Systemic Amyloidosis – Insights by Cardiovascular Magnetic Resonance

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 0.9 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

Systemic amyloidosis in England: an epidemiological study.

Epidemiological studies of systemic amyloidosis are scarce and the burden of disease in England has not previously been estimated. In 1999, the National Health Service commissioned the National Amyloidosis Centre (NAC) to provide a national clinical service for all patients with amyloidosis. Data for all individuals referred to the NAC is held on a comprehensive central database, and these were compared with English death certificate data for amyloidosis from 2000 to 2008, obtained from the Office of National Statistics. Amyloidosis was stated on death certificates of 2543 individuals, representing 0·58/1000 recorded deaths. During the same period, 1143 amyloidosis patients followed at the NAC died, 903 (79%) of whom had amyloidosis recorded on their death certificates. The estimated minimum incidence of systemic amyloidosis in the English population in 2008, based on new referrals to the NAC, was 0·4/100 000 population. The incidence peaked at age 60-79 years. Systemic AL amyloidosis was the most common type with an estimated minimum incidence of 0·3/100 000 population. Although there are various limitations to this study, the available data suggest the incidence of systemic amyloidosis in England exceeds 0·8/100 000 of the population

Senile Systemic Amyloidosis: Clinical Features at Presentation and Outcome

Background Cardiac amyloidosis is a fatal disease whose prognosis and treatment rely on identification of the amyloid type. In our aging population transthyretin amyloidosis (ATTRwt) is common and must be differentiated from other amyloid types. We report the clinical presentation, natural history, and prognostic features of ATTRwt compared with cardiac‐isolated AL amyloidosis and calculate the probability of disease diagnosis of ATTRwt from baseline factors. Methods and Results All patients with biopsy‐proven ATTRwt (102 cases) and isolated cardiac AL (36 cases) seen from 2002 to 2011 at the UK National Amyloidosis Center were included. Median survival from the onset of symptoms was 6.07 years in the ATTRwt group and 1.7 years in the AL group. Positive troponin, a pacemaker, and increasing New York Heart Association (NYHA) class were associated with worse survival in ATTRwt patients on univariate analysis. All patients with isolated cardiac AL and 24.1% of patients with ATTRwt had evidence of a plasma cell dyscrasia. Older age and lower N‐terminal pro‐B‐type natriuretic peptide (NT pro‐BNP) were factors significantly associated with ATTRwt. Patients aged 70 years and younger with an NT pro‐BNP <183 pmol/L were more likely to have ATTRwt, as were patients older than 70 years with an NT pro‐BNP <1420 pmol/L. Conclusions Factors at baseline associated with a worse outcome in ATTRwt are positive troponin T, a pacemaker, and NYHA class IV symptoms. The age of the patient at diagnosis and NT pro‐BNP level can aid in distinguishing ATTRwt from AL amyloidosis

Cardiac T1 Mapping and Extracellular Volume (ECV) in clinical practice: a comprehensive review.

Cardiovascular Magnetic Resonance is increasingly used to differentiate the aetiology of cardiomyopathies. Late Gadolinium Enhancement (LGE) is the reference standard for non-invasive imaging of myocardial scar and focal fibrosis and is valuable in the differential diagnosis of ischaemic versus non-ischaemic cardiomyopathy. Diffuse fibrosis may go undetected on LGE imaging. Tissue characterisation with parametric mapping methods has the potential to detect and quantify both focal and diffuse alterations in myocardial structure not assessable by LGE. Native and post-contrast T1 mapping in particular has shown promise as a novel biomarker to support diagnostic, therapeutic and prognostic decision making in ischaemic and non-ischaemic cardiomyopathies as well as in patients with acute chest pain syndromes. Furthermore, changes in the myocardium over time may be assessed longitudinally with this non-invasive tissue characterisation method

Towards accurate and precise T1 and extracellular volume mapping in the myocardium: a guide to current pitfalls and their solutions

Mapping of the longitudinal relaxation time (T1) and extracellular volume (ECV) offers a means of identifying pathological changes in myocardial tissue, including diffuse changes that may be invisible to existing T1-weighted methods. This technique has recently shown strong clinical utility for pathologies such as Anderson- Fabry disease and amyloidosis and has generated clinical interest as a possible means of detecting small changes in diffuse fibrosis; however, scatter in T1 and ECV estimates offers challenges for detecting these changes, and bias limits comparisons between sites and vendors. There are several technical and physiological pitfalls that influence the accuracy (bias) and precision (repeatability) of T1 and ECV mapping methods. The goal of this review is to describe the most significant of these, and detail current solutions, in order to aid scientists and clinicians to maximise the utility of T1 mapping in their clinical or research setting. A detailed summary of technical and physiological factors, issues relating to contrast agents, and specific disease-related issues is provided, along with some considerations on the future directions of the field. Towards accurate and precise T1 and extracellular volume mapping in the myocardium: a guide to current pitfalls and their solutions. Available from: https://www.researchgate.net/publication/317548806_Towards_accurate_and_precise_T1_and_extracellular_volume_mapping_in_the_myocardium_a_guide_to_current_pitfalls_and_their_solutions [accessed Jun 13, 2017]

T1 mapping in cardiac MRI

Quantitative myocardial and blood T1 have recently achieved clinical utility in numerous pathologies, as they provide non-invasive tissue characterization with the potential to replace invasive biopsy. Native T1 time (no contrast agent), changes with myocardial extracellular water (edema, focal or diffuse fibrosis), fat, iron, and amyloid protein content. After contrast, the extracellular volume fraction (ECV) estimates the size of the extracellular space and identifies interstitial disease. Spatially resolved quantification of these biomarkers (so-called T1 mapping and ECV mapping) are steadily becoming diagnostic and prognostically useful tests for several heart muscle diseases, influencing clinical decision-making with a pending second consensus statement due mid-2017. This review outlines the physics involved in estimating T1 times and summarizes the disease-specific clinical and research impacts of T1 and ECV to date. We conclude by highlighting some of the remaining challenges such as their community-wide delivery, quality control, and standardization for clinical practice