Subclinical cardiomyopathy in premanifest carriers of late-onset hereditary transthyretin amyloidosis with polyneuropathy.

BACKGROUND

Cardiac involvement is a common presentation of late-onset hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN). This study explored phenotypes of cardiac amyloidosis and their clinical and neurological correlates in the premanifest stage.

METHODS

Premanifest carriers with the transthyretin p.A117S variant were enrolled. Healthy controls and ATTRv-PN patients with stage 1 polyneuropathy disability (PND) were enrolled for comparison. The risk of cardiomyopathy was estimated by the Mayo ATTR-CM score, and cardiomyopathy was evaluated by echocardiography, 99mTc-pyrophosphate (PYP) single-photon emission computed tomography (SPECT) imaging, cardiac magnetic resonance imaging (CMR), and serum natriuretic peptide (NT-proBNP). Neuropathy was assessed using clinical questionnaires, skin biopsy, neurophysiology, and quantitative sensory testing.

RESULTS

Thirty-two premanifest carriers with transthyretin variants (31 p.A117s) were enrolled, along with 63 controls and 11 ATTRv-PN patients (9 p.A117S). None of the carriers had polyneuropathy or showed high-risk Mayo ATTR-CM score, while 38% had carpal tunnel syndrome and 16% had increased radiotracer uptake on 99mTc-PYP SPECT imaging. Compared with controls, carriers demonstrated a greater extracellular volume (ECV), longer myocardial native T1, and greater left ventricular mass index on CMR, indicating subclinical cardiac amyloidosis. ATTRv-PN patients had markedly greater amyloid burden across these cardiac imaging. Among carriers, CMR parameters and 99mTc-PYP SPECT uptake were significantly correlated with nerve degeneration. Higher 99mTc-PYP SPECT uptake was associated with increased NT-proBNP, native T1, ECV, autonomic and sensory dysfunction, and presence of CTS.

CONCLUSIONS

Subclinical cardiomyopathy, as shown by nuclear medicine imaging and CMR, is common and linked to neuropathic changes among ATTRv-PN premanifest carriers carrying predominant p.A117S variant, and may facilitate early and accurate diagnosis and intervention for ATTRv-PN.