Background: Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure in older individuals. We sought to characterize the natural history of ATTR-CM and compare outcomes and quality of life among patients with acquired and hereditary forms of the disease. Methods: We studied 711 patients with wild-type ATTR-CM, 205 with hereditary ATTR-CM associated with the V122I variant (V122I-hATTR-CM), and 118 with non-V122I-hATTR-CM at the UK National Amyloidosis Center between 2000 and 2017. Patients underwent prospective protocolized evaluations comprising assessment of cardiac parameters, functional status by 6-minute walk test, quality of life according to the Kansas City Cardiomyopathy Questionnaire, and survival. Hospital service usage pre- and postdiagnosis was established using English central health records in a subset of patients. Results: There was substantial diagnostic delay, with patients using hospital services a median (interquartile range) of 17 (9–27) times during the 3 years before diagnosis, by which time quality of life was poor; diagnosis of wild-type ATTR-CM was delayed >4 years after presentation with cardiac symptoms in 42% of cases. Patients with V122I-hATTR-CM were more impaired functionally ( P <0.001) and had worse measures of cardiac disease ( P <0.001) at the time of diagnosis, a greater decline in quality of life, and poorer survival ( P <0.001) in comparison with the other subgroups. Conclusions: ATTR-CM is an inexorably progressive and eventually fatal cardiomyopathy associated with poor quality of life. Diagnosis is often delayed for many years after symptoms develop. Improved awareness and wider use of recently validated diagnostic imaging methods are urgently required for patients to benefit from recent therapeutic developments.

Key Points CyBorD achieves excellent outcome in noncardiac patients with AL amyloidosis and can rescue subjects with reversible heart damage. The outcome of high-risk patients remains poor, but response to CyBorD can also improve survival in this group.

This article reports the largest series of patients with systemic AL amyloidosis to date treated with first-line bortezomib. With relatively mature follow-up, the data indicate the importance of a stringent dFLC response (difference in involved and uninvolved light chains) as a predictor of prolonged response.