Variant-specific differences in hereditary transthyretin cardiac amyloidosis

Abstract Background Hereditary transthyretin cardiac amyloidosis (ATTRv-CM) is a progressive infiltrative disease that is caused by deposition of amyloid fibrils at the cardiac level caused by rare genetic variants. Although different pathogenic variants in transthyretin (TTR) have been shown to cause different phenotypes (i.e. cardiac vs neurological vs mixed phenotypes), no studies have been performed specifically scrutinizing if there are variant-specific differences in ATTRv-CM. Purpose To determine the variant-specific differences penetrance and clinical parameters for ATTRv-CM. Methods We included 357 individuals with a pathogenic TTR variant (65.5% male; median age 67.0 IQR:56.3-75.4 years; 33.6% relatives) from 14 different centers from 6 countries. The primary endpoint, ATTRv-CM diagnosis, was defined as the presence of (1) cardiac tracer uptake in bone scintigraphy; or (2) transthyretin-positive cardiac biopsy. The secondary endpoint, major adverse cardiac events (MACE), was a composite of heart failure (NYHA³II) and pacemaker-requiring conduction disorders. Results At baseline, 250 (70%) had ATTRv-CM of whom 80% (n=199/250) presented with a MACE. Overall, 124 (34.7%), 79 (22.1%), 55 (15.4%), and 99 (27.7%) individuals had a Ile88Leu, Val50Met, Val142Ile, and infrequently identified variants (IIV) (15 variants in the cohort), respectively. Individuals with IIV progressed significantly faster to ATTRv-CM and MACE as compared to other variants (Figure 1; both p0.001). Of note, individuals with the Val50Met variant were less likely to present with a MACE if diagnosed with ATTRv-CM at baseline, suggesting that Val50Met variant carriers are being diagnosed with a significantly less severe cardiac phenotype as compared to those with other variants (66.7% vs. 82.4%; p=0.017). Expectedly, individuals with the Val50Met variant were significantly more likely to have neurological amyloidosis (p0.001). Considering variant-specific differences at baseline evaluation, in individuals with a Val50Met variant absence of left ventricular hypertrophy was significantly more observed (p0.05). No statistically significant differences in ‘red flags’ for ATTRv-CM were objectified on electrocardiograms and laboratory tests (p0.05)(Table 1). Conclusions Individuals with a IIV have a more severe cardiomyopathy, suggesting that carriers of less prevalent pathogenic TTR variant may benefit from closer cardiac monitoring. In contrast, individuals with a Val50Met variant are being diagnosed at a prognostically favorable cardiac disease stage, which might be explained by early referral due to extracardiac amyloidosis prior to the cardiac onset or potential disparities between ethnic groups. These findings show that variant-specific differences are present, which may warrant a variant-specific approach in cardiac management for pathogenic TTR variant carriers.Table 1.Baseline Characteristics Progression to ATTRv-CM and MACE