Diffusion tensor imaging reveals myocardial architectural differences between porcine and primate hearts with potential implications for cardiac xenotransplantation

Abstract

Although pig-to-baboon cardiac xenotransplantation has become increasingly successful, challenges remain in its clinical translation, particularly in addressing xenograft overgrowth. While several causes can be managed through genetic modifications and hemodynamic control, growth persists. Research on myocardial architecture and interspecies variation is limited. This study employs diffusion tensor imaging to probe the orientation of cardiomyocytes and their aggregations and aims to investigate whether these parameters may act as intrinsic factors, contributing to xenograft overgrowth in a setting of extrinsic hemodynamic mismatch. Five pig and five baboon ex-vivo hearts were compared by cardiac diffusion tensor magnetic resonance imaging. Myocardial architecture was assessed by quantifying helical, intrusion and E3-angles in left ventricle, septum and right ventricle. Notable differences were found in E3-angles of the left ventricle. The E3 angle was closer to 0° throughout the baboon myocardium. The epicardial E3-angle differed by -9°, midwall by -17.1°, and endocardial by -23.7° The myocardial architecture observed in baboon hearts may support a greater contractional deformation, potentially reflecting an enhanced contractile potential as compared to the porcine heart. Further ex- and in-vivo investigation of both pre- and post-transplantation animals is warranted to assess the exact functional implications of these myocardial architecture differences.

Fig. 1

Myocardial zones and angle definitions. (a) A schematic representation of the myocardial segmentation zones. 1–6 correspond to the basal third, 7–12 to the equatorial third, and 13–16 to the apical third. (b) The global coordinate system of the heart. (c) The local coordinate system with 3 planes (A, B, C) and in relation to those, the definitions of the 3 angles of interest. The cylinder signifies the individual cardiomyocyte, while the box is the cardiomyocyte aggregations. α measures the helical angle, β the intrusional angle, and γ the E3-angle.

Fig. 2

Overview of methods. The flow diagram shows the methodological approach to the data analysis. (a-b) Initially, a gradient echo sequence is performed, followed by the diffusion-weighted sequence (left pig, right: baboon). (c) Then a manual segmentation and morphological analysis is performed. (d) Based on the segmentation, the diffusion tensor is calculated, along with the epicardial tangent. Based on the diffusion tensor and the epicardial tangent, the 3 angles are calculated in each voxel. (e) A schematic representation of each angle is presented alongside the short axis maps of the angles. The helical angle is the angle between the primary eigenvector and the local horizontal plane. The intrusion angle is the angle between the primary eigenvector and the local epicardial tangential plane. The E3-angle is the angle between the tertiary eigenvector and the local epicardial tangential plane.

Fig. 3

Histograms of cardiomyocyte angles. Comparison of the relative frequency of helical, intrusion, and E3-angles in the left ventricle, septum and right ventricle. Data for helical and intrusion angle are reported as medians (interquartile range), the E3-angle data are reported as circular means shown as arrowheads. *: Statistically significant as per the Mann–Whitney U test.

Fig. 4

Progression of cardiomyocyte angles through the ventricular wall. The helical, intrusion and E3-angles are displayed as a function of the myocardial level % in the left ventricle, septum and right ventricle. 0% correspond to the endocardium and 100% correspond to the epicardium. Data for helical and intrusion angle are reported as medians (interquartile range), the E3-angle data are reported as circular means (CI). *: Statistically significant as per Mann–Whitney U test.

Fig. 5

E3-maps. Representative E3-maps at the mid-equatorial level of one of the baboon (right) and pig (left) hearts. (Please note that they are not scaled 1:1).