Dipyridamole and vascular healing following stent implantation

Trevor Simard; Richard Jung; Pietro Di Santo; Alisha Labinaz; Spencer Short; Pouya Motazedian; Shan Dhaliwal; Dhruv Sarma; Adil Rasheed; F Daniel Ramirez; Michael Froeschl; Marino Labinaz; David R Holmes; Mohamad Alkhouli; Benjamin Hibbert

doi:10.3389/fcvm.2023.1130304

Dipyridamole and vascular healing following stent implantation

Front Cardiovasc Med. 2023 Sep 8:10:1130304. doi: 10.3389/fcvm.2023.1130304. eCollection 2023.

Authors

Trevor Simard^#^{1

2

3}, Richard Jung^#^{2

3}, Pietro Di Santo², Alisha Labinaz², Spencer Short², Pouya Motazedian², Shan Dhaliwal², Dhruv Sarma¹, Adil Rasheed^{2

4}, F Daniel Ramirez², Michael Froeschl², Marino Labinaz², David R Holmes¹, Mohamad Alkhouli¹, Benjamin Hibbert^{1

2

3}

Affiliations

¹ Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, United States.
² CAPITAL research group, Division of Cardiology, University of Ottawa Heart Institute, Ottawa, ON, Canada.
³ Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
⁴ Department of BMI, Faculty of Medicine, Ottawa, ON, Canada.

^# Contributed equally.

Abstract

Introduction: 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 (n = 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%, p = 0.03) and a 36.2% relative increase in optimally healed stent struts (37.8 ± 2.8% vs. 54.6 ± 2.5%, p < 0.0001). Atherosclerosis demonstrated attenuated effect with no difference in NI burden (15.2 ± 1.0% vs. 16.9 ± 0.8%, p = 0.22) and only a 14.2% relative increase in strut healing (68.3 ± 4.1% vs. 78.7 ± 2.5%, p = 0.02). DP treated rabbits had a 44.6% (p = 0.045) relative reduction in NI SMC content. In vitro 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.

Conclusion: 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.

Keywords: adenosine; adenosine receptor 2B; dipyridamole; in-stent restenosis (ISR); neointima; optical coherence tomograhy (OCT); proliferation and apoptosis; vascular smooth muscle (VSMC).

Grants and funding

This work was supported by the UOHIAMO AFP Innovations Funding Competition for Innovative Clinical Projects and CFI (Canadian Foundation for Innovation). The Vered-Beanlands Endowed Fellowship (TS). The Canadian Institutes of Health Research [Vanier Research Graduate Scholarship (RGJ) and Banting Postdoctoral Fellowship (FDR)], the Royal College of Physicians and Surgeons of Canada [Detweiler Travelling Fellowship (FDR)].