Knockdown of swine leukocyte antigen expression in porcine lung transplants enables graft survival without immunosuppression.

Immune rejection remains the major obstacle to long-term survival of allogeneic lung transplants. The expression of major histocompatibility complex molecules and minor histocompatibility antigens triggers allogeneic immune responses that can lead to allograft rejection. Transplant outcomes therefore depend on long-term immunosuppression, which is associated with severe side effects. To address this problem, we investigated the effect of genetically engineered transplants with permanently down-regulated swine leukocyte antigen (SLA) expression to prevent rejection in a porcine allogeneic lung transplantation (LTx) model. Minipig donor lungs with unmodified SLA expression (control group, n = 7) or with modified SLA expression (treatment group, n = 7) were used to evaluate the effects of SLA knockdown on allograft survival and on the nature and strength of immune responses after terminating an initial 4-week period of immunosuppression after LTx. Genetic engineering to down-regulate SLA expression was achieved during ex vivo lung perfusion by lentiviral transduction of short hairpin RNAs targeting mRNAs encoding ß2-microglobulin and class II transactivator. Whereas all grafts in the control group were rejected within 3 months, five of seven animals in the treatment group maintained graft survival without immunosuppression during the 2-year monitoring period. Compared with controls, SLA-silenced lung recipients had lower donor-specific antibodies and proinflammatory cytokine concentrations in the serum. Together, these data demonstrate a survival benefit of SLA-down-regulated lung transplants in the absence of immunosuppression.

A Novel Artificial Coronary Plaque to Model Coronary Heart Disease.

BACKGROUND: Experimental coronary artery interventions are currently being performed on non-diseased blood vessels in healthy animals. To provide a more realistic pathoanatomical scenario for investigations on novel interventional and surgical therapies, we aimed to fabricate a stenotic lesion, mimicking the morphology and structure of a human atherosclerotic plaque. METHODS: In an interdisciplinary setting, we engineered a casting mold to create an atherosclerotic plaque with the dimensions to fit in a porcine coronary artery. Oscillatory rheology experiments took place along with long-term stability tests assessed by microscopic examination and weight monitoring. For the implantability in future in vivo setups, we performed a cytotoxicity assessment, inserted the plaque in resected pig hearts, and performed diagnostic imaging to visualize the plaque in its final position. RESULTS: The most promising composition consists of gelatin, cholesterol, phospholipids, hydroxyapatite, and fine-grained calcium carbonate. It can be inserted in the coronary artery of human-sized pig hearts, producing a local partial stenosis and interacting like the atherosclerotic plaque by stretching and shrinking with the vessel wall and surrounding tissue. CONCLUSION: This artificial atherosclerotic plaque model works as a simulating tool for future medical testing and could be crucial for further specified research on coronary artery disease and is going to help to provide information about the optimal interventional and surgical care of the disease.

Hypoxic perfusion of pulmonary arterial vasa vasorum increases pulmonary arterial pressure.

The pathophysiology of pulmonary hypertension (PH) is not fully understood. Here, we tested the hypothesis that hypoxic perfusion of the vasa vasorum of the pulmonary arterial (PA) wall causes PH. Young adult pig lungs were explanted and placed into a modified ex vivo lung perfusion unit (organ care system, OCS) allowing the separate adjustment of parameters for mechanical ventilation, as well as PA perfusion and bronchial arterial (BA) perfusion. The PA vasa vasorum are branches of the BA. The lungs were used either as the control group (n = 3) or the intervention group (n = 8). The protocol for the intervention group was as follows: normoxic ventilation and perfusion (steady state), hypoxic BA perfusion, steady state, and hypoxic BA perfusion. During hypoxic BA perfusion, ventilation and PA perfusion maintained normal. Control lungs were kept under steady-state conditions for 105 min. During the experiments, PA pressure (PAP) and blood gas analysis were frequently monitored. Hypoxic perfusion of the BA resulted in an increase in systolic and mean PAP, a reaction that was reversible upon normoxic BA perfusion. The PAP increase was reproducible during the second hypoxic BA perfusion. Under control conditions, the PAP stayed constant until about 80 min of the experiment. In conclusion, the results of the current study prove that hypoxic perfusion of the vasa vasorum of the PA directly increases PAP in an ex situ lung perfusion setup, suggesting that PA vasa vasorum function and wall ischemia may contribute to the development of PH.NEW & NOTEWORTHY Hypoxic perfusion of the vasa vasorum of the pulmonary artery directly increased pulmonary arterial pressure in an ex vivo lung perfusion setup. This suggests that the function of pulmonary arterial vasa vasorum and wall ischemia may contribute to the development of pulmonary hypertension.

Five-year results from a prospective, single-arm European trial on decellularized allografts for aortic valve replacement-the ARISE Study and ARISE Registry Data.

OBJECTIVES: Decellularized aortic homografts (DAH) were introduced as a new option for aortic valve replacement for young patients. METHODS: A prospective, EU-funded, single-arm, multicentre study in 8 centres evaluating non-cryopreserved DAH for aortic valve replacement. RESULTS: A total of 144 patients (99 male) were prospectively enrolled in the ARISE Trial between October 2015 and October 2018 with a median age of 30.4 years [interquartile range (IQR) 15.9-55.1]; 45% had undergone previous cardiac operations, with 19% having 2 or more previous procedures. The mean implanted DAH diameter was 22.6 mm (standard deviation 2.4). The median operation duration was 312 min (IQR 234-417), the median cardiopulmonary bypass time was 154 min (IQR 118-212) and the median cross-clamp time 121 min (IQR 93-150). No postoperative bypass grafting or renal replacement therapy were required. Two early deaths occurred, 1 due to a LCA thrombus on day 3 and 1 due ventricular arrhythmia 5 h postoperation. There were 3 late deaths, 1 death due to endocarditis 4 months postoperatively and 2 unrelated deaths after 5 and 7 years due to cancer and Morbus Wegener resulting in a total mortality of 3.47%. After a median follow-up of 5.9 years [IQR 5.1-6.4, mean 5.5 years. (standard deviation 1.3) max. 7.6 years], the primary efficacy end-points peak gradient with median 11.0 mmHg (IQR 7.8-17.6) and regurgitation of median 0.5 (IQR 0-0.5) of grade 0-3 were excellent. At 5 years, freedom from death/reoperation/endocarditis/bleeding/thromboembolism were 97.9%/93.5%/96.4%/99.2%/99.3%, respectively. CONCLUSIONS: The 5-year results of the prospective multicentre ARISE trial continue to show DAH to be safe for aortic valve replacement with excellent haemodynamics.

Public controversy and citizens' attitude formation about animal research: A case for scholarship and recommendations on conflicts at the science-society interface.

Activist groups attack animal research and put scientists and their institutions under pressure, whereas scientists often remain silent. We report an interdisciplinary research project driven by a communication science perspective on how citizens respond to news reports about animal research (3 experiments, overall N = 765) and a German science-initiated information platform ("Tierversuche verstehen"; controlled user study, N = 100). Findings demonstrate that a critical journalist perspective within neutral, two-sided news reports (e.g., skeptical expert statements or images of suffering animals) does not affect citizen opinion strongly. Information media provided by scientific institutions seem to be welcomed even by citizens who hold critical prior attitudes. From these results, we develop a set of recommendations for future public communication of animal research that builds on best practices in organizational and crisis communication. These suggestions are intended to empower animal researchers to actively participate in public debate to support citizens' informed attitude formation.

Mechano-chemo-biological model of atherosclerosis formation based on the outside-in theory.

Atherosclerosis is a disease in blood vessels that often results in plaque formation and lumen narrowing. It is an inflammatory response of the tissue caused by disruptions in the vessel wall nourishment. Blood vessels are nourished by nutrients originating from the blood of the lumen. In medium-sized and larger vessels, nutrients are additionally provided from outside through a network of capillaries called vasa vasorum. It has recently been hypothesized (Haverich in Circulation 135:205-207, 2017) that the root of atherosclerotic diseases is the malfunction of the vasa vasorum. This, so-called outside-in theory, is supported by a recently developed numerical model (Soleimani et al. in Arch Comput Methods Eng 28:4263-4282, 2021) accounting for the inflammation initiation in the adventitial layer of the blood vessel. Building on the previous findings, this work proposes an extended material model for atherosclerosis formation that is based on the outside-in theory. Beside the description of growth kinematics and nutrient diffusion, the roles of monocytes, macrophages, foam cells, smooth muscle cells and collagen are accounted for in a nonlinear continuum mechanics framework. Cells are activated due to a lack of vessel wall nourishment and proliferate, migrate, differentiate and synthesize collagen, leading to the formation of a plaque. Numerical studies show that the onset of atherosclerosis can qualitatively be reproduced and back the new theory.

Acute Aortic Dissection Type A in Younger Patients (< 60 Years Old) - Does Full Arch Replacement Provide Benefits Compared to Limited Approach?

ABSTRACT Introduction: Acute aortic dissection Stanford type A (AADA) is a surgical emergency associated with high morbidity and mortality. Although surgical management has improved, the optimal therapy is a matter of debate. Different surgical strategies have been proposed for patients under 60 years old. This paper evaluates the postoperative outcome and the need for secondary aortic operation after a limited surgical approach (proximal arch replacement) vs. extended arch repair. Methods: Between January 2000 and January 2018, 530 patients received surgical treatment for AADA at our hospital; 182 were under 60 years old and were enrolled in this study - Group A (n=68), limited arch repair (proximal arch replacement), and group B (n=114), extended arch repair (> proximal arch replacement). Results: More pericardial tamponade (P=0.005) and preoperative mechanical resuscitation (P=0.014) were seen in Group A. More need for renal replacement therapy (P=0.047) was seen in the full arch group. Mechanical ventilation time (P=0.022) and intensive care unit stay (P<0.001) were shorter in the limited repair group. Thirty-day mortality was comparable (P=0.117). New onset of postoperative stroke was comparable (Group A four patients [5.9%] vs. Group B 15 patients [13.2%]; P=0.120). Long-term follow-up did not differ significantly for secondary aortic surgery. Conclusion: Even though young patients received only limited arch repair, the outcome was comparable. Full-arch replacement was not beneficial in the long-time follow-up. A limited approach is justified in the cohort of young AADA patients. Exemptions, like known Marfan syndrome and the presence of an intimal tear in the arch, should be considered.

Asistencia ventricular intracorpórea en falla cardiaca terminal / Left ventricular assistant devices for end-stage heart failure: report of two cases

In the last 2 decades, there have been significant advances in medical treatment of heart failure. However, there is a group of patients who are refractory to the available medical therapy and progress inevitably to a state of end-stage heart failure, whose only therapeutic alternative is cardiac transplantation. But this is an option limited by the scarce availability of donors. Therefore many patients die waiting for an organ. Recently, extra or intracorporeal left ventricular devices have emerged as a viable alternative for patients with end-stage heart failure waiting for a heart transplant. These devices discharge the left ventricle, increasing cardiac output and improving systemic perfusion. This year, in our hospital we began a left ventricular device implantation program for the most severely ill patients on the waiting list for cardiac transplantation. We report two males aged 30 and 53 years, in whom a left ventricular device was successfully implanted, using a minimally invasive surgical technique developed at the University of Hannover in Germany.