Impaired in vitro growth response of plasma-treated cardiomyocytes predicts poor outcome in patients with transthyretin amyloidosis.
Impaired in vitro growth response of plasma-treated cardiomyocytes predicts poor outcome in patients with transthyretin amyloidosis.
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DOI：
10.1007/s00392-020-01801-y
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发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
Konstandin MH
中科院分区：
文献类型：
--
作者：
Hein S;Furkel J;Knoll M;Aus dem Siepen F;Schönland S;Hegenbart U;Katus HA;Kristen AV;Konstandin MH
讨论了患者血浆中的转甲状腺素淀粉样蛋白对心肌细胞的直接毒性作用。然而，没有关于这一假定效应与临床结果的相关性的数据。在这项单中心前瞻性研究中，我们分析了在患者血浆存在的情况下，体外苯肾上腺素刺激后的细胞肥大，并将细胞生长反应与表型和预后相关。自动化显微镜和图像分析的进步使细胞形态的高通量分析成为可能。应用Incell显微镜系统，对89例转甲状腺素淀粉样变性患者和16例对照组患者血浆治疗后心肌细胞大小的变化进行了定量研究。为此，我们提出了一个新的指标，我们称之为肥厚指数，定义为在苯肾上腺素刺激后细胞大小的差异，归一化到未刺激的细胞大小。使用COX比例风险模型对多个终点(HTX：死亡/心脏移植；DMP：心脏失代偿；MACE：合并)的预后价值进行评估。用健康对照组和遗传性转甲状腺素样淀粉样变性合并多发性神经病患者的血浆处理的细胞，在苯肾上腺素刺激后肥大指数增加，而遗传性心脏淀粉样变性或野生型转甲状腺素样变患者血浆处理后的刺激反应明显减弱。在单因素分析中，肥厚指数与HTX(高风险比：0.12[0.02-0.58]，p = 0.004)、DMP：(HR 0.26[0.11-0.62]，p = 0.003)和MACE(HR 0.24[0.11-0.55]，p <； 0.001)相关。其预后价值与已确定的危险因素、心肌肌钙蛋白T或N末端前激素和脑利钠肽(NTproBNP)无关。体外用患者血浆刺激后心肌细胞生长反应减弱是ATR患者不良心脏事件的独立危险因素。在线版本包含补充材料，可在10.1007/s00392-020-01801-y获得。
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. 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). Attenuated cardiomyocyte growth response after stimulation with patient plasma in vitro is an independent risk factor for adverse cardiac events in ATTR patients The online version contains supplementary material available at 10.1007/s00392-020-01801-y.
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12.3
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Carpenter AE;Jones TR;Lamprecht MR;Clarke C;Kang IH;Friman O;Guertin DA;Chang JH;Lindquist RA;Moffat J;Golland P;Sabatini DM
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