Diagnosis and treatment of transthyretin‐related amyloidosis cardiomyopathy

Abstract

Transthyretin-related amyloidosis (ATTR) is a subgroup of amyloidosis that results from extracellular misassembled and toxic amyloid deposits affecting multiple organ systems, and cardiac tissues in particular. Because ATTR often presents as heart failure with preserved ejection fraction (HFpEF), it has been largely underdiagnosed. Once considered incurable with a grave prognosis, ATTR cardiomyopathy has seen the development of promising alternatives for diagnosis and treatment, with early diagnosis and treatment of ATTR cardiomyopathy highly beneficial due to its high mortality rate. For instance, diagnosing ATTR cardiomyopathy previously required a cardiac biopsy, but new modalities, such as cardiac magnetic resonance imaging and radionuclide bone scans, show promise in accurately diagnosing ATTR cardiomyopathy. Ongoing research and clinical trials have focused on identifying new treatments which primarily target amyloid fiber formation by inhibiting TTR gene expression, stabilizing the TTR tetramer, preventing oligomer aggregation, or affecting degradation of amyloid fibers. In this review, we describe the advances made in the diagnosis and treatment of ATTR in order to increase awareness of the disease and encourage a lower threshold for ATTR workup. Our review also highlights the need for improving the screening, diagnosis, and treatment guidelines for ATTR cardiomyopathy. K E Y W O R D S heart disease, physical diagnosis/cardiovascular, treatment 1 | BACKGROUND Transthyretin (TTR)-related amyloidosis (ATTR), a rare and underdiagnosed disease, mainly affects the cardiac and peripheral nerves and is fatal if not treated in time. 1 Primarily synthesized in the liver, TTR is a protein that transports vitamin A and thyroxine in plasma and cerebrospinal fluid. 2 The mechanism of transportation involves four oligomers that attach to each other to form two dimers, which in turn form a TTR tetramer that contains the hormone binding site. 2 Through gene mutation or aging of the protein, TTR can become unstable and break up into oligomers, which aggregate into insoluble fibrils called TTR amyloid that deposit into extracellular space or tissues, causing ATTR. 3 Based on the type of precursor and misfolded protein amyloids, there are different types of amyloid diseases from ATTR to light chain amyloidosis (AL), which is caused by aggregation of immunoglobulin light chains produced by plasma cells in the bone marrow. 4 Depending on the type of precursor protein, different protein amyloids target Catherine Teng and Pengyang Li contributed equally to this review article.

A Late Diagnosis of Transthyretin Amyloidosis

“…The finding of a wall thickness greater than 12 mm in the absence of other heart conditions, such as aortic valve disease or systemic hypertension, should warrant a strong suspicion of cardiac amyloidosis [5,7].…”

“…This results in a phenotypic expression most common in younger females of African descent [ 4 ]. This has diagnostic implications for first-degree family relatives, as they are inherited as autosomal dominant disorders [ 5 ].…”

“…The noninvasive modalities that can suggest the diagnosis include echocardiography, cardiac magnetic resonance (CMR), EKG, and serum biomarker testing (B-type natriuretic peptide [BNP] and cardiac troponin). The finding of a wall thickness greater than 12 mm in the absence of other heart conditions, such as aortic valve disease or systemic hypertension, should warrant a strong suspicion of cardiac amyloidosis [ 5 , 7 ].…”

Data Mining for the Identification of Known and Candidate Transthyretin Amyloidosis Variants in the Saudi Population

“…A recently published Japanese expert opinion recommended periodic clinical assessment as well as various investigations in monitoring asymptomatic gene mutation carriers [31]. With the advent of drugs that help stabilize the TTR tetramer, reduce tissue deposition and possibly slow disease progression, [34] an early diagnosis guided by genetic screening should be strongly pursued. Such drugs may well prove to be more effective if administered before the development of overt tissue involvement and organ damage.…”

Restrictive cardiomyopathy: from genetics and clinical overview to animal modeling

“…In contrast, ATTR amyloidosis is more common in patients older than 80 years [3,25] and is prevalent among patients with heart failure, especially HFpEF [26]. However, the true prevalence of RCM in ATTR remains largely unknown [27].…”