Selina Hein1, Jennifer Furkel2, Maximilian Knoll3, Fabian Aus dem Siepen2, Stefan Schönland4, Ute Hegenbart4, Hugo A Katus2,5, Arnt V Kristen2, Mathias H Konstandin6,7. 1. Department of Cardiology, Angiology and Pulmonology, University Hospital Heidelberg, INF 410, 69120, Heidelberg, Germany. selina.hein@med.uni-heidelberg.de. 2. Department of Cardiology, Angiology and Pulmonology, University Hospital Heidelberg, INF 410, 69120, Heidelberg, Germany. 3. Department of Radiation Oncology, Heidelberg Ion-Beam Therapy Center (HIT), German Cancer Research Center, Heidelberg University Hospital (UKHD), Heidelberg, Germany. 4. Department of Hematology, Oncology and Rheumatology, Heidelberg University, Heidelberg, Germany. 5. DZHK (German Center for Cardiovascular Research), Site Heidelberg/Mannheim, Heidelberg, Germany. 6. Department of Cardiology, Angiology and Pulmonology, University Hospital Heidelberg, INF 410, 69120, Heidelberg, Germany. mathias.konstandin@med.uni-heidelberg.de. 7. DZHK (German Center for Cardiovascular Research), Site Heidelberg/Mannheim, Heidelberg, Germany. mathias.konstandin@med.uni-heidelberg.de.
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.
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 transthyretinpatient 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 ATTRpatients.
Authors: Shikha Mishra; Jian Guan; Eva Plovie; David C Seldin; Lawreen H Connors; Giampaolo Merlini; Rodney H Falk; Calum A MacRae; Ronglih Liao Journal: Am J Physiol Heart Circ Physiol Date: 2013-04-26 Impact factor: 4.733
Authors: Rafat A Siddiqui; Saame Raza Shaikh; Richard Kovacs; William Stillwell; Gary Zaloga Journal: J Cell Biochem Date: 2004-08-15 Impact factor: 4.429
Authors: Jennifer Furkel; Maximilian Knoll; Shabana Din; Nicolai V Bogert; Timon Seeger; Norbert Frey; Amir Abdollahi; Hugo A Katus; Mathias H Konstandin Journal: Cell Rep Med Date: 2021-11-03