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Xenografts Show Signs of Concentric Hypertrophy and Dynamic Left Ventricular Outflow Tract Obstruction after Orthotopic Pig-to-baboon Heart Transplantation

Längin, Matthias ; Buttgereit, Ines ; Reichart, Bruno ; Panelli, Alessandro ; Radan, Julia ; Mokelke, Maren ; Bender, Martin ; Michel, Sebastian ; Ellgass, Reinhard and Ying, Jiawei , et al. (2023) In Transplantation 107(12). p.328-338
Abstract

Background. Orthotopic cardiac xenotransplantation has seen substantial advancement in the last years and the initiation of a clinical pilot study is close. However, donor organ overgrowth has been a major hurdle for preclinical experiments, resulting in loss of function and the decease of the recipient. A better understanding of the pathogenesis of organ overgrowth after xenotransplantation is necessary before clinical application. Methods. Hearts from genetically modified (GGTA1-KO, hCD46/hTBM transgenic) juvenile pigs were orthotopically transplanted into male baboons. Group I (control, n = 3) received immunosuppression based on costimulation blockade, group II (growth inhibition, n = 9) was additionally treated with mechanistic... (More)

Background. Orthotopic cardiac xenotransplantation has seen substantial advancement in the last years and the initiation of a clinical pilot study is close. However, donor organ overgrowth has been a major hurdle for preclinical experiments, resulting in loss of function and the decease of the recipient. A better understanding of the pathogenesis of organ overgrowth after xenotransplantation is necessary before clinical application. Methods. Hearts from genetically modified (GGTA1-KO, hCD46/hTBM transgenic) juvenile pigs were orthotopically transplanted into male baboons. Group I (control, n = 3) received immunosuppression based on costimulation blockade, group II (growth inhibition, n = 9) was additionally treated with mechanistic target of rapamycin inhibitor, antihypertensive medication, and fast corticoid tapering. Thyroid hormones and insulin-like growth factor 1 were measured before transplantation and before euthanasia, left ventricular (LV) growth was assessed by echocardiography, and hemodynamic data were recorded via a wireless implant. Results. Insulin-like growth factor 1 was higher in baboons than in donor piglets but dropped to porcine levels at the end of the experiments in group I. LV mass increase was 10-fold faster in group I than in group II. This increase was caused by nonphysiological LV wall enlargement. Additionally, pressure gradients between LV and the ascending aorta developed, and signs of dynamic left ventricular outflow tract (LVOT) obstruction appeared. Conclusions. After orthotopic xenotransplantation in baboon recipients, untreated porcine hearts showed rapidly progressing concentric hypertrophy with dynamic LVOT obstruction, mimicking hypertrophic obstructive cardiomyopathy in humans. Antihypertensive and antiproliferative drugs reduced growth rate and inhibited LVOT obstruction, thereby preventing loss of function.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Transplantation
volume
107
issue
12
pages
328 - 338
publisher
Lippincott Williams & Wilkins
external identifiers
  • pmid:37643028
  • scopus:85178494626
ISSN
0041-1337
DOI
10.1097/TP.0000000000004765
language
English
LU publication?
yes
additional info
Funding Information: Financial support was provided by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) TRR 127. Publisher Copyright: © 2023 Lippincott Williams and Wilkins. All rights reserved.
id
42aca4c8-3127-4d81-ab79-1bdc0a8b8544
date added to LUP
2023-12-21 09:57:24
date last changed
2024-04-05 17:07:39
@article{42aca4c8-3127-4d81-ab79-1bdc0a8b8544,
  abstract     = {{<p>Background. Orthotopic cardiac xenotransplantation has seen substantial advancement in the last years and the initiation of a clinical pilot study is close. However, donor organ overgrowth has been a major hurdle for preclinical experiments, resulting in loss of function and the decease of the recipient. A better understanding of the pathogenesis of organ overgrowth after xenotransplantation is necessary before clinical application. Methods. Hearts from genetically modified (GGTA1-KO, hCD46/hTBM transgenic) juvenile pigs were orthotopically transplanted into male baboons. Group I (control, n = 3) received immunosuppression based on costimulation blockade, group II (growth inhibition, n = 9) was additionally treated with mechanistic target of rapamycin inhibitor, antihypertensive medication, and fast corticoid tapering. Thyroid hormones and insulin-like growth factor 1 were measured before transplantation and before euthanasia, left ventricular (LV) growth was assessed by echocardiography, and hemodynamic data were recorded via a wireless implant. Results. Insulin-like growth factor 1 was higher in baboons than in donor piglets but dropped to porcine levels at the end of the experiments in group I. LV mass increase was 10-fold faster in group I than in group II. This increase was caused by nonphysiological LV wall enlargement. Additionally, pressure gradients between LV and the ascending aorta developed, and signs of dynamic left ventricular outflow tract (LVOT) obstruction appeared. Conclusions. After orthotopic xenotransplantation in baboon recipients, untreated porcine hearts showed rapidly progressing concentric hypertrophy with dynamic LVOT obstruction, mimicking hypertrophic obstructive cardiomyopathy in humans. Antihypertensive and antiproliferative drugs reduced growth rate and inhibited LVOT obstruction, thereby preventing loss of function.</p>}},
  author       = {{Längin, Matthias and Buttgereit, Ines and Reichart, Bruno and Panelli, Alessandro and Radan, Julia and Mokelke, Maren and Bender, Martin and Michel, Sebastian and Ellgass, Reinhard and Ying, Jiawei and Fresch, Ann Kathrin and Mayr, Tanja and Steen, Stig and Paskevicius, Audrius and Egerer, Stefanie and Bähr, Andrea and Kessler, Barbara and Klymiuk, Nikolai and Binder, Uli and Skerra, Arne and Ledderose, Stephan and Müller, Susanna and Walz, Christoph and Hagl, Christian and Wolf, Eckhard and Ayares, David and Brenner, Paolo and Neumann, Elisabeth and Abicht, Jan Michael}},
  issn         = {{0041-1337}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{12}},
  pages        = {{328--338}},
  publisher    = {{Lippincott Williams & Wilkins}},
  series       = {{Transplantation}},
  title        = {{Xenografts Show Signs of Concentric Hypertrophy and Dynamic Left Ventricular Outflow Tract Obstruction after Orthotopic Pig-to-baboon Heart Transplantation}},
  url          = {{http://dx.doi.org/10.1097/TP.0000000000004765}},
  doi          = {{10.1097/TP.0000000000004765}},
  volume       = {{107}},
  year         = {{2023}},
}