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Page 2 of 4 Sinagra et al. Vessel Plus 2022;6:44 https://dx.doi.org/10.20517/2574-1209.2021.143

Cardiac amyloidosis: no more a needle in a haystack
In the contemporary era, CA has emerged as a relatively prevalent and underdiagnosed cause of heart
[2,5]
failure (HF), associated with significant morbidity and mortality worldwide . As underlined by Canepa
et al. on the changing disease prevalence, the exact epidemiological figures of CA are still under
[6]
investigation. AL has traditionally been considered the most common form of systemic amyloidosis with
recent data reporting an incidence of ≈ 1 per 100,000 individuals per year with cardiac involvement in half
of the cases . However, available estimates of CA prevalence and incidence are subject to referral bias, and
[2]
longitudinal surveys (i.e., the Transthyretin Amyloidosis Outcomes Survey) suggest ATTR amyloidosis to
be significantly more prevalent than previously thought . CA, especially ATTR amyloidosis, was found to
[2,7]
be more frequent in specific populations, e.g., 4% of subjects undergoing bilateral carpal tunnel surgery
(CTS), 10% of patients with unexplained cardiac hypertrophy at the time of CTS , 13% of individuals
[8]
hospitalized for HF with preserved ejection fraction, 5% of patients with hypertrophic cardiomyopathy, and
16% of patients with “paradoxical” low-flow low-gradient aortic stenosis .
[5]
A cutting-edge step forward for diagnosis was the possibility in achieving a non-invasive confirmation of
ATTR-CA in the presence of high-grade cardiac retention (Perugini grade 2–3) in patients without
monoclonal components (99% accuracy, 100% specificity) [9,10] . However, controversies and pitfalls of bone
tracer scintigraphy exist, as critically pointed out by Mattana et al. . Although this approach has increased
[11]
the diagnostic yield and the chance of earlier disease recognition, a consistent diagnostic delay still remains
(≈ 34 months from symptoms onset to diagnosis) . In addition, the non-invasive algorithm suffers from
[12]
some limitations in real-world applications, as in patients with intense cardiac retention at scintigraphy and
monoclonal gammopathy of undetermined significance requiring histological evidence of amyloid deposits
or in the presence of false-negative scintigraphy results due to peculiar TTR mutations (i.e., Phe84Leu and
Ser97Tyr) [9,10] . In this scenario, cardiac magnetic resonance and positron emission tomography can aid
clinicians in the diagnosis and management of the disease, as discussed by Pica et al. and Genovesi
[13]
et al. . Awareness of the pros and cons of each diagnostic strategy in CA is gaining increasing importance
[14]
in daily activity, especially in light of treatment and prognostic implications , as reviewed by Porcari
[15]
et al. . Furthermore, the presence of TTR mutations should be assessed in all patients with ATTR
[16]
amyloidosis to distinguish between wtTTR and vTTR. The clinical translation of genetic testing in TTR
amyloidosis with a focus on genotype–phenotype correlations and the management of asymptomatic
carriers and familial screening was addressed by Scirpa et al. .
[17]

The unmet need for prognostic prediction in CA
Current prognostic stratification in AL- and ATTR-CA relies completely on scores integrating few specific
biomarkers, but more clinical and instrumental parameters are emerging as relevant in the natural history of
CA , as discussed by Camerini et al. and Licordari et al. . In this evolving scenario, the need for
[18]
[19]
[17]
accurate prognostic stratification to guide identification of the best candidates to specific therapies emerges.
CA: a treatable disease
Treatment strategies for ATTR and AL amyloidosis have evolved significantly since orthotopic liver
transplantation — the very first specific therapy for ATTR—was first performed in 1990 . Progress in
[20]
knowledge about the “amyloidogenic cascade” has led to novel therapies including TTR stabilizers and TTR
synthesis inhibitors for ATTR amyloidosis, chemotherapy and stem cell transplantation for AL amyloidosis,
and cardiac transplantation for selected patients with advanced HF . Tafamidis was demonstrated to
[20]
reduce all-cause mortality and cardiovascular hospitalizations in the ATTR-ACT (Safety and Efficacy of
Tafamidis in Patients with Transthyretin Cardiomyopathy”), while Inotersen and Patisiran have been
[20]
shown to drop hepatic TTR production by ≈ 80% in patients with vATTR amyloidosis with neuropathy .
As discussed by Di Nora et al. , AL-CA was previously considered a contraindication to heart transplant
[21]