Publications by authors named "Maximilian Y Emmert"

179 Publications

3D-microtissue derived secretome as a cell-free approach for enhanced mineralization of scaffolds in the chorioallantoic membrane model.

Sci Rep 2021 Mar 8;11(1):5418. Epub 2021 Mar 8.

Division of Surgical Research, University Hospital of Zurich, Zurich, Switzerland.

Bone regeneration is a complex process and the clinical translation of tissue engineered constructs (TECs) remains a challenge. The combination of biomaterials and mesenchymal stem cells (MSCs) may enhance the healing process through paracrine effects. Here, we investigated the influence of cell format in combination with a collagen scaffold on key factors in bone healing process, such as mineralization, cell infiltration, vascularization, and ECM production. MSCs as single cells (2D-SCs), assembled into microtissues (3D-MTs) or their corresponding secretomes were combined with a collagen scaffold and incubated on the chicken embryo chorioallantoic membrane (CAM) for 7 days. A comprehensive quantitative analysis was performed on a cellular level by histology and by microcomputed tomography (microCT). In all experimental groups, accumulation of collagen and glycosaminoglycan within the scaffold was observed over time. A pronounced cell infiltration and vascularization from the interface to the surface region of the CAM was detected. The 3D-MT secretome showed a significant mineralization of the biomaterial using microCT compared to all other conditions. Furthermore, it revealed a homogeneous distribution pattern of mineralization deposits in contrast to the cell-based scaffolds, where mineralization was only at the surface. Therefore, the secretome of MSCs assembled into 3D-MTs may represent an interesting therapeutic strategy for a next-generation bone healing concept.
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http://dx.doi.org/10.1038/s41598-021-84123-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940489PMC
March 2021

Toward next-generation advanced therapies: extracellular vesicles and cell therapy - partners or competitors?

Regen Med 2021 Mar 24;16(3):215-218. Epub 2021 Feb 24.

Department of Cardiothoracic and Vascular Surgery, German Heart Center Berlin, 13353 Berlin, Germany.

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http://dx.doi.org/10.2217/rme-2020-0138DOI Listing
March 2021

Computational modelling to reduce outcome variability in tissue-engineered heart valves.

Eur Heart J 2021 Feb 23. Epub 2021 Feb 23.

Institute for Regenerative Medicine, University of Zurich, Zurich, Switzerland.

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http://dx.doi.org/10.1093/eurheartj/ehab034DOI Listing
February 2021

Xenotransplantation in the era of a zoonotic pandemic.

Eur Heart J 2021 Apr;42(14):1283-1285

Department of Cardiothoracic and Vascular Surgery, German Heart Center Berlin, Germany.

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http://dx.doi.org/10.1093/eurheartj/ehaa1101DOI Listing
April 2021

Local electromechanical alterations determine the left ventricle rotational dynamics in CRT-eligible heart failure patients.

Sci Rep 2021 Feb 5;11(1):3267. Epub 2021 Feb 5.

Department of Cardiology and Structural Heart Disease, Medical University of Silesia, Ziołowa 45-47, Katowice, Poland.

Left ventricle, LV wringing wall motion relies on physiological muscle fiber orientation, fibrotic status, and electromechanics (EM). The loss of proper EM activation can lead to rigid-body-type (RBT) LV rotation, which is associated with advanced heart failure (HF) and challenges in resynchronization. To describe the EM coupling and scar tissue burden with respect to rotational patterns observed on the LV in patients with ischemic heart failure with reduced ejection fraction (HFrEF) left bundle branch block (LBBB). Thirty patients with HFrEF/LBBB underwent EM analysis of the left ventricle using an invasive electro-mechanical catheter mapping system (NOGA XP, Biosense Webster). The following parameters were evaluated: rotation angle; rotation velocity; unipolar/bipolar voltage; local activation time, LAT; local electro-mechanical delay, LEMD; total electro-mechanical delay, TEMD. Patients underwent late-gadolinium enhancement cMRI when possible. The different LV rotation pattern served as sole parameter for patients' grouping into two categories: wringing rotation (Group A, n = 6) and RBT rotation (Group B, n = 24). All parameters were aggregated into a nine segment, three sector and whole LV models, and compared at multiple scales. Segmental statistical analysis in Group B revealed significant inhomogeneities, across the LV, regarding voltage level, scar burdening, and LEMD changes: correlation analysis showed correspondently a loss of synchronization between electrical (LAT) and mechanical activation (TEMD). On contrary, Group A (relatively low number of patients) did not present significant differences in LEMD across LV segments, therefore electrical (LAT) and mechanical (TEMD) activation were well synchronized. Fibrosis burden was in general associated with areas of low voltage. The rotational behavior of LV in HF/LBBB patients is determined by the local alteration of EM coupling. These findings serve as a strong basic groundwork for a hypothesis that EM analysis may predict CRT response.Clinical trial registration: SUM No. KNW/0022/KB1/17/15.
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http://dx.doi.org/10.1038/s41598-021-82793-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865069PMC
February 2021

Geometry influences inflammatory host cell response and remodeling in tissue-engineered heart valves in-vivo.

Sci Rep 2020 11 16;10(1):19882. Epub 2020 Nov 16.

Institute for Regenerative Medicine (IREM), University of Zurich, Wagistrasse 12, 8952, Schlieren, Switzerland.

Regenerative tissue-engineered matrix-based heart valves (TEM-based TEHVs) may become an alternative to currently-used bioprostheses for transcatheter valve replacement. We recently identified TEM-based TEHVs-geometry as one key-factor guiding their remodeling towards successful long-term performance or failure. While our first-generation TEHVs, with a simple, non-physiological valve-geometry, failed over time due to leaflet-wall fusion phenomena, our second-generation TEHVs, with a computational modeling-inspired design, showed native-like remodeling resulting in long-term performance. However, a thorough understanding on how TEHV-geometry impacts the underlying host cell response, which in return determines tissue remodeling, is not yet fully understood. To assess that, we here present a comparative samples evaluation derived from our first- and second-generation TEHVs. We performed an in-depth qualitative and quantitative (immuno-)histological analysis focusing on key-players of the inflammatory and remodeling cascades (M1/M2 macrophages, α-SMA- and endothelial cells). First-generation TEHVs were prone to chronic inflammation, showing a high presence of macrophages and α-SMA-cells, hinge-area thickening, and delayed endothelialization. Second-generation TEHVs presented with negligible amounts of macrophages and α-SMA-cells, absence of hinge-area thickening, and early endothelialization. Our results suggest that TEHV-geometry can significantly influence the host cell response by determining the infiltration and presence of macrophages and α-SMA-cells, which play a crucial role in orchestrating TEHV remodeling.
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http://dx.doi.org/10.1038/s41598-020-76322-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669851PMC
November 2020

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

Biomolecules 2020 09 22;10(9). Epub 2020 Sep 22.

Department of Cardiothoracic and Vascular Surgery, German Heart Center Berlin, 13353 Berlin, Germany.

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.
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http://dx.doi.org/10.3390/biom10091353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565205PMC
September 2020

Next-generation tissue-engineered heart valves with repair, remodelling and regeneration capacity.

Nat Rev Cardiol 2021 Feb 9;18(2):92-116. Epub 2020 Sep 9.

Institute for Regenerative Medicine, University of Zurich, Zurich, Switzerland.

Valvular heart disease is a major cause of morbidity and mortality worldwide. Surgical valve repair or replacement has been the standard of care for patients with valvular heart disease for many decades, but transcatheter heart valve therapy has revolutionized the field in the past 15 years. However, despite the tremendous technical evolution of transcatheter heart valves, to date, the clinically available heart valve prostheses for surgical and transcatheter replacement have considerable limitations. The design of next-generation tissue-engineered heart valves (TEHVs) with repair, remodelling and regenerative capacity can address these limitations, and TEHVs could become a promising therapeutic alternative for patients with valvular disease. In this Review, we present a comprehensive overview of current clinically adopted heart valve replacement options, with a focus on transcatheter prostheses. We discuss the various concepts of heart valve tissue engineering underlying the design of next-generation TEHVs, focusing on off-the-shelf technologies. We also summarize the latest preclinical and clinical evidence for the use of these TEHVs and describe the current scientific, regulatory and clinical challenges associated with the safe and broad clinical translation of this technology.
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http://dx.doi.org/10.1038/s41569-020-0422-8DOI Listing
February 2021

Preservation solutions to improve graft patency: The devil is in the detail.

J Cardiothorac Surg 2020 08 27;15(1):228. Epub 2020 Aug 27.

Department of Cardiovascular Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany.

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http://dx.doi.org/10.1186/s13019-020-01267-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457275PMC
August 2020

Tissue engineered heart valves for transcatheter aortic valve implantation: current state, challenges, and future developments.

Expert Rev Cardiovasc Ther 2020 Oct 23;18(10):681-696. Epub 2020 Sep 23.

Institute for Regenerative Medicine, University of Zurich , Zurich, Switzerland.

Introduction: The establishment of transcatheter aortic valve implantation (TAVI) has revolutionized the treatment of severe aortic stenosis. However, with TAVI being approved for low-risk patients, valve durability is becoming of central importance. Here, we summarize how tissue engineered heart valves (TEHVs) may provide a clinically-relevant durable valve replacement compatible with TAVI.

Areas Covered: Since its introduction, TAVI prostheses have advanced in design and development. However, TAVI bioprostheses are based on fixed xenogeneic materials prone to progressive degeneration. Transcatheter TEHVs may have the potential to overcome the drawbacks of current TAVI bioprostheses, with their remodeling, self-repair, and growth capacities. So far, performance and remodeling of transcatheter TEHV with in-situ regenerative potential were demonstrated in the low-pressure system, with acute performance proved in the systemic circulation. However, several challenges remain to be solved to ensure a safe clinical translation of TEHVs for TAVI approaches.

Expert Opinion: With TAVI rapidly evolving, the establishment of long-term valve durability represents the top priority to reduce the rate of patient re-interventions, remove the associated risks and adverse events, and improve patients' life quality worldwide. With long-term performance and remodeling proved, TEHVs may represent the next-generation technology for a life-long TAVI prosthesis.
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http://dx.doi.org/10.1080/14779072.2020.1792777DOI Listing
October 2020

Human Cardiac Organoids for Modeling Genetic Cardiomyopathy.

Cells 2020 07 20;9(7). Epub 2020 Jul 20.

Institute for Regenerative Medicine, University of Zurich, 8952 Schlieren, Switzerland.

Genetic cardiomyopathies are characterized by changes in the function and structure of the myocardium. The development of a novel in vitro model could help to better emulate healthy and diseased human heart conditions and may improve the understanding of disease mechanisms. In this study, for the first time, we demonstrated the generation of cardiac organoids using a triculture approach of human induced pluripotent stem-cell-derived cardiomyocytes (hiPS-CMs)-from healthy subjects and cardiomyopathy patients-human cardiac microvascular endothelial cells (HCMECs) and human cardiac fibroblasts (HCFs). We assessed the organoids' suitability as a 3D cellular model for the representation of phenotypical features of healthy and cardiomyopathic hearts. We observed clear differences in structure and beating behavior between the organoid groups, depending on the type of hiPS-CMs (healthy versus cardiomyopathic) used. Organoids may thus prove a promising tool for the design and testing of patient-specific treatments as well as provide a platform for safer and more efficacious drug development.
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http://dx.doi.org/10.3390/cells9071733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409052PMC
July 2020

Transcatheter aortic valve implantation and its impact on mitral valve geometry and function.

J Card Surg 2020 Sep 11;35(9):2185-2193. Epub 2020 Jul 11.

Department of Cardiothoracic and Vascular Surgery, German Heart Center Berlin, Berlin, Germany.

Background: The aim of this study was to evaluate the impact of transcatheter aortic valve implantation (TAVI) on mitral valve geometry and function.

Methods: Eighty-four patients underwent TAVI. Forty-four (52%) patients received a balloon-expandable valve and 40 (48%) were implanted with a self-expandable valve. All patients underwent three-dimensional-volumetric transesophageal echocardiography of the mitral valve before and immediately after TAVI. A dedicated software was used for assisted semiautomatic measurement of mitral annular geometry.

Results: During systole, the anterior to posterior (AP) diameter was significantly reduced after the procedure (3.4 ± 0.5 cm vs 3.2 ± 0.5 cm; P < .05). The mitral annular area (10.8 ± 2.8cm vs 9.9 ± 2.6cm ; P < .05) as well as the tenting area (1.6 ± 0.7 cm vs 1.2 ± 0.6 cm ; P < .001) measured at mid-systole were reduced after TAVI. Diastolic measures were similar. Patients treated with balloon-expandable valves showed a significantly larger reduction in the AP diameter compared to self-expandable valves (-0.25 cm vs -0.11 cm; P < .05). The reduction of the annular area was higher in the balloon-expandable group (-1.2 ± 1.59 vs -0.22 ± 1.41; P < .05). Grade of mitral regurgitation did improve or remained stable after TAVI.

Conclusion: TAVI significantly impacts the mitral valve and mitral annular geometry and morphology. The choice of the prosthesis (balloon- vs self-expandable) may be relevant for those changes.
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http://dx.doi.org/10.1111/jocs.14734DOI Listing
September 2020

Reliability and Influence on Decision Making of fully-automated vs. semi-automated Software Packages for Procedural Planning in TAVI.

Sci Rep 2020 07 1;10(1):10746. Epub 2020 Jul 1.

Department of Cardiothoracic and Vascular Surgery, German Heart Center, Berlin, Germany.

Precise procedural planning is crucial to achieve excellent results in patients undergoing Transcatheter aortic valve implantation (TAVI). The aim of this study was to compare the semi-automated 3mensio (3 m) software to the fully-automated HeartNavigator3 (HN) software. We randomly selected 100 patients from our in-house TAVI-registry and compared aortic annulus and perimeter as well as coronary distances between 3m-measurements and post-hoc HN-measurements. Finally, we retrospectively simulated prosthesis choice based on HN-measurements and analyzed the differences compared to routinely used 3 m based strategy. We observed significant differences between the two software packages regarding area (3 m 464 ± 88 mm², HN 482 ± 96 mm², p < 0.001), perimeter (3 m 77 ± 7 mm, HN 79 ± 8 mm, p < 0.001) and coronary distances (LCA: 3 m 13 ± 3 mm, HN 12 ± 3 mm, p < 0.001; RCA: 3 m 16 ± 3 mm, HN 15 ± 3 mm, p < 0.001). Prosthesis choice simulation based on newly obtained HN-measurements would have led to a decision change in 18% of patients, with a further reduction to 4% following manual adjustment of HN-measurements. The fully-automatic HN-software provides higher values for annular metrics and lower annulus-to-coronary-ostia distances compared to 3m-software. Measurement differences did not influence clinical outcome. Both, the HN-software and the 3m-software are sophisticated, reliable and easy to use for the clinician. Manual adjustment of HN-measurements may increase precision in complex aortic annulus anatomy.
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http://dx.doi.org/10.1038/s41598-020-67111-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329903PMC
July 2020

Cardiac electrophysiology: purpose tailored animal models for complex conditions.

Eur Heart J 2020 06;41(21):2037

Department of Cardiothoracic and Vascular Surgery, German Heart Institute Berlin, Germany.

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http://dx.doi.org/10.1093/eurheartj/ehaa328DOI Listing
June 2020

Endothelial damage inhibitors for improvement of saphenous vein graft patency in coronary artery bypass grafting.

Minerva Cardioangiol 2020 Oct 23;68(5):480-488. Epub 2020 Apr 23.

Department of Cardiovascular Surgery, Charite University of Medicine, Berlin, Germany.

The saphenous vein graft (SVG) remains the most commonly used conduit in coronary artery bypass grafting (CABG). In light of this further research must be aimed at the development of strategies to optimize SVG patency and thereby improve both short- and long-term outcomes of CABG surgery. SVG patency in large part depends on the protection of the structural and functional integrity of the vascular endothelium at the time of conduit harvesting, including optimal storage conditions to prevent endothelial damage. This review provides an overview of currently available storage and preservation solutions, including novel endothelial damage inhibitors, and their role in mitigating endothelial damage and vein graft failure.
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http://dx.doi.org/10.23736/S0026-4725.20.05234-2DOI Listing
October 2020

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

Front Bioeng Biotechnol 2020 20;8:149. Epub 2020 Mar 20.

Department for Cardiovascular and Thoracic Surgery, German Heart Center Berlin, Berlin, Germany.

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 (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.
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http://dx.doi.org/10.3389/fbioe.2020.00149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099408PMC
March 2020

Computed Tomography-based evaluation of porcine cardiac dimensions to assist in pre-study planning and optimized model selection for pre-clinical research.

Sci Rep 2020 04 7;10(1):6020. Epub 2020 Apr 7.

Division of Surgical Research, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

The pig (Sus Scrofa Domestica) is an accepted model for preclinical evaluation of prosthetic heart valves and trans-catheter implantation techniques. Understanding porcine cardiac dimensions through three-dimensional computed tomography (CT), increases preclinical study success, leading to higher cost efficiency and to the observance of the obligation to the 3 R principles. Cardiac CT images of twenty-four Swiss large white pigs were segmented; aortic root, mitral valve, pulmonary trunk, tricuspid valve, as well as the aorto-mitral angle and left atrial height were analyzed. Correlation coefficient (r) was calculated in relation to body weight. In Swiss large white pigs, valvular dimensions, length of the pulmonary artery and ascending aorta as well as left atrial height correlate with body weight. Coronary ostia heights and aorto-mitral angle size can be neglected in animal size selection; no changes were found for either of the two parameters with increasing body weight.
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http://dx.doi.org/10.1038/s41598-020-63044-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138799PMC
April 2020

Epicardial left atrial appendage occlusion with a new medical device: assessment of procedural feasibility, safety and efficacy in a large animal model.

J Cardiothorac Surg 2020 Apr 3;15(1):56. Epub 2020 Apr 3.

Department of Cardiovascular Surgery, Charité Universitätsmedizin Berlin, Berlin, Germany.

Background: Left atrial appendage occlusion (LAAO) represents a treatment alternative to anticoagulation in patients with atrial fibrillation. We evaluate a novel device for epicardial LAAO in a translational canine model.

Methods: Nine hounds (n = 9) were used to assess usability, safety, and efficacy of the TigerPaw Pro (TPP) device for epicardial LAAO. Following baseline imaging (intra-cardiac echocardiography (ICE) and angiography) and intraoperative visual inspection, usability was tested via a ``closure/re-opening`` maneuver followed by deployment of a total of twenty TPP devices (n = 20) on the left and right atrial appendages respectively. Procedural safety was evaluated by assessing for adverse-events via direct Epicardial inspection and endocardial imaging. Efficacy evaluation included assessment of device positioning, presence of residual stumps and completeness of closure. Post-mortem evaluation was performed to confirm safety and efficacy.

Results: Usability testing of all TPP devices was successful (n = 20;100%, delivery-time range 22-120 s) without any procedural adverse-events (tissue damage or tears, bleeding, vessel-impingement, structural impact). All devices fully traversed the ostium (n = 18) or appendage body (n = 2), and conformed smoothly to adjacent cardiac anatomy. In nineteen deployments (n = 19;95%), all device connector pairs were fully engaged, while in one TPP device the most distal pair remained unengaged. ICE and post-mortem inspections revealed complete closure of all appendage ostia (n = 18;100%) and only in one case a small residual stump was detected. Intraoperative safety findings were further confirmed post-mortem. Devices created a nearly smooth line of closure via symmetric endocardial tissue-coaptation.

Conclusions: In this preclinical model, the TPP demonstrated good ease of use for ostial access, ability to re-position (after engagement) and rapid deployment, while achieving safe and effective LAAO.
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http://dx.doi.org/10.1186/s13019-020-01096-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118967PMC
April 2020

NAD+ the disregarded molecule in cardiac metabolism.

Eur Heart J 2020 03;41(9):983-986

Deutsches Herzzentrum Berlin (DHZB) Department of Cardiothoracic and Vascular Surgery Charité Universitätsmedizin Berlin, Germany. Translational Cardiovascular Technologies, ETH Zurich, Zurich, Switzerland.

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http://dx.doi.org/10.1093/eurheartj/ehaa044DOI Listing
March 2020

Differential Leaflet Remodeling of Bone Marrow Cell Pre-Seeded Versus Nonseeded Bioresorbable Transcatheter Pulmonary Valve Replacements.

JACC Basic Transl Sci 2020 Jan 11;5(1):15-31. Epub 2019 Dec 11.

Institute for Regenerative Medicine, University of Zürich, Zürich, Switzerland.

This study showed that bone marrow mononuclear cell pre-seeding had detrimental effects on functionality and in situ remodeling of bioresorbable bisurea-modified polycarbonate (PC-BU)-based tissue-engineered heart valves (TEHVs) used as transcatheter pulmonary valve replacement in sheep. We also showed heterogeneous valve and leaflet remodeling, which affects PC-BU TEHV safety, challenging their potential for clinical translation. We suggest that bone marrow mononuclear cell pre-seeding should not be used in combination with PC-BU TEHVs. A better understanding of cell-scaffold interaction and in situ remodeling processes is needed to improve transcatheter valve design and polymer absorption rates for a safe and clinically relevant translation of this approach.
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http://dx.doi.org/10.1016/j.jacbts.2019.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000873PMC
January 2020

Sequential multidetector computed tomography assessments after venous graft treatment solution in coronary artery bypass grafting.

J Thorac Cardiovasc Surg 2019 Nov 9. Epub 2019 Nov 9.

Department of Cardiovascular Surgery, Charité Universitätsmedizin Berlin, Berlin, Germany; Department of Cardiothoracic and Vascular Surgery, German Heart Center Berlin, Berlin, Germany.

Objectives: To assess the effect of DuraGraft (Somahlution Inc, Jupiter, Fla), an intraoperative graft treatment, on saphenous vein grafts in patients undergoing isolated coronary artery bypass grafting.

Methods: Within patients, 2 saphenous vein grafts were randomized to DuraGraft or heparinized saline. Multidetector computed tomography angiography at 1, 3, and 12 months assessed change in wall thickness (primary end point at 3 months), lumen diameter, and maximum narrowing for the whole graft and the proximal 5-cm segment. Safety end points included graft occlusion, death, myocardial infarction, and repeat revascularization.

Results: At 3 months, no significant changes were observed between DuraGraft- and saline-treated grafts (125 each) for wall thickness, lumen diameter, and maximum narrowing. At 12 months, DuraGraft-treated grafts demonstrated smaller mean wall thickness, overall (0.12 ± 0.06 vs 0.20 ± 0.31 mm; P = .02) and in the proximal segment (0.11 ± 0.03 vs 0.21 ± 0.33 mm; P = .01). Changes in wall thickness were greater in the proximal segment of saline-treated grafts (0.09 ± 0.29 vs 0.00 ± 0.03 mm; P = .04). Increase in maximum graft narrowing was larger in the proximal segment in the saline-treated grafts (4.7% ± 12.7% vs 0.2% ± 3.8%; P = .01). Nine DuraGraft and 11 saline grafts had occluded or thrombosed. One myocardial infarction was associated with a saline graft occlusion. No deaths or revascularizations were observed.

Conclusions: DuraGraft demonstrated a favorable effect on wall thickness at 12 months, particularly in the proximal segment. Longer-term follow-up in larger studies is needed to evaluate the effect on clinical outcomes.
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http://dx.doi.org/10.1016/j.jtcvs.2019.10.115DOI Listing
November 2019

Novel multimodal MRI and MicroCT imaging approach to quantify angiogenesis and 3D vascular architecture of biomaterials.

Sci Rep 2019 12 19;9(1):19474. Epub 2019 Dec 19.

Institute for Regenerative Medicine, University of Zurich, Zurich, Switzerland.

Quantitative assessment of functional perfusion capacity and vessel architecture is critical when validating biomaterials for regenerative medicine purposes and requires high-tech analytical methods. Here, combining two clinically relevant imaging techniques, (magnetic resonance imaging; MRI and microcomputed tomography; MicroCT) and using the chorioallantoic membrane (CAM) assay, we present and validate a novel functional and morphological three-dimensional (3D) analysis strategy to study neovascularization in biomaterials relevant for bone regeneration. Using our new pump-assisted approach, the two scaffolds, Optimaix (laminar structure mimicking entities of the diaphysis) and DegraPol (highly porous resembling spongy bone), were shown to directly affect the architecture of the ingrowing neovasculature. Perfusion capacity (MRI) and total vessel volume (MicroCT) strongly correlated for both biomaterials, suggesting that our approach allows for a comprehensive evaluation of the vascularization pattern and efficiency of biomaterials. Being compliant with the 3R-principles (replacement, reduction and refinement), the well-established and easy-to-handle CAM model offers many advantages such as low costs, immune-incompetence and short experimental times with high-grade read-outs when compared to conventional animal models. Therefore, combined with our imaging-guided approach it represents a powerful tool to study angiogenesis in biomaterials.
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http://dx.doi.org/10.1038/s41598-019-55411-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923434PMC
December 2019

Intraoperative storage of saphenous vein grafts in coronary artery bypass grafting.

Expert Rev Med Devices 2019 Nov 30;16(11):989-997. Epub 2019 Oct 30.

Department of Cardiothoracic and Vascular Surgery, German Heart Center Berlin, Berlin, Germany.

: Saline is not biocompatible with saphenous vein grafts and does not protect against ischemia reperfusion injury. We compared normal heparinized saline with DuraGraft, a new graft-storage solution, in in-vitro and ex-vivo assays to evaluate the effects on cells and vascular graft tissue.: Human saphenous vein (HSV) segments and isolated pig mammary veins (PMVs) were flushed and submerged in heparinized DuraGraft or heparinized saline for prespecified times. Following exposure, HSV segments were evaluated for viability and tissue morphology, and PMVs underwent histological assessments, to evaluate vein morphology and effects on the vascular endothelium. The performance of saline versus DuraGraft was compared in an ISO-compliant biocompatibility assay for cytotoxicity.: Loss of HSV graft-cell viability was observed as early as 15 minutes post-exposure to saline whereas viability was maintained up to 5 hours' exposure to DuraGraft. Histological analyses performed with PMVs demonstrated endothelial damage in PMVs stored in saline. Cytotoxicity assays demonstrated that saline-induced microscopically visible cell damage occurred within 60 minutes. DuraGraft-treated cells did not show evidence of damage or reactivity.: Normal saline caused damage to vascular endothelium, loss of graft cell viability, and mediated cell damage; no evidence of damage or reactivity was observed in DuraGraft-exposed cells.
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http://dx.doi.org/10.1080/17434440.2019.1682996DOI Listing
November 2019

Artificial intelligence-assisted care in medicine: a revolution or yet another blunt weapon?

Eur Heart J 2019 10;40(40):3286-3289

Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; Department of Cardiothoracic Surgery, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.

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http://dx.doi.org/10.1093/eurheartj/ehz701DOI Listing
October 2019

A novel endothelial damage inhibitor for the treatment of vascular conduits in coronary artery bypass grafting: protocol and rationale for the European, multicentre, prospective, observational DuraGraft registry.

J Cardiothorac Surg 2019 Oct 15;14(1):174. Epub 2019 Oct 15.

Department of Cardiovascular Surgery, Charité Universitätsmedizin Berlin, Berlin, Germany.

Background: Vein graft disease (VGD) impairs graft patency rates and long-term outcomes after coronary artery bypass grafting (CABG). DuraGraft is a novel endothelial-damage inhibitor developed to efficiently protect the structural and functional integrity of the vascular endothelium. The DuraGraft registry will evaluate the long-term clinical outcomes of DuraGraft in patients undergoing CABG procedures.

Methods: This ongoing multicentre, prospective observational registry will enrol 3000 patients undergoing an isolated CABG procedure or a combined procedure (ie, CABG plus valve surgery or other surgery) with at least one saphenous vein grafts or one free arterial graft (ie, radial artery or mammary artery). If a patient is enrolled, all free grafts (SVG and arterial will be treated with DuraGraft. Data on baseline, clinical, and angiographic characteristics as well as procedural and clinical events will be collected. The primary outcome measure is the occurrence of a major adverse cardiac event (MACE; defined as death, non-fatal myocardial-infarction, or need for repeat-revascularisation). Secondary outcome measures are the occurrence of major adverse cardiac and cerebrovascular events (MACCE; defined as death, non-fatal myocardial-infarction, repeat-revascularisation, or stroke), patient-reported quality of life, and health-economic data. Patient assessments will be performed during hospitalisation, at 1-month, 1-year, and annually thereafter to 5 years post-CABG. Events will be adjudicated by an independent clinical events committee. This European, multi-institutional registry will provide detailed insights into clinical outcome associated with DuraGraft.

Discussion: This European, multi-institutional registry will provide detailed insights into clinical outcome associated with the use of DuraGraft. Beyond that, and given the comprehensive data sets comprising of patient, procedural, and graft parameters that are being collected, the registry will enable for multiple subgroup analyses targeting focus groups or specific clinical questions. These may include analysis of subpopulations such as patients with diabetes or multimorbid high-risk patients (patient level), evaluation of relevance of harvesting technique including endoscopic versus open conduit harvesting (procedural level), or particular graft-specific aspects (conduit level).

Trial Registration: ClinicalTrials.gov NCT02922088 . Registered October 3, 2016.

Ethics And Dissemination: The regional ethics committees have approved the registry. Results will be submitted for publication.
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http://dx.doi.org/10.1186/s13019-019-1010-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794868PMC
October 2019

The link between exosomes phenotype and mode of action in the context of cardioprotection.

Eur Heart J 2019 10;40(40):3361

German Heart Center Berlin, Department for Cardiothoracic and Vascular Surgery, Augustenburger Platz 1, Berlin, Germany.

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http://dx.doi.org/10.1093/eurheartj/ehz693DOI Listing
October 2019

Incidence and characteristics of left atrial appendage stumps after device-enabled epicardial closure.

Interact Cardiovasc Thorac Surg 2019 11;29(5):663-669

Clinic for Cardiovascular Surgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Objectives: High success rates for left atrial appendage (LAA) exclusion with the AtriClip (Atricure, USA) device have been reported in the literature. This study evaluated the presence and characteristics of residual LAA stumps after AtriClip LAA exclusion using postoperative short- and long-term computed tomography angiography (CTA).

Methods: In this retrospective analysis, 43 of 291 consecutive patients undergoing cardiac surgery with concomitant LAA occlusion using the AtriClip device were identified with available postoperative short- and long-term follow-up by CTA. LAA patency and the absence or the size of a present residual LAA stump were assessed on 2-dimensional multiplanar reconstructions, on maximum intensity projection images and on volume-rendered 3-dimensional computed tomography reconstructions. Based on current recommendations, the threshold for a significant LAA stump length was defined <10 mm.

Results: The LAA was successfully occluded in all 43 patients (100%) as confirmed by intraoperative transoesophageal echocardiography and CTA imaging with a mean follow-up duration of 7.1 ± 0.8 years post-implant. The absence of blood flow in the excluded LAA was confirmed in all cases. In 31 of 43 patients (72%), no residual stump (0 mm) was observed creating a smooth endocardial surface, CTA revealed residual LAA stumps in 11/43 patients (26%) with a length <10 mm and a significant residual stump with a depth of >10 mm (12 mm) in 1 patient (2%). The mean length, width and depth of the residual stumps were 5.8 ± 2.1, 4.4 ± 1.2 and 7.3 ± 2.3 mm, respectively.

Conclusions: This study investigated the incidence of residual stump formation (>10 mm) after LAA closure with the AtriClip device based on CTA imaging data obtained during short- and long-term follow-up. While no LAA stump was detectable in the majority of patients, a non-significant LAA stump (<10 mm) was present in 26% of cases, indicating a favourable LAA occlusion profile for the AtriClip device. However, although a LAA stump length <10 mm is currently considered clinically safe, this definition needs further attention in future studies with regards to its potential clinical implications.
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http://dx.doi.org/10.1093/icvts/ivz176DOI Listing
November 2019

What will surgical coronary revascularization look like in 25 years?

Curr Opin Cardiol 2019 11;34(6):637-644

Department of Cardiovascular Surgery, Charité-Universitätsmedizin Berlin.

Purpose Of Review: Coronary artery bypass grafting evolved in incremental but significant steps since its introduction. Here, we provide an update on operative techniques, choice of conduits, patient selection/decision-making and primary and secondary prevention measures with potential of influencing the future of coronary artery bypass grafting (CABG) surgery.

Recent Findings: Associated mortality of off-pump CABG (OPCAB) procedures performed in high-volume OPCAB centers (≥164 cases per year) and by experienced surgeons (≥48 cases per year) was reduced compared with on-pump CABG with two or more grafts suggesting a volume-based dependency of outcomes in CABG procedures with high-technical complexity. Ten-year results from the recent Arterial Revascularization Trial showed no significant between-group difference for the primary and secondary outcome. Total arterial revascularization using composite bilateral internal mammary artery-Y-conduits through a limited access mini-thoracotomy was not only shown to be feasible but a safe and reproducible procedure with excellent midterm outcomes. The most recent Randomized Trial of Endoscopic or Open Vein-Graft Harvesting for Coronary-Artery Bypass (REGROUP) trial demonstrated no significant difference between open vein-graft harvesting and endoscopic vein-graft harvesting in the occurrence of major adverse cardiac events.

Summary: Adherence to the most recent guidelines on myocardial revascularization is a key component for providing state-of the CABG surgery. Trends to lesser invasiveness in surgical coronary revascularization will gain momentum and is expected - with further improvements - to be the mainstay of future surgical coronary revascularization strategies.
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http://dx.doi.org/10.1097/HCO.0000000000000680DOI Listing
November 2019