Role of Novel Biomarkers Associated With In-stent Restenosis After Percutaneous Coronary Intervention

To study the relation between ISR and neutrophil-to-lymphocyte ratio (NLR), novel biomarkers (high-sensitivity CRP (hs-CRP), bone morphogenetic protein-2 (BMP-2) and other risk factors (age, sex, smoking, hypertension, diabetes, obesity, chronic kidney disease (CKD; creatinine clearance).

Coronary artery disease (CAD) is the most common cardiovascular disease and remains a major global public health problem \[1\]. Due to the benefits of a shorter procedure time and reduced invasiveness, percutaneous coronary intervention (PCI) has become the predominant choice for coronary revascularization in patients with both stable and unstable CAD. However, in-stent restenosis (ISR) remains the leading problem after PCI, especially in patients with type 2 diabetes mellitus (T2DM) \[2,3\]. Diabetes mellitus is also regarded as one of the most powerful clinical predictors of ISR after drug-eluting stent (DES) implantation, which was also the case during the BMS era\[4,5\]. Although interventional approaches and pharmacological therapies have improved in recent years \[6\], ISR remains a problem; therefore, it is still important and useful to identify biomarkers that can predict ISR.

Bone morphogenetic protein-2 (BMP-2), a member of the transforming growth factor (TGF) superfamily, plays a significant role in both physiological and pathological vascular processes \[7,8\]. Recent studies have found that BMP-2 signalling is also associated with vascular disease, including atherosclerosis, vascular inflammation, vascular calcification and plaque instability \[9,10\]. Although diabetes has a well-known association with an increased risk for cardiovascular disease, the associated pathogenesis is not completely understood. In vitro studies have shown that high glucose concentrations are associated with increased expression of BMP-2 \[11\]. Plasma BMP-2 concentrations positively correlated with plaque burden and plaque calcification, which also positively correlated with plasma HbA1c. These findings suggest that BMP-2 may have a role in hyperglycaemia-induced calcification \[12\]. Endothelial dysfunction caused by stent implantation induces inflammation, which may also stimulate SMC proliferation \[13-14\]. Previous studies have revealed that chronic inflammation and fibrin deposition frequently persist for approximately 3 months after DES implantation, following the replacement of type III collagen by type I collagen and vascular smooth muscle cell (VSMC) proliferation \[15\]. Although the timing of intimal SMC proliferation is not clear, the migration of cells from within the plaque to the expanding neointima is the dominant factor that leads to ISR \[15, 16\]. BMP-2 is highly expressed in human vessels, and VSMCs are a significant source of BMP-2 \[17,18\]. In addition, several studies have indicated that BMP-2 promotes the migration of VSMCs by inducing the SMC phenotype towards a synthetic state and is closely associated with inflammation \[8,19\].Several studies have reported the clinical impact of hs-CRP levels in the chronic phase on clinical outcomes in CAD patients who underwent PCI. Hsieh et al. reported that higher hs-CRP levels (\>3.0 mg/L) at 9-month follow-up angiography after PCI were associated with higher incidence of overall mortality and future clinical cardiovascular outcomes, including restenosis \[20\]. These findings indicate that hs-CRP could offer a useful biomarker for predicting the risk of adverse cardiovascular events or mortality in CAD patients after PCI.

These results are supported by the fact that inflammation underlies many of the processes contributing to atherogenesis and plaque destabilization. It has been indicated that hs-CRP may contribute to the development of arteriosclerosis in the presence of modified low-density lipoprotein (LDL) such as oxidized LDL \[21\].

This suggests that the type of stent is only one factor to consider when searching for additional promoters of ISR. The present study aimed to detect the clinical, biological, imagistic and procedural factors associated with ISR.

What is the meaning of ISR?ISR was defined as the narrowing of the lumen diameter of the target vessel ≥50%, including the coronary arteries in the stent and the ≤5 mm area adjacent to the stent \[8\]

Eligibility Criteria:
Inclusion Criteria:

* Patients with previously implanted 3rd generation DES (Sirolimus, Biolimus, Everolimus, Zotarolimus), whatever the duration since implantation or the setting of implantation or the number of implanted stents, and who are presenting to our institute along the coming two years for CA±PCI because of recurrent chest pain with suspicious of ISR or other newly developed lesions.

Exclusion Criteria:

* • Previous CABG

  * ACS within the last 2ms before the index CA for those undergoing assessment of hs-CRP \& BMP-2
  * Heart failure with reduced EF\<40%
  * Severe liver or kidney disease
  * Autoimmune, inflammatory, or malignant diseases
  * Non-available previous PCI CD \& report