Abstract
Background: Hereditary transthyretin amyloidosis (ATTRv) is a rare, autosomal dominant multisystem disease caused by pathogenic variants in the transthyretin (TTR) gene. Although ATTRv is classically categorized into "cardiac" and "neurologic" phenotypes, recent evidence suggests a more complex and overlapping disease spectrum. Objectives: This study investigates the relationship between neurological staging and cardiac involvement through an integrated assessment of patients with confirmed TTR mutations. Methods and Results: Fifty-eight patients with genetically confirmed ATTRv (41% female, mean age 60 ± 15 years) were evaluated. Genotypes included Phe64Leu, Val30Met, Val122Ile, and others. Patients were stratified by neurological stage: G0 (asymptomatic carriers), G1 (symptomatic but ambulatory), and G2 (requiring walking support). Cardiac assessment included clinical evaluation, echocardiography with tissue Doppler, global longitudinal strain (GLS), and NT-proBNP levels. Cardiac markers worsened with neurological stage. NT-proBNP, left ventricular mass index, maximal wall thickness, and E/E' ratio increased progressively, while GLS declined (G0: -19%, G1: -14%, G2: -13%; p < 0.001), indicating a progressive structural and functional myocardial disease. Ejection fraction remained preserved. Neurological stage independently predicted cardiac dysfunction after age adjustment. Conclusions: This is the first study to assess cardiac abnormalities across neurological stages in a well-characterized cohort of ATTRv patients. Cardiac involvement in ATTRv begins early, even in asymptomatic carriers, and progresses with neurological deterioration. GLS and diastolic parameters are sensitive indicators of early myocardial dysfunction, highlighting the need for integrated neurologic and cardiac monitoring in all patients with ATTRv, regardless of initial phenotype.