Genetic Determinants of the Coronary Microvascular Obstruction in PCI

Study Overview
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Brief Summary
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Myocardial infarction (MI) remains one of the most common causes of death. Percutaneous coronary intervention (PCI) is the main treatment option to restore blood flow through the infarction-related coronary artery (IRA) in MI patients. Performing PCI significantly reduces mortality, but in 5-10% cases, PCI is complicated by the development of coronary microvascular obstruction (CMVO, no-reflow). CMVO is defined as the absence of adequate myocardial perfusion, despite the restoration of the IRA lumen. The development of CMVO significantly worsens the prognosis and increases mortality. CMVO has a complex pathogenesis and is development due to following mechanisms: distal microembolism, ischemia-reperfusion injury, persistent endothelial dysfunction, and individual predisposition. These mechanisms can be implemented simultaneously and have different severity. The most significant predictors of CMVO occurrence are: age, time from pain onset to reperfusion, severity of acute heart failure, ineffective thrombolytic therapy, collateral blood flow according to the Rentrop classification, severity of IRA thrombosis according to Thrombolysis in Myocardial Infarction (TIMI) thrombus grade, initial IRA blood flow according to TIMI flow grade, implantation of 3 or more stents, direct IRA stenting, neutrophil and blood glucose levels. Difficulties in CMVO predicting are caused by the pathogenetic heterogeneity of this complication. Even the best models are moderately accurate. This can be explained by the fact that the models don't use genetic factors that determine endothelial function, microcirculation, hemostasis, and inflammation. Identification of the genetic determinants of the CMVO development can help create a new diagnostic system for CMVO predicting.

Detailed Description
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The aim of the study to identify the genetic determinants of the coronary microvascular obstruction development during percutaneous coronary interventions in myocardial infarction patients. The study investigates the role of some variants of single nucleotide polymorphism (SNP) as predictors of CMVO development. Selected SNPs that are associated with the mechanisms of CMVO development (according to literature). Hypothesis: selected SNPs are independent genetic predictors of the development of CMVO during PCI in MI patients. Study design: matched case-control study. Sample size: 80 patients. Patients must have inclusion criteria, haven't exclusion criteria, and sign an informed consent. Division into 2 groups in the ratio 1:1. Group 1 (CMVO+): 40 patients with MI who were detected the CMVO after PCI. The second group (CMVO-, control): 40 patients with MI who weren't detected CMVO after PCI. Groups are matched by sex and age. The sample size (80 patients) was determined in accordance with the following parameters: alpha error - 5%, study power - 80%, group size ratio - 1:1, minimum odds ratio for detection - 4.0, prevalence SNP in the population - 12-69% (average 50%). CMVO (no-reflow) is defined as inadequate myocardial perfusion after successful mechanical restoration of blood flow through the IRA (according to the 2017 European Society of Cardiology STEMI guidelines). CMVO criteria (there must be at least one criterion): 1) IRA blood flow is less than 3 points according to TIMI flow grade; 2) myocardial perfusion less than 2 points according to Myocardial blush grade (MBG). Other causes of IRA obstruction (spasm, dissection, thromboembolism) must be excluded. Research stages: 1) assessment of inclusion / exclusion criteria; 2) signing informed consent; 3) taking blood for genetic analysis (performed in the operating room immediately after PCI); 4) processing of blood samples and their transportation to the laboratory; 5) filling out the patient's register card (contains information about the treatment and outcomes); 6) performing genetic analysis; 7) statistical processing of the obtained results. The registration card is filled in at the end of hospitalization. Purpose: 1) comparison of SNP variants and outcomes; 2) multivariate analysis of SNP variants and other CMVO predictors. The card contains the following data: information about PCI, risk factors for the CMVO development, laboratory data (general blood count, biochemical blood test, etc.), examination data (ECG, ECG monitoring, echocardiography, six-minute walk test), information about complications and outcomes. These laboratory tests and instrumental studies are used in accordance with routine hospital protocols for the treatment of MI patients (the using is not associated with the investigation). Venous peripheral blood is used for genetic testing. Blood sampling is performed directly in the operating room after PCI. Selected SNPs from the CardioGenetics Hypertension panel, CardioGenetics Thrombophilia panel and Genetics of Folate Metabolism panel from the DNA-Technology company (Russia). Also used a set of reagents for the detection of Lys198Asn polymorphism in the EDN1 gene SNP-Express-Cardiogenetics RT from Litekh Company (Russia). SNPs are determined by real-time polymerase chain reaction with high resolution melt curve analysis using TaqMan fluorescent probes. The following SNPs are analyzed (SNP identifier and gene): rs4961 (ADD1); rs699 и rs4762 (AGT); rs5186 (AGTR1); rs1403543 (AGTR2); rs1799998 (CYP11B2); rs5443 (GNB3); rs2070744 и rs1799983 (eNOS); rs1799963 (F2); rs6025 (F5); rs6046 (F7); rs5985 (F13); rs1800790 (FGB); rs1126643 (ITGA2-α2); rs5918 (ITGB3-β3); rs1799762 (PAI-1); rs1801133 (MTHFR); rs1801131 (MTHFR); rs1805087 (MTR); rs1801394 (MTRR); rs5370 (EDN1). Expected results: it will be proved or disproved that some variants of SNP are independent predictors of the development of CMVO during PCI in patients with myocardial infarction.

Official Title
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Identification of Genetic Determinants of the Coronary Microvascular Obstruction Development in Percutaneous Coronary Interventions

Conditions
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Myocardial Infarction, No-Reflow Phenomenon

Intervention / Treatment
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* Genetic: different variants of SNPs that may be associated with the coronary microvascular obstruction development


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: informed consent to participate in the study; male or female 18 years of age or older; type 1 ST-segment elevation MI (according to the criteria of the fourth universal definition of myocardial infarction and current clinical guidelines); blood sampling in the operating room (immediately after PCI) and signing the informed consent; for the CMVO+ group: CMVO because of PCI (CMVO is registered according to the criteria from the European Society of Cardiology clinical guidelines); for the CMVO- group: absence of CMVO after PCI; patient should compliance by sex and age (±5 years) with pair in the CMVO+ group. Exclusion Criteria: late admission (more than 48 hours from the onset of anginal pain) or early post-infarction angina pectoris; not 1 type MI; complications during PCI (dissection, perforation or acute intraoperative thrombosis of the IRA); death during PCI, not due to the CMVO development; concomitant terminal pathology (not associated with MI) with a life expectancy less than 1 month.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| CMVO+ (patients has presented CMVO in PCI)<br>Patients with 1 type MI that has presented CMVO in emergency PCI. | Genetic: different variants of SNPs that may be associated with the coronary microvascular obstruction development<br>* Some variants of SNPs determine endothelial function, microcirculation, hemostasis, and inflammation in MI patients. They may be associated with the development of coronary microvascular obstruction during emergency PCI. A link between the different SNPs and the CMVO development will be established. SNP will be determined by real-time polymerase chain reaction with high-resolution melting curve analysis using TaqMan fluorescent probes.<br>|
| CMVO- (patients hasn't presented CMVO in PCI)<br>Patients with 1 type MI that hasn't presented CMVO in emergency PCI. | Genetic: different variants of SNPs that may be associated with the coronary microvascular obstruction development<br>* Some variants of SNPs determine endothelial function, microcirculation, hemostasis, and inflammation in MI patients. They may be associated with the development of coronary microvascular obstruction during emergency PCI. A link between the different SNPs and the CMVO development will be established. SNP will be determined by real-time polymerase chain reaction with high-resolution melting curve analysis using TaqMan fluorescent probes.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hospital mortality rate | Death during index hospitalization. | up to 7-15 days after PCI | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Left Ventricle ejection fraction | Echo-cardiography, four-chamber projection, Simpson's method. | 7-10 day after PCI | 
| Six-minute walk test | Distance in meters that a patient can walk in 6 minutes. Based on the test, the class of chronic heart failure according to New York Heart Association (NYHA) classification is determined. | 7-10 day after PCI | 
| N-terminal pro-brain natriuretic peptide | Level of N-terminal pro-brain natriuretic peptide in pg/ml | 7-10 day after PCI | 
| Ventricular fibrillation | Ventricular fibrillation during index hospitalization | up to 7-15 days after PCI | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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coronary microvascular obstruction, no-reflow phenomenon, myocardial infarction, percutaneous coronary intervention, single nucleotide polymorphism, genetics