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Page 4 of 7 Di Nora et al. Vessel Plus 2022;6:46 https://dx.doi.org/10.20517/2574-1209.2021.126

Heart Transplantation in TTR Amyloidosis
The decision to proceed with heart transplantation in ATTR might be different in wild-type vs. variant
ATTR amyloidosis. Thus, patients affected by variant ATTR amyloidosis are younger than those with wild-
type ATTR and might benefit from heart transplantation after careful candidate selection. Moreover,
patients with ATTR variant showed increased cardiac tropism, which is known to heavily infiltrate the
native heart early in the disease course. For these reasons, variant ATTR amyloidosis patients should be
regularly investigated to identify the best frame for heart transplantation according to NYHA class, NT-
proBNP, systolic and diastolic function, CPET parameters, RM parameters, and extra-cardiac organ
function [34-36] .

Patients with wild-type TTR amyloidosis and isolated cardiac involvement should be considered for HTx,
and the data available suggest that post-transplant prognosis for this subgroup of patients is comparable to
that of transplantation for other reasons. ATTR amyloidosis is predominantly a disease of the elderly, and
progression is usually slow; thus, it is reasonable that it could be too slow to significantly damage the
transplanted heart. However, knowing that age is a limit in the donor organ offers, ATTR amyloidosis is a
rare indication for cardiac transplant, and the number of cases reported in the literature is small. In a group
of seven patients with wild-type TTR with HTx between 2007 and 2015, the three-year survival was 100%,
[24]
and the one death was due to a neoplastic reason . However, symptomatic gastrointestinal and peripheral
nerve involvement by wild-type ATTR developed subsequently. In another series, two patients with wild-
type ATTR amyloidosis were transplanted in 2012 and 2017, respectively, and they are in good clinical
conditions, without relapse of amyloidosis in the donor grafts . Before the recent news about new drugs
[29]
for this disease with good results , HTx has offered the greatest chance of long-term survival for wild-type
[37]
ATTR amyloidosis patients; however, a change in the therapeutical approach is already ongoing after the
latest evidence , leading to HTx having a marginal role in this subgroup of patients.
[38]
Open issues in HTx for cardiac amyloidosis
Some open issues related to the referral of systemic disease patients for HTx are largely debated. Effectively,
with the limited number of donors, public scrutiny of the HTx results, and apparent inferior survival in
amyloidosis patients compared to transplant recipients for other causes, only large programs can afford to
take the risk of performing cardiac transplants in CA. Moreover, being unquestionable that outcomes in AL
amyloidosis are better after chemotherapy and ASCT, the number of transplant centers is further limited to
those where there are close cooperating programs between the transplant and the cancer centers and that
are used with ASCT. Effectively, transplant hospitals always struggle with the option of guaranteeing a very
rare resource to patients with a systemic and progressive disease [39-41] , but the choice of having extended
marginal donors could be a chance, trying to afford this ethical dilemma . The option of using extended
[42]
donor criteria for these recipients supports the ethical question of whether transplantation is an option in
[41]
these patients besides the shortage of donor organs.

Another crucial point is related to the criteria adopted to exclude these patients from HTx programs.
According to the DANGER protocol published in 2009, patients showing diarrhea (D: such as weight loss or
malabsorption), autonomic nervous system (A: heart rate variability and syncopes), nutritional status (N:
decline of serum protein or weight), gastrointestinal tract involvement (G: gut biopsy or known
gastrointestinal bleeding), impaired elimination (E: kidney function), and respiratory tract involvement (R:
[42]
evaluated by spirometry and computed tomography) are not considered for HTx . Hence, the choice of
transplanting these patients must be considered according to a case-by-case evaluation [Table 2]. As for all
patients, HTx candidates should be evaluated for their general conditions, as survival is critically dependent
[43]
on different patient characteristics, such as extra-cardiac amyloid deposits and patient age . Lastly, a
surveillance protocol based on monthly or three-monthly evaluations is necessary to monitor and prevent