In this trial, patisiran improved multiple clinical manifestations of hereditary transthyretin amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO ClinicalTrials.gov number, NCT01960348 .).

In patients with transthyretin amyloid cardiomyopathy, tafamidis was associated with reductions in all-cause mortality and cardiovascular-related hospitalizations and reduced the decline in functional capacity and quality of life as compared with placebo. (Funded by Pfizer; ATTR-ACT ClinicalTrials.gov number, NCT01994889 .).

Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.

Cardiomyopathy is a manifestation of transthyretin amyloidosis (ATTR), which is an underrecognized systemic disease whereby the transthyretin protein misfolds to form fibrils that deposit in various tissues and organs. ATTR amyloidosis is debilitating and associated with poor life expectancy, especially in those with cardiac dysfunction, but a variety of treatment options have recently become available. Considered a rare disease, ATTR amyloidosis may be more prevalent than thought, particularly in older persons. Diagnosis is often delayed because of a lack of disease awareness and the heterogeneity of symptoms at presentation. Given the recent availability of effective treatments, early recognition and diagnosis are especially critical because treatment is likely more effective earlier in the disease course. The Amyloidosis Research Consortium recently convened a group of experts in ATTR amyloidosis who, through an iterative process, agreed on best practices for suspicion, diagnosis, and characterization of disease. This review describes these consensus recommendations for ATTR associated with cardiomyopathy as a resource to aid cardiologists and others in the recognition and diagnosis of ATTR associated with cardiomyopathy. Included in this review is an overview of red flag signs and symptoms and a recommended diagnostic approach, including testing for monoclonal protein, scintigraphy, or biopsy and, if ATTR associated with cardiomyopathy is identified, TTR genotyping.

BACKGROUND Transthyretin amyloidosis (ATTR) is a heterogeneous disorder with multiorgan involvement and a genetic or nongenetic basis. OBJECTIVES We described ATTR in the United States in the THAOS (Transthyretin Amyloidosis Outcomes Survey) registry. METHODS Demographic, clinical, and genetic features of patients enrolled in the THAOS registry in the United States (n = 390) were compared to other regions of the world (ROW) (n = 2,140) with a focus on the phenotypic expression and survival in the majority of U.S. subjects with Val122Ile (n = 91) and wild-type ATTR (n = 189). RESULTS U.S. subjects are older (70 vs. 46 years), more often male (85.4% vs. 50.6%) and more often of African descent (25.4% vs. 0.5%) than ROW. A significantly higher percentage of U.S. patients with ATTR amyloid seen at cardiology sites had wild-type disease than the ROW (50.5% vs. 26.2%). In the United States, 34 different mutations (n = 201) have been reported, with the most common being Val122Ile (n = 91; 45.3%) and Thr60Ala (n = 41; 20.4%). Overall, 91 of 107 patients with Val122Ile (85%) were from the United States, where Val122Ile subjects were younger and more often women and black than wild-type patients, and had similar cardiac phenotype but a greater burden of neurologic symptoms (pain, numbness, tingling, and walking disability) and worse quality of life. Advancing age and lower mean arterial pressure, but not the presence of a TTR mutation, were independently associated with higher mortality from a multivariate analysis of survival. CONCLUSIONS In the THAOS registry, ATTR in the United States is overwhelmingly a disorder of older adult males with a cardiac-predominant phenotype. Val122Ile is the most common TTR mutation, and neurologic phenotypic expression differs between wild-type disease and Val122Ile, but survival from enrollment in THAOS does not. CLINICAL TRIAL NCT00628745