Abstract
AbstractBACKGROUNDHereditary transthyretin amyloid cardiomyopathy (ATTRv-CM) is being increasingly diagnosed due to enhanced awareness and availability of newer therapeutics. MultipleTTRvariants have been described worldwide, but with uncertain disease penetrance. The characteristics and outcomes of “previously undiagnosed” pathogenic-likely pathogenic (P/LP)TTRvariant (genotype or G+; cardiac phenotype or P-) carriers are unknown which has important prognostic and therapeutic implications, especially for affected family members. This descriptive study aimed to delineate phenotype and cardiac penetrance in “previously undiagnosed” G+P-family members of ATTRv probands.METHODSDemographic, electrocardiographic (ECG), genetic, and imaging (echocardiography, cardiac technetium-99m pyrophosphate (PYP) and magnetic resonance imaging) data were analyzed. The prediction effect of selected baseline characteristics for ATTRv-CM development was evaluated. Kaplan-Meier and Cox regression methods were used to describe risk and predictors of ATTRv-CM development in family members.RESULTSThere were 85 G+P-family members identified. Mean age was 48.5±11.7 years, 39% were male, 18% had a diagnosis of peripheral neuropathy, 15% with a history of carpal tunnel syndrome, and 4% had atrioventricular block at baseline. Of these, 55 patients had follow-up imaging studies. After a median 6.8-year follow-up, 22% developed ATTR-CM with a 10-year estimated risk of 29.5% (95% CI 7.9-46.0). Cardiac penetrance increased with increasing family member’s age. Proband’s diagnosis age (p=0.0096) and artificial intelligence (AI)-ECG prediction (p=0.0091) were promising baseline predictors of time to ATTRv-CM development.CONCLUSIONIn previously undiagnosed G+P-ATTRv family members, the incidence of subsequent CM is high. Predictors for CM development such as proband’s diagnosis age and AI-determined ECG probability of ATTR-CM require further investigation.
Publisher
Cold Spring Harbor Laboratory