Mechanical circulatory support (MCS) using left ventricular assist devices (LVAD) have considerably improved the quality of life and survival rate of patients with end-stage heart failure. Despite substantial technological progress, major challenges with regard to VAD-specific and VAD-related infections have hitherto hindered the broader application of this promising therapy approach. Driveline infections (DLI) range among the main adverse events experienced in LVAD patients. However, many centers still apply their own protocol for driveline exit site (DLES) care and an international standard on prevention, reduction and early treatment of DLI after the perioperative period has not yet been defined. In March 2019, VAD coordinators and cardiac surgeons from Germany and Austria met to develop a standard of care procedure (SOP) as well as a new staging approach with recommended actions for treatment of VAD carriers. In this Driveline Expert STagINg and carE (DESTINE) study group we developed a 10-step SOP for DLES care with emphasis on essentials such as clean and save preparation, sterile dressing change and secure driveline immobilization. An advanced wound staging approach was defined with recommended actions for prevention, early detection and stage-related management of DLI. Broad consensus was reached on the fact that an interdisciplinary approach both in DLES care and DLES healing disorder awareness is required to prolong infect-free survival times on MCS as well as to ensure high patient compliance and quality of life. In conclusion, a new detailed SOP for appropriate DLES care and an advanced wound staging approach for prevention and management of DLI were defined on an expert level applicable for VAD clinicians, practitioners and care givers in Central Europe.

Bone marrow stem cell clonal dysfunction by somatic mutation is suspected to affect post-infarction myocardial regeneration after coronary bypass surgery (CABG). Transcriptome and variant expression analysis was studied in the phase 3 PERFECT trial post myocardial infarction CABG and CD133+ bone marrow derived hematopoetic stem cells showing difference in left ventricular ejection fraction (∆LVEF) myocardial regeneration Responders (n=14; ∆LVEF +16% day 180/0) and Non-responders (n=9; ∆LVEF -1.1% day 180/0). Subsequently, the findings have been validated in an independent patient cohort (n=14) as well as in two preclinical mouse models investigating SH2B3/LNK antisense or knockout deficient conditions. 1. Clinical: R differed from NR in a total of 161 genes in differential expression (n=23, q<0•05) and 872 genes in coexpression analysis (n=23, q<0•05). Machine Learning clustering analysis revealed distinct RvsNR preoperative gene-expression signatures in peripheral blood acorrelated to SH2B3 (p<0.05). Mutation analysis revealed increased specific variants in RvsNR. (R: 48 genes; NR: 224 genes). 2. Preclinical:SH2B3/LNK-silenced hematopoietic stem cell (HSC) clones displayed significant overgrowth of myeloid and immune cells in bone marrow, peripheral blood, and tissue at day 160 after competitive bone-marrow transplantation into mice. SH2B3/LNK−/− mice demonstrated enhanced cardiac repair through augmenting the kinetics of bone marrow-derived endothelial progenitor cells, increased capillary density in ischemic myocardium, and reduced left ventricular fibrosis with preserved cardiac function. 3. Validation: Evaluation analysis in 14 additional patients revealed 85% RvsNR (12/14 patients) prediction accuracy for the identified biomarker signature. Myocardial repair is affected by HSC gene response and somatic mutation. Machine Learning can be utilized to identify and predict pathological HSC response. German Ministry of Research and Education (BMBF): Reference and Translation Center for Cardiac Stem Cell Therapy - FKZ0312138A and FKZ031L0106C, German Ministry of Research and Education (BMBF): Collaborative research center - DFG:SFB738 and Center of Excellence - DFG:EC-REBIRTH), European Social Fonds: ESF/IV-WM-B34-0011/08, ESF/IV-WM-B34-0030/10, and Miltenyi Biotec GmbH, Bergisch-Gladbach, Germany. Japanese Ministry of Health : Health and Labour Sciences Research Grant (H14-trans-001, H17-trans-002) ClinicalTrials.gov NCT00950274

Ischemic heart failure is the leading cause of mortality worldwide. An early boost of intracardiac regenerative key mechanisms and angiogenetic niche signaling in cardiac mesenchymal stem cells (MSCs) could improve myocardial infarction (MI) healing. Epicardial erythropoietin (EPO; 300 U kg⁻¹) was compared with intraperitoneal and intramyocardial EPO treatments after acute MI in rats (n=156). Real-time PCR and confocal microscopy revealed that epicardial EPO treatment enhanced levels of intracardiac regenerative key indicators (SDF-1, CXCR4, CD34, Bcl-2, cyclin D1, Cdc2 and MMP2), induced transforming growth factor β (TGF-β)/WNT signaling in intramyocardial MSC niches through the direct activation of AKT and upregulation of upstream signals FOS and Fzd7, and augmented intracardiac mesenchymal proliferation 24 h after MI. Cardiac catheterization and tissue analysis showed superior cardiac functions, beneficial remodeling and increased capillary density 6 weeks after MI. Concomitant fluorescence-activated cell sorting, co-cultures with neonatal cardiomyocytes, angiogenesis assays, ELISA, western blotting and RAMAN spectroscopy demonstrated that EPO could promote cardiomyogenic differentiation that was specific of tissue origin and enhance paracrine angiogenetic activity in cardiac CD45⁻CD44⁺DDR2⁺ MSCs. Epicardial EPO delivery might be the optimal route for efficient upregulation of regenerative key signals after acute MI. Early EPO-mediated stimulation of mesenchymal proliferation, synergistic angiogenesis with cardiac MSCs and direct induction of TGF-β/WNT signaling in intramyocardial cardiac MSCs could initiate an accelerated healing process that enhances cardiac recovery.

At present, intensive investigation aims at the creation of optimal valvular prostheses. We introduced and tested the applicability and functionality of two advanced cell‐plus‐matrix seeding technologies, spray‐assisted bioprocessing (SaBP) and laser‐assisted bioprocessing (LaBP), for autologous tissue engineering (TE) of bioresorbable artificial grafts. For SaBP, human mesenchymal stem cells (HMSCs), umbilical cord vein endothelial cells (HUVECs) and fibrin were simultaneously spray‐administered on poly(ε‐caprolactone) (PCL) substrates. For LaBP, HUVECs and HMSCs were separately laser‐printed in stripes, followed by fibrin sealing. Three‐leaflet valves were manufactured following TE of electrospun PCL tissue equivalents. Grafts were monitored in vitro under static and dynamic conditions in bioreactors. SaBP and LaBP resulted in TE of grafts with homogeneous cell distribution and accurate cell pattern, respectively. The engineered valves demonstrated immediate sufficient performance, complete cell coating, proliferation, engraftment, HUVEC‐mediated invasion, HMSC differentiation and extracellular matrix deposition. SaBP revealed higher efficiency, with at least 12‐fold shorter processing time than the applied LaBP set‐up. LaBP realized coating with higher cell density and minimal cell–scaffold distance. Fibrin and PCL stability remain issues for improvement. The introduced TE technologies resulted in complete valvular cell‐plus‐matrix coating, excellent engraftment and HMSCs differentiation. SaBP might have potential for intraoperative table‐side TE considering the procedural duration and ease of implementation. LaBP might accelerate engraftment with precise patterns. Copyright © 2012 John Wiley & Sons, Ltd.

In-depth knowledge of the mechanisms induced by early postischemic cardiac endogenous mesenchymal stem cells (MSCs) in the acutely ischemic heart could advance our understanding of cardiac regeneration. Herein, we aimed to identify, isolate, and initially characterize the origin, kinetics and fate of cardiac MSCs. This was facilitated by in vivo genetic cell fate mapping through green fluorescent protein (GFP) expression under the control of vimentin induction after acute myocardial infarction (MI). Following permanent ligation of the left anterior descending coronary artery in CreER⁺ mTom/mGFP⁺ mice, vimentin/GFP⁺ cells revealed ischemia-responsive activation, survival, and local enrichment inside the peri-infarction border zone. Fluorescence-activated cell sorting (FACS)-isolated vimentin/GFP⁺ cells could be strongly expanded in vitro with clonogenic precursor formation and revealed MSC-typical cell morphology. Flow-cytometric analyses demonstrated an increase in cardiac vimentin/GFP⁺ cells in the ischemic heart, from a 0.6% cardiac mononuclear cell (MNC) fraction at 24 h to 1.6% at 72 h following MI. Sca-1⁺CD45^– cells within the vimentin/GFP⁺ subtype of this MNC fraction increased from 35.2% at 24 h to 74.6% at 72 h after MI. The cardiac postischemic vimentin/GFP⁺ MNC subtype showed multipotent adipogenic, chondrogenic, and osteogenic differentiation potential, which is distinctive for MSCs. In conclusion, we demonstrated a seemingly proliferative first response of vimentin- induced cardiac endogenous MSCs in the acutely ischemic heart. Genetically, GFP-targeted in vivo cell tracking, isolation, and in vitro expansion of this cardiac MSC subtype could help to clarify their reparative status in inflammation, fibrogenesis, cell turnover, tissue homeostasis, and myocardial regeneration.

Redo transcatheter aortic valve implantation (TAVI) in patients with prior transapical SAPIEN 3 valves carries a significant risk of coronary obstruction (CO). Chimney stenting is an established strategy to maintain coronary perfusion in high-risk valve-in-valve (ViV) procedures. We treated an 87-year-old cachectic woman with BMI of 16.9 kg/m² who presented with cardiac decompensation due to severe restenosis of a 20 mm SAPIEN 3 valve implanted using a transapical approach in 2017. Computed tomography revealed index prosthesis frame extension beyond the sinotubular junction at the right coronary sinus, posing a risk of RCA occlusion. A staged transfemoral redo-TAVI using a 23 mm Medtronic Evolut FX+ valve was performed followed by deployment of the pre-positioned stent in the so-called chimney technique. The RCA guidewire and undeployed coronary stent were positioned in advance as a protective measure before valve deployment. During valve deployment, inferior ST-segment elevation occurred, prompting stent implantation in order to restore RCA patency. Angiography confirmed preserved coronary flow and optimal valve function. Careful preprocedural evaluation—including CT-based assessment of coronary height, sinus anatomy, and virtual valve modeling—is essential to minimize the risk of CO in ViV or redo-TAVI procedures. The chimney technique provides an effective bailout strategy for acute coronary obstruction, while procedural strategies such as commissural alignment and the cusp-overlap technique can optimize procedural and hemodynamic outcomes. Pre-emptive coronary protection using chimney stenting enables safe and effective redo transfemoral TAVI in patients with complex anatomy and prior transapical valve implantation, ensuring hemodynamic success and minimizing complications.