Clinical trial NCT05355532: Genetic Determinants of the Coronary Microvascular Obstruction in PCI
Official title: Identification of Genetic Determinants of the Coronary Microvascular Obstruction Development in Percutaneous Coronary Interventions
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Myocardial Infarction
No-Reflow Phenomenon
Keywords: coronary microvascular obstruction
no-reflow phenomenon
myocardial infarction
percutaneous coronary intervention
single nucleotide polymorphism
genetics
Lead sponsor: Privolzhsky Research Medical University
Sponsor class: OTHER
First posted: 2022-05-02
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Patients with 1 type MI after emergency PCI

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. informed consent to participate in the study;
2. male or female 18 years of age or older;
3. type 1 ST-segment elevation MI (according to the criteria of the fourth universal definition of myocardial infarction and current clinical guidelines);
4. blood sampling in the operating room (immediately after PCI) and signing the informed consent;
5. for the "CMVO+" group: CMVO because of PCI (CMVO is registered according to the criteria from the European Society of Cardiology clinical guidelines);
6. 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:

1. late admission (more than 48 hours from the onset of anginal pain) or early post-infarction angina pectoris;
2. not 1 type MI;
3. complications during PCI (dissection, perforation or acute intraoperative thrombosis of the IRA);
4. death during PCI, not due to the CMVO development;
5. concomitant terminal pathology (not associated with MI) with a life expectancy less than 1 month.

Primary outcomes:
measure: Hospital mortality rate
timeFrame: up to 7-15 days after PCI
Secondary outcomes:
measure: Left Ventricle ejection fraction
timeFrame: 7-10 day after PCI
measure: Six-minute walk test
timeFrame: 7-10 day after PCI
measure: N-terminal pro-brain natriuretic peptide
timeFrame: 7-10 day after PCI
measure: Ventricular fibrillation
timeFrame: up to 7-15 days after PCI
Other outcomes:
Locations:
city: Nizhny Novgorod
country: Russian Federation
facility: City Clinical Hospital No. 13 of the Avtozavodsky District of Nizhny Novgorod
state: Nizhny Novgorod Region
city: Nizhny Novgorod
country: Russian Federation
facility: Central Research Laboratory of the Privolzhsky Research Medical University
state: Nizhny Novgorod Region
Study officials:
affiliation: Privolzhsky Research Medical University
name: Ilya Pochinka, MD
role: STUDY_CHAIR
References:
citation: Pochinka IG, Shchelchkova NA, Frolov AA, Pershin VI, Maksimova NS, Kuzmichev RV, Budkina ML, Predeina IV, inventors. Privolzhsky Research Medical University, assignee. Method of diagnosing genetic predisposition to development of phenomenon of coronary microvascular obstruction during percutaneous coronary interventions in patients with myocardial infarction with ST segment elevation. Russian Federation patent RU 2,811,933. 2023 Oct 26.
citation: Frolov AA, Pochinka IG, Shakhov BE, Mukhin AS, Frolov IA, Barinova MK, Sharabrin EG. Using an Artificial Neural Network to Predict Coronary Microvascular Obstruction (No-Reflow Phenomenon) during Percutaneous Coronary Interventions in Patients with Myocardial Infarction. Sovrem Tekhnologii Med. 2021;13(6):6-13. doi: 10.17691/stm2021.13.6.01. Epub 2021 Dec 28.