Citations

BACKGROUND: Atherothrombosis, which underlies most acute coronary syndromes and is driven by intraplaque thrombosis, preferentially occurs in regions of disturbed blood flow (d-flow). Although LATS1/2 (large tumor suppressor kinases 1 and 2) are known regulators of endothelial mechanotransduction, the mechanisms by which d-flow connects endothelial senescence, proliferation, and intraplaque thrombosis remain poorly understood. METHODS: We investigated endothelial cell (EC)-specific roles of Lats1/2 using inducible EC-specific knockout mice in a partial carotid ligation model. Spatial multiomics of human and mouse plaques was performed using imaging mass cytometry, COMET sequential immunofluorescence, and spatial metabolomics. RESULTS: Tamoxifen-induced deletion of both Lats1 and Lats2 (homozygous) in ECs caused fatal edema and increased vascular permeability. In contrast, Lats1 het ( ± ) / Lats2 homo ( −/−) -EC-specific knockout mice survived and developed spontaneous atherothrombotic plaques with neovascularization. Spatial proteomics revealed that LATS1/2 loss induced a senescence-associated stemness phenotype driven by CD38 upregulation. Spatial metabolomics showed sulfite and taurine accumulation, indicating SUOX (sulfite oxidase) deficiency. CD38 suppressed SUOX, demonstrated a switch into the reverse mode of mitochondrial complex V, increased succinate dehydrogenase activity, and promoted ATP consumption. Despite ATP depletion, glutamate metabolism and the citric acid cycle flux increased, sustaining EC proliferation under energetic stress. This senescence-associated stemness state promoted both proliferation and senescence, leading to fragile, leaky neovessels and intraplaque thrombotic lesions. Pharmacological CD38 inhibition attenuated these phenotypes. Similar EC states were observed in human plaques. CONCLUSIONS: Loss of Lats1/2 in ECs induces a CD38-associated senescence-associated stemness-like phenotype that promotes intraplaque thrombosis through mitochondrial metabolic reprogramming, including changes consistent with reverse-mode operation of mitochondrial complex V. These findings define a mechanistic link between disturbed flow, endothelial metabolic reprogramming, and intraplaque thrombosis and hemorrhage.

Summary of Background Data: Although pseudoangina is most commonly caused by cervical disc herniation, several cases have been described where thoracic herniation produced symptoms of pseudoangina. If thoracic herniation can produce angina-like pain, then it is important to consider whether pathology of the thoracolumbar spine, in general, can trigger false pain syndromes distinct from pseudoangina. Objective: We seek to provide the most comprehensive study regarding the diagnosis and treatment of spinal conditions causing false pain syndromes. Study Design: Systematic review of the current literature using PRISMA 2020 recommendations. Methods: We queried the literature and systematically selected relevant studies according to PRISMA guidelines. Results: Across 22 selected studies, the sample size was 30 patients, and a total of 26 met the criteria for statistical analysis. Seven (26.9%) of these patients presented with a chief complaint of pseudoangina resulting from thoracic disc herniation. 73.1% (19/26) of patients exhibited pain mimicking visceral origin. Overall, 13/19 (68.4%) patients exhibited thoracic spine disease only and 4/19 (21.1%) patients were affected at lumbar levels only, while 2 (10.5%) patients exhibited thoracolumbar herniation. Presentations included abdominal pain (11/19) mimicking appendicitis or pancreatitis, flank pain mimicking renal colic (8/19), and 2 cases of scrotal pain/orchalgia. Symptom durations ranged from acute (<24 h) to 7 years. Treatments were reported for 18/19 patients and all treated patients reported alleviated pain. Seven out of 18 patients were managed conservatively while 11/18 were treated surgically. Misdiagnosis resulted in unnecessary surgery (pancreaticojejunostomy) or other invasive procedures. Conclusions: In spinal disorders manifesting with atypical pain syndromes, delay in proper diagnosis and unnecessary treatments can, unfortunately, cause prolonged patient suffering and increased cost of health care. As a result, some have proposed that spinal screening should be incorporated into clinical examinations involving false pain syndromes.

OBJECTIVE Antifibrinolytics, such as tranexamic acid (TXA), have been shown to decrease intraoperative blood loss across multiple surgical disciplines. However, they carry the theoretical risk of thromboembolic events secondary to induced hypercoagulability. Therefore, the aim of this study was to systematically review the available literature and perform a meta-analysis on the use of TXA in meningioma resection to assess thromboembolic risks. METHODS The PubMed, Web of Science, and Google Scholar databases were reviewed for all randomized controlled trials presenting primary data on TXA use during resection of intracranial meningiomas. Data were gathered on operative duration, venous thromboembolic complications, deep venous thrombosis, use of allogeneic blood transfusion, estimated blood loss (EBL), and postoperative hemoglobin. Patients who received TXA were compared with controls who did not receive TXA intraoperatively using random-effects models. RESULTS A total of 508 unique articles were identified, of which 493 underwent full-text review. Ultimately, 6 studies with 381 total patients (190 receiving TXA) were included in the final analysis. All 6 trials were randomized, blinded, and placebo controlled with a TXA administration rate of a 20-mg/kg load followed by a 1-mg/kg/hr infusion. All studies were performed in lower-middle-income countries. There were no reported instances of venous thromboembolism (VTE) in the TXA and non-TXA cohorts. Patients receiving TXA exhibited fewer allogeneic transfusions (21.5% vs 41.6% [OR 0.26, 95% CI 0.09–0.77], p = 0.02) and lower EBL (MD −282.48 mL [95% CI −367.77 to −197.20 mL], p < 0.001) compared with patients who did not receive TXA, and they also had lower rates of perioperative complications (10.7% vs 19.9% [OR 0.47, 95% CI 0.2–0.95], p = 0.04). CONCLUSIONS Current literature suggests that TXA is not associated with increased risk for VTE when administered during resection of intracranial meningioma. TXA appears to decrease intraoperative blood loss and allogeneic transfusion requirements during meningioma resection and thus may improve the safety of surgical management of this pathology.