Abstract
Objective: 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.Methods: 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 (n = 25) or sham (n = 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.Result: 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, p = 0.026; ΔVEGFR-2: −171(-844 to +1,166) vs. −517(−1,549 to +1,407) pg/ml, p = 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), p = 0.008] post-intervention. The fold changes tended to be higher in ECP group, although was not statistically different from sham [fold changes ECP = 4.6 (0.3–36.5) vs. sham 2.8 (0–15), p = 0.33)].Conclusion: 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).
Highlights
Refractory angina (RA), typically occurring in patients with advanced, often diffuse coronary artery disease (CAD), is described as angina that is still present despite optimal pharmacologic, intervention, or surgery which has been provided for >3 months [1]
Due to scientific gaps in the effect of External counterpulsation (ECP) on angiogenesis and miRNA-92a, this study aims to evaluate the effect of ECP therapy on angiogenesis represented by vascular endothelial growth factor-A (VEGF-A) and vascular endovascular growth factor receptor-2 (VEGFR-2) and flow-sensitive miR92a in patients with RA
Our study population consisted of 50 patients with RA who have been documented as having CAD, 25 patients in the ECP group, and 25 patients in the sham group
Summary
Refractory angina (RA), typically occurring in patients with advanced, often diffuse coronary artery disease (CAD), is described as angina that is still present despite optimal pharmacologic, intervention, or surgery which has been provided for >3 months [1]. It is an emergent problem in patients with advanced CAD due to an aging population and improved survival from CAD [2, 3]. The cuffs are inflated in early diastole to boost coronary artery perfusion, venous return, and deflated simultaneously in systole to reduce systemic vascular resistance, cardiac workload, and enhance systemic perfusion [4]. Increased shear stress in coronary circulation by ECP treatment is proposed as a principal underlying mechanism, resulting in multiple downstream favorable mechanisms, including an increase in angiogenesis, collateral circulation, improved endothelial function, and reduced arterial stiffness [4, 6, 7]
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