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[This retracts the article DOI: 10.1016/j.jvssci.2020.09.002.].
This study evaluated the presence, production rate, and in vitro angiogenic properties of quality-and-quantity culture mononuclear cells-derived extracellular vesicles (QQMNC-EVs). Peripheral blood from three healthy volunteers was processed into five groups: QQMNC-EVs, QQMNCs, peripheral blood mononuclear cell-derived EVs (PBMNC-EVs), CD34+-EVs, and late endothelial progenitor cell-derived EVs (late EPC-EVs). EVs were identified and characterized using nanoparticle tracking analysis, flow cytometry, western blot analysis, and electron microscopy. EV production rates were quantified, and angiogenesis was evaluated via tube length formation assay. QQMNC-EVs were identified and met established EVs criteria. QQMNCs produced the highest EVs yield. This was significantly higher than CD34+ cells (P = .044), late EPCs (P = .004), and PBMNCs (P = .046). At low concentration, QQMNC-EVs showed angiogenic effects comparable with CD34+-EVs and late EPC-EVs, significantly greater than PBMNC-EVs (P = .018). At high concentration, QQMNC-EVs produced the highest tube length formation, demonstrating a dose-dependent effect. This was significantly higher than CD34+-EVs (P = .018), late EPC-EVs (P = .011), and PBMNC-EVs (P = .002). QQMNC-EVs were successfully identified and showed in vitro angiogenic efficacy, highlighting their potential as a novel therapeutic strategy for patients with no-option chronic limb-threatening ischemia. Extracellular vesicles (EVs) were successfully identified and characterized from QQMNCs and had the highest production rate among the four cell groups: QQMNCs, standard peripheral blood mononuclear cells, CD34+ cells, and late endothelial progenitor cells. Moreover, QQMNC-EVs produced markedly higher tube length formation than standard mononuclear cell-derived EVs. These findings in angiogenic efficacy in vitro highlight their potential as a novel optional therapeutic strategy. Further investigation may advance treatment options for patients with no-option chronic limb-threatening ischemia.
Vascular smooth muscle cells (VSMCs) are the primary component of the medial layer of the vessel wall, where they maintain structural integrity and regulate vascular tone. Their dysfunction contributes to vascular diseases such as aortic aneurysms and atherosclerosis. Although VSMCs isolated from thoracic and abdominal aortic regions are widely used in experimental studies, their functional differences have not been systematically compared. In this study, we examined functional and phenotypic differences between VSMCs isolated from the descending thoracic (Th-SMCs) and abdominal aortas of male C57BL/6J mice under controlled in vitro conditions. Both cell types maintained high α-smooth muscle actin expression across passages, supporting smooth muscle lineage identity. Functionally, Th-SMCs demonstrated significantly greater migratory and proliferative capacities compared with abdominal SMCs. Under sublethal oxidative stress, Th-SMCs exhibited higher relative viability, accompanied by higher basal expression of antioxidant-related transcripts, including Nrf2, Catalase, and Sod1. These findings highlight intrinsic differences between region-specific VSMCs and underscore the importance of considering anatomical origin for in vitro models. Incorporating region-specific VSMCs may enhance experimental relevance and contribute to a better understanding of the mechanisms underlying regional vascular diseases. Vascular smooth muscle cells (VSMCs) play a key role in the development of vascular diseases. This study demonstrates that VSMCs isolated from the descending thoracic and abdominal aortic regions exhibit distinct functional behaviors under in vitro conditions. These region-specific differences highlight the importance of carefully selecting and reporting the anatomical origin of VSMCs in experimental studies, which may improve the physiological relevance and interpretability of vascular research models.
The abdominal aorta is the most frequent site of aneurysm development including mostly localized abdominal aortic aneurysms (AAAs) but also more extensive pathologies like thoracoabdominal aneurysms (TAAAs). This study compares histologic features including inflammation, fibrosis, and angiogenesis in samples from the abdominal aneurysm wall from patients with AAAs (n = 272) and TAAAs (n = 24) after open repair. Both cohorts show a similar pathomorphology and a patient-centered propensity score-matching for age, sex, clinical presentation, maximum diameter, comorbidities, smoking, and basic medication reveals no significant differences for the basic histologic features investigated. These exploratory results can be interpreted towards a possible transferability of basic and translational research results for a nonsurgical treatment of patients with AAAs and TAAAs. Abdominal aortic aneurysm is by far the most frequent aortic aneurysm-yet basic scientific knowledge is limited, and clinical studies on aneurysm growth abrogation have not shown beneficial effects. Data and understanding on more extensive disease, such as thoracoabdominal aortic aneurysms is even more scarce. This manuscript provides a first hint that pathomechanisms based on histomorphology might be comparable between abdominal aortic aneurysm samples and abdominal wall samples from patients with thoracoabdominal aortic aneurysms in a well-matched propensity-scored analysis. Thus, results from translational research on aneurysm growth alterations could be applicable for both entities.
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Different zone 0 endograft designs have been introduced. This study sought to assess postimplantation hemodynamic changes induced by zone 0 endografts, with varied configuration of side branches, using computational models. Twenty-nine patients who underwent zone 0 endovascular repair with single-, double-, or triple-branched endografts (n = 7, n = 11, n = 11, respectively), using different configurations of antegrade (A) and retrograde (R) branches, were included. Computational simulations were used to assess postimplantation changes in peak flow rate, systolic blood pressure (SBP) and time-averaged wall shear stress (TAWSS) at the innominate artery (IA), right subclavian artery, right common carotid artery (CCA), left CCA (LCCA), left subclavian artery (LSA), and distal aortic arch, as well as the total displacement force (DF) of the endograft. Regardless of orientation, IA side branch implantation increased the IA peak flow rate across all endograft designs, an effect significant only in single-branched devices (+70%, P = .02). This increase was accompanied by a significant decrease in peak flow in the LCCA and LSA for single- (P = .02 and P = .02, respectively) and double-branched devices (P = .01 and P < .001, respectively), whereas no such effect was observed with triple-branched devices. Notably, the two antegrade branches supplying the IA and LCCA and one retrograde branch to the LSA- and three retrograde branches (3R)-triple-branched designs had the opposite effect on LCCA blood flow (+8.3% vs -6.7% [P = .02], respectively), although their impact on LSA flow did not differ significantly (-7.5% vs -8.1% [P = .92], respectively). This resulted in disparate effects on distal arch flow (-0.3% vs +6.3% [P = .02], respectively). Postimplantation alteration in distal arch flow was progressively attenuated with more branches. The preimplantation to postimplantation SBP differences in the IA, LCCA, and LSA mirrored the corresponding changes in peak flow. Elevated peak flow in the IAs led to a significant postimplantation increase in the TAWSS across all device designs. In contrast, the LSA side branches with retrograde orientation in the two antegrade branches supplying the IA and LCCA and one retrograde branch to the LSA-triple-branched and 3R-triple-branched endografts demonstrated marked increases in TAWSS (36.1% vs 50.2%, respectively), despite there being no significant change in the mean flow rate. Although maximum DF varied between devices (single-branched, 32.8 N; double-branched, 23.9 N; 2A+1-triple-branched, 22.9 N; 3R-triple-branched, 28.9 N), a post hoc analysis showed that branch configuration did not significantly influence DF. The hemodynamic stability within the aortic arch improves with a greater number of endograft side branches. Retrograde branch orientation does not significantly affect flow rates or SBP in the supra-aortic vessels. Among the evaluated designs, the triple-retrograde-branched configuration demonstrated the most favorable flow characteristics. Using patient-specific computational fluid dynamics simulations, this study compared the postimplantation local hemodynamic effects of single-, double-, and triple-branched endografts, using different configurations of antegrade and retrograde branches, in complex zone 0 aortic arch repair. Our study suggests two key findings: first, more branching improves hemodynamic stability by steadying blood flow, and second, the specific orientation of retrograde side branches does not affect the supra-aortic arteries. Properly validated, these findings may help to optimize branched endograft selection, ensuring stable hemodynamics for long-term patient success and device durability.
Medial arterial calcification (MAC) is prevalent in peripheral artery disease (PAD), yet its distribution and clinical significance in infrapopliteal arteries remain poorly defined. Prior histopathological studies of distal tibial segments have not evaluated MAC as a vessel-level lesion. Peroneal arteries (PAs) are frequently regarded as relatively spared revascularization targets based on angiographic assessment alone, despite limited histological validation and emerging evidence that arterial medial remodeling contributes independently to limb ischemia. Accordingly, it remains unclear whether MAC in PAD reflects a diffuse distal arterial phenotype shared across tibial and peroneal segments or a segment-specific process. This single-center prospective pilot study included 14 patients and 14 limbs (13 patients with PAD and 1 control without PAD) undergoing below-knee amputation. Paired anterior tibial arteries (ATAs) and PAs were harvested, formalin fixed, and paraffin embedded. Hematoxylin and eosin staining was used to assess arterial architecture, intimal plaque, and medial remodeling. MAC was graded 0 to 4 using Alizarin Red staining according to circumferential extent and thickness. Clinical variables included age, sex, ethnicity, diabetes mellitus (DM), hemoglobin A1c, end-stage renal disease stage, smoking status, glucagon-like peptide-1 receptor agonist use, Rutherford category, and limb outcomes. The cohort included 92.3% males with an average age of 69.0 ± 10 years and a high prevalence of DM, consistent with larger PAD series. Moderate to severe (grades 3-4) MAC was common in limbs with PAD. Within-patient concordance of MAC grades between paired ATA and PA was high, with most pairs differing by ≤1 grade, supporting a diffuse rather than a segment-specific distal arterial phenotype. A greater MAC burden was observed in patients with DM, advanced end-stage renal disease, and higher Rutherford categories, but these exploratory associations were not statistically significant. Directional trends were observed between histological MAC burden and adverse limb outcomes, consistent with prior radiographic studies. In this pilot human tissue study, MAC appears to represent a shared distal arterial phenotype across ATAs and PAs in PAD rather than a segment-specific lesion. Histology-confirmed MAC burden provides biologic validation of distal calcification patterning and may help to refine our understanding of infrapopliteal disease in advanced PAD. Larger, multicenter studies are warranted to define the prognostic utility of MAC-based indices and to determine how tissue-level calcification patterns relate to clinical imaging and revascularization strategies. In advanced peripheral artery disease, medial arterial calcification (MAC) appears to be a shared distal arterial phenotype rather than a lesion confined to a single infrapopliteal vessel. The high concordance between paired anterior tibial artery and peroneal artery specimens suggests that the histological assessment of one distal artery may reflect limb-wide MAC burden, which could help to refine the risk stratification and interpretation of infrapopliteal disease. These findings also support the concept that the peroneal artery is not histologically spared in severe peripheral artery disease, despite its frequent consideration as a revascularization target. Larger studies integrating tissue histology, imaging, and clinical outcomes are needed to determine whether MAC burden can improve prediction of limb loss and guide procedural planning.
Thoracic duct outflow obstruction is a recognized cause of refractory lymphatic leakage; however, the physiological consequences of such obstruction on thoracic duct pressure and its relationship to central venous pressure have not been fully characterized in vivo. This study aimed to evaluate changes in thoracic duct pressure and the pressure gradient between the thoracic duct and the central venous system in an experimental model of thoracic duct outflow obstruction. In a swine model, thoracic duct pressure and central venous pressure were directly measured using intravascular catheters positioned at matched vertebral levels. Thoracic duct embolization was performed at the upper thoracic level using coils and cyanoacrylate and was used as an experimental model of thoracic duct outflow obstruction. Pressure measurements were obtained before embolization and after confirmation of complete thoracic duct occlusion. Changes in thoracic duct pressure, central venous pressure, and the pressure relationship between the two systems were analyzed using paired statistical comparisons. Thoracic duct outflow obstruction resulted in a significant increase in upstream thoracic duct pressure, with a median increase of approximately 6 to 8 mmHg compared with preobstruction values. Following obstruction, thoracic duct pressure consistently exceeded central venous pressure, creating a pressure gradient indicative of lymphatic hypertension. In contrast, central venous pressure did not change significantly after thoracic duct obstruction. No consistent cranio-caudal longitudinal pressure gradient along the thoracic duct was identified. Thoracic duct outflow obstruction induces lymphatic hypertension, as demonstrated by an increase in thoracic duct pressure relative to central venous pressure. This experimentally demonstrated pressure gradient provides physiological support for decompressive interventions by demonstrating a pressure gradient favorable for lymphatic drainage into the venous system. By directly quantifying intralymphatic and venous pressures in vivo, this study offers mechanistic insight into the pathophysiology of lymphatic leakage associated with thoracic duct obstruction and may help inform treatment selection between occlusive and decompressive strategies in lymphatic interventions. Thoracic duct outflow obstruction is a cause of lymphatic leakage, yet the consequences of obstruction on thoracic duct pressure and its relationship to central venous pressure have remained unclear. In this experimental study, in vivo measurements demonstrated that thoracic duct outflow obstruction results in an increase in thoracic duct pressure, creating a pressure gradient relative to central venous pressure. This pressure relationship reflects lymphatic hypertension caused by outflow obstruction and supports decompressive interventions aimed at restoring lymphatic outflow.
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Thoracic aortic aneurysm (TAA) development involves disruption of extracellular matrix structural proteins such as collagen and elastin. An increased level of Galectin-3 (Gal-3), a β-galactoside-binding lectin, was reported in ascending aortic aneurysmal patients. To examine the role of Gal-3 on TAA formation in mice, two models were used: administration of lysyl oxidase inhibitor, β-aminopropionitrile (BAPN 0.5%, 0.3%, and 0.1% wt/vol) to 3- to 4 -week-old male and female Gal-3 wild-type (WT) or deficient knockout (KO) mice for 4 weeks in drinking water; and 8- to 10-week-old Gal-3 WT or KO mice were infused with either saline or angiotensin II (AngII) via osmotic mini-pumps for 28 days. High or low doses of BAPN administration promoted TAA rupture-induced death equivalently in both WT and KO male (WT = 64%; KO = 73%) and female (WT = 41%; KO = 54%) mice compared with controls. Similarly, AngII infusion caused a significantly increased, but equivalent, dilation of thoracic aortas in both male and female Gal-3 and Gal-3 KO mice compared with controls. Histological analysis revealed increased elastin fragmentation and collagen accumulation in both BAPN- and AngII-infused male and female WT and KO mice compared with controls. These findings suggest that Gal-3 deficiency did not influence either BAPN- or AngII-induced TAA formation or rupture in mice.
Abdominal aortic aneurysms (AAAs) arise through complex pathogenesis, and good methods of risk stratification have proved elusive. Further, the lack of medical options short of surgery for treatment, and the requirement for dedicated imaging for identification, result in delayed diagnosis and hamper patient outcomes. Application of circulating biomarkers to effectively assess disease presence and predict progression would improve clinical management and support patient well-being. Exploration for suitable circulating biomarkers of AAAs is still very much in process; however, no disease-specific biomarker has yet been established for effective diagnosis and prognosis. This review aims to contribute enhanced tools for utilizing biomarkers for risk stratification and management of AAA disease. Utilizing MEDLINE/PubMed, we summarize 44 recent publications covering circulating AAA biomarkers. The biomarkers were categorized and tiered into six subgroups by study design, with prospective studies tiered higher than retrospective observational studies. The classification system separately describes a list of post-interventional monitoring biomarkers. Part of the review also deals with recent approaches to identifying potential AAA biomarkers by genetic inference. Forty individual circulating biomarkers, two plasma protein panels (consisting of 9 or 7 proteins), one plasma-multiomic study, and two micro-RNA (miR) panels revealed correlations to AAA disease risk. Among those, many have already been established as biomarkers for other cardiovascular diseases, meaning feasibility has been proven but disease specificity is lacking. Multiple circulating proteins and miRs have been investigated for their utility as AAA-specific diagnostic or prognostic biomarkers. This work may ultimately identify not only novel AAA biomarkers that are specific for cell type, proteins, metabolites, genetic polymorphisms, and miRNA, but permit framing of comprehensive networks of disease-participating molecules. More robust data with higher disease sensitivity and specificity are needed, along with more multi-centered longitudinal clinical studies with large sample sizes.
The treatment of carotid artery stenosis (CAS) for stroke prevention is a matter of debate due to conflicting data, missing recent data, and advances in medical treatment options but also in interventional techniques and surgery. Therefore, the establishment of an easily available marker for brain damage might be a key tool in this patient group to guide treatment. A retrospective cross-sectional study was conducted leveraging a vascular surgery biobank of 95 patients aged 60 to 80 years. Serum neurofilament light chain (sNfL) and serum glial fibrillary acid protein (sGFAP) were evaluated using highly sensitive electrochemiluminescence immunoassays and z-scores. Discriminatory performance was assessed to differentiate between 19 symptomatic and 76 asymptomatic patients with CAS and their correlation with the degree of stenosis according to ultrasound-based North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria. SNfL levels were markedly elevated in symptomatic compared with asymptomatic patients (median 17.4 vs 3.8 pg/mL; P < .001). sNfL robustly discriminated between these patients (area under the curve = 0.83; 95% confidence interval, 0.72-0.94), as did the NfL z-score (area under the curve = 0.83; 95% confidence interval, 0.71-0.95). Interestingly, within the asymptomatic cohort, sNfL levels demonstrated a significant, positive correlation with the degree of stenosis (Spearman's ρ = 0.24; P = .036). Serum levels of SGFAP were also associated with symptomatic status, albeit with a P-value >.05 (0.1 vs 0.1 pg/mL; (P = .057). The study provides evidence of increased sNfL in symptomatic vs asymptomatic CAS and, of note, of ongoing neuronal or glial damage in some patients with clinically asymptomatic CAS, with a positive correlation between sNfL and the degree of CAS. sNfL is a promising and already accessible blood biomarker that may guide therapeutic decisions in this patient population. The role of sGFAP remains elusive and must be evaluated in larger studies. The CREST-2 trial has recently highlighted the high efficacy of intensive medical management in asymptomatic carotid artery stenosis (CAS), making the selection of patients for revascularization increasingly complex. Our study addresses this challenge by evaluating serum neurofilament light chain (sNfL) and serum glial fibrillary acid protein (sGFAP) as an objective biomarker for neuronal injury. Using individualized z-scores, we demonstrate that sNfL effectively differentiates symptomatic status (area under the curve = 0.828) and significantly correlates with the degree of stenosis in asymptomatic cohorts. These results suggest that sNfL can detect subclinical "silent" damage, providing a valuable biological tool to pinpoint high-risk patients who may require intervention beyond medical therapy alone. This represents a significant step toward personalized stroke prevention and refined risk stratification in the highly debated field of CAS management.
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Intestinal ischemia-reperfusion (I/R) injury is a major complication of aortic occlusion during resuscitative thoracotomy or resuscitative endovascular balloon occlusion of the aorta. We investigated whether targeted intra-arterial delivery of hemoglobin vesicles (HbVs) attenuates intestinal I/R injury in a rat thoracic aortic cross-clamping model. Male Wistar rats underwent 60 minutes of thoracic aortic occlusion followed by 60 minutes of reperfusion. Animals received intra-arterial HbV (1.25 mL/kg every 10 minutes; n = 5) or saline (n = 5) via the femoral artery; sham animals (n = 3) underwent instrumentation only. Compared with saline controls, HbV-treated rats demonstrated higher postreperfusion systolic blood pressure (56 ± 4 mm Hg vs 34 ± 8 mm Hg; P = .002) and lower plasma lactate levels (2.7 ± 0.4 mmol/L vs 7.5 ± 0.4 mmol/L; P < .001). Intestinal injury was significantly attenuated in the HbV group, with lower Chiu scores (median 2.0 vs 4.0; P = .018), reduced terminal deoxynucleotidyl transferase dUTP nick end labeling-positive area fraction (P = .003), and decreased inducible nitric oxide synthase-positive area fraction (P = .006). Targeted intra-arterial HbV administration significantly reduced early intestinal I/R injury in this exploratory proof-of-concept model and may represent a promising adjunctive oxygen-carrying strategy to protect distal organs during prolonged aortic occlusion.
Adipocytes express renin-angiotensin system (RAS) components, including angiotensinogen (Agt), the precursor to angiotensin II (AngII), and the angiotensin type 1a receptor (AT1aR). The RAS contributes to atherosclerosis, and AngII infusion causes abdominal aortic aneurysm (AAA) formation. We studied effects of adipocyte Agt or AT1aR deficiency on diet-induced atherosclerosis and AngII-induced AAAs in male low-density lipoprotein receptor (Ldlr)-deficient mice. For atherosclerosis, adipocyte Agt- or AT1aR-deficient Ldlr-deficient mice and littermate controls were fed a Western diet for 3 months. For AAAs, adipocyte Agt- or AT1aR-deficient Ldlr -/- mice and littermate controls were fed a Western diet and infused with AngII (1000 ng/kg/min) for 28 days. Atherosclerosis was quantified en face in the aortic arch by the percent of intimal surface area covered by an atherosclerotic lesion. Serum (cholesterol, triglyceride) and plasma renin activity were quantified at study end point. AAAs were quantified in vivo by ultrasound quantification of abdominal aortic lumen diameters in anesthetized mice or at study end point by quantifying maximal external abdominal aortic diameter and AAA incidence (percent). Systolic blood pressure was quantified in AngII-infused mice by tail cuff plethysmography. Adipocyte size was quantified in tissue sections of white adipose tissue. Male Ldlr -/- mice were fed a standard diet or a Western diet (1 or 3 months) and Agt or AT1aR messenger RNA (mRNA) abundance quantified in periaortic fat (PAF) by reverse transcriptase polymerase chain reaction. There was no effect of adipocyte Agt deficiency on body weight, serum cholesterol concentrations, or atherosclerotic lesions of Western diet-fed Ldlr -/- mice. Adipocyte Agt deficiency had no effect on body weight, serum cholesterol concentrations, abdominal aortic lumen diameter, AAA incidence, or atherosclerosis of AngII-infused Ldlr -/- mice. There was no effect of adipocyte AT1aR deficiency on body weight, serum cholesterol concentrations, or atherosclerotic lesions of Western diet-fed Ldlr -/- mice. Control, but not adipocyte AT1aR-deficient mice lost weight during AngII infusion. The size of adipocytes in white adipose tissue was increased in adipocyte AT1aR-deficient mice with no significant influences on abdominal aortic lumen diameter, AAA incidence, or atherosclerosis of AngII-infused mice. In mice fed a Western diet for 1 or 3 months, Agt mRNA abundance in abdominal PAF increased over time in both diet groups, with modest diet-induced decreases in thoracic PAF Agt mRNA abundance. There was an effect of diet duration on AT1aR mRNA abundance in thoracic PAF, and an interaction between diet and time on abdominal PAF AT1aR mRNA abundance. Adipocyte Agt or AT1aR deficiency had minimal effects on atherosclerosis or AngII-induced AAAs. However, adipocyte AT1aR-deficient mice exhibited increased adipocyte size. Western diet-induced regulation of Agt or AT1aR mRNA abundance in PAF may have contributed to these findings. These studies address the role of components of the renin-angiotensin system (RAS), namely, angiotensinogen and angiotensin type 1a receptors, within adipocytes on experimental disease models of atherosclerosis and abdominal aortic aneurysms. Adipocytes express these RAS components and dysfunctional adipose tissue in humans has been linked both to atherosclerosis and abdominal aortic aneurysm severity. Our findings do not support a major role for these adipocyte RAS components in either disease model. Thus, although drugs targeting the RAS may be beneficial in the treatment of these disorders, they are likely not more effective in the obese population experiencing either of these disorders.
Oxidative stress and inflammation are widely recognized as central mechanisms in the pathogenesis of abdominal aortic aneurysm. This study sought to examine the potential protective properties of montelukast in a rat model of aortic aneurysm. Male Sprague-Dawley rats were randomly allocated into three experimental groups. Abdominal aortic aneurysm was induced using the calcium chloride (CaCl2) model, in which gauze soaked in 0.5 M CaCl2 was placed directly onto the adventitial surface of the infrarenal abdominal aorta for 15 minutes. After induction, the treatment group received daily intraperitoneal injections of montelukast (10 mg/kg) for 4 consecutive weeks. At the study end point, animals were euthanized, and infrarenal aortic tissues were harvested for biochemical and histological evaluations. Measured parameters included matrix metalloproteinase (MMP)-2 and MMP-9 expression, myeloperoxidase (MPO) activity, and 8-hydroxy-2'-deoxyguanosine levels. Antioxidant capacity was assessed through superoxide dismutase (SOD) activity assays. Histopathological examinations were performed, and statistical analysis was conducted using GraphPad Prism v.5. Exposure to CaCl2 triggered pronounced oxidative injury and inflammation, as evidenced by elevated 8-hydroxy-2'-deoxyguanosine levels, increased MPO activity, reduced SOD activity, and upregulated MMP-2 and MMP-9 expression. Montelukast administration markedly attenuated these changes, normalizing oxidative and inflammatory markers while improving histopathological architecture. Montelukast effectively counteracted CaCl2-induced aortic damage. The protective effects of montelukast appear to be mediated through suppression of MMP activity, restoration of SOD levels, and reduction of MPO-driven oxidative injury. By mitigating both inflammatory and oxidative mechanisms, montelukast contributes to the preservation of aortic wall structure. Abdominal aortic aneurysm remains a major vascular disorder without an effective pharmacological therapy to slow its progression. In this experimental study, montelukast, a leukotriene receptor antagonist widely used in asthma, attenuated abdominal aortic aneurysm formation in rats and was associated with increased superoxide dismutase activity, reduced myeloperoxidase levels, and suppressed matrix metalloproteinase activation. These combined antioxidant, anti-inflammatory, and matrix-stabilizing effects preserved aortic wall integrity. Given montelukast's established safety and clinical availability, these findings support its potential for future clinical investigation as a pharmacological approach to limit aneurysm progression.
Carotid plaque vulnerability is a current feature that aids in the decision-making for ischemic stroke risk. Proteomic analysis of plaque tissue can reveal molecular indicators of instability that complement imaging findings. We sought to identify a proteomic signature distinguishing vulnerable from stable carotid plaques in patients undergoing endarterectomy, with the aim of uncovering candidate biomarkers for potential diagnostic and therapeutic targets. Twenty-eight carotid plaque specimens were collected from 27 patients (including 1 patient with bilateral endarterectomy). Samples were classified as vulnerable (n = 14) or nonvulnerable (n = 14) based on preoperative magnetic resonance angiography with vessel wall imaging. A tandem mass tag-based multiplexing strategy followed by mass spectrometric analysis was used to profile the proteomes of all samples. Normalized and log2-transformed protein intensities were compared using two-sample t tests with unequal variances, and P values were adjusted for multiple testing with the Benjamini-Hochberg method to obtain false discovery rate q values. Proteins with a q value of ≤0.25 were designated high-confidence candidates, and those with a P value of <.05 but a q value of >0.25 were considered exploratory. From 3267 proteins identified, 398 reached nominal significance (P < .05). From those, 29 reached at least log2(fold-change) of +1, whereas 3 of -1 log2(fold change), yielding a total of 32 proteins. Fifteen were significant for a q value ≤0.25. All were upregulated in vulnerable lesions and these included: matrix-degrading enzymes (matrix metalloproteinase [MMP]7, MMP9, MMP1, and ADAM-like decysin-1), neutrophil-derived effectors (azurocidin, cathelicidin antimicrobial peptide, lactotransferrin, and myeloperoxidase), inflammatory regulators (interleukin-1 receptor antagonist and interleukin-4-induced protein), glycolytic enzymes (hexokinase-3 and hexokinase-2), and lipid-handling proteins (lipoprotein-associated phospholipase A2, apolipoprotein B, and paraoxonase-1). An additional 17 exploratory proteins showed nominal significance (P < .05, q > 0.25) with at least log2(fold-change) of 1, and 366 proteins with nominal significance but with a log2(fold-change) of <1. Our proteomic profiling delineates a robust vulnerability signature marked by enhanced proteolysis, neutrophil activation, inflammatory signaling, metabolic reprogramming, and lipid dysregulation. High-confidence proteins emerged as tissue biomarkers of plaque instability. Validating their association with future cerebrovascular events is the next step toward clinically actionable stroke prediction. Exploratory candidates warrant further analysis.
We have recently demonstrated that muscle sympathetic nerve activity and normetanephrine levels are transiently increased for several days immediately after acute type B aortic dissection. We now report other markers of sympathetic activation, natriuresis and inflammation over the same time frame. In 13 patients with known acute type B aortic dissection (median age, 71 years; 95% confidence interval, 29-89 years), we undertook serial measurements of catecholamine metabolites including normetanephrine, metanephrine, and their second messenger cyclic adenosine monophosphate; renin and aldosterone; N terminal-pro-brain natriuretic peptide (NT-proBNP), and its second messenger cyclic, guanosine monophosphate; C-type natriuretic peptide; the inflammatory growth differentiation factor 15; the stress hormone copeptin; mid-regional-proadrenomedullin; and the marker of cardiac muscle damage Troponin T. Venous sampling times were on admission, then 12 hours, 24 hours, 1 week, and 6 weeks later. Serial measurements were also undertaken in 12 controls (median age, 61 years; 95% confidence interval, 25-86 years) who presented with chest pain. During the first week after dissection, normetanephrine levels were increased: 617 to 792 vs 425 to 489 pmol/L in controls (analysis of variance [ANOVA] P = .01). There was also a simultaneous increase in NT-proBNP levels: 49 to 93 vs 14-21 pmol/L (ANOVA P = .07), and growth differentiation factor 15 levels: 1507 to 2873 vs 1146 to 1448 pg/mL (ANOVA P = .01) over the same period. The increase in normetanephrine levels during the week after type B dissection confirms sympathetic nerve activity as a likely mechanism for hypertension in these patients. This surge of sympathetic activity may be partially antagonized by a simultaneous increase in NT-proBNP, which is possibly triggered by acute inflammation and oxidative stress caused by the dissection. This pilot study focused on assessing the timeline of neuroendocrine hormone release in acute type B aortic dissection. Our results demonstrated an increase in normetanephrine levels suggesting the involvement of the sympathetic nerve activity in driving hypertension in the acute setting of type B aortic dissection. There was also a concurrent increase in N-terminal pro-brain natriuretic peptide and growth differentiation factor 15 levels seen, suggesting an underlying inflammatory process and vascular stress. These can be the focus of future research in the development of pharmaceutical targets or the use of natriuretic drugs and anti-inflammatory agents in the mainstay treatment of type B aortic dissection.