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Myeloperoxidase is a signature enzyme of polymorphonuclear neutrophils in mice and humans. Being a component of circulating white blood cells, myeloperoxidase plays multiple roles in various organs and tissues and facilitates their crosstalk. Here, we describe the current knowledge on the tissue- and lineage-specific expression of myeloperoxidase, its well-studied enzymatic activity and incoherently understood non-enzymatic role in various cell types and tissues. Further, we elaborate on Myeloperoxidase (MPO) in the complex context of cardiovascular disease, innate and autoimmune response, development and progression of cancer and neurodegenerative diseases.

ObjectiveTo assess temporal trends of patient baseline characteristics, risk profile and outcome of transcatheter aortic valve implantation (TAVI) between 2013 and 2020.BackgroundGuideline recommendations and increasing confidence in TAVI therapy may have changed the selection of TAVI patients.MethodsBaseline risk profile and VARC-2 outcome of 15,344 patients undergoing TAVI at 5 high volume centers in Germany over the time period 2013–2020 was analyzed.ResultsOver the 8 years, annual TAVI volumes more than doubled from 1071 in 2013 to 2996 in 2020. The baseline surgical risk estimated by the Society of Thoracic Surgeons (STS) score declined from 7.2 ± 6.2% to 4.6 ± 3.7% (P < 0.001) as a consequence of lower comorbidity burden, whereas mean age remained unchanged (2013 81.0 ± 6.1; 2020 80.8 ± 6.4; P = 0.976) with patients ≥ 80 years accounting for about two-third of the treated cohort.Periprocedural complications including bleeding (2013 24.5%; 2020 12.1%; P < 0.001), vascular complications (2013 20.7%; 2020 11.7%; P < 0.001) and new permanent pacemaker implantation (2013 20.1%; 2020 13.8%, P < 0.001) decreased significantly. Similarly, the 30-day mortality decreased from 5.4% to 2.1% (P < 0.001), but remained high in high-risk patients (STS > 8% 2013 7.5%; 2020 6.9%; P = 0.778).ConclusionFrom 2013 to 2020, mortality and burden of complications following TAVI procedure significantly decreased in a large multicenter registry from Germany. Proportion of elderly patients remained stable, while the surgical risk profile decreased.

Identification and treatment of abdominal aortic aneurysm (AAA) remain among the most prominent challenges in vascular medicine. MicroRNAs (miRNAs) are crucial regulators of cardiovascular pathology and represent intriguing targets to limit AAA expansion. Here we show, by using two established murine models of AAA disease along with human aortic tissue and plasma analysis, that miR-24 is a key regulator of vascular inflammation and AAA pathology. In vivo and in vitro studies reveal chitinase 3-like 1 (Chi3l1) to be a major target and effector under the control of miR-24, regulating cytokine synthesis in macrophages as well as their survival, promoting aortic smooth muscle cell migration and cytokine production, and stimulating adhesion molecule expression in vascular endothelial cells. We further show that modulation of miR-24 alters AAA progression in animal models, and that miR-24 and CHI3L1 represent novel plasma biomarkers of AAA disease progression in humans. Abdominal aortic aneurysm (AAA) is a potentially fatal and often asymptomatic disease whose causes remain unclear. Here the authors show that a microRNA, miR-24, and its target, the glycoprotein chitinase 3-like 1, represent key regulators of AAA development.

Introduction This study investigated the use of dual-energy spectral detector computed tomography (CT) and virtual monoenergetic imaging (VMI) reconstructions in pre-interventional transcatheter aortic valve replacement (TAVR) planning. We aimed to determine the minimum required contrast medium (CM) amount to maintain diagnostic CT imaging quality for TAVR planning. Methods In this prospective clinical trial, TAVR candidates received a standardized dual-layer spectral detector CT protocol. The CM amount (Iohexol 350 mg iodine/mL, standardized flow rate 3 mL/s) was reduced systematically after 15 patients by 10 mL, starting at 60 mL (institutional standard). We evaluated standard, and 40- and 60-keV VMI reconstructions. For image quality, we measured signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and diameters in multiple vessel sections (i.e., aortic annulus: diameter, perimeter, area; aorta/arteries: minimal diameter). Mixed regression models (MRM), including interaction terms and clinical characteristics, were used for comparison. Results Sixty consecutive patients (mean age, 79.4 ± 7.5 years; 28 females, 46.7%) were included. In pre-TAVR CT, the CM reduction to 40 mL is possible without affecting the image quality (MRM: SNR: –1.1, p  = 0.726; CNR: 0.0, p  = 0.999). VMI 40-keV reconstructions showed better results than standard reconstructions with significantly higher SNR (+ 6.04, p  < 0.001). Reduction to 30 mL CM resulted in a significant loss of quality (MRM: SNR: –12.9, p  < 0.001; CNR: –13.9, p  < 0.001), regardless of the reconstruction. Across the reconstructions, we observed no differences in the metric evaluation ( p  > 0.914). Conclusion Among TAVR candidates undergoing pre-interventional CT at a dual-layer spectral detector system, applying 40 mL CM is sufficient to maintain diagnostic image quality. VMI 40-keV reconstructions improve the vessel attenuation and are recommended for evaluation. Clinical relevance statement Contrast medium reduction to 40 mL in pre-interventional transcatheter aortic valve replacement CT using dual-energy CT maintains image quality, while 40-keV virtual monoenergetic imaging reconstructions enhance vessel attenuation. These results offer valuable recommendations for interventional transcatheter aortic valve replacement evaluation and potentially improve nephroprotection in patients with compromised renal function. Key Points • Patients undergoing transcatheter aortic valve replacement (TAVR), requiring pre-interventional CT, are often multimorbid with impaired renal function. • Using a spectral detector dual-layer CT, contrast medium reduction to 40 mL is feasible, maintaining diagnostic image quality. • The additional application of virtual monoenergetic image reconstructions with 40 keV improves vessel attenuation significantly in clinical practice.

Abdominal aortic aneurysm (AAA) remains a significant public health challenge, primarily due to its high mortality rate and the lack of effective preventive and causal strategies. This study aims to establish an improved translational triple-hit porcine model of AAA and to compare it with human AAA disease. AAA was induced in four juvenile domestic pigs by balloon catheter-based aortic dilation, enzyme-mediated extracellular matrix (ECM) degradation, and lysyl oxidase inhibition. The porcine AAA model was characterized by proteomics, histological investigation, and cytokine profiling, and compared with natural occurred human AAA disease. Infrarenal AAA was successfully established with sustained aortic dilation (> 150% of baseline diameter) occurring within 7–14 days post induction and maintained through day 28. Proteomic analysis of porcine AAA tissue identified significant shifts in protein abundance, including downregulation of proteins associated with vascular smooth muscle cell function and ECM integrity, and upregulation of immune-related proteins. Comparative analysis of porcine and human aortic tissues revealed reduced medial elastic fiber content and length, along with increased calcification in porcine AAA, reflecting structural and pathological changes observed in human AAA. Systemic cytokine profiling revealed significant increases in both pro-inflammatory and anti-inflammatory cytokines following AAA induction in pigs, with a cytokine profile largely comparable to that observed in human AAA patients. These findings suggest that the refined porcine AAA model offers a reliable and reproducible platform for investigating AAA progression and evaluating potential therapeutic interventions prior to clinical implementation.

Objective: The aim of this study was to evaluate non-hyperemic resting pressure ratios (NHPRs), especially the novel “resting full-cycle ratio” (RFR; lowest pressure distal to the stenosis/aortic pressure during the entire cardiac cycle), compared to the gold standard fractional flow reserve (FFR) in a “real-world” setting. Methods: The study included patients undergoing coronary pressure wire studies at one German University Hospital. No patients were excluded based on any baseline or procedural characteristics, except for insufficient quality of traces. The diagnostic performance of four NHPRs vs. FFR ≤ 0.80 was tested. Morphological characteristics of stenoses were analyzed by quantitative coronary angiography. Results: 617 patients with 712 coronary lesions were included. RFR showed a significant correlation with FFR ( r = 0.766, p < 0.01). Diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of RFR were 78% (95% confidence interval = 75; 81), 72% (65; 78), 81% (77; 84), 63% (57; 69), and 86% (83; 89). Relevant predictors for discordance of RFR ≤ 0.89/FFR > 0.8 were LAD lesions, peripheral artery disease, age, female sex and non-focal stenoses. Predictors for discordance of RFR > 0.89/FFR ≤ 0.8 included non-LCX lesions, percent diameter stenosis and previous percutaneous coronary intervention in the target vessel. RFR and all other NHPRs were highly correlated with each other. Conclusion: All NHPRs have a similar correlation with the gold standard FFR and may facilitate the acceptance and implementation of physiological assessments of lesion severity. However, we found ~20% discordant results between NHPRs and FFR in our “all-comers” German cohort.

Abdominal aortic aneurysm (AAA) is a life-threatening condition characterized by chronic vascular inflammation and progressive aortic wall deterioration. MLKL-driven necroptosis, a highly inflammatory form of cell death, has been implicated in several cardiovascular pathologies; however, its role in AAA remains incompletely understood. Using the aortic elastase-perfusion model, we investigated the impact of necroptosis deficiency on AAA progression in necroptosis-deficient transgenic mice, including RIPK1 kinase-inactive ( Ripk1 D138N/D138N ), MLKL knockout ( Mlkl −/− ), and MLKL phospho-deficient ( Mlkl AA ) animals. Ultrasound analysis revealed that, compared to WT animals, the necroptosis-deficient animals were protected from aneurysm formation, exhibiting preserved aortic structure, reduced immune cell infiltration, and attenuated extracellular matrix remodeling. Bulk mRNAseq revealed significant downregulation of genes associated with fibrinolysis, immune cell activation/migration, inflammation, complement and coagulation cascades in necroptosis-deficient animals. Bone marrow transplantation experiments demonstrated that MLKL deficiency in smooth muscle cells (SMCs), rather than in myeloid cells, was primarily responsible for the protective phenotype. Furthermore, consistent with previous reports, necroptosis induction in MLKL-expressing human and primary mouse SMCs led to increased secretion of proinflammatory cytokines. Live-cell imaging revealed that necroptotic SMCs promote activation and migration of HL60-differentiated polymorphonuclear neutrophils. Collectively, these findings demonstrate that necroptotic SMC death and resulting leukocyte activation play a causative role in AAA development and suggest that pharmacological inhibition of MLKL may represent a promising treatment strategy for AAA disease.

Aortic valve stenosis (AS) is the most common valve disease requiring therapeutic intervention. Even though the incidence of AS has been continuously rising and AS is associated with significant morbidity and mortality, to date, no medical treatments have been identified that can modify disease progression. This unmet medical need is likely attributed to an incomplete understanding of the molecular mechanism driving disease development. To investigate the pathophysiology leading to AS, reliable and reproducible animal models that mimic human pathophysiology are needed. We have tested and expanded the protocols of a wire-injury induced AS mouse model. For this model, coronary wires were used to apply shear stress to the aortic valve cusps with increasing intensity. These protocols allowed distinction of mild, moderate and severe wire-injury. Upon moderate or severe injury, AS developed with a significant increase in aortic valve peak blood flow velocity. While moderate injury promoted solitary AS, severe-injury induced mixed aortic valve disease with concomitant mild to moderate aortic regurgitation. The changes in aortic valve function were reflected by dilation and hypertrophy of the left ventricle, as well as a decreased left ventricular ejection fraction. Histological analysis revealed the classic hallmarks of human disease with aortic valve thickening, increased macrophage infiltration, fibrosis and calcification. This new mouse model of AS promotes functional and morphological changes similar to moderate and severe human AS. It can be used to investigate the pathomechanisms contributing to AS development and to test novel therapeutic strategies.

Background Despite major advances, transcatheter aortic valve replacement (TAVR) is still associated with procedure‐specific complications. Although previous studies reported lower bleeding rates in patients receiving protamine for heparin reversal, the optimal protamine‐to‐heparin dosing ratio is unknown. Hypothesis The aim of this study was a comparison of two different heparin antagonization regimens for the prevention of bleeding complications after TAVR. Methods The study included 1446 patients undergoing TAVR, of whom 623 received partial and 823 full heparin antagonization. The primary endpoint was a composite of 30‐day mortality, life‐threatening, and major bleeding. Safety endpoints included stroke and myocardial infarction at 30 days. Results Full antagonization of heparin resulted in lower rates of the primary endpoint as compared to partial heparin reversal (5.6% vs. 10.4%, p < .01), which was mainly driven by lower rates of life‐threatening (0.5% vs. 1.6%, p = .05) and major bleeding (3.2% vs. 7.5%, p < .01). Moreover, the incidence of major vascular complications was significantly lower in patients with full heparin reversal (3.5% vs. 7.5%, p < .01). The need for red‐blood‐cell transfusion was lower in patients receiving full as compared to partial heparin antagonization (10.4% vs. 15.9%, p < .01). No differences were observed in the incidence of stroke and myocardial infarction between patients with full and partial heparin reversal (2.2% vs. 2.6%, p = .73 and 0.2% vs. 0.4%, p = .64, respectively). Conclusions Full heparin antagonization resulted in significantly lower rates of life‐threatening and major bleeding after TAVR as compared to partial heparin reversal. The occurrence of stroke and myocardial infarction was low and comparable between both groups. Optimal protamine‐to‐heparin dosing ratio for the prevention of bleeding complications after TAVR. Full antagonization of heparin was associated with a reduction of life‐threatening bleeding by 69% and major bleedings by 57%, compared to patients with partial heparin reversal. Whereas partial antagonization of heparin was associated with a relative increase of the post‐interventional drop in hemoglobin by 13% and red blood cell transfusion by 53%, as compared to full heparin antagonization. life‐threat., life‐threatening; RBC, red blood cell; TAVR, transcatheter aortic valve replacement.

Myocardial infarction (MI) is a significant contributor to morbidity and mortality worldwide. Many individuals who survive the acute event continue to experience heart failure (HF), with inflammatory and healing processes post-MI playing a pivotal role. Polymorphonuclear neutrophils (PMN) and monocytes infiltrate the infarcted area, where PMN release high amounts of the heme enzyme myeloperoxidase (MPO). MPO has numerous inflammatory properties and MPO plasma levels are correlated with prognosis and severity of MI. While studies have focused on MPO inhibition and controlling PMN infiltration into the infarcted tissue, less is known on MPO's role in monocyte function. Here, we combined human data with mouse and cell studies to examine the role of MPO on monocyte activation and migration. We revealed a correlation between plasma MPO levels and monocyte activation in a patient study. Using a mouse model of MI, we demonstrated that MPO deficiency led to an increase in splenic monocytes and a decrease in cardiac monocytes compared to wildtype mice (WT). In vitro studies further showed that MPO induces monocyte migration, with upregulation of the chemokine receptor CCR2 and upregulation of inflammatory pathways identified as underlying mechanisms. Taken together, we identify MPO as a pro-inflammatory mediator of splenic monocyte recruitment and activation post-MI and provide mechanistic insight for novel therapeutic strategies after ischemic injury.