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The American Journal of Emergency... Dec 2023Acute limb ischemia is a rare but serious condition that carries with it a high rate of morbidity and mortality. (Review)
Review
INTRODUCTION
Acute limb ischemia is a rare but serious condition that carries with it a high rate of morbidity and mortality.
OBJECTIVE
This review highlights the pearls and pitfalls of acute limb ischemia, including presentation, diagnosis, and management in the emergency department (ED) based on current evidence.
DISCUSSION
Acute limb ischemia is defined as a sudden decrease in limb perfusion resulting in cessation of blood flow and nutrient and oxygen delivery to the tissues. This leads to cellular injury and necrosis, ultimately resulting in limb loss and potentially systemic symptoms with significant morbidity and mortality. There are several etiologies including native arterial thrombosis, arterial thrombosis after an intervention, arterial embolus, and arterial injury. Patients with acute limb ischemia most commonly present with severe pain and sensory changes in the initial stages, with prolonged ischemia resulting in weakness, sensory loss, and color changes to the affected limb. The emergency clinician should consult the vascular specialist as soon as ischemia is suspected, as the diagnosis should be based on the history and examination. Computed tomography angiography is the first line imaging modality, as it provides valuable information concerning the vasculature and surrounding tissues. Doppler ultrasound of the distal pulses may also be obtained to evaluate for arterial and venous flow. Once identified, management includes intravenous unfractionated heparin and vascular specialist consultation for revascularization.
CONCLUSIONS
An understanding of acute limb ischemia can assist emergency clinicians in diagnosing and managing this potentially deadly disease.
Topics: Humans; Heparin; Prevalence; Ischemia; Arterial Occlusive Diseases; Thrombosis; Peripheral Vascular Diseases; Acute Disease
PubMed: 37844359
DOI: 10.1016/j.ajem.2023.09.052 -
Journal of Neuroinflammation Oct 2023Stroke is the most common cause of long-term disability and places a high economic burden on the global healthcare system. Functional outcomes from stroke are largely...
Stroke is the most common cause of long-term disability and places a high economic burden on the global healthcare system. Functional outcomes from stroke are largely determined by the extent of ischemic injury, however, there is growing recognition that systemic inflammatory responses also contribute to outcomes. Mast cells (MCs) rapidly respond to injury and release histamine (HA), a pro-inflammatory neurotransmitter that enhances inflammation. The gut serves as a major reservoir of HA. We hypothesized that cromolyn, a mast cell stabilizer that prevents the release of inflammatory mediators, would decrease peripheral and central inflammation, reduce MC trafficking to the brain, and improve stroke outcomes. We used the transient middle cerebral artery occlusion (MCAO) model of ischemic stroke in aged (18 mo) male mice to investigate the role of MC in neuroinflammation post-stroke. After MCAO we treated mice with 25 mg/kg body weight of cromolyn (MC stabilizer) by oral gavage. Cromolyn was administered at 3 h, 10 h, 24 h and every 24 h for 3 days post-stroke. Three control groups were used. One group underwent a sham surgery and was treated with cromolyn, one received sham surgery with PBS vehicle and the third underwent MCAO with PBS vehicle. Mice were euthanized at 24 h and 3 days post-stroke. Cromolyn administration significantly reduced MC numbers in the brain at both 24 h and 3 days post-stroke. Infarct volume was not significantly different between groups, however improved functional outcomes were seen at 3 days post-stroke in mice that received cromolyn. Treatment with cromolyn reduced plasma histamine and IL-6 levels in both the 24-h and 3-day cohorts. Gut MCs numbers were significantly reduced after cromolyn treatment at 24 h and 3 days after stroke. To determine if MC trafficking from the gut to the brain occurred after injury, GFPMCs were adoptively transferred to c-kit MC knock-out animals prior to MCAO. 24 h after stroke, elevated MC recruitment was seen in the ischemic brain. Preventing MC histamine release by cromolyn improved gut barrier integrity and an improvement in stroke-induced dysbiosis was seen with treatment. Our results show that preventing MC histamine release possesses prevents post-stroke neuroinflammation and improves neurological and functional outcomes.
Topics: Humans; Mice; Male; Animals; Histamine Release; Mast Cells; Cromolyn Sodium; Histamine; Neuroinflammatory Diseases; Stroke; Inflammation; Infarction, Middle Cerebral Artery; Ischemia
PubMed: 37805585
DOI: 10.1186/s12974-023-02887-7 -
Biomedicine & Pharmacotherapy =... Oct 2023Cannabinoids are vasoactive substances that act as key regulators of arterial tone in the blood vessels supplying peripheral tissues and the central nervous system. This...
BACKGROUND AND PURPOSE
Cannabinoids are vasoactive substances that act as key regulators of arterial tone in the blood vessels supplying peripheral tissues and the central nervous system. This study aimed to investigate the potential of R-(+)-WIN55212-2 (WIN), a cannabinoid receptor 1 agonist (CB1), as a treatment for retinal ischemia/reperfusion (I/R) injury.
EXPERIMENTAL APPROACH
Male Wistar rats were subjected to retinal I/R injury by increasing intraocular pressure in the anterior chamber. The rats were randomly divided into four groups: normal control, I/R, vehicle (pre-treated with dimethyl sulfoxide [DMSO] via intraperitoneal injection), and experimental (pre-treated with WIN at a dose of 1 ml/kg via intraperitoneal injection). The rats were sacrificed at different time points of reperfusion (1 hour, 3 hours, 6 hours, and 1 day) after inducing retinal I/R injury, and their retinas were collected for analysis. Oxygen-glucose deprived/reperfusion (OGD/R) was performed by initially perfusing the retinas with oxygenated artificial cerebrospinal fluid (ACSF), then switching to an OGD solution to simulate ischemia, followed by another perfusion with ACSF. Pericyte contraction and the "no-reflow" phenomenon were observed using infrared differential interference contrast (IR-DIC) microscopy and immunohistochemistry. Western blot, enzyme-linked immunosorbent assay (ELISA), and nitric oxide (NO) detection were used to explore the potential mechanism.
KEY RESULTS
In both the OGD/R and I/R models, retinal pericytes exhibited persistent contraction even after reperfusion. The ability of WIN to regulate the tone of retinal pericytes and capillaries was specifically blocked by the BKCa inhibitor iberiotoxin (100 nM). WIN demonstrated a protective effect against retinal I/R injury by preserving blood flow in vessels containing pericytes. Pretreatment with WIN alleviated the persistent contraction and apoptosis of retinal pericytes in I/R-induced rats, accompanied by a reduction in intracellular calcium ion (Ca) concentration. The expression of CB1 decreased in a time-dependent manner in the I/R group. After I/R injury, endothelium-derived nitric oxide (eNOS) levels were reduced at all time points, which was successfully reversed by WIN therapy except for the 1 day group. Additionally, the downregulation of cyclic guanosine monophosphate (cGMP) and BKCa expression at 3 hours, 6 hours, and 1 day after I/R injury was restored by pretreatment of WIN.
CONCLUSIONS & IMPLICATIONS
WIN exerted its protective effects on retinal I/R injury by inhibiting the contraction and apoptosis of pericytes through the CB1-eNOS-cGMP-BKCa signaling pathway, thus ameliorated the occlusion of retinal capillaries.
Topics: Rats; Male; Animals; Pericytes; Microcirculation; Rats, Wistar; Cannabinoid Receptor Agonists; Benzoxazines; Ischemia; Reperfusion Injury
PubMed: 37572634
DOI: 10.1016/j.biopha.2023.115197 -
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 -
CNS Neuroscience & Therapeutics Apr 2024Peripheral immune cells infiltrating into the brain trigger neuroinflammation after an ischemic stroke. Partial immune cells reprogram their function for neural repair....
AIMS
Peripheral immune cells infiltrating into the brain trigger neuroinflammation after an ischemic stroke. Partial immune cells reprogram their function for neural repair. Which immune cells promote ischemic brain recovery needs further identification.
METHODS
We performed single-cell transcriptomic profiling of CD45 immune cells isolated from the ischemic hemisphere at subacute (5 days) and chronic (14 days) stages after ischemic stroke.
RESULTS
A subset of phagocytic macrophages was associated with neuron projection regeneration and tissue remodeling. We also identified a unique type of T cells with highly expressed macrophage markers, including C1q, Apoe, Hexb, and Fcer1g, which showed high abilities in tissue remodeling, myelination regulation, wound healing, and anti-neuroinflammation. Moreover, natural killer cells decreased cytotoxicity and increased energy and metabolic function in the chronic stage after ischemic stroke. Two subgroups of neutrophils upregulated CCL signals to recruit peripheral immune cells and released CXCL2 to keep self-recruiting at the chronic stage.
CONCLUSIONS
We identified subsets of peripheral immune cells that may provide potential therapeutic targets for promoting poststroke recovery.
Topics: Mice; Animals; Infarction, Middle Cerebral Artery; Stroke; Macrophages; Brain; Ischemic Stroke
PubMed: 37905680
DOI: 10.1111/cns.14518 -
Clinical and Translational Science Nov 2023This study measured serum high mobility group box 1 (HMGB1) levels in patients with acute myocardial infarction (AMI) and/or heart failure (HF) and evaluated their...
This study measured serum high mobility group box 1 (HMGB1) levels in patients with acute myocardial infarction (AMI) and/or heart failure (HF) and evaluated their relationship with peripheral inflammatory biomarkers and cardiac biomarkers, which have not been reported before. Of the patients, 55 had AMI without HF (AMI ), 42 had AMI with HF (AMI ), and 60 had HF without AMI (HF ) compared with 50 healthy controls. Blood samples were collected to assess serum HMGB1 levels and blood test-related inflammatory biomarkers (e.g., erythrocyte sedimentation rate [ESR], hs-CRP, uric acid, and white blood cell count) and cardiac biomarkers (e.g., MYO, cTnI, CKMB, CK, NT-proBNP, LDH, aspartate aminotransferase [AST], and alanine aminotransferase [ALT]). Compared to healthy controls, three groups of patients, especially those with AMI , had significantly higher levels of serum HMGB1. All tested inflammatory biomarkers (except uric acid) were significantly positively correlated with HMGB1 in patients with AMI patients but not in patients with non-AMI. In addition, all tested cardiac biomarkers (except NT-proBNP in AMI ) were significantly higher in patients with AMI than in control individuals. The levels of MYO, cTnI, CKMB, CK, AST, and ALT were not significantly changed in patients with HF compared to control individuals, but were still much lower than those in patients with AMI (except ALT). In all patients, the levels of NT-proBNP, and cTnI were significantly correlated with HMGB1 levels. Except for MYO, LDH, AST, and ALT, all cardiac biomarkers in AMI and AMI showed a significant correlation with HMGB1. Among risk factors, hypertension, diabetes, previous heart disease, and reduced left ventricular ejection fraction showed a significant correlation with HMGB1 in all disease groups.
Topics: Humans; Biomarkers; Heart Failure; HMGB1 Protein; Myocardial Infarction; Stroke Volume; Uric Acid; Ventricular Function, Left
PubMed: 37775976
DOI: 10.1111/cts.13630 -
Phytotherapy Research : PTR Dec 2023The ischemic brain can dialogue with peripheral tissues through the immune system. Ginkgo biloba extract (EGb) was used to regulate various neurological disorders;...
The ischemic brain can dialogue with peripheral tissues through the immune system. Ginkgo biloba extract (EGb) was used to regulate various neurological disorders; however, the impact of EGb on ischemic stroke is still unclear. Here, we aimed to investigate whether immunomodulation has participated in the beneficial effects of EGb on ischemia/reperfusion (I/R) brain injury. Mice were orally administered with EGb once daily for 7 days before the induction of I/R. Neurobehavioral scores, infarct volume, and brain inflammation were determined. The proportion of CD4 T cells was detected by flow cytometry. EGb significantly lowered neurobehavioral scores, infarct volume, and the level of inflammatory cytokines in I/R mice. Interestingly, EGb altered the proportion of CD4 T cells, particularly increasing the proportion of Treg cells. Depletion of Treg cells weakened the neuroprotective effects of EGb on ischemic stroke; furthermore, EGb decreased the expression of HIF-1α and HK2 and promoted the differentiation of Treg cells in vitro. EGb suppressed the HIF-1α/HK2 signaling pathway to promote the differentiation of Treg cells and ameliorate ischemic stroke in mice. The expansion effect of EGb on Treg cells could be exploited as part of future stroke therapy.
Topics: Mice; Animals; Ginkgo biloba; Ischemic Stroke; T-Lymphocytes, Regulatory; Plant Extracts; Infarction
PubMed: 37655539
DOI: 10.1002/ptr.7988 -
The American Journal of Cardiology Oct 2023Sacubitril-valsartan is an angiotensin receptor-neprilysin inhibitor (ARNI) associated with a decreased risk of death and hospitalization for selected patients with... (Meta-Analysis)
Meta-Analysis Review
Sacubitril-valsartan is an angiotensin receptor-neprilysin inhibitor (ARNI) associated with a decreased risk of death and hospitalization for selected patients with heart failure (HF). However, its association with improved atherosclerotic cardiovascular disease (ASCVD) events remains unclear. We performed a meta-analysis to evaluate the association of ARNI with ASCVD events in patients with HF. We systematically searched PubMed, Embase, Cochrane, and ClinicalTrials.gov for studies comparing ARNIs with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) in terms of myocardial infarction, stroke, angina pectoris, peripheral artery disease, and the composite end point in patients with HF. A total of 8 randomized controlled trials were included, with 17,541 patients assigned to either the ARNI (8,764 patients) or ACEi/ARB (8,777 patients) groups. The incidence of composite end point (risk ratio [RR] 1.03, 95% confidence interval [CI] 0.93 to 1.13, p = 0.63), myocardial infarction (RR 1.02, 95% CI 0.81 to 1.30, p = 0.85), angina pectoris (RR 0.96, 95% CI 0.80 to 1.17, p = 0.70), and stroke (RR 0.99, 95% CI 0.85 to 1.16, p = 0.93) were not statistically different between the ARNI and ACEi/ARB groups. However, ARNI was associated with a higher incidence of peripheral artery disease (RR 1.63, 95% CI 1.05 to 2.52, p = 0.03). In conclusion, this meta-analysis found no association between ARNI therapy and improved ASCVD events in patients with HF.
Topics: Humans; Angiotensin-Converting Enzyme Inhibitors; Angiotensin Receptor Antagonists; Neprilysin; Cardiovascular Diseases; Randomized Controlled Trials as Topic; Atherosclerosis; Antihypertensive Agents; Peripheral Arterial Disease; Angina Pectoris; Myocardial Infarction; Stroke; Heart Failure; Antiviral Agents
PubMed: 37619492
DOI: 10.1016/j.amjcard.2023.07.154 -
Polish Archives of Internal Medicine Oct 2023Despite availability of effective preventive therapies based on guidelines, patients with vascular diseases continue to be at a high risk for recurrent ischemic events.... (Review)
Review
Despite availability of effective preventive therapies based on guidelines, patients with vascular diseases continue to be at a high risk for recurrent ischemic events. Therefore, novel therapeutic strategies are required to further reduce the residual risk present in these patients. Platelet aggregation and fibrin organization are involved in arterial thrombosis. Rivaroxaban is capable of targeting both processes and has a synergistic effect when used in combination with acetylsalicylic acid (ASA), providing the so‑called dual pathway inhibition (DPI). The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial showed that the DPI (a combination of rivaroxaban at 2.5 mg twice daily [vascular dose] and ASA at 100 mg once daily) reduced cardiovascular death, stroke, or myocardial infarction by 24% in patients with chronic coronary artery disease (CAD) and peripheral artery disease (PAD). Subsequently, the VOYAGER PAD (Vascular Outcomes Study of ASA Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD) trial confirmed the effectiveness of the vascular dose of rivaroxaban in patients with PAD after lower‑extremity revascularization, as compared with ASA alone. Therefore, DPI is recommended in the patients with CAD (+/- PAD) or symptomatic PAD at a high risk of ischemia. The purpose of this review is to examine the clinical benefits and practical implications of DPI in the CAD and PAD patients.
Topics: Humans; Rivaroxaban; Cardiovascular Diseases; Platelet Aggregation Inhibitors; Outpatients; Factor Xa Inhibitors; Drug Therapy, Combination; Aspirin; Peripheral Arterial Disease; Ischemia
PubMed: 37738024
DOI: 10.20452/pamw.16566 -
Methodist DeBakey Cardiovascular Journal 2023Peripheral arterial disease (PAD) represents a global health concern with a rising prevalence attributed to factors such as obesity, diabetes, aging, and smoking. Among... (Review)
Review
Peripheral arterial disease (PAD) represents a global health concern with a rising prevalence attributed to factors such as obesity, diabetes, aging, and smoking. Among patients with PAD, chronic limb-threatening ischemia (CLTI) is the most severe manifestation, associated with substantial morbidity and mortality. While revascularization remains the primary therapy for CLTI, not all patients are candidates for such interventions, highlighting the need for alternative approaches. Impaired angiogenesis, the growth of new blood vessels, is a central feature of PAD, and despite decades of research, effective clinical treatments remain elusive. Epigenetics, the study of heritable changes in gene expression, has gained prominence in understanding PAD pathogenesis. Here, we explore the role of epigenetic regulation in angiogenesis within the context of PAD, with a focus on long non-coding RNAs and fibroblast-endothelial cell transdifferentiation. Additionally, we discuss the interplay between metabolic control and epigenetic regulation, providing insights into potential novel therapeutic avenues for improving PAD treatments. This review aims to offer a concise update on the application of epigenetics in angiogenesis and PAD research, inspiring further investigations in this promising field.
Topics: Humans; Epigenesis, Genetic; Peripheral Arterial Disease; Ischemia
PubMed: 38028966
DOI: 10.14797/mdcvj.1294