Amyloidosis Conferences

"What we want from an imaging modality, ultimately in diseases, and more specifically in amyloidosis," Professor Marianna Fontana shared with delegates of the 3rd European ATTR meeting "is that we want to be able to track changes over time and assess treatment response and guide treatment strategy by assessing treatment response, and by doing so we want to be able to change prognosis."

Professor Fontana believes we are making some progress towards achieving these goals in transthyretin-mediated amyloidosis with cardiomyopathy (ATTR-CM), but that we still have a way to go. In her presentation at this year's EU-ATTR meeting, Professor Fontana discussed the use of cardiac imaging in ATTR-CM, beginning with the three most widely used imaging modalities for diagnosing amyloidosis: echocardiography, cardiac magnetic resonance (CMR) imaging and bone scintigraphy.

Echocardiography

Echocardiography is the first-line modality used for patients with heart failure and it allows stratification of the probability of presence/ absence of amyloidosis. Common findings that increase the probability of amyloidosis include:

• concentric hypertrophy (commonly asymmetric)
• atrial dilatation
• speckled appearance of myocardium
• preserved LV ejection fraction, but significantly reduced longitudinal function
• restrictive filling pattern
• pleural and pericardial effusions

However, Professor Fontana highlights that these signs are not specific to ATTR-CM. In fact, pleural and pericardial effusions are more commonly seen in AL amyloidosis. So how can we increase specificity for ATTR‑CM?

Professor Fontana explains that measuring longitudinal strain by echocardiography could help. This technique assesses the extent and timing of myocardial deformation during systole, expressed as the peak mean negative strain for each segment (basal, mid, apical). Apical sparing (ie relative preservation of apical contraction compared with the basal segments) is typical of ATTR-CM and gives a characteristic 'bulls-eye' appearance when plotted.

Another issue with echocardiography is that it does not directly image the myocardial substrate, and whilst it can predict the probability of amyloidosis, it cannot be used for a definitive diagnosis.

CMR imaging

For over 15 years, we have known that CMR imaging with late gadolinium enhancement (LGE) can be used to identify myocardial infiltration (ie the presence of amyloid deposits in the myocardium). After administration of the contrast, patients with amyloidosis show a characteristic pattern of global subendocardial LGE. However, whilst this is a highly accurate technique for diagnosis, it showed little utility for predicting prognosis.¹

Professor Fontana explains how phase-sensitive inversion recovery (PSIR) in CMR has helped to refine this modality; using CMR PSIR, we can detect three distinct patterns:

1. No LGE
2. Subendocardial LGE
3. Transmural LGE

A higher extent of transmural LGE has been associated with increased extracellular volume and worse clinical outcomes, meaning that this technique can now be used to predict prognosis.¹

Bone scintigraphy

Bone scintigraphy, as Professor Fontana explains, is an extremely simple technique with high sensitivity and specificity for ATTR-CM. It compares cardiac versus bone uptake of a technetium-labelled bisphosphonate, with higher degrees of cardiac uptake indicating higher grades:²

• Healthy - no cardiac uptake
• Grade 1 - mild cardiac uptake with no attenuation of bone uptake
• Grade 2 - moderate cardiac uptake, greater than bone
• Grade 3 - strong cardiac uptake with little or no bone signal

How can we combine these techniques to diagnose ATTR-CM?

"Echo[cardiography], CMR and DPD [bone scintigraphy], so a combination of these three techniques, can be very usefully used to make a diagnosis of cardiac amyloidosis [ATTR-CM]," Professor Fontana explained in her talk, referring to a diagnostic algorithm published in 2016.³

For patients with HF, syncope, or bradyarrhythmia, an echocardiogram and/or CMR can raise suspicion of ATTR-CM in the first instance. For patients with potential ATTR-CM, bone scintigraphy should then be carried out, followed by detection of monoclonal gammopathy.

• Grade 0: CMR imaging should be carried out or reviewed
• Grade 1: the patient should receive specialist assessment (ie histological confirmation and typing of amyloid) to determine what form of amyloidosis they have
• Grade 2-3 with monoclonal gammopathy: the patient should receive specialist assessment to determine what form of amyloidosis they have
• Grade 2-3 without monoclonal gammopathy: ATTR-CM can be confirmed and TTR genotyping should be used to determine if this is wild type or variant

How can we measure the cardiac amyloid burden and track changes over time?

In ATTR-CM, amyloid deposits sit in the space between the cells, thus increasing the extracellular volume (ECV). This means that ECV correlates with the amyloid burden. Increased ECV versus healthy patients can be seen for patients with a number of hypertrophic diseases, but the difference in ATTR-CM is especially high. ECV can be measured using T1 CMR imaging, where modified look-locker inversion recovery (MOLLI) T1 mapping scans are performed pre and post administration of contrast producing a pixel-by-pixel quantification of the ECV. ECV correlates with prognosis in ATTR-CM, and Professor Fontana used an example of two patients with similar LV mass and degree of diastolic failure, but vast differences in ECV (39% versus 62%), to illustrate why mapping of ECV can be a useful tool in identifying a patient’s stage of disease.

Importantly, changes in ECV can also be used to track patients’ responses to treatment. Professor Fontana finished her talk by presenting results from a prospective study of 16 patients receiving 3-weekly intravenous patisiran and 16 control patients. CMR imaging, blood biomarkers, 6-minute walk test and echocardiography were all conducted at baseline and 12 months after the start of treatment. At 12 months, no changes were observed in any echocardiography parameters (eg cardiac structure, strain, systolic/ diastolic function), however patients treated with patisiran did show a greater reduction in ECV versus control patients (adjusted mean difference between groups was -6.2% (95% CI:-9.5% to -3.0%, p=0.001).

Conclusions

Echocardiography is the first line of imaging for patients with heart failure and can indicate the presence or absence of ATTR-CM; CMR imaging and bone scintigraphy are crucial in confirming diagnosis and allow visualisation of the disease and phenotype; ECV mapping allows us to understand and measure myocardial process and track changes over time. So which modality is best? Professor Fontana concluded her talk by answering this question:

"The question is not which is the best imaging modality, but which is the best and most appropriate at each step of the diagnostic pathway."

AL: amyloid light chain; CI: confidence interval; DPD: diphosphono-1,2-propanodicarboxylic acid; LV: left ventricular

Based on: Fontana M. Cardiac imaging in ATTR amyloidosis. Presented at the 3rd European ATTR amyloidosis meeting for patients and doctors, 6-8 September 2021.