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Page 2 of 11 Shah et al. Vessel Plus 2021;5:53 https://dx.doi.org/10.20517/2574-1209.2021.76

[1]
thyroxine hormone and retinol-binding protein . The full scope of its physiologic role and mechanism of
degradation remain incompletely elucidated; however, the predominant hypothesis is that the protein is
naturally unstable and prone to misfolding in-vivo. TTR protein can be either wild-type (ATTRwt) or one of
many pathologic variants (ATTRv). Misfolded TTR protein molecules aggregate into amyloid fibrils and
deposit in several organs of the body. However, the myocardium and autonomic nervous system appear to
[2]
be most susceptible . Individual survival is most strongly correlated with the degree of myocardial
deposition and the resultant severity of restrictive physiology .
[3]
ATTR has a male-predominant distribution and appears to be more common than previously estimated.
Myocardial ATTRwt deposition may be present in up to 10% of all elderly patients with heart failure and
[4]
one-third of elderly patients with heart failure with preserved ejection fraction . Additionally, the p.V142I,
[5]
formerly referred to as V122I, variant may be present in up to 3.4% of all African Americans and up to 10%
of African Americans with heart failure . Median survival after initial diagnosis is 3.6 years for ATTRwt
[6]
and 2.5 years for ATTRv due to the p.V142I mutation.

The cornerstone of treatment in ATTR-CM remains prompt diagnosis, particularly in high-risk
populations. Cardiac amyloidosis is initially suspected based on characteristic findings on echocardiography
and/or cardiac magnetic resonance imaging. Alternative types of cardiac amyloidosis, specifically light chain
amyloidosis (AL), are then screened for with the use of serum-free light chain testing and immunofixation
electrophoresis testing . Definitive diagnosis of ATTR previously required endomyocardial biopsy, but now
[7]
99m
can more readily be made using scintigraphy with bone-avid radiotracers such as Tc-pyrophosphate, 99m
Tc-3,3-diphosphono-1,2-propanodicarboxylicacid, and Tc-hydroxymethylene diphosphonate . Once AL
99m
[8]
amyloidosis is ruled out on laboratory testing, a diagnosis of ATTR-CM should be followed up with genetic
testing to differentiate ATTRwt from ATTRv. Hereditary amyloidosis should prompt genetic counseling,
screening of first-degree family members, and evaluation and treatment of neuropathy, which is more
common in ATTRv. Biomarkers such as circulating retinol-binding protein 4 or misfolded ATTR oligomers
may serve supplementary roles in select populations; however, further studies are required before their
routine clinical use.

Symptomatic management includes diuresis with loop diuretics, blood pressure control if needed without
[9]
causing orthostatic hypotension, and arrhythmia management . Patients with cardiac amyloidosis typically
poorly tolerate many of the cornerstones of conventional heart failure therapy, especially beta-blockers. The
role of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and angiotensin receptor-
neprilysin inhibitors remains unknown.

More recently, disease-specific pharmacotherapies for ATTR-CM have emerged and become more readily
available. These advances in the pharmacotherapeutic management of the disease have shown significant
improvements in both patient morbidity and mortality. Pharmacotherapy can be subdivided into the
following categories: (1) TTR silencing through mRNA knockdown or silencing; (2) TTR stabilization; and
(3) TTR resorption or extraction [Table 1]. As these classes of medications target distinct steps in the
production and degradation of the TTR molecule, combination therapy is possible, and indeed may be
beneficial.

TTR SILENCING
Small interfering messenger RNA
Production of the TTR molecule, whether wild-type or variant, can be reduced by inhibiting the translation
of its associated messenger RNA (mRNA). Through the activity of small interfering RNA (siRNA),