The Effect of Tafamidis on Circulating Endothelial Progenitor Cells in Patients with Transthyretin Cardiac Amyloidosis,Cardiovascular Drugs and Therapy

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The Effect of Tafamidis on Circulating Endothelial Progenitor Cells in Patients with Transthyretin Cardiac Amyloidosis
Cardiovascular Drugs and Therapy ( IF 3.1 ) Pub Date : 2021-09-22 , DOI: 10.1007/s10557-021-07265-0
Osnat Itzhaki Ben Zadok _{1,

2} , Dorit Leshem-Lev _{2,

3} , Tuvia Ben-Gal _{1,

2} , Ashraf Hamdan _{1,

2} , Nili Schamroth Pravda _{1,

2} , Tali Steinmetz _{2,

4} , Irit Kandinov _{1,

2} , Ilit Ovadia _{1,

2} , Ran Kornowski _{1,

2} , Alon Eisen _{1,

2}

Affiliation

Aims

Endothelial microvascular dysfunction is a known mechanism of vascular pathology in cardiac amyloidosis (CA). Scientific evidence regarding the possible protective role of the amyloid transthyretin (ATTR) stabilizer, tafamidis, is lacking. Circulating endothelial progenitor cells (cEPCs) have an important role in the process of vascular repair. We aimed to examine the effect of tafamidis on cEPCs.

Methods and Results

Study population included patients with ATTR-CA. cEPCs were assessed using flow cytometry by the expression of CD34⁽⁺⁾/CD133⁽⁺⁾ and vascular endothelial growth factor receptor (VEGFR)-2⁽⁺⁾ and by the formation of colony-forming units (CFUs) and production of VEGF. Tests were repeated at pre-specified time-points up to 12 months following the initiation of tafamidis. Included were 18 ATTR-CA patients at a median age of 77 (IQR 71, 85) years and male predominance (n = 15, 83%). Following the initiation of tafamidis and during 12 months of drug treatment, there was a gradual increase in the levels of CD34⁽⁺⁾/VEGFR-2⁽⁺⁾ (0.43 to 2.42% (IQR 1.53, 2.91)%, p = 0.002) and CD133⁽⁺⁾/VEGFR-2⁽⁺⁾ (0.49 to 1.64% (IQR 0.97, 2.90)%, p = 0.004). Functionally, increase in EPCs-CFUs was microscopically evident following treatment with tafamidis (from 0.5 CFUs (IQR 0.0, 1.0) to 3.0 (IQR 1.3, 3.8) p < 0.001) with a concomitant increase in EPC’s viability as demonstrated by an MTT assay (from 0.12 (IQR 0.03, 0.16) to 0.30 (IQR 0.18, 0.33), p < 0.001). VEGF levels increased following treatment (from 54 (IQR 52, 72) to 107 (IQR 62, 129) pg/ml, p = 0.039).

Conclusions

Tafamidis induced the activation of the cEPCs pathway, possibly promoting endothelial repair in ATTR-CA.

中文翻译：

Tafamidis 对转甲状腺素蛋白心脏淀粉样变性患者循环内皮祖细胞的影响

目标

内皮微血管功能障碍是心脏淀粉样变性 (CA) 中已知的血管病理学机制。缺乏关于淀粉样蛋白转甲状腺素蛋白 (ATTR) 稳定剂 tafamidis 可能具有保护作用的科学证据。循环内皮祖细胞 (cEPC) 在血管修复过程中具有重要作用。我们旨在检查 tafamidis 对 cEPC 的影响。

方法和结果

研究人群包括 ATTR-CA 患者。使用流式细胞术通过 CD34 ⁽⁺⁾ /CD133 ⁽⁺⁾和血管内皮生长因子受体 (VEGFR)-2 ⁽⁺⁾的表达以及集落形成单位 (CFU) 的形成和 VEGF 的产生来评估 cEPC。在 tafamidis 开始后的 12 个月内，在预先指定的时间点重复测试。包括 18 名 ATTR-CA 患者，中位年龄为 77（IQR 71, 85）岁，男性占优势（n = 15, 83%）。^{在开始使用 tafamidis 和 12 个月的药物治疗期间，CD34 (+)} /VEGFR-2 ⁽⁺⁾水平逐渐升高(0.43 至 2.42% (IQR 1.53, 2.91)%, p = 0.002) 和 CD133 ⁽⁺⁾ /VEGFR-2 ⁽⁺⁾ (0.49 至 1.64% (IQR 0.97, 2.90)%, p = 0.004)。在功能上，用 tafamidis 治疗后，EPCs-CFUs 的增加在显微镜下是明显的（从 0.5 CFUs (IQR 0.0, 1.0) 到 3.0 (IQR 1.3, 3.8) p < 0.001），同时 EPC 的活力也随之增加，如 MTT 分析所示（从 0.12 (IQR 0.03, 0.16) 到 0.30 (IQR 0.18, 0.33), p < 0.001)。治疗后 VEGF 水平增加（从 54 (IQR 52, 72) 到 107 (IQR 62, 129) pg/ml，p = 0.039）。