The Clinical Prediction Factors of Non Chronic Total Occlusion Lesions Progression in Patients Underwent Percutaneous Coronary Intervention for Chronic Total Occlusion Lesions

Backgroud :To investigate the clinical prediction factors of non chronic total occlusion lesions progression in patients underwent percutaneous coronary intervention(PCI) for chronic total occlusion lesions. Methods: A total of 450 unstable angina patients (57.1 ± 9.2 years) underwent PCI from January 2016 to December 2018 in Beijing Anzhen Hospital were enrolled in this study. All patients underwent PCI as treatment for chronic total occlusion lesions. Clinical and angiographic follow-up were performed in 12 months. All patients were divided into non chronic total occlusion lesions(NCTOL) progression group (205 cases) and the control group (275 cases) according to angiographic follow-up outcome in 12 months. The clinical and angiographic features were analyzed. Results: levels of adenosine diphosphate (ADP) induced platelet aggregation rate(ADP-IPA) (51.89 ± 14.81 vs 39.63 ± 17.12 (cid:0) P <0.01), lipoprotein(a)(Lp(a))(0.22 ± 0.26 vs 0.14 ± 0.18,P < 0.05) in NCTOL progression group were signicantly higher than those in the control group. Logistic regression showed that ADP induced PAR (odds ratio =1.047, 95% condence interval:1.014-1.082, P = 0.005), Lp(a) (odds ratio =11.972, 95% condence interval: 1.230 -116.570, P = 0.033) were independent predictors of NCTOL progression. Partial correlation analysis showed that ADP-IPA was positively correlated with NCTOL progression( r = 0. 351,P < 0. 001) .Receiver operating characteristic(ROC) curve showed that the boundary point of ADP-IPA to predict NCTOL progression was 30%, the sensitivity was 86.2% and the specicity was 68.9%. Conclusions: ADP-IPA may be an valuable predictor for NCTOL progression .in unstable angina patients underwent percutaneous coronary intervention(PCI) for chronic total occlusion lesions.


Introduction
Chronic total occlusions (CTOs) are de ned as coronary artery lesions with thrombolysis in myocardial infarction (TIMI) grade ow of 0 (true CTO)or TIMI grade ow 1(functional CTO)and present for more than or equal to 3 months.CTOs are not seldom in coronary artery disease patients,Fefer et al found that CTOs were found in 14.7% coronary artery disease patients underwent coronary angiography. PCI for CTOs was a most challenging procedure in the eld of PCI.However, with recent improvements in technology including the introduction of dedicated CTO wires, balloons, re nement in the operator technique and appropriate patient selection, success rate of PCI with CTOs has risen to 90% in some centers and PCI for CTOs was recommended as IIa class in 2011ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. [2] .However,Park et al [3] reported that the rate of nonculprit lesiosns(NCL) progression in patients underwent PCI for culprit lesions was 7% in one year,14% in 2 years and 16% in 3 years.Non-culprit lesions(NCL)progression in coronary artery disease patients underwent PCI for culprit lesions indicated that diffuse and active in ammation occur in both vulnerable and stable plaques of the entire coronary tree and NCL progression could be the most signi cant factor that affects the progonsis in coronary artery disease patients .
Recent studies about PCI for CTO lesions in coronary artery disease patients were not seldom however non chronic total occlusion lesions(NCTOL) progression in coronary artery disease patients underwent PCI for CTO lesions has not been studied. In this study ,we investigated the the clinical prediction factors of non chronic total occlusion lesions progression in coronary artery disease patients underwent percutaneous coronary intervention(PCI) for chronic total occlusion lesions .

Methods
All participants or their family members were informed about the potential publication of their identities and images, and all of them completed consent forms. All procedures and protocols were approved by All patients were divided into non chronic total occlusion lesions(NCTOL) progression group ( 205 cases) and the control group (275 cases) according to angiographic follow-up outcome in 12 months.
The main exclusion criteria included the following: previous percutaneous coronary intervention (PCI) in CTO artery (n = 6) CTO artery with excessive proximal tortuosity or severe calci cation (n = 14), left ventricular ejection fraction <35% (n = 15), lack of clinical and angiographic follow-up (n = 26), in-hospital death after PCI (n = 11), myocardial infarction within 2 w of PCI to exclude potential subacute stent thrombosis of the intervened arterial segment (n = 9), and repeated PCI of CTO lesions for restenosis or progression (n = 43).
Coronary angiography was performed using the Judkins method, and coronary artery lesion classi cation was based on the American College of Cardiology/American Heart Association guidelines [3] .Stents were implanted using a routine method, and the procedure succeeded with residual stenosis <20%, TIMI ow grade of 3 and no acute complications (death, myocardial infarction, emergency coronary artery bypass grafting (CABG)), and no major adverse cardiac events (cardiac death, myocardial infarction, target vessel revascularization). Clinical and angiography follow-up was performed for 12 months.
NCTOLs were de ned as those with a diameter of stenosis <70%. All patients underwent PCI for the CTO lesions.
Quantitative coronary angiography was performed during the rst angiography. Follow-up angiography was performed by two independent investigators who were blinded to the results. We categorized the lesions in accordance with the American College of Cardiology/American Heart Association. Classi cation was performed on the basis of the morphological characteristics of lesions that cause signi cant stenosis of the coronary arteries. [3] These include two categories of simple lesions (A or B1 lesions) and complex lesions (B2 or C).
The collected data included demographic information, medical history, coronary artery disease risk factor status, detailed coronary angiographic information, biomarkers associated with coronary atherosclerosis at the time of baseline PCI, and coronary angiographic information at the time of angiographic follow-up.
All clinical, laboratory, and coronary angiographic data were evaluated by two independent investigators who were not involved in the angiographic procedures.
De nition of NCTOL progression [3] : 1. The stenosis degree of the NCTOL was ≥50% at the time of baseline PCI, and the degree of NCTOL progression was ≥10% at the time of angiographic follow-up. 2.
The stenosis degree of the NCTOL was <50% at the time of baseline PCI, and the degree of NCTOL progression was ≥30% at the time of angiographic follow-up. 3. The degree of NCTOL progression ≥30%, while there were no NCTOLs at the time of baseline PCI. 4. NCTOL progression to total occlusion.

Results
Between January 2016 and December 2018, 964 unstable angina patients underwent PCI treatment for CTO lesions.of those 450 patients (350 men and 100 women) underwent angiographic follow-up in 12 months There were 305 (235 men and 70 women) patients without NCTOL progression (the control group) and 145 (115 men and 30 women) patients with NCTOL progression (the progression group) according to angiographic follow-up outcome in 12 months.
There were signi cant differences in Lp(a) and adenosine diphosphate (ADP)induced platelet aggregation rate ADP-IPA between the two groups (all P<0.0001)( Table 1).
Angiographic characteristics between two groups showed that Stent length in NCTOL progression group was shorter than that in the control group 28.79 ± 23.93 vs 43.87 ± 30.35,P < 0.05 . There were no signi cant differences in other angiographic characteristics between two groups( Table 2).

Discussion
In this study, there were 450 patients underwent angiographic follow-up after PCI for CTO lesion in 12 months, and there were 145 patients with NCTOL progression , the progression rate of NCTOL was 32.2%. however,Park et al investigated the progresion rate of nonclprit lesions in STEMI patients after primary PCI, and showed that the progression rate of NCL in STEMI patients after primary PCI was 7.7% [3] . It indicated that the progression of NCTOL was an important factor that affected the prognosis of CAD patients after successful PCI for CTO lesions.
In this study, we found that ADP-induced PAR may be a predictor of the progression of NCTOL .in patients underwent PCI for chronic total occlusion lesions and partial correlation analysis also indicated that ADPinduced PAR was positively correlated with NCTOL progression (r = 0.231, P=0.001).
ADP is one of the most important agonists of platelet activation. ADP induces platelet shape change, exposure of brinogen binding sites, aggregation, and in ux and intracellular mobilization of Ca 2+ . ADPinduced platelet aggregation is important for maintaining normal hemostasis.but aberrant platelet aggregation manifests itself pathophysiologically in myocardial ischemia, stroke, and atherosclerosis. Clopidogrel is an ADP receptor antagonist and can irreversibly inhibit adenosine diphosphate (ADP)induced platelet aggregation,long-term administration of clopidogrel was associated with a modest but statistically signi cant advantage over aspirin in reducing adverse cardiovascular outcomes in CAD patients underwent PCI.However ,there were 25-50 CAD patients received clopidogrel therapy without adeqate inhibitation of ADP-induced platelet aggregation [4] , and the poor inhibitation of ADP-induced platelet aggregation may be associated with adverse cardiovascular outcomes. Li Q and colleagues [5] found that CAD patients with high ADP-induced platelet aggregation have high risk of major adverse cardiac and cerebrovascular event (MACCE) after PCI. PCI procedure may cause endothelial cells injure, activate the excessive proliferation of smooth muscle cells and platelet adhesion and aggregation,leading to stenosis and thrombosis [6][7][8] .Complex PCI may cause more endothelial cells injure than simple PCI it was essential for patients underwent complex PCI such as PCI for CTO lesions to detect platelet function .Moreover, coronary artery lesions were not fully coved by stents may cause instent thrombus , it was involved in platelet activation [9,10] . This study showed that stent length in NCTOL progression group was shorter than that in the control group,it indicated that coronary artery lesions were not fully covered by stents may be involved in NCTOL progression.
This study showed that NCTOL progression was important cause of recurrent PCI in CAD patients after PCI for CTO lesions and NCTOL progression may be the most important factor that affects the prognosis of CAD patients after successful PCI for CTO lesions.ADP-IPA may be a predictor of the progression of NCTOL .in patients underwent PCI for chronic total occlusion lesions, and it was essential to detect platelet function and adeaqute antiplatelet therapy.

Conclusions
ADP-IPA may be an valuable predictor for NCTOL progression .in unstable angina patients underwent percutaneous coronary intervention(PCI) for chronic total occlusion lesions.   Figure 1