Ambari Ade Meidian, Lilihata Gracia, Zuhri Ervan, Ekawati Elok, Wijaya Shoma Adhi, Dwiputra Bambang, Sukmawan Renan, Radi Basuni, Haryana Sofia Mubarika, Adiarto Suko, Hanafy Dicky A, Zamroni Dian, Elen Elen, Mangkuanom Arwin S, Santoso Anwar
Department of Cardiology and Vascular Medicine, Faculty of Medicine Universitas Indonesia - National Cardiovascular Center Harapan Kita, Jakarta, Indonesia.
Division of Cardiovascular Research and Development, National Cardiovascular Center Harapan Kita, Jakarta, Indonesia.
Front Cardiovasc Med. 2021 Oct 25;8:761112. doi: 10.3389/fcvm.2021.761112. eCollection 2021.
External counterpulsation (ECP) provides long-term benefits of improved anginal frequency and exercise tolerance in patients with refractory angina (RA). This is postulated as a result of improved angiogenesis and endothelial function through an increase in shear stress. Angiogenesis is mainly represented by vascular endothelial growth factor-A (VEGF-A) and its receptor, vascular endothelial growth factor receptor-2 (VEGFR-2). The microRNA-92a (miR-92a) is a flow-sensitive miRNA that regulates atherosclerosis and angiogenesis in response to shear stress. Thus, ECP beneficial effect might be achieved through interaction between VEGF-A, VEGFR-2, and miR-92a. This study aims to evaluate the ECP effect on VEGF-A, VEGFR-2, and miR-92a in patients with RA in a sham-controlled manner. This was a randomized sham-controlled trial, enrolling 50 patients with RA who have coronary artery disease (CAD). Participants were randomized (1:1 ratio) to 35 sessions of either ECP ( = 25) or sham ( = 25), each session lasting for 1 h. Plasma levels of VEGF-A and VEGFR-2 were assayed by the ELISA technique. The quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was performed to measure miR-92a circulating levels in plasma. External counterpulsation significantly preserved VEGF-A and VEGFR-2 level compared to sham [ΔVEGF-A: 1 (-139 to 160) vs.-136 (-237 to 67) pg/ml, = 0.026; ΔVEGFR-2: -171(-844 to +1,166) vs. -517(-1,549 to +1,407) pg/ml, = 0.021, respectively]. Circulating miR-92a increased significantly in ECP [5.1 (4.2-6.4) to 5.9 (4.8-6.4), p < 0.001] and sham [5.2 (4.1-9.4) to 5.6 (4.8-6.3), = 0.008] post-intervention. The tended to be higher in ECP group, although was not statistically different from sham [ ECP = 4.6 (0.3-36.5) vs. sham 2.8 (0-15), = 0.33)]. External counterpulsation improved angiogenesis by preserving VEGF-A and VEGFR-2 levels. Both ECP and sham increased miR-92a significantly, yet the changes were not different between the two groups. (Study registered on www.clinicaltrials.gov, no: NCT03991871, August 8, 2019, and received a grant from the National Health Research and Development of Ministry of Health of Indonesia, No: HK.02.02/I/27/2020).
体外反搏（ECP）可为难治性心绞痛（RA）患者带来长期益处，改善心绞痛发作频率和运动耐量。据推测，这是由于剪切应力增加促进了血管生成和内皮功能改善所致。血管生成主要由血管内皮生长因子-A（VEGF-A）及其受体血管内皮生长因子受体-2（VEGFR-2）介导。微小RNA-92a（miR-92a）是一种对血流敏感的微小RNA，可响应剪切应力调节动脉粥样硬化和血管生成。因此，ECP的有益作用可能是通过VEGF-A、VEGFR-2和miR-92a之间的相互作用实现的。本研究旨在采用假对照方式评估ECP对RA患者VEGF-A、VEGFR-2和miR-92a的影响。这是一项随机假对照试验，纳入了50例患有冠状动脉疾病（CAD）的RA患者。参与者按1:1比例随机分为ECP组（n = 25）或假治疗组（n = 25），每组接受35次治疗，每次治疗持续1小时。采用酶联免疫吸附测定（ELISA）技术检测血浆VEGF-A和VEGFR-2水平。运用定量逆转录聚合酶链反应（qRT-PCR）检测血浆中miR-92a的循环水平。与假治疗组相比，体外反搏显著维持了VEGF-A和VEGFR-2水平[VEGF-A变化量：1（-139至160）pg/ml vs. -136（-237至67）pg/ml，P = 0.026；VEGFR-2变化量：-171（-844至 +1,166）pg/ml vs. -517（-1,549至 +1,407）pg/ml，P = 0.021]。干预后，ECP组[5.1（4.2 - 6.4）至5.9（4.8 - 6.4），P < 0.001]和假治疗组[5.2（4.1 - 9.4）至5.6（4.8 - 6.3），P = 0.008]血浆中循环miR-92a均显著增加。ECP组的变化趋势虽高于假治疗组，但差异无统计学意义[ECP组变化量 = 4.6（0.3 - 36.5），假治疗组变化量 = 2.8（0 - 15），P = 0.33]。体外反搏通过维持VEGF-A和VEGFR-2水平改善了血管生成。ECP组和假治疗组均使miR-92a显著增加，但两组间变化无差异。（该研究已在www.clinicaltrials.gov注册，注册号：NCT03991871，注册时间：2019年8月8日，并获得印度尼西亚卫生部国家卫生研究与发展局资助，资助号：HK.02.02/I/27/2020）
