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Page 2 of 14 Porcari et al. Vessel Plus 2022;6:33 https://dx.doi.org/10.20517/2574-1209.2021.134

INTRODUCTION
Cardiac amyloidosis (CA) is characterized by extracellular deposition of misfolded proteins, mostly
immunoglobulin light chains (AL) produced by an abnormal clonal proliferation of bone marrow plasma
cells and transthyretin (TTR) protein. In TTR amyloidosis (ATTR), the mechanism leading to tissue
infiltration are related to age-related failure of homoeostatic mechanisms in wild-type TTR (wtTTR) or
[1]
destabilizing mutations in variant TTR (vTTR) . The epidemiology of CA is rapidly evolving due to
increased awareness of disease, identification of clinical red flags, and the possibility to achieve a non-
[2,3]
invasive diagnosis with cardiac scintigraphy with bone tracers .

Furthermore, the availability of novel therapeutic strategies both in AL and ATTR-CA with proven impact
[4,5]
on survival has provided a new impulse towards an early diagnosis : bortezomib and daratumumab for AL
amyloidosis and TTR stabilizers, small interfering RNA, and antisense oligonucleotides for ATTR
[6,7]
[4]
amyloidosis . While chemotherapy has long been studied for the treatment of AL-CA and can improve
overall outcome, data of a survival benefit from specific treatments for ATTR-CA currently come from a
single clinical trial . Therefore, a multidisciplinary approach is essential for the management of these
[8]
[9]
patients . CA is currently recognized as a relatively prevalent, still under-diagnosed disease and an
emerging cause of heart failure (HF) and mortality . In particular, specific populations have been reported
[10]
at increased prevalence of ATTR-CA : 13% of patients with HF with preserved ejection fraction
[10]
(HFpEF) , 5% of patients with a previous diagnosis of hypertrophic cardiomyopathy, 10% of patients with
[11]
[12]
unexplained cardiac hypertrophy at the time of carpal tunnel syndrome , and 16% of those with severe
calcific aortic valve stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI) [13,14] [Table 1].
The epidemiology of the disease, the contemporary natural history of CA, and the identification of tools for
accurate prognostic stratification are the fundamental questions awaiting clarification. In this evolving
scenario, the optimal “supportive” treatments for CA patients with HF represents a largely unexplored
[15]
field . This review focuses on the effectiveness and tolerability of evidence-based HF medication, rate vs.
rhythm control in atrial fibrillation (AF), thromboembolic risk and anticoagulation therapies, replacement
of severe AS, impact of implantable cardioverter defibrillator (ICD) on survival, and usefulness of cardiac
resynchronization therapy (CRT) [Figure 1]. The aim is to provide practical suggestions for daily clinical
activity in the management of patients with CA.

Pathophysiology and mechanisms of cardiac damage in AL and TTR CA
While AL-CA results from a plasma cell dyscrasia where clonal plasma cells produce monoclonal amyloid
precursors, ATTR-CA derives from the cardiac infiltration by wtTTR or vTTR proteins produced mostly by
the liver . Although the atria and ventricles are typically involved, amyloid can infiltrate every area of the
[2]
[16]
heart [Figure 2]. Cardiac damage results from a double-hit process involving amyloid deposition and a
direct “toxic” effect exerted by circulating preamyloid proteins causing oxidative stress and mitochondrial
damage, especially for free light chains [17-19] . TTR oligomers and protofibrils have been demonstrated to
induce nerve cytotoxicity by caspase-3 activation, triggering the onset of programmed cell death .
[20]
Although exposure of cardiomyocytes to TTR protofilaments is thought to be mediated by a similar
mechanism, conclusive evidence of a direct cardiac damage is currently lacking. Thickened biventricular
walls, dilatation of both atria, and poor diastolic filling due to noncompliant ventricles are hallmarks of
CA . The increase in myocardial mass determines a progressively smaller ventricular cavity size, resulting
[16]
[21]
in a condition of fixed end-diastolic volume (i.e., pre-load) . In this model of cardiomyopathy, right and
left ventricular ejection fraction (LVEF) tend to be preserved up until higher burdens of cardiac infiltration.
In the presence of overt restrictive pathophysiology, severe dilatation of both atria occurs, cardiac output
becomes critically dependent on heart rate, and arterial hypotension is established, reflecting the most