Sirolimus and Mimetics: Modulator Sine Qua Non for Cardiac Xenotransplantation?

The last decade has seen Promethean advances in cardiac xenotransplantation, led by genetic editing of porcine xenografts, such that they lack the most immunogenic antigens. Nonetheless, cardiac xenotransplants have reached an apparently insuperable survival limit of around 50 days. Immunity is not only provoked by alien antigens but equally by the absence of self-antigens. This is the frequently overlooked "missing self" rejection. It is amenable to inhibition by sirolimus and other mammalian target of rapamycin (mTOR) signaling suppressors. In this hypothesis, it is posited the next step in cardiac xenograft longevity requires overcoming missing self-rejection by exploitation of mTOR pathways. Further, it is suggested that sirolimus and analogs have other benefits, which strongly militate in favor of their use. Hypertrophy is a commonly reported feature of porcine-human xenotransplantation. mTOR inhibition has been shown to temper cardiac remodeling involved in the development of cardiac hypertrophy and specifically prevent this mode of cardiac failure in porcine-baboon cardiac xenotransplantation models. Secondly there is a longevity mismatch. Typical human lifespan is 5-10 times that of porcine longevity. Hence porcine xenografts age more rapidly. It cannot be overlooked that pigs are essentially the result of 10 500 years of artificial selection for precocious maturation and maximum accumulation of muscle and fat. Significantly, suppression of mTOR signaling has been identified as a key pathway in senolysis, healthy aging and increased longevity; thus potentially addressing this human-porcine mismatch. It is suggested here that pleiotropic functions of sirolimus and mimetics render these agents sine qua non for successful longevous xenotransplantation.