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Brain & Heart Transforming transthyretin cardiac amyloidosis

and left ventricular hypertrophy. In postmortem studies, ATTR-CM. Once considered a rare and untreatable
1
amyloid deposits have been detected in approximately condition, ATTR-CM is now increasingly recognized
25% of unselected older patients. However, owing to as a disease that can be diagnosed and treated, thereby
the non-specific nature of the symptoms, CA is often significantly improving patient outcomes. Considering
8,9
underdiagnosed. In addition, 13 – 19% of individuals the median survival rate of 2 – 6 years after diagnosis, early
suffering from HF with a preserved ejection fraction identification and intervention are crucial to improving the
present with amyloid involvement. Fatigue and dyspnea quality of life and survival of patients with ATTR-CM. 10,11
1
are common symptoms of HF in older adults. These The primary goals of treating ATTR-CM are to
manifestations should prompt physicians to consider CA improve organ function, manage symptoms, and slow or
in their differential diagnosis, as these signs are frequently halt disease progression. Traditional HF therapies, such
observed in patients with this condition. Amyloid fibrils as beta-blockers and angiotensin-converting enzyme
can also accumulate in the atrium and conduction system, inhibitors or angiotensin II receptor blockers, which
causing arrhythmias, heart block, and atrial tachycardias, address the symptoms of HF, do not target the underlying
including atrial fibrillation, thus further complicating the cause of amyloid deposition. Consequently, a significant
10
clinical picture. CA, particularly in older patients with focus has been placed on developing disease-modifying
HF, has been increasingly recognized among the medical therapies that directly address the pathology of ATTR-CM.
community. 2 Current treatments for ATTR-CM aim to either reduce the
The pathophysiology of CA involves the accumulation production of TTR or stabilize the TTR tetramer, thereby
of misfolded proteins within the myocardium, resulting preventing its dissociation and subsequent amyloid fibril
in restrictive cardiomyopathy. One of the key proteins formation. 2
involved in this process is transthyretin (TTR), a protein Tafamidis, a TTR stabilizer that has been shown to
produced primarily in the liver. TTR plays a crucial role significantly improve outcomes in patients with ATTR-CM,
in the transport of thyroxine and retinol-binding proteins. is one of the most promising treatment options. The drug
However, under pathological conditions, TTR can mediates its action by binding to the thyroxine-binding
misfold, leading to the formation of amyloid fibrils that are site on the TTR tetramer, which stabilizes the protein
deposited in the heart and other organs. 3 and prevents it from dissociating into amyloidogenic
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Structurally, TTR is a homotetramer composed of four monomers. The landmark ATTR-ACT trial demonstrated
identical monomers, each comprising 127 amino acids the efficacy of tafamidis in treating ATTR-CM. In
arranged in a barrel-like structure. As the dissociation of particular, the results showed that tafamidis significantly
the TTR tetramer into monomers is the rate-limiting step reduces the mortality and functional decline rates in
12
in amyloid formation, the stability of the TTR tetramer is patients with ATTR-CM. The trial included patients with
critical. Once dissociated, the misfolded TTR monomers the wild-type and variant forms of ATTR-CM and found
3
aggregate into amyloid fibrils, which are then deposited in that tafamidis improved survival rates and reduced the
the myocardium, leading to TTR amyloid cardiomyopathy number of cardiovascular event-related hospitalizations.
4
(ATTR-CM). The amyloidogenic potential of TTR is Importantly, tafamidis was also shown to improve the
exacerbated by aging, which may explain the increased quality of life of patients by slowing the progression
prevalence of CA in older populations. Amyloid deposits of functional limitations, thereby allowing patients to
formed from TTR are classified into two main types: maintain their independence for longer periods. 12
wild-type ATTR (ATTRwt) and variant ATTR (ATTRv). In light of these findings, tafamidis has emerged as the
ATTRwt, also referred to as senile CA, occurs sporadically first Food and Drug Administration-approved treatment
in older individuals, whereas ATTRv is an inherited type of for ATTR-CM, representing a major milestone in the
disease caused by mutations in the TTR gene. 4,5 management of this condition. Considering its ability to
In recent years, ATTR-CM has gained significant stabilize TTR and prevent amyloid deposition, tafamidis
attention due to its increasing prevalence as well as is considered a cornerstone of therapy for patients with
7
advancements in diagnostic methods and the introduction ATTR-CM. However, despite its efficacy, tafamidis is not
of targeted therapies. Traditional methods for diagnosing a curative option. Although the drug can slow disease
CA involved invasive procedures such as endomyocardial progression, it does not reverse existing amyloid deposits,
biopsy. However, recent innovations, such as non-invasive highlighting the importance of early diagnosis and
8
nuclear scintigraphy, allow the diagnosis of ATTR-CM intervention.
without the need for biopsy. These advancements have CA is a complex condition that is frequently undiagnosed,
6,7
led to a paradigm shift in the way clinicians approach particularly in older patients with HF. The development of

Volume 2 Issue 4 (2024) 2 doi: 10.36922/bh.4250