Abstract

Xenotransplantation is thought to have the potential to solve the critical shortage of donor’s hearts with the development of genetically modified organ-source pigs and improvement of immunosuppressive strategies. As an appropriate preclinical animal model, the pig-to-baboon cardiac xenotransplantation model has been widely adopted. Traditionally, the evaluation of cardiac xenograft function in a pig-to-baboon model has been accomplished by means of palpation, ultrasound and biopsy. However, those methods pose increased risk of complications such as bleeding, infection, and apnea, leading to increased morbidity and mortality. Telemetric monitoring systems have been widely applied in the life science research involving a wide variety of animal models. These systems enable non-invasive, reliable and continuous measurements of cardiac xenograft function and provide information valuable for the improved understanding of transplantation pathophysiology. Importantly, these systems do not only avoid repeated anesthesia of the animals but also allow measurements independent from the effects of anesthetics. In preclinical pig-to-baboon xenotransplantations, telemetry systems have only been used in the heterotopic abdominal experiments. The aim of this study was the evaluation of a telemetry system for the monitoring of cardiac xenograft function after heterotopic thoracic cardiac xenotransplantation. Seven baboons underwent heterotopic thoracic cardiac xenotransplantation, for which double or triple transgenic pigs were used as donors. Hemodynamic parameters such as left ventricular peak systolic pressure (LVPSP), left ventricular end diastolic pressure (LVEDP), heart rate (HR), maximal rate of rise or decline of left ventricular pressure (±dP/dtmax), deviation of S-T segment, and the duration and amplitude of QRS complex in electrocardiogram (QRSA) were continuously monitored, using a telemetry system (DSI, St. Paul, MN, USA). Postoperatively, the serum levels of anti-pig antibodies (APA) were analyzed using a hemolytic assay with pig erythrocytes and the serum level of troponin was determined by the clinical laboratory on a daily basis. Based on the changes of troponin levels and APA levels, the baboons were grouped into elevated and unelevated. All parameters were compared between groups and between days. During the last two days of their survival, LVPSP, HR, +dP/dtmax, -dP/dtmax and QRSA were significantly lower in the baboons with elevated troponin compared to the group with unelevated troponin. Regarding specifically the group of baboons with elevation of troponin, the following observation was made: LVPSP, HR, -dP/dtmax, and QRSA decreased significantly on the day elevation of troponin was observed and the next day. In addition, The decrease of the parameter +dP/dtmax was significant one day after troponin increased. In contrast, the analysis of the group of baboons with elevated anti-pig antibodies revealed no significant changes in hemodynamic or electrocardiographic parameters before and after the rise of antibodies. In conclusion, this study demonstrates the ability of the telemetry system to assess changes in xenograft function in the heterotopic thoracic pig-to-baboon cardiac xenotransplant model. In particular, the parameters LVPSP, HR, ±dP/dtmax and QRSA are perceived to be reliable indicators of myocardial damage associated with graft rejection at an early stage following cardiac xenotransplantation. The use of the telemetry system might help to guide immunosuppressive therapy and further improve graft survival in future experiments.