Deep phenotyping of p.(V142I)‐associated variant ATTR amyloid cardiomyopathy: distinct from wild‐type ATTR amyloidosis?

Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognised cause of heart failure. 3-4% of individuals of African descent carry a TTR gene mutation encoding the p.(V142I) variant, a powerful risk factor for development of variant ATTR-CM; this equates to 1.6 million carriers in the USA. We undertook deep phenotyping of p.(V142I)-ATTRv-CM and comparison with wild-type ATTR-CM (ATTRwt-CM).A retrospective study of 413 patients with p.(V142I)-associated ATTR-CM (ATTRv-CM) who attended the UK National Amyloidosis Centre was conducted. Patients underwent evaluation at time of diagnosis, including clinical, echocardiography, and biomarker analysis; a subgroup had cardiac magnetic resonance imaging (CMR). Four hundred and thirteen patients with wild-type ATTR-CM (ATTRwt-CM), matched for independent predictors of prognosis (age, NAC Stage, decade of first presentation), were used as a comparator group. At time of diagnosis, patients with ATTRv-CM had significant functional impairment by NYHA classification (NHYA ≥ III; 38%) and 6-minute walk test distance (median 276 metres). Median 5-year survival in ATTRv-CM patients was 31 months vs 59 months in matched patients with ATTRwt-CM (p<0.001). Patients with ATTRv-CM had significant impairment of functional parameters by echocardiography including biventricular impairment, high burden of regurgitant valvular disease and low cardiac output. Multivariable analysis revealed the prognostic importance of RV dysfunction. CMR and histological analysis revealed myocyte atrophy and widespread myocardial infiltration in ATTRv-CM.p.(V142I)-ATTRv-CM has an aggressive phenotype characterised by myocyte loss and widespread myocardial infiltration which may account for frequent biventricular failure and poor prognosis in this ATTR-CM genotypic subgroup. This article is protected by copyright. All rights reserved.