Simard Trevor, Jung Richard, Di Santo Pietro, Labinaz Alisha, Short Spencer, Motazedian Pouya, Dhaliwal Shan, Sarma Dhruv, Rasheed Adil, Ramirez F Daniel, Froeschl Michael, Labinaz Marino, Holmes David R, Alkhouli Mohamad, Hibbert Benjamin
Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, United States.
CAPITAL research group, Division of Cardiology, University of Ottawa Heart Institute, Ottawa, ON, Canada.
Front Cardiovasc Med. 2023 Sep 8;10:1130304. doi: 10.3389/fcvm.2023.1130304. eCollection 2023.
Patients undergoing coronary stent implantation incur a 2% annual rate of adverse events, largely driven by in-stent restenosis (ISR) due to neointimal (NI) tissue proliferation, a process in which smooth muscle cell (SMC) biology may play a central role. Dipyridamole (DP) is an approved therapeutic agent with data supporting improved vascular patency rates. Pre-clinical data supports that DP may enact its vasculoprotective effects via adenosine receptor-A2B (ADOR-A2B). We sought to evaluate the efficacy of DP to mitigate ISR in a pre-clinical rabbit stent model.
METHODS & RESULTS: 24 New Zealand White Rabbits were divided into two cohorts-non-atherosclerosis and atherosclerosis ( = 12/cohort, 6 male and 6 female). Following stent implantation, rabbits were randomized 1:1 to control or oral dipyridamole therapy for 6 weeks followed by optical coherence tomography (OCT) and histology assessment of NI burden and stent strut healing. Compared to control, DP demonstrated a 16.6% relative reduction in NI volume (14.7 ± 0.8% vs. 12.5 ± 0.4%, = 0.03) and a 36.2% relative increase in optimally healed stent struts (37.8 ± 2.8% vs. 54.6 ± 2.5%, < 0.0001). Atherosclerosis demonstrated attenuated effect with no difference in NI burden (15.2 ± 1.0% vs. 16.9 ± 0.8%, = 0.22) and only a 14.2% relative increase in strut healing (68.3 ± 4.1% vs. 78.7 ± 2.5%, = 0.02). DP treated rabbits had a 44.6% ( = 0.045) relative reduction in NI SMC content. assessment of DP and coronary artery SMCs yielded dose-dependent reduction in SMC migration and proliferation. Selective small molecule antagonism of ADOR-A2B abrogated the effects of DP on SMC proliferation. DP modulated SMC phenotypic switching with ADOR-A2B siRNA knockdown supporting its role in the observed effects.
Dipyridamole reduces NI proliferation and improves stent healing in a preclinical model of stent implantation with conventional antiplatelets. Atherosclerosis attenuates the observed effect. Clinical trials of DP as an adjunctive agent may be warranted to evaluate for clinical efficacy in stent outcomes.
接受冠状动脉支架植入术的患者每年发生不良事件的发生率为2%，这主要是由新生内膜（NI）组织增生导致的支架内再狭窄（ISR）引起的，在这个过程中平滑肌细胞（SMC）生物学可能起着核心作用。双嘧达莫（DP）是一种已获批准的治疗药物，有数据支持其可提高血管通畅率。临床前数据表明，DP可能通过腺苷受体-A2B（ADOR-A2B）发挥其血管保护作用。我们试图在临床前兔支架模型中评估DP减轻ISR的疗效。
将24只新西兰白兔分为两个队列——非动脉粥样硬化组和动脉粥样硬化组（每组12只，6只雄性和6只雌性）。支架植入后，将兔子按1:1随机分为对照组或口服双嘧达莫治疗组，持续6周，随后进行光学相干断层扫描（OCT）以及对NI负荷和支架支柱愈合情况进行组织学评估。与对照组相比，DP使NI体积相对减少了16.6%（14.7±0.8%对12.5±0.4%，P=0.03），最佳愈合的支架支柱相对增加了36.2%（37.8±2.8%对54.6±2.5%，P<0.0001）。动脉粥样硬化表现出减弱的效应，NI负荷无差异（15.2±1.0%对16.9±0.8%，P=0.22），支架支柱愈合仅相对增加了14.2%（68.3±4.1%对78.7±2.5%，P=0.02）。接受DP治疗的兔子NI SMC含量相对降低了44.6%（P=0.045）。对DP和冠状动脉SMC的评估显示，SMC迁移和增殖呈剂量依赖性降低。ADOR-A2B的选择性小分子拮抗作用消除了DP对SMC增殖的影响。DP通过ADOR-A2B siRNA敲低调节SMC表型转换，支持其在观察到的效应中的作用。
在使用传统抗血小板药物的支架植入临床前模型中，双嘧达莫可减少NI增殖并改善支架愈合。动脉粥样硬化减弱了观察到的效应。作为辅助药物的DP的临床试验可能有必要评估其在支架治疗结果方面的临床疗效。
