Introduction:

Amyloidosis is a disease in which abnormal proteins infiltrate organs, causing dysfunction. Amyloid is categorized by the type of protein and its folding. One of the most common types of amyloidosis is light chain (AL) amyloidosis. In AL amyloidosis plasma cell dyscrasias create excess immunoglobulin light chains, which form abnormal proteins that deposit in tissues including the heart, kidney, and liver(1). The worst prognosis in AL amyloidosis occurs with infiltration of the heart, which leads to myocardial thickening and heart failure(2). One popular treatment of AL amyloidosis is autologous hematopoietic stem cell transplantation (ASCT), which prevents further deposition of abnormal proteins. Organ response and progression is currently monitored with non-specific biomarkers like liver size and serum alkaline phosphatase. Amyloid infiltration causes increased tissue stiffness (3), including within the heart and liver. Shear wave elastography is an emerging imaging approach for measuring myocardial stiffness in vivo (4-13). Recently, cardiac magnetic resonance elastography (MRE) reported that patients with cardiac amyloidosis have significantly elevated myocardial stiffness (12) compared to healthy age-matched controls and that cardiac stiffness decreased 3-months after ASCT therapy(14). The goal of this study is to evaluate the feasibility of using magnetic resonance elastography (MRE) to monitor changes in stiffness in multiple organs (heart, liver, kidney, and spleen) before and after ASCT therapy for AL amyloidosis.

Methods:

Five patients with AL amyloidosis were enrolled in this study prior to undergoing ASCT, and after receiving institutional review board and written informed consent approval. All subjects underwent cardiac and abdominal MRI/MRE prior to therapy (baseline) and at their scheduled approximate 3 month follow-up visit. Three patients had ASCT as part of their first line therapy; whereas 2 had ASCT as part of second line therapy. All patients achieved hematologic complete response to therapy. The mean age at time of enrollment to the MRE study was 58 (median: 59, max: 66, min: 51), with a mean follow-up time of 117.6 days (median: 114, max: 130, min: 106). MRE imaging was performed in 3 acquisitions using a vibration frequency of 140 Hz (heart), 60Hz (liver, spleen), and 90Hz (kidney) and 3 separate passive drivers using the same procedure as previously described (15). Two 1.5 hour imaging sessions at each timepoint were used to acquire all clinical cardiac MRI and multi-organ MRE data. The absolute change in mean stiffness (Δµ) before and after therapy adjusted to 100 day follow-up times was calculated for each organ. At 9 months post ASCT, a clinician with extensive experience in assessing AL amyloidosis, blinded to the MRE results, used internationally accepted methodology(16-18) to assess amyloid organ involvement and therapy response in the heart, liver, and kidney of each patient. A linear mixed effect model with Δµ as the outcome variable, and organ type, and amyloid involvement as fixed effects was used to determine the impact of ASCT on tissue stiffness. A Wilcoxon rank sum test was also applied by comparing the Δµ from organs with known amyloid involvement to those without. A p-value of less than 0.05 was considered statistically significant.

Results:

Center-slice elastogram images of the left ventricle (LV) myocardium, liver (L), spleen (S), and kidney (K) for all 5 volunteers at baseline (B) and at their follow-up (FU) visit are shown in Figure 1. Absolute change in mean organ stiffness (kPa) for each of the 5 patients is plotted (circles) in Figure 2. A visual comparison between the percent change in endogenous T1-relaxation, cardiac ejection fraction and MRE measurements are given in Figure 3. In patients numbers 2, 3, and 4, the EF reduced post therapy, while the T1 increased in patients 2 and 3, and decreased in patient 4, at the 3 month follow-up timepoint. Table 1 gives the output coefficients from the linear fixed-effect model. This model shows that organs with clinically detected organ involvement had a significant decrease in stiffness at the 3 month imaging timepoint as measured by MRE. A simpler comparison between the changes in absolute stiffness between organs that had organ involvement with those that did not, are plotted in Figure 4. Organs with amyloid involvement all significantly decreased in stiffness (p = 0.047).

Discussion and Conclusions:

This study demonstrates that organs with known amyloid involvement under effective plasma cell directed therapy like ASCT become less stiff as measured by MRE. Furthermore, these results indicate that ASCT affects the biomechanics of multiple organs (kidney, liver, heart, and spleen) and that MRE is a sensitive and feasible quantitative technique for monitoring these changes as early as 3 months post-therapy. In this cohort all organs with amyloid involvement eventually responded to therapy, although 1 (patient #2) responded after the 9-month clinical assessment. This suggests that MRE may be a sensitive tool for detecting early organ response. The 3 patients with cardiac amyloid involvement had reduced ejection fractions (<3.9%) at their 3-month follow-up despite having lower stiffness. Also, one patient with 14% decrease in endogenous T1 showed the least change in cardiac stiffness. Interactions between biomechanical changes and the MRI cardiac functional measurements are still not well understood and require future study. The results provide motivation for further evaluation of MRE-based biomarkers for assessing treatment response in AL amyloidosis patients.

Acknowledgements

We would like to thank Kathy Brown for recruiting and scheduling all patient exams. This work was supported by the National Institutes of Health grants K12HD65987-11 and by internal grants funded by Mayo Clinic, Department of Radiology.

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