Publications by authors named "Axel Haverich"

739 Publications

Sex differences in outcomes following less-invasive left ventricular assist device implantation.

Ann Cardiothorac Surg 2021 Mar;10(2):255-267

Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.

Background: Worse outcomes in women compared to men undergoing left ventricular assist device (LVAD) implantation remain an underestimated problem in heart failure (HF) patients. With device miniaturization, less-invasive LVAD implantation techniques have gained relevance, but their impact on outcomes in women is unknown. This study investigates sex-related differences in patients undergoing LVAD implantation through less-invasive procedures.

Methods: This retrospective single-center cohort study included patients who underwent isolated LVAD implantation between 2011 and 2018 through less-invasive techniques. Propensity score matching (PSM) was utilized to balance preoperative heterogeneity. Primary endpoint was two-year survival, and secondary endpoints included long-term survival, surgical outcomes and postoperative adverse events.

Results: Baseline analysis of 191 patients (females 18.3%) showed differences in terms of age [female (median, 52; IQR, 47-61); male (median, 58.5; IQR, 49-66); P=0.005], underlying diagnosis (P<0.001), INTERMACS profile (P=0.009), history of previous cardiac surgery (P=0.049) and preoperative creatinine values [female (median, 110; IQR, 71-146); male (median, 126; IQR, 9-168); P=0.049]. Over a follow-up of 460.68 patient-years, Kaplan-Meyer analysis showed better survival in females (P=0.027) and a similar probability of cardiac transplantation (P=0.288). After PSM, females showed higher needs for intraoperative fresh frozen plasma (P=0.044) and platelets (P=0.001) but comparable postoperative outcomes. No sex-related differences were noticed regarding two-year outcomes, long-term survival and adverse events. LVAD-related infections remained the most common complication with males experiencing more pump infections than women (P=0.050).

Conclusions: Patients receiving less-invasive LVAD implantation do not show significant sex-related differences in short and long-term outcomes and survival. Prospective studies are needed to evaluate the role of less-invasive techniques in reducing sex-based disparities after LVAD implantation.
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http://dx.doi.org/10.21037/acs-2020-cfmcs-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033266PMC
March 2021

Mechanical circulatory support in coronavirus disease-2019-positive patients with severe respiratory failure.

Interact Cardiovasc Thorac Surg 2021 Apr 5. Epub 2021 Apr 5.

Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.

Objectives: Treatment of severe acute respiratory distress syndrome (ARDS) induced by severe acute respiratory syndrome coronavirus 2 has been heavily debated. Our goal was to describe our findings in patients with severe ARDS due to severe coronavirus disease 2019 (sCOVID-19) treated with venovenous extracorporeal membrane oxygenation (vv-ECMO).

Methods: We retrospectively examined all patients treated with vv-ECMO for severe ARDS due to acute respiratory syndrome coronavirus 2.

Results: In total, 13 patients were treated with vv-ECMO in our medical centre. The mean patient age was 48.1 years. Most patients were obese (69%) and male (85%). All patients were mechanically ventilated before ECMO. The mean time from intubation to proning was 16.6 h; the time from start of prone therapy to vv-ECMO implantation was 155.1 h. The mean total ECMO run time was 358 h. Significant reduction of positive end-expiratory pressure (P = 0.02), peak pressure (P = 0.001) and minute volume (P = 0.03) could be achieved after implantation of vv-ECMO. All patients showed an inflammatory response. Overall mortality was 30.7%: 1 patient died of mesenteric ischaemia; 3 patients died of multiple organ failure. A worse prognosis was seen in patients with highly elevated concentrations of interleukin-6.

Conclusions: The use of vv-ECMO in patients with sCOVID-19-induced ARDS is safe and associated with improved respiratory ventilation settings. The rate of immune system involvement plays a pivotal role in the development and outcome of sCOVID-19.
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http://dx.doi.org/10.1093/icvts/ivab087DOI Listing
April 2021

Native and prosthetic graft infections of the thoracic aorta: surgical management.

Eur J Cardiothorac Surg 2021 Mar 30. Epub 2021 Mar 30.

Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.

Objectives: Infection of the native aorta or after previous open or endovascular repair of the thoracic aorta is associated with high risks for morbidity and mortality. We analysed the outcome after surgical management of a native mycotic aneurysm or of prosthetic graft infection of the descending aorta.

Methods: From June 2000 to May 2019, a total of 39 patients underwent surgery in our centre for infection of the native descending aorta (n = 19 [49%], group A) or a prosthetic descending aorta [n = 20 (51%), group B]. In the 20 patients in group B, a total of 8 patients had prior open aortic repair with a prosthesis and 12 patients had a previous endovascular graft repair.

Results: The cohort patients had a mean age of 57 ± 14; 62% were men (n = 24). The most common symptoms at the time of presentation included fever, thoracic or abdominal pain and active bleeding. Emergency surgery was performed in 11 patients (28%); 3 patients had emergency endovascular stent grafts implanted during thoracic endovascular aortic repair for aortic rupture before further open repair. The 30-day mortality was 42% in group A and 35% in group B. The 90-day mortality was 47% in group A and 45% in group B. Pathogens could be identified in approximately half of the patients (46%). The most commonly identified pathogens were Staphylococcus aureus in 6 patients (15%) and Staphylococcus epidermidis in 4 patients (10%). Survival of the entire group (including patients with both native and prosthetic graft infections) was 44 ± 8%, 39 ± 8% and 39 ± 8% at 1, 2 and 3 years after surgery. The percentage of patients who survived the initial perioperative period was 81 ± 9%, 71 ± 9% and 71 ± 10% at 1, 2 and 3 years after surgery.

Conclusions: Patients with infection of the descending aorta, either native or prosthetic, are associated with both high morbidity and mortality. However, patients who survive the initial perioperative period have an acceptable long-term prognosis. In emergency situations, thoracic endovascular aortic repair may help to stabilize patients and serve as bridge to open repair.
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http://dx.doi.org/10.1093/ejcts/ezab143DOI Listing
March 2021

Aortic valve-sparing root replacement with Tirone E. David's reimplantation technique: single-centre 25-year experience.

Eur J Cardiothorac Surg 2021 Mar 29. Epub 2021 Mar 29.

Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.

Objectives: Tirone E. David described aortic valve-sparing root reimplantion (AVSRR) almost 30 years ago. At our centre, we adopted this operation in 1993, and since then, we have performed >700 operations over a time period of >25 years. In this report, we present our single-centre experience.

Methods: Between 1993 and 2019, a total of 732 patients underwent AVSRR at our centre. The mean age was 53 ± 15 and 522 (71%) were male. Marfan syndrome was present in 117 (16%) patients and bicuspid aortic valve in 81 (11%). The indication for surgery was aortic root aneurysm in 588 (80%) patients and acute aortic dissection in 144 (20%) patients.

Results: Mini-sternotomy was performed in 74 (10%) patients. A straight tube graft (David I) was used in 677 (92%) and a Valsalva-graft in 55 (8%) patients. Cusp plasty was done in 83 (11%) patients. Concomitant cardiac procedures were performed in 438 (60%) patients. Overall in-hospital mortality was 3.8% (n = 29) and 1.9% (n = 11) in elective cases. Postoperative echocardiography was available for 671 patients and showed aortic insufficiency (AI) ≤I° in 647 (96%) patients. The mean follow-up time was 10 ± 6.7 years and comprised a total of 7307 patient-years. The 1-, 5-, 10- and 15-year survival rates were: 93%, 88%, 77% and 65%, respectively. The rates for freedom from valve-related reoperation at 1, 5, 10 and 15 years after initial surgery were 97%, 93%, 88% and 85%, respectively. Cox regression analysis identified age [odds ratio (OR) = 0.975, 95% confidence interval (CI) = 0.955-0.995, P = 0.016], hyperlipidaemia (OR = 1.980, 95% CI = 1.175-3.335, P = 0.010), preoperative level of left ventricular ejection function (OR = 1.749, 95% CI = 1.024-2.987, P = 0.041) and postoperative degree of AI (OR = 1.880, 95% CI = 1.532-2.308, P ≤ 0.001) as risk factors for the future AI or reoperation.

Conclusions: David procedure can be performed extremely safely, with low risks for perioperative morbidity and mortality, both in elective situations via minimally invasive access and in emergent settings for acute aortic type A dissection. Regarding long-term outcome, David's AVSRR seems to provide excellent clinical results and sustainable function of the aortic valve in the majority of patients almost 3 decades after its introduction.
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http://dx.doi.org/10.1093/ejcts/ezab136DOI Listing
March 2021

Lateral Thoracotomy for Ventricular Assist Device Implantation: A Meta-Analysis of Literature.

ASAIO J 2021 Feb 4. Epub 2021 Feb 4.

From the *Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany †Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany ‡Cardio-Thoracic Surgery Department, Maastricht University Medical Centre (MUMC), Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands.

The use of lateral thoracotomy (LT) for implanting left ventricular assist devices (LVADs) is worldwide increasing, although the available evidence for its positive effects compared with conventional sternotomy (CS) is limited. This systematic review and meta-analysis analyzes the outcomes of LT compared with CS in patients undergoing implantation of a centrifugal continuous-flow LVAD. Four databases and 1,053 publications were screened until December 2019. Articles including patients undergoing implantation of a centrifugal continuous-flow LVAD through LT were included. A meta-analysis to compare LT and CS was performed to summarize evidences from studies including both LT and CS patients extracted from the same population. Primary outcome measure was in-hospital or 30-day mortality. Eight studies reporting on 730 patients undergoing LVAD implantation through LT (n = 242) or CS (n = 488) were included in the meta-analysis. Left thoracotomy showed lower in-hospital/30-day mortality (odds ratio [OR]: 0.520, 95% confidence interval [CI]: 0.27-0.99, p = 0.050), shorter intensive care unit (ICU) stay (mean difference [MD]: 3.29, CI: 1.76-4.82, p < 0.001), lower incidence of severe right heart failure (OR: 0.41; CI: 0.19-0.87, p = 0.020) and postoperative right ventricular assist device (RVAD) implantation (OR: 0.27, CI: 0.10-0.76, p = 0.010), fewer perioperative transfusions (MD: 0.75, CI: 0.36-1.14, p < 0.001), and lower incidence of renal failure (OR: 0.45, CI: 0.20-1.01, p = 0.050) and device-related infections (OR: 0.45, CI: 0.20-1.01, p = 0.050), respectively. This meta-analysis demonstrates that implantation of a centrifugal continuous-flow LVAD system via LT benefits from higher short-term survival, less right heart failure, lower postoperative RVAD need, shorter ICU stay, less transfusions, lower risk of device-related infections and kidney failure. Prospective studies are needed for further proof.
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http://dx.doi.org/10.1097/MAT.0000000000001359DOI Listing
February 2021

Midterm outcomes with a sutureless aortic bioprosthesis in a prospective multicenter cohort study.

J Thorac Cardiovasc Surg 2021 Jan 13. Epub 2021 Jan 13.

Cardio-thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.

Objective: The objective of this study was to report midterm clinical outcomes with a self-expandable sutureless aortic valve.

Methods: Between 2010 and 2013, 658 patients at 25 European institutions received the Perceval sutureless valve (LivaNova Plc, London, United Kingdom). Mean follow-up was 3.8 years; late cumulative follow-up was 2325.2 patient-years.

Results: The mean age of the population was 78.3 ± 5.6 years and 40.0% (n = 263) were 80 years of age or older; mean Society of Thoracic Surgeons-Predicted Risk of Mortality score was 7.2 ± 7.4. Concomitant procedures were performed in 31.5% (n = 207) of patients. Overall duration of cardiopulmonary bypass time was 64.8 ± 25.2 minutes and aortic cross-clamping time was 40.7 ± 18.1 minutes. Thirty-day all-cause mortality was 3.7% (23 patients), with an observed:expected ratio of 0.51. Overall survival was 91.6% at 1 year, 88.5% at 2 years, and 72.7% at 5 years. Peak and mean gradients remained stable during follow-up, and were 17.8 ± 11.3 mm Hg and 9.0 ± 6.3 mm Hg, respectively, at 5 years. Preoperatively, 33.4% of those who received the Perceval valve (n = 210) were in New York Heart Association functional class I or II versus 93.1% (n = 242) at 5 years.

Conclusions: This series, representing, to our knowledge, the longest follow-up with sutureless technology in a prospective, multicenter study, shows that aortic replacement using sutureless valves is associated with low mortality and morbidity and good hemodynamic performance.
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http://dx.doi.org/10.1016/j.jtcvs.2020.12.109DOI Listing
January 2021

Five-year outcomes of patients supported with HeartMate 3: a single-centre experience.

Eur J Cardiothorac Surg 2021 Feb 15. Epub 2021 Feb 15.

Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.

Objectives: The HeartMate 3 left ventricular assist device was first implanted in 2014 and received the Conformité Européenne mark in 2015. Since then, several trials demonstrated its high haemocompatibility associated with good survival and low adverse events rates. Herein, we report our institutional experience with patients supported with HeartMate 3 for 5 years.

Methods: This prospective cohort study included patients receiving a HeartMate 3 implantation in 2014 as part of the HeartMate 3 Conformité Européenne Mark clinical trial. Patients had follow-up visits every 3 months while on left ventricular assist device support, and all patients completed the 5-year follow-up. The primary end point was survival at 5 years. Secondary end points included adverse events, health status and quality of life.

Results: Eight patients (men: 75%) aged 59 years (min-max: 52-66 years) were enrolled. At 5 years, survival was 100%. Patients remained on support for a median time of 1825 days (min-max: 101-1825 days); 2 patients successfully received cardiac transplants. No right heart failure, haemolysis, pump thrombosis, pump malfunction or neurological events occurred in any patients. A driveline infection was observed in 6 patients (0.25 events/patient-year). Compared to baseline, a significant improvement in quality of life and in New York Heart Association functional class was noted after the implant and for the whole follow-up time. A slight decline in kidney function and in the 6-min walk test results occurred after 3 years.

Conclusions: This study reports the longest single-centre follow-up of the HeartMate 3, showing excellent haemocompatibility over time with high survival and low complication rates at 5 years.
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http://dx.doi.org/10.1093/ejcts/ezab018DOI Listing
February 2021

Is total aortic arch replacement with the frozen elephant trunk procedure reasonable in elderly patients?

Eur J Cardiothorac Surg 2021 Feb 14. Epub 2021 Feb 14.

Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.

Objectives: Total aortic arch replacement is an invasive procedure with significant risks for complications. These risks are even higher in older, multimorbid patients. The current trends in demographic changes in western countries with an ageing population will aggravate this issue. In this study, we present our experience with total aortic arch replacement using the frozen elephant trunk (FET) technique in septuagenarians. We compared the results of septuagenarians with those of younger patients and analysed if there was an improvement in outcome over time.

Methods: Between August 2001 and March 2020, 225 patients underwent non-urgent FET procedure at our institution. There were 75 patients aged ≥70 years (mean age 74 ± 4) who were assigned to group A, and 150 patients aged <70 years (mean age of 57 ± 11) who were assigned to group B. In groups A and B, the indications for surgery were chronic dissection (21% vs 53%), aortic aneurysm (78% vs 45%) and penetrating atherosclerotic ulcer (1% vs 2%).

Results: The rate for temporary dialysis was significantly higher in group A than in group B (29% vs 13%, P = 0.003), although the majority recovered kidney function. Rates for re-exploration for bleeding and stroke were comparable in both groups. In-hospital mortality was significantly higher in group A than in group B (24% vs 13%, P = 0.037). Logistic regression analysis showed that age >70 years was an independent statistically significant risk factor for in-hospital mortality (odds ratio = 2.513, 95% confidence interval = 1.197-5.278, P-value = 0.015). Follow-up was complete for 100% of patients and comprised a total of 1073 patient-years with a mean follow-up time of 4.8 ± 4.5 years. The 1- and 5-year survival rates were 68% and 49% in group A, and 85% and 71% in group B, respectively (log rank, P < 0.001). Survival did not significantly improve over time.

Discussion: Total aortic arch replacement using the FET technique has a significantly higher risk for perioperative morbidity and mortality in septuagenarians than in younger patients. Long-term survival is significantly impaired in older patients. We recommend thorough patient selection of those who require total aortic arch replacement, and optimization of perioperative management to improve outcomes.
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http://dx.doi.org/10.1093/ejcts/ezab063DOI Listing
February 2021

Residual immune response towards decellularized homografts may be highly individual.

Eur J Cardiothorac Surg 2020 Dec 3. Epub 2020 Dec 3.

Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Hannover Medical School, Hannover, Germany.

Objectives: Decellularized homograft valves (DHVs) have shown promising clinical results, particularly in the treatment of congenital heart disease. However, DHV appears to elicit an immune response in a subset of young patients, indicated by early valve degeneration. As the decellularization process is quality controlled for each DHV, we hypothesized that there may be residual immunogenicity within the extracellular matrix of DHV.

Methods: A semi-quantitative dot blot analysis was established to screen for preformed recipient antibodies using secondary anti-human antibodies. Fifteen DHV samples (7 aortic, 8 pulmonary) were solubilized and exposed to serum from 20 healthy controls.

Results: The sera from young controls (n = 10, 18-25 years) showed significantly stronger binding of preformed antibodies than sera from older individuals (n = 10, 48-73 years). The difference between the means of arbitrary units was 15.1 ± 6.5 (P = 0.0315). There was high intraindividual variance in the mean amounts of arbitrary units of antibody binding with some healthy controls showing >10 times higher antibody binding towards 2 different DHV. The amount of preformed antibodies bound to DHVs was higher in aortic than in pulmonary DHVs. The mean number of antibody binding (in arbitrary units) was 17.2 ± 4.5 in aortic and 14.5 ± 4.7 in pulmonary DHV (P = 0.27). The amount of preformed antibodies bound to pulmonary DHVs was statistically significantly higher in the sera of healthy males (n = 10) than in the sera of healthy females (n = 10). The mean number of arbitrary units was 17.2 ± 4.2 in male and 11.7 ± 5.3 in female sera (P = 0.036). Antibody binding to aortic DHV was also higher in males, but not significant (18.8 ± 5.0 vs 15.6 ± 4.0). Blood group (ABO) incompatibility between the serum from controls and DHV showed no impact on antibody binding, and there was no age-related impact among DHV donors.

Conclusions: Residual immunogenicity of decellularized homografts appears to exist despite almost complete cell removal. The established dot blot method allows a semi-quantitative assessment of the individual immune response towards extracellular DHV components and potentially the possibility of preoperative homograft matching.
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http://dx.doi.org/10.1093/ejcts/ezaa393DOI Listing
December 2020

A 3-Layered Bioartificial Blood Vessel with Physiological Wall Architecture Generated by Mechanical Stimulation.

Ann Biomed Eng 2021 Jan 22. Epub 2021 Jan 22.

Lower Saxony Centre for Biomedical Engineering, Implant Research and Development (NIFE), Hannover Medical School, Stadtfelddamm 34, 30625, Hannover, Germany.

The generation of cellularized bioartificial blood vessels resembling all three layers of the natural vessel wall with physiological morphology and cell alignment is a long pursued goal in vascular tissue engineering. Simultaneous culture of all three layers under physiological mechanical conditions requires highly sophisticated perfusion techniques and still today remains a key challenge. Here, three-layered bioartificial vessels based on fibrin matrices were generated using a stepwise molding technique. Adipose-derived stem cells (ASC) were differentiated to smooth muscle cells (SMC) and integrated in a compacted tubular fibrin matrix to resemble the tunica media. The tunica adventitia-equivalent containing human umbilical vein endothelial cells (HUVEC) and ASC in a low concentration fibrin matrix was molded around it. Luminal seeding with HUVEC resembled the tunica intima. Subsequently, constructs were exposed to physiological mechanical stimulation in a pulsatile bioreactor for 72 h. Compared to statically incubated controls, mechanical stimulation induced physiological cell alignment in each layer: Luminal endothelial cells showed longitudinal alignment, cells in the media-layer were aligned circumferentially and expressed characteristic SMC marker proteins. HUVEC in the adventitia-layer formed longitudinally aligned microvascular tubes resembling vasa vasorum capillaries. Thus, physiologically organized three-layered bioartificial vessels were successfully manufactured by stepwise fibrin molding with subsequent mechanical stimulation.
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http://dx.doi.org/10.1007/s10439-021-02728-9DOI Listing
January 2021

Hemodynamic Assessment of Hollow-Fiber Membrane Oxygenators Using Computational Fluid Dynamics in Heterogeneous Membrane Models.

J Biomech Eng 2021 Jan 19. Epub 2021 Jan 19.

Lower Saxony Centre for Biomedical Engineering, Implant Research and Development (NIFE), Hannover Medical School, Germany; Department of Cardiothoracic, Transplantation and Vascular Surgery (HTTG), Hannover Medical School, Hannover, Germany; German Centre for Lung Research (DZL), BREATH, Hannover, Lower Saxony, Germany; Cardiopulmonary Regenerative Engineering (CARE) Group, Centre for Biological Engineering (CBE), Wolfson School of Mechanical, Electrical and Manufacturing Engineering, Loughborough University, Loughborough, United Kingdom.

Extracorporeal membrane oxygenation (ECMO) has been used clinically for more than 40 years as a bridge to transplantation, with hollow-fiber membrane (HFM) oxygenators gaining in popularity due to their high gas transfer and low flow resistance. In spite of the technological advances in ECMO devices, the inevitable contact of the perfused blood with the polymer hollow-fiber gas-exchange membrane, and the subsequent thrombus formation, limits their clinical usage to only 2-4 weeks. In addition, the inhomogeneous flow in the device can further enhance thrombus formation and limit gas-transport efficiency. Endothelialisation of the blood contacting surfaces of ECMO devices offers a potential solution to their inherent thrombogenicity. However, abnormal shear stresses and inhomogeneous blood flow might affect the function and activation status of the seeded endothelial cells (ECs). In this study, the blood flow through two HFM oxygenators, including the commercially-available iLA® MiniLung Petite Novalung (Xenios AG, Germany) and an experimental one for the rat animal model, was modelled using computational fluid dynamics (CFD), with a view to assessing the magnitude and distribution of the shear stress on the wall of the hollow fibers and flow fields in the oxygenators. This work demonstrated significant inhomogeneity in the flow dynamics of both oxygenators, with regions of high hollow-fiber wall shear stress and regions of stagnant flow, implying both regions of increased flow-induced blood damage and a variable flow-induced stimulation on seeded ECs in a biohybrid setting.
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http://dx.doi.org/10.1115/1.4049808DOI Listing
January 2021

Impact of unilateral diaphragm elevation on postoperative outcomes in bilateral lung transplantation - a retrospective single-center study.

Transpl Int 2021 Mar 23;34(3):474-487. Epub 2021 Jan 23.

Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany.

This study evaluated the impact of unilateral diaphragm elevation following bilateral lung transplantation on postoperative course. Patient data for all lung transplantations performed at our institution between 01/2010 and 12/2019 were reviewed. Presence of right or left diaphragm elevation was retrospectively evaluated using serial chest X-rays performed while patients were standing and breathing spontaneously. Right elevation was defined by a > 40 mm difference between right and left diaphragmatic height. Left elevation was present if the left diaphragm was at the same height or higher than the right diaphragm. In total, 1093/1213 (90%) lung transplant recipients were included. Of these, 255 (23%) patients exhibited radiologic evidence of diaphragm elevation (right, 55%; left 45%; permanent, 62%). Postoperative course did not differ between groups. Forced expiratory volume in 1 second, forced vital capacity and total lung capacity were lower at 1-year follow-up in patients with permanent than in patients with transient or absent diaphragmatic elevation (P = 0.038, P < 0.001, P = 0.002, respectively). Graft survival did not differ between these groups (P = 0.597). Radiologic evidence of diaphragm elevation was found in 23% of our lung transplant recipients. While lung function tests were worse in patients with permanent elevation, diaphragm elevation did not have any relevant impact on outcomes.
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http://dx.doi.org/10.1111/tri.13812DOI Listing
March 2021

Targeting bioenergetics is key to counteracting the drug-tolerant state of biofilm-grown bacteria.

PLoS Pathog 2020 12 22;16(12):e1009126. Epub 2020 Dec 22.

Institute of Molecular Bacteriology, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany.

Embedded in an extracellular matrix, biofilm-residing bacteria are protected from diverse physicochemical insults. In accordance, in the human host the general recalcitrance of biofilm-grown bacteria hinders successful eradication of chronic, biofilm-associated infections. In this study, we demonstrate that upon addition of promethazine, an FDA approved drug, antibiotic tolerance of in vitro biofilm-grown bacteria can be abolished. We show that following the addition of promethazine, diverse antibiotics are capable of efficiently killing biofilm-residing cells at minimal inhibitory concentrations. Synergistic effects could also be observed in a murine in vivo model system. PMZ was shown to increase membrane potential and interfere with bacterial respiration. Of note, antibiotic killing activity was elevated when PMZ was added to cells grown under environmental conditions that induce low intracellular proton levels. Our results imply that biofilm-grown bacteria avoid antibiotic killing and become tolerant by counteracting intracellular alkalization through the adaptation of metabolic and transport functions. Abrogation of antibiotic tolerance by interfering with the cell's bioenergetics promises to pave the way for successful eradication of biofilm-associated infections. Repurposing promethazine as a biofilm-sensitizing drug has the potential to accelerate the introduction of new treatments for recalcitrant, biofilm-associated infections into the clinic.
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http://dx.doi.org/10.1371/journal.ppat.1009126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787680PMC
December 2020

Application of MR diffusion imaging for non-invasive assessment of acute kidney injury after lung transplantation.

Medicine (Baltimore) 2020 Dec;99(49):e22445

Department of Nephrology.

To assess whether MR diffusion imaging may be applied for non-invasive detection of renal changes correlating with clinical diagnosis of acute kidney injury (AKI) in patients after lung transplantation (lutx).Fifty-four patients (mean age 49.6, range 26-64 years) after lutx were enrolled in a prospective clinical study and underwent functional MR imaging of the kidneys in the early postoperative period. Baseline s-creatinine ranged from 39 to 112 μmol/L. For comparison, 14 healthy volunteers (mean age 42.1, range 24-59 years) underwent magnetic resonance imaging (MRI) using the same protocol. Renal tissue injury was evaluated using quantification of diffusion and diffusion anisotropy with diffusion-weighted (DWI) and diffusion-tensor imaging (DTI). Renal function was monitored and AKI was defined according to Acute-Kidney-Injury-Network criteria. Statistical analysis comprised one-way ANOVA and Pearson correlation.67% of lutx patients (36/54) developed AKI, 47% (17/36) had AKI stage 1, 42% (15/36) AKI stage 2, and 8% (3/36) severe AKI stage 3. Renal apparent diffusion coefficients (ADCs) were reduced in patients with AKI, but preserved in transplant patients without AKI and healthy volunteers (2.07 ± 0.02 vs 2.18 ± 0.05 vs 2.21 ± 0.03 × 10 mm/s, P < .05). Diffusion anisotropy was reduced in all lutx recipients compared with healthy volunteers (AKI: 0.27 ± 0.01 vs no AKI: 0.28 ± 0.01 vs healthy: 0.33 ± 0.02; P < .01). Reduction of renal ADC correlated significantly with acute loss of renal function after lutx (decrease of renal function in the postoperative period and glomerular filtration rate on the day of MRI).MR diffusion imaging enables non-invasive assessment of renal changes correlating with AKI early after lutx. Reduction of diffusion anisotropy was present in all patients after lutx, whereas marked reduction of renal ADC was observed only in the group of lutx recipients with AKI and correlated with renal function impairment.
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http://dx.doi.org/10.1097/MD.0000000000022445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717793PMC
December 2020

Dual Function of iPSC-Derived Pericyte-Like Cells in Vascularization and Fibrosis-Related Cardiac Tissue Remodeling In Vitro.

Int J Mol Sci 2020 Nov 25;21(23). Epub 2020 Nov 25.

Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany.

Myocardial interstitial fibrosis (MIF) is characterized by excessive extracellular matrix (ECM) deposition, increased myocardial stiffness, functional weakening, and compensatory cardiomyocyte (CM) hypertrophy. Fibroblasts (Fbs) are considered the principal source of ECM, but the contribution of perivascular cells, including pericytes (PCs), has gained attention, since MIF develops primarily around small vessels. The pathogenesis of MIF is difficult to study in humans because of the pleiotropy of mutually influencing pathomechanisms, unpredictable side effects, and the lack of available patient samples. Human pluripotent stem cells (hPSCs) offer the unique opportunity for the de novo formation of bioartificial cardiac tissue (BCT) using a variety of different cardiovascular cell types to model aspects of MIF pathogenesis in vitro. Here, we have optimized a protocol for the derivation of hPSC-derived PC-like cells (iPSC-PCs) and present a BCT in vitro model of MIF that shows their central influence on interstitial collagen deposition and myocardial tissue stiffening. This model was used to study the interplay of different cell types-i.e., hPSC-derived CMs, endothelial cells (ECs), and iPSC-PCs or primary Fbs, respectively. While iPSC-PCs improved the sarcomere structure and supported vascularization in a PC-like fashion, the functional and histological parameters of BCTs revealed EC- and PC-mediated effects on fibrosis-related cardiac tissue remodeling.
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http://dx.doi.org/10.3390/ijms21238947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728071PMC
November 2020

Three-step preoperative sequential planning for pulmonary valve replacement in repaired tetralogy of Fallot using computed tomography.

Eur J Cardiothorac Surg 2020 Nov 22. Epub 2020 Nov 22.

Department of Cardiothoracic, Transplant, and Vascular Surgery, Hannover Medical School, Hannover, Germany.

Objectives: Our goal was to compare results between a standard computed tomography (CT)-based strategy, the 'three-step preoperative sequential planning' (3-step PSP), for pulmonary valve replacement in repaired tetralogy of Fallot versus a conventional planning approach.

Methods: We carried out a retrospective study with unmatched and matched groups. The 3-step PSP comprised the planning of mediastinal re-entry, cannulation for cardiopulmonary bypass (CPB) and the main procedure, using standard 3-dimensional videos. Operative times (skin incision to CPB, CPB time, end of CPB to skin closure and cross-clamp time) as well as postoperative length of stay and in-hospital mortality were compared.

Results: Eighty-two patients (49% classical tetralogy of Fallot) underwent an operation (85% with pulmonary homograft) with 1.22% in-hospital mortality. The 3-step PSP (n = 14) and the conventional planning (n = 68) groups were compared. There were no statistically significant differences in the preoperative characteristics. Differences were observed in the total operative time (P = 0.009), skin incision to CPB (P = 0.034) and cross-clamp times (74 ± 33 vs 108 ± 47 min; P = 0.006), favouring the 3-step PSP group. Eight matched pairs were compared showing differences in the total operative time (263 ± 44 vs 360 ± 66 min; P = 0.008), CPB time (123 ± 34 vs 190 ± 43 min; P = 0.008) and postoperative length of stay (P = 0.031), favouring the 3-step PSP group.

Conclusions: In patients with repaired tetralogy of Fallot undergoing pulmonary valve replacement, preoperative planning using a standard CT-based strategy, the 3-step PSP, is associated with shorter operative times and shorter postoperative length of stay.
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http://dx.doi.org/10.1093/ejcts/ezaa346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954262PMC
November 2020

Delayed non-myeloablative irradiation to induce long-term allograft acceptance in a large animal lung transplantation model.

Transpl Immunol 2021 Apr 27;65:101350. Epub 2020 Oct 27.

Division of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; German Centre for Lung Research, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Electronic address:

We previously induced long-term allograft acceptance in an allogeneic lung transplantation (LTx) model in miniature swine using perioperative non-myeloablative irradiation (IRR) combined with infusion of donor specific alloantigen. In order to improve clinical applicability, we delayed induction with irradiation in this study. Left sided single LTx was performed in minipigs. Group 1 received non-myeloablative irradiation (7Gy thymus and 1.5Gy whole body IRR) before LTx and a perioperative donor specific splenocyte infusion (SpTx). Group 2 received perioperative SpTx but delayed IRR three days after LTx. Group 3 was exposed to delayed IRR without SpTx. Whereas 4 out of 7 animals from the non-delayed group never rejected their grafts and were electively sacrificed on postoperative day (POD) +500, all animals from group 2 rejected their grafts before POD 108. In group 3, 3 out of 8 animals developed long-term allograft acceptance. In all groups, donor leukocyte chimerism peaked up to 20% in peripheral blood one hour after reperfusion of the lung. Group 1 maintained prolonged chimerism beyond POD 7, whereas chimerism levels in groups 2 and 3 decreased continuously thereafter. Delayed irradiation has the potential to improve long-term graft survival, yet not as efficient as a perioperative conditioning protocol.
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http://dx.doi.org/10.1016/j.trim.2020.101350DOI Listing
April 2021

Re-endothelialization of non-detergent decellularized porcine vessels.

Artif Organs 2021 Apr 21;45(4):E53-E64. Epub 2020 Nov 21.

Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.

Tissue engineering utilizes an interdisciplinary approach to generate constructs for the treatment and repair of diseased organs. Generation of small vessels as vascular grafts or as envisioned central vessel for vascularized constructs is still a challenge. Here, the decellularization of porcine vessels by a non-detergent based protocol was developed and investigated. Perfusion-decellularization with sodium hydroxide solution resulted in removal of cellular material throughout the whole length of the vessel while preserving structural and mechanical integrity. A re-endothelialization of the retrieved matrix with human umbilical vein endothelial cells and cardiac endothelial cells was achieved through rotation-based seeding employing a custom-made bioreactor. A confluent monolayer was detected on the entire luminal surface. Thus, a non-detergent-based decellularization method allowing the re-endothelialization of the luminal surface was developed in this study, thereby paving the way for future implementation of the resulting construct as vascular graft or as central vessel for tissue engineered constructs in need of a perfusion system with readily available anastomosis sites.
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http://dx.doi.org/10.1111/aor.13836DOI Listing
April 2021

Dot blots of solubilized extracellular matrix allow quantification of human antibodies bound to epitopes present in decellularized porcine pulmonary heart valves.

Xenotransplantation 2021 01 17;28(1):e12646. Epub 2020 Sep 17.

Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Hannover Medical School, Hannover, Germany.

Background: The present study reports the development of a sensitive dot blot protocol for determining the level of preformed antibodies against porcine heart valve tissue derived from wild-type (WT) and α-Gal-KO (GGTA1-KO) pigs in human sera.

Methods: The assay uses decellularized and solubilized heart valve tissue; antibody binding found in this dot blot assay could be correlated with antibody titers of preformed anti-α-Gal and anti-Neu5Gc antibodies detected by a sensitive ELISA.

Results: The ultimate protocol had an inter-assay variance of 9.5% and an intra-assay variance of 9.2%, showing that the test is reliable and highly reproducible. With the aid of this dot blot assay, we found significant variation with regard to antibody contents among twelve human sera. Binding of preformed antibodies to WT tissue was significantly higher than to GGTA1-KO tissue.

Conclusions: The dot blot assay described herein could be a valuable tool to measure preformed antibody levels in human sera against unknown epitopes on decellularized tissue prior to implantation. Ultimately, this prescreening may allow a matching of the porcine xenograft with the respective human recipients in demand and thus may become an important tool for graft long-term survival similar to current allotransplantation settings.
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http://dx.doi.org/10.1111/xen.12646DOI Listing
January 2021

All for one and one for all-new multifunctional sternal retractor.

J Thorac Dis 2020 Aug;12(8):4581-4583

Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany.

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http://dx.doi.org/10.21037/jtd-20-1051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475550PMC
August 2020

Echocardiographic guided, transatrial closure of a patent foramen ovale.

J Cardiothorac Surg 2020 Sep 14;15(1):255. Epub 2020 Sep 14.

Division of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Carl-Neuberg- Strasse 1, 30625, Hannover, Germany.

Background: The management of an incidental patent foramen ovale found during planned cardiac surgery remains a challenge, and current guidelines are not helpful. Although evidence is accumulating, that closure of an incidental found patent foramen ovale might be beneficial, especially in planned off-pump procedures, the diagnosis of a formerly unknown patent foramen ovale with the patient on the operation table has vast consequences by making it necessary to switch to on pump, bi-caval cannulation for patent foramen ovale closure. We therefore developed a technique for transatrial closure of a patent foramen ovale, guided by transesophageal echocardiography.

Results: We have performed this surgery in 9 patients. None of them had a previously diagnosed patent foramen ovale. Mean age was 74 (±5) years, Operation time was 175 min (± 34 min), Clamp time 35 min (± 16 min) and Cardiopulmonary bypass time 80 (±17 min). Mortality was 0%. Periprocedural transesophageal echocardiography revealed closure of the patent foramen ovale in all cases.

Conclusion: We report a new surgical method for transoesophageal echocardiography controlled closure of a patent foramen ovale without the need for an atriotomy. This new technique is especially useful for the closure of patent foramen ovale in the setting of on-pump and off-pump coronary artery bypass graft surgeries alike.
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http://dx.doi.org/10.1186/s13019-020-01289-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491112PMC
September 2020

Flying after left ventricular assist device implantation.

Artif Organs 2021 Mar 20;45(3):230-235. Epub 2020 Oct 20.

Department of Cardiac-, Thoracic-, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.

Literature on the air travel activities of patients supported by permanent mechanical assist devices is rare. To the best of our knowledge, no air travel guidelines or fitness prerequisites exist on whether and when ventricular assist device (VAD) patients are allowed to travel by plane after device implantation. In this study, we evaluated the topic of air travel after VAD implantation. This working group aimed to produce a report on air travel passengers supported by VADs, regarding their fitness to fly. Fifty left ventricular assist device (LVAD) patients were surveyed in a worldwide multicenter study. The single survey was performed with a multimethod design, including interviews conducted face-to-face, online, and on phone. Out of 50 patients, 97% described their traveling by aircraft as perfect and uneventful during the flight. Eighty-five percent of the study participants consulted their medical practitioner before the flight. No patient reported the occurrence of a severe condition associated with flying. LVAD alarms, especially low flow alarms, did not occur in any of the devices. Thirty-five percent of the surveyed patients, however, stated a major problem pertaining to the security check procedures at the airport. The results of this study suggest that commercial air travel is safe for stable patients on permanent VAD support and traveling can be resumed securely after VAD implantation. Conscientious preparation by packing necessary devices, fluids, medications, and careful preparation for the airport security check is recommended.
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http://dx.doi.org/10.1111/aor.13815DOI Listing
March 2021

Characterization of Tissue Engineered Endothelial Cell Networks in Composite Collagen-Agarose Hydrogels.

Gels 2020 Sep 3;6(3). Epub 2020 Sep 3.

Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany.

Scaffolds constitute an important element in vascularized tissues and are therefore investigated for providing the desired mechanical stability and enabling vasculogenesis and angiogenesis. In this study, supplementation of hydrogels containing either Matrigel and rat tail collagen I (Matrigel/rCOL) or human collagen (hCOL) with SeaPlaque agarose were analyzed with regard to construct thickness and formation and characteristics of endothelial cell (EC) networks compared to constructs without agarose. Additionally, the effect of increased rCOL content in Matrigel/rCOL constructs was studied. An increase of rCOL content from 1 mg/mL to 3 mg/mL resulted in an increase of construct thickness by approximately 160%. The high rCOL content, however, impaired the formation of an EC network. The supplementation of Matrigel/rCOL with agarose increased the thickness of the hydrogel construct by approximately 100% while supporting the formation of a stable EC network. The use of hCOL/agarose composite hydrogels led to a slight increase in the thickness of the 3D hydrogel construct and supported the formation of a multi-layered EC network compared to control constructs. Our findings suggest that agarose/collagen-based composite hydrogels are promising candidates for tissue engineering of vascularized constructs as cell viability is maintained and the formation of a stable and multi-layered EC network is supported.
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http://dx.doi.org/10.3390/gels6030027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559300PMC
September 2020

Intraoperative Extracorporeal Circulatory Support in Lung Transplantation for Pulmonary Fibrosis.

Ann Thorac Surg 2021 04 3;111(4):1316-1324. Epub 2020 Sep 3.

Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany; German Centre for Lung Research (DZL/BREATH), Hannover, Germany.

Background: Venous-arterial extracorporeal membrane oxygenation (ECMO) is an established technique for intraoperative cardiopulmonary support in patients undergoing lung transplantation. Patients with pulmonary fibrosis have a higher risk to require it. The aim of this study was to identify risk factors for the need of intraoperative ECMO use.

Methods: Records of patients undergoing lung transplantation for pulmonary fibrosis at our institution between January 2010 and May 2018 were retrospectively reviewed. Univariate logistic regression analysis was used for statistical identification of risk factors.

Results: There were 105 patients (34%) who required intraoperative ECMO support (ECMO+ group), and 203 (66%) did not (ECMO- group). Preoperative proof of pulmonary hypertension was identified as a risk factor for intraoperative ECMO support (odds ratio [OR], 3.8; 95% confidence interval [CI], 2.2-6.5; P < .01). Revealed mean pulmonary arterial pressure values exceeding 50 mm Hg and pulmonary vascular resistance values exceeding 9.4 Wood units were identified as risk factors for the need of intraoperative ECMO use with a prediction probability of 70%. Increased recipient body surface area (OR, 0.2; 95% CI, 0.1-0.5; P < .01) emerged as a protective factor against intraoperative ECMO (Hosmer-Lemeshow statistic, P = .71) as well as higher cardiac output (OR, 0.7; 95% CI, 0.6-0.9; P < .01). The postoperative course was more complicated in the ECMO+ group, whereas survival at 5 years did not differ among groups (70% vs 69%, P = .79).

Conclusions: Pulmonary hypertension with elevated pulmonary vascular resistance values predicts the need of intraoperative ECMO in patients receiving lung transplantation for pulmonary fibrosis. Although the postoperative course was more complicated in the ECMO+ group, long-term survival did not differ significantly.
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http://dx.doi.org/10.1016/j.athoracsur.2020.06.083DOI Listing
April 2021

Abdominal Surgery in Patients with Ventricular Assist Devices: a Single-Center Report.

ASAIO J 2020 08;66(8):890-898

From the Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany.

This study was performed to evaluate the incidence and outcome of patients with ventricular assist devices (VADs) undergoing abdominal surgery at our institution. A total of 604 adult patients who underwent VAD implantation between February 2004 and February 2018 were analyzed retrospectively with a median follow-up time of 66 (6-174) months. Thirty-nine patients (6.5%) underwent abdominal surgery. Elective surgical procedures were performed in 22 patients (56.4%), mainly for abdominal wall hernia repairs, partial colectomies, and cholecystectomies. Early after elective abdominal surgery no patient died, resulting in a median survival of 23 (1-78) months. Emergency surgery was performed in 17 patients (43.6%). The most common emergency indications were intestinal ischemia and/or perforation. Eight patients undergoing emergent surgery (44.4%) died within the first 30 days after primary abdominal operation, mainly due to sepsis and consecutive multiple organ failure, resulting in a dismal median survival of one month (0-52). Patients undergoing abdominal surgery had significantly lower rates of realized heart-transplantation (p = 0.031) and a significantly higher rate of VAD exchange, before or after abdominal surgery, due to thromboses or infections (p = 0.037). Nonetheless, overall survival after primary VAD implantation in these patients (median 38 months; 0-107) was not significantly impaired when compared to all other patients undergoing VAD implantation (median 30 months; 0-171). In summary, elective abdominal surgery can be performed safely when well planned by an experienced multidisciplinary team. Abdominal complications in VAD patients requiring emergent surgery, however, lead to a significant increase in short-term morbidity and a high 30-day mortality rate.
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http://dx.doi.org/10.1097/MAT.0000000000001085DOI Listing
August 2020

Toward a Long-Term Artificial Lung.

ASAIO J 2020 08;66(8):847-854

Department of Anesthesiology, Medical Faculty, RWTH Aachen University, Aachen, Germany.

Only a very small portion of end-stage organ failures can be treated by transplantation because of the shortage of donor organs. Although artificial long-term organ support such as ventricular assist devices provide therapeutic options serving as a bridge-to-transplantation or destination therapy for end-stage heart failure, suitable long-term artificial lung systems are still at an early stage of development. Although a short-term use of an extracorporeal lung support is feasible today, the currently available technical solutions do not permit the long-term use of lung replacement systems in terms of an implantable artificial lung. This is currently limited by a variety of factors: biocompatibility problems lead to clot formation within the system, especially in areas with unphysiological flow conditions. In addition, proteins, cells, and fibrin are deposited on the membranes, decreasing gas exchange performance and thus, limiting long-term use. Coordinated basic and translational scientific research to solve these problems is therefore necessary to enable the long-term use and implantation of an artificial lung. Strategies for improving the biocompatibility of foreign surfaces, for new anticoagulation regimes, for optimization of gas and blood flow, and for miniaturization of these systems must be found. These strategies must be validated by in vitro and in vivo tests, which remain to be developed. In addition, the influence of long-term support on the pathophysiology must be considered. These challenges require well-connected interdisciplinary teams from the natural and material sciences, engineering, and medicine, which take the necessary steps toward the development of an artificial implantable lung.
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http://dx.doi.org/10.1097/MAT.0000000000001139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386861PMC
August 2020

Hypothermic preservation of endothelialized gas-exchange membranes.

Artif Organs 2020 Dec 13;44(12):e552-e565. Epub 2020 Aug 13.

Lower Saxony Center for Biomedical Engineering, Implant Research and Development, Hannover Medical School, Hannover, Germany.

Endothelialization of the blood contacting surfaces of blood-contacting medical devices, such as cardiovascular prostheses or biohybrid oxygenators, represents a plausible strategy for increasing their hemocompatibility. Nevertheless, isolation and expansion of autologous endothelial cells (ECs) usually requires multiple processing steps and time to obtain sufficient cell numbers. This excludes endothelialization from application in acute situations. Off-the-shelf availability of cell-seeded biohybrid devices could be potentially facilitated by hypothermic storage. In this study, the survival of cord-blood-derived endothelial colony forming cells (ECFCs) that were seeded onto polymethylpentene (PMP) gas-exchange membranes and stored for up to 2 weeks in different commercially available and commonly used preservation media was measured. While storage at 4°C in normal growth medium (EGM-2) for 3 days resulted in massive disruption of the ECFC monolayer and a significant decline in viability, ECFC monolayers preserved in Chillprotec could recover after up to 14 days with negligible effects on their integrity and viability. ECFC monolayers preserved in Celsior, HTS-FRS, or Rokepie medium showed a significant decrease in viability after 7 days or longer periods. These results demonstrated the feasibility of hypothermic preservation of ECFC monolayers on gas-exchange membranes for up to 2 weeks, with potential application on the preservation of pre-endothelialized oxygenators and further biohybrid cardiovascular devices.
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http://dx.doi.org/10.1111/aor.13776DOI Listing
December 2020

Hematopoietic stem-cell senescence and myocardial repair - Coronary artery disease genotype/phenotype analysis of post-MI myocardial regeneration response induced by CABG/CD133+ bone marrow hematopoietic stem cell treatment in RCT PERFECT Phase 3.

EBioMedicine 2020 Jul 4;57:102862. Epub 2020 Jul 4.

Reference and Translation Center for Cardiac Stem Cell Therapy, Department Life, Light and Matter and Department of cardiac surgery, University Medicine Rostock, Schillingallee 35, 18055 Rostock, Germany. Electronic address:

Background: Bone marrow stem cell clonal dysfunction by somatic mutation is suspected to affect post-infarction myocardial regeneration after coronary bypass surgery (CABG).

Methods: 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.

Findings: 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.

Interpretation: Myocardial repair is affected by HSC gene response and somatic mutation. Machine Learning can be utilized to identify and predict pathological HSC response.

Funding: 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) TRIAL REGISTRATION: ClinicalTrials.gov NCT00950274.
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http://dx.doi.org/10.1016/j.ebiom.2020.102862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339012PMC
July 2020

Employers With Metabolic Syndrome and Increased Depression/Anxiety Severity Profit Most From Structured Exercise Intervention for Work Ability and Quality of Life.

Front Psychiatry 2020 18;11:562. Epub 2020 Jun 18.

Institute of Sports Medicine, Hannover Medical School, Hannover, Germany.

Background: Major depressive disorder and anxiety disorders are associated with less productivity, earlier retirement, and more sick-days at the workplace. These associations also exist for patients with metabolic syndrome. For both, exercise is a generally recommended part of multimodal treatments. However, for individuals with metabolic syndrome, in which depression and anxiety is more prevalent and severe, evidence for the efficacy of exercise interventions is limited.

Methods: Company employees with diagnosed metabolic syndrome (n=314, age: 48 ± 8 yrs) were randomized to a 6-month exercise intervention (150 min per week) or wait-list control. Participants received individual recommendations for exercise activities by personal meetings, telephone, or a smartphone app. Physical activities were supervised and adapted using activity monitor data transferred to a central database. Work ability (work ability index), depression severity and anxiety severity [hospital anxiety and depression scale (HADS)], and health-related quality of live [short form 36 (SF-36)] were assessed.

Results: We included 314 subjects from which 287 finished the intervention. Total work ability, depression- and anxiety severity, and the mental component score of the SF-36 improved after 6 months exercise compared to controls. After baseline stratification for normal (HADS scores 0-7) and increased depression- and anxiety scores (HADS scores 8-21) individuals with increased severity scores had similar age, body composition, blood lipids, and cardiorespiratory fitness compared to those with normal scores, but lower total work ability and component sum scores of health-related quality of life. After 6 months total work ability increased in the exercise group compared to controls with the magnitude of the observed increase being significantly greater for subjects with increased depression- and anxiety severity at baseline compared to those with normal severity scores.

Conclusions: A 6-month exercise intervention for company employees with metabolic syndrome showed strongest effects on self-perceived work ability in individuals with mild to severe depression- and anxiety severity. This suggests exercise programs offered to workers with metabolic syndrome not only reduces individual disease risk but may also reduce healthcare and employers costs arising from metabolic syndrome and mental disease conditions.

Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03293264.
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http://dx.doi.org/10.3389/fpsyt.2020.00562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314973PMC
June 2020