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Page 2 of 13 Canepa et al. Vessel Plus 2022;6:30 https://dx.doi.org/10.20517/2574-1209.2021.106

Keywords: Amyloidosis, transthyretin, light chain, epidemiology, heart failure, aortic stenosis, hypertrophic
cardiomyopathy, hypertrophy

INTRODUCTION
Cardiac amyloidosis (CA) is an infiltrative disease of the myocardium, in which different proteins may
[1]
deposit within the myocardial interstitium causing an increase in cardiac wall thickness, progressive
cardiac dysfunction and heart failure (HF), conduction disturbances, and arrhythmias . The two most
[2]
prevalent forms of CA are due to the deposition of: (1) immunoglobulin light chains (AL) produced from
plasma cells in the context of plasma cell dyscrasia (among which is multiple myeloma) ; and (2)
[3]
[4]
transthyretin (TTR) . Transthyretin-related CA (ATTR-CA) is a result of either a genetic mutation in the
gene coding for this protein (ATTRv-CA, variant) or advanced age (ATTRwt-CA, wild-type or senile),
which determines TTR tetramer dimerization and subsequent formation of aggregation of monomers
within the myocardium.

In this narrative review, we summarize the most recent evidence concerning the changing epidemiology of
CA. Then, some final remarks are made concerning open challenges in its diagnostic workup and
therapeutic management, highlighting the importance of adhering to the recommended CA diagnostic
algorithm to avoid misdiagnosis and discussing the opportunity of screening populations at risk of CA to
initiate disease-specific treatments. Pertinent articles were identified through a MEDLINE search of the
English language literature up to April 2021, followed by a manual selection of manuscripts discussing the
abovementioned topics and considered most relevant by the authors.

WHAT IS KNOWN ABOUT THE EPIDEMIOLOGY OF CARDIAC AMYLOIDOSIS
Systemic amyloidosis is listed among rare diseases within international rare diseases’ databases such as
Orphanet (www.orpha.net) and NORD (https://rarediseases.org). A prevalence lower than 1/2000 has been
estimated for AL and ATTR amyloidosis, which is why both conditions are nowadays considered rare.
Nonetheless, when one refers specifically to amyloidosis with cardiac involvement, updated epidemiological
data are lacking (as discussed below), and it is in the opinion of renowned experts worldwide that the
prevalence of some forms of CA, including AL-CA and ATTRwt-CA, might actually be higher than it is
[3,4]
usually believed . CA is, indeed, difficult and challenging to diagnose, with about a third of all AL-CA
patients being seen on average by more than four specialists before reaching final diagnosis . Significant
[5]
[6]
delays in diagnosis also exists for ATTR-CA . However, the epidemiological scenario of CA is rapidly
evolving and this condition is increasingly diagnosed , particularly because of two recent discoveries: first,
[3,4]
the possibility of performing a non-invasive diagnosis of ATTR-CA in a vast majority of cases and, second,
the demonstrated efficacy of specific treatments aiming at interrupting the progression of myocardial TTR
infiltration. Indeed, the algorithm proposed by Gillmore et al. in 2016 (and still considered the reference
[7]
diagnostic standard for ATTR-CA by the most recent Position Paper of the European Society of Cardiology
on CA ) introduced the possibility of a non-biopsy diagnosis of ATTR-CA by means of bone scintigraphy
[2]
in the vast majority of cases. Two years later, the results of the Tafamidis in Transthyretin Amyloid
Cardiomyopathy Clinical Trial (ATTR-ACT) were presented, showing the safety and efficacy of tafamidis -
a selective TTR kinetic stabilizer - in reducing all-cause mortality and cardiovascular-related
hospitalizations in heart failure (HF) patients diagnosed with ATTR-CA [Figure 1] . These advancements
[8]
in the diagnostics and therapeutics of ATTR-CA are expected to have a positive impact on reducing
diagnostic delays in AL-CA and potentially increasing its incidence and prevalence.