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Open Access 01-04-2021 | Amyloidosis | Original Paper

Impaired in vitro growth response of plasma-treated cardiomyocytes predicts poor outcome in patients with transthyretin amyloidosis

Authors: Selina Hein, Jennifer Furkel, Maximilian Knoll, Fabian aus dem Siepen, Stefan Schönland, Ute Hegenbart, Hugo A. Katus, Arnt V. Kristen, Mathias H. Konstandin

Published in: Clinical Research in Cardiology | Issue 4/2021

Abstract

Objectives

Direct toxic effects of transthyretin amyloid in patient plasma upon cardiomyocytes are discussed. However, no data regarding the relevance of this putative effect for clinical outcome are available. In this monocentric prospective study, we analyzed cellular hypertrophy after phenylephrine stimulation in vitro in the presence of patient plasma and correlated the cellular growth response with phenotype and prognosis.

Methods and results

Progress in automated microscopy and image analysis allows high-throughput analysis of cell morphology. Using the InCell microscopy system, changes in cardiomyocyte’s size after treatment with patient plasma from 89 patients suffering from transthyretin amyloidosis and 16 controls were quantified. For this purpose, we propose a novel metric that we named Hypertrophic Index, defined as difference in cell size after phenylephrine stimulation normalized to the unstimulated cell size. Its prognostic value was assessed for multiple endpoints (HTX: death/heart transplantation; DMP: cardiac decompensation; MACE: combined) using Cox proportional hazard models. Cells treated with plasma from healthy controls and hereditary transthyretin amyloidosis with polyneuropathy showed an increase in Hypertrophic Index after phenylephrine stimulation, whereas stimulation after treatment with hereditary cardiac amyloidosis or wild-type transthyretin patient plasma showed a significantly attenuated response. Hypertrophic Index was associated in univariate analyses with HTX (hazard ratio (HR) high vs low: 0.12 [0.02–0.58], p = 0.004), DMP: (HR 0.26 [0.11–0.62], p = 0.003) and MACE (HR 0.24 [0.11–0.55], p < 0.001). Its prognostic value was independent of established risk factors, cardiac TroponinT or N-terminal prohormone brain natriuretic peptide (NTproBNP).

Conclusions

Attenuated cardiomyocyte growth response after stimulation with patient plasma in vitro is an independent risk factor for adverse cardiac events in ATTR patients

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Title: Impaired in vitro growth response of plasma-treated cardiomyocytes predicts poor outcome in patients with transthyretin amyloidosis
Authors: Selina Hein
Jennifer Furkel
Maximilian Knoll
Fabian aus dem Siepen
Stefan Schönland
Ute Hegenbart
Hugo A. Katus
Arnt V. Kristen
Mathias H. Konstandin
Publication date: 01-04-2021
Publisher: Springer Berlin Heidelberg
Keyword: Amyloidosis
Published in: Clinical Research in Cardiology / Issue 4/2021
Print ISSN: 1861-0684
Electronic ISSN: 1861-0692
DOI: https://doi.org/10.1007/s00392-020-01801-y

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