Commentary: One more obstacle knocked out

Central MessageCardiac xenografts from genetically engineered pigs with growth hormone receptor knockout developed minimal growth and maintained function for >6 months after transplantation into recipient baboons.See Article page e69. Cardiac xenografts from genetically engineered pigs with growth hormone receptor knockout developed minimal growth and maintained function for >6 months after transplantation into recipient baboons. See Article page e69. The success of pig-to-baboon life-supporting cardiac xenotransplantation reported by Längin and colleagues1Längin M. Mayr T. Reichart B. Michel S. Buchholz S. Guethoff S. et al.Consistent success in life-supporting porcine cardiac xenotransplantation.Nature. 2018; 564: 430-433Crossref PubMed Scopus (280) Google Scholar in Nature was a notable milestone toward turning xenotransplantation into clinical reality. However, the authors observed left ventricular hypertrophy, which led to life-limiting diastolic heart failure around 1 month post-transplant. Although the cardiac overgrowth could be controlled with antihypertensive therapy and temsirolimus, it poses a significant obstacle to clinical translation. The current study, conducted by Goerlich and colleagues,2Goerlich C.E. Griffith B. Hanna P. Hong S.N. Ayares D. Singh A.K. et al.The growth of xenotransplanted hearts can be reduced with growth hormone receptor knockout pig donors.J Thorac Cardiovasc Surg. 2023; 165: e69-e81Abstract Full Text Full Text PDF Scopus (26) Google Scholar demonstrated that cardiac xenografts from genetically engineered pigs with growth hormone receptor (GHR) knockout (KO) underwent minimal growth with preserved function for more than 6 months without adjunctive therapies. Cardiac xenograft overgrowth was thought to be driven by both the intrinsic cause, a response to the growth hormone in recipients,3Iwase H. Ball S. Adams K. Eyestone W. Walters A. Cooper D.K.C. Growth hormone receptor knockout: relevance to xenotransplantation.Xenotransplantation. 2021; 28: e12652Crossref PubMed Scopus (22) Google Scholar and the extrinsic cause, an adaption to the increased afterload.4Längin M. Konrad M. Reichart B. Mayr T. Vandewiele S. Postrach J. et al.Hemodynamic evaluation of anesthetized baboons and piglets by transpulmonary thermodilution: normal values and interspecies differences with respect to xenotransplantation.Xenotransplantation. 2020; 27: e12576Crossref PubMed Scopus (19) Google Scholar One of this article's key findings showed that the intrinsic cause seemed to be the main driving force in this multifactorial mechanism. This achievement was encouraging, given that aggressive blood pressure control to overcome the physiologic mismatch may not be well tolerated in adult human recipients, and temsirolimus has not been approved for clinical use post-transplantation. Another notable finding was that the addition of multiple genetic manipulations seems to increase the longevity of xenografts. Compared with the donor pigs used by the Munich group,1Längin M. Mayr T. Reichart B. Michel S. Buchholz S. Guethoff S. et al.Consistent success in life-supporting porcine cardiac xenotransplantation.Nature. 2018; 564: 430-433Crossref PubMed Scopus (280) Google Scholar the GHR intact pigs in this study had additional KO of carbohydrate antigens and knockin of human proteins in complement regulation, thromboregulation, and anti-inflammation. Although limited by the small sample sizes in both studies, these genetic modifications delayed xenograft overgrowth and functional deterioration by almost 2 months. This observation suggests a possibility of improving xenograft's immune-compatibility by adopting a combination of genetic modifications. The importance of immune-compatibility should not be overlooked, as the current aggressive immunosuppression regime with both B-cell and T-cell suppression, co-stimulation blockade, and multiple cytokine pathway inhibitors might render human recipients very susceptible to post-transplant infection. Although the achievements deserve applause, a few questions require clarification for clinical translation. First, the underlying reasons behind the differences in the terminal physiology of the 2 groups are unexplained. Why did the GHR intact xenografts develop inflammation and space-filling defects, whereas the GHR KO ones had normal histology? Second, adult human heart to body weight ratio (range 0.45%-0.61%)5Wingren C.J. Ottosson A. Postmortem heart weight modelled using piecewise linear regression in 27,645 medicolegal autopsy cases.Forensic Sci Int. 2015; 252: 157-162Crossref PubMed Scopus (30) Google Scholar is greater than that of pigs, and average adult human weight is much greater than that of baboons. The size and maturity of donor pigs for adults, and for children whose afterload is changing with time, need to be determined. Moreover, the mechanism of nonischemic continuous preservation to prevent perioperative cardiac xenograft dysfunction remains unclear. Finally, with the ventricular assist devices increasingly being used as a bridge-to-transplantation and destination therapy6Pierson III, R.N. Burdorf L. Madsen J.C. Lewis G.D. D'Alessandro D.A. Pig-to-human heart transplantation: who goes first?.Am J Transplant. 2020; 20: 2669-2674Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar and the advent of various total artificial hearts,7Arabía F.A. The total artificial heart: where are we?.Cardiol Rev. 2020; 28: 275-282Crossref PubMed Scopus (7) Google Scholar an ethical question of xenotransplantation over mechanical support will inevitably be raised when it comes to conduct the first clinical trial of pig-to-human xenotransplantation. In conclusion, this study overcomes the obstacle of xenograft overgrowth by using genetically engineered pigs with KO of GHR and multiple genetic modification. The growth of xenotransplanted hearts can be reduced with growth hormone receptor knockout pig donorsThe Journal of Thoracic and Cardiovascular SurgeryVol. 165Issue 2PreviewGenetically engineered 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 1 month after transplantation. Grafts function for up to 6 months, but only after administration of temsirolimus and afterload-reducing agents to reduce this growth. In this study we investigated the growth and hemodynamics of growth hormone receptor (GHR) knockout xenografts, without the use of adjuncts to prevent intrinsic graft growth after transplantation. Full-Text PDF