Diffusion Tensor Cardiovascular Magnetic Resonance in Cardiac Amyloidosis

Abstract

Background Cardiac amyloidosis (CA) is a disease of interstitial myocardial infiltration, usually by light chains or transthyretin. We used diffusion tensor cardiovascular magnetic resonance (DT-CMR) to noninvasively assess the effects of amyloid infiltration on the cardiac microstructure. Methods DT-CMR was performed at diastole and systole in 20 CA, 11 hypertrophic cardiomyopathy, and 10 control subjects with calculation of mean diffusivity, fractional anisotropy, and sheetlet orientation (secondary eigenvector angle). Results Mean diffusivity was elevated and fractional anisotropy reduced in CA compared with both controls and hypertrophic cardiomyopathy (P<0.001). In CA, mean diffusivity was correlated with extracellular volume (r=0.68, P=0.004), and fractional anisotropy was inversely correlated with circumferential strain (r=-0.65, P=0.02). In CA, diastolic secondary eigenvector angle was elevated, and secondary eigenvector angle mobility was reduced compared with controls (both P<0.001). Diastolic secondary eigenvector angle was correlated with amyloid burden measured by extracellular volume in transthyretin, but not light chain amyloidosis. Conclusions DT-CMR can characterize the microstructural effects of amyloid infiltration and is a contrast-free method to identify the location and extent of the expanded disorganized myocardium. The diffusion biomarkers mean diffusivity and fractional anisotropy effectively discriminate CA from hypertrophic cardiomyopathy. DT-CMR demonstrated that failure of sheetlet relaxation in diastole correlated with extracellular volume in transthyretin, but not light chain amyloidosis. This indicates that different mechanisms may be responsible for impaired contractility in CA, with an amyloid burden effect in transthyretin, but an idiosyncratic effect in light chain amyloidosis. Consequently, DT-CMR offers a contrast-free tool to identify novel pathophysiology, improve diagnostics, and monitor disease through noninvasive microstructural assessment.

Keywords: amyloid; diffusion tensor imaging; extracellular space; magnetic resonance imaging; myocardium.

Figure 1. Diastolic E2A is elevated in cardiac amyloid

E2A is an index of sheetlet orientation. The bars show mean and standard deviation. In panel A diastolic E2A in amyloid patients (yellow and green) was significantly elevated compared to diastolic E2A in controls (blue), p<0.001. Example maps in panel B show a predominance of low E2A over the control LV slice (blue) in diastole that changed to predominantly higher E2A in systole (more red pixels). In both cardiac amyloidosis and HCM, the diastolic maps showed a greater extent of higher E2A in diastole (more red than blue).

Figure 2. Diffusivity biomarkers differ significantly in cardiac amyloid

In panel A, mean diffusivity (MD) was significantly higher in cardiac amyloidosis (p<0.001) at both cardiac phases, with clear separation from HCM and controls. In panel B, fractional anisotropy (FA) was significantly reduced (p<0.001) at both cardiac phases. A lower FA reflects greater disorganisation of the underlying microstructure.

Figure 3. Receiver operating characteristic curves for diffusion biomarkers

Panel A shows the ROC curve for mean diffusivity and panel B shows the ROC curve for fractional anisotropy.

Figure 4. MD and FA map the location and extent of amyloid deposition

Example maps from are shown. The left column shows control maps including a reference ECV map. The control MD map is blue and FA map is red. The second column shows HCM data; elevated ECV in the hypertrophied septum matching with elevated MD (red) and FA (green). The AL and ATTR maps show spatial co-location of the areas of elevated MD, reduced FA and amyloid burden as shown by the ECV. Control ECV map is reproduced from [29], licensed under a Creative Commons Attribution (CC-BY) license.

Figure 5. MD and FA correlate with ECV

MD significantly correlated with ECV (r=0.68, p=0.004), suggesting MD reflects the expanded extracellular volume resulting from amyloid deposition (Panel 4A). Conversely, the inverse correlation of FA with ECV had a p-value of 0.05 (Panel 4B).

Figure 6. Segmental agreement of abnormal MD and FA with ECV derangement

Using a 12-segment model for the LV slice, segments of elevated MD and reduced FA co-located with segments of raised ECV (>33%). The HCM and CA segments showed marked clustering, as shown in the grey boxes within which the ECV, FA and MD values are abnormal.

Figure 7. Diastolic E2A correlates with ECV in ATTR, but not in AL

There was a significant correlation between diastolic E2A and ECV in ATTR, (r=0.77 and p= 0.03). However, this was not true for AL, where there was no correlation (r=0.05 and p=0.9). This suggests that there may be an amyloid dose-dependent relationship of diastolic E2A elevation in ATTR, but an idiosyncratic effect in AL.