Introduction:
Coronary artery stenting is the predominant percutaneous coronary intervention for coronary artery disease. Despite its efficacy, stenting induces significant vascular and endothelial damage, triggering inflammation, repair, and neointimal hyperplasia. The endothelium's self-repair relies on mature endothelial cell migration and recruitment of Circulating Endothelial Progenitor Cells (EPCs). Drug-eluting stents, while effective, disrupt natural healing processes. Enhancing re-endothelialization post-stenting through methods like attracting EPCs with anti-CD34 antibody-coated stents aims to expedite repair, potentially reducing neointimal hyperplasia and stent thrombosis. Studies explore interventions like statins, exercise, estrogen, cytokines, and even endothelial cell or EPC seeding on stents to optimize this re-endothelialization process.
What Is the Purpose of Stenting?
Cardiovascular diseases, responsible for 31% of global deaths, pose a significant health burden. Among these, coronary artery disease (CAD) stands out as a leading cause of cardiovascular-related fatalities. CAD results from the accumulation of fatty and fibrous materials, forming atherosclerotic lesions in coronary arteries, ultimately leading to arterial occlusion). While these lesions can block blood flow, clinical complications often arise from thrombus formation, causing myocardial ischemia and infarction.
Percutaneous coronary intervention (PCI), a non-surgical revascularization technique, is widely used to address Obstructive Coronary Arteries. Intracoronary stent implantation, a key PCI method, has improved acute outcomes. Still, long-term success is impeded by age and comorbidities, with stent thrombosis and re-stenosis remaining the primary challenges. Stent placement induces mechanical vascular injury, leading to endothelial denudation, platelet activation, thrombosis, and stenosis.
Type 2 Diabetes and PCI Outcomes:
Type 2 diabetes mellitus adversely affects PCI outcomes, characterized by hyperglycemia and insulin resistance, leading to endothelial dysfunction. Diabetic patients face a higher risk of coronary lesions, occlusive restenosis, and platelet dysfunction, increasing stent thrombosis risk. Addressing these challenges requires understanding the disturbed endothelial cell function in diabetes and exploring interventions to enhance PCI outcomes in diabetic populations.
Rapid Endothelialization for Improved PCI Outcomes:
Facilitating rapid endothelialization post-stent implantation is crucial for preventing stent thrombosis. Rapid endothelialization provides anti-thrombotic and anti-adhesive properties, reducing complications like stenosis.
Pathogenesis of Stent Thrombosis:
Role of Endothelial Cells:
Coronary stents, serving as scaffolds for vessel walls, have evolved from bare metal to drug-eluting and bioresorbable types. Stent thrombosis, a critical complication, involves complex factors, including device, procedure, patient status, and lesion type. The pathophysiological response to stent implantation triggers wound healing processes involving endothelial cell denudation, platelet activation, inflammation, and smooth muscle cell dysregulation, leading to in-stent restenosis.
Endothelial Cells and Stent Endothelialization:
Endothelial cells play a pivotal role in protecting against thrombosis and inflammation. Impaired endothelial function, as seen in endothelial injury, contributes to thrombosis, leukocyte recruitment, and smooth muscle cell dysregulation. Achieving optimal stent endothelialization involves considering factors like stent design, surface topography, material biocompatibility, and drug effects. Strategies to enhance endothelialization include promoting a healthy endothelium layer, aligning cells, and addressing the impact of drugs and polymers in stent composition. Dual antiplatelet therapy post-PCI aims to reduce thrombotic events.
How Does Endothelialization Occur?
Endothelialization of stents occurs through two primary mechanisms: proliferation and migration of resident cells at the injury site and homing and adhesion of circulating endothelial progenitor cells (EPCs). While mature endothelial cells have limited proliferation capacity, EPCs, circulating in the blood, play a crucial role in endothelialization by differentiating into mature endothelial cells and participating in angiogenesis.
Various sub-populations of EPCs, such as early EPCs and late EPCs, have been identified, with late EPCs recognized as "true EPCs" due to their ability to differentiate into stable mature endothelial cells. Recent single-cell RNA-sequencing analysis studies identified specific markers in late EPCs, highlighting their distinct gene expression profile.
Biofunctionalization strategies involving molecules like antibodies, proteins, peptides, and aptamers have been proposed to induce stent endothelialization. Monoclonal antibodies against CD34, as seen in the Genous EPC capture stent and COMBO bio-engineered stent, were initially promising but showed mixed results in recent clinical studies.
The COMBO stent, incorporating sirolimus-releasing polymer and CD34 coating, demonstrated non-inferiority to other drug-eluting stents but exhibited higher rates of target vessel failure. Specificity issues with CD34 antibody and the risk of hyperplastic reactions highlight the need for alternative strategies in stent biofunctionalization.
Other approaches, including growth factors like VEGF and mobilization using chemokines, have been explored, but their lack of specificity for EPCs raises concerns. Short peptide ligands and aptamers, such as RGD and EPC-specific peptides, offer promising alternatives due to their specificity and ease of incorporation.
What Are the Challenges Faced During Stent Endothelialization?
Stent endothelialization with circulating endothelial progenitor cells (EPCs) faces several challenges. One major obstacle is the low number of EPCs in the blood, exacerbated by diseases like diabetes. Strategies to augment EPC numbers, such as pharmacological induction using agents like statins, may be necessary. The HEALING IIB study observed a 5.6-fold increase in EPC numbers with statin therapy, and combining this with EPC-capturing stents resulted in optimal stent coverage. Boosting EPC numbers could also involve using multiple capturing molecules, incorporating chemokine or growth-factor-releasing nanoparticles in stent coatings, or administering autologous EPCs locally or systemically.
Another challenge is the variability in regenerative potential among patients, influenced by factors like diabetes or cardiovascular diseases. The success of in situ endothelialization relies on intrinsic regenerative potential, and any impairment in this aspect affects the rate of endothelialization. Diabetes, in particular, impairs EPC function and regenerative ability, reducing stent coverage potential. Therefore, enhancing endothelial and EPC function in these patients, potentially through antidiabetic drugs with endothelial and cardioprotective effects, should be a focus to improve endothelialization, especially in conjunction with stent biofunctionalization.
Conclusion:
In conclusion, achieving successful stent endothelialization with endothelial progenitor cells (EPCs) presents challenges, including low numbers of circulating EPCs, particularly in conditions like diabetes. Strategies to boost EPC numbers, such as pharmacological induction and innovative stent biofunctionalization approaches, offer potential solutions. Additionally, addressing the variability in regenerative potential among patients, especially those with comorbidities, is crucial. Enhancing endothelial and EPC function, possibly through specific drugs, emerges as a key consideration for improving the efficacy of stent endothelialization strategies. Further research and innovative approaches are warranted to overcome these challenges and advance the field of vascular stent technologies.
