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

these findings are related to those previously described showing an increasing likelihood of ATTR-CA in
patients diagnosed with HCM at ≥ 40 years of age, the potential for a HCM misdiagnosis and missed CA
diagnosis in these patients should be carefully considered. Further complicating the matter, several works
are available describing the possibility of ATTR-CA presenting with features usually related to HCM, such
as asymmetric LVH primarily involving the interventricular septum and left ventricular outflow tract
obstruction. A cardiac magnetic resonance study of 263 patients with a definite diagnosis of ATTR-CA
found asymmetric septal LVH in 79% of cases , and cases of ATTR-CA patients with outflow tract
[54]
obstruction at rest or during stress have been reported [55,56] .

The increasing possibility of misdiagnosing HCM in patients with suspected ATTR-CA is not only due to
the abovementioned changes in epidemiology of HCM and its overlapping features with ATTR-CA, but
[57]
also to the progressive increase in survival observed in HCM patients, with longevity to 90 years or older .
This allows, as in the case of AS patients described above, for the presence of a dual pathology responsible
for the LVH of these subjects, i.e., an innate sarcomeric mutation plus an age-related infiltrative disease.

The changing epidemiology of ATTR-CA intersects with these evolving concepts in the epidemiology of
HFpEF, AS, and HCM. Greater attention to the diagnostic and therapeutic pathways of patients affected by
these conditions is therefore warranted in the near future and should involve not only cardiologists but also
all physicians taking care of these patients. Knowledge of the changing epidemiology of these conditions
should allow bringing ATTR-CA patients earlier at diagnosis and treatment.

UNDERSTANDING THE EPIDEMIOLOGY OF CARDIAC AMYLOIDOSIS: CAVEATS AND
PITFALLS
Screening the abovementioned at-risk conditions will likely be the key for earlier diagnosis and treatment of
ATTR-CA in the next future. However, all screening procedures must strike a balance between the
proportions of false positives and false negatives that they will tolerate. This is especially true for those
screening procedures whose the risk-benefit ratio has not yet been fully elucidated, such as in the case of
ATTR-CA. Screening procedure are often designed to avoid false negatives, because it is generally
considered worse to miss a case than to do an unnecessary complete diagnostic workup. On the other end,
the cost of unnecessary investigations as well as the possibility of needlessly exposing a patient to unpleasant
[58]
or life-threatening procedures makes it important to keep the false alarm rate low as well . These issues
apply to ATTR-CA screening as well, for which some important remarks are worth being made [Figure 1].

Never forget to screen properly for AL-CA
The prognosis of AL-CA is significantly worse than that of ATTR-CA (usually in the range of months vs.
years), thus delaying AL-CA diagnosis can significantly and adversely impact prognosis for affected
patients . Unfortunately, ATTR-CA misdiagnosis due to failure to properly exclude AL-CA in patients
[59]
with a positive cardiac scintigraphy still represents a major issue [59-61] . Notably, a monoclonal gammopathy
of undetermined significance might be present in up to 40% of patients with ATTR-CA . In the presence
[62]
of a monoclonal gammopathy, a tissue biopsy with amyloid typing is recommended to establish a diagnosis
of amyloidosis. An endomyocardial biopsy is necessary to assess for cardiac involvement especially in those
cases with a negative extracardiac biopsy but a high suspicion of CA . However, this is an invasive
[2,7]
procedure that is performed only by a few institutions and whose interpretation requires specific techniques
and expertise . Myocardial uptake in AL-CA represents one of the greatest issues with false-positive results
[63]
at bone scintigraphy. This has been demonstrated in as many as 27% of patients with endomyocardial
biopsy-confirmed AL-CA and grade 2 or 3 cardiac uptake on planar images . The mechanisms for the
[2,7]
differential uptake of bone tracers in ATTR-CA vs. AL-CA are unknown and may be related to