Mechanical Fingerprint of Senescence in Endothelial Cells.

Endothelial senescence entails alterations of the healthy cell phenotype, which accumulate over time and contribute to cardiovascular disease. Mechanical aspects regulating cell adhesion, force generation, and the response to flow contribute to the senescence-associated drift; however, they remain largely unexplored. Here, we exploit force microscopy to resolve variations of the cell anchoring to the substrate and the tractions generated upon aging in the nanonewton (nN) range. Senescent endothelial cells display a multifold increase in the levels of basal adhesion and force generation supported by mature and strong focal adhesions. The enhanced mechanical interaction with the substrate yields static endothelial monolayers that polarize in response to flow but fail the process of coordinated cell shape remodeling and reorientation. The emerging picture indicates that senescence reinforces the local cell interaction with the substrate and may therefore prevent endothelial denudation; however, it compromises the ability to functionally adapt to the local hemodynamic conditions.

A clinical study to evaluate the safe and effective use of a new, single use stethoscope cover to enable reduction in pathogen transmission during auscultation.

Objectives: Stethoscopes carry a significant risk for pathogen transmission. Here, the safe use and performance of a new, non-sterile, single-use stethoscope cover (SC), that is impermeable for pathogens, was investigated by different healthcare professionals (HCPs) in the postoperative care setting of an intensive care unit (ICU). Methods: Fifty-four patients underwent routine auscultations with the use of the SC (Stethoglove®, Stethoglove GmbH, Hamburg, Germany). The participating HCPs (n = 34) rated each auscultation with the SC on a 5-point Likert scale. The mean ratings of acoustic quality and the SC handling were defined as primary and secondary performance endpoint. Results: 534 auscultations with the SC were performed (average 15.7/user) on the lungs (36.1%), the abdomen (33.2%), the heart (28.8%), or other body-sites (1.9%). No adverse device-effects occurred. The acoustic quality was rated at 4.2 ± 0.7 (mean) with a total of 86.1% of all auscultations being rated at least as 4/5, and with no rating as below 2. The SC handling was rated at 3.7 ± 0.8 (mean) with a total of 96.4% of all auscultations being rated at least 3/5. Conclusion: Using a real-world setting, this study demonstrates that the SC can be safely and effectively used as cover for stethoscopes during auscultation. The SC may therefore represent a useful and easy-to-implement tool for preventing stethoscope-mediated infections.Study Registration: EUDAMED no. CIV-21-09-037762.

Endothelial damage inhibitor preserves the integrity of venous endothelial cells from patients undergoing coronary bypass surgery.

OBJECTIVES: Despite the success of coronary artery bypass graft (CABG) surgery using autologous saphenous vein grafts (SVGs), nearly 50% of patients experience vein graft disease within 10 years of surgery. One contributing factor to early vein graft disease is endothelial damage during short-term storage of SVGs in inappropriate solutions. Our aim was to evaluate the effects of a novel endothelial damage inhibitor (EDI) on SVGs from patients undergoing elective CABG surgery and on venous endothelial cells (VECs) derived from these SVGs. METHODS: SVGs from 11 patients participating in an ongoing clinical registry (NCT02922088) were included in this study, and incubated with both full electrolyte solution (FES) or EDI for 1 h and then examined histologically. In 8 of 11 patients, VECs were isolated from untreated grafts, incubated with both FES and EDI for 2 h under hypothermic stress conditions and then analysed for activation of an inflammatory phenotype, cell damage and cytotoxicity, as well as endothelial integrity and barrier function. RESULTS: The EDI was superior to FES in protecting the endothelium in SVGs (74 ± 8% versus 56 ± 8%, P < 0.001). Besides confirming that the EDI prevents apoptosis in SVG-derived VECs, we also showed that the EDI temporarily reduces adherens junctions in VECs while protecting focal adhesions compared to FES. CONCLUSIONS: The EDI protects the connectivity and function of the SVG endothelium. Our data suggest that the EDI can preserve focal adhesions in VECs during short-term storage after graft harvesting. This might explain the superiority of the EDI in maintaining most of the endothelium in venous CABG surgery conduits.

The path to a hemocompatible cardiovascular implant: Advances and challenges of current endothelialization strategies.

Cardiovascular (CV) implants are still associated with thrombogenicity due to insufficient hemocompatibility. Endothelialization of their luminal surface is a promising strategy to increase their hemocompatibility. In this review, we provide a collection of research studies and review articles aiming to summarize the recent efforts on surface modifications of CV implants, including stents, grafts, valves, and ventricular assist devises. We focus in particular on the implementation of micrometer or nanoscale surface modifications, physical characteristics of known biomaterials (such as wetness and stiffness), and surface morphological features (such as gratings, fibers, pores, and pits). We also review how biomechanical signals originating from the endothelial cell for surface interaction can be directed by topography engineering approaches toward the survival of the endothelium and its long-term adaptation. Finally, we summarize the regulatory and economic challenges that may prevent clinical implementation of endothelialized CV implants.

Anisotropic topographies restore endothelial monolayer integrity and promote the proliferation of senescent endothelial cells.

Thrombogenicity remains a major issue in cardiovascular implants (CVIs). Complete surficial coverage of CVIs by a monolayer of endothelial cells (ECs) prior to implantation represents a promising strategy but is hampered by the overall logistical complexity and the high number of cells required. Consequently, extensive cell expansion is necessary, which may eventually lead to replicative senescence. Considering that micro-structured surfaces with anisotropic topography may promote endothelialization, we investigated the impact of gratings on the biomechanical properties and the replicative capacity of senescent ECs. After cultivation on gridded surfaces, the cells showed significant improvements in terms of adherens junction integrity, cell elongation, and orientation of the actin filaments, as well as enhanced yes-associated protein nuclear translocation and cell proliferation. Our data therefore suggest that micro-structured surfaces with anisotropic topographies may improve long-term endothelialization of CVIs.

Building an interdisciplinary program of cardiovascular research at the Swiss Federal Institute of Technology- the ETHeart story.

In this backstory, researchers from Swiss Federal Institute of Technology (ETH Zurich) who initiated an interdisciplinary program to generate innovative solutions for different cardiovascular diseases, such as myocardial infarction, valvular replacement, and movement-based rehabilitation therapy, discuss the benefits and challenges of interdisciplinary research.

MicroRNA Mediated Cardioprotection - Is There a Path to Clinical Translation?

In the past 20 years, there have been several approaches to achieve cardioprotection or cardiac regeneration using a vast variety of cell therapies and remote ischemic pre-conditioning (RIPC). To date, substantial proof that either cell therapy or RIPC has the potential for clinically relevant cardiac repair or regeneration of cardiac tissue is still pending. Preclinical trials indicate that the secretome of cells in situ (during RIPC) as well as of transplanted cells may exhibit cardioprotective properties in the acute setting of cardiac injury. The secretome generally consists of cell-specific cytokines and extracellular vesicles (EVs) containing microRNAs (miRNAs). It is currently hypothesized that a subset of known miRNAs play a crucial part in the facilitation of cardioprotective effects. miRNAs are small non-coding RNA molecules that inhibit post-transcriptional translation of messenger RNAs (mRNAs) and play an important role in gene translation regulation. It is also known that one miRNAs usually targets multiple mRNAs. This makes predictability of pharmacokinetics and mechanism of action very difficult and could in part explain the inferior performance of various progenitor cells in clinical studies. Identification of miRNAs involved in cardioprotection and remodeling, the composition of miRNA profiles, and the exact mechanism of action are important to the design of future cell-based but also cell-free cardioprotective therapeutics. This review will give a description of miRNA with cardioprotective properties and a current overview on known mechanism of action and potential missing links. Additionally, we will give an outlook on the potential for clinical translation of miRNAs in the setting of myocardial infarction and heart failure.

MiRNA Profiles of Extracellular Vesicles Secreted by Mesenchymal Stromal Cells-Can They Predict Potential Off-Target Effects?

The cardioprotective properties of extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) are currently being investigated in preclinical studies. Although microRNAs (miRNAs) encapsulated in EVs have been identified as one component responsible for the cardioprotective effect of MSCs, their potential off-target effects have not been sufficiently characterized. In the present study, we aimed to investigate the miRNA profile of EVs isolated from MSCs that were derived from cord blood (CB) and adipose tissue (AT). The identified miRNAs were then compared to known targets from the literature to discover possible adverse effects prior to clinical use. Our data show that while many cardioprotective miRNAs such as miR-22-3p, miR-26a-5p, miR-29c-3p, and miR-125b-5p were present in CB- and AT-MSC-derived EVs, a large number of known oncogenic and tumor suppressor miRNAs such as miR-16-5p, miR-23a-3p, and miR-191-5p were also detected. These findings highlight the importance of quality assessment for therapeutically applied EV preparations.