Diffusion tensor imaging and histology of developing hearts

Abstract

Diffusion tensor imaging (DTI) has emerged as a promising method for noninvasive quantification of myocardial microstructure. However, the origin and behavior of DTI measurements during myocardial normal development and remodeling remain poorly understood. In this work, conventional and bicompartmental DTI in addition to three-dimensional histological correlation were performed in a sheep model of myocardial development from third trimester to postnatal 5-months of age. Comparing the earliest time points in the third trimester to the postnatal 5-months group, the scalar transverse diffusivities preferentially increased in both left ventricle (LV) and right ventricle (RV): secondary eigenvalues D2 increased by 54% (LV) and 36% (RV), whereas tertiary eigenvalue D3 increased by 85% (LV) and 67% (RV). The longitudinal diffusivity D1 changes were small, which lead to a decrease in fractional anisotropy (FA) by 41% (LV) and 33% (RV) in 5-months vs. fetal hearts. Histological analysis suggested that myocardial development is associated with hyperplasia in the early stages of the third trimester followed by myocyte growth in the later stages up to 5-months of age (increased average myocyte width by 198%, myocyte length by 128%, and decreased nucleus density by 70% between preterm and postnatal 5 months hearts.) In few histological samples (N=6), correlations were observed between DTI longitudinal diffusivity and myocyte length (r=0.86, P<0.05), and transverse diffusivity vs. myocyte width (r=0.96, P<0.01). Linear regression analysis showed that transverse diffusivities are more affected by changes in myocyte size and nucleus density changes than longitudinal diffusivity, which is consistent with predictions of classical models of diffusion in porous media. Furthermore, primary and secondary DTI eigenvectors during development changed significantly. Collectively, the findings demonstrate a potential role for DTI to monitor and quantify myocardial development, and potentially cardiac disease.

Microarchitecture of the hearts in term and former‐preterm lambs using diffusion tensor imaging

“…The appearance of the absolute sheetlet angle maps in the LV of term lambs (Figure 4) was consistent with previous DTI studies in healthy hearts (Abdullah et al, 2016; Chen et al, 2005; Cheng et al, 2012; Ferreira et al, 2014). The absolute sheetlet angles in the LV of former‐preterm lambs appeared to be reduced, relative to the term‐born lambs, as shown in the sheetlet angle map in Figure 4.…”

“…Normal transmural heterogeneity of fractional anisotropy was seen in the LV, as reported in previous studies (Jiang et al, 2007; McGill et al, 2015); however, no regional differences were found. The fractional anisotropy values in this study are consistent with previous findings in term lambs at 5 months of age (Abdullah et al, 2016). Histologically validated DTI studies of developing prenatal and postnatal hearts have shown that fractional anisotropy changes throughout development, potentially due to changes in cell size and shape (Abdullah et al, 2016; Chen et al, 2005), although the direction in which this change occurs is unclear.…”

“…The fractional anisotropy values in this study are consistent with previous findings in term lambs at 5 months of age (Abdullah et al, 2016). Histologically validated DTI studies of developing prenatal and postnatal hearts have shown that fractional anisotropy changes throughout development, potentially due to changes in cell size and shape (Abdullah et al, 2016; Chen et al, 2005), although the direction in which this change occurs is unclear. It is likely that fractional anisotropy increases during gestation (Mekkaoui et al, 2013; Pervolaraki et al, 2013), then decreases throughout postnatal life (Abdullah et al, 2016), due to other confounding factors that influence fractional anisotropy such as cardiomyocyte shape (Abdullah et al, 2016).…”

“…To date, however, little is known of the long‐term effects of preterm birth on cardiomyocyte organization in the LV, the major pumping chamber of the heart postnatally. One previous ex vivo DTI study has found that cardiomyocyte organization changes throughout development in sheep (Abdullah et al, 2016). Given that gross cardiac structure is altered as a result of preterm birth (Aye et al, 2017; Cox et al, 2019; Kowalski et al, 2016; Lee, Kimball, Daniels, Khoury, & Meyer, 1992; Lewandowski et al, 2013; Lewandowski, Augustine, et al, 2013; Mann, Bogaev, & Buckberg, 2010), it is likely that the 3D microstructural architecture of the heart is also altered; this is addressed in the present study, where we used ex vivo DTI in fixed hearts from lambs at 5 months term‐equivalent age (TEA) (approximately equivalent to 6 years of age in children) that were born either preterm or at term.…”

“…Overall, this cardiac microstructure is essential for efficient cardiac output and stable cardiomyocyte ATP consumption (Vendelin, Bovendeerd, Engelbrecht, & Arts, 2002). Importantly, cardiomyocyte microstructure changes throughout development (Abdullah et al, 2016; Notomi et al, 2006), throughout the cardiac cycle (Ferreira et al, 2014), and is altered in diseased hearts (Abdullah et al, 2014; Ferreira et al, 2014; Gotschy et al, 2019; Winklhofer et al, 2014).…”