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BACKGROUND: There is limited information on the mode of arrhythmia initiation in idiopathic ventricular fibrillation (IVF). A non-pause-dependent mechanism has been suggested to be the rule. OBJECTIVES: The aim of this study was to assess the mode and characteristics of initiation of polymorphic ventricular tachycardia (PVT) in patients with short or long-coupled PVT/IVF included in THESIS (THerapy Efficacy in Short or long-coupled idiopathic ventricular fibrillation: an International Survey), a multicenter study involving 287 IVF patients treated with drugs or radiofrequency ablation. METHODS: We reviewed the initiation of 410 episodes of ≥1 PVT triplet in 180 patients (58.3% females; age 39.6 ± 13.6 years) with IVF. The incidence of pause-dependency arrhythmia initiation (prolongation by >20 ms of the preceding cycle length) was assessed. RESULTS: Most arrhythmias (n = 295; 72%) occurred during baseline supraventricular rhythm without ambient premature ventricular complexes (PVCs), whereas 106 (25.9%) occurred during baseline rhythm including PVCs. Nine (2.2%) arrhythmias occurred during atrial/ventricular pacing and were excluded from further analysis. Mode of PVT initiation was pause-dependent in 45 (15.6%) and 64 (60.4%) of instances in the first and second settings, respectively, for a total of 109 of 401 (27.2%). More than one type of pause-dependent and/or non-pause-dependent initiation (mean: 2.6) occurred in 94.4% of patients with ≥4 events. Coupling intervals of initiating PVCs were <350 ms, 350-500 ms, and >500 ms in 76.6%, 20.72%, and 2.7% of arrhythmia initiations, respectively. CONCLUSIONS: Pause-dependent initiation occurred in more than a quarter of arrhythmic episodes in IVF patients. PVCs having long (between 350 and 500 ms) and very long (>500 ms) coupling intervals were observed at the initiation of nearly a quarter of PVT episodes.
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BACKGROUND: Postoperative atrial fibrillation (POAF) represents the most common complication following cardiac surgery. Approximately one-third of patients experiencing POAF transition to atrial fibrillation within a year, challenging the notion of POAF as merely a transient event. Soluble ST2 (sST2) is an established biomarker regarding fibrosis and myocardial stretch, however, its role in predicting the onset of POAF remains unclear. METHODS: Preoperative sST2 levels have been assessed in 496 individuals with no prior history of AF who underwent elective cardiac surgery, including valve, coronary artery bypass graft surgery, or a combined procedure. RESULTS: The average age was 70 years, and 29.4 % were female. Overall, 42.3 % developed POAF. sST2 levels were found to be significantly higher in patients with POAF. Interestingly, sST2 was only predictive of POAF in females with an adjusted OR of 1.894 (95 %CI:1.103-3.253; p = 0.021) and not males (OR:1.091; 95 %CI:0.849-1.402; p = 0.495). Furthermore, within a linear regression model it was observed that for every 1 ng/mL increase in sST2 levels, the average POAF duration extended by 39.5 min (95 %CI:15.8-63.4 min; p = 0.001). CONCLUSION: sST2 predicts the onset of POAF in women but not men undergoing cardiac surgery. Furthermore, sST2 levels were associated with the subsequent burden of POAF. Thus, assessment of sST2 in addition to clinical risk factors could improve risk stratification for development of POAF following elective cardiac surgery.
Subject(s)
Atrial Fibrillation , Cardiac Surgical Procedures , Interleukin-1 Receptor-Like 1 Protein , Postmenopause , Postoperative Complications , Humans , Atrial Fibrillation/etiology , Interleukin-1 Receptor-Like 1 Protein/blood , Female , Aged , Cardiac Surgical Procedures/adverse effects , Male , Postoperative Complications/etiology , Postoperative Complications/blood , Middle Aged , Biomarkers/blood , SolubilityABSTRACT
BACKGROUND: Achalasia is an esophageal motor disorder characterized by aperistalsis and the failure of the relaxation of the lower esophageal sphincter. We want to find out whether external compression or recurrent micro-aspiration of undigested food has a functional effect on the airway. METHODS: The aim of this research was to analyze the influence of achalasia on the peak expiratory flow and flow-volume curve. All of the 110 patients performed spirometry. RESULTS: The mean diameter of the esophagus was 5.4 ± 2.1 cm, and nine of the patients had mega-esophagus. Seven patients had a plateau in the inspiratory part of the flow-volume curve, which coincides with the patients who had mega-esophagus. The rest of the patients had a plateau in the expiration part of the curve. The existence of a plateau in the diameter of the esophagus of more than 5 cm was significant (p 0.003). Statistical significance between the existence of a plateau and a lowered PEF (PEF < 80) has been proven (p 0.001). Also, a statistical significance between the subtype and diameter of more than 4 cm has been proved. There was no significant improvement in the PEF values after operation. In total, 20.9% of patients had a spirometry abnormality finding. The frequency of the improvement in the spirometry values after surgery did not differ significantly by achalasia subtype. The improvement in FEV1 was statistically significant compared to the FVC values. CONCLUSIONS: Awareness of the influence of achalasia on the pulmonary parameters is important because low values of PEF with a plateau on the spirometry loop can lead to misdiagnosis. The recognition of various patterns of the spirometry loop may help in identifying airway obstruction caused by another non-pulmonary disease such as achalasia.
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Background and Objectives: Lung cancer is the second most common form of cancer in the world for both men and women as well as the most common cause of cancer-related deaths worldwide. The aim of this study is to summarize the radiological characteristics between primary lung adenocarcinoma subtypes and to correlate them with FDG uptake on PET-CT. Materials and Methods: This retrospective study included 102 patients with pathohistologically confirmed lung adenocarcinoma. A PET-CT examination was performed on some of the patients and the values of SUVmax were also correlated with the histological and morphological characteristics of the masses in the lungs. Results: The results of this analysis showed that the mean size of AIS-MIA (adenocarcinoma in situ and minimally invasive adenocarcinoma) cancer was significantly lower than for all other cancer types, while the mean size of the acinar cancer was smaller than in the solid type of cancer. Metastases were significantly more frequent in solid adenocarcinoma than in acinar, lepidic, and AIS-MIA cancer subtypes. The maximum standardized FDG uptake was significantly lower in AIS-MIA than in all other cancer types and in the acinar predominant subtype compared to solid cancer. Papillary predominant adenocarcinoma had higher odds of developing contralateral lymph node involvement compared to other types. Solid adenocarcinoma was associated with higher odds of having metastases and with higher SUVmax. AIS-MIA was associated with lower odds of one unit increase in tumor size and ipsilateral lymph node involvement. Conclusions: The correlation between histopathological and radiological findings is crucial for accurate diagnosis and staging. By integrating both sets of data, clinicians can enhance diagnostic accuracy and determine the optimal treatment plan.
Subject(s)
Adenocarcinoma of Lung , Lung Neoplasms , Positron Emission Tomography Computed Tomography , Humans , Male , Female , Retrospective Studies , Positron Emission Tomography Computed Tomography/methods , Middle Aged , Aged , Adenocarcinoma of Lung/diagnostic imaging , Adenocarcinoma of Lung/pathology , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/pathology , Lung Neoplasms/classification , Adenocarcinoma/diagnostic imaging , Adenocarcinoma/pathology , Adenocarcinoma/classification , Fluorodeoxyglucose F18 , Adult , Aged, 80 and overABSTRACT
Although previous studies indicated that chronic alcohol abuse (CAA) and alcoholic liver cirrhosis (ALC) are associated with increased bone fragility, understanding bone fragility determinants is still modest in these individuals. We used a comprehensive individualized clinical fracture risk assessment approach (vertebral osteodensitometry, femoral osteodensitometry and geometry, and serum bone turnover biomarkers) to compare adult male patients with ALC who have not previously had femoral or vertebral fractures (n = 39), patients with CAA (without liver cirrhosis, n = 78) who have not previously had femoral or vertebral fractures and healthy age- and sex-matched controls (n = 43). Our data suggested that intertrochanteric bone mineral density was significantly lower in ALC and CAA patients than in controls. Also, the trabecular bone score was considerably lower in ALC patients compared with CAA and control individuals. The most significant inter-group differences in femoral geometry were noted on the femoral shaft. Patients with ALC and CAA have a higher 10-year risk of major osteoporotic fractures compared to the controls. Analysis of bone turnover biomarkers showed increased osteoprotegerin and beta-C-terminal telopeptide serum concentrations and decreased insulin growth factor-1 concentrations in patients with ALC compared to CAA and control groups. Our data revealed that bone alterations are present in patients with ALC and CAA even if they did not sustain a nontraumatic bone fracture, but it is also indicative that current bone-assessing clinical methods are not entirely reliable. Thus, future studies should focus on developing a reliable integrative clinical tool that can be used to accurately predict and prevent bone fracture occurrences in patients with ALC and CAA.
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INTRODUCTION: Growth differentiation factor 8 (GDF-8, myostatin) has been proposed for the management of adult heart failure (HF). Its potential role in pediatric HF patients is unknown. We sought to investigate its diagnostic performance in adult versus pediatric HF. METHODS: GDF-8 was measured prospectively in pediatric and adult HF patients and in matching controls. HF was defined as the combination of typical symptoms and impaired left ventricular systolic function. Diagnostic performance for the detection of HF was evaluated by receiver operating characteristic (ROC) analysis. RESULTS: We enrolled 137 patients with HF (85 pediatric) and 67 healthy controls (47 pediatric). Neither pediatric nor adult HF patients had significantly different GDF-8 levels compared to the reference groups (3.53 vs 3.46 ng/mL, p = 0.334, and 6.87 vs 8.15 ng/mL, p = 0.063, respectively), but pediatric HF patients had significantly lower GDF-8 levels compared to adult patients (p < 0.001). ROC analysis showed no significant improvement adding GDF-8 to NT-proBNP, age and sex (area under the curve (AUC): 0.870 vs 0.868, p = 0.614) in children and neither in addition to age nor sex in adult HF patients (AUC: 0.74 vs 0.62, p = 0.110). CONCLUSION: GDF-8 did not accurately differentiate between HF patients and normal comparators in neither adults nor in children.
Subject(s)
Heart Failure , Myostatin , Adult , Child , Humans , Biomarkers , Heart Failure/diagnosis , Natriuretic Peptide, Brain , Peptide Fragments , Ventricular Function, LeftABSTRACT
Small bowel obstruction is a frequent medical condition with various causes, the most common being postoperative adhesions, volvulus, intussusception, hernias, and tumors. A bezoar-induced blockage of the small intestine is a rare condition that accounts for approximately 4% of all small bowel obstruction cases. Herein, we present the case report of a 71-year-old patient with diffuse abdominal pain caused by a small bowel obstruction due to a calcified bezoar (bezoar egg) resulting from a post-radiation intestinal stricture. The patient underwent a small bowel excision with the extraction of the bezoar, after which a full recovery was made.
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Foreign body ingestion is a frequently encountered emergency in healthcare institutions. It mostly affects pediatric populations, although it can also affect adults with developmental delays, those with psychiatric diseases, drug abusers, and prisoners. Endoscopy is a diagnostic and treatment method for suspected foreign body ingestion. In this article, we discuss a 45-year-old tailor who swallowed a sewing pin while at work. The abdominal X-ray showed a needle-shaped metal shadow in the stomach region. During an upper endoscopy, it was discovered that a sewing pin with a sharp edge was stuck in the pylorus. The sewing pin was extracted endoscopically, and the patient was discharged the same day in good condition. Since the estimated risk of complications of foreign body ingestion in the adult population is about 35%, and the most common complications include impaction, laceration, bleeding, or perforation of the gastrointestinal wall, endoscopic or surgical removal is necessary. This also emphasizes the importance of a careful endoscopic evaluation of some at-risk occupations for foreign body ingestion with or without gastrointestinal complaints.
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BACKGROUND: Using proteomics, we aimed to reveal molecular types of human atherosclerotic lesions and study their associations with histology, imaging, and cardiovascular outcomes. METHODS: Two hundred nineteen carotid endarterectomy samples were procured from 120 patients. A sequential protein extraction protocol was employed in conjunction with multiplexed, discovery proteomics. To focus on extracellular proteins, parallel reaction monitoring was employed for targeted proteomics. Proteomic signatures were integrated with bulk, single-cell, and spatial RNA-sequencing data, and validated in 200 patients from the Athero-Express Biobank study. RESULTS: This extensive proteomics analysis identified plaque inflammation and calcification signatures, which were inversely correlated and validated using targeted proteomics. The inflammation signature was characterized by the presence of neutrophil-derived proteins, such as S100A8/9 (calprotectin) and myeloperoxidase, whereas the calcification signature included fetuin-A, osteopontin, and gamma-carboxylated proteins. The proteomics data also revealed sex differences in atherosclerosis, with large-aggregating proteoglycans versican and aggrecan being more abundant in females and exhibiting an inverse correlation with estradiol levels. The integration of RNA-sequencing data attributed the inflammation signature predominantly to neutrophils and macrophages, and the calcification and sex signatures to smooth muscle cells, except for certain plasma proteins that were not expressed but retained in plaques, such as fetuin-A. Dimensionality reduction and machine learning techniques were applied to identify 4 distinct plaque phenotypes based on proteomics data. A protein signature of 4 key proteins (calponin, protein C, serpin H1, and versican) predicted future cardiovascular mortality with an area under the curve of 75% and 67.5% in the discovery and validation cohort, respectively, surpassing the prognostic performance of imaging and histology. CONCLUSIONS: Plaque proteomics redefined clinically relevant patient groups with distinct outcomes, identifying subgroups of male and female patients with elevated risk of future cardiovascular events.
Subject(s)
Atherosclerosis , Calcinosis , Female , Humans , Male , Proteomics , Sex Characteristics , Versicans , alpha-2-HS-GlycoproteinABSTRACT
Interleukin (IL-33) and the ST2 receptor are implicated in the pathogenesis of atherosclerosis. Soluble ST2 (sST2), which negatively regulates IL-33 signaling, is an established biomarker in coronary artery disease and heart failure. Here we aimed to investigate the association of sST2 with carotid atherosclerotic plaque morphology, symptom presentation, and the prognostic value of sST2 in patients undergoing carotid endarterectomy. A total of 170 consecutive patients with high-grade asymptomatic or symptomatic carotid artery stenosis undergoing carotid endarterectomy were included in the study. The patients were followed up for 10 years, and the primary endpoint was defined as a composite of adverse cardiovascular events and cardiovascular mortality, with all-cause mortality as the secondary endpoint. The baseline sST2 showed no association with carotid plaque morphology assessed using carotid duplex ultrasound (B 0.051, 95% CI -0.145-0.248, p = 0.609), nor with modified histological AHA classification based on morphological description following surgery (B -0.032, 95% CI -0.194-0.130, p = 0.698). Furthermore, sST2 was not associated with baseline clinical symptoms (B -0.105, 95% CI -0.432-0.214, p = 0.517). On the other hand, sST2 was an independent predictor for long-term adverse cardiovascular events after adjustment for age, sex, and coronary artery disease (HR 1.4, 95% CI 1.0-2.4, p = 0.048), but not for all-cause mortality (HR 1.2, 95% CI 0.8-1.7, p = 0.301). Patients with high baseline sST2 levels had a significantly higher adverse cardiovascular event rate as compared to patients with lower sST2 (log-rank p < 0.001). Although IL-33 and ST2 play a role in the pathogenesis of atherosclerosis, sST2 is not associated with carotid plaque morphology. However, sST2 is an excellent prognostic marker for long-term adverse cardiovascular outcomes in patients with high-grade carotid artery stenosis.
Subject(s)
Atherosclerosis , Carotid Stenosis , Coronary Artery Disease , Plaque, Atherosclerotic , Humans , Plaque, Atherosclerotic/pathology , Carotid Stenosis/complications , Carotid Stenosis/surgery , Coronary Artery Disease/diagnosis , Interleukin-33 , Interleukin-1 Receptor-Like 1 Protein , Atherosclerosis/complications , BiomarkersABSTRACT
OBJECTIVE: Carotid atherosclerosis is an important cause of cerebral ischaemic stroke. Sonographic plaque characteristics are inappropriate for exact prediction of possible future ischaemic events. Additional markers are needed to predict the clinical outcome in high grade carotid stenosis. This study aimed to test extracellular matrix metalloproteinase inducer (EMMPRIN), due to its involvement in plaque formation and destabilisation, as a potential marker of high risk vulnerable plaques. METHODS: EMMPRIN was analysed in pre-operative serum samples from patients with symptomatic and asymptomatic carotid artery stenosis by a specific ELISA. Pre-operative duplex sonography classified the atherosclerotic plaque due to echogenicity. Histopathological analysis of vulnerable and non-vulnerable plaques was based on the American Heart Association (AHA) classification. RESULTS: The study included 265 patients undergoing carotid endarterectomy: 90 (m:f, 69:21) patients with symptomatic and 175 (m:f, 118:57) with asymptomatic disease. Analysis of circulating EMMPRIN revealed significantly higher levels in patients with echolucent plaques (4 480; IQR 3 745, 6 144 pg/mL) compared with echogenic plaques (4 159; IQR 3 418, 5 402 pg/mL; p = .025). Asymptomatic patients with vulnerable plaques had significantly higher levels of EMMPRIN (4 875; IQR 3 850, 7 016 pg/mL) compared with non-vulnerable plaques (4 109; IQR 3 433, 5 402 pg/mL; p < .001). In logistic regression analysis, duplex sonography combined with age, gender, and clinical risk factors predicted vulnerable plaques in asymptomatic patients with an AUC of 0.71 (95% CI 0.61 - 0.80). EMMPRIN significantly improved the AUC in asymptomatic patients (AUC 0.79; 95% CI 0.71 - 0.87; p = .014). CONCLUSION: Patients with high risk plaques according to ultrasound and histopathological characteristics demonstrated increased serum EMMPRIN levels. EMMPRIN on top of clinical risk factors, including age, gender, and duplex sonography may be used for pre-operative risk stratification in asymptomatic patients.
Subject(s)
Brain Ischemia , Carotid Stenosis , Plaque, Atherosclerotic , Stroke , Humans , Carotid Stenosis/complications , Carotid Stenosis/diagnostic imaging , Carotid Stenosis/surgery , Plaque, Atherosclerotic/pathology , Basigin , Carotid Arteries/pathologyABSTRACT
OBJECTIVES: Epistaxis is the most common otolaryngological emergency and one-third of epistaxis patients regularly take low-dose acetylsalicylic acid (ASA) for the prevention of cardiovascular disease (CVD). The shift in contemporary guidelines identifies little benefit of ASA intake in patients who have not previously had an infarction. Existing evidence confirms ASA intake as a factor for severe epistaxis, while the evidence concerning its impact on recurrence is ambiguous. There are no available studies which justify the administration of these drugs nor are there any studies correlating the effects of these drugs to the SCORE2 CVD risk stratifying scale. STUDY DESIGN: A retrospective analysis of all admitted epistaxis patients in a tertiary academic hospital for the 10 year period 2011 to 2021. METHODS: Patient data were analysed using the hospital information software. A recurrence was defined as an epistaxis episode requiring hospital readmittance for at least one night. Patients taking anticoagulants were excluded (N = 421). RESULTS: 444 patients were included: 246 were taking ASA and 198 were not (NoASA). ASA patients had more frequent recurrence in general (p = 0.03), more recurrences per patient (p = 0.002), and more changes in bleeding localisation (p = 0.04). Recurrence in the ASA group was associated with lower haemoglobin values (HR 0.62, p < 0.0001), while surgery (HR 6.83, p < 0.0001) was associated with recurrence in the NoASA group. ASA patients had a statistically significant (r 0.33, p = 0.032) correlation between the total number of epistaxis recurrences and SCORE2. The indication for drug intake was highly questionable in as much as 40% of ASA patients. Follow-up time was 5.27 years. CONCLUSIONS: Epistaxis patients taking prophylactic ASA are significantly more burdened by recurrence, because they have more frequent recurrences, a greater number of recurrences per patient, and more changes in bleeding localisations when compared to control patients. The drug indication is questionable in up to 40% of ASA patients, exposing them unnecessarily to recurrence.
Subject(s)
Aspirin , Cardiovascular Diseases , Humans , Aspirin/adverse effects , Retrospective Studies , Epistaxis , Anticoagulants , Cardiovascular Diseases/prevention & control , RecurrenceABSTRACT
BACKGROUND: Within the presented prospective study, we aimed to illuminate the effect of long-term physical exercise on serum levels of adipsin (complement factor D) and angiopoietin-like 4 (ANGPTL4). Although past studies already outlined the effects of acute exercise, our trial design aimed to depict the development under long-term physical activity conditions. METHODS: Ninety-eight participants were included in the study and were asked to perform eight months of moderate physical activity for at least 150 minutes/week and/or vigorous-intensity exercise for at least 75 minutes/week. According to initial performance and performance gain throughout the study period, four groups were formed and subsequently compared. Blood sampling for the determination of routine laboratory parameters was done at baseline, after 2, 6, and 8 months. Additionally, adipsin and ANGPTL4 serum levels were concurrently quantified using commercially available ELISA kits. RESULTS: The study cohort consisted of 61.2% male participants with an average age of 49.3±6.7 years. Adipsin and ANGPTL4 were found to be strongly increased by long-term physical exercise. Participants displaying a performance gain of >2.9% throughout the study showed significantly increased serum levels of both biomarkers. CONCLUSIONS: Serum levels of adipsin and ANGPTL4 were closely tied to the individual performance gain of the participating probands. An association of adipsin levels, initial performance, and serum triglycerides was found at baseline. Interestingly, this interrelationship was not detectable after eight months of physical training. This finding might indicate adipsin's involvement in linking triglyceride-balance to individual performance and energy demands in a homeostatic state.
Subject(s)
Complement Factor D , Exercise , Adult , Female , Humans , Male , Middle Aged , Angiopoietin-Like Protein 4 , Biomarkers , Prospective Studies , TriglyceridesABSTRACT
The maximal aortic diameter is the only clinically applied predictor of abdominal aortic aneurysm (AAA) progression and indicator for surgical repair. Circulating biomarkers resulting from AAA pathogenesis are attractive candidates for the diagnosis and prognosis of aneurysmal disease. Due to the reported role of interleukin 33 in AAA development, we investigated the corresponding circulating receptor molecules of soluble suppression of tumorigenesis 2 (sST2) in AAA patients regarding their marker potential in diagnosis and prognosis. We conducted a single-center retrospective cohort study in a diagnostic setting, measuring the circulating serum sST2 protein levels of 47 AAA patients under surveillance, matched with 25 peripheral artery disease (PAD) patients and 25 healthy controls. In a prognostic setting, we analyzed the longitudinal monitoring data of 50 monitored AAA patients. Slow versus fast AAA progression was defined as a <2 or ≥2 mm increase in AAA diameter over 6 months and a <4 or ≥4 mm increase over 12 months. Additionally, the association of circulating serum sST2 and AAA growth was investigated using a specifically tailored log-linear mixed model. Serum sST2 concentrations were significantly increased in AAA patients compared with healthy individuals: the median of AAA patient cohort was 112.72 ng/mL (p = 0.025) and that of AAA patient cohort 2 was 14.32 ng/mL (p = 0.039) versus healthy controls (8.82 ng/mL). Likewise, PAD patients showed significantly elevated sST2 protein levels compared with healthy controls (the median was 12.10 ng/mL; p = 0.048) but similar concentrations to AAA patients. Additionally, sST2 protein levels were found to be unsuited to identifying fast AAA progression over short-term periods of 6 or 12 months, which was confirmed by a log-linear mixed model. In conclusion, the significantly elevated protein levels of sST2 detected in patients with vascular disease may be useful in the early diagnosis of AAA but cannot distinguish between AAA and PAD or predict AAA progression.
Subject(s)
Aortic Aneurysm, Abdominal , Aortic Aneurysm, Abdominal/pathology , Biomarkers , Cohort Studies , Humans , Interleukin-1 Receptor-Like 1 Protein , Retrospective StudiesABSTRACT
Regular physical exercise was found to be associated with an improved immune response in previous studies. RANTES and CD40L play a pivotal role in host defense, and individuals lacking adequate expression are prone to virus and opportunistic infections. A total of 98 participants were enrolled in this study. The probands were asked to perform moderate physical activity, and bicycle stress tests were performed at the baseline and after 8 months of training to evaluate individual performance. RANTES and CD40L were found to be increased by long-term physical exercise. In particular, probands with a performance gain of ≥3% displayed a pronounced elevation of both markers, paired with a decrease in circulating IL6 levels and an improved lipid profile. In summary, we were able to highlight rising levels of serum RANTES and CD40L under the conditions of physical exercise. Taking their role in host defense into account, a conjunction of physical activity and the adaptive immune system could therefore be assumed. Furthermore, low inflammatory profiles in probands with a significant performance gain suggest a modulation through exercise rather than a generalized pro-inflammatory status.
Subject(s)
CD40 Ligand , Chemokine CCL5 , Adaptive Immunity , Biomarkers , CD40 Ligand/metabolism , Exercise/physiology , HumansABSTRACT
In this review, we focus on the actual understanding of the role of IL-33 in vascular biology in the context of the historical development since the description of IL-33 as a member of IL-1 superfamily and the ligand for ST2 receptor in 2005. We summarize recent data on the biology, structure and signaling of this dual-function factor with both nuclear and extracellular cytokine properties. We describe cellular sources of IL-33, particularly within vascular wall, changes in its expression in different cardio-vascular conditions and mechanisms of IL-33 release. Additionally, we summarize the regulators of IL-33 expression as well as the effects of IL-33 itself in cells of the vasculature and in monocytes/macrophages in vitro combined with the consequences of IL-33 modulation in models of vascular diseases in vivo. Described in murine atherosclerosis models as well as in macrophages as an atheroprotective cytokine, extracellular IL-33 induces proinflammatory, prothrombotic and proangiogenic activation of human endothelial cells, which are processes known to be involved in the development and progression of atherosclerosis. We, therefore, discuss that IL-33 can possess both protective and harmful effects in experimental models of vascular pathologies depending on experimental conditions, type and dose of administration or method of modulation.
Subject(s)
Atherosclerosis/metabolism , Interleukin-33/metabolism , Animals , Atherosclerosis/immunology , Atherosclerosis/physiopathology , Endothelial Cells , Gene Expression Regulation , Humans , Interleukin-33/genetics , Interleukin-33/physiology , Macrophages/metabolism , Monocytes/metabolism , Signal TransductionABSTRACT
BACKGROUND: Inflammation is a key process during atherosclerotic lesion development and propagation. Recent evidence showed clearly that especially the inhibition of interleukin (IL)-1ß reduced atherosclerotic adverse events in human patients. Fatty acid oxidation (FAO) was previously demonstrated to interact with the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) pathway which is required for mature IL-1ß secretion. To understand possible anti-inflammatory properties of FAO inhibition, we tested the effect of pharmacological FAO inhibition using the inhibitor for long-chain 3-ketoacyl coenzyme A thiolase trimetazidine on atherosclerotic plaque development and inflammation. EXPERIMENTAL APPROACH: The effect of FAO inhibition was determined in LDL-R-/- male mice on a C57/BL6 background. In vitro effects of trimetazidine treatment were analyzed in human umbilical vein endothelial cells and human monocyte derived macrophages. KEY RESULTS: We were able to demonstrate that inhibition of FAO reduced atherosclerotic plaque growth. We did not find direct anti-inflammatory properties of trimetazidine in endothelial cells or macrophages in vitro. However, we found that the activation of the NLRP3 system and the secretion of IL-1ß were significantly reduced in macrophages after FAO inhibition. These results were confirmed in atherosclerotic lesions of mice treated with trimetazidine as they showed a significant reduction of IL-1ß and cleaved caspase-1 in the atherosclerotic lesion as well as of IL-1ß and IL-18 in the circulation. CONCLUSION: Overall, we therefore suggest that the main mechanism of reducing inflammation of trimetazidine and FAO inhibition is the reduction of the NLRP-3 activation leading to reduced levels of the proinflammatory cytokine IL-1ß.
Subject(s)
Atherosclerosis/prevention & control , Fatty Acids/metabolism , Macrophages/drug effects , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Receptors, LDL/metabolism , Animals , Cytokines/genetics , Cytokines/metabolism , Gene Expression Regulation/drug effects , Human Umbilical Vein Endothelial Cells , Humans , Inflammasomes/drug effects , Inflammasomes/metabolism , Lipid Metabolism , Macrophages/metabolism , Male , Mice , Mice, Knockout , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Oxidation-Reduction , Receptors, LDL/genetics , Trimetazidine/pharmacology , Vasodilator Agents/pharmacologyABSTRACT
BACKGROUND: Monocyte-platelet aggregates (MPAs) are a sensitive marker of in vivo platelet activation in acute coronary syndrome (ACS) and associated with clinical outcomes. MicroRNAs (miRs) play an important role in the regulation of platelet activation, and may influence MPA formation. Both, miRs and MPA, could be influenced by the type of P2Y12 inhibitor. AIM: To study the association of platelet-related miRs with MPA formation in ACS patients on dual antiplatelet therapy (DAPT), and to compare miRs and MPA levels between prasugrel- and ticagrelor-treated patients. METHODS AND RESULTS: We analyzed 10 circulating platelet-related miRs in 160 consecutive ACS patients on DAPT with low-dose aspirin and either prasugrel (n = 80) or ticagrelor (n = 80). MPA formation was measured by flow cytometry without addition of platelet agonists and after simulation with the toll-like receptor (TLR)-1/2 agonist Pam3CSK4, adenosine diphosphate (ADP), or arachidonic acid (AA). In multivariate regression analyses, we identified miR-21 (ß = 9.50, 95% confidence interval [CI]: 1.60-17.40, p = 0.019) and miR-126 (ß = 7.50, 95% CI: 0.55-14.44, p = 0.035) as independent predictors of increased MPA formation in vivo and after TLR-1/2 stimulation. In contrast, none of the investigated miRs was independently associated with MPA formation after stimulation with ADP or AA. Platelet-related miR expression and MPA formation did not differ significantly between prasugrel- and ticagrelor-treated patients. CONCLUSION: Platelet-related miR-21 and miR-126 are associated with MPA formation in ACS patients on DAPT. miRs and MPA levels were similar in prasugrel- and ticagrelor-treated patients.
Subject(s)
Acute Coronary Syndrome/blood , Acute Coronary Syndrome/therapy , Aspirin/pharmacology , Blood Platelets/cytology , Monocytes/cytology , Prasugrel Hydrochloride/pharmacology , Purinergic P2Y Receptor Antagonists/pharmacology , Receptors, Purinergic P2Y12/chemistry , Ticagrelor/pharmacology , Aged , Female , Humans , Male , MicroRNAs/genetics , MicroRNAs/metabolism , Middle Aged , Platelet Activation , Platelet Aggregation Inhibitors/pharmacologyABSTRACT
Chronic obstructive pulmonary disease (COPD) is an inflammatory condition with constantly increasing mortality rates. Interleukin (IL)-33 and its decoy receptor, soluble suppression of tumorigenicity 2 (sST2), play a central role in the inflammatory response during infection. sST2 was suggested as a factor in the pathogenesis of COPD and emerged as a predictor of mortality in other non-communicable diseases. The role of sST2 as a predictor of mortality remains unclear in COPD yet. In this cohort study, we measured circulating concentrations of IL-33 and sST2 in the serum of patients with stable COPD (n = 59), patients with acute exacerbation of COPD (n = 29) and smoking (n = 20) and non-smoking controls (n = 20), using commercially available ELISAs, and investigated the prognostic role of sST2 in stable COPD. sST2 levels were significantly higher in COPD patients and smokers compared with non-smoking controls. We identified systolic blood pressure, forced expiratory volume in 1 s (FEV1% predicted), neutrophil count, lactate dehydrogenase and pack-years index as independent predictors of sST2 levels. During a median follow-up time of 10.6 years, 28 patients (47.5%) died. sST2 was an independent predictor of all-cause mortality in patients with COPD with a hazard ratio of 2.9 (95% CI 1.1-8.4, p = 0.035) per one standard deviation after adjustment for age, sex, pack-years, FEV1% predicted and C-reactive protein (CRP). sST2 concentrations are associated with severity of disease and long-term outcome in patients with COPD.