The growth of xenotransplanted hearts can be reduced with growth hormone receptor knockout pig donors.

Abstract: Objective Genetically engineered (GE) pigs are thought to be an alternative organ source for patients in end-stage heart failure unable to receive a timely allograft. However, cardiac xenografts exhibit growth and diastolic heart failure within one month after transplantation. Grafts function for up to 6 months, but only after administration of temsirolimus and afterload reducing agents to reduce this growth. Here we investigate the growth and hemodynamics of growth hormone receptor (GHR) knockout xenografts, without the use of adjuncts to prevent intrinsic graft growth after transplantation. Methods GE pig hearts were transplanted orthotopically into weight-matched baboons between 15-30kg, utilizing continuous perfusion preservation prior to implantation (n=5). Xenografts included knockout of carbohydrate antigens and knockin of human transgenes for thromboregulation, complement regulation and inflammation reduction (grafts with intact growth hormone, n=2). Three grafts contained the additional knockout of GHR (growth hormone receptor knockout grafts, n=3). TTEs were obtained twice monthly and comprehensively analyzed by a blinded cardiologist. Hemodynamics were measured longitudinally after transplantation. Results All xenografts demonstrate life-supporting function after transplantation. There is no difference in intrinsic growth, as measured by septal and posterior wall thickness and LV mass, on TTE out to one month in either growth hormone receptor knockout or growth hormone receptor intact grafts. However, hypertrophy of both the septal and posterior wall is markedly elevated by 2 months post-transplantation. There is minimal hypertrophy out to 6 months in growth hormone receptor knockout grafts. Physiologic mismatch is present in all grafts after transplantation, which is largely independent of growth. Conclusions Xenografts with growth hormone receptor knockout demonstrate reduced post-transplantation xenograft growth by echocardiography greater than 6 months after transplantation, without the need for other adjuncts.