The Impact of Lesion Complexity and the CHA2DS2-VASc Score on Spontaneous Reperfusion in Patients with ST-Segment Elevation Myocardial Infarction

Background In patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI), a patent infarct-related artery (IRA) on initial angiography is defined as spontaneous reperfusion (SR). Objective The present study aimed to determine the impact of lesion complexity and the CHA2DS2-VASc score on SR in patients with STEMI. Methods A total number of 1,641 consecutive patients with STEMI undergoing primary PCI were assessed for this study. Patients were divided into 2 groups, those with SR, SR(+) (n = 239), and those without SR, SR(−) (n = 1402), according to their initial angiography and SR status. CHA2DS2-VASc scores were calculated for all patients. The lesion complexity of coronary artery disease was assessed with the SYNTAX score. Results The CHA2DS2-VASc and SYNTAX scores were significantly lower in the SR(+) group compared to the SR(−) (mean CHA2DS2-VASc, 1.36 ± 0.64 vs. 2.01 ± 0.80, p < 0.001; mean SYNTAX score, 15.51 ± 5.94 vs. 17.08 ± 8.29, p < 0.001). After the multivariate regression analysis, a lower CHA2DS2-VASc (OR = 0.288, p < 0.001), SYNTAX score (OR = 0.920, p=0.007), uric acid (OR = 0.868, p=0.005), CRP (OR = 0.939, p=0.001), BNP (OR = 0.998, p=0.004), and troponin (OR = 0.991, p=0.001) were independent predictors of SR. In-hospital mortality rates were significantly lower in the SR(+) group compared to the SR(−) (0% vs. 6.7%, p < 0.001). Conclusion Our study demonstrated that lesion complexity and the CHA2DS2-VASc score are independently associated with spontaneous reperfusion.


Introduction
Acute coronary syndromes (ACS) are the leading causes of death worldwide [1]. e plaque rupture and erosion followed by thrombus formation within the vessel lumen are significant etiologies in the pathophysiology of ACS [2]. e absence of collateral perfusion in the setting of complete coronary occlusion results in acute ST-segment elevation myocardial infarction (STEMI). STEMI patients initially undergo cardiac catheterization after being admitted to the hospital and are often evaluated and treated with percutaneous coronary intervention (PCI). PCI is a first-choice reperfusion therapy for STEMI patients if an experienced team is available to intervene promptly. Guidelines recommend a maximum expected delay of 60 min from STEMI diagnosis to primary PCI (wire crossing) at hospitals capable of primary PCI [3,4]. Besides, thrombolytic therapy has been an alternative reperfusion strategy if primary PCI cannot be performed timely. In such patients, the primary goal of treatment is to prevent myocardial necrosis after achieving reperfusion. Meaningfully, reperfusion is of prime importance for an ischemic tissue to maintain its vitality. Spontaneous reperfusion (SR) is defined as the achievement of initial thrombolysis in myocardial infarction (TIMI) grade 3 flow in the infarction-related artery (IRA) before reperfusion therapy. SR is seen in 7% to 27% of patients with acute STEMI [5]. In STEMI patients, the achievement of early TIMI grade 3 flow in the IRA increases the ventricular performance and reduces mortality rate [6]. Among STEMI patients undergoing primary PCI, those with SR on coronary angiography (CAG) have a better prognosis than patients without spontaneous blood flow [7,8].
Despite many related risk classification systems described in the literature, there is no standardized approach to the prediction of SR. e CHA 2 DS 2 -VASc score is a simple, easy-to-remember, valid, and practical scoring system that is used for estimating cardioembolic risk in patients with nonvalvular atrial fibrillation (AF) and for determining indications for anticoagulant therapy [9]. e parameters used in the CHA 2 DS 2 -VASc score also involve the mutual risk factors for coronary artery disease (CAD). Recently, the CHA 2 DS 2 -VASc score has become a predictor of ischemic stroke and cardiovascular events in cases of CAD without AF [10,11]. Nevertheless, to our knowledge, the relationship between the CHA 2 DS 2 -VASc score and SR is yet to be investigated. e present study was designed to examine the relationship between the CHA 2 DS 2 -VASc score, lesion complexity and SR in STEMI patients undergoing primary PCI.

Materials and Methods
e retrospective, cross-sectional study included a total of 1,641 consecutive patients who were admitted to our hospital with a prediagnosis of STEMI within 12 hours from symptom onset and underwent primary PCI, between 2012 and 2017. STEMI was diagnosed in the presence of the following criteria based on the European Society of Cardiology (ESC) Guidelines [12]: (i) new ST-segment elevation at the J point in two contiguous leads with the cut-off value greater than 0.1 mV in all leads other than V2 or V3 and (ii) in leads V2-V3, a cut-off value of ≥0.2 mV in men aged ≥40 years, ≥0.25 in men aged <40 years, or ≥0.15 mV in women. SR was defined as the presence of TIMI grade 3 flow in the IRA on baseline CAG.
Patients with AF, history of anticoagulant and/or antithrombotic treatment within the last one month, endstage renal disease (estimated glomerular filtration rate ≤ 30 mL/min/1.73 m 2 ), malignancy, sepsis, prior myocardial infarction, prior PCI or open-heart surgery, moderate-to-severe valvular heart disease, and those aged less than 18 years were excluded from the study (Figure 1).
Demographic and clinical characteristics, including age, gender, smoking status, hypertension (HT), diabetes mellitus (DM), hyperlipidemia (HLD), current drug use, and physical examination findings, were recorded for each patient. e laboratory analysis of venous blood samples from all patients at the time of admission to the emergency department was performed using an automated chemistry analyzer (Roche Diagnostic Modular Systems, Tokyo, Japan).
Echocardiographic measurements were performed in accordance with the American Society of Echocardiography (ASE) guidelines using a Vivid 7 GE Medical System (GE Healthcare, Horten, Norway), and the left ventricular ejection fraction (LVEF) was calculated based on the modified Simpson method [13].
Heart failure with reduced EF (HFrEF) was diagnosed in the presence of risk factors, abnormal electrocardiogram, clinical signs (e.g., elevated jugular venous pressure, hepatojugular reflux, and laterally displaced apical impulse), symptoms of heart failure (e.g., reduced exercise tolerance, paroxysmal nocturnal dyspnea, breathlessness, and orthopnoea), and/or objective evidence of reduced LVEF, along with a reduced EF of <50% assessed by echocardiography [14]. Hypertension (HT) was defined as a persistent elevation of systolic blood pressure (SBP) of ≥140 mmHg and/or diastolic blood pressure (DBP) of ≥90 mmHg or a history of antihypertensive drug use. DM was defined as a fasting blood glucose level of ≥126 mg/dL or a history of antidiabetic drug use. Peripheral artery disease (PAD) was defined as the presence of stenosis of >50% in arteries other than the coronary arteries. Vascular disease was defined as the presence of previous myocardial infarction, peripheral artery disease, or aortic plaque. e CHA 2 DS 2 -VASc and the Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) I scores were calculated for each patient using the following parameters: HFrEF (C), HT (H), aged over 75 years (A2), DM (D), stroke (S2), vascular disease (V), aged 65 years to 74 years (A), and female gender (sex category [Sc]). e CHA 2 DS 2 -VASc score was calculated by assigning 1 point for each of the parameters including HFrEF, HT, DM, age 65 years to 74 years, female gender, and presence of vascular diseases and by assigning 2 points for the history of stroke and age >75 years [9]. Accordingly, the maximum CHA 2 DS 2 -VASc was calculated as 9 points.

Ethical Statement.
All participants gave written informed consent to the study. e study protocol was approved by our institutional ethical committee and was conducted by following the Declaration of Helsinki and good clinical practice guidelines.

Coronary Angiography.
All the patients underwent CAG (Siemens Axiom Artis zee 2011; Siemens Health-care, Erlangen, Germany) according to recent guidelines [15]. Angiograms were obtained for the left coronary system in standard 4 different angles (left anterior oblique cranial, left anterior oblique caudal, anteroposterior cranial, right anterior oblique cranial, and right anterior oblique caudal views) and for the right coronary system in standard 2 different angles (left anterior oblique and right anterior oblique) and were recorded to digital memory. e revascularization of IRA for all participants was completed in the same session with CAG. Coronary lesions were evaluated by two experienced interventional cardiologists blinded to all clinical data. A significant and severe coronary artery stenosis was defined as the presence of a lumen reduction of ≥50% in at least one major epicardial coronary artery [16]. e SYNTAX score was calculated before the wiring or predilatation of IRA from the angiographic analysis of coronary lesions with ≥50% stenosis in vessels ≥1.5 mm in diameter, using the original SYNTAX score website (http:// www.syntaxscore.com) [17]. e SYNTAX score is calculated by a computer program consisting of 12 sequential and interactive questions that are divided into two groups: the first three questions determine the dominance, the total number of lesions, and the vessel segments involved per lesion. When determining the severity of CAD, the SYNTAX score was calculated based on the total number, functional significance, and localizations of lesions detected on CAG and based on the presence of total occlusion, bifurcation, trifurcation, distal vessel bed, and thrombus formation. In patients with severe CAD, TIMI was graded as follows: grade 0: no perfusion, grade 1: penetration without perfusion, grade 2: partial perfusion, and grade 3: complete perfusion. SR was defined as the achievement of TIMI grade 3 flow in IRA on the baseline CAG [18]. e study population was divided into two groups, the SR (+) and SR (-) groups, based on CAG.
e two groups were compared in terms of CHA 2 DS 2 -VASc, demographics, clinical, echocardiographic, and laboratory results.

Intervention
Procedure. PCI was chosen as reperfusion therapy for subjects included in the present study. CAG was performed using the standard Judkins technique through the femoral route with a 6-7 Fr guiding catheter. Mostly, drug-coated metal stents were used. All the patients received acetylsalicylic acid (loading dose of 300 mg, maintenance dose of 100 mg), heparin (100 U/kg) intravenously, and a loading dose of 600 mg, followed by a maintenance dose of 75 mg of clopidogrel once every day or a loading dose of 180 mg, followed by a maintenance dose of 90 mg of ticagrelor twice every day or a loading dose of 60 mg, followed by a maintenance dose of 10 mg of prasugrel once every day. Procedural decisions regarding thrombus aspiration and balloon catheter use, stent diameter, length, and type were left to the attending operator's discretion. ). e normal distribution of data was analyzed using the Kolmogorov-Smirnov test. Continuous data were expressed as mean ± standard deviation (SD) and median (interquartile range; IQR  ). Categorical data were expressed as a number (n) and percentage (%). Differences between categorical variables were determined using Fisher's exact test and/or Chi-square test, and unpaired samples were compared using Student's t-test or Mann-Whitney U test where appropriate. Univariate and multivariate logistic regression analyses were used to identify the independent variables of SR. After performing univariate analysis, significant variables with a p-value <0.05 were selected into the multivariate logistic regression analysis using the stepwise method. e results of univariate and multivariate regression analyses were presented as odds ratio (OR) with 95% confidence interval (CI). e optimal cut-off value of the International Journal of Clinical Practice CHA 2 DS 2 -VASc score, which has the highest overall sensitivity and specificity in predicting SR, was determined using the receiver operating characteristic (ROC) curve with the Youden index. e area under the curve (AUC) comparisons of the predictors for SR was performed using the DeLong method [19]. Significance was assumed at a twosided p-value of <0.05.

Results
Spontaneous reperfusion was detected in 239 out of 1,641 STEMI patients ( Parameters that were found to affect SR development in the logistic regression analysis were further analyzed using univariate and multivariate analyses. Univariate analysis was conducted with the parameters including age, gender, BMI, HT, DM, smoking status, antiplatelet therapy received at the emergency department, CHA 2 DS 2 -VASc and SYNTAX scores, uric acid, Cre, TSH, CRP, BNP, and troponin. Of these, age, DM, antiplatelet therapy received at the emergency department, CHA 2 DS 2 -VASc and SYNTAX scores, uric acid, Cre, CRP, BNP, and troponin were found to be statistically significant, and hence, they were further analyzed by multivariate analysis, in which CHA 2 DS 2 -VASc score, SYNTAX score, uric acid, CRP, BNP, and troponin were found to be the independent predictors of SR development (CHA 2 DS 2 -VASc, OR � 0.288, p < 0.001; SYNTAX, OR � 0.920, p � 0.007; uric acid, OR � 0.868, p � 0.005; CRP, OR � 0.939, p � 0.001; BNP, OR � 0.998, p � 0.004; troponin, OR � 0.991, p � 0.001). However, although LVEF was found to be statistically significant in both groups, it was not included in the logistic regression model since decreased LVEF was considered to be associated with the outcome rather than to be a predictor of SR (Table 2). e ROC curve analysis provided a cut-off value of ≤1 for the CHA 2 DS 2 -VASc score to predict the SR of STEMI patients with 56.1% sensitivity and 73.3% specificity (AUC: 0.703, 95% CI: 0.681-0.725, p < 0.001) ( Table 3). e pairwise comparison of ROC curves revealed that the CHA 2 DS 2 -VASc score had statistically better discriminatory power than the remaining determinants for predicting SR in STEMI patients undergoing primary PCI (Table 4, Figure 2).

Discussion
e present study investigated the relationship between the CHA 2 DS 2 -VASc score and SR development in patients with STEMI who underwent CAG. e results indicated that the CHA 2 DS 2 -VASc and SYNTAX I scores were significantly lower in the SR group compared to the non-SR group, inhospital mortality rates were significantly lower in the SR group, and the CHA 2 DS 2 -VASc score, uric acid, CRP, BNP, and troponin were found to be the independent predictors of SR.
Acute coronary syndromes remain a leading cause of morbidity and mortality worldwide [1]. STEMI is a clinical condition that arises from the rupture and erosion of the delicate atheromatous plaque followed by its complete obstruction because of thrombus formation. In patients presenting with STEMI, early clinical evaluation is of paramount importance for diagnosis and treatment. In such patients, CAG is commonly used for diagnosis and treatment purposes, and SR is diagnosed as the presence of TIMI grade 3 flow in IRA on the baseline CAG [20].
ere is no consensus in the literature regarding the correct timing of the intervention to be performed in STEMI patients with SR who underwent delayed PCI or emergency intervention, with some reporting similar clinical outcomes independent of the timing of the intervention. More importantly, the authors noted that patients who presented with the clinical signs of reperfusion achieved favorable outcomes, despite the lack of immediate intervention [21]. e presence of SR on pre-PCI angiography is an independent marker of high procedural success and has been associated with a smaller infarction area and a better shortand long-term prognosis [6,[22][23][24][25][26]. Accordingly, it should be recognized that early prediction of SR in STEMI patients is highly important. e incidence of SR in STEMI patients has been reported to be between 7% and 27% in the literature  International Journal of Clinical Practice 5 [5], and it was found to be 14.6% (239 out of 1,641 patients) in our study. e CHA 2 DS 2 -VASc score is a simple, easy-to-remember, valid, and practical scoring system used for predicting cardioembolic risk in patients with nonvalvular AF and for determining the indications for anticoagulant therapy. In recent studies, this scoring system is a predictor of ischemic stroke and adverse cardiovascular events, including death in cases of CAD without AF. Additionally, it has been associated with mortality in patients with stable angina and ACS [27,28]. A previous study suggested that the CHA 2 DS 2 -VASc score could be used for predicting the severity of CAD [28]. Moreover, another study indicated that the CHA 2 DS 2 -VASc score could be a marker of the noreflow phenomenon in both STEMI and NSTEMI patients [29,30]. In some other studies, the CHA 2 DS 2 -VASc score has been reported to be a predictor of adverse cardiovascular events and mortality in patients with Takotsubo syndrome without AF [31]. Similarly, it has also been shown that the CHA 2 DS 2 -VASc score is a predictor of stroke and death in patients with sick sinus syndrome following pacemaker implantation [32]. Additionally, Yilmaz et al. showed that    International Journal of Clinical Practice the CHA 2 DS 2 -VASc score was a predictor of in-stent restenosis [33]. To our knowledge, there has been no study in the existing literature investigating the relationship between SR development and the CHA 2 DS 2 -VASc score in STEMI patients.
e present study evaluated a total of 1,641 consecutive patients who underwent CAG because of STEMI and revealed that the CHA 2 DS 2 -VASc score was significantly lower in the SR group compared to the non-SR group. Moreover, multivariate analysis indicated that the CHA 2 DS 2 -VASc score, uric acid, CRP, BNP, and troponin were found to be the independent predictors of SR development.
e SYNTAX score is commonly used in the quantification of the severity of CAD [17]. is scoring system has been shown to be an independent predictor of major adverse cardiac and cerebral events (MACCE) in patients treated with coronary artery bypass grafting (CABG) and PCI [30,34]. Moreover, increased SYNTAX scores have been reported to be associated with contrast nephropathy and new-onset AF [35,36]. On the other hand, the severity of CAD determined by the SYNTAX score is associated with the arterial stiffness assessed by pulse wave velocity (PWV) [37]. A previous study also showed that the SYNTAX score and the Killip classes from 2 to 4 were significantly higher in STEMI patients without SR [38]. In the present study, the SYNTAX score was significantly lower in the SR group compared to the non-SR group.
A study showed that in-hospital mortality was almost nonexistent in patients with SR, while it was remarkably high in patients without SR [6,[21][22][23][24][25]. Similarly, in our study, inhospital mortality rate was significantly lower in the SR group compared to the non-SR group (0% vs. 6.7%, p < 0.001).
Terkelsen et al. reported that patients with spontaneous ST-resolution had a lower peak level of troponin and a better LVEF value [26]. Additionally, it is commonly known that the detection of spontaneous ST-resolution on an electrocardiogram indicates microvascular circulation, and thus, it is more desirable than the detection of SR on angiography [39]. In our study, the LVEF value was significantly higher in the SR group compared to the non-SR group, whereas troponin level was lower in the SR group compared to the non-SR group.

Limitations of the Study.
Retrospective nature is the major limitation of the present study. Larger-scale prospective studies with more patients should be done to maintain more accurate prognostic information.

Conclusion
Our results indicated that lower CHA 2 DS 2 -VASc and SYNTAX scores are associated with SR development in STEMI patients. To the best of our knowledge, this is the first study to examine the relationship between the CHA 2 DS 2 -VASc score and SR development in STEMI patients. e ROC analysis indicated that the CHA 2 DS 2 -VASc score at a cut-off value of ≤1 may predict SR development. Based on the finding, we conclude that the CHA 2 DS 2 -VASc score is a useful predictor of SR development in STEMI patients. Furthermore, larger-scale studies are needed to pave the way for widespread use of this scoring system in clinical practice.

Data Availability
Data will be shared upon request.

Conflicts of Interest
e authors declare that they have no conflicts of interest.

Authors' Contributions
GA and HAB carried out the studies, participated in collecting data, and drafted the manuscript. GA, AA, HAB, and OG performed the statistical analysis and participated in its design. GA, ST,İS, andÖG participated in the acquisition, analysis, interpretation of data, and drafting of the manuscript. All authors read and approved the final manuscript.