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Page 8 of 13 De Gaspari et al. Vessel Plus 2022;6:57 https://dx.doi.org/10.20517/2574-1209.2022.05

Histological features
Ventricular myocardium
Deposition of amyloid in the myocardium can be quite variable. Infiltration has been described in terms of
percentual or semiquantitative quantification, pattern, and localization. In whole hearts, the trabecular layer
[41]
seems to be the most involved from the infiltration process . Amyloid patterns are non-homogeneously
defined in different papers, with variable descriptions of segmental, nodular, perifiber, pericellular, and
diffuse deposition. Amyloid is variably associated with myocardial fibrosis, often described only as mild
interstitial fibrosis but in some cases with significant extent, especially in cases with intramyocardial
vascular involvement [50,51] . Cardiomyocytes adjacent to amyloid deposits can show non-specific alterations
[52]
such as perinuclear halos, cytoplasmic vacuolization, and cell atrophy . The presence itself of the misfolded
proteins has been hypothesized as a cause of direct damage to the cardiomyocytes via apoptotic cell death,
leading to cardiac dysfunction and subsequent heart failure [19,53,54] .

The presence of amyloid fibrils inside the myocardium can have a direct cytotoxic effect, for both AL and
TTR fragments [17,55] . This direct damage can contribute to the upregulation of an inflammatory response,
positively correlating with disease severity. Histologically proven myocardial inflammation in CA has been
linked with the worst prognosis in a large series of EMB, particularly in CA-AL . However, different
[56]
studies reported variable results in terms of association of myocardial inflammation and amyloidosis: no
stress about inflammation is put in the notable autopsy series [38-42] , whereas, in EMB papers, there is varied
description of clusters of histiocytes, myocardial edema, and eventually plurifocal interstitial CD3+
lymphocytes in association with amyloid [51,52,57] . Isolated reports on the concomitant presence of CA and
acute myocarditis are quite frequent, including in the recent context of SARS-CoV-2-associated myocardial
injury [58-60] .

Atria
Atrial involvement by amyloid deposits is very common. The buildup can be both intramyocardial and
endocardial, the latter also being evident at gross analysis as a rugged or beadlike appearance, if very marked
and diffuse [39,40] . In ATTR as well, atrial infiltration by amyloid, in particular of the left atrium, has been
linked to a progressive increase in stiffness correlating with poor prognosis . A different form of atrial
[61]
involvement can be found in the so-called “isolated atrial amyloidosis” (IAA) caused by the accumulation of
atrial natriuretic peptide or factor (ANF). IAA has typically fine deposits, unlike AL-CA and ATTR in
which large plaques can occur [62,63] . This form appears to be age-related and has been commonly associated
with heart failure, in which ANF levels are usually very high [64,65] .

Vessels
Vascular involvement in CA is frequent and variegated. While epicardial main coronary vessels are typically
spared from the condition (or limitedly involved without significant luminal obstruction), intramyocardial
arteries, veins, and capillaries are usually involved in different grades by the deposits [39,42,66] . The vasa
vasorum of the epicardial coronary arteries also has considerable amyloid buildups. A peculiar phenotype of
intramural vessel involvement by amyloid with vascular obstruction has been widely described, sometimes
linked with myocardial necrosis as well as acute onset of heart failure mimicking acute myocarditis [67-70] . This
microvascular amyloid infiltration coupled with ischemic damage could explain the frequent elevation of
troponin levels even in the absence of epicardial coronary lesions [71,72] . Vascular involvement is far more
frequent in CA-AL compared to ATTR, acting as a relevant prognostic factor as well [40,50,73] .

A different form of vascular amyloidosis is the isolated aortic amyloidosis caused by the buildup of a fibril
different from light chains and TTR: the precursor is lactadherin and the accumulating fragment is called