Quantitative-imaging in cardiac transthyretin amyloidosis (I-CARE)

Systemic amyloidosis represents a spectrum of conditions characterised by
disordered protein folding and formation. The two predominant forms affecting
the heart are amyloid light-chain (AL) and amyloidosis transthyretin (ATTR).
Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is gradually progressive and
is ultimately fatal if left untreated. It is characterised by deposition of
amyloid fibrils from liver-derived transthyretin (TTR) in the myocardial
extracellular space. Microcalcification has been described in association with
these deposits. ATTR-CM can be classified as sporadic, associated with the
deposition of wild-type transthyretin (ATTRwt), or hereditary, associated with
genetic variants of TTR (ATTRv). Historically, there has been a mismatch
between the number of clinical diagnoses of ATTR-CM and autopsy findings where
cardiac ATTR amyloid deposits have been observed in up to a quarter of elderly
individuals. In recent years, greater awareness of ATTR-CM as an
underrecognized cause of heart failure, coupled with an ageing population and
advances in diagnostic techniques have resulted in a dramatic increase in new
clinical diagnoses of ATTR-CM. For example, the prevalence of ATTR-CM is
currently estimated at ~1 in 7 patients with heart failure with preserved
ejection fraction (HFpEF) and 1 in 6 with severe aortic stenosis (AS) requiring
transcatheter aortic valve replacement. Based upon these statistics and the
growing population of elderly people in Europe (100 million), the prevalence of
ATTR-CM in Europe can be estimated at up to a million patients. We aim to
investigate myocardial microcalcification in TTR amyloid using 18F-sodium
fluoride PET/CT, a tracer with high affinity for developing cardiovascular
microcalcification. In particular, we seek to establish that bone tracers bind
to microcalcification in the myocardium, and then establish whether the degree
of microcalcification is associated with ATTR-CM burden and whether changes in
microcalcification can be tracked with disease progression and in response to
therapy in ATTRCM. We will use 18F-SodiumFluoride because it is a cheap, well
established and widely available PET bone tracer with exciting potential in
patients with ATTR-CM [25]. Similar to the SPECT bone tracers, we have also
demonstrated in a small pilot study that 18F-fluoride PET demonstrates
increased uptake in ATTR-CM, again likely due to the underlying myocardial
microcalcification. However, a key added advantage of using PET rather than
SPECT to image ATTR-CM, is that PET provides sensitive and fully quantitative
measurements of microcalcification both within the heart and in extra-cardiac
structures (also commonly affected in ATTR). We are here to make use of this
quantitative ability of PET to fully investigate the relationship between
myocardial microcalcification and ATTR-CM.

Furthermore, ATTR-CM poses a risk on arrhythmia due to amyloid infiltration of
the cardiac conduction system and the myocardial tissue. Iodine-123 labelled
metaiodobenzylguanidine ([123I]MIBG) imaging can determine the damage to the
cardiac sympathetic innervation in ATTR-CM. In ATTR variant (ATTRv) patients
[123I]MIBG scintigraphy can detect myocardial denervation before signs of
amyloidosis are even evident on echocardiography. The value of [123I]MIBG
scintigraphy in wild type ATTR (ATTRwt) -CM has not yet been studied in detail.
Based on a small pilot study (unpublished data), [123I]MIBG scintigraphy is
abnormal in patients with ATTRwt and harbours prognostic value in these
patients, as in ATTRv-CM. [123I]MIBG imaging provides us with the opportunity
to evaluate the effect of treatment with tafamidis on myocardial denervation in
ATTR-CM. This will help to identify responders and non-responders to treatment
with tafamidis at an early stage, therewith improving treatment strategy
options for patients with until now still a limited prognosis. Finally I-CARE
will be able, for the first time to our knowledge, compare 18F-NaF and
[123I]MIBG in ATTR-CM patients using tafamidis.

This study has been transitioned to CTIS with ID 2024-513310-36-01 check the CTIS register for the current data.

Primairy objectives
1. To determine the presence and extent of myocardial microcalcification and
myocardial denervation in ATTR-CM;
2. To quantify the burden of myocardial microcalcification and myocardial
denervation in ATTR-CM;
3. To assess whether myocardial microcalcification and myocardial denervation
is reduced is improved following treatment for ATTR-CM.

Secondary objectives
1. To determine whether there is a threshold of myocardial microcalcification
or myocardial denervation associated with the presence of ATTR-CM;
2. To determine whether myocardial microcalcification and myocardial
denervation correlates with disease progression or treatment regression in
patients with ATTR-CM.

In this international study, we will investigate the role of myocardial
microcalcification in ATTR-CM within 4 work packages (WP). The MIBG scan will
be researched in the UMCG as single-center.

Burden/risk: a cumulative radiation burden of 15.40mSv for the first 5-15
ATTR-CM patients and 14.34mSv for the later ATTR-CM patients and 4.27mSv for
the control group. Allergy to gadolinium.
Benefit: insight in imaging technique (18F-NaF) for early and accurate
detection of cardiac amyloidosis and the effect of clinical therapy.