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Case Reports
. 2022 Jul 7;387(1):35-44.
doi: 10.1056/NEJMoa2201422. Epub 2022 Jun 22.

Genetically Modified Porcine-to-Human Cardiac Xenotransplantation

Bartley P Griffith  1 , Corbin E Goerlich  1 , Avneesh K Singh  1 , Martine Rothblatt  1 , Christine L Lau  1 , Aakash Shah  1 , Marc Lorber  1 , Alison Grazioli  1 , Kapil K Saharia  1 , Susie N Hong  1 , Susan M Joseph  1 , David Ayares  1 , Muhammad M Mohiuddin  1
Affiliations
Case Reports

Genetically Modified Porcine-to-Human Cardiac Xenotransplantation

Bartley P Griffith et al. N Engl J Med. .

Abstract

A 57-year-old man with nonischemic cardiomyopathy who was dependent on venoarterial extracorporeal membrane oxygenation (ECMO) and was not a candidate for standard therapeutics, including a traditional allograft, received a heart from a genetically modified pig source animal that had 10 individual gene edits. Immunosuppression was based on CD40 blockade. The patient was weaned from ECMO, and the xenograft functioned normally without apparent rejection. Sudden diastolic thickening and failure of the xenograft occurred on day 49 after transplantation, and life support was withdrawn on day 60. On autopsy, the xenograft was found to be edematous, having nearly doubled in weight. Histologic examination revealed scattered myocyte necrosis, interstitial edema, and red-cell extravasation, without evidence of microvascular thrombosis - findings that were not consistent with typical rejection. Studies are under way to identify the mechanisms responsible for these changes. (Funded by the University of Maryland Medical Center and School of Medicine.).

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Figures

Figure 1.
Figure 1.. Chest Radiography.
Panel A is a chest radiograph obtained before transplantation, showing cardiomegaly. Panel B is a chest radiograph obtained after transplantation, showing the xenograft in situ.
Figure 2.
Figure 2.. Transthoracic Echocardiography.
Transthoracic echocardiography of the transplanted xenograft obtained on day 19 after transplantation (Panel A, parasternal short axis) showed normal xenograft function, normal global longitudinal strain, and normal left ventricular posterior wall thickness in end diastole. Transthoracic echocardiography performed on day 49 (Panel B), before cannulation for venoarterial extracorporeal membrane oxygenation (ECMO), showed preserved systolic function, less negative (i.e., more abnormal) global longitudinal strain, and increased thickness of the left ventricular posterior wall in end diastole.
Figure 3.
Figure 3.. Clinical Details and Test Results during the Postoperative Course.
Mean fluorescence intensity (MFI) values were normalized to a positive control (assigned a value of 100%). Global longitudinal strain is expressed in Panel B as the absolute value; strain is typically reported as a negative percentage. G-CSF denotes granulocyte colony-stimulating factor, IVIG intravenous immune globulin, and LVEF left ventricular ejection fraction.
Figure 4.
Figure 4.. Histologic Assessments.
The first endomyocardial biopsy (Panel A, day 34 after transplantation) showed normal histologic characteristics. The second endomyocardial biopsy (Panel B, day 50) showed interstitial red-cell extravasation, fragmentation, and edema without cellular infiltrate or intravascular thrombosis. The third endomyocardial biopsy (Panel C, day 56) showed some resolution of interstitial edema and red-cell extravasation but also showed evidence of necrotic myocytes. The septum at autopsy (Panels D and E, day 60) showed interstitial edema and red-cell extravasation, myocardial necrosis, scant fibrosis, and central nuclei.
See this image and copyright information in PMC

Comment in

References

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