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Pharmaceutics Apr 2024To better understand ischaemia-related molecular alterations, temporal changes in angiogenic Aminopeptidase N (APN/CD13) expression and glucose metabolism were assessed...
BACKGROUND
To better understand ischaemia-related molecular alterations, temporal changes in angiogenic Aminopeptidase N (APN/CD13) expression and glucose metabolism were assessed with PET using a rat model of peripheral arterial disease (PAD).
METHODS
The mechanical occlusion of the base of the left hindlimb triggered using a tourniquet was applied to establish the ischaemia/reperfusion injury model in Fischer-344 rats. 2-[F]FDG and [Ga]Ga-NOTA-c(NGR) PET imaging performed 1, 3, 5, 7, and 10 days post-ischaemia induction was followed by Western blotting and immunohistochemical staining for APN/CD13 in ischaemic and control muscle tissue extracts.
RESULTS
Due to a cellular adaptation to hypoxia, a gradual increase in [Ga]Ga-NOTA-c(NGR) and 2-[F]FDG uptake was observed from post-intervention day 1 to 7 in the ischaemic hindlimbs, which was followed by a drop on day 10. Conforming pronounced angiogenic recovery, the NGR accretion of the ischaemic extremities differed significantly from the controls 5, 7, and 10 days after ischaemia induction ( ≤ 0.05), which correlated with the Western blot and immunohistochemical results. No remarkable radioactivity was depicted between the normally perfused hindlimbs of either the ischaemic or the control groups.
CONCLUSIONS
The PET-based longitudinal assessment of angiogenesis-associated APN/CD13 expression and glucose metabolism during ischaemia may continue to broaden our knowledge on the pathophysiology of PAD.
PubMed: 38675203
DOI: 10.3390/pharmaceutics16040542 -
International Journal of Molecular... Apr 2024The circadian rhythms generated by the master biological clock located in the brain's hypothalamus influence central physiological processes. At the molecular level, a... (Review)
Review
The circadian rhythms generated by the master biological clock located in the brain's hypothalamus influence central physiological processes. At the molecular level, a core set of clock genes interact to form transcription-translation feedback loops that provide the molecular basis of the circadian rhythm. In animal models of disease, a desynchronization of clock genes in peripheral tissues with the central master clock has been detected. Interestingly, patients with vascular dementia have sleep disorders and irregular sleep patterns. These alterations in circadian rhythms impact hormonal levels, cardiovascular health (including blood pressure regulation and blood vessel function), and the pattern of expression and activity of antioxidant enzymes. Additionally, oxidative stress in vascular dementia can arise from ischemia-reperfusion injury, amyloid-beta production, the abnormal phosphorylation of tau protein, and alterations in neurotransmitters, among others. Several signaling pathways are involved in the pathogenesis of vascular dementia. While the precise mechanisms linking circadian rhythms and vascular dementia are still being studied, there is evidence to suggest that maintaining healthy sleep patterns and supporting proper circadian rhythm function may be important for reducing the risk of vascular dementia. Here, we reviewed the main mechanisms of action of molecular targets related to the circadian cycle and oxidative stress in vascular dementia.
Topics: Animals; Humans; Circadian Clocks; Circadian Rhythm; Dementia, Vascular; Oxidative Stress; Signal Transduction; Molecular Targeted Therapy
PubMed: 38673986
DOI: 10.3390/ijms25084401 -
Journal of Clinical Medicine Apr 2024The presence of a primary cardiac tumor in a pediatric patient is a rare echocardiographic finding.
BACKGROUND
The presence of a primary cardiac tumor in a pediatric patient is a rare echocardiographic finding.
CASE REPORT
We report the case of an 11-year-old female patient with multiple peripheral embolisms, due to a gigantic left ventricular tumor, with a unique echocardiographic appearance. The patient was referred to the emergency department due to acute pain and loss of sensitivity in both of her legs. Past medical history was significant for acute lymphoblastic leukemia. Upon physical examination, suspicion of bilateral lower leg ischemia was raised. Doppler arterial ultrasound of both legs confirmed the suspicion mentioned above, as the right lower extremity suffered from partial arterial occlusion of the external iliac artery and total occlusion of the femoral arteries. Meanwhile, in the left lower extremity, the occlusion was localized in the proximal tibio-peroneal artery. Cardiac sonography revealed a massive, mobile, left ventricular intracavitary mass. Aside from its large dimensions (6.3 cm by 3 cm), its aspect was striking as well as it had very mobile and friable edges. Emergency bilateral endarterectomy and excision of the left ventricular tumor were performed alongside systemic anticoagulant therapy, with excellent results, as no tumoral residual masses could be seen in the left ventricle, and the arterial blood flow was restored completely in both lower extremities. The histopathological aspect of the excised masses was that of a myxoma. The patient recovered well after surgery and was discharged on postoperative day 14.
CONCLUSION
Despite only a handful of cases of cardiac myxomas being reported due to their rarity in the pediatric population, clinical presentation with peripheric embolism triggered a high index of suspicion of embolic mechanism in our patient and prompted a rapid assessment and successful management.
PubMed: 38673460
DOI: 10.3390/jcm13082189 -
Biomedicines Apr 2024Chronic limb-threatening ischemia (CLTI), the advanced stage of peripheral arterial disease, is diagnosed in the presence of ischemic rest pain, non-healing ulcers, or... (Review)
Review
BACKGROUND
Chronic limb-threatening ischemia (CLTI), the advanced stage of peripheral arterial disease, is diagnosed in the presence of ischemic rest pain, non-healing ulcers, or gangrene. Several studies have demonstrated that inflammation and endothelial dysfunction are some of the main substrates of CLTI.
METHODS
A narrative review was conducted and reported according to PRISMA guidelines. Three databases were searched-Web of Science, Medline, and EMBASE-for the studies assessing CLTI and the biological markers related to it.
RESULTS
We included 22 studies, and all the markers identified (C-reactive protein, D-dimers, fibrinogen, cytokines, IL-6, TNF-α, ICAM-1 (Intracellular Adhesion Molecule-1), VCAM-1 (Vascular Cell Adhesion Molecule-1), neutrophile-to-lymphocytes ratio (NLR), IL-8, Pentraxin-3, neutrophil gelatinase-associated lipocalin (NGAL), calprotectin, E-selectin, P-selectin, neopterin, High-Mobility Group Box-1 protein (HGMB-1), Osteoprotegerin (OPG) and Sortilin) were positively associated with advanced CLTI, with major limb or major cardiovascular events in these patients.
CONCLUSIONS
All the studied markers had increased values in patients with CLTI, especially when associated with diabetes mellitus, proving a very important association between diabetes and major limb or cardiovascular events in these patients. There is a need for more studies to validate these markers in terms of diagnosis or prognosis in CLTI patients and in trying to find new medical strategies that target inflammation or endothelial dysfunction in these patients.
PubMed: 38672153
DOI: 10.3390/biomedicines12040798 -
Frontiers in Immunology 2024Kikuchi-Fujimoto disease (KFD) is a benign, self-limiting illness that can progress to systemic lupus erythematosus (SLE) in approximately 30% of cases. Neurological...
Kikuchi-Fujimoto disease (KFD) is a benign, self-limiting illness that can progress to systemic lupus erythematosus (SLE) in approximately 30% of cases. Neurological injuries can occur in both diseases, albeit with distinct presentations. Venous sinus thrombosis is a serious cerebrovascular complication in patients with neuropsychiatric SLE but is rarely observed in patients with KFD. The involvement of various antibodies, particularly antiphospholipid antibodies, can cause vascular endothelial cell injury, resulting in focal cerebral ischemia and intracranial vascular embolism in SLE. However, there are cases in which thrombotic pathology occurs without antiphospholipid antibody positivity, attributed to vascular lesions. In this report, we present a case of KFD and lupus encephalopathy featuring cerebral venous sinus thrombosis, despite the patient being negative for antiphospholipid antibody. We also conducted a comparative analysis of C3 and C4 levels in cerebrospinal fluid (CSF) and peripheral blood, along with the protein ratio in CSF and serum, to elucidate the pathological changes and characteristics of lupus encephalopathy.
Topics: Humans; Histiocytic Necrotizing Lymphadenitis; Sinus Thrombosis, Intracranial; Lupus Erythematosus, Systemic; Female; Adult
PubMed: 38665917
DOI: 10.3389/fimmu.2024.1389993 -
Internal Medicine (Tokyo, Japan) Jul 2024A 29-year-old Japanese woman was admitted to our hospital with a fever, cardiogenic shock, and cardiac arrest. Laboratory data indicated multiple organ failure in...
A 29-year-old Japanese woman was admitted to our hospital with a fever, cardiogenic shock, and cardiac arrest. Laboratory data indicated multiple organ failure in addition to hemoconcentration, hypoalbuminemia, and myocardial damage. The coronary angiography findings were normal, and fulminant myocarditis was suspected. Venoarterial peripheral extracorporeal membrane oxygenation and an Impella CP left ventricular assist device were initiated, along with the administration of positive inotropic agents. However, hypovolemic shock and hypoalbuminemia progressed along with severe anemia, and the patient died 18 hours after admission. The patient was diagnosed with systemic capillary leak syndrome associated with coronavirus disease 2019.
Topics: Humans; Capillary Leak Syndrome; Female; COVID-19; Adult; Fatal Outcome; SARS-CoV-2; Extracorporeal Membrane Oxygenation; Shock, Cardiogenic
PubMed: 38658337
DOI: 10.2169/internalmedicine.3637-24 -
Journal of Cardiology Cases Apr 2024Aortic mural thrombus (AMT) in the absence of aneurysm or atherosclerosis is a rare clinical finding and an uncommon cause of peripheral arterial embolization. AMT in a...
UNLABELLED
Aortic mural thrombus (AMT) in the absence of aneurysm or atherosclerosis is a rare clinical finding and an uncommon cause of peripheral arterial embolization. AMT in a normal artery is usually attributed to systemic hypercoagulability. We describe a case of subacute lower limb ischemia due to AMT associated with active ulcerative colitis (UC). A 46-year-old man with active UC was referred to our hospital for the evaluation and treatment of left leg pain. Ultrasound and contrast computed tomography showed occlusion of the left popliteal artery, and an AMT in the abdominal aorta between the inferior mesenteric artery and the aortic bifurcation. We started anticoagulant therapy, intravenous infliximab, and cytapheresis. Four weeks after initiating anticoagulation therapy, we were able to successfully treat the AMT with anticoagulation therapy without surgical thrombectomy. The inflammatory status of ulcerative colitis was also under control, and AMT had not recurred at 1 year after treatment. Invasive therapies are often selected to treat AMT. However, if a patient's hypercoagulable state is controlled, AMT can safely be treated with anticoagulation therapy alone without recurrence.
LEARNING OBJECTIVE
Aortic mural thrombus (AMT) in the absence of aneurysm or atherosclerosis is a rare clinical finding and an uncommon cause of peripheral arterial embolization. AMT in a normal artery is usually attributed to systemic hypercoagulability. We describe a case of subacute lower limb ischemia due to AMT associated with active ulcerative colitis. We controlled the ulcerative colitis condition and successfully treated the AMT with anticoagulation therapy alone.
PubMed: 38646077
DOI: 10.1016/j.jccase.2023.12.006 -
Journal of the American Heart... May 2024The extent and consequences of ischemia in patients with chronic limb-threatening ischemia (CLTI) may change rapidly, and delays from diagnosis to revascularization may...
Association Between Diagnosis-to-Limb Revascularization Time and Clinical Outcomes in Outpatients With Chronic Limb-Threatening Ischemia: Insights From the CLIPPER Cohort.
BACKGROUND
The extent and consequences of ischemia in patients with chronic limb-threatening ischemia (CLTI) may change rapidly, and delays from diagnosis to revascularization may worsen outcomes. We sought to describe the association between time from diagnosis to endovascular lower extremity revascularization (diagnosis-to-limb revascularization [D2L] time) and clinical outcomes in outpatients with CLTI.
METHODS AND RESULTS
In the CLIPPER cohort, comprising patients between 66 and 86 years old diagnosed with CLTI betweeen 2010 and 2019, we used Medicare claims data to identify patients who underwent outpatient endovascular revascularization within 180 days of diagnosis. We described the risk-adjusted association between D2L time and clinical outcomes. Among 1 130 065 patients aged between 66 and 86 years with CLTI, 99 221 (8.8%) underwent outpatient endovascular lower extremity revascularization within 180 days of their CLTI diagnosis. Among patients with D2L time <30 days, there was no association between D2L time and all-cause death or major lower extremity amputation. However, among patients with D2L time >30 days, each additional 10-day increase in D2L time was associated with a 2.5% greater risk of major amputation (hazard ratio, 1.025 [95% CI, 1.014-1.036]). There was no association between D2L time and all-cause death.
CONCLUSIONS
A delay of >30 days from CLTI diagnosis to lower extremity endovascular revascularization was associated with an increased risk of major lower extremity amputation among patients undergoing outpatient endovascular revascularization. Improving systems of care to reduce D2L time could reduce amputations.
Topics: Humans; Aged; Male; Female; Aged, 80 and over; Endovascular Procedures; Chronic Limb-Threatening Ischemia; United States; Amputation, Surgical; Time-to-Treatment; Time Factors; Treatment Outcome; Limb Salvage; Retrospective Studies; Medicare; Lower Extremity; Risk Factors; Peripheral Arterial Disease; Outpatients; Risk Assessment; Ischemia
PubMed: 38639376
DOI: 10.1161/JAHA.123.033898 -
Predicting Outcomes Following Lower Extremity Endovascular Revascularization Using Machine Learning.Journal of the American Heart... May 2024Lower extremity endovascular revascularization for peripheral artery disease carries nonnegligible perioperative risks; however, outcome prediction tools remain limited....
BACKGROUND
Lower extremity endovascular revascularization for peripheral artery disease carries nonnegligible perioperative risks; however, outcome prediction tools remain limited. Using machine learning, we developed automated algorithms that predict 30-day outcomes following lower extremity endovascular revascularization.
METHODS AND RESULTS
The National Surgical Quality Improvement Program targeted vascular database was used to identify patients who underwent lower extremity endovascular revascularization (angioplasty, stent, or atherectomy) for peripheral artery disease between 2011 and 2021. Input features included 38 preoperative demographic/clinical variables. The primary outcome was 30-day postprocedural major adverse limb event (composite of major reintervention, untreated loss of patency, or major amputation) or death. Data were split into training (70%) and test (30%) sets. Using 10-fold cross-validation, 6 machine learning models were trained using preoperative features. The primary model evaluation metric was area under the receiver operating characteristic curve. Overall, 21 886 patients were included, and 30-day major adverse limb event/death occurred in 1964 (9.0%) individuals. The best performing model for predicting 30-day major adverse limb event/death was extreme gradient boosting, achieving an area under the receiver operating characteristic curve of 0.93 (95% CI, 0.92-0.94). In comparison, logistic regression had an area under the receiver operating characteristic curve of 0.72 (95% CI, 0.70-0.74). The calibration plot showed good agreement between predicted and observed event probabilities with a Brier score of 0.09. The top 3 predictive features in our algorithm were (1) chronic limb-threatening ischemia, (2) tibial intervention, and (3) congestive heart failure.
CONCLUSIONS
Our machine learning models accurately predict 30-day outcomes following lower extremity endovascular revascularization using preoperative data with good discrimination and calibration. Prospective validation is warranted to assess for generalizability and external validity.
Topics: Humans; Machine Learning; Male; Female; Peripheral Arterial Disease; Aged; Lower Extremity; Endovascular Procedures; Risk Assessment; Middle Aged; Treatment Outcome; Amputation, Surgical; Risk Factors; Retrospective Studies; Databases, Factual; Time Factors; Stents; Limb Salvage
PubMed: 38639373
DOI: 10.1161/JAHA.123.033194 -
Journal of the American Heart... May 2024Cellular therapies have been investigated to improve blood flow and prevent amputation in peripheral artery disease with limited efficacy in clinical trials....
BACKGROUND
Cellular therapies have been investigated to improve blood flow and prevent amputation in peripheral artery disease with limited efficacy in clinical trials. Alginate-encapsulated mesenchymal stromal cells (eMSCs) demonstrated improved retention and survival and promoted vascular generation in murine hind limb ischemia through their secretome, but large animal evaluation is necessary for human applicability. We sought to determine the efficacy of eMSCs for peripheral artery disease-induced limb ischemia through assessment in our durable swine hind limb ischemia model.
METHODS AND RESULTS
Autologous bone marrow eMSCs or empty alginate capsules were intramuscularly injected 2 weeks post-hind limb ischemia establishment (N=4/group). Improvements were quantified for 4 weeks through walkway gait analysis, contrast angiography, blood pressures, fluorescent microsphere perfusion, and muscle morphology and histology. Capsules remained intact with mesenchymal stromal cells retained for 4 weeks. Adenosine-induced perfusion deficits and muscle atrophy in ischemic limbs were significantly improved by eMSCs versus empty capsules (mean±SD, 1.07±0.19 versus 0.41±0.16, =0.002 for perfusion ratios and 2.79±0.12 versus 1.90±0.62 g/kg, =0.029 for ischemic muscle mass). Force- and temporal-associated walkway parameters normalized (ratio, 0.63±0.35 at week 3 versus 1.02±0.19 preligation; =0.17), and compensatory footfall patterning was diminished in eMSC-administered swine (12.58±8.46% versus 34.85±15.26%; =0.043). Delivery of eMSCs was associated with trending benefits in collateralization, local neovascularization, and muscle fibrosis. Hypoxia-cultured porcine mesenchymal stromal cells secreted vascular endothelial growth factor and tissue inhibitor of metalloproteinase 2.
CONCLUSIONS
This study demonstrates the promise of the mesenchymal stromal cell secretome at improving peripheral artery disease outcomes and the potential for this novel swine model to serve as a component of the preclinical pipeline for advanced therapies.
Topics: Animals; Mesenchymal Stem Cell Transplantation; Hindlimb; Alginates; Disease Models, Animal; Mesenchymal Stem Cells; Ischemia; Swine; Neovascularization, Physiologic; Peripheral Arterial Disease; Injections, Intramuscular; Regional Blood Flow; Muscle, Skeletal; Translational Research, Biomedical; Cells, Cultured
PubMed: 38639336
DOI: 10.1161/JAHA.123.029880