence and type of SDB were assessed the night prior to surgery with the use of portable SDB-monitoring. RESULTS: Patients with SDB experienced significantly more often postoperative MPCs than patients without SDB (24% vs 7%; P < .001). Multivariable logistic regression analysis showed that CSA (OR, 4.68 [95% CI, 1.78-12.26]; P = .002), heart failure (OR, 2.65 [95% CI, 1.11-6.31]; P = .028), and a history of transient ischemic attack or stroke (OR, 2.73 [95% CI, 1.07-6.94]; P = .035) were associated significantly with postoperative MPCs. Compared with patients without MPCs, those with postoperative MPCs had a significantly longer hospital stay (median days, 9 [25th/75th percentile, 7/13] vs 19 [25th/75th percentile, 11/38]; P < .001). INTERPRETATION: Among established risk factors for postoperative MPCs, CSA, heart failure, and history of transient ischemic attack or stroke were associated significantly with postoperative MPCs. Our findings contribute to the identification of patients who are at high-risk for postoperative MPCs. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02877745.

15.
PLoS One ; 15(12): e0243844, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33301470

RESUMO

AIMS: Obstructive sleep apnea (OSA) is a widespread disease with high global socio-economic impact. However, detailed pathomechanisms are still unclear, partly because current animal models of OSA do not simulate spontaneous airway obstruction. We tested whether polytetrafluoroethylene (PTFE) injection into the tongue induces spontaneous obstructive apneas. METHODS AND RESULTS: PTFE (100 µl) was injected into the tongue of 31 male C57BL/6 mice and 28 mice were used as control. Spontaneous apneas and inspiratory flow limitations were recorded by whole-body plethysmography and mRNA expression of the hypoxia marker KDM6A was quantified by qPCR. Left ventricular function was assessed by echocardiography and ventricular CaMKII expression was measured by Western blotting. After PTFE injection, mice showed features of OSA such as significantly increased tongue diameters that were associated with significantly and sustained increased frequencies of inspiratory flow limitations and apneas. Decreased KDM6A mRNA levels indicated chronic hypoxemia. 8 weeks after surgery, PTFE-treated mice showed a significantly reduced left ventricular ejection fraction. Moreover, the severity of diastolic dysfunction (measured as E/e') correlated significantly with the frequency of apneas. Accordingly, CaMKII expression was significantly increased in PTFE mice and correlated significantly with the frequency of apneas. CONCLUSIONS: We describe here the first mouse model of spontaneous inspiratory flow limitations, obstructive apneas, and hypoxia by tongue enlargement due to PTFE injection. These mice develop systolic and diastolic dysfunction and increased CaMKII expression. This mouse model offers great opportunities to investigate the effects of obstructive apneas.


Assuntos
Contração Miocárdica , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/fisiopatologia , Língua/patologia , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/fisiopatologia , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Diástole , Modelos Animais de Doenças , Eletrocardiografia , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inalação , Injeções , Pulmão/patologia , Masculino , Camundongos Endogâmicos C57BL , Miocárdio/patologia , Tamanho do Órgão , Politetrafluoretileno/administração & dosagem , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Apneia Obstrutiva do Sono/diagnóstico por imagem , Sístole , Disfunção Ventricular Esquerda/diagnóstico por imagem
16.
Front Cell Dev Biol ; 8: 592893, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33195263

RESUMO

Brugada syndrome (BrS) is one of the major causes of sudden cardiac death in young people, while the underlying mechanisms are not completely understood. Here, we investigated the pathophysiological phenotypes and mechanisms using induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) from two BrS patients (BrS-CMs) carrying a heterozygous SCN5A mutation p.S1812X. Compared to CMs derived from healthy controls (Ctrl-CMs), BrS-CMs displayed a 50% reduction of I Na density, a 69.5% reduction of NaV1.5 expression, and the impaired localization of NaV1.5 and connexin 43 (Cx43) at the cell surface. BrS-CMs exhibited reduced action potential (AP) upstroke velocity and conduction slowing. The I to in BrS-CMs was significantly augmented, and the I CaL window current probability was increased. Our data indicate that the electrophysiological mechanisms underlying arrhythmia in BrS-CMs may involve both depolarization and repolarization disorders. Cilostazol and milrinone showed dramatic inhibitions of I to in BrS-CMs and alleviated the arrhythmic activity, suggesting their therapeutic potential for BrS patients.

17.
Eur J Heart Fail ; 22(12): 2248-2257, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33017071

RESUMO

AIMS: Coronavirus disease 2019 (COVID-19) is a widespread pandemic with an increased morbidity and mortality, especially for patients with cardiovascular diseases. Angiotensin-converting enzyme 2 (ACE2) has been identified as necessary cell entry point for SARS-CoV-2. Previous animal studies have demonstrated an increased ACE2 expression following treatment with either angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) that have led to a massive precariousness regarding the optimal cardiovascular therapy during this pandemic. METHODS AND RESULTS: We have measured ACE2 mRNA expression using real-time quantitative polymerase chain reaction in atrial biopsies of 81 patients undergoing coronary artery bypass grafting and we compared 62 patients that received ACEi/ARB vs. 19 patients that were not ACEi/ARB-treated. We found atrial ACE2 mRNA expression to be significantly increased in patients treated with an ACEi or an ARB, independent of potential confounding comorbidities. Interestingly, the cardiac ACE2 mRNA expression correlated significantly with the expression in white blood cells of 22 patients encouraging further evaluation if the latter may be used as a surrogate for the former. Similarly, analysis of 18 ventricular biopsies revealed a significant and independent increase in ACE2 mRNA expression in patients with end-stage heart failure that were treated with ACEi/ARB. On the other hand, cardiac unloading with a left ventricular assist device significantly reduced ventricular ACE2 mRNA expression. CONCLUSION: Treatment with ACEi/ARB is independently associated with an increased myocardial ACE2 mRNA expression in patients with coronary artery disease and in patients with end-stage heart failure. Further trials are needed to test whether this association is deleterious for patients with COVID-19, or possibly protective. Nevertheless, haemodynamic factors seem to be equally important for regulation of cardiac ACE2 mRNA expression.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Enzima de Conversão de Angiotensina 2/genética , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , COVID-19 , Leucócitos/metabolismo , Miocárdio/metabolismo , RNA Mensageiro/metabolismo , Receptores de Coronavírus/genética , Idoso , Ponte de Artéria Coronária , Doença da Artéria Coronariana/cirurgia , Feminino , Insuficiência Cardíaca/terapia , Coração Auxiliar , Hemodinâmica , Humanos , Masculino , Pessoa de Meia-Idade , SARS-CoV-2
18.
J Vis Exp ; (163)2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32955493

RESUMO

We describe a method for two-dimensional (2D) visualization and quantification of the distribution of labile (i.e., reversibly adsorbed) inorganic nutrient (e.g., P, Fe, Mn) and contaminant (e.g., As, Cd, Pb) solute species in the soil adjacent to plant roots (the 'rhizosphere') at sub-millimeter (~100 µm) spatial resolution. The method combines sink-based solute sampling by the diffusive gradients in thin films (DGT) technique with spatially resolved chemical analysis by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). The DGT technique is based on thin hydrogels with homogeneously distributed analyte-selective binding phases. The variety of available binding phases allows for the preparation of different DGT gel types following simple gel fabrication procedures. For DGT gel deployment in the rhizosphere, plants are grown in flat, transparent growth containers (rhizotrons), which enable minimal invasive access to a soil-grown root system. After a pre-growth period, DGT gels are applied to selected regions of interest for in situ solute sampling in the rhizosphere. Afterwards, DGT gels are retrieved and prepared for subsequent chemical analysis of the bound solutes using LA-ICP-MS line-scan imaging. Application of internal normalization using 13C and external calibration using matrix-matched gel standards further allows for the quantification of the 2D solute fluxes. This method is unique in its capability to generate quantitative, sub-mm scale 2D images of multi-element solute fluxes in soil-plant environments, exceeding the achievable spatial resolution of other methods for measuring solute gradients in the rhizosphere substantially. We present the application and evaluation of the method for imaging multiple cationic and anionic solute species in the rhizosphere of terrestrial plants and highlight the possibility of combining this method with complementary solute imaging techniques.


Assuntos
Nutrientes/química , Plantas/química , Solo/química
19.
ESC Heart Fail ; 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32946200

RESUMO

AIMS: Recent clinical trials have proven gliflozins to be cardioprotective in diabetic and non-diabetic patients. However, the underlying mechanisms are incompletely understood. A potential inhibition of cardiac Na+ /H+ exchanger 1 (NHE1) has been suggested in animal models. We investigated the effect of empagliflozin on NHE1 activity in human atrial cardiomyocytes. METHODS AND RESULTS: Expression of NHE1 was assessed in human atrial and ventricular tissue via western blotting. NHE activity was measured as the maximal slope of pH recovery after NH4 + pulse in isolated carboxy-seminaphtarhodafluor 1 (SNARF1)-acetoxymethylester-loaded murine ventricular and human atrial cardiomyocytes. NHE1 is abundantly expressed in human atrial and ventricular tissue. Interestingly, compared with patients without heart failure (HF), atrial NHE1 expression was significantly increased in patients with HF with preserved ejection fraction and atrial fibrillation. The largest increase in atrial and ventricular NHE1 expression, however, was observed in patients with end-stage HF undergoing heart transplantation. Importantly, acute exposure to empagliflozin (1 µmol/L, 10 min) significantly inhibited NHE activity to a similar extent in human atrial myocytes and mouse ventricular myocytes. This inhibition was also achieved by incubation with the well-described selective NHE inhibitor cariporide (10 µmol/L, 10 min). CONCLUSIONS: This is the first study systematically analysing NHE1 expression in human atrial and ventricular myocardium of HF patients. We show that empagliflozin inhibits NHE in human cardiomyocytes. The extent of NHE inhibition was comparable with cariporide and may potentially contribute to the improved outcome of patients in clinical trials.

20.
BMC Musculoskelet Disord ; 21(1): 568, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32825813

RESUMO

BACKGROUND: Foehn describes a wind which occurs in areas with close proximity to mountains. The presence of foehn wind is associated with worsening health conditions. This study analyzes the correlation between a foehn typical circulation and the incidence for suffering a severe trauma. METHODS: This is a retrospective, multicentre observational register study. The years from 2013 to 2016 were analyzed for the presence of foehn winds. A logistic regression analysis with the number of daily admitted trauma patients as the primary target value was performed in dependence of foehn winds. Southern Bavaria is a typical foehn wind region. Individuals were treated in 37 hospitals of Southern Bavaria which participate in the TraumaRegister DGU®, an international register that includes all severe trauma patients, mainly in Germany. We analyzed patients with an Injury Severity Score (ISS) of at least nine with admission to intensive care units or prior death in the emergency room. RESULTS: 6215 patients were enrolled in this study. A foehn-typical circulation was present on 65 days (4.5%). 301 patients (5%) suffered a trauma with an ISS ≥ 9 on a foehn day. The mean ISS was 20.2 (9-75). On average, 4.3 patients (0-15 patients) were admitted on a daily basis due to a severe trauma. The multivariate regression analysis revealed a daily increase of 0.87 individuals (p = 0.004; 95% CI 0.23-1.47) on foehn days. During spring 1.07 patients (p = < 0.001; 95% CI 0.72-1.42), in summer 1.98 patients (p = < 0.001; 95% CI 1.63-2.32), in fall 0.63 (p = < 0.001; 95% CI 0.28-0.97) and on Saturdays, 0.59 patients (p = < 0.001; 95% CI 0.24-0.93) were additionally admitted due to severe trauma. CONCLUSION: Foehn winds are significantly associated with severe trauma in trauma centers of the TraumaNetzwerk DGU®.


Assuntos
Traumatismo Múltiplo , Vento , Alemanha/epidemiologia , Humanos , Incidência , Escala de Gravidade do Ferimento , Sistema de Registros , Estudos Retrospectivos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...