Wild-Type Transthyretin Amyloid Cardiomyopathy: A Missed Cause of Heart Failure With Preserved Ejection Fraction With Evolving Treatment Implications.

Heart failure is a devastating but heterogeneous disease. Although ischemic heart disease and hypertension account for a significant portion of heart failure, the precise cause and pathophysiology of many other forms of heart failure are less clear. This is particularly underscored by our repeated failed attempts to identify effective treatments for heart failure with preserved ejection fraction (HFpEF). It is only through accurate etiologic diagnoses and understanding of the causes of heart failure, in particular HFpEF, associated with high mortality, that we can offer more precisely targeted therapies in the future.1Article see p 282Amyloid heart disease is a devastating cause of heart failure, resulting from the deposition of misfolded or misassembled protein fibrils (amyloid) in the cardiac extracellular matrix. Amyloid deposition impairs diastolic and subsequently systolic cardiac function and has been thought to be rare. Amyloid heart disease could be secondary to hematological disorders such as multiple myeloma with deposition of excessive circulating immunoglobulin light chains in the heart (AL amyloidosis) or abnormal proteins resulting from systemic inflammatory disease leading to production of amyloid A, an acute-phase reactant (AA type; Figure 1).Figure 1. Comparison of the subtypes of amyloid cardiomyopathy in terms of cause, specific features, survival, prognostic factors, and examples of therapy. The chart includes the common types of systemic amyloidosis (AL and AA forms), as well as the transthyretin (TTR) varieties, including the wild-type form (ATTRwt). AA indicates amyloid A; AL, amyloid caused by light-chain deposition; ASO, antisense oligonucleotide; BNP, brain natriuretic peptide; HR, heart rate; LVEF, left ventricular ejection fraction; siRNA, small interference RNA; and Tx, transplantation.However, more recently, there has been increased recognition of cardiac amyloidosis caused by the deposition of transthyretin, which is a circulating 127–amino acid protein made in the liver to transport hormones such as thyroxine and retinol. Transthyretins …