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Integrated Analysis of Cardiac Genetic and Structural Alterations in Left Ventricular Hypertrophy using the Supertoroidal Model
Choukri Mekkaoui1, Howard H Chen1, Iris Y Chen1, Ronglih Liao2, William J Kostis3, Timothy G Reese1, Marcel P Jackowski4, and David E Sosnovik1

1Harvard Medical School - Massachusetts General Hospital, Boston, MA, United States, 2Brigham and Woman’s Hospital, Harvard Medical School, Boston, MA, United States, 3Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, United States, 4University of São Paulo, São Paulo, Brazil

Synopsis

Response to disease occurs over many scales ranging from individual gene expression to whole organ physiology. We employed the supertoroidal model of the diffusion tensor to study the interaction between gene expression and microstructure of the heart. Left ventricular hypertrophy (LVH) was induced in C57Bl6 mice through aortic banding, and characterization of the cardiac microstructure was performed in vivo with DTI. The supertoroidal model was constrained by both diffusion information and gene expression data related to cardiomyocyte hypertrophy and myofiber orientation. Our model enabled further characterization of LVH by unifying information at different scales and across domains.

Purpose

Response to disease occurs over many scales ranging from individual gene expression to whole organ physiology. Changes in the genome, transcriptome, proteome, metabolome, and ultimate structure of the heart have been described in a broad range of diseases.1,2 While of interest in isolation, an approach that integrates cardiac genetic and structural data would enable study of the interaction between these disparate domains in a variety of cardiac pathophysiology (Figure 1). Here, our unified analysis employs the multidimensional property of the supertoroidal model of the diffusion tensor3 to study the interaction between gene expression and microstructure of the heart.

Methods

Left ventricular hypertrophy (LVH) was induced in C57Bl6 mice through banding of the transverse thoracic aorta for 4 weeks. In vivo diffusion tensor MRI (DTI) was performed in these aortic-banded mice (n=6) and in healthy, age-matched controls (n=6), on a 9.4T scanner (Bruker) equipped with a 1500 mT/m gradient insert.4 Two averages were acquired using a velocity-compensated pulsed gradient spin echo diffusion sequence at mid-systole with resolution of 156 µm3, b-value of 0 and 580 s/mm2, and 24 diffusion-encoding directions. Physiologic parameters were maintained to ensure normal left ventricular loading conditions. The supertoroidal model encodes the diffusion eigensystem described by the local dyadic diffusion tensor.5 Gene expression analysis of 31,556 genes was performed with the Affymetrix mouse array in the same aortic-banded mice and controls. Upregulated genes were classified based on their ability to influence cardiomyocyte hypertrophy or myofiber orientation, and were used to parameterize the shape (η1 and η2) of the supertoroid, respectively (Figure 2). An index of diffusivity derived from the toroidal model, the toroidal volume (TV),5 was then quantified with and without the genomic information.

Results

Supertoroids computed from the mice with LVH are more closely packed and have less sphericity (Figure 3). A rightward (positive) shift in the orientation of the supertoroids in the free wall of the LV was seen in the banded mice, and was also present in the tractograms. Aortic banding was associated with differential expression of 890 genes and a greater than 3-fold upregulation of 48 genes. Upregulated genes encoding for cardiomyocyte hypertrophy included myosin heavy chain 7 (MYH7). This was increased by 5-fold and was used to constrain η1 proportionally, further decreasing the sphericity of the supertoroids (Figure 4). Over 10 genes with the potential to influence the extracellular matrix and myofiber orientation were upregulated, including tissue inhibitor of metalloproteinase 1 (TIMP1), which was used to constrain η2, leading to a more ellipsoidal geometry. Constraining the supertoroids by both η1 and η2 markedly altered the shape of supertoroids, producing a composite representation of changes in gene expression and diffusivity. TV provided a quantitative measure of disease impact. Compared to normal myocardium,TV was reduced in LVH and showed significant further reductions when constrained by MYH7 and TIMP1.

Discussion and Conclusion

Using an aortic-banded mouse model, we have shown how the interaction of multiple genetic factors influences the myofiber architecture. The supertoroidal model provides a basis for the integration of data from diverse domains, such as gene expression and tissue microstructure derived from DTI. This work is our first effort toward a multi-domain framework for the characterization and quantification of a disease process, in this case left ventricular hypertrophy. The supertoroidal model provides a mathematical relationship that captures the interaction between information at different scales and across domains, which can be evaluated both spatially and statistically, providing additional insight into the underlying pathology.

Acknowledgements

No acknowledgement found.

References

1. Mekkaoui C, Huang S, Chen HH, Dai G, et al. Fiber architecture in remodeled myocardium revealed with a quantitative diffusion CMR tractography framework and histological validation. J Cardiovasc Magn Reson. 2012;14:70.

2. Mekkaoui C, Reese TG, Jackowski MP, et al. Diffusion Tractography of the Entire Left Ventricle by Using Free-breathing Accelerated Simultaneous Multisection Imaging. Radiology. 2016:152613.

3. Mekkaoui C, Jackowski M, Martuzzi R, et al. Supertoroidal-based fusion of cardiac DT-MRI with molecular and physiological information. J Cardiovasc Magn Reson. 2010.

4. Sosnovik DE, Mekkaoui C, Huang S, et al. Microstructural impact of ischemia and bone marrow-derived cell therapy revealed with diffusion tensor magnetic resonance imaging tractography of the heart in vivo. Circulation. 2014;129:1731-41.

5. Mekkaoui C, Metellus P, Kostis WJ, et al. Diffusion Tensor Imaging in Patients with Glioblastoma Multiforme Using the Supertoroidal Model. PloS one. 2016;11:e0146693.


Figures

Figure 1. Multi-domain approach to disease characterization. DTI is used to interrogate the properties of the cardiac microstructure, which are depicted using the supertoroidal model. Data from diverse domains such as gene expression can be used to further constrain the model, which can be evaluated both spatially and statistically.

Figure 2. Changes in gene expression in response to aortic banding and left ventricular hypertrophy. Genes associated with cardiomyocyte hypertrophy, such as myosin heavy chain 7 (MYH7), and changes in the extracellular matrix, such as tissue inhibitor of matrix metalloproteinase 1 (TIMP1), were highly upregulated. The upregulation of MYH7 and TIMP1 were used to constrain the shape parameters η1 and η2 of the supertoroid, respectively, enabling a composite representation of gene expression and myocardial microstructure derived from DTI.

Figure 3. In vivo DTI of the cardiac microstructure in a normal mouse and an aortic-banded mouse. The supertoroidal glyphs are color-coded and oriented by myofiber helix angle (HA). A magnified view of the glyphs in the subepicardium of the lateral wall of the LV is shown in the inset. The glyphs in the hypertrophied heart are more densely packed and elongated than those in the normal heart. In addition, the myofibers in the free wall of the aortic-banded heart have undergone a rightward shift. This is also evident in tractography of the LV free wall of the aortic-banded hearts.

Figure 4. Constraint of the supertoroidal shape by degree of gene expression. Constraint of η1 by MYH7 overexpression causes the glyphs to develop edges while constraint of η2 by the degree of TIMP1 overexpression causes the glyphs to become more ellipsoidal. Constraint by both MYH7 and TIMP1 (η1 and η2) causes a proportionally blended shape change in the supertoroids. This integrated multi-domain representation can be quantified by the toroidal volume (TV). The reduction in diffusivity represented by TV indicates that the myocardial structure is significantly perturbed in LVH.

Proc. Intl. Soc. Mag. Reson. Med. 25 (2017)
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