Cardiomyopathy correlates to nerve damage in p.A117S late-onset transthyretin amyloid polyneuropathy

Abstract

Objective: Late-onset hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is often associated with heart involvement. Recent advances in cardiac imaging allow the detection of cardiac amyloidosis. This study aimed to explore cardiomyopathy by cardiac imaging and its clinical correlates with polyneuropathy in late-onset ATTRv-PN.

Methods: Polyneuropathy was assessed by intraepidermal nerve fiber (IENF) density, nerve conduction study (NCS), autonomic function tests, quantitative sensory testing, and clinical questionnaires. Cardiomyopathy was evaluated by echocardiography, ^99m Tc-pyrophosphate (PYP) single-photon emission computed tomography (SPECT) imaging, cardiac magnetic resonance imaging (CMR), and serum Pro-B-type natriuretic peptide. Healthy controls and patients with Brugada syndrome were enrolled for comparison of CMR.

Results: Fifty late-onset ATTRv-PN patients (38 men, 46 with p. A117S mutation), aged 63.7 ± 5.5 years, of polyneuropathy disability stage 1-4 were enrolled. All patients presented polyneuropathy in NCS, and 74.5% of patients had reduced IENF density in distal legs. All patients showed significant radiotracer uptake in the heart on ^99m Tc-PYP SPECT imaging, and 87.8% of patients had abnormally increased left ventricular (LV) septum thickness on echocardiography. CMR showed longer myocardial native T1, larger extracellular volume, greater LV mass index, and higher LV mass to end-diastolic volume ratio in ATTRv-PN patients than healthy controls and patients with Brugada syndrome. These CMR parameters were associated with skin denervation, absent sympathetic skin responses, elevated thermal thresholds, worsened NCS profiles, and functional deficits of polyneuropathy.

Interpretation: Late-onset ATTRv-PN coexisted with cardiomyopathy regardless of the clinical severity of polyneuropathy. The cardiac amyloid burden revealed by CMR was correlated with pathophysiology and clinical disability of nerve degeneration.

Figure 1

Myocardial native T1 and extracellular volume measurements on cardiac magnetic resonance imaging in a control subject and age‐ and gender‐matched representative patients with Brugada syndrome and hereditary transthyretin amyloidosis with polyneuropathy (ATTRv‐PN). The regions of interest were drawn in the middle septum of the left ventricle on the myocardial native T1 (top row, msec) and extracellular volume (bottom row, %) maps. The myocardial native T1 and extracellular volume of the ATTRv‐PN patient were much longer and larger than those of the healthy subject and the patient with Brugada syndrome. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 2

Comparison of cardiac magnetic resonance imaging among healthy controls and patients with Brugada syndrome and hereditary transthyretin amyloidosis with polyneuropathy (ATTRv‐PN). (A) The myocardial native T1 was significantly longer, (B) the extracellular volume was much larger, (C) the left ventricular mass index was remarkably greater, and (D) the left ventricular mass to end‐diastolic volume ratio was markedly higher in patients with ATTRv‐PN than in healthy controls and patients with Brugada syndrome. **p < 0.001.