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Title: Systemic amyloidosis : insights by cardiovascular magnetic resonance
Author: Banypersad, S. M.
ISNI:       0000 0004 5359 3647
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2015
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Systemic amyloidosis is the exemplar infiltrative, extracellular disease. Although it is a multi-organ disorder, cardiac involvement drives prognosis. Survival is worst in the AL amyloidosis subtype. It can affect any age and any race. There is no direct test for amyloid burden and there is no treatment for amyloidosis, there is only treatment for the underlying condition. Earlier diagnosis permits prompt treatment and improves survival. A number of imaging modalities exist to non-invasively detect cardiac disease but all have limitations. Cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) imaging provides the highest sensitivity for early detection. However, this also has its shortcomings. There is currently no non-invasive method of directly measuring amyloid burden in the extracellular space. New therapies are pending – but their development needs new surrogate endpoints and new tests are therefore desperately needed. T1 mapping permits tissue abnormalities to be directly visualised in a simple scan – the colour changes being instantly recognisable, either before contrast (pre contrast or native T1 mapping) or after, when the myocardial extracellular volume (ECV) can be measured. In a collaboration between the National Amyloidosis Centre and the Heart Hospital, I explored the possibility and potential that T1 mapping might measure cardiac (and other organ) involvement in systemic amyloidosis using EQ-MRI. In early clinical exploration in systemic AL amyloid, I showed that native myocardial T1 was elevated in cardiac amyloidosis and tracked disease, particularly early disease. Mean pre contrast myocardial T1 as measured by ShMOLLI was higher in patients at 1086 ± 90msec, compared to healthy volunteers of 958 ± 20msec (P<0.001). Myocardial T1 times showed a stepwise elevation as the probability for cardiac involvement increased: 1009 ± 31msec without cardiac involvement, 1048 ± 48msec with possible cardiac involvement, 1140 ± 61msec with definite cardiac involvement (P<0.001). Using contrast to measure the ECV, I was able to non-invasively and directly measure the amyloid burden in the heart for the first time. Mean cardiac ECV was greater in patients compared to healthy volunteers with a wider range (0.44 ± 0.12 vs 0.25 ± 0.02, P<0.001) and tracked pre-test probability of cardiac involvement by conventional parameters (P<0.001). ECV also tracked conventional measures of disease severity and correlated with survival with a median ECV of 0.45 being the best model for assessing survival: HR 3.84 (1.53 – 9.61), P=0.004. I demonstrated good reproducibility of the technique with an ICC of > 0.9 for both the FLASH IR and ShMOLLI techniques of T1 mapping and good agreement of ECV derived from both techniques. In pilot studies, I also demonstrated by serial scanning that changes (including regression) over time could be measured. In other organs, I showed that the amyloid burden could be measured and was higher in amyloidosis compared to healthy volunteer: ECV 0.32 vs 0.29 (P<0.001) for liver, 0.39 vs 0.34 (P<0.001) for spleen and 0.16 vs 0.09 (P<0.001) for skeletal muscle. These ECVs also tracked current conventional measures of disease severity by nuclear scintigraphy. These results demonstrate that the interstitial volume in patients with systemic AL amyloidosis can be measured non invasively in the heart, liver, spleen and skeletal muscle and that this correlates with existing markers of disease and survival. Pre contrast myocardial T1 was a good alternative measure for the heart. In conclusion, the work in this thesis has enabled a deeper understanding of cardiac amyloidosis, disease processes and stages. It has pioneered a new prognostic marker that is also able to identify some patients with cardiac involvement that were previously unrecognised. Novel subtypes are now recognised (e.g. cardiac amyloidosis with no LVH) and it has also allowed direct quantification of the liver and spleen. ECV is a new and powerful biomarker that has already been adopted by industry allowing development of new therapies and providing hope that an end to the scourge of this disease is near.
Supervisor: Moon, J. C. C. ; Hawkins, P. N. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available