Cardiac Transthyretin-derived Amyloidosis

The aim of this thesis was to improve the diagnosis of cardiac ATTR in patients
presenting with HFpEF and TTR gene mutation carriers. The first part focused on the
early detection of cardiac involvement in patients a!ected by hereditary transthyretin
amyloidosis (ATTRv). The second part described strategies to identify cardiac ATTR
in the general HFpEF population.
In chapter 2 we described a Dutch family with a novel TTR mutation and showed that
this mutation was characterised mainly by heart failure at relative high age. The systemic
nature of this type of ATTRv was reflected by the presence of bi-lateral carpal tunnel
syndrome and the early signs of polyneuropathy. The systemic nature of ATTRv was
further emphasized in chapter 3. Here, we demonstrated in the Groningen Amyloid
Cohort (GAC) consisting of patients with proven ATTRv with di!erent genotypes that
cardiac involvement was present in ~50% of the patients at the time of diagnosing
amyloidosis, irrespective of genotype or initial clinical presentation. We showed that
cardiac involvement determined the survival of ATTRv patients. NT-proBNP was
shown to be an e!ective and easy to use screening tool for the detection of cardiac
involvement in ATTRv. In chapter 4 we described the value of echocardiographic
deformation imaging, i.e. global longitudinal strain (GLS), in a population consisting
of individuals presenting at our centre because of familial screening for ATTRv. We
demonstrated that a combination of GLS and NT-proBNP may detect cardiac pathology
at an earlier stage than the bone scintigraphy, the current non-invasive gold standard
for diagnosis of cardiac ATTR.
Part two of this thesis described studies on diagnosing cardiac ATTR in patients with
HFpEF. In chapter 5 we described the rationale for screening for the presence of
ATTRwt in the general HFpEF population. The clinical hallmarks of ATTRwt were
described, and we suggested that ATTRwt should be considered in elderly patients with
HF and in which either a specific echocardiographic pattern is present or the medical
history reveals bi-lateral carpal syndrome. A bone scintigraphy should be performed in
these patients to finally diagnose ATTRwt. In chapter 6 we investigated the prevalence
of ATTRwt in HFpEF/HFmrEF patients. In this selected population we reported an
ATTRwt prevalence of 5%. In addition, we demonstrated that patients with cardiac
amyloidosis had a distinctly di!erent biomarker pattern as compared to HFpEF/
HFmrEF patients without cardiac amyloidosis. Serum levels of the three biomarkers
GLB1, S100A4, and HGF were most distinctive and we demonstrated that this triplet
was able to identify ATTRwt patients within a HFpEF/HFmrEF patient population. In
chapter 7 we described the interplay between ATTRwt or isolated atrial amyloidosis
(IAA) and atrial fibrillation (AF) in patients with HFpEF. Both HFpEF and AF are very
common diseases that occur often in combination and aggravate each other.
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Summary, discussion and future perspectives
In conclusion, this thesis contributes to the awareness of early detection of cardiac
involvement of ATTRv and to the identification of ATTRwt in patients with heart
failure.