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Translational Medicine in Brain Stem Death and Heart Transplantation.

T medicine is not as suitable as other branches of medicine for the conduction of large clinical trials in human patients. Therefore, animal experimentation has always played a major role in the evolution of cardiac transplantation. Dogs were first animal models used in transplantation and their use in renal, heart, liver, lung, bone marrow, pancreas, and pancreatic islet transplantation has been important for facilitating surgical training and understanding the donor–recipient immune interaction. Nevertheless, during the last years, the use of canine animal models has been limited mainly for ethical reasons. Nonhuman primates, although very similar to humans as regards to their immune system, may not represent the reference animal model because of major expense, complexity of care, and low rate of fecundity. On the other hand, the porcine model is slowly replacing other animal models since a more similar anatomy and immunology and adaptability to experimental conditions. In addition, porcine organs could potentially offer future insights in xenotransplantation. In heart transplantation (HTx), there is a specific topic of interest: the effects of brain stem death (BSD) on myocardial function and its implications for the organ management and posttransplant outcomes. In the past 20 years, BSD has been known to cause important cardiocirculatory consequences, mediated by a catecholamine release resulting in direct cardiomyocyte injury, hemodynamic changes in before and afterload, and reductions in coronary perfusion. Subsequent ventricular dysfunction is commonly seen after BSD and can cause almost 25% of potential donor organ nonacceptance. Nevertheless, recent observations show that after an accurate donor management, ventricular dysfunction can be reverted and those hearts can be transplanted without penalizing outcomes. Animal models have been central in the study of BSD effects on cardiac function and the development of assessment and treatment techniques to manage its consequences in HTx. In this well-conducted systematic review, the authors succeed in the difficult task of gathering the existing evidence on this issue. Admirably, after identifying all those studies that included complex animal models incorporating both donor BSD and HTx, See Hoe et al grouped the information according to different model characteristics, namely general animal characteristics, methodological features of BSD development, HTx methods, and outcome measures of cardiac function in donor and recipient. Nevertheless, the resulting framework is quite heterogeneous. In fact, different animal models have been included and each of these required different Htx techniques (heterotopic for rodents, orthotopic for pigs and dogs). In addition, BSD was induced in several ways, from decapitation to balloon catheter inflation, and the duration of BSD to HTx ranged from 1 to 6 hours in rodents to up to 24 hours in large animal models, which may have affected graft function differently. Finally, cardiac function was not evaluated in a significant proportion of the studies (7/21), or was evaluated in a variety of ways; from graft manual palpation to left ventricle (LV) pressure–volume relationship analysis and LV ejection fraction measured by echocardiogram or magnetic resonance. Important translational challenges need to be acknowledged, since some animal models included in the present review may not mimic perfectly the human HTx clinical setting. In fact, almost half of the studies were conducted in rodent models, which, although less expensive and more manageable than large animals, require a heterotopic transplant, an unusual indication in current clinical practice. Furthermore, length of BSD before Htx in the real-world clinical scenario is approximately 35 hours, significantly higher than that of the animal models included in the review, which could clearly impact the applicability of animal model outcomes. Most studies (21/29) did not report length or method of heart preservation, which is a capital risk factor for graft dysfunction. Even the pressure– volume relationship analysis used in most animal models is not readily available in clinical practice, where we need to rely mostly on noninvasive techniques such as echocardiographic LV ejection fraction. While animal models can be very illustrative of the acute setting and the perioperative period, resource and time limitations explain the paucity of animal studies focusing on long-term prognosis and complications. For instance, there is a lack of data from animal studies regarding coronary allograft vasculopathy Commentary