Genetic Determinants of the Coronary Microvascular Obstruction in PCI

Myocardial Infarction Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05355532
• Other study ID #: CMVO-SNP-2022
• Status: Completed
• Start date: April 11, 2022
• Est. completion date: March 25, 2023

Study information

• Verified date: April 2022
• Source: Privolzhsky Research Medical University
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 80
• Est. completion date: March 25, 2023
• Est. primary completion date: March 5, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Infarction
• Myocardial Infarction
• No-Reflow Phenomenon

Intervention

Genetic:
• different variants of SNPs that may be associated with the coronary microvascular obstruction development
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.

Locations

Country	Name	City	State
Russian Federation	Central Research Laboratory of the Privolzhsky Research Medical University	Nizhny Novgorod	Nizhny Novgorod Region
Russian Federation	City Clinical Hospital No. 13 of the Avtozavodsky District of Nizhny Novgorod	Nizhny Novgorod	Nizhny Novgorod Region

Sponsors (1)

Lead Sponsor	Collaborator
Privolzhsky Research Medical University

Country where clinical trial is conducted

Russian Federation, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Hospital mortality rate	Death during index hospitalization.	up to 7-15 days after PCI
Secondary	Left Ventricle ejection fraction	Echo-cardiography, four-chamber projection, Simpson's method.	7-10 day after PCI
Secondary	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
Secondary	N-terminal pro-brain natriuretic peptide	Level of N-terminal pro-brain natriuretic peptide in pg/ml	7-10 day after PCI
Secondary	Ventricular fibrillation	Ventricular fibrillation during index hospitalization	up to 7-15 days after PCI