Deep Phenotyping of p.(V142I)-Associated Variant Transthyretin Amyloid Cardiomyopathy: Distinct from Wild-Type Transthyretin Amyloidosis?
Yousuf Razvi, Adam Ioannou, Rishi Patel, Liza Chacko, Nina Karia, Mattia Riefolo, Aldostefano Porcari, Muhammad U. Rauf, Neasa Starr, Sashiananthan Ganesananthan, Iona Blakeney, Nandita Kaza, Stefano Filisetti, Roos Eline Bolhuis, Dorota Rowczenio, Janet A. Gilbertson, David F. Hutt, Shameem Mahmood, Helen J. Lachmann, Ashutosh Wechalekar, Tushar Kotecha, Daniel Knight, Gerry Coghlan, Aviva Petrie, Carol Whelan, Lucia Venneri, Ana Martinez–Naharro, Philip N. Hawkins, Marianna Fontana, Julian D. Gillmore
Abstract
AIMS: Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure. A total of 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 (ATTRv-CM); this equates to 1.6 million carriers in the United States. We undertook deep phenotyping of p.(V142I)-ATTRv-CM and comparison with wild-type ATTR-CM (ATTRwt-CM). METHODS AND RESULTS: A retrospective study of 413 patients with p.(V142I) ATTRv-CM who attended the UK National Amyloidosis Centre (NAC) was conducted. Patients underwent evaluation at time of diagnosis, including clinical, echocardiography, and biomarker analysis; a subgroup had cardiac magnetic resonance (CMR) imaging. A total of 413 patients with 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 New York Heart Association classification (NHYA class ≥ III; 38%) and 6-min walk test distance (median 276 m). Median 5-year survival in ATTRv-CM patients was 31 versus 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 right ventricular dysfunction. CMR and histological analysis revealed myocyte atrophy and widespread myocardial infiltration in ATTRv-CM. CONCLUSION: p.(V142I)-ATTRv-CM has an aggressive phenotype characterized by myocyte loss and widespread myocardial infiltration which may account for frequent biventricular failure and poor prognosis in this ATTR-CM genotypic subgroup.