Translational Insights Into Myocardial Deformation and Fibrosis in Hypertrophic Cardiomyopathy Using Diffusion Tensor MRI

Figures

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  Central Illustration. Fractional Anisotropy as a Marker for Myocardial Remodeling Schematic overview of the study design, methodology, and key findings in human hypertrophic cardiomyopathy (HCM) patients and Mybpc3 knock-in (KI) mice. Human participants underwent in vivo cardiac MRI with late gadolinium enhancement (LGE) and diffusion tensor imaging (cDTI), while mice were studied using ex vivo cDTI, histology and scanning electron microscopy. Results showed reduced fractional anisotropy (FA) in both cohorts, despite preserved ejection fraction (EF) in patients, and low EF in mice. FA correlated with strain in humans and with interstitial fibrosis in mice, while helix angle transmurality (HAT) was increased in HCM mice. Collectively, the findings demonstrate that FA is a sensitive surrogate of myocardial deformation and fibrosis, reflecting microstructural disorganization in HCM beyond conventional MRI parameters. MRI = magnetic resonance imaging; Mybpc3 = myosin binding protein C3; WT = wild-type.

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  Figure 1. Cardiac Chamber Quantifications in the Human Cohort (A) Bull's eye plots show an increase in segmental wall thickness in HCM patients compared to healthy individuals. HCM patients showed significantly (B) increased LV maximal wall thickness, whereas (C) left ventricular ejection fraction remains unchanged. (D) Comparison of global circumferential strain, longitudinal strain, and radial strain showing no significant differences in strain values across groups, whereas (E) left atrial emptying fraction is reduced in HCM patients compared to controls. HCM = hypertrophic cardiomyopathy.

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  Figure 2. cDTI Analysis Reveals Low Fractional Anisotropy in Hypertrophic Cardiomyopathy Patients (A) Representative mean diffusivity (MD), fractional anisotropy (FA) and helix angle (HA) maps of a male control and male HCM subject. (B) cDTI shows lower FA in HCM patients but no significant difference in MD or HAT vs healthy controls. Abbreviations as in Figure 1.

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  Figure 3. Significant Correlation Between Fractional Anisotropy and Strain in Hypertrophic Cardiomyopathy Patients Scatter plots showing the relationships between fractional anisotropy (FA) and global circumferential strain (A), longitudinal strain (B), and radial strain (C) for HCM patients (n = 10) demonstrated significant correlations. In contrast, no significant correlations were observed between Helix angle transmurality (HAT) or mean diffusivity (MD) and any strain parameters. Linear regression lines with shaded CIs are shown, with corresponding R2 and P values indicating the strength and significance of the associations.

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  Figure 4. Fractional Anisotropy Is Significantly Decreased in Hypertrophic Cardiomyopathy Late Gadolinium Enhancement Positive Patients (A) Representative images of an LGE-male subject (left) and an LGE + male subject (right) with arrows highlighting myocardial focal fibrosis in the HCM heart. (B) Distribution of LGE-negative (LGE−) and LGE-positive (LGE+) patients by sex. (C) Comparison of FA (mean ± SEM) between LGE+ and LGE− groups. LGE = late gadolinium enhancement; other abbreviation as in Figure 1.

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  Figure 5. Hypertrophic Cardiomyopathy-Knock-in Mice Exhibit Severe Cardiac Systolic and Diastolic Dysfunction KI mice exhibit (A) a uniform increase in segmental wall thickness, with more pronounced thickening in the lateral segments, (B) significantly increased left ventricular wall thickness, and (C) reduced left ventricular ejection fraction. (D) Strain analysis reveals significant reductions in strain. (E) Left atrial emptying fraction is significantly decreased in KI mice. KI = knock-in; WT = wild-type.

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  Figure 6. Knock-in Mice Exhibit Lower Fractional Anisotropy and Higher Helix Angle Transmurality (A) Representative maps of mean diffusivity (MD), fractional anisotropy (FA), and helix angle (HA) in female wild-type (WT) and knocked-in (KI) mice and (B) boxplots confirming reduced FA and elevated helix angle transmurality (HAT) in KI mice compared to control.

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  Figure 7. Hypertrophic Cardiomyopathy Mice Show No Significant cDTI and Strain Correlation Scatter plots showing the relationships between mean diffusivity (MD), fractional anisotropy (FA), Helix angle transmurality (HAT) and (A) global circumferential strain, (B) longitudinal strain, and (C) radial strain for HCM mice (n = 6) showing no significant correlations. Linear regression lines with shaded CIs are shown, with corresponding rho and P values indicating the strength and significance of the associations.

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  Figure 8. Fractional Anisotropy Correlates With Interstitial Fibrosis in Mice (A-i) Scanning electron microscopy reveals regional myocyte disarray in KI mice compared to WT controls (Color-coded arrows: yellow = Z-disc, magenta = mitochondria, blue = intercalated disc), (A-ii) with quantification of Z-disc offset not showing a significant increase in KI. (B i-iii) No significant correlations have been found between cDTI parameters and Z-disc offset. (C i-ii) Picrosirius red staining of mid-sections of mouse hearts demonstrate increased collagen deposition (black arrows) in KI compared to WT. (D i-iii) Correlation analysis between cDTI parameters and collagen area fraction reveals strong negative correlation with fractional anisotropy (FA). cDTI = cardiac diffusion tensor imaging; HAT = Helix angle transmurality; MD = mean diffusivity; other abbreviations a sin Figure 5.