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Bioscience Reports Jul 2023The mortality of heart failure after acute myocardial infarction (AMI) remains high. The aim of the present study was to analyze hub genes and immune infiltration in...
The mortality of heart failure after acute myocardial infarction (AMI) remains high. The aim of the present study was to analyze hub genes and immune infiltration in patients with AMI and heart failure (HF). The study utilized five publicly available gene expression datasets from peripheral blood in patients with AMI who either developed or did not develop HF. The unbiased patterns of 24 immune cell were estimated by xCell algorithm. Single-cell RNA sequencing data were used to examine the immune cell infiltration in heart failure patients. Hub genes were validated by quantitative reverse transcription-PCR (RT-qPCR). In comparison with the coronary heart disease (CHD) group, immune infiltration analysis of AMI patients showed that macrophages M1, macrophages, monocytes, natural killer (NK) cells, and NKT cells were the five most highly activated cell types. Five common immune-related genes (S100A12, AQP9, CSF3R, S100A9, and CD14) were identified as hub genes associated with AMI. Using RT-qPCR, we confirmed FOS, DUSP1, CXCL8, and NFKBIA as the potential biomarkers to identify AMI patients at risk of HF. The study identified several transcripts that differentiate between AMI and CHD, and between HF and non-HF patients. These findings could improve our understanding of the immune response in AMI and HF, and allow for early identification of AMI patients at risk of HF.
Topics: Humans; Heart Failure; Myocardial Infarction; Risk Assessment; Monocytes; Biomarkers
PubMed: 37334672
DOI: 10.1042/BSR20222552 -
Circulation. Cardiovascular... Jan 2024
Topics: Humans; Chronic Limb-Threatening Ischemia; Treatment Outcome; Peripheral Arterial Disease; Chronic Disease; Ischemia; Limb Salvage; Retrospective Studies; Risk Factors; Endovascular Procedures
PubMed: 38152882
DOI: 10.1161/CIRCINTERVENTIONS.123.013693 -
Current Cardiology Reports Nov 2023Peripheral artery disease (PAD) is an increasingly prevalent but frequently underdiagnosed condition that can be associated with high rates of morbidity and mortality.... (Review)
Review
PURPOSE OF REVIEW
Peripheral artery disease (PAD) is an increasingly prevalent but frequently underdiagnosed condition that can be associated with high rates of morbidity and mortality. While an initial noninvasive approach is the cornerstone of management, revascularization is often pursued for patients with treatment-refractory claudication or chronic limb-threatening ischemia (CLTI). In this review, we discuss the current state of endovascular interventions for PAD and explore the many new emerging technologies.
RECENT FINDINGS
The last decade has resulted in numerous advances in PAD interventions including the ongoing evolution of drug-coated devices, novel approaches to complex lesions, and contemporary evidence from large clinical trials for CLTI. Advances in endovascular management have allowed for increasingly complex lesions to be tackled percutaneously. Future directions for the field include the continued evolution in device technology, continued development of state-of-the-art techniques to revascularization of complex lesions, and increased collaboration between a largely multidisciplinary field.
Topics: Humans; Risk Factors; Endovascular Procedures; Treatment Outcome; Peripheral Arterial Disease; Intermittent Claudication; Ischemia; Limb Salvage; Retrospective Studies; Chronic Disease
PubMed: 37804391
DOI: 10.1007/s11886-023-01973-9 -
European Heart Journal Oct 2023Dipeptidyl peptidase 3 (DPP3) is a protease involved in the degradation of angiotensin II which disturbs peripheral blood pressure regulation and compromises left...
BACKGROUND AND AIMS
Dipeptidyl peptidase 3 (DPP3) is a protease involved in the degradation of angiotensin II which disturbs peripheral blood pressure regulation and compromises left ventricular function. This study examined the relationship of circulating DPP3 (cDPP3) with cardiogenic shock (CS) and mortality in patients presenting with acute coronary syndromes (ACS).
METHODS
Plasma cDPP3 levels were assessed at baseline and 12-24 h after presentation in patients with ACS prospectively enrolled into the multi-centre SPUM-ACS study (n = 4787).
RESULTS
Circulating DPP3 levels were associated with in-hospital CS when accounting for established risk factors including the ORBI risk score [per log-2 increase, hazard ratio (HR) 1.38, 95% confidence interval (CI) 1.05-1.82, P = .021]. High cDPP3 was an independent predictor of mortality at 30 days (HR 1.87, 95% CI 1.36-2.58, P < .001) and at one year (HR 1.61, 95% CI 1.28-2.02, P < .001) after adjustment for established risk factors and the GRACE 2.0 score. Compared to values within the normal range, persistently elevated cDPP3 levels at 12-24 h were associated with 13.4-fold increased 30-day mortality risk (HR 13.42, 95% CI 4.86-37.09, P < .001) and 5.8-fold increased 1-year mortality risk (HR 5.79, 95% CI 2.70-12.42, P < .001). Results were consistent across various patient subgroups.
CONCLUSIONS
This study identifies cDPP3 as a novel marker of CS and increased mortality in patients with ACS. Circulating DPP3 offers prognostic information beyond established risk factors and improves early risk assessment.
Topics: Humans; Shock, Cardiogenic; Acute Coronary Syndrome; Prognosis; Risk Factors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
PubMed: 37632743
DOI: 10.1093/eurheartj/ehad545 -
International Journal of Molecular... Nov 2023Critical limb ischemia incidence and prevalence have increased over the years. However, there are no successful treatments to improve quality of life and to reduce the... (Review)
Review
Critical limb ischemia incidence and prevalence have increased over the years. However, there are no successful treatments to improve quality of life and to reduce the risk of cardiovascular and limb events in these patients. Advanced regenerative therapies have focused their interest on the generation of new blood vessels to repair tissue damage through the use of stem cells. One of the most promising sources of stem cells with high potential in cell-based therapy is adipose-derived stem cells (ASCs). ASCs are adult mesenchymal stem cells that are relatively abundant and ubiquitous and are characterized by a multilineage capacity and low immunogenicity. The proangiogenic benefits of ASCs may be ascribed to: (a) paracrine secretion of proangiogenic molecules that may stimulate angiogenesis; (b) secretion of microvesicles/exosomes that are also considered as a novel therapeutic prospect for treating ischemic diseases; and (c) their differentiation capability toward endothelial cells (ECs). Although we know the proangiogenic effects of ASCs, the therapeutic efficacy of ASCs after transplantation in peripheral artery diseases patients is still relatively low. In this review, we evidence the potential therapeutic use of ASCs in ischemic regenerative medicine. We also highlight the main challenges in the differentiation of these cells into functional ECs. However, significant efforts are still needed to ascertain relevant transcription factors, intracellular signaling and interlinking pathways in endothelial differentiation.
Topics: Adult; Humans; Adipose Tissue; Endothelial Cells; Quality of Life; Ischemia; Stem Cells; Peripheral Arterial Disease; Cell Differentiation; Neovascularization, Physiologic
PubMed: 38069074
DOI: 10.3390/ijms242316752 -
Genome Medicine Nov 2023Chronic limb-threatening ischemia (CLTI), a severe manifestation of peripheral arterial disease (PAD), is associated with a 1-year limb amputation rate of approximately...
BACKGROUND
Chronic limb-threatening ischemia (CLTI), a severe manifestation of peripheral arterial disease (PAD), is associated with a 1-year limb amputation rate of approximately 15-20% and substantial mortality. A key feature of CLTI is the compromised regenerative ability of skeletal muscle; however, the mechanisms responsible for this impairment are not yet fully understood. In this study, we aim to delineate pathological changes at both the cellular and transcriptomic levels, as well as in cell-cell signaling pathways, associated with compromised muscle regeneration in limb ischemia in both human tissue samples and murine models of CLTI.
METHODS
We performed single-cell transcriptome analysis of ischemic and non-ischemic muscle from the same CLTI patients and from a murine model of CLTI. In both datasets, we analyzed gene expression changes in macrophage and muscle satellite cell (MuSC) populations as well as differential cell-cell signaling interactions and differentiation trajectories.
RESULTS
Single-cell transcriptomic profiling and immunofluorescence analysis of CLTI patient skeletal muscle demonstrated that ischemic-damaged tissue displays a pro-inflammatory macrophage signature. Comparable results were observed in a murine CLTI model. Moreover, integrated analyses of both human and murine datasets revealed premature differentiation of MuSCs to be a key feature of failed muscle regeneration in the ischemic limb. Furthermore, in silico inferences of intercellular communication and in vitro assays highlight the importance of macrophage-MuSC signaling in ischemia induced muscle injuries.
CONCLUSIONS
Collectively, our research provides the first single-cell transcriptome atlases of skeletal muscle from CLTI patients and a murine CLTI model, emphasizing the crucial role of macrophages and inflammation in regulating muscle regeneration in CLTI through interactions with MuSCs.
Topics: Humans; Animals; Mice; Satellite Cells, Skeletal Muscle; Muscle, Skeletal; Ischemia; Cell Differentiation; Regeneration; Macrophages; Risk Factors; Treatment Outcome; Retrospective Studies
PubMed: 37950327
DOI: 10.1186/s13073-023-01250-y -
Brain, Behavior, and Immunity Feb 2024Acute cerebral ischemia triggers a profound inflammatory response. While macrophages polarized to an M2-like phenotype clear debris and facilitate tissue repair,...
Acute cerebral ischemia triggers a profound inflammatory response. While macrophages polarized to an M2-like phenotype clear debris and facilitate tissue repair, aberrant or prolonged macrophage activation is counterproductive to recovery. The inhibitory immune checkpoint Programmed Cell Death Protein 1 (PD-1) is upregulated on macrophage precursors (monocytes) in the blood after acute cerebrovascular injury. To investigate the therapeutic potential of PD-1 activation, we immunophenotyped circulating monocytes from patients and found that PD-1 expression was upregulated in the acute period after stroke. Murine studies using a temporary middle cerebral artery (MCA) occlusion (MCAO) model showed that intraperitoneal administration of soluble Programmed Death Ligand-1 (sPD-L1) significantly decreased brain edema and improved overall survival. Mice receiving sPD-L1 also had higher performance scores short-term, and more closely resembled sham animals on assessments of long-term functional recovery. These clinical and radiographic benefits were abrogated in global and myeloid-specific PD-1 knockout animals, confirming PD-1+ monocytes as the therapeutic target of sPD-L1. Single-cell RNA sequencing revealed that treatment skewed monocyte maturation to a non-classical Ly6C, CD43, PD-L1+ phenotype. These data support peripheral activation of PD-1 on inflammatory monocytes as a therapeutic strategy to treat neuroinflammation after acute ischemic stroke.
Topics: Humans; Mice; Animals; Monocytes; Ischemic Stroke; Brain Edema; Programmed Cell Death 1 Receptor; B7-H1 Antigen; Infarction, Middle Cerebral Artery
PubMed: 38070624
DOI: 10.1016/j.bbi.2023.12.007 -
Journal of the American Heart... Aug 2023Background Peripheral arterial disease and critical limb ischemia are cardiovascular complications associated with vascular insufficiency, oxidative metabolic...
Background Peripheral arterial disease and critical limb ischemia are cardiovascular complications associated with vascular insufficiency, oxidative metabolic dysfunction, and myopathy in the limbs. Estrogen-related receptor gamma (ERRγ) has emerged as a dual regulator of paracrine angiogenesis and oxidative metabolism through transgenic mouse studies. Here our objective was to investigate whether postischemic intramuscular targeting of ERRγ via gene therapy promotes ischemic recovery in a preclinical model of peripheral arterial disease/critical limb ischemia. Methods and Results Adeno-associated virus 9 (AAV9) gene delivery vector was developed and first tested via intramuscular injection in murine skeletal muscle. AAV9-Esrrg robustly increased ERRγ protein expression, induced angiogenic and oxidative genes, and boosted capillary density and succinate dehydrogenase oxidative metabolic activity in skeletal muscles of C57Bl/6J mice. Next, hindlimb ischemia was induced via unilateral femoral vessel ligation in mice, followed by intramuscular AAV9-Esrrg (or AAV9-green fluorescent protein) gene delivery 24 hours after injury. ERRγ overexpression increased ischemic neoangiogenesis and markers of endothelial activation, and significantly improved ischemic revascularization measured using laser Doppler flowmetry. Moreover, ERRγ overexpression restored succinate dehydrogenase oxidative metabolic capacity in ischemic muscle, which correlated with increased mitochondrial respiratory complex protein expression. Most importantly, myofiber size to number quantification revealed that AAV9-Esrrg restores myofibrillar size and mitigates ischemia-induced myopathy. Conclusions These results demonstrate that intramuscular AAV9-Esrrg delivery rescues ischemic pathology after hindlimb ischemia, underscoring that gene therapy or pharmacological activation could be a promising strategy for the management of peripheral arterial disease/critical limb ischemia.
Topics: Mice; Animals; Succinate Dehydrogenase; Chronic Limb-Threatening Ischemia; Neovascularization, Physiologic; Muscle, Skeletal; Genetic Therapy; Mice, Transgenic; Peripheral Arterial Disease; Ischemia; Estrogens; Hindlimb; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 37548153
DOI: 10.1161/JAHA.122.028880 -
The Canadian Journal of Cardiology Dec 2023Recent studies have shown that breast arterial calcification (BAC) detected on screening mammography is linked to cardiovascular diseases via medial calcification.... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Recent studies have shown that breast arterial calcification (BAC) detected on screening mammography is linked to cardiovascular diseases via medial calcification. However, its effect on cardiovascular outcomes remains unclear. Therefore, we conducted a meta-analysis to determine the effect of BAC on cardiovascular outcomes in patients.
METHODS
Three electronic databases (Pubmed, Embase, and Scopus) were searched on May 1, 2022, for studies examining the relationship between BAC and cardiovascular outcomes including cardiac death, acute myocardial infarction, ischemic heart disease, stroke, peripheral artery disease, and heart failure. A random-effects meta-analysis model was used to summarise the studies.
RESULTS
A total of 5 longitudinal studies were included with a combined cohort of 87,865 patients. Significantly, the pooled risk ratio (RR) of the association between BAC and cardiac death was 2.06 (P < 0.00001). BAC was associated with a significantly increased risk of developing other cardiovascular diseases, such as ischemic/hemorrhagic stroke (RR 1.51; P = 0.003), ischemic stroke (RR 1.82; P < 0.00001), peripheral vascular disease (RR 1.24; P = 0.003), and heart failure (RR 1.84; P < 0.00001). There was no significant relationship for developing myocardial infarction or for total cardiovascular diseases.
CONCLUSIONS
Our findings suggest that BAC was associated with an increased risk of cardiovascular mortality, and certain cardiovascular outcomes. There is thus a potential to use BAC as a sex-specific cardiovascular risk assessment tool. Furthermore, there is a need for more widespread reporting of BAC to better understand the pathophysiologic mechanisms behind its correlation with cardiovascular disease and to apply it in clinical practice.
Topics: Female; Male; Humans; Cardiovascular Diseases; Breast; Mammography; Breast Neoplasms; Risk Factors; Early Detection of Cancer; Breast Diseases; Myocardial Infarction; Heart Failure; Death
PubMed: 37506765
DOI: 10.1016/j.cjca.2023.07.024 -
Journal of Neuroinflammation Sep 2023Receptor-interacting protein kinase 2 (RIPK2) is a serine/threonine kinase whose activity propagates inflammatory signaling through its association with pattern...
BACKGROUND
Receptor-interacting protein kinase 2 (RIPK2) is a serine/threonine kinase whose activity propagates inflammatory signaling through its association with pattern recognition receptors (PRRs) and subsequent TAK1, NF-κB, and MAPK pathway activation. After stroke, dead and dying cells release a host of damage-associated molecular patterns (DAMPs) that activate PRRs and initiate a robust inflammatory response. We hypothesize that RIPK2 plays a damaging role in the progression of stroke injury by enhancing the neuroinflammatory response to stroke and that global genetic deletion or microglia-specific conditional deletion of Ripk2 will be protective following ischemic stroke.
METHODS
Adult (3-6 months) male mice were subjected to 45 min of transient middle cerebral artery occlusion (tMCAO) followed by 24 h, 48 h, or 28 days of reperfusion. Aged male and female mice (18-24 months) were subjected to permanent ischemic stroke and sacrificed 48 h later. Infarct volumes were calculated using TTC staining (24-48 h) or Cresyl violet staining (28d). Sensorimotor tests (weight grip, vertical grid, and open field) were performed at indicated timepoints. Blood-brain barrier (BBB) damage, tight junction proteins, matrix metalloproteinase-9 (MMP-9), and neuroinflammatory markers were assessed via immunoblotting, ELISA, immunohistochemistry, and RT-qPCR. Differential gene expression profiles were generated through bulk RNA sequencing and nanoString.
RESULTS
Global genetic deletion of Ripk2 resulted in decreased infarct sizes and reduced neuroinflammatory markers 24 h after stroke compared to wild-type controls. Ripk2 global deletion also improved both acute and long-term behavioral outcomes with powerful effects on reducing infarct volume and mortality at 28d post-stroke. Conditional deletion of microglial Ripk2 (mKO) partially recapitulated our results in global Ripk2 deficient mice, showing reductive effects on infarct volume and improved behavioral outcomes within 48 h of injury. Finally, bulk transcriptomic profiling and nanoString data demonstrated that Ripk2 deficiency in microglia decreases genes associated with MAPK and NF-κB signaling, dampening the neuroinflammatory response after stroke injury by reducing immune cell activation and peripheral immune cell invasion.
CONCLUSIONS
These results reveal a hitherto unknown role for RIPK2 in the pathogenesis of ischemic stroke injury, with microglia playing a distinct role. This study identifies RIPK2 as a potent propagator of neuroinflammatory signaling, highlighting its potential as a therapeutic target for post-stroke intervention.
Topics: Female; Mice; Male; Animals; Microglia; Neuroinflammatory Diseases; NF-kappa B; Stroke; Infarction, Middle Cerebral Artery; Inflammation; Infarction; Ischemic Stroke; Protein Kinases; Brain Ischemia
PubMed: 37777791
DOI: 10.1186/s12974-023-02907-6