Abstract
Neointimal hyperplasia (NIH) is a pathological vascular response to injury, characterized by excessive smooth muscle cell (SMC) proliferation and extracellular matrix (ECM) deposition, leading to lumen narrowing. It remains a major cause of restenosis following percutaneous coronary intervention (PCI), bypass grafting, and hemodialysis access failure. This review comprehensively examines the pathophysiology of NIH, current prevention strategies (pharmacological, mechanical, and bioengineering approaches), guideline-based recommendations, and emerging therapies. Future directions, including gene therapy, targeted drug delivery, and artificial intelligence (AI)-guided interventions, are also discussed.
1. Introduction
1.1 Definition
Neointimal hyperplasia (NIH) is the abnormal thickening of the arterial intima due to SMC migration, proliferation, and ECM accumulation, typically triggered by endothelial injury (e.g., angioplasty, stenting, or vascular surgery).
1.2 Clinical Significance
- Primary cause of in-stent restenosis (ISR) (20–30% with bare-metal stents, <10% with drug-eluting stents).
- Major contributor to vein graft failure (40–50% occlusion at 10 years post-CABG).
- Leading reason for hemodialysis access dysfunction (50% failure within 1 year).
1.3 Types of NIH
- Focal NIH: Localized to stent edges or injury sites.
- Diffuse NIH: Widespread proliferation, common in vein grafts.
- Occlusive NIH: Complete vessel blockage (e.g., AV fistulas).
2. Pathophysiology of Neointimal Hyperplasia
2.1 Initiation: Endothelial Injury
Balloon angioplasty, stent deployment, or surgical trauma denudes the endothelium, exposing subintimal collagen and von Willebrand factor (vWF).
Platelet activation → Release of PDGF, TGF-β, and thrombin → SMC stimulation.
2.2 Inflammatory Phase
- Macrophage infiltration (M1 phenotype) secretes IL-6, TNF-α, and MMPs, degrading ECM and facilitating SMC migration.
- Neutrophil recruitment amplifies oxidative stress via ROS (e.g., NADPH oxidase).
2.3 Proliferative Phase
- SMC Phenotypic Switch: Contractile → Synthetic phenotype (↑ proliferation, ↓ differentiation).
- ECM Deposition: Collagen, proteoglycans (versican, decorin) expand the neointima.
2.4 Remodeling Phase
- Negative remodeling: Constrictive fibrosis → lumen loss.
- Positive remodeling: Rare; outward expansion preserves flow.
2.5 Key Molecular Pathways
- PDGF/PDGFR: Drives SMC migration.
- mTOR/PI3K-Akt: Mediates cell cycle progression (↓ by sirolimus/paclitaxel).
- TGF-β/Smad: Promotes fibrosis.
3. Prevention and Treatment Strategies
3.1 Mechanical Approaches
Drug-Eluting Stents (DES)
- Sirolimus/Paclitaxel: Inhibit mTOR, arresting SMC proliferation.
- Everolimus/Zotarolimus: Newer agents with improved safety.
- Guidelines: ESC/EACTS recommend DES over BMS for most PCI cases (Class I).
Drug-Coated Balloons (DCB)
Paclitaxel delivery without permanent implants (ideal for ISR, small vessels).
Bioresorbable Scaffolds
Temporary stents (e.g., Absorb GT1) reduce chronic inflammation.
3.2 Pharmacological Therapies
Antiplatelet Agents
- DAPT (Aspirin + P2Y12 inhibitors): 6–12 months post-PCI (ESC Guidelines).
- Vorapaxar (PAR-1 inhibitor): Investigational for vein graft patency.
Antiproliferative Drugs
- mTOR Inhibitors: Systemic sirolimus trials (limited by toxicity).
- Colchicine: Anti-inflammatory (COLCOT trial: ↓ restenosis).
Novel Agents
- SGLT2 Inhibitors: Reduce oxidative stress (EMPA-REG OUTCOME).
- IL-1β Antagonists (Canakinumab): CANTOS trial showed reduced vascular events.
3.3 Local Drug Delivery
- Perivascular wraps (e.g., paclitaxel-eluting meshes in CABG).
- Nanoparticles: Targeted delivery of siRNA (e.g., inclisiran for PCSK9 inhibition).
3.4 Gene and Cell-Based Therapies
Gene Therapy:
- siRNA against c-Myc or E2F: Suppresses SMC proliferation.
- VEGF Gene Transfer: Promotes re-endothelialization.
Endothelial Progenitor Cell (EPC) Capture Stents: Accelerate healing.
4. Guideline Recommendations
| Society | Key Recommendations |
|---|---|
| ESC/EACTS (2023) | DES preferred over BMS (Class I); DAPT for 6–12 months. |
| ACC/AHA (2021) | DCB for ISR (Class IIa); statins for all PCI patients. |
| KDIGO (2020) | Surveillance fistulography for hemodialysis access. |
5. Innovations and Future Directions
Precision Medicine
- Genetic testing (CYP2C19 for clopidogrel response).
- AI-based plaque analysis (predicting NIH risk).
Bioengineered Vascular Grafts
Decellularized scaffolds seeded with autologous cells.
Immune Modulation
Anti-inflammatory cytokines (IL-10, TGF-β nanoparticles).
3D-Printed Stents
Patient-specific designs to minimize shear stress.
6. Conclusion
NIH remains a complex vascular response to injury, driven by inflammation, SMC proliferation, and ECM remodeling. While DES and DCBs have revolutionized care, emerging therapies (gene editing, bioresorbable implants, and AI-driven interventions) promise further advancements. Multimodal strategies—combining mechanical, pharmacological, and biological approaches—are essential to optimize outcomes.
Key Takeaways for Clinicians
- First-line: DES + DAPT for PCI.
- Second-line: DCB for ISR.
- Future: Personalized therapies targeting genetic and inflammatory pathways.