The heterotopic heart transplantation in mice as a small animal model to study mechanical unloading – Establishment of the procedure, perioperative management and postoperative scoring

Abstract

Background Unloading of failing hearts by left ventricular assist devices induces an extensive cardiac remodeling which may lead to a reversal of the initial phenotype–or to its deterioration. The mechanisms underlying these processes are unclear. Hypothesis Heterotopic heart transplantion (hHTX) is an accepted model for the study of mechanical unloading in rodents. The wide variety of genetically modified strains in mice provides an unique opportunity to examine remodeling pathways. However, the procedure is technically demanding and has not been extensively used in this area. To support investigators adopting this method, we present our experience establishing the abdominal hHTX in mice and describe refinements to the technique. Methods In this model, the transplanted heart is vascularised but implanted in series, and therefore does not contribute to systemic circulation and results in a complete mechanical unloading of the donor heart. Training followed a systematic program using a combination of literature, video tutorials, cadaveric training, direct observation and training in live animals. Results Successful transplantation was defined as a recipient surviving > 24 hours with a palpable, beating apex in the transplanted heart and was achieved after 20 transplants in live animals. A success rate of 90% was reached after 60 transplants. Operative time was shown to decrease in correlation with increasing number of procedures from 200 minutes to 45 minutes after 60 operations. Cold/warm ischemia time improved from 45/100 to 10/20 minutes. Key factors for success and trouble shootings were identified. Conclusion Abdominal hHTX in the mouse may enable future examination of specific pathways in unloading induced myocardial remodeling. Establishment of the technique, however, is challenging. Structured training programs utilising a variety of training methods can help to expedite the process. Postoperative management, including daily scoring increases animal wellbeing and helps to predict survival.

Gene Therapy for Cardiac Transplantation

“…Heterotopic heart transplantation (HHT) is when the transplanted heart is placed in an ectopic position inside of the recipient without the removal of the recipient's native heart. Intra-abdominal HHT is primarily used to investigate transplantation biology and is also suitable for studying unloading induced changes in the heart [47]. The heart of a donor animal is explanted and subsequently transplanted into the abdomen of a recipient animal.…”

Animal Models in Allogenic Solid Organ Transplantation

“…In order to achieve the desired and reproducible results in small animal solid organ transplantation models, there is the necessity of training. A certain number of operations and a timeframe of at least a couple of months or sometimes even years can be necessary, which might hinder the wider use of these techniques [39][40][41][42][43][44][45].…”

“…During this procedure, the heart of the donor animal is explanted and transplanted heterotopically into the abdomen of the recipient animal with the donor's ascending aorta anastomosed to the recipients infrarenal aorta, and the donor's pulmonary artery anastomosed to the recipient's inferior vena cava [41,[65][66][67]. This recipient surgical procedure can also be performed using cervical vessels.…”

Biomarkers from subcutaneous engineered tissues predict acute rejection of organ allografts

“…In this work, we investigated the potential of analyzing gene expression from the implanted scaffolds to predict allograft rejection. Scaffolds were implanted subcutaneously in murine skin transplant (STx) and heterotopic HTx recipients ( 30 , 31 ). We performed initial studies in mice deficient in mature T cells and induced ACAR by adoptive T cell transfer, which enabled a focus on alloimmune injury responses and reduced immune modifications from ischemia-reperfusion injury (IRI) and wound healing dynamics.…”