FAP plasma-induced cellular toxicity

Niemietz, Christoph; Chandhok, Gursimran; Fleischhauer, Lutz; Ballmaier, Paula; Sauer, Vanessa; Guttmann, Sarah; Zibert, Andree; Schmidt, Hartmut

doi:10.1080/13506129.2017.1278692

Cited by 1 publication

(2 citation statements)

References 6 publications

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“…In contrast to other so-far established biomarkers quantified in absolute numbers for their concentration, the HI represents a functional novel innovative approach integrating the significance of multiple agents in the plasma of patients into one read-out parameter. The exact underlying mechanism for altered hypertrophic response in our assay remains cryptic, while it can be speculated that the amyloid itself, catecholamines, inflammatory markers, antibodies, effects by cellular immunity or other not yet identified mediators will affect the final read-out [4,5,[34][35][36][37].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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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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Section: Discussionmentioning

confidence: 99%

“…In the very recent past, direct toxic effects of amyloid upon cardiomyocytes have been proposed mainly for light chain amyloidosis (AL) but also for ATTR [3][4][5]. In general the heart as post-mitotic organ reacts to increased work load demand and stress with hypertrophic growth.…”

Section: Introductionmentioning

confidence: 99%