Disease-Modifying Pharmacological Therapies for Transthyretin Cardiac Amyloidosis
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MEDICINE
Disease-Modifying Pharmacological Therapies for Transthyretin Cardiac Amyloidosis Jay H. Park 1
&
Laura F. Cei 1 & Keyur B. Shah 1
Accepted: 17 July 2020 # Springer Nature Switzerland AG 2020
Abstract Transthyretin-related cardiac amyloidosis is a disease that is poorly understood and challenging to manage; however, pharmacotherapeutic developments in recent years has raised awareness and promoted earlier diagnosis. Transthyretin protein is a thyroid hormone-binding protein which transports thyroxine from the bloodstream to the brain, and cardiac involvement is either acquired or hereditary. This protein can misfold and lead to abnormal fibril formation, causing the extracellular deposition of ATTR into the heart. Further fibril deposition leads to irreversible organ dysfunction. Disease-modifying pharmacological therapies can be divided into three categories: ATTR stabilizers (diflunisal, tafamidis, and AG10), ATTR silencers (patisiran and inotersen), and ATTR disruptors (doxycycline and ursodeoxycholic acid and polyphenol (-)-epigallocatechin gallate). This manuscript reviews these emerging pharmacological treatments available and under study for ATTR cardiac amyloidosis. Keywords ATTR . Cardiac amyloidosis cardiomyopathy . Heart failure . Transthyretin . Pharmacological treatment
Introduction The amyloidoses are classified as a group of diseases related to protein misfolding wherein uncontrolled fibrillogenesis result in amyloid deposits. Over thirty proteins have been identified as being amyloidogenic. These proteins deposit into tissues and organs locally or systemically, including the liver, central nervous system, skin, and heart. These misfolded proteins disrupt the normal function of the organs, thus inducing a range of symptoms dependent upon the pattern of protein trafficking and deposition (Fig. 1) [1, 2]. Immunoglobulin light chain, also known as AL or primary amyloidosis, and transthyretin amyloidosis, also known as ATTR, are the two most commonly diagnosed types of cardiac amyloidosis [3]. Transthyretin (TTR) is a homotetramer protein primarily produced in the liver as well as in the choroid plexus. Its function is to transport
This article is part of the Topical Collection on Medicine * Keyur B. Shah [email protected] 1
Heart Failure/Transplantation, Division of Cardiology, The Pauley Heart Center, Virginia Commonwealth University, MCV Campus, P.O. Box 980204, Richmond, VA 23298-0204, USA
thyroxine and retinol protein [4, 5]. A genetic mutation or age-related factors may destabilize the tetramer causing the quaternary structure to form unstable monomers, leading to monomer misfolding and amyloid fibril formation. These fibrils then deposit into the heart or the nervous system, thus, initiating organ dysfunction [6]. ATTR is further broken down into two subtypes: mutant transthyretin (ATTRm) and wild type transthyretin (ATTRwt). ATTRwt is a genetically unaltered protein that is amyloidogenic and is considered to be sporadic in nature with symptom manifestation later in life.
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