Recent Progress in the Development and Clinical Application of New Drugs for Transthyretin Cardiac Amyloidosis

Published: Nov 30, 2023
Category
Scientific Articles
Key Information
Source
National Library of Medicine
Year
2023
summary/abstract

Abstract:

Transthyretincardiac amyloidosis is a rare disease that has gained significant attention in recent years because of misfolding of transthyretin fibrils produced by the liver, leading to their deposition in the myocardium. The disease has an insidious onset, nonspecific clinical manifestations, and historically lacked effective drugs, making early diagnosis and treatment challenging. The survival time of patients largely depends on the extent of heart involvement at the time of diagnosis, and conventional treatments for cardiovascular disease do not provide significant benefits. Effective management of the disease requires treatment of its underlying cause. Orthotopic liver transplantation and combined hepato-heart transplantation have been clinically effective means of treating transthyretin cardiac amyloidosis mutants for many years. However, transplantation has many limitations in clinical practice. In recent years, the development of new drugs has brought new hope to patients. This review presents the latest advances in drug development and clinical application to provide a reference for clinicians managing transthyretin cardiac amyloidosis.

Key Words: cardiac amyloidosis, transthyretin, heart failure, medication, therapy

INTRODUCTION

Transthyretin cardiac amyloidosis (ATTR-CA), also known as transthyretin amyloid cardiomyopathy, is one of the 2 most common types of cardiac amyloidosis (CA), and advanced cardiac amyloidosis is physiologically characterized as a restrictive cardiomyopathy. Amyloidosis is a systemic disease characterized by the misfolding of protein structures to form insoluble abnormal amyloid fibrils that are deposited in tissues and cause organ dysfunction. There are more than 30 types of proteins that form amyloid fibrils and cause amyloidosis. The most common type of protein that causes cardiac amyloidosis is immunoglobulin light-chain cardiac amyloidosis (AL-CA), which is caused by the clonal plasma cells secreting immunoglobulin light chain (AL), and transthyretin (TTR), a protein produced by the liver (formerly known as prealbumin) that causes ATTR-CA.–

TTR amyloidosis (ATTR) is divided into hereditary/variants (ATTRv) and wild type (ATTRwt) based on whether TTR has a gene mutation. More than 150 mutations in the TTR genes have been shown to cause ATTRv, and Val30Met is the most common mutation, associated primarily with neuropathy. It is endemic in Portugal, Japan, Sweden, and Majorca. The 4 mutations, namely Val122Ile, Leu111Met, Thr60Ala, and Ile68Leu, represent the predominant causative variants of ATTR-CA. Val122Ile is primarily prevalent among individuals of African American descent while Thr60Ala is more frequently observed in individuals of Irish heritage. The remaining 2 mutations are more commonly encountered in populations from Denmark and Italy. The clinical phenotypes of ATTRv amyloidosis include primary cardiomyopathy, polyneuropathy, and mixed type. ATTRwt is the transthyretin gene sequence that is normal, late-onset, predominantly male syndrome of cardiac amyloidosis, which mainly impairs the heart, kidney, thyroid, tendon and ligament tissues (hand, root canal, and ligamentum flavum), lung, and peripheral nerves, common in men older than 60 years, aging may contribute to its onset. Despite underdiagnosis and missed diagnosis, more than 50,000 patients have ATTRv amyloidosis worldwide., The 2016 ATTR Large Multicenter Study of THAOS (Clinical Trial Number NCT00628745) showed a high proportion of patients with ATTRv worldwide, with patients with ATTRwt accounting for only 12%. Transthyretin amyloidosis also has extracardiac manifestations, but its survival mainly depends on cardiac involvement, which is inferred to be one of the causes of heart failure in the elderly. Patients with ATTR-CA have a poor quality of life, a high rate of misdiagnosis, and low survival rates after diagnosis. Traditional biomarkers of heart failure, such as natriuretic peptide and cardiac troponin, are associated with risk but not specific, and ATTR-CA–specific biomarkers are currently undergoing clinical trials. 40% of patients with ATTR-CA experience more than 4 years of repeated hospitalizations before receiving a definitive diagnosis. The median survival after diagnosis is 2.6 years for ATTRv-CA and 3.6–4.8 years for ATTRwt-CA., In addition, 13% of patients with preserved ejection fraction (HFpEF) is caused by ATTRwt amyloid. Table ​Table11external link, opens in a new tab presents the clinical features. In recent years, there has been an exponential increase in the incidence and prevalence of CA, especially ATTR amyloidosis. Currently, patients with ATTR-CA show a more favorable cardiovascular prognosis than patients with AL-CA, which is associated with therapeutic agents that have been developed in recent years.

Authors
Juan Zhou, BNg, Yanfang Li, MPH, Jing Geng, MNS, Hong Zhou, MNS, Lian Liu, MD, PhD and Xiaochun Peng, MD, PhD