Early cardiac sympathetic denervation in hereditary transthyretin amyloidosis: 123I-metaiodobenzylguanidine findings and correlation with skin biopsy

Background: Hereditary transthyretin amyloidosis (ATTRv) is a multisystem disorder caused by misfolded TTR deposition, leading to neuropathy and cardiomyopathy. Early identification of subclinical involvement remains difficult. We evaluated cardiac sympathetic innervation and small fiber neuropathy in symptomatic patients and asymptomatic carriers (AC) using 123I-metaiodobenzylguanidine (123I-mIBG) scintigraphy, skin biopsy and nerve conduction studies to assess cutaneous silent period (CSP). Methods: In this cross-sectional study, 14 symptomatic patients, 18 AC and 32 healthy controls (HC) underwent 123I-mIBG imaging to determine early and late heart-to-mediastinum ratios (e-H/M, l-H/M) and summed scores (ESS, LSS). Skin biopsies quantified intraepidermal (IENFD) and piloerector muscle nerve fiber density (PMNFD) in upper and lower limbs. Cutaneous silent period (CSP) assessed A-δ fiber function. Correlations between 123I-mIBG and years from predicted age of disease onset (delta-PADO) were analyzed in AC. Results: l-H/M was reduced in AC versus HC (1.73 ± 0.23 vs 1.94 ± 0.19; p < 0.05) and further in patients (1.37 ± 0.25; p < 0.01). Delta-PADO correlated with e-H/M (p < 0.05), ESS (p < 0.01) and LSS (p < 0.01). Half of AC showed reduced lower-limb IENFD. CSP latencies were prolonged or absent in advanced cases. Conclusion: Reduced l-H/M indicates early cardiac sympathetic denervation in AC, preceding clinical symptoms. Combined 123I-mIBG and skin biopsy improves early detection and risk stratification in ATTRv.