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1.
ESC Heart Fail ; 2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34850596

RESUMO

AIMS: Heart failure (HF) and atrial fibrillation (AF) frequently coexist and are both associated with increased levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP). It is known that AF impairs the diagnostic accuracy of NT-proBNP for HF. The aim of the present study was to compare the diagnostic and predictive accuracy of NT-proBNP for HF and AF in stable outpatients with cardiovascular risk factors. METHODS AND RESULTS: Data were obtained from the DIAST-CHF trial, a prospective cohort study that recruited individuals with cardiovascular risk factors and followed them up for 12 years. Data were validated in three independent population-based cohorts using the same inclusion/exclusion criteria: LIFE-Adult (n = 2869), SHIP (n = 2013), and SHIP-TREND (n = 2408). Serum levels of NT-proBNP were taken once at baseline. The DIAST-CHF study enrolled 1727 study participants (47.7% female, mean age 66.9 ± 8.1 years). At baseline, patients without AF or HF (n = 1375) had a median NT-proBNP of 94 pg/mL (interquartile range 51;181). In patients with AF (n = 93), NT-proBNP amounted to 667 (215;1130) pg/mL. It was significantly higher than in the first group (P < 0.001) and compared with those with only HF [n = 201; 158 (66;363) pg/mL; P < 0.001]. The highest levels of NT-proBNP [868 (213;1397) pg/mL] were measured in patients with concomitant HF and AF (n = 58; P < 0.001 vs. control and vs. HF, P = 1.0 vs. AF). In patients with AF, NT-proBNP levels did not differ between those with HF and preserved ejection fraction (EF) > 50% [n = 38; 603 (175;1070) pg/mL] and those without HF (P = 1.0). Receiver-operating characteristic curves of NT-proBNP showed a similar area under the curve (AUC) for the detection of AF at baseline (0.84, 95% CI [0.79-0.88]) and for HF with EF < 50% (0.78 [0.72-0.85]; P = 0.18). The AUC for HF with EF > 50% was significantly lower (0.61 [0.56-0.65]) than for AF (P = 0.001). During follow-up, AF was newly diagnosed in 157 (9.1%) and HF in 141 (9.6%) study participants. NT-proBNP was a better predictor of incident AF during the first 2 years (AUC: 0.79 [0.75-0.83]) than of newly diagnosed HF (0.59 [0.55-0.63]; P < 0.001). Data were validated in three independent population-based cohorts (LIFE-Adult, n = 2869; SHIP, n = 2013; and SHIP-TREND, n = 2408). CONCLUSIONS: In stable outpatients, NT-proBNP is a better marker for prevalent and incident AF than for HF. In AF patients, the diagnostic value of NT-proBNP for HF with EF > 50% is very limited.

2.
Cells ; 10(12)2021 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-34944024

RESUMO

BACKGROUND: Protease-activated receptor 1 (PAR1) and toll-like receptors (TLRs) are inflammatory mediators contributing to atherogenesis and atherothrombosis. Vorapaxar, which selectively antagonizes PAR1-signaling, is an approved, add-on antiplatelet therapy for secondary prevention. The non-hemostatic, platelet-independent, pleiotropic effects of vorapaxar have not yet been studied. METHODS AND RESULTS: Cellular targets of PAR1 signaling in the vasculature were identified in three patient cohorts with atherosclerotic disease. Evaluation of plasma biomarkers (n = 190) and gene expression in endomyocardial biopsies (EMBs) (n = 12) revealed that PAR1 expression correlated with endothelial activation and vascular inflammation. PAR1 colocalized with TLR2/4 in human carotid plaques and was associated with TLR2/4 gene transcription in EMBs. In addition, vorapaxar reduced atherosclerotic lesion size in apolipoprotein E-knock out (ApoEko) mice. This reduction was associated with reduced expression of vascular adhesion molecules and TLR2/4 presence, both in isolated murine endothelial cells and the aorta. Thrombin-induced uptake of oxLDL was augmented by additional TLR2/4 stimulation and abrogated by vorapaxar. Plaque-infiltrating pro-inflammatory cells were reduced in vorapaxar-treated ApoEko mice. A shift toward M2 macrophages paralleled a decreased transcription of pro-inflammatory cytokines and chemokines. CONCLUSIONS: PAR1 inhibition with vorapaxar may be effective in reducing residual thrombo-inflammatory event risk in patients with atherosclerosis independent of its effect on platelets.

3.
J Am Heart Assoc ; 10(22): e021116, 2021 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-34743534

RESUMO

Background Lower cardiorespiratory fitness (CRF) is associated with an increased risk for cardiovascular disease. However, very little information is available about the association between lower CRF and right ventricular (RV) remodeling. We investigated the relationship between CRF and RV structure and function in a large, aging, and largely sedentary adult population-based cohort. Methods and Results We used cross-sectional data of 2844 subjects (1486 women; median age, 51 years; interquartile range, 40-62 years) from the population-based cohort SHIP (Study of Health in Pomerania) with echocardiography, of which 941 also had cardiac magnetic resonance imaging. We analyzed the associations of peak oxygen uptake with RV parameters determined by both imaging techniques using multivariable-adjusted linear regression models. In echocardiography, a 1 L/min lower peak oxygen uptake was associated with a 1.18 mm (95% CI, 0.66-1.71; P<0.001) smaller RV end-diastolic diameter and a 1.41 mm (95% CI, 0.90-1.92; P<0.001) narrower RV end-diastolic outflow tract diameter. Similarly, using cardiac magnetic resonance imaging measurements, a 1 L/min lower peak oxygen uptake was associated with a 23.5 mL (95% CI, 18.7-28.4; P<0.001) smaller RV end-diastolic volume, a 13.0 mL (95% CI, 9.81-16.2; P<0.001) lower RV end-systolic volume, and a 10.7 mL/beat (95% CI, 8.10-13.3; P<0.001) lower RV stroke volume. Conclusions Our results indicate a significant association between CRF and RV remodeling. Lower CRF was associated with smaller RV chamber and lower RV systolic function, stroke volume, and cardiac output.

4.
Int J Public Health ; 66: 633909, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34744587

RESUMO

Objectives: An inverse relationship between education and cardiovascular risk has been described, however, the combined association of education, income, and neighborhood socioeconomic status with macrovascular disease is less clear. The aim of this study was to evaluate the association of educational level, equivalent household income and area deprivation with macrovascular disease in Germany. Methods: Cross-sectional data from two representative German population-based studies, SHIP-TREND (n = 3,731) and KORA-F4 (n = 2,870), were analyzed. Multivariable logistic regression models were applied to estimate odds ratios and 95% confidence intervals for the association between socioeconomic determinants and macrovascular disease (defined as self-reported myocardial infarction or stroke). Results: The study showed a higher odds of prevalent macrovascular disease in men with low and middle educational level compared to men with high education. Area deprivation and equivalent income were not related to myocardial infarction or stroke in any of the models. Conclusion: Educational level, but not income or area deprivation, is significantly related to the macrovascular disease in men. Effective prevention of macrovascular disease should therefore start with investing in individual education.


Assuntos
Escolaridade , Doenças Vasculares , Estudos de Coortes , Estudos Transversais , Alemanha/epidemiologia , Humanos , Renda/estatística & dados numéricos , Masculino , Áreas de Pobreza , Fatores de Risco , Doenças Vasculares/epidemiologia
5.
Cardiovasc Diabetol ; 20(1): 223, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34781939

RESUMO

BACKGROUND: Biomarkers may contribute to improved cardiovascular risk estimation. Glycated hemoglobin A1c (HbA1c) is used to monitor the quality of diabetes treatment. Its strength of association with cardiovascular outcomes in the general population remains uncertain. This study aims to assess the association of HbA1c with cardiovascular outcomes in the general population. METHODS: Data from six prospective population-based cohort studies across Europe comprising 36,180 participants were analyzed. HbA1c was evaluated in conjunction with classical cardiovascular risk factors (CVRFs) for association with cardiovascular mortality, cardiovascular disease (CVD) incidence, and overall mortality in subjects without diabetes (N = 32,496) and with diabetes (N = 3684). RESULTS: Kaplan-Meier curves showed higher event rates with increasing HbA1c levels (log-rank-test: p < 0.001). Cox regression analysis revealed significant associations between HbA1c (in mmol/mol) in the total study population and the examined outcomes. Thus, a hazard ratio (HR) of 1.16 (95% confidence interval (CI) 1.02-1.31, p = 0.02) for cardiovascular mortality, 1.13 (95% CI 1.03-1.24, p = 0.01) for CVD incidence, and 1.09 (95% CI 1.02-1.17, p = 0.01) for overall mortality was observed per 10 mmol/mol increase in HbA1c. The association with CVD incidence and overall mortality was also observed in study participants without diabetes with increased HbA1c levels (HR 1.12; 95% CI 1.01-1.25, p = 0.04) and HR 1.10; 95% CI 1.01-1.20, p = 0.02) respectively. HbA1c cut-off values of 39.9 mmol/mol (5.8%), 36.6 mmol/mol (5.5%), and 38.8 mmol/mol (5.7%) for cardiovascular mortality, CVD incidence, and overall mortality, showed also an increased risk. CONCLUSIONS: HbA1c is independently associated with cardiovascular mortality, overall mortality and cardiovascular disease in the general European population. A mostly monotonically increasing relationship was observed between HbA1c levels and outcomes. Elevated HbA1c levels were associated with cardiovascular disease incidence and overall mortality in participants without diabetes underlining the importance of HbA1c levels in the overall population.

6.
J Am Heart Assoc ; 10(17): e020994, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34465186

RESUMO

Background Hypertrophy of the left ventricle (LV) has recently been associated with adverse changes of brain structure in older adults, notably increased burden of white matter hyperintensities (WMHs). Whether greater LV size or mass is also related to WMH burden in middle-aged adults is currently unclear. In addition, its relation with alterations in cortical thickness (CT) has not been studied to date. Methods and Results Data from 1602 participants of the population-based SHIP (Study of Health in Pomerania) with LV ejection fraction >40% and no history of myocardial infarction were included (aged 21-82 years; median age, 49 years; 53% women). Participants underwent both echocardiography and magnetic resonance imaging of the head. Imaging markers of brain aging (ie, CT and WMH volume) were determined from magnetic resonance imaging scans. LV mass and diameter were associated with lower global CT and greater WMH volume, while adjusting for age, sex, body height, fat-free body mass, and intracranial volume. Moreover, thicknesses of the interventricular septum and posterior wall were also associated with lower global CT. These associations could not be explained by cardiovascular risk factors (including hypertension), inflammatory markers, or sociodemographic factors. Regional analyses showed distinct spatial patterns of lower CT in association with LV diameter and posterior wall thickness. Conclusions LV diameter and mass are associated with lower global and regional CT as well as greater WMH burden in the general population. These findings highlight the brain structural underpinnings of the associations of LV hypertrophy with cognitive decline and dementia.

7.
Artigo em Inglês | MEDLINE | ID: mdl-34472725

RESUMO

BACKGROUND: Septic cardiomyopathy worsens the prognosis of critically ill patients. Clinical data suggest that interleukin-1ß (IL-1ß), activated by the NLRP3 inflammasome, compromises cardiac function. Whether or not deleting Nlrp3 would prevent cardiac atrophy and improve diastolic cardiac function in sepsis was unclear. Here, we investigated the role of NLRP3/IL-1ß in sepsis-induced cardiomyopathy and cardiac atrophy. METHODS: Male Nlrp3 knockout (KO) and wild-type (WT) mice were exposed to polymicrobial sepsis by caecal ligation and puncture (CLP) surgery (KO, n = 27; WT, n = 33) to induce septic cardiomyopathy. Sham-treated mice served as controls (KO, n = 11; WT, n = 16). Heart weights and morphology, echocardiography and analyses of gene and protein expression were used to evaluate septic cardiomyopathy and cardiac atrophy. IL-1ß effects on primary and immortalized cardiomyocytes were investigated by morphological and molecular analyses. IonOptix and real-time deformability cytometry (RT-DC) analysis were used to investigate functional and mechanical effects of IL-1ß on cardiomyocytes. RESULTS: Heart morphology and echocardiography revealed preserved systolic (stroke volume: WT sham vs. WT CLP: 33.1 ± 7.2 µL vs. 24.6 ± 8.7 µL, P < 0.05; KO sham vs. KO CLP: 28.3 ± 8.1 µL vs. 29.9 ± 9.9 µL, n.s.; P < 0.05 vs. WT CLP) and diastolic (peak E wave velocity: WT sham vs. WT CLP: 750 ± 132 vs. 522 ± 200 mm/s, P < 0.001; KO sham vs. KO CLP: 709 ± 152 vs. 639 ± 165 mm/s, n.s.; P < 0.05 vs. WT CLP) cardiac function and attenuated cardiac (heart weight-tibia length ratio: WT CLP vs. WT sham: -26.6%, P < 0.05; KO CLP vs. KO sham: -3.3%, n.s.; P < 0.05 vs. WT CLP) and cardiomyocyte atrophy in KO mice during sepsis. IonOptix measurements showed that IL-1ß decreased contractility (cell shortening: IL-1ß: -15.4 ± 2.3%, P < 0.001 vs. vehicle, IL-1RA: -6.1 ± 3.3%, P < 0.05 vs. IL-1ß) and relaxation of adult rat ventricular cardiomyocytes (time-to-50% relengthening: IL-1ß: 2071 ± 225 ms, P < 0.001 vs. vehicle, IL-1RA: 564 ± 247 ms, P < 0.001 vs. IL-1ß), which was attenuated by an IL-1 receptor antagonist (IL-1RA). RT-DC analysis indicated that IL-1ß reduced cardiomyocyte size (P < 0.001) and deformation (P < 0.05). RNA sequencing showed that genes involved in NF-κB signalling, autophagy and lysosomal protein degradation were enriched in hearts of septic WT but not in septic KO mice. Western blotting and qPCR disclosed that IL-1ß activated NF-κB and its target genes, caused atrophy and decreased myosin protein in myocytes, which was accompanied by an increased autophagy gene expression. These effects were attenuated by IL-1RA. CONCLUSIONS: IL-1ß causes atrophy, impairs contractility and relaxation and decreases deformation of cardiomyocytes. Because NLRP3/IL-1ß pathway inhibition attenuates cardiac atrophy and cardiomyopathy in sepsis, it could be useful to prevent septic cardiomyopathy.

8.
ESC Heart Fail ; 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34480422

RESUMO

AIMS: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. METHODS AND RESULTS: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 × 10-8 under an additive genetic model. CONCLUSIONS: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.

9.
Pneumologie ; 2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34341979

RESUMO

OBJECTIVES: Prior studies have investigated possible links between blood pressure, antihypertensive medication, especially beta-blockers and impairment of lung function. The aim of our study was to investigate an association between blood pressure, antihypertensive medication, focusing on beta-blockers, and its influence on lung function parameters in our adult population. METHODS: From the two analysed cohorts of the population-based Study of Health in Pomerania (SHIP-1 and SHIP-TREND), pooled data for interview-based information, lung function variables including bodyplethysmography and blood pressure variables were used to perform adjusted linear regression analyses. Association analyses were conducted for the pooled population. RESULTS: Within the whole pooled population we found some minor statistically significant interrelations in the multivariate analyses for blood pressure and lung function parameters. Statistical correlation between lung function and blood pressure were significant but too weak to be deemed clinically relevant.We also found interrelations between lung function and use of beta-blocker medication. Within the subgroup of individuals with antihypertensive medication containing beta-blockers compared to the reference group we found lower dynamic and static volumes e. g. for FEV1 (-70 ml), FVC (-90 ml), a reduction of TLC (-130 ml) and ITGV (-100 ml), however we did not find an increase in airway resistance (Rtot). CONCLUSION: Based on the data of SHIP-1 and SHIP TREND our results confirm a minor association between blood pressure and lung function. More importantly, we have seen a significant decrease of lung volumes for hypertensive patients with beta- blocker medication as described in literature before. To the best of our knowledge, we are the first to examine the interrelation between blood pressure, medication and lung function in an epidemiological study using data of spirometry, body plethysmography and CO transfer.

10.
N Engl J Med ; 2021 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-34459570

RESUMO

BACKGROUND: Myocardial infarction is a frequent cause of out-of-hospital cardiac arrest. However, the benefits of early coronary angiography and revascularization in resuscitated patients without electrocardiographic evidence of ST-segment elevation are unclear. METHODS: In this multicenter trial, we randomly assigned 554 patients with successfully resuscitated out-of-hospital cardiac arrest of possible coronary origin to undergo either immediate coronary angiography (immediate-angiography group) or initial intensive care assessment with delayed or selective angiography (delayed-angiography group). All the patients had no evidence of ST-segment elevation on postresuscitation electrocardiography. The primary end point was death from any cause at 30 days. Secondary end points included a composite of death from any cause or severe neurologic deficit at 30 days. RESULTS: A total of 530 of 554 patients (95.7%) were included in the primary analysis. At 30 days, 143 of 265 patients (54.0%) in the immediate-angiography group and 122 of 265 patients (46.0%) in the delayed-angiography group had died (hazard ratio, 1.28; 95% confidence interval [CI], 1.00 to 1.63; P = 0.06). The composite of death or severe neurologic deficit occurred more frequently in the immediate-angiography group (in 164 of 255 patients [64.3%]) than in the delayed-angiography group (in 138 of 248 patients [55.6%]), for a relative risk of 1.16 (95% CI, 1.00 to 1.34). Values for peak troponin release and for the incidence of moderate or severe bleeding, stroke, and renal-replacement therapy were similar in the two groups. CONCLUSIONS: Among patients with resuscitated out-of-hospital cardiac arrest without ST-segment elevation, a strategy of performing immediate angiography provided no benefit over a delayed or selective strategy with respect to the 30-day risk of death from any cause. (Funded by the German Center for Cardiovascular Research; TOMAHAWK ClinicalTrials.gov number, NCT02750462.).

11.
Int J Mol Sci ; 22(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199303

RESUMO

The main purpose of new stent technologies is to overcome unfavorable material-related incompatibilities by producing bio- and hemo-compatible polymers with anti-inflammatory and anti-thrombogenic properties. In this context, wettability is an important surface property, which has a major impact on the biological response of blood cells. However, the influence of local hemodynamic changes also influences blood cell activation. Therefore, we investigated biodegradable polymers with different wettability to identify possible aspects for a better prediction of blood compatibility. We applied shear rates of 100 s-1 and 1500 s-1 and assessed platelet and monocyte activation as well as the formation of CD62P+ monocyte-bound platelets via flow cytometry. Aggregation of circulating platelets induced by collagen was assessed by light transmission aggregometry. Via live cell imaging, leukocytes were tracked on biomaterial surfaces to assess their average velocity. Monocyte adhesion on biomaterials was determined by fluorescence microscopy. In response to low shear rates of 100 s-1, activation of circulating platelets and monocytes as well as the formation of CD62P+ monocyte-bound platelets corresponded to the wettability of the underlying material with the most favorable conditions on more hydrophilic surfaces. Under high shear rates, however, blood compatibility cannot only be predicted by the concept of wettability. We assume that the mechanisms of blood cell-polymer interactions do not allow for a rule-of-thumb prediction of the blood compatibility of a material, which makes extensive in vitro testing mandatory.


Assuntos
Plaquetas/citologia , Comunicação Celular/efeitos dos fármacos , Monócitos/citologia , Monócitos/efeitos dos fármacos , Poliésteres/farmacologia , Plaquetas/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Humanos , Agregação Plaquetária/efeitos dos fármacos , Água , Molhabilidade
12.
J Inflamm Res ; 14: 2883-2896, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34234513

RESUMO

Purpose: Periodontitis is an inflammatory disease of the oral cavity with an alarmingly high prevalence within the adult population. The signaling lipid sphingosine-1-phosphate (S1P) plays a crucial role in inflammatory and immunomodulatory responses. In addition to cardiovascular disease, sepsis and tumor entities, S1P has been recently identified as both mediator and biomarker in osteoporosis. We hypothesized that S1P may play a role in periodontitis as an inflammation-prone bone destructive disorder. The goal of our study was to evaluate associations between periodontitis and S1P serum concentrations in the Study of Health in Pomerania (SHIP)-Trend cohort. In addition, we investigated the expression of S1P metabolizing enzymes in inflamed gingival tissue. Patients and Methods: We analyzed data from 3371 participants (51.6% women) of the SHIP-Trend cohort. Periodontal parameters and baseline characteristics were assessed. Serum S1P was measured by liquid chromatography tandem mass spectrometry. The expression of S1P metabolizing enzymes was determined by immunofluorescence staining of human gingival tissue. Results: S1P serum concentrations were significantly increased in subjects with both moderate and severe periodontitis, assessed as probing depth and clinical attachment loss. In contrast, no significant association of S1P was seen with caries variables (number and percentage of decayed or filled surfaces). S1P concentrations significantly increased with increasing high-sensitivity C-reactive protein (hs-CRP) levels. Interestingly, inflamed compared to normal human gingival tissue exhibited elevated expression levels of the S1P-generating enzyme sphingosine kinase 1 (SphK1). Conclusion: We report an intriguingly significant association of various periodontal parameters with serum levels of the inflammatory lipid mediator S1P. Our data point towards a key role of S1P during periodontitis pathology. Modulation of local S1P levels or its signaling properties may represent a potential future therapeutic strategy to prevent or to retard periodontitis progression and possibly reduce periodontitis-related tooth loss.

13.
BMC Mol Cell Biol ; 22(1): 32, 2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34078283

RESUMO

BACKGROUND: Endothelial healing after deployment of cardiovascular devices is particularly important in the context of clinical outcome. It is therefore of great interest to develop tools for a precise prediction of endothelial growth after injury in the process of implant deployment. For experimental investigation of re-endothelialization in vitro cell migration assays are routinely used. However, semi-automatic analyses of live cell images are often based on gray value distributions and are as such limited by image quality and user dependence. The rise of deep learning algorithms offers promising opportunities for application in medical image analysis. Here, we present an intelligent cell detection (iCD) approach for comprehensive assay analysis to obtain essential characteristics on cell and population scale. RESULTS: In an in vitro wound healing assay, we compared conventional analysis methods with our iCD approach. Therefore we determined cell density and cell velocity on cell scale and the movement of the cell layer as well as the gap closure between two cell monolayers on population scale. Our data demonstrate that cell density analysis based on deep learning algorithms is superior to an adaptive threshold method regarding robustness against image distortion. In addition, results on cell scale obtained with iCD are in agreement with manually velocity detection, while conventional methods, such as Cell Image Velocimetry (CIV), underestimate cell velocity by a factor of 0.5. Further, we found that iCD analysis of the monolayer movement gave results just as well as manual freehand detection, while conventional methods again shows more frayed leading edge detection compared to manual detection. Analysis of monolayer edge protrusion by ICD also produced results, which are close to manual estimation with an relative error of 11.7%. In comparison, the conventional Canny method gave a relative error of 76.4%. CONCLUSION: The results of our experiments indicate that deep learning algorithms such as our iCD have the ability to outperform conventional methods in the field of wound healing analysis. The combined analysis on cell and population scale using iCD is very well suited for timesaving and high quality wound healing analysis enabling the research community to gain detailed understanding of endothelial movement.


Assuntos
Rastreamento de Células/métodos , Aprendizado Profundo , Cicatrização , Endotélio Vascular/citologia , Humanos
14.
Sci Rep ; 11(1): 10547, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34006958

RESUMO

Previous studies on the association between thyroid function and body composition are conflicting and showed strong differences across age groups. Our aim was to clarify age-specific associations of serum thyroid-stimulating hormone (TSH) levels with markers of body composition including body mass index (BMI), waist circumference, fat mass (FM), fat-free mass (FFM) and body cell mass (BCM). We used data from two independent population-based cohorts within the framework of the Study of Health in Pomerania. The study population included 5656 individuals aged 20 to 90 years. Markers of body composition were measured by bioelectrical impedance analysis. Serum TSH levels were significantly positively associated with BMI (ß = 0.16; 95% confidence interval [CI]: 0.06 to 0.27), waist circumference (ß = 0.35; 95% CI: 0.08 to 0.62) and FM (ß = 0.32; 95% CI: 0.12 to 0.52), but not with FFM and BCM. Interaction analysis revealed positive associations of serum TSH levels with BMI, waist circumference, FM, FFM and BCM in individuals older than 60 years, while no such associations were observed in younger individuals. We demonstrated that lower serum TSH levels were accompanied with lower values of BMI, waist circumference, FM, FFM, and BCM in the elderly, while no such associations were observed in younger individuals.


Assuntos
Composição Corporal , Tireotropina/sangue , Adulto , Idoso , Índice de Massa Corporal , Estudos Transversais , Impedância Elétrica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Circunferência da Cintura
15.
Front Physiol ; 12: 614878, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995116

RESUMO

The ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway (ALP) are the main proteolytic systems involved in cellular homeostasis. Since cardiomyocytes, as terminally differentiated cells, lack the ability to share damaged proteins with their daughter cells, they are especially reliant on these protein degradation systems for their proper function. Alterations of the UPS and ALP have been reported in a wide range of cardiac diseases, including cardiomyopathies. In this study, we determined whether the UPS and ALP are altered in a mouse model of eccentric left ventricular (LV) hypertrophy expressing both cyclin T1 and Gαq under the control of the cardiac-specific α-myosin heavy chain promoter (double transgenic; DTG). Compared to wild-type (WT) littermates, DTG mice showed higher end-diastolic (ED) LV wall thicknesses and diameter with preserved ejection fraction (EF). The cardiomyopathic phenotype was further confirmed by an upregulation of the fetal gene program and genes associated with fibrosis as well as a downregulation of genes involved in Ca2+ handling. Likewise, higher NT-proBNP levels were detected in DTG mice. Investigation of the UPS showed elevated steady-state levels of (poly)ubiquitinated proteins without alterations of all proteasomal activities in DTG mice. Evaluation of ALP key marker revealed a mixed pattern with higher protein levels of microtubule-associated protein 1 light chain 3 beta (LC3)-I and lysosomal-associated membrane protein-2, lower protein levels of beclin-1 and FYVE and coiled-coil domain-containing protein 1 (FYCO1) and unchanged protein levels of p62/SQSTM1 in DTG mice when compared to WT. At transcriptional level, a > 1.2-fold expression was observed for Erbb2, Hdac6, Lamp2, Nrg1, and Sqstm1, while a < 0.8-fold expression was revealed for Fyco1 in DTG mice. The results related to the ALP suggested overall a repression of the ALP during the initiation process, but an induction of the ALP at the level of autophagosome-lysosome fusion and the delivery of ubiquitinated cargo to the ALP for degradation.

16.
Cancer Immunol Immunother ; 70(12): 3405-3419, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33870463

RESUMO

BACKGROUND: Mlh1-knock-out-driven mismatch-repair-deficient (dMMR) tumors can be targeted immunologically. By applying therapeutic tumor vaccination, tumor growth is delayed but escape mechanisms evolve, including upregulation of immune-checkpoint molecules (LAG-3, PD-L1). To counteract immune escape, we investigated the therapeutic activity of a combined tumor vaccine-immune-checkpoint inhibitor therapy using α-PD-L1. DESIGN: In this trial, Mlh1-knock-out mice with established gastrointestinal tumors received single or thrice injections of α-PD-L1 monoclonal antibody clone 6E11 (2.5 mg/kg bw, q2w, i.v.) either alone or in combination with the vaccine. Longitudinal flow cytometry and PET/CT imaging studies were followed by ex vivo functional immunological and gene expression assays. RESULTS: 6E11 monotherapy slightly increased median overall survival (mOS: 6.0 weeks vs. control 4.0 weeks). Increasing the number of injections (n = 3) improved therapy outcome (mOS: 9.2 weeks) and was significantly boosted by combining 6E11 with the vaccine (mOS: 19.4 weeks vs. 10.2 weeks vaccine monotherapy). Accompanying PET/CT imaging confirmed treatment-induced tumor growth control, with the strongest inhibition in the combination group. Three mice (30%) achieved a complete remission and showed long-term survival. Decreased levels of circulating splenic and intratumoral myeloid-derived suppressor cells (MDSC) and decreased numbers of immune-checkpoint-expressing splenic T cells (LAG-3, CTLA-4) accompanied therapeutic effects. Gene expression and protein analysis of residual tumors revealed downregulation of PI3K/Akt/Wnt-and TGF-signaling, leading to T cell infiltration, reduced numbers of macrophages, neutrophils and MDSC. CONCLUSIONS: By successful uncoupling of the PD-1/PD-L1 axis, we provide further evidence for the safe and successful application of immunotherapies to combat dMMR-driven malignancies that warrants further investigation.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Vacinas Anticâncer/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Gastrointestinais/tratamento farmacológico , Inibidores de Checkpoint Imunológico/farmacologia , Síndromes Neoplásicas Hereditárias/tratamento farmacológico , Vacinas Combinadas/farmacologia , Animais , Antígeno B7-H1/metabolismo , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Neoplasias Gastrointestinais/metabolismo , Imunoterapia/métodos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/metabolismo , Camundongos , Camundongos Knockout , Proteína 1 Homóloga a MutL/metabolismo , Células Supressoras Mieloides/metabolismo , Síndromes Neoplásicas Hereditárias/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos
17.
Int J Mol Sci ; 22(4)2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33670449

RESUMO

With more than 25 million people affected, heart failure (HF) is a global threat. As energy production pathways are known to play a pivotal role in HF, we sought here to identify key metabolic changes in ischemic- and non-ischemic HF by using a multi-OMICS approach. Serum metabolites and mRNAseq and epigenetic DNA methylation profiles were analyzed from blood and left ventricular heart biopsy specimens of the same individuals. In total we collected serum from n = 82 patients with Dilated Cardiomyopathy (DCM) and n = 51 controls in the screening stage. We identified several metabolites involved in glycolysis and citric acid cycle to be elevated up to 5.7-fold in DCM (p = 1.7 × 10-6). Interestingly, cardiac mRNA and epigenetic changes of genes encoding rate-limiting enzymes of these pathways could also be found and validated in our second stage of metabolite assessment in n = 52 DCM, n = 39 ischemic HF and n = 57 controls. In conclusion, we identified a new set of metabolomic biomarkers for HF. We were able to identify underlying biological cascades that potentially represent suitable intervention targets.


Assuntos
Biomarcadores/metabolismo , Cardiomiopatia Dilatada/genética , Epigenômica/métodos , Perfilação da Expressão Gênica/métodos , Insuficiência Cardíaca/genética , Metabolômica/métodos , Adulto , Idoso , Biomarcadores/sangue , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/metabolismo , Estudos de Coortes , Epigênese Genética , Feminino , Glicólise/genética , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Componente Principal
18.
Liver Int ; 41(8): 1841-1852, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33683798

RESUMO

BACKGROUND: Iron status has been linked with impaired glucose metabolism (IGM), type 2 diabetes mellitus (T2DM) and the metabolic syndrome (MetS), but the role of hepatic steatosis or iron overload on these associations remains uncertain. METHODS: We analysed data from 2310 participants without known T2DM of the population-based Study of Health in Pomerania (SHIP-TREND, Germany) through logistic regression models. We tested additive and multiplicative interactions between ferritin and hepatic steatosis or iron overload. RESULTS: Serum ferritin was positively associated with IGM (OR per 100 µg/L: 1.11 [1.01, 1.23]), T2DM (OR per 100 µg/L: 1.20 [1.06, 1.36]) and MetS (OR per 100 µg/L: 1.11 [1.02, 1.20]) in the total population as well as in participants without hepatic iron overload. However, the synergistic effect of higher ferritin concentrations and hepatic iron overload showed stronger associations with IGM and T2DM. Similarly, while ferritin was positively associated with T2DM and MetS even in the absence of hepatic steatosis, the synergistic effect of higher ferritin concentrations and hepatic steatosis showed stronger associations with IGM, T2DM and MetS. Transferrin was associated with isolated impaired glucose tolerance but not with T2DM and MetS. CONCLUSIONS: Our study suggests that ferritin may be associated with glucose metabolism disorders and MetS even in people without hepatic steatosis or iron overload. However, in individuals with higher ferritin concentrations, the presence of hepatic steatosis may indicate stronger risk for glucose metabolism disorders and MetS, while the presence of hepatic iron overload may indicate stronger risk only for glucose metabolism disorders.


Assuntos
Diabetes Mellitus Tipo 2 , Sobrecarga de Ferro , Síndrome Metabólica , Alemanha/epidemiologia , Humanos , Ferro , Síndrome Metabólica/epidemiologia
19.
Clin Res Cardiol ; 110(10): 1564-1573, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33774696

RESUMO

AIMS: Observational evidence suggests that physical activity (PA) is inversely and sedentarism positively related with cardiovascular disease risk. We performed a two-sample Mendelian randomization (MR) analysis to examine whether genetically predicted PA and sedentary behavior are related to coronary artery disease, myocardial infarction, and ischemic stroke. METHODS AND RESULTS: We used single nucleotide polymorphisms (SNPs) associated with self-reported moderate to vigorous PA (n = 17), accelerometer based PA (n = 7) and accelerometer fraction of accelerations > 425 milli-gravities (n = 7) as well as sedentary behavior (n = 6) in the UK Biobank as instrumental variables in a two sample MR approach to assess whether these exposures are related to coronary artery disease and myocardial infarction in the CARDIoGRAMplusC4D genome-wide association study (GWAS) or ischemic stroke in the MEGASTROKE GWAS. The study population included 42,096 cases of coronary artery disease (99,121 controls), 27,509 cases of myocardial infarction (99,121 controls), and 34,217 cases of ischemic stroke (404,630 controls). We found no associations between genetically predicted self-reported moderate to vigorous PA, accelerometer-based PA or accelerometer fraction of accelerations > 425 milli-gravities as well as sedentary behavior with coronary artery disease, myocardial infarction, and ischemic stroke. CONCLUSIONS: These results do not support a causal relationship between PA and sedentary behavior with risk of coronary artery disease, myocardial infarction, and ischemic stroke. Hence, previous observational studies may have been biased.

20.
PLoS Comput Biol ; 17(2): e1008735, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33577591

RESUMO

In this work, we introduce an entirely data-driven and automated approach to reveal disease-associated biomarker and risk factor networks from heterogeneous and high-dimensional healthcare data. Our workflow is based on Bayesian networks, which are a popular tool for analyzing the interplay of biomarkers. Usually, data require extensive manual preprocessing and dimension reduction to allow for effective learning of Bayesian networks. For heterogeneous data, this preprocessing is hard to automatize and typically requires domain-specific prior knowledge. We here combine Bayesian network learning with hierarchical variable clustering in order to detect groups of similar features and learn interactions between them entirely automated. We present an optimization algorithm for the adaptive refinement of such group Bayesian networks to account for a specific target variable, like a disease. The combination of Bayesian networks, clustering, and refinement yields low-dimensional but disease-specific interaction networks. These networks provide easily interpretable, yet accurate models of biomarker interdependencies. We test our method extensively on simulated data, as well as on data from the Study of Health in Pomerania (SHIP-TREND), and demonstrate its effectiveness using non-alcoholic fatty liver disease and hypertension as examples. We show that the group network models outperform available biomarker scores, while at the same time, they provide an easily interpretable interaction network.


Assuntos
Biomarcadores/metabolismo , Doença/genética , Informática Médica/métodos , Algoritmos , Teorema de Bayes , Análise por Conglomerados , Biologia Computacional/métodos , Simulação por Computador , Atenção à Saúde , Redes Reguladoras de Genes , Humanos , Hipertensão/genética , Distribuição Normal , Reconhecimento Automatizado de Padrão , Reprodutibilidade dos Testes , Vinho
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