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The following protocol describes our workflow for isolation and quantification of plasma extracellular vesicles (EVs). It requires limited sample volume so that the scientific value of specimens is maximized. These steps include isolation of vesicles by automated size exclusion chromatography and quantification by tunable resistive pulse sensing. This workflow optimizes reproducibility by minimizing variations in processing, handling, and storage of EVs. EVs have significant diagnostic and therapeutic potential, but clinical application is limited by disparate methods of data collection. This standardized protocol is scalable and ensures efficient recovery of physiologically intact EVs that may be used in a variety of downstream biochemical and functional analyses. Simultaneous measurement quantifies EV concentration and size distribution absolutely. Absolute quantification corrects for variations in EV number and size, offering a novel method of standardization in downstream applications.

The impact of cardiovascular and neurologic complications on infective endocarditis (IE) are well studied, yet the prevalence and significance of pulmonary complications in IE is not defined. To better characterize the multifaceted nature of IE management, we aimed to describe the occurrence and significance of pulmonary complications in IE, including among persons with IE related to drug use. Hospitalizations of adult ([greater than or equal to]18 years old) patients diagnosed with IE were identified in the 2016 National Inpatient Sample using ICD-10 codes. Multivariable logistic and linear regression were used to compare IE patient outcomes between those with and without pulmonary complications and to identify predictors of pulmonary complications. Interaction terms were used to assess the impact of drug-use IE (DU-IE) and pulmonary complications on inpatient outcomes. In 2016, there were an estimated 88,995 hospitalizations of patients diagnosed with IE. Of these hospitalizations,15,490 (17%) were drug-use related. Drug-use IE (DU-IE) had the highest odds of pulmonary complications (OR 2.97, 95% CI 2.50, 3.45). At least one pulmonary complication was identified in 6,580 (7%) of IE patients. DU-IE hospitalizations were more likely to have a diagnosis of pyothorax (3% vs. 1%, p<0.001), lung abscess (3% vs. <1%, p<0.001), and septic pulmonary embolism (27% vs. 2%, p<0.001). Pulmonary complications were associated with longer average lengths of stay (CIE 7.22 days 95% CI 6.11, 8.32), higher hospital charges (CIE 78.51 thousand dollars 95% CI 57.44, 99.57), more frequent post-discharge transfers (acute care: OR 1.37, 95% CI 1.09, 1.71; long-term care: OR 2.19, 95% CI 1.83, 2.61), and increased odds of inpatient mortality (OR 1.81 95% CI 1.39, 2.35). IE with pulmonary complications is associated with worse outcomes. Patients with DU-IE have a particularly high prevalence of pulmonary complications that may require timely thoracic surgical intervention, likely owing to right-sided valve involvement. More research is needed to determine optimal management strategies for complications to improve patient outcomes.

Thoracic aortic aneurysm (TAA) results from dysregulated remodeling of the extracellular matrix mediated by matrix metalloproteinase (MMP) activity. Previous studies identified elevated membrane type-1 MMP (MT1-MMP) abundance and activity during TAA development and suggested aortic fibroblasts as a potential key source. Herein, we extended our understanding of the role of MT1-MMP during TAA development using various MT1-MMP transgenic mouse strains. MT1-MMP deficient (MT1-MMP+/−) mice exhibited reduced MT1-MMP abundance, activity, and collagen volume fraction following TAA induction, concomitant with reduced aortic dilatation. TAA tissue from wild-type and MT1-MMP+/− mice showed a similar reduction in thin collagen fibers, while the MT1-MMP+/− mice displayed no change in thick collagen fibers. The role of fibroblast-derived MT1-MMP was examined using a conditional fibroblast-specific tamoxifen-inducible MT1-MMP knockout strain (FbMT1KO). TAA-induced changes in aortic diameter and MT1-MMP abundance were attenuated in FbMT1KO mice. Using aortic fibroblasts isolated from multiple mouse strains expressing different levels of MT1-MMP, a significant correlation between MT1-MMP abundance and TGF-β activation was observed. Importantly, treatment with MT1-MMP activity-neutralizing antibody or TGF-β neutralizing antibody resulted in the attenuation aortic dilatation. Together, these findings suggest that fibroblast-derived MT1-MMP is required for TAA development, in part through its ability to induce TGF-β signaling.

The prevalence of atherosclerotic disease continues to increase, and despite significant reductions in major cardiovascular events with current medical interventions, an additional therapeutic window exists. Atherosclerotic plaque growth is a complex integration of cholesterol penetration, inflammatory cell infiltration, vascular smooth muscle cell (VSMC) migration, and neovascular invasion. A family of matrix-degrading proteases, the matrix metalloproteinases (MMPs), contributes to all phases of vascular remodeling. The contribution of specific MMPs to endothelial cell integrity and VSMC migration in atherosclerotic lesion initiation and progression has been confirmed by the increased expression of these proteases in plasma and plaque specimens. Endogenous blockade of MMPs by the tissue inhibitors of metalloproteinases (TIMPs) may attenuate proteolysis in some regions, but the progression of matrix degeneration suggests that MMPs predominate in atherosclerotic plaque, precipitating vulnerability. Plaque neovascularization also contributes to instability and, coupling the known role of MMPs in angiogenesis to that of atherosclerotic plaque growth, interest in targeting MMPs to facilitate plaque stabilization continues to accumulate. This article aims to review the contributions of MMPs and TIMPs to atherosclerotic plaque expansion, neovascularization, and rupture vulnerability with an interest in promoting targeted therapies to improve plaque stabilization and decrease the risk of major cardiovascular events.

The effect of an initial surgical approach (in comparison with initial medical therapy) in acute type A intramural hematoma remains insufficiently explored. We designed a pooled analysis of Kaplan–Meier-derived individual patient data from studies with follow-up for overall survival (all-cause death). Restricted mean survival time was calculated to evaluate lifetime gain or loss. The Risk of Bias in Non-Randomized Studies of Interventions tool (ROBINS-I) was used to assess risk of bias. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) was applied to assess certainty of evidence. Eight studies met our eligibility criteria, including a total of 654 patients (311 patients treated with surgery and 343 patients treated with medical therapy alone). All the studies were non-randomized and observational. The median follow-up was 4.6 years (interquartile range 1.0 to 7.7). Patients who underwent surgery had a significantly lower risk of mortality compared with patients receiving medical therapy alone (hazard ratio 0.51, 95% confidence interval 0.35 to 0.74, p <0.001). The restricted mean survival time was overall 1.1 years greater with surgery compared with medical therapy, and this difference was statistically significant (p <0.001), which means that surgery is associated with lifetime gain. The overall risk of bias (ROBINS-I) was considered moderate-to-serious and the certainty of evidence (GRADE) was deemed to be low. In conclusion, in the overall follow-up, surgery as the initial approach was associated with better late survival and lifetime gain in comparison with medical therapy alone in the setting of acute type A aortic intramural hematoma; however, high-quality randomized trials are warranted to establish the efficacy of the surgical strategy.

Background: With the improvement in postoperative complications and long-term survival post LVAD, continuing to improve clinical outcomes will require efforts to decrease long-term complications. The purpose of this study is to describe the incidence of mechanical pump failure requiring surgery, which we define as pump failure secondary to either outflow graft compression, outflow graft obstruction, or pump thrombosis requiring surgical intervention. Methods: 141 consecutive adult patients who underwent HeartMate3 Implantation using the “cut-then-sew” implantation technique between September 2015 and September 2021 were included in our study. The primary outcome measure was mechanical pump complication (outflow graft obstruction and or pump thrombosis) requiring surgical intervention. Secondary outcome measures included incidence of bleeding, stroke, renal failure, length of stay, and overall survival. Median follow up was 27.3 months. Results: Eleven (7.8%) of patients developed mechanical pump complications. Six patients developed outflow graft obstruction. Five patients developed acute pump thrombosis. Median time to a mechanical complication was 828 days. Of the 11 patients who underwent surgery, 10 patients (90%) survived to discharge. Overall survival at 1, 3, and 5 years was 82.9%, 69.1% and 55.2% respectively for the entire cohort. Conclusion: The mechanical pump complication rate of 7.8% which is quite high may be related to duration of follow up, as the median time to mechanical complication was 828 days. This study highlights an important late complication that occurs post LVAD implantation.Visual Abstract

Thoracic aortic aneurysms (TAAs) are potentially devastating, and due to their asymptomatic behavior, pose a serious health risk characterized by the lack of medical treatment options and high rates of surgical morbidity and mortality. Independent of the inciting stimuli (biochemical/mechanical), TAA development proceeds by a multifactorial process influenced by both cellular and extracellular mechanisms, resulting in alterations of the structure and composition of the vascular extracellular matrix (ECM). While the role of enhanced ECM proteolysis in TAA formation remains undisputed, little attention has been focused on the upstream signaling events that drive the remodeling process. Recent evidence highlighting the dysregulation of transforming growth factor-β (TGF-β) signaling in ascending TAAs from Marfan syndrome patients has stimulated an interest in this intracellular signaling pathway. However, paradoxical discoveries have implicated both enhanced TGF-β signaling and loss of function TGF-β receptor mutations, in aneurysm formation; obfuscating a clear functional role for TGF-β in aneurysm development. In an effort to elucidate this subject, TGF-β signaling and its role in vascular remodeling and pathology will be reviewed, with the aim of identifying potential mechanisms of how TGF-β signaling may contribute to the formation and progression of TAA.

This review article presents an appraisal of pioneering technologies poised to revolutionize the diagnosis and management of aortic aneurysm disease, with a primary focus on the thoracic aorta while encompassing insights into abdominal manifestations. Our comprehensive analysis is rooted in an exhaustive survey of contemporary and historical research, delving into the realms of machine learning (ML) and computer-assisted diagnostics. This overview draws heavily upon relevant studies, including Siemens’ published field report and many peer-reviewed publications. At the core of our survey lies an in-depth examination of ML-driven diagnostic advancements, dissecting an array of algorithmic suites to unveil the foundational concepts anchoring computer-assisted diagnostics and medical image processing. Our review extends to a discussion of circulating biomarkers, synthesizing insights gleaned from our prior research endeavors alongside contemporary studies gathered from the PubMed Central database. We elucidate the prevalent challenges and envisage the potential fusion of AI-guided aortic measurements and sophisticated ML frameworks with the computational analyses of pertinent biomarkers. By framing current scientific insights, we contemplate the transformative prospect of translating fundamental research into practical diagnostic tools. This narrative not only illuminates present strides, but also forecasts promising trajectories in the clinical evaluation and therapeutic management of aortic aneurysm disease.

Objective: Thoracic aortic aneurysms (TAAs) develop by a multifactorial process involving maladaptive signaling pathways that alter the aortic vascular environment. Transforming growth factor-beta (TGF-β) has been implicated in regulating the structure and composition of the extracellular matrix by differential activation of various intracellular signaling pathways. However, whether and to what degree TGF-β signaling contributes to TAA development remains unclear. Accordingly, the hypothesis that alterations in TGF-β signaling occur during aneurysm formation was tested in a murine model of TAA. Methods: TAAs were surgically induced in mice (C57BL/6J) and aortas were analyzed at predetermined time points (1, 2, and 4 weeks post-TAA induction). Quantitative real-time PCR (QPCR) was performed to evaluate the expression of 84 relevant TGF-β superfamily genes, and the protein levels of key signaling intermediates were measured by immunoblotting. Results were compared to unoperated reference control mice. Results: QPCR revealed increased expression of TGF-β superfamily ligands (Gdf-2, -6, -7, Inhba), ligand inhibitors (Bmper, Chrd, Gsc), and transcriptional regulators (Dlx2, Evi1), among other genes (Cdkn2b, Igf1, IL-6). Protein levels of TGF-β receptor II , Smad2, Smad1/5/8, phospho-Smad1/5/8, and Smurf1 were increased from control values post-TAA induction. Both TGF-β receptor I and Smad4 were decreased from control values, while ALK-1 levels remained unchanged. Conclusions: These alterations in the TGF-β pathway suggest a mechanism by which primary signaling is switched from a TGF-βR I /Smad2-dependent response, to an ALK-1/Smad1/5/8 response, representing a significant change in signaling outcome, which may enhance matrix degradation.

Children with functional single ventricle heart disease are commonly palliated down a staged clinical pathway toward a Fontan completion procedure (total cavopulmonary connection). The Fontan physiology is fraught with long-term complications associated with lower body systemic venous hypertension, eventually resulting in significant morbidity and mortality. The bidirectional Glenn shunt or superior cavopulmonary connection (SCPC) is commonly the transitional stage in single ventricle surgical management and provides excellent palliation. Some studies have demonstrated lower morbidity and mortality with the SCPC when compared with the Fontan. Unfortunately the durability of the SCPC is significantly limited by the development of pulmonary arteriovenous malformations (PAVMs) which have been commonly attributed to the absence of hepatic venous blood flow and the lack of pulsatile flow to the affected lungs. Abnormal angiogenesis has been suggested as a final common pathway to PAVM development. Understanding these fundamental mechanisms through the investigation of angiogenic pathways associated with the pathogenesis of PAVMs would help to develop medical therapies that could prevent or reverse this complication following SCPC. Such therapies could improve the longevity of the SCPC, potentially eliminate or significantly postpone the Fontan completion with its associated complications, and improve long-term survival in children with single ventricle disease.