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Page 4 of 13 De Gaspari et al. Vessel Plus 2022;6:57 https://dx.doi.org/10.20517/2574-1209.2022.05

Immunoglobulin light chains can cause cardiac impairment both by mechanical stress due to deposition
and by direct toxicity; this could explain the fact that sometimes AL-CA is clinically more severe than other
types of amyloidosis given an apparently similar degree of amyloid deposition in the heart [17-19] .Since
patients affected by AL amyloidosis commonly have an underlying plasma cell dyscrasia ranging from
monoclonal gammopathy of uncertain significance (MGUS) to multiple myeloma, the main treatment is
chemotherapy to address the plasma cell proliferation, with regimens including bortezomib,
cyclophosphamide, and dexamethasone. The aim of this strategy is to rapidly reduce the production of
amyloidogenic light chains to limit the progressive damage to the involved organs, considering that the
resolution of amyloid deposits is virtually impossible.

TTR amyloidosis
TTR amyloidosis (ATTR) occurs when dissociated TTR monomers misfold and assemble into amyloid
fibrils. TTR is a tetramer protein produced primarily in the liver that becomes amyloidogenic when it
dissociates into monomers. Two types of fibrils have been recognized as responsible for ATTR: Type A
consists of C-terminal ATTR fragments and full-length TTR, whereas Type B consists only of full-length
[20]
TTR. Every patient contains ATTR deposits of either Type A or B fibrils . Two distinct types of ATTR
exist: hereditary or mutated (ATTRmt) and wild-type (ATTRwt), also referred to as senile systemic
amyloidosis, age-related amyloidosis, or senile cardiac amyloidosis. Type A fibrils appear to occur in most
TTR variants including ATTRwt, while Type B fibrils are seen in some ATTRmt mutations . ATTRmt is a
[21]
rare autosomal dominant condition caused by mutations in the TTR gene. The most common mutation in
ATTRmt is Val30Met. Clinical manifestations are mainly cardiovascular, neurological, or mixed .
[22]
ATTRmt patients are usually younger than ATTRwt patients, with a median age at onset of 39. Phenotypic
heterogeneity is wide and results from different factors: the different TTR mutations, the geographic region
of the patient, and the Val30Met aggregation (endemic or nonendemic). The curative therapy for ATTRmt
is ortothopic liver transplantation or combined heart-liver transplantation, which can provide a sort of
surgical gene therapy in particular for amyloidotic cardiomyopathy . For patients with ATTR
[23]
cardiomyopathy, new promising disease-modifying therapies have been developed, with specific targets
including TTR silencing, TTR stabilization, and TTR disruption. TTR protein silencers (patisiran and
inotersen) target the hepatic synthesis of TTR. Tafamidis and diflunisal are TTR stabilizers with the former
being the only authorized drug for the treatment of ATTR cardiomyopathy. Other agents are under
investigation for a role in TTR disruption (tauroursodeoxycholic acid and monoclonal antibodies), but their
[24]
benefits are uncertain .

CLINICAL DIAGNOSIS
CA diagnosis can be reached through invasive or non-invasive strategies, the latter available only for ATTR.
The disease should be suspected when typical signs and symptoms appear, the so-called “red flags”:
proteinuria (even mild), macroglossia, skin bruises, and carpal tunnel syndrome. For what concerns the
heart, congestive heart failure coupled with unexplained left ventricular (LV) hypertrophy at imaging is a
prominent feature. Additional signs that can suggest CA are persistent troponin elevation, disproportionally
low QRS voltage at the electrocardiogram (ECG), or early conduction system disease. The presence of
discrepancy between a low-voltage ECG and an increased LV wall thickness on two-dimensional
echocardiography is highly suggestive of cardiac amyloidosis (particularly AL amyloidosis) .
[25]

Non-invasive diagnosis (without histological sampling) is possible only for cardiac ATTR when a
combination of clinical and imaging findings is documented: typical echocardiographic or cardiac magnetic
resonance (CMR) findings need to be present in addition to positive scintigraphy [ Tc-pyrophosphate
99m
(PYP), 99m Tc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD), or 99m Tc-hydroxymethylene