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Background: The ACURATE neo2 is a contemporary transcatheter aortic valve implantation (TAVI) system approved for the treatment of severe aortic stenosis in Europe. The ACURATE neo2 has not been evaluated in bicuspid aortic valve (BAV) stenosis., Aims: We sought to evaluate the safety and efficacy of ACURATE neo2 in patients with BAV stenosis., Methods: We retrospectively analysed consecutive severe BAV stenosis patients undergoing TAVI with ACURATE neo2 at 10 European centres. Imaging data from preprocedural multislice computed tomography, pre- and postprocedural echocardiography, and procedural cinefluoroscopy were evaluated by a core laboratory. Valve Academic Research Consortium 3 (VARC-3)-defined 30-day procedure safety and efficacy were the primary endpoints. Adverse events were site-reported according to VARC-3 criteria., Results: Among 181 patients with BAV stenosis treated with the ACURATE neo2, the mean age was 77.5±7.2 years, 58.0% were female, and the Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) score was 2.3% (1.6-3.7%). Most procedures were transfemoral, and predilatation was performed in all cases. A second valve was required in 4 cases (2.2%). VARC-3-defined technical success was 95.6%. The primary endpoints of device success and early safety occurred in 90.6% and 82.3%, respectively. At 30 days, cardiovascular death occurred in 2.2% (N=4) and stroke in 1.6% (N=3). Core laboratory-adjudicated echocardiography reported an effective orifice area of 2.0 (1.7-2.5) cm 2 and a mean transvalvular gradient of 6.5 (4.6-9.0) mmHg. Half of all cases (51.2%) had no paravalvular leak, while moderate leak occurred in 4.3%. A new permanent pacemaker was required in 11 patients (6.5%)., Conclusions: The ACURATE neo2 demonstrated favourable clinical outcomes and bioprosthetic valve performance at 30 days in selected patients with severe BAV stenosis.

Background: There are different definitions of periprocedural myocardial infarction (PPMI) both in terms of thresholds for cardiac biomarkers and the ancillary criteria for myocardial ischemia. Cardiac Troponin I (cTnI) and cardiac Troponin T (cTnT) are used interchangeably to diagnose PPMI., Objectives: This study evaluated the frequency of periprocedural myocardial injury and infarction as defined by the Society of Cardiovascular Angiography & Interventions (SCAI), the Academic Research Consortium-2 (ARC-2), and the 4th Universal definition of MI (4UDMI) stratified using cTnT versus cTnI, among patients with chronic coronary syndrome (CCS) and unstable angina., Results: Among 830 patients, PPMI rates according to the SCAI, ARC2 and 4UDMI criteria were 4.34 %, 2.05 %, and 4.94 % respectively, with higher rates seen for all definitions when using cTnI versus cTnT (SCAI: 9.84 % vs. 1.91 %, p < 0.001; ARC 2: 3.15 % vs. 1.56 %, p = 0.136; and 4UDMI 5.91 % vs. 4.51 %, p = 0.391). Minor and major periprocedural myocardial injury was respectively observed in 58.31 % and 27.10 % of patients, with rates of both significantly higher when using cTnI versus cTnT (Minor: 69.29 % vs. 53.47 %, p < 0.001, Major: 49.21 % vs. 17.36 %, p < 0.001)., Conclusions: Among patients with CCS and unstable angina, PPMIs defined by SCAI occurred more frequently when using cTnI as opposed to cTnT, whereas the type of troponin had no impact on the incidence of PPMIs according to the ARC-2 and 4UDMI., Competing Interests: Declaration of competing interest Dr. Ninomiya reports a grant from Abbott Medical Japan outside the submitted work. Dr. Kotoku has received a grant for studying overseas from Fukuda Foundation for Medical Technology. Dr. Serruys reports institutional grants from Sinomedical Sciences Technology, SMT (Sahajanand Medical technologies), Meril Life sciences, Philips/Volcano, Xeltis, and HeartFlow, outside the submitted work. Dr. Onuma reports institutional grants from Sinomedical Sciences Technology, SMT (Sahajanand Medical technologies), Meril Life sciences, Philips/Volcano, Xeltis, and HeartFlow, outside the submitted work. Dr. Sabate is a consultant for Abbott vascular and iVascular outside the submitted work. Dr. Mollmann is a consultant for Abbott vascular, Boston Scientific, Medtronic and SMT outside the submitted work., (Copyright © 2024. Published by Elsevier Inc.)

A total of 1001 subjects (82.0 years, 62.5% female, 63.7% NYHA III/IV at baseline) with severe aortic stenosis at high surgical risk were enrolled in the prospective CONFIDENCE registry and treated with a Portico™ transcatheter heart valve (THV) using either a first-generation delivery system (DS) or the FlexNav™ DS. The objective of this registry is to characterize the procedural safety and device performance of the Portico™ THV at 30 days. The study collected 'standard-of-care' clinical and device performance data, with adverse events adjudicated by an independent clinical event committee according to the Valve Academic Research Consortium-2 criteria. The implantation of a single Portico™ THV was successful in 97.5% of subjects. The 30-day all-cause mortality, cardiovascular mortality, and disabling stroke rates were 2.6%, 2.1%, and 1.8%, respectively. A new pacemaker was implanted in 19.0% of subjects at 30 days. At 30 days, the effective orifice area and mean gradient values were 1.82 cm 2 and 7.1 mmHg, respectively. The 30-day rate of moderate paravalvular leak (PVL) was 2.1%, with no occurrence of severe PVL. The Portico™ THV demonstrated improved hemodynamic performance and low rates of safety events at 30 days in a large cohort of subjects implanted with the Portico™ THV with either the first-generation DS or FlexNav™ DS.

The study quantitatively analyzes and compares the pharmacokinetics (PK) of methylprednisolone (MPL) in humans upon administration of various dosage forms. The PK parameters and profiles of MPL in healthy subjects were collected from 22 literature sources. A minimal physiologically based pharmacokinetic (mPBPK) model consisting of blood and two tissue (lumped liver and kidney, remainder) compartments with nonlinear tissue partitioning was applied to describe MPL disposition. Overall 18 plasma concentration profiles were well captured and 85% of PK parameters reasonably estimated. The clearance (CL) of MPL averaged 336 mL/h/kg and appeared slightly nonlinear across a dosage range of 5 to 800 mg, the distribution volume (V d ) averaged 1.17 L/kg, and the model predicted elimination half-life (t 1/2 ) was 2.6 h. Rapid prodrug conversion was found for intravenous MPL sodium succinate (MPSS) with a t 1/2 of 1.7 min, and followed by MPL phosphate (MPPS) 3.8 min, MPL hemisuccinate (MPHS) 16 min, and MPL suleptanate (MPSP) 2.9 h. Their bioavailabilities (F) varied slightly from 60 to 73%. Intramuscular doses showed an absorption rate constant (k a ) of 1.5 h -1 for MPSS and 96 h -1 for MPSP. Oral doses of 5 formulations were examined. Medrol exhibited greatest absorption with F of 74% and k a of 2.1 h -1 , while one generic product had F of 32.6%. This study demonstrated the utility of a mechanistic mPBPK disposition model for comparing MPL formation from various esters, absorption from several oral dose formulations, and modest variability across numerous PK studies in healthy humans., Competing Interests: Declarations. Conflict of Interest: The authors declare that there are no conflicts of interest., (© 2025. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Introduction: Patients with end-stage kidney disease (ESRD) represent a high-risk population in terms of both development of and death by cardiovascular diseases. Outcome data of ESRD patients with severe aortic valve stenosis (AS) treated by transcatheter aortic valve implantation (AVI) are scarce. We aim to compare the outcome of ESRD patients undergoing transfemoral (TF) or transapical (TA) AVI. Methods: From June 2006 to December 2019, 176 consecutive patients with ESRD receiving chronic hemodialysis underwent TF- or TA-AVI at two German heart centers. The primary outcome measure was 1-year all-cause mortality. Other outcomes included VARC-3 defined device success and early safety. Results: The cohort comprised 61 (34.7%) patients receiving TA-AVI and 115 (65.3%) patients receiving TF-AVI. Perioperative risk, assessed using the EuroScore II, was not different between groups. VARC-3 defined device success (52.5% vs. 80.0%, p < 0.001) and early safety (27.9% vs. 45.2%, p = 0.025) were lower in TA-AVI patients compared to the TF-AVI group. The 30-day mortality was 4.7-fold higher in TA- compared TF-AVI patients (24.6% vs. 5.2%, p < 0.001). The 1-year mortality was higher in TA- compared with TF-AVI patients (57.3% vs. 27.8%, p < 0.001). By applying a Cox regression analysis, it was found that TA-AVI was the only independent factor associated with 1-year all-cause mortality (HRadj 2.65 (95%-CI 1.63-4.30), p < 0.001). Conclusions: In ESRD patients, TA-AVI was associated with worse early outcomes and increased mortality up to 1 year compared to the TF-AVI. Transfemoral access is recommended, when feasible, in ESRD patients undergoing TAVI. [ABSTRACT FROM AUTHOR]

Approximately 50% of individuals eligible for transcatheter aortic valve implantation (TAVI) have coronary artery disease (CAD). The influence of CAD, both its prevalence and severity, on post-TAVI clinical results has yielded conflicting findings. Recent research has shown positive results for the use of computed tomography angiography and functional percutaneous evaluation of coronary lesions in the pre-TAVI assessment, besides the classic coronary angiography. As we anticipate the outcomes of current randomized studies, it has become common practice to perform invasive revascularization on TAVI patients with obstructive CAD. Furthermore, there is a lack of comprehensive data about the occurrence, features, and treatment of coronary incidents after TAVI. There is also growing concern about the possible difficulties in accessing the coronary arteries in patients who need coronary angiography with or without intervention after TAVI. This review presents a comprehensive analysis of the contemporary treatment options of CAD in patients undergoing TAVI. In this context, it examines the incidence of CAD in TAVI candidates; its clinical significance; the assessment and management of CAD before, concomitant, and after the procedure, including patients' unresolved concerns; and possible future aspects. [ABSTRACT FROM AUTHOR]

Fire plays a pivotal role in driving ecological shifts between Mediterranean‐type vegetation and subtropical ecosystems in South Africa. This study investigates long‐term environmental dynamics and ecological regime changes at the Mediterranean‐type vegetation /subtropical boundary using a 6000‐year palaeoecological sequence from the Baviaanskloof – a region of South Africa characterized by high levels of biodiversity and climate dynamism. Combining fossil pollen and microcharcoal data from a rock hyrax Procavia capensis midden, we analyse vegetation responses to environmental changes. Our findings reveal that Mediterranean‐type vegetation resilience prevailed until ca 2800 cal year BP when a major fire event triggered a transition to a subtropical thicket‐dominated environment. This abrupt ecological turnover underscores the significance of fire as a major driver of vegetation change at the Mediterranean‐type vegetation /subtropical boundary. Our study emphasizes the vulnerability of Mediterranean‐type vegetation ecosystems to global environmental change, suggesting potential implications for similar biome boundaries worldwide. By integrating multi‐proxy palaeoecological evidence, we gain insights into the resilience and vulnerability of these ecosystems, aiding in understanding future responses to climate change scenarios. [ABSTRACT FROM AUTHOR]

Introduction: Direct oral anticoagulant (DOAC) dose adjustment is based on age, renal function, and body weight. There is a paucity of data describing the factors associated with the prescription of inappropriate dosage and their impact on clinical outcomes among patients receiving transcatheter aortic valve implantation (TAVI). Methods: In a single-center study, 432 patients who were on long-term DOAC therapy and underwent TAVI between 2015 and 2022 were included. We analyzed the predictors and outcomes of inappropriate dosing of DOACs; namely apixaban, dabigatran, edoxaban, and rivaroxaban. A composite endpoint, including all-cause mortality, life-threatening/major bleeding, stroke, peripheral thromboembolic complications, or myocardial infarction, was assessed after 1 year. Results: In this TAVI cohort, inappropriate DOAC dosing was observed in 20.6% of patients. Inappropriate DOAC dosage was related to female gender (adj. odds ratio [OR] 2.72, 95% confidence interval [CI] 1.64–4.51, p < 0.001) as well as lower estimated glomerular filtration rate (eGFR) (adj. OR 0.99, 95% CI 0.98–1.00, p = 0.019), and to the administration of non-rivaroxaban DOACs (adj. OR 0.28, 95% CI 0.16–0.50, p < 0.001). After 1 year, patients on both appropriate and inappropriate DOAC dosage exhibited comparable rates of the composite endpoint (OR 0.88, 95% CI 0.53–1.46, p = 0.622). Old age (adj. OR 1.05, 95% CI 1.01–1.10, p = 0.018) as well as anemia (adj. OR 0.86, 95% CI 0.75–0.99, p = 0.031) emerged as independent predictors of the composite endpoint. Conclusions: In this TAVI cohort, female gender and renal insufficiency were associated with inappropriate DOAC dosage, whereas rivaroxaban was linked to appropriate dosing. Inadequate DOAC dosage did not translate into a worse outcome in our TAVI population. Trial Registration: Prospective Segeberg TAVI Registry (ClinicalTrials.gov identifier: NCT03192774). [ABSTRACT FROM AUTHOR]

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Arteriogenesis is an inflammatory driven mechanism, describing the growth of a natural bypass from pre-existing collateral arteries to compensate for an occluded artery. The complement system component C3 is a potent natural inflammatory activator. Here, we investigated its impact on the process of collateral artery growth using C3-deficient (C3 −/−) and wildtype control mice in a murine hindlimb model of arteriogenesis. Induction of arteriogenesis by unilateral femoral artery ligation resulted in decreased perfusion recovery in C3 −/− mice on day 7 as shown by Laser Doppler imaging. Immunofluorescence staining revealed a reduced vascular cell proliferation in C3 −/− mice. Gene expression analysis displayed a significant reduction in monocyte chemoattractant protein-1 (MCP-1) expression in C3 −/− mice. Interestingly, 3 days after induction of arteriogenesis, the number of macrophages (CD68+) recruited to growing collaterals was not affected by C3 deficiency. However, a significant reduction in inflammatory M1-like polarized macrophages (CD68+/MRC1−) was noted. Forced mast cell activation by Compound 48/80 as well as exogenous MCP-1 application rescued the number of M1-like polarized macrophages along with perfusion recovery in C3 −/− mice. In summary, this study demonstrates that complement C3 influences arteriogenesis by mediating MCP-1 expression, which is essential for the induction and enhancement of sterile inflammation. [ABSTRACT FROM AUTHOR]

Background: Ticagrelor is a novel oral antiplatelet agent which can selectively inhibit P2Y12 receptor. Bleeding and dyspnea are common adverse reactions of ticagrelor in clinic. The side effects of ticagrelor are correlated with the plasma concentration of ticagrelor. Objective: This study aimed to evaluate the catalytic characteristics of 22 CYP3A4 alleles identified in the Chinese Han population on the metabolism of ticagrelor in vitro, focusing on the effect of CYP3A4 polymorphism on ticagrelor metabolism. Methods: In this study, insect cells were used to express 22 CYP3A4 variants, which were then incubated with 1–50 µM ticagrelor at 37 °C for 30 minutes to obtain the metabolite (AR-C124910XX). AR-C124910XX was detected by UHPLC-MS/MS to calculate the kinetic parameters, including Km, Vmax and CLint. Results: Compared to the wild-type, most CYP3A4 alleles exhibited significant differences in intrinsic clearance. The intrinsic clearance of CYP3A4*11, *18 and *33 was much higher than that of wild-type; four variants exhibited similar intrinsic clearance values as the wild-type enzyme; The remaining 14 variants showed significantly reduced intrinsic clearance values, ranging from 1.48% to 75.11% of the wild-type; CYP3A4*30 displayed weak or no activity. Conclusion: This study conducted a comprehensive assessment of the effect of CYP3A4 variants on ticagrelor's metabolism. The results suggested that there is allele-specific activity towards ticagrelor in vitro. These findings can provide some insights and predictions for treatment strategies and risk assessments associated with ticagrelor in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Precise implantation could play a crucial role in the technical success of transcatheter aortic valve replacement (TAVR) for some prostheses. The impact of an accidental implantation depth (ID) outside the recommended range has not been assessed for the ACURATE neo2 (NEO2). Methods: Data from 1839 patients with severe native aortic stenosis treated with the NEO2 prosthesis were evaluated. We compared the results of prostheses implanted in an ID both inside and outside the recommendations. The outcome assessment followed the Valve Academic Research Consortium-3 criteria. Results: Patients were retrospectively divided into high (<3 mm; n = 412), optimal (3–7 mm; n = 1236), and low (>7 mm; n = 169) implantations. Technical success (94.7% vs. 94.7% vs. 91.7%, p = 0.296) and device success were high (90.1% vs. 89.3% vs. 84.6%, p = 0.112) without differences between groups. Rates of relevant paravalvular regurgitation (PVL; >mild or VinV due to PVL) were comparable (1.2% vs. 1.8% vs. 1.2%, p = 0.759). Even when hemodynamics were superior in the high-implantation group, with greater iEOA (1.01 cm2/m2 vs. 0.95 cm2/m2 vs. 0.92 cm2/m2, p < 0.001), spontaneous embolization or after post-dilatation was more common. Low implantation was associated with a higher rate of associated pacemaker implantation (PPI) (6.1% vs. 8.8% vs. 14.8%, p = 0.001). Conclusions: Implantation with the ACURATE neo2 showed excellent hemodynamic results, including low gradients and a small number of relevant PVL, in line with a high technical success rate that was irrespective of the ID. A favorable outcome can also be achieved in accidental low or high positions. Low implantation was associated with a higher rate of associated pacemaker implantation. Deliberately high implantation should be avoided due to the risk of embolization. [ABSTRACT FROM AUTHOR]

Obesity is a chronic disease that is rapidly increasing in prevalence and affects more than 600 million adults worldwide, and this figure is estimated to increase by at least double by 2030. In the United States, more than one-third of the adult population is either overweight or obese. The global obesity epidemic is a major risk factor for the development of life-threatening arrhythmias occurring in patients with long QT, particularly in conditions where multiple heart-rate-corrected QT-interval-prolonging mechanisms are simultaneously present. In obesity, excess dietary fat in adipose tissue stimulates the release of immunomodulatory cytokines such as interleukin (IL)-6, leading to a state of chronic inflammation in patients. Over the last decade, increasing evidence has been found to support IL-6 signaling as a powerful predictor of the severity of heart diseases and increased risk for ventricular arrhythmias. IL-6′s pro-inflammatory effects are mediated via trans-signaling and may represent a novel arrhythmogenic risk factor in obese hearts. The first selective inhibitor of IL-6 trans-signaling, olamkicept, has shown encouraging results in phase II clinical studies for inflammatory bowel disease. Nevertheless, the connection between IL-6 trans-signaling and obesity-linked ventricular arrhythmias remains unexplored. Therefore, understanding how IL-6 trans-signaling elicits a cellular pro-arrhythmic phenotype and its use as an anti-arrhythmic target in a model of obesity remain unmet clinical needs. [ABSTRACT FROM AUTHOR]

In this narrative review, we investigate the essential role played by the computed tomography Aortic Valve Calcium Score (AVCS) in the cardiovascular diagnostic landscape, with a special focus on its implications for clinical practice and scientific research. Calcific aortic valve stenosis is the most prevalent type of aortic stenosis (AS) in industrialized countries, and due to the aging population, its prevalence is increasing. While transthoracic echocardiography (TTE) remains the gold standard, AVCS stands out as an essential complementary tool in evaluating patients with AS. The advantage of AVCS is its independence from flow; this allows for a more precise evaluation of patients with discordant findings in TTE. Further clinical applications of AVCS include in the assessment of patients before transcatheter aortic valve replacement (TAVR), as it helps in predicting outcomes and provides prognostic information post-TAVR. Additionally, we describe different AVCS thresholds regarding gender and the anatomical variations of the aortic valve. Finally, we discuss various scientific studies where AVCS was applied. As AVCS has some limitations, due to the pathophysiologies of AS extending beyond calcification and gender differences, scientists strive to validate contrast-enhanced AVCS. Furthermore, research on developing radiation-free methods of measuring calcium content is ongoing. [ABSTRACT FROM AUTHOR]

Pneumonia stands as the leading infectious cause of childhood mortality annually, underscoring its significant impact on pediatric health. Although dexamethasone (DXMS) is effective for treating pulmonary inflammation, its therapeutic potential is compromised by systemic side effects and suboptimal carrier systems. To address this issue, the current study introduces solid lipid nanoparticles encapsulating hydrophobic dexamethasone palmitate (DXMS-Pal-SLNs) as an anti-inflammatory nanoplatform to treat pneumonia. The specialized nanoparticle formulation is characterized by high drug loading efficiency, low drug leakage and excellent colloidal stability in particular during nebulization and is proficiently designed to target alveolar macrophages in deep lung regions via local delivery with the nebulization administration. In vitro analyses revealed substantial reductions in the secretions of tumor necrosis factor-α and interleukin-6 from alveolar macrophages, highlighting the potential efficacy of DXMS-Pal-SLNs in alleviating pneumonia-related inflammation. Similarly, in vivo experiments showed a significant reduction in the levels of these cytokines in the lungs of mice experiencing lipopolysaccharide-induced pulmonary inflammation after the administration of DXMS-Pal-SLNs via nebulization. Furthermore, the study demonstrated that DXMS-Pal-SLNs effectively control acute infections without causing pulmonary infiltration or excessive recruitment of immunocytes in lung tissues. These findings highlight the potential of nebulized DXMS-Pal-SLNs as a promising therapeutic strategy for mitigating pneumonia-related inflammations. [ABSTRACT FROM AUTHOR]

Background: The frequency and prognostic value of coronary no-reflow (CNR) was investigated in studies that have used an outdated reperfusion therapy in terms of stent technology and antithrombotic drugs. We assessed the association of CNR with adverse outcomes in patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DES) and newer antithrombotic drugs, ticagrelor or prasugrel. Methods: This study included 3100 patients with AMI who underwent PCI with current DES and third-generation P2Y12 inhibitors. CNR was defined as Thrombolysis in Myocardial Infarction (TIMI) blood flow grade ≤ 2 at the end of PCI. The primary end point was 1-year incidence of net adverse clinical and cerebral events—a composite end point of death of any cause, myocardial infarction, stroke or major bleeding. Results: CNR was diagnosed in 130 patients (4.2%). The primary end point occurred in 28 patients in the CNR group and 354 patients in the reflow group (cumulative incidence 23.2% and 12.8%; adjusted hazard ratio = 1.53, 95% confidence interval 1.01–2.33; P = 0.049). The 1-year incidences of death or myocardial infarction (14.6% vs. 7.6%; P = 0.003), myocardial infarction (8.8% vs. 3.9%; P = 0.007) and major bleeding (10.9% vs. 5.6%; P = 0.008) were significantly higher in patients with CNR than patients with reflow. The risk of adverse events in patients with CNR was highest within the first 30 days after PCI. Conclusion: In patients with AMI undergoing PCI with current DES and third generation P2Y12 receptor inhibitors, CNR was associated with a higher risk of adverse outcomes at 1 year. [ABSTRACT FROM AUTHOR]

Takotsubo syndrome (TTS) is a particular form of acute heart failure that can be challenging to distinguish from acute coronary syndrome at presentation. TTS was previously considered a benign self‐limiting condition, but it is now known to be associated with substantial short‐ and long‐term morbidity and mortality. Because of the poor understanding of its underlying pathophysiology, there are few evidence‐based interventions to treat TTS. The hypotheses formulated so far can be grouped into endogenous adrenergic surge, psychological stress or preexisting psychiatric illness, coronary vasospasm with microvascular dysfunction, metabolic and energetic alterations, and inflammatory mechanisms. Current evidence demonstrates that the infiltration of immune cells such as macrophages and neutrophils play a pivotal role in TTS. At baseline, resident macrophages were the dominant subset in cardiac macrophages, however, it underwent a shift from resident macrophages to monocyte‐derived infiltrating macrophages in TTS. Depletion of macrophages and monocytes in mice strongly protected them from isoprenaline‐induced cardiac dysfunction. It is probable that immune cells, especially macrophages, may be new targets for the treatment of TTS. [ABSTRACT FROM AUTHOR]