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Page 8 of 13 Canepa et al. Vessel Plus 2022;6:30 https://dx.doi.org/10.20517/2574-1209.2021.106

including endomyocardial biopsy should be judged on an individual basis.

The diagnostic accuracy of bone scintigraphy has to date been primarily demonstrated in highly selected
[60]
patients evaluated at CA referral centers . Its sensitivity and specificity are expected to significantly
decrease when moving to larger populations of less selected individuals. This will soon become a very
relevant issue, with patients having false-positive and false-negative results being exposed, respectively, to
further inappropriate (and sometimes invasive) testing or prevented from receiving early disease-modifying
treatments. Although the use of SPECT is recommended by the latest expert recommendations [55,64] , this
procedure is seldom performed and still not embedded in the diagnostic algorithms for CA. In the words of
experts, “the systematic addition of SPECT to planar imaging could be considered to be the most important
[61]
addition to the noninvasive testing pathway for CA in the last several years” . Needless to say, this test
should always be complemented with other imaging techniques such as advanced echocardiography and
cardiac magnetic resonance, and the information obtained from different methodologies should be
[2]
integrated to provide the greatest diagnostic accuracy .

Always perform genetic testing in confirmed ATTR-CA cases
Genetic counseling and testing in cases of ATTR-CA is recommended by multiple societies [74,75] .
Nonetheless, screening of elderly populations is increasingly bringing to ATTR-CA diagnosis patients with
associated HFpEF or AS who are in their eighth or ninth decade of life. These patients are frequently
assumed to have a senile form of the disease, and use of genetic testing has been generally inconsistent in
these populations. For example, genetic TTR testing was not routinely performed in patients diagnosed with
ATTR-CA in two recent AS study [24,27] , whereas in several other studies it was generally done only in patients
with a positive bone scintigraphy. Nevertheless, as discussed above, it is known that some mutations may
not lead to positive bone scintigraphy even in the presence of ATTRv-CA [2,73] . This possibility should be at
least taken into account, especially in those patients who have negative bone scintigraphy but in whom a
definitive diagnosis is not reached (i.e., “unspecified”) as it was reported in two recent studies [21,30] . Even in
the context of referral center for CA, genetic testing for transthyretin mutations is currently performed in
about 70% of patients with confirmed ATTR-CA . Failure to test, even in elderly ATTR-CA patients, may
[61]
result in missed opportunities to identify and counsel family members at risk and to offer certain therapies
that are only approved for patients with ATTRv-CA.

Cost-effectiveness of diagnosing and treating ATTR-CA later in life
Patients screened because considered at risk (particularly HFpEF and AS ones) are frequently diagnosed
with ATTR-CA in their eight decade of life [20,21,24,25,27,28] . In some cases, the diagnosis of ATTR-CA comes at a
time when the patient has just undergone the treatment of a major cardiovascular conditions, such as AS
with valve replacement [24,26,27] (which should significantly ameliorate their prognosis), or during one of
multiple HF hospitalizations [20,21] (which represent indicators of poor outcomes). Not only the very old age
and recent AS treatment or HF hospitalization, but also the great burden of comorbidities that usually occur
in these patients might make any estimation of their life expectancy quite difficult, regardless of the
presence of ATTR-CA. Prescription of costly medications in this setting is not straightforward; it should be
not taken for granted but carefully evaluated and justified. In addition, these ATTR-CA populations do not
[8]
exactly match those enrolled in clinical trials in which treatment with tafamidis has proven to be effective ,
and the potential prognostic impact of this therapy in these selected populations has yet to be demonstrated.
On the contrary, preliminary analysis showed that patients treated with tafamidis at earlier stages of the
ATTR-CA disease seemed to gain the greatest prognostic benefits .
[8]