Advances in Cardiovascular Pharmacotherapy. V. Molecular Targets in Transthyretin Amyloid Cardiomyopathy

Transthyretin amyloid cardiomyopathy (ATTR-CM) is an infiltrative disease that occurs when the tetrameric transthyretin complex dissociates into its constituent monomers, which then misfold, aggregate, and accumulate as amyloid fibrils in the myocardial extracellular matrix. The amyloid deposits thicken and stiffen the myocardium, interfering with cardiac function and leading to the development of heart failure. Chronic exposure to cytotoxic circulating amyloid precursors contributes to further myocardial damage. Once considered rare, ATTR-CM is now recognized as the most common form of cardiac amyloidosis, occurring in variant and wild types. Amyloid formation in variant ATTR-CM results from an inherited, defective transthyretin gene that causes an amino acid substitution, which renders the protein more vulnerable to instability, dissociation, and monomer misfolding. Wild type ATTR-CM originates from a normal gene and occurs primarily in the elderly. A comprehensive understanding of the molecular basis of ATTR-CM has led to the development of 3 new classes of drugs that stabilize transthyretin, silence its genetic expression, or act to degrade amyloid fibrils within the myocardium. These groundbreaking advances are transforming ATTR-CM from debilitating, uniformly fatal disease to a manageable chronic condition with extended life-expectancy and preserved quality of life. This review discusses the pathophysiology of ATTR-CM, reviews the clinical trials demonstrating the efficacy of drugs that stabilize transthyretin or silence its expression, describes the preliminary use of monoclonal antibodies to degrade amyloid fibrils and reverse the disease's structural and functional consequences, and lastly, comments on the potential anesthetic implications of these new disease-modifying therapies.