Transthyretin gene silencing therapy in Val50Met familial amyloid polyneuropathy with associated cardiomyopathy
P Monteiro, T Peixoto, D Ribeiro, M Santos, A Campinas, S Fernandes, M Oliveira, A Meireles, A Luz, P RodriguesAbstract
Background information
RNA-targeted transthyretin (TTR) silencers, including antisense oligonucleotides and small interfering RNA therapies, are established disease-modifying agents for variant transthyretin amyloidosis (ATTRv) with polyneuropathy. The role of a small interfering RNA (vutrisiran) in TTR amyloid cardiomyopathy has already been shown in a randomized clinical trial, but only 6 patients had the "Portuguese" TTR variant (Val50Met). Moreover, there are no officially approved treatments specifically for mixed phenotypes.
Purpose
Our study describes real-world experience in a cohort of patients with Val50Met ATTRv with a neurologic indication for having been treated with TTR silencers, who had coexisting confirmed amyloid cardiomyopathy (AC).
Methods
We performed a single-centre retrospective study including all patients with Val50Met TTR variant followed at our Cardiology clinic who were treated with TTR silencers due to their polyneuropathy, but who also had diagnosed AC, ergo a mixed phenotype. Baseline clinical, laboratory and echocardiographic data were collected. Patients with ≥2 visits while on therapy were included in the follow-up analysis. Cardiac stabilisation was defined as <30% increase in NT-proBNP, <5% absolute decrease in left ventricular ejection fraction (LVEF), and <2 mm increase in wall thickness.
Results
Thirty-seven patients were enrolled (67.6% male; median age 66 years). Most patients (78.4%) had received tafamidis 20 mg before starting a silencer. Initial treatment consisted of patisiran (70.3%), inotersen (18.9%) or vutrisiran (10.8%). Twenty-seven patients met criteria for follow-up (mean 29.5 months). Cardiac stabilisation was seen in 51.9%: echocardiographic stability was observed in 74.1% for wall thickness and 66.7% for LVEF, and NT-proBNP stability was achieved in 81.5%. NYHA class remained stable or improved in most patients, with 11.1% worsening; diuretic therapy was initiated or intensified in 22.2% patients. New pacemaker implantation occurred in 22.2% cases and new atrial arrhythmias in 11.1%. No heart failure hospitalisations or organ transplants occurred, and 11.1% patients died during follow-up.
Discussion and conclusions
In this real-world cohort of patients with Val50Met vATTR, TTR silencers were associated with stabilisation of key structural, functional and biomarker parameters, in 51% of the patients, alongside a favourable overall clinical trajectory in most. These findings support a potential role for RNA-silencing therapy in patients with mixed phenotype ATTRv amyloidosis, although larger prospective studies are needed. Expanding data about transthyretin hereditary and wild-type amyloidosis may refine future management of cardiac disease in these patients.For image description, please refer to the figure legend and surrounding text.