-
BioRxiv : the Preprint Server For... Jun 2024Type 2 diabetes mellitus (T2DM) is associated with poor outcome after stroke. Peripheral monocytes play a critical role in the secondary injury and recovery of damaged...
UNLABELLED
Type 2 diabetes mellitus (T2DM) is associated with poor outcome after stroke. Peripheral monocytes play a critical role in the secondary injury and recovery of damaged brain tissue after stroke, but the underlying mechanisms are largely unclear. To investigate transcriptome changes and molecular networks across monocyte subsets in response to T2DM and stroke, we performed single-cell RNA-sequencing (scRNAseq) from peripheral blood mononuclear cells and bulk RNA-sequencing from blood monocytes from four groups of adult mice, consisting of T2DM model and normoglycemic control mice with or without ischemic stroke. Via scRNAseq we found that T2DM expands the monocyte population at the expense of lymphocytes, which was validated by flow cytometry. Among the monocytes, T2DM also disproportionally increased the inflammatory subsets with Ly6C+ and negative MHC class II expression (MO.6C+II-). Conversely, monocytes from control mice without stroke are enriched with steady-state classical monocyte subset of MO.6C+II+ but with the least percentage of MO.6C+II- subtype. Apart from enhancing inflammation and coagulation, enrichment analysis from both scRNAseq and bulk RNAseq revealed that T2DM specifically suppressed type-1 and type-2 interferon signaling pathways crucial for antigen presentation and the induction of ischemia tolerance. Preconditioning by lipopolysaccharide conferred neuroprotection against ischemic brain injury in but not in mice and coincided with a lesser induction of brain Interferon-regulatory-factor-3 in the brains of the latter mice. Our results suggest that the increased diversity and altered transcriptome in the monocytes of T2DM mice underlie the worse stroke outcome by exacerbating secondary injury and potentiating stroke-induced immunosuppression.
SIGNIFICANCE STATEMENT
The mechanisms involved in the detrimental diabetic effect on stroke are largely unclear. We show here, for the first time, that peripheral monocytes have disproportionally altered the subsets and changed transcriptome under diabetes and/or stroke conditions. Moreover, genes in the IFN-related signaling pathways are suppressed in the diabetic monocytes, which underscores the immunosuppression and impaired ischemic tolerance under the T2DM condition. Our data raise a possibility that malfunctioned monocytes may systemically and focally affect the host, leading to the poor outcome of diabetes in the setting of stroke. The results yield important clues to molecular mechanisms involved in the detrimental diabetic effect on stroke outcome.
PubMed: 38895236
DOI: 10.1101/2024.06.03.597050 -
Journal of Clinical Medicine May 2024: Cardiorenal syndrome (CRS) is a disorder of the heart and kidneys, with one type of organ dysfunction affecting the other. The pathophysiology is complex, and its...
: Cardiorenal syndrome (CRS) is a disorder of the heart and kidneys, with one type of organ dysfunction affecting the other. The pathophysiology is complex, and its actual description has been questioned. We used clustering analysis to identify clinically relevant phenogroups among patients with CRS. : Data for patients admitted from 1 January 2012 to 31 December 2012 were collected from the French national medico-administrative database. Patients with a diagnosis of heart failure and chronic kidney disease and at least 5 years of follow-up were included. : In total, 13,665 patients were included and four clusters were identified. Cluster 1 could be described as the vascular-diabetes cluster. It comprised 1930 patients (14.1%), among which 60% had diabetes, 94% had coronary artery disease (CAD), and 80% had peripheral artery disease (PAD). Cluster 2 could be described as the vascular cluster. It comprised 2487 patients (18.2%), among which 33% had diabetes, 85% had CAD, and 78% had PAD. Cluster 3 could be described as the metabolic cluster. It comprised 2163 patients (15.8%), among which 87% had diabetes, 67% dyslipidemia, and 62% obesity. Cluster 4 comprised 7085 patients (51.8%) and could be described as the low-vascular cluster. The vascular cluster was the only one associated with a higher risk of cardiovascular death (HR: 1.48 [1.32-1.66]). The metabolic cluster was associated with a higher risk of kidney replacement therapy (HR: 1.33 [1.17-1.51]). : Our study supports a new classification of CRS based on the vascular aspect of pathophysiology differentiating microvascular or macrovascular lesions. These results could have an impact on patients' medical treatment.
PubMed: 38892870
DOI: 10.3390/jcm13113159 -
International Journal of Molecular... May 2024The utility of serum glial fibrillary acidic protein (GFAP) in acute ischemic stroke (AIS) has been extensively studied in recent years. Here, we aimed to assess its...
The utility of serum glial fibrillary acidic protein (GFAP) in acute ischemic stroke (AIS) has been extensively studied in recent years. Here, we aimed to assess its potential role as a cargo protein of extracellular vesicles (EVs) secreted by astrocytes (ADEVs) in response to brain ischemia. Plasma samples from eighteen AIS patients at 24 h (D1), 7 days (D7), and one month (M1) post-symptoms onset, and nine age, sex, and cardiovascular risk factor-matched healthy controls were obtained to isolate EVs using the Exoquick ULTRA EV kit. Subsets of presumed ADEVs were identified further by the expression of the glutamate aspartate transporter (GLAST) as a specific marker of astrocytes with the Basic Exo-Flow Capture kit. Western blotting has tested the presence of GFAP in ADEV cargo. Post-stroke ADEV GFAP levels were elevated at D1 and D7 but not M1 compared to controls ( = 0.007, = 0.019, and = 0.344, respectively). Significant differences were highlighted in ADEV GFAP content at the three time points studied (n = 12, = 0.027) and between D1 and M1 (z = 2.65, = 0.023). A positive correlation was observed between the modified Rankin Scale (mRS) at D7 and ADEV GFAP at D1 (r = 0.58, = 0.010) and D7 (r = 0.57, = 0.013), respectively. ADEV GFAP may dynamically reflect changes during the first month post-ischemia. Profiling ADEVs from peripheral blood could provide a new way to assess the central nervous system pathology.
Topics: Humans; Glial Fibrillary Acidic Protein; Extracellular Vesicles; Male; Female; Ischemic Stroke; Astrocytes; Pilot Projects; Aged; Middle Aged; Biomarkers; Aged, 80 and over; Brain Ischemia; Case-Control Studies
PubMed: 38891912
DOI: 10.3390/ijms25115726 -
Scientific Reports Jun 2024Lipid metabolism is an important part of the heart's energy supply. The expression pattern and molecular mechanism of lipid metabolism-related genes (LMRGs) in acute...
Lipid metabolism is an important part of the heart's energy supply. The expression pattern and molecular mechanism of lipid metabolism-related genes (LMRGs) in acute myocardial infarction (AMI) are still unclear, and the link between lipid metabolism and immunity is far from being elucidated. In this study, 23 Common differentially expressed LMRGs were discovered in the AMI-related mRNA microarray datasets GSE61144 and GSE60993. These genes were mainly related to "leukotriene production involved in inflammatory response", "lipoxygenase pathway", "metabolic pathways", and "regulation of lipolysis in adipocytes" pathways. 12 LMRGs (ACSL1, ADCY4, ALOX5, ALOX5AP, CCL5, CEBPB, CEBPD, CREB5, GAB2, PISD, RARRES3, and ZNF467) were significantly differentially expressed in the validation dataset GSE62646 with their AUC > 0.7 except for ALOX5AP (AUC = 0.699). Immune infiltration analysis and Pearson correlation analysis explored the immune characteristics of AMI, as well as the relationship between these identified LMRGs and immune response. Lastly, the up-regulation of ACSL1, ALOX5AP, CEBPB, and GAB2 was confirmed in the mouse AMI model. Taken together, LMRGs ACSL1, ALOX5AP, CEBPB, and GAB2 are significantly upregulated in AMI patients' blood, peripheral blood of AMI mice, myocardial tissue of AMI mice, and therefore might be new potential biomarkers for AMI.
Topics: Myocardial Infarction; Lipid Metabolism; Humans; 5-Lipoxygenase-Activating Proteins; Gene Expression Profiling; Animals; Arachidonate 5-Lipoxygenase; Gene Expression Regulation; Mice; Male; Coenzyme A Ligases
PubMed: 38890389
DOI: 10.1038/s41598-024-65022-3 -
Experimental Physiology Jun 2024Skeletal muscle atrophy and dysfunction commonly accompany cardiovascular diseases such as peripheral arterial disease and may be partially attributable to systemic...
Skeletal muscle atrophy and dysfunction commonly accompany cardiovascular diseases such as peripheral arterial disease and may be partially attributable to systemic inflammation. We sought to determine whether acute systemic inflammation in a model of hindlimb ischaemia (HLI) could affect skeletal muscle macrophage infiltration, fibre size, or capillarization, independent of the ischaemia. Eight-week-old C57BL/6 male mice underwent either Sham or HLI surgery, and were killed 1, 3, or 7 days post-surgery. Circulating inflammatory cytokine concentrations were measured, as well as immune cell infiltration and morphology of skeletal muscle from both limbs of HLI and Sham mice. In HLI compared with Sham mice at day 1, plasma interleukin-1β levels were 216% higher (0.48 ± 0.10 vs. 0.15 ± 0.01 pg/μL, P = 0.005) and decreased by day 3. This was followed by increased macrophage presence in muscle from both ischaemic and non-ischaemic limbs of HLI mice by day 7 (7.3- and 2.3-fold greater than Sham, respectively, P < 0.0001). In HLI mice, muscle from the ischaemic limb had 21% lower fibre cross-sectional area than the non-ischaemic limb (724 ± 28 vs. 916 ± 46 μm, P = 0.01), but the non-ischaemic limb of HLI mice was no different from Sham. This shows that HLI induces acute systemic inflammation accompanied by immune infiltration in both ischaemic and remote skeletal muscle; however, this did not induce skeletal muscle atrophy in remote muscle within the 7-day time course of this study. This effect of local skeletal muscle ischaemia on the inflammatory status of remote skeletal muscle may signal a priming of muscle for subsequent atrophy over a longer time course. HIGHLIGHTS: What is the central question of this study? Does hindlimb ischaemia-induced inflammation cause acute immune, inflammatory and morphological alterations in remote non-ischaemic skeletal muscle? What is the main finding and its importance? Hindlimb ischaemia induced systemic inflammation with subsequent neutrophil and macrophage infiltration in both ischaemic and non-ischaemic skeletal muscle; however, morphological changes did not occur in non-ischaemic muscle within 7 days. These immune alterations may have functional implications that take longer than 7 days to manifest, and subsequent or prolonged systemic inflammation and immune infiltration of muscle could lead to morphological changes and functional decline.
PubMed: 38888281
DOI: 10.1113/EP091901 -
Journal of the American Heart... Jun 2024Popliteal artery aneurysms (PAAs) are the most common peripheral aneurysm. However, due to its rarity, the cumulative body of evidence regarding patient patterns,...
BACKGROUND
Popliteal artery aneurysms (PAAs) are the most common peripheral aneurysm. However, due to its rarity, the cumulative body of evidence regarding patient patterns, treatment strategies, and perioperative outcomes is limited. This analysis aims to investigate distinct phenotypical patient profiles and associated treatment and outcomes in patients with a PAA by performing an unsupervised clustering analysis of the POPART (Practice of Popliteal Artery Aneurysm Repair and Therapy) registry.
METHODS AND RESULTS
A cluster analysis (using k-means clustering) was performed on data obtained from the multicenter POPART registry (42 centers from Germany and Luxembourg). Sensitivity analyses were conducted to explore validity and stability. Using 2 clusters, patients were primarily separated by the absence or presence of clinical symptoms. Within the cluster of symptomatic patients, the main difference between patients with acute limb ischemia presentation and nonemergency symptomatic patients was PAA diameter. When using 6 clusters, patients were primarily grouped by comorbidities, with patients with acute limb ischemia forming a separate cluster. Despite markedly different risk profiles, perioperative complication rates appeared to be positively associated with the proportion of emergency patients. However, clusters with a higher proportion of patients having any symptoms before treatment experienced a lower rate of perioperative complications.
CONCLUSIONS
The conducted analyses revealed both an insight to the public health reality of PAA care as well as patients with PAA at elevated risk for adverse outcomes. This analysis suggests that the preoperative clinic is a far more crucial adjunct to the patient's preoperative risk assessment than the patient's epidemiological profile by itself.
Topics: Humans; Registries; Popliteal Artery; Aneurysm; Male; Female; Aged; Cluster Analysis; Germany; Risk Factors; Middle Aged; Treatment Outcome; Risk Assessment; Aged, 80 and over; Endovascular Procedures; Postoperative Complications; Popliteal Artery Aneurysm
PubMed: 38879461
DOI: 10.1161/JAHA.124.034429 -
The Journal of Surgical Research Jun 2024The influence of pack-year history and smoking cessation timing on postoperative morbidity and mortality in a highly comorbid cohort is uncertain. We examined whether...
INTRODUCTION
The influence of pack-year history and smoking cessation timing on postoperative morbidity and mortality in a highly comorbid cohort is uncertain. We examined whether the association between smoking and adverse postoperative events is modified by pack-year history and smoking cessation timing.
METHODS
We collected single-institution, retrospective data from consecutive patients undergoing open operations for carotid, aortic, and infrainguinal arterial disease. Active smoking was defined as smoking on the day of the index surgical intervention. Duration of smoking cessation was calculated as the time between smoking cessation and index surgery. The primary outcome was a composite of 30-day mortality and morbidity. Logistic and time-to-event Cox regressions estimated associations with interactions between cessation duration and pack-year history for nonactive smokers.
RESULTS
Between 2010 and 2019, 1087 patients underwent 1640 high-risk vascular interventions. Median pack-year history was 40.0 pack-years (interquartile range [IQR]: 20.0-60.0) among nonactive smokers and 46.0 pack-years (IQR: 31.0-61.0) among active smokers (P < 0.001). The median smoking cessation time was 15.5 y (IQR: 4.4-30.9). Smoking status did not independently predict an increased risk of postoperative mortality or morbidity (odds ratio [OR] = 0.99, P = 0.96). Among nonactive smokers, neither smoking cessation duration (OR = 0.99, P = 0.16) nor pack-year history (OR = 1.00, P = 0.88) were significantly associated with adverse events (interaction P = 0.11).
CONCLUSIONS
After high-risk vascular interventions in a single institution, active smoking, cessation period, and pack-year history are not associated with an increased risk of postoperative morbidity or mortality-highlighting the benefit of cessation as independent of frequency or intensity.
PubMed: 38878328
DOI: 10.1016/j.jss.2024.05.028 -
Stem Cells and Development Jun 2024Prolonged tissue ischemia and inflammation lead to organ deterioration and are often accompanied by microvasculature rarefaction, fibrosis, and elevated systemic Activin...
Prolonged tissue ischemia and inflammation lead to organ deterioration and are often accompanied by microvasculature rarefaction, fibrosis, and elevated systemic Activin A (ActA), the level of which frequently correlates with disease severity. Mesenchymal stromal cells are prevalent in the perivascular niche and are likely involved in tissue homeostasis and pathology. This study investigated the effects of inflammatory cells on modulation of phenotype of adipose stromal cell (ASC) and the role of ActA in this process. Peripheral blood mononuclear cells were activated with LPS (aPBMC) and presented to ASC. Expression of smooth muscle/myofibroblast markers and ActA, TGFβ1-3 and CTGF was assessed in ASC. Silencing approaches were used to dissect the signaling cascade of aPBMC-induced acquisition of a myofibroblast phenotype by ASC. ASC co-cultured with aPBMC or exposed to the secretome of aPBMC upregulated smooth muscle cell markers αSMA, SM22α, and Calponin I, increased contractility, and initiated expression of ActA. IL-1β was sufficient to replicate this response, whereas blocking IL-1β eliminated aPBMC effects. ASC-derived ActA stimulated CTGF and αSMA expression in ASC; the latter independent of CTGF. Induction of αSMA in ASC by IL-1β or ActA-enriched media relied on extracellular enzymatic activity. ActA upregulated mRNA levels of several extracellular matrix proteins in ASC, albeit to a lesser degree than TGFβ1, and marginally increased cell contractility. In conclusion, the study suggests that aPBMC induce myofibroblast phenotype with weak fibrotic activity in perivascular progenitors, like ASC, through the IL-1β-ActA signaling axis, which also promotes CTGF secretion and these effects require ActA extracellular enzymatic processing.
PubMed: 38877807
DOI: 10.1089/scd.2024.0092 -
Age and Ageing Jun 2024Peripheral artery disease (PAD) is the lower limb manifestation of systemic atherosclerotic disease. PAD may initially present with symptoms of intermittent... (Review)
Review
Peripheral artery disease (PAD) is the lower limb manifestation of systemic atherosclerotic disease. PAD may initially present with symptoms of intermittent claudication, whilst chronic limb-threatening ischaemia (CLTI), the end stage of PAD, presents with rest pain and/or tissue loss. PAD is an age-related condition present in over 10% of those aged ≥65 in high-income countries. Guidelines regarding definition, diagnosis and staging of PAD and CLTI have been updated to reflect the changing patterns and presentations of disease given the increasing prevalence of diabetes. Recent research has changed guidelines on optimal medical therapy, with low-dose anticoagulant plus aspirin recommended in some patients. Recently published randomised trials highlight where bypass-first or endovascular-first approaches may be optimal in infra-inguinal disease. New techniques in endovascular surgery have increased minimally invasive options for ever more complex disease. Increasing recognition has been given to the complexity of patients with CLTI where a high prevalence of both frailty and cognitive impairment are present and a significant burden of multi-morbidity and polypharmacy. Despite advances in minimally invasive revascularisation techniques and reduction in amputation incidence, survival remains poor for many with CLTI. Shared decision-making is essential, and conservative management is often appropriate for older patients. There is emerging evidence of the benefit of specialist geriatric team input in the perioperative management of older patients undergoing surgery for CLTI. Recent UK guidelines now recommend screening for frailty, cognitive impairment and delirium in older vascular surgery patients as well as recommending all vascular surgery services have support and input from specialist geriatrics teams.
Topics: Humans; Peripheral Arterial Disease; Aged; Endovascular Procedures; Risk Factors; Chronic Limb-Threatening Ischemia; Vascular Surgical Procedures; Age Factors; Practice Guidelines as Topic
PubMed: 38877714
DOI: 10.1093/ageing/afae114 -
Journal of the Korean Society of... May 2024To examine the technical considerations of endovascular treatment for aortoiliac occlusive disease (AIOD) based on a 10-year experience in Songklanagarind Hospital.
PURPOSE
To examine the technical considerations of endovascular treatment for aortoiliac occlusive disease (AIOD) based on a 10-year experience in Songklanagarind Hospital.
MATERIALS AND METHODS
This retrospective cohort study included 210 patients who underwent endovascular treatment for symptomatic AIOD between January 2010 and December 2020. The patients' clinical and lesion characteristics, including technical considerations of the procedure, were collected, analyzed, and stratified using the Transatlantic Inter-Society Consensus (TASC).
RESULTS
Most patients (80%) in this study had chronic limb-threatening ischemia lesions, with an occlusion rate of 37%. The technical success rate of TASC C & D was lower than that of TASC A & B, 84.4% vs. 99.2% ≤ 0.001. A technical success rate of 93.3% (14/15) was found for the femoral and brachial approach, compared with a success rate of 89.0% (57/64) for the unibifemoral approach in TASC C & D, without a statistically significant difference ( = 0.076). However, the puncture site complications in this route were up to 17.6%, which is the highest rate compared with other techniques. These complications could be treated either conservatively or minimally invasively.
CONCLUSION
In cases of failed femoral access, simultaneous femoral and brachial approaches improved the technical success rate of endovascular recanalization of TASC C & D aortoiliac occlusions.
PubMed: 38873374
DOI: 10.3348/jksr.2023.0116