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Page 2 of 11 Scirpa et al. Vessel Plus 2022;6:52 https://dx.doi.org/10.20517/2574-1209.2021.74

TTR protein in different tissues, particularly in the heart and the autonomic and peripheral nerve fibers.
TTR infiltration in the myocardium causes infiltrative cardiomyopathy characterized by progressive
[1]
diastolic and systolic dysfunction, leading to heart failure . The dissociation of the TTR tetramer into
monomers, followed by misfolding and assembling in amyloid fibrils, may be promoted by a single point
mutation in the TTR gene (hereditary, ATTRv) or by aging (wild type, ATTRwt) . The supposed
[1]
mechanisms of the latter form are still largely unknown; some aging-related processes are probably involved
in protein destabilization, considering that all protein-misfolding diseases have age-related penetrance.
ATTRv is an autosomal-dominant disease associated with more than 100 different pathogenic mutations in
the TTR gene . The diverse mutations are associated with extremely heterogeneous clinical manifestations
[2]
ranging from a predominant cardiac involvement to an exclusively neurological one, with a variety of mixed
[1,3]
phenotypes . There are no demonstrated correlations among gene localization of the different TTR
mutations, protein dysfunction, and clinical phenotype. Amyloid fibrils may contain two different types of
fibrils: Type A, composed of amixture of C-terminal fragments and full-length TTR, and Type B, formed
only by full-length TTR. Type A fibrils are more frequent, while Type B fibrils, up to date, are an exception
[4,5]
and have been found in a limited number of TTR mutations, such as Phe64Leu and Val30Met .
While ATTRv is still considered a rare condition, ATTRwt cardiac amyloidosis is now increasingly
recognized and represents one of the most important causes of heart failure with preserved ejection fraction
(HFpEF); in fact, TTR deposits can be seen in up to 30% of older adults with HFpEF who undergo
autopsy .
[6]

The recent meaningful increase of identified cases over the past five years is the result of the growing
awareness of the disease, together with the availability of non-invasive diagnostic tests such as bone
[7]
scintigraphy . Moreover, the advent of new drugs, which seem to be able to slow down the amyloidogenic
process, has revolutionized the clinical approach to this disease, especially because the effectiveness of the
new therapies is maximum in the early stages .
[8]
Clinical spectrum of ATTRv
In contrast to ATTRwt, in which the infiltration is limited to the heart and soft tissues, ATTRv has a wider
clinical spectrum, depending on the type of TTR mutation and the degree of organ involvement. Mainly, it
affects the peripheral and autonomic nervous systems and/or the heart. On the basis of the extent of these
two organs impairment, three phenotypes of ATTRv can be distinguished: neurological, cardiac, and mixed
[9]
form . In an Italian cohort, the vast majority of the affected patients had neurological involvement, while
about two-thirds had cardiac involvement; a significant minority (15%) had an exclusive cardiac
phenotype .
[10]

Neurological involvement consists largely in peripheral sensory-motor polyneuropathy, which firstly affects
lower extremity small sensory fibers with early impairment of pain and temperature sensation. Autonomic
[11]
neuropathy may dominate the phenotypic expression or be an early sign of the disease .

Cardiac involvement results in restrictive cardiomyopathy characterized by left and right ventricular
hypertrophy and advanced diastolic dysfunction with preserved ejection fraction. Indeed, fibrils infiltration
in the myocardium leads to increased wall thickness (pseudo-hypertrophy). Although heart failure usually
dictates the clinical course of cardiac amyloidosis, amyloid infiltration causes a wide extent of myocardial
derangement, which may result in several other clinical manifestations, including tachy- and
bradyarrhythmias [3,9,12] .