The association of mean platelet volume to lymphocyte ratio and no- reflow in patients with myocardial infarction undergoing primary percutaneous coronary intervention

Introduction The acute coronary and cerebro-cardiac events as first cardiovascular manifestation have same pathophysiologic mechanisms (i.e., atherosclerosis and thrombosis).1 The improvement of technology, introducing new and powerful anti-thrombotic treatments may result in increased complexity of percutaneous coronary interventions (PCIs), and consequently, higher intervention risk. Indeed, many patients are suffering from myocardial infarction (MI) after the intervention; especially due to the consequences of decreased blood flow.2 Although myocardial damage may gradually occur, the formation of platelet plaques in blood circulation could lead to the obstruction of blood supply to the myocardium, and this event is associated with a potentially negative effect on the prognosis of the disease.3 The primary and delayed prognosis of patients with acute MI are mainly related with three major variables, including left ventricle function, the sensitivity to ventricular arrhythmias and post-reperfusion remained ischemia.4,5 The no-reflow phenomenon occurs in a significant number of patients with ST-elevation myocardial infarction (STEMI) undergoing primary reperfusion. 6 By remarkable using of primary PCI, it is important to the better diagnosis and treatment of “no-reflow”, then, researchers focus on issue which plays a central role in researches for improvement of aforementioned effects. The clinical and laboratory experiences show that “no-reflow” is associated with necrosis of cardiac muscles, which is known as a predictor of mortality.6-8 Currently, the data of other studies and analysis of controlled clinical trials demonstrate that white blood cell-related indices (e.g., platelet/lymphocyte ratio and neutrophil/lymphocyte ratio) are associated with higher mortality rate, repeated MI, and severe outcomes after acute coronary syndrome (ACS). The inflammation plays a special role in the initiation and progression of atherosclerosis process.9 Nowadays, the ratio of mean platelet volume to lymphocyte (MPV/lymphocyte) is suggested as a thrombotic and inflammatory marker which has been mainly evaluated in cases with malignant Original Article


Introduction
The acute coronary and cerebro-cardiac events as first cardiovascular manifestation have same pathophysiologic mechanisms (i.e., atherosclerosis and thrombosis). 1 The improvement of technology, introducing new and powerful anti-thrombotic treatments may result in increased complexity of percutaneous coronary interventions (PCIs), and consequently, higher intervention risk. Indeed, many patients are suffering from myocardial infarction (MI) after the intervention; especially due to the consequences of decreased blood flow. 2 Although myocardial damage may gradually occur, the formation of platelet plaques in blood circulation could lead to the obstruction of blood supply to the myocardium, and this event is associated with a potentially negative effect on the prognosis of the disease. 3 The primary and delayed prognosis of patients with acute MI are mainly related with three major variables, including left ventricle function, the sensitivity to ventricular arrhythmias and post-reperfusion remained ischemia. 4,5 The no-reflow phenomenon occurs in a significant number of patients with ST-elevation myocardial infarction (STEMI) undergoing primary reperfusion. 6 By remarkable using of primary PCI, it is important to the better diagnosis and treatment of "no-reflow", then, researchers focus on issue which plays a central role in researches for improvement of aforementioned effects. The clinical and laboratory experiences show that "no-reflow" is associated with necrosis of cardiac muscles, which is known as a predictor of mortality. [6][7][8] Currently, the data of other studies and analysis of controlled clinical trials demonstrate that white blood cell-related indices (e.g., platelet/lymphocyte ratio and neutrophil/lymphocyte ratio) are associated with higher mortality rate, repeated MI, and severe outcomes after acute coronary syndrome (ACS). The inflammation plays a special role in the initiation and progression of atherosclerosis process. 9 Nowadays, the ratio of mean platelet volume to lymphocyte (MPV/lymphocyte) is suggested as a thrombotic and inflammatory marker which has been mainly evaluated in cases with malignant

Original Article
Article History: tumors. 10 This ratio is followed by inconsistent results. It reflects hemostatic and inflammatory pathways in blood disorders. 11 However, there is a lack of information about the ratio and the association with other undesired events in patients with cardiovascular diseases. 12 Hence, this ratio might have a significant role in the determination of disease severity and response to treatment based on "noreflow" grading in patients with AMI undergoing PCI. Therefore, we aimed to evaluate this ratio effect on "noreflow" event in such cases.

Materials and Methods
This cross-sectional study was conducted for evaluation of the "no-reflow" phenomenon in two phases, on 845 cases with AMI undergoing PCI who were referred to Shahid Madani hospital in 2018. Informed consent was obtained from the participants, and the laboratory tests and echocardiographic evaluations were done. The demographic data (including age, weight, etiology of MI, history of hypertension, diabetes mellitus, hyperlipidemia, smoking, renal failure, cardiac surgery, duration of disease, drugs, type of treatment, etc), imaging studies, angiographic findings (e.g., infarcted coronary vessels, the diameter of vessels, length of injury, the ejection fraction (EF) of left ventricle), hospitalization indices (e.g., the first time of inflation symptom of balloon, incidental antithrombotic event, clopidogrel loading dose, number of the stents, heparin administration before randomization, and third-degree of supply disorder) and laboratory data (e.g., white blood cell, platelet, creatinine [Cr], erythrocyte sedimentation rate, chain reactive polymerase) were recorded.

Analysis of angiographic study and definition of "noreflow"
• The coronary angiography was performed based on the standard criteria. The off-line analysis of digital angiograms was done in the central lab by using automated diagnostic systems (blinded operator). The primary PCI (mainly by replacement of stent) and taking care during treatment courses were performed. The anticoagulant drugs (i.e., clopidogrel 600 mg as a loading dose and, following 75 mg/d for minimum four weeks to 6 months and aspirin 200 mg per day by unlimited dose) were administered. The epicardial blood circulation in the area of the infarcted artery and myocardial perfusion rate were graded based on TIMI (thrombolysis in MI). The diagnosis of "noreflow" is made by the following criteria: • The documented angiographic re-opening view of obstructed coronary vessels, the successful replacement of stent without any sign of vessel restriction and supply limitation (< 50%), and the obvious no-reflow, spasm or thrombosis. • The documented angiographic evaluation in view of TIMI <2, or TIMI = 3 with myocardial reperfusion grade = 0 (TMPG) or 1 at least 10 minutes after PCI. TMPG is referred to no entrance of contrast media, and TMPG1 is equivalent to the slow entrance of media or unsuccessful media exiting from vessels. The 50% or more stricture of coronary vessels is known as vessel stricture. If two epicardial vessels are involved more than 50%, this is named to multivessel involvement. PCI is considered as successful primary PCI when remained stricture rate based on TIMI grading is < 10%. The data were analyzed by descriptive methods (mean ± standard deviation and frequency-percentage). Independent samples t test and Mann-Whitney U Test were used for the comparison of MPV/lymphocyte ratio when variables were normal and non-parametric, respectively. The normal distribution of data was analyzed using the Kolmogorov-Smirnov test. P value < 0.05 was considered statistically significant.

Results
Of 845 patients with STEMI, the incidence of angiographic no-reflow was 28% (n = 245). The demographic, laboratory and angiographic variables are shown in Table 1.
As outlined in this table, the cases in the normal-flow group were younger and had a lower rate of comorbid disease and higher successful history of the prior coronary artery bypass graft. It was more likely that no-reflow has occurred in women with a higher level of Cr, hypercholesterolemia, C-reactive protein (CRP), and platelet to lymphocyte ratio (PLR). In terms of angiographic study, the involvement of multiple vessels, which is resulted in a prolonged time to the placement of balloon, delayed time up to re-opening of occluded vessels and lower TIMI after PCI were observed in the no-reflow group. The stent diameter, Ejection Fraction (EF), and resolution of electrocardiographic changes were higher in the normal-flow group. It meant that there was a significant association with higher MPV to lymphocyte ratio and no-reflow ( Table 2).
The univariate and multivariate predictors of no-reflow are listed in Table 3. The multivariate analysis showed that gender, smoking, diabetes mellitus, higher WBC count, serum Cr levels, prolonged time to balloon placement, multi-vessel involvement and chronicity were more powerful predictors for the no-reflow phenomenon.

Discussion
The results of our study demonstrated interesting findings, which show that basic demographic characterization (i.e., age, gender, co-morbid diseases, and smoking), laboratory tests (i.e., higher cholesterol and Cr level, MPV, hs-CRP, MPV to lymphocyte ratio) and angiographic data (i.e., the number of involved arteries, delayed time up to reopening of occluded vessels, history of anterior MI, TIMI and the characteristics of the stent) have an impact on the no-reflow phenomenon and its incidence in cases with  STEMI. The higher MPV and lower count of lymphocyte mean enhanced coagulation activity in such patients. On the other hand, it could be explained by long-term decreased perfusion of ischemic heart tissues due to delayed performance of PCI, the more narrow applied stents, and the lowered consumption rate of anticoagulant drugs, which is also reinforced by underlying conditions such as the previous history of hyperlipidemia. This survey suggested the power of the mentioned ratio in the prediction of no-reflow. However, the most important question is "what is the effect of no-reflow on the prognosis of STEMI?". Here, we could state the there is a significant correlation between mortality after MI and the no-reflow phenomenon and this event will be decreased by elimination or eradication of some variables which can play a role in this scenario. Yildiz et al evaluated the MPV/lymphocyte ratio for the prediction of "no-reflow" in patients with ST-elevation MI (undergoing PCI). TIMI was surveyed in 287 cases who were treated with primary PCI and classified in 3 groups according to PLR. The indices of TIMI were calculated during pre-and post-treatment periods. The cut-off value for MPV/lymphocyte ratio and neutrophil to lymphocyte ratio (NLR) were equal with approximately 160 and 5.9, respectively. The specificity and sensitivity were about 75% and 71%, respectively. These findings showed that the high levels of pre-treatment MPV/lymphocyte ratio and NLR were supposed as important and independent prognostic factors. 11 The other study by Kurtul et al assessed the evaluation of the relationship between MPV/ lymphocyte ratio and "no-reflow" after primary PCI. Overall, 520 cases with STEMI were evaluated within 12 hours after onset of symptoms in 2 groups: cases with "normal flow" (TIMI = 3) and "without flow" (TIMI = 0-1 or 2). The results showed that 403 and 117 (22.5%) patients were "normal flow" and " no-reflow", respectively. The second group had significantly higher PLR. The MPV/ lymphocyte ratio and total stent length were independent prognostic factors after primary PCI (PPCI) so that preintervention ratio could be considered as mainstay cue for the prediction of PPCI outcomes. 13 Currently, it has been suggested that anemia is associated with increased mortality rate, re-infarction and severe consequences after ACS. Lawler et al showed that 4 4519 of 23 3144 cases had anemia who were elderly and had a higher prevalence of diabetes, heart failure, cerebral disease and history of bleeding. 10,14

Conclusion
The present study showed that no-reflow is an important event which is followed by a higher mortality rate. For having the prognostication value of this phenomenon, the evaluation of contributing simple factors, such as MPV, MPV to lymphocyte ratio and TIMI could help to prevent the no-reflow and resultant mortality.

Conflict of interest
The authors stated that they had no conflict of interest.

Ethical Approval
This study was approved by the ethical committee of Tabriz University of Medical Sciences (No. IR.TBZMED.

REC.1398.1271).
Author's Contributions AS carried out the design and coordinated the study, participated in fundus exams. PD participated in neonate's examinations and follow ups. AAA provide assistance in the design of the study, neonate's examinations and follow ups. AS provided assistance in statistical analysis and manuscript preparation. AAA and PD assisted in data gathering and participated in manuscript editing.

Funding
There was no funding support