Impacts of Telomeric Length, Chronic Hypoxia, Senescence, and Senescence-Associated Secretory Phenotype on the Development of Thoracic Aortic Aneurysm.

Thoracic aortic aneurysm (TAA) is an age-related and life-threatening vascular disease. Telomere shortening is a predictor of age-related diseases, and its progression is associated with premature vascular disease. The aim of the present work was to investigate the impacts of chronic hypoxia and telomeric DNA damage on cellular homeostasis and vascular degeneration of TAA. We analyzed healthy and aortic aneurysm specimens (215 samples) for telomere length (TL), chronic DNA damage, and resulting changes in cellular homeostasis, focusing on senescence and apoptosis. Compared with healthy thoracic aorta (HTA), patients with tricuspid aortic valve (TAV) showed telomere shortening with increasing TAA size, in contrast to genetically predisposed bicuspid aortic valve (BAV). In addition, TL was associated with chronic hypoxia and telomeric DNA damage and with the induction of senescence-associated secretory phenotype (SASP). TAA-TAV specimens showed a significant difference in SASP-marker expression of IL-6, NF-κB, mTOR, and cell-cycle regulators (γH2AX, Rb, p53, p21), compared to HTA and TAA-BAV. Furthermore, we observed an increase in CD163+ macrophages and a correlation between hypoxic DNA damage and the number of aortic telocytes. We conclude that chronic hypoxia is associated with telomeric DNA damage and the induction of SASP in a diseased aortic wall, promising a new therapeutic target.

Left Ventricular Reverse Remodeling after Surgical Aortic Valve Replacement for Aortic Regurgitation-An Explorative Study.

BACKGROUND: The timing of treatment for chronic aortic valve regurgitation (AR), especially in asymptomatic patients, is gaining attention since less invasive strategies have become available. The aim of the present study was to evaluate left ventricular reverse remodeling after aortic valve replacement (AVR) for severe AR. METHODS: Patients (n = 25) who underwent surgical AVR for severe AR with left ventricular ejection fraction (LVEF) less than 55% were included in this study. Preprocedural and follow-up clinical and echocardiographic measurements of LVEF and left ventricular (LV) diameters were retrospectively analyzed. RESULTS: Mean LVEF increased significantly following surgical AVR (p < 0.0001). LV diameters showed a clear regression (p = 0.0088). Younger patients and those receiving a mechanical valve tended to have less improved LVEF on follow-up than patients over 60 years or the ones who were implanted with a biological prosthesis (p = 0.0239 and p = 0.069, respectively). Gender had no effect on the degree of LVEF improvement (p = 0.4908). CONCLUSIONS: We demonstrated significant LV reverse remodeling following AVR for AR. However, more data are needed on LV functional and geometrical improvement comparing the different types of valve prostheses to provide an optimal treatment strategy.

First-in-men experience with a novel frozen elephant trunk prosthesis featuring an endovascular side branch for left subclavian artery connection.

OBJECTIVES: The objective of this study was to enhance the efficiency of aortic arch replacement through the development of a novel frozen elephant trunk (FET) prosthesis with an endovascular side branch for left subclavian artery (LSA) connection. After successful pre-clinical testing, the feasibility and safety of implementing this innovative prosthesis in human subjects were investigated. METHODS: Between September 2020 and September 2021, 4 patients (mean age 67) with conditions such as penetrating ulcer, non A-non B aortic dissection and chronic arch aneurysm underwent surgery utilizing the customized device. Surgeries were performed under high moderate hypothermia (27°C), employing bilateral selective antegrade cerebral perfusion (SACP) and distal aortic perfusion. Anastomosis of the FET prosthesis with the aortic arch occurred in zone 1, followed by separate reimplantation of the left common carotid artery and the brachiocephalic artery. RESULTS: All patients were discharged in good clinical condition. The mean aortic cross-clamp, antegrade selective cerebral perfusion and distal aortic perfusion times were 111, 71 and 31 min, respectively. Endovascular extension of the side branch for the LSA was required in all cases to prevent endoleak formation. One patient received a stent graft extension at the end of the operation, while 2 others underwent the procedure during their hospital stay. One patient was diagnosed with an endoleak at the first follow-up after 3 months, and endoleak sealing was achieved via the brachial artery with an extension stent graft. CONCLUSIONS: Preliminary clinical outcomes suggest that the newly designed FET prosthesis shows promise in simplifying total arch replacement. These initial findings provide a foundation for planned clinical studies to further assess the effectiveness of this modified surgical hybrid graft, with particular attention to the length and diameter of the LSA sidearm.

Long-Term Results with 187 Frozen Elephant Trunk Procedures.

The frozen elephant trunk (FET) technique is an established therapeutic option in the treatment of complex aortic diseases. We report our long-term clinical outcomes after FET repair. A total of 187 consecutive patients underwent FET repair at our department between 8/2005 and 3/2023. Indications included acute and chronic aortic dissections and thoracic aneurysms. Endpoints included operative morbidity and mortality, long-term survival, and the need for reinterventions. Operative mortality, spinal cord injury and permanent stroke rates were: 9.6%, 2.7% and 10.2%, respectively. At five years, overall survival was 69.9 ± 3.9% and freedom from aortic-related death was 82.5 ± 3.0%, whereas at ten years, overall survival was 53.0 ± 5.5% and freedom from aortic-related death was 75.8 ± 4.8%. Sixty-one reinterventions on the thoracic aorta were necessary. Freedom from secondary interventions at ten years was 44.7 ± 6.4% overall (63.1 ± 10.0% for acute dissections, 40.8 ± 10.3% for chronic dissections and 28.9 ± 13.1% for aneurysms, respectively). The high reintervention rate for chronic dissections and for aneurysms is related to the pre-existing aortic pathology. Late aortic growth of untreated segments with potentially fatal outcome occurs even after ten years, so careful annual follow-up is mandatory in this patient cohort.

Application of tiny-TIM as a mechanistic tool to investigate the in vitro performance of different itraconazole formulations under physiologically relevant conditions.

The increasing number of poorly water-soluble compounds in drug development is one of the major challenges in oral drug delivery nowadays. For rational formulation development, biopharmaceutical tools are needed that closely simulate the conditions present within the human gastrointestinal (GI) tract in order to early predict the potential effect of important factors like meal intake or acid-reducing agents on oral bioavailability. The tiny-TIM system equipped with the advanced gastric compartment is one of the most realistic in vitro models for the simulation of the physiological processes occurring in human stomach and small intestine. In the present study, this model was applied to study the in vitro performance of an ASD-based formulation of itraconazole under different clinically relevant conditions. Apart from the assessment of the bioaccessible fraction (i.e., the fraction available for drug absorption), the implementation of two additional sampling ports enabled the measurement of intraluminal concentration profiles. Along with solubility experiments in biorelevant media, deeper mechanistic insights into drug product performance in different prandial states as well as in case of gastric pH modification could be generated. The comparison of the in vitro data with published in vivo data revealed that the model successfully predicted the effect of food intake as well as of modified gastric pH conditions on the bioavailability of itraconazole from this formulation. In contrast, the negative food effect observed for an oral solution formulation could not be predicted. For this cyclodextrin-based formulation, the formulation effect on permeation needs to be considered. Nonetheless, the data presented in this study showed that tiny-TIM is an interesting tool to mechanistically study the impact of different physiological conditions on drug release from oral drug products.

Mucin-Protected Caco-2 Assay to Study Drug Permeation in the Presence of Complex Biorelevant Media.

The poor solubility and permeability of compounds beyond Lipinski's Rule of Five (bRo5) are major challenges for cell-based permeability assays. Due to their incompatibility with gastrointestinal components in biorelevant media, the exploration of important questions addressing food effects is limited. Thus, we established a robust mucin-protected Caco-2 assay to allow the assessment of drug permeation in complex biorelevant media. To do that, the assay conditions were first optimized with dependence of the concentration of porcine mucin added to the cells. Mucin-specific effects on drug permeability were evaluated by analyzing cell permeability values for 15 reference drugs (BCS class I-IV). Secondly, a sigmoidal relationship between mucin-dependent permeability and fraction absorbed in human (fa) was established. A case study with venetoclax (BCS class IV) was performed to investigate the impact of medium complexity and the prandial state on drug permeation. Luminal fluids obtained from the tiny-TIM system showed a higher solubilization capacity for venetoclax, and a better read-out for the drug permeability, as compared to FaSSIF or FeSSIF media. In conclusion, the mucin-protected Caco-2 assay combined with biorelevant media improves the mechanistic understanding of drug permeation and addresses complex biopharmaceutical questions, such as food effects on oral drug absorption.

(Sub)micron particles forming in aqueous dispersions of amorphous solid dispersions of the poorly soluble drug ABT-199: A combined particle optical counting and field-flow fractionation study.

The dispersive behavior of three different amorphous solid dispersion (ASD) formulations of the poorly soluble ABT-199 (Venetoclax) were studied in aqueous and biomimetic media and spontaneously forming supramolecular associates and particles analysed. To this end, the aqueous dispersions were fractionated into a submicron (colloidal) and micrometer-sized particle-fraction by bench-top centrifugation. The submicron fraction was characterized by Asymmetric Flow Field-Flow Fractionation in conjunction with Multi-angle Laser Light Scattering (AF4-MALLS), Dynamic Light Scattering (DLS) and zeta potential analysis. The micron particle fraction was characterized by Single Particle Optical Sensing (SPOS) and light microscopy. Furthermore, drug contents were monitored in terms of total dispersed drug and apparently dissolved drug in the submicron fraction. Despite the fact, that all three formulations showed decent dispersive behavior with almost the complete drug content rapidly dispersed, substantial differences were identified between two of the formulations and the third one: ABT-199/12 and ABT-199/20 showed pronounced precipitation of the drug in form of micrometer particles, a phenomenon described as glass liquid phase separation (GLPS) and only a marginal fraction of the drug was found in the submicron-fraction, i.e. associated with 3 to 4 different supramolecular assemblies (micelles), irrespective whether buffer or fasted state simulated intestinal fluid (FaSSIF) were used as dispersion media. In contrast, ABT-199/40 showed pronounced formation of a wide variety of supramolecular assemblies (micelles) along with substantial association of the drug with all of these, but reduced glass liquid phase separation.