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Abstract
Background:
The shortage of human hearts for allotransplantation makes xenotransplantation a possible option for controllable organ providers. To detect acute xenograft rejection, invasive biopsy seems inevitable; however, this occasionally results in poor incision wound healing or infection. To date, no method of noninvasive imaging for early detection of xenograft rejection has been established. We hypothesized that ultrasound speckle tracking would better detect xenograft failure than routine left ventricular ejection fractions (EF).
Methods:
From August 2013 to July 2015, a total of six cardiac heterotopic xenotransplants ( 1, 3-galactosyltransferase gene-knockout porcine heart) into cynomolgus monkeys were monitored with echocardiography every 3 to 7 days. M-mode and two-dimensional (2D)-EF measurements and myocardial strain analyses were performed. Cardiac xenograft pathology was reviewed from the immediate postoperative biopsy, as well as the necropsy.
Results:
Myocardial speckle tracking analysis was feasible in all six cases. The longest survival was 43 days. Only one pathology-proven immunologic rejection occurred. Cardiac xenograft failure appeared as two types: a dilated pattern with decreased EF or a myocardial-thickening pattern with preserved EF. Both antibody-mediated rejection (n=1) and sepsis-induced myocardial dysfunction (n=2) revealed decreased radial or circumferential strains, but normal-range EF. Xenograft functional decline was significant with respect to radial or circumferential strain (P=0.028), but not to conventional M-mode or 2D-EFs (P=0.600, P=0.340, respectively).
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Fig. 1.
A donor heart (41.6 g) from a transgenic pig ( 1,3-galactosyltransferase gene-knockout, blood type A, 4-week-old, 6.7 kg) was transplanted into a cynomolgus monkey (blood type A, 5.5-year-old, 6.7 kg). Case number 3, pictured here, survived 43 days. (A, B) Hematoxylin and eosin staining of donor left ventricular walls at necropsy shows severe congestion, hemorrhages, myocyte necrosis, conspicuous endothelial cell changes, intravascular mononuclear cells (×400). No cellular rejection is present (International Society of Heart and Lung Transplantation [ISHLT] acute cellular rejection grade 0R). (C) Immunoglobulin G (IgG) staining of the donor left ventricular myocardium shows a positive stain in the necrotic area (×400). (D) Diffuse, multifocal capillary C4d staining with strong intensity of the corresponding specimen confirmed antibody-mediated rejection (ISHLT antibody mediated rejection) (×400).
Fig. 2.
A donor heart (37.5 g) from a transgenic pig ( 1,3-galactosyltransferase gene-knockout, blood type A, 6.4 kg) expressing human complement regulatory protein CD46 was transplanted into a cynomolgus monkey (blood type A, 5.3 kg). Case number 4, pictured here, survived 38 days. An M-mode tracing echocardiogram of the mid-level of the left ventricular (LV) short axis view compared with (A) immediate postoperative and (B) just before expiry. Two-dimensional echocardiograms of the mid-level LV short axis view at the end-systolic phase, (C) different from at the immediate postoperative, (D) just before expiry note the markedly thickened LV walls with a very small LV cavity. (E) Radial strain of the corresponding short-axis view measures 5.408% at immediate postoperative (F) decreasing to 0.050% just before expiry. (G) Hematoxylin and eosin staining of the cardiac xenograft LV walls immediately postoperative from an open biopsy shows a relatively normal myocardium (×400). (H) At autopsy (postoperative day 38), multifocal bacterial colonies with microabscesses (arrows) confirmed the sepsis-involved myocardium (×100).
Fig. 3.
In a total of six cases, changes of echocardiographic parameters of the left ventricular (LV) dimension or function between immediate postoperative (postoperative day [POD] 0) and just before expiry (POD X) are compared using a Wilcoxon signed-rank test. Radial and circumferential strain show significant changes (P=0.028). Blue lines with round points represent LV eccentric dilatation; red dots with triangular points represents LV concentric thickening. (A) LV end-diastolic cavity dimension (EDD), (B) LV end-systolic cavity dimension (ESD), (C) interventricular septum (IVS), (D) LV posterior wall dimension (PWD), (E) M-mode LV ejection fraction by Teichholz's method (M-mode EF), (F) two-dimensional LV ejection fraction by Simpson's method (2D-EF), (G) radial strain, and (H) circumferential strain.
Table 1.
Six cases of xenotransplantationl recipient survival and cardiac xenograft functional parameters
Abbreviations: LV, left ventricular; EDD, LV end-diastolic cavity dimension; ESD, LV end-systolic cavity dimension; Wall, LV wall thickness; M-EF, M-mode LV ejection fractionby Teichholz's method; ZD-EF, two-dimensional LV ejection fraction by Simpson's method; RS, peak systolic radial strain; CS, peak systolic Circumferential strain; ISHLT, InternationalSociety of Heart and Lung Transplantation; AMR, antibody mediated rejection.
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