Early cardiovascular autonomic failure in ATTRv predicts poor prognosis and may respond to disease-modifying therapy

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Background Hereditary transthyretin amyloidosis (ATTRv) is a life-threatening, but treatable disease presenting with autonomic dysfunction. This study investigates the progression of autonomic failure, response to treatment, and the impact of autonomic failure in ATTRv. Methods Clinical features and autonomic function test (AFT) results were evaluated in 126 patients (40 had treatment) and 12 asymptomatic TTR variant carriers. A subgroup had follow-up (FU) AFT. Kaplan-Meier estimates compared survival time between participants with and without neurogenic orthostatic hypotension (nOH), and logistic regression assessed its impact on mortality. Results Patients treated early with disease modifying therapies (DMT) had slower progression and did not develop nOH. In 59 individuals with repeat AFT, autonomic dysfunction worsened, with a decline in the Valsalva ratio (p = 0.002), even in early-stage disease (p = 0.019; median disease duration at FU 4 years). nOH at first assessment predicted worse outcome (mean survival time in individuals with nOH 7.0 vs. 14.9 years without nOH, p < 0.001) and death (OR = 5.27; 95%CI: 1.94 − 14.31; p = 0.001). Conclusions The early development of autonomic dysfunction and nOH is an independent predictive factor for shorter survival in ATTRv. Autonomic testing is a valuable biomarker to capture disease progression. Prospective studies need to confirm the benefit of DMT on autonomic dysfunction.