Study rationale: to evaluate clinical and prognostic relevance of microvascular dysfunction, coronary flow reserve and cardioprotective effects of iv administration of esmolol in patients with myocardial infarction.

First substudy is an open randomized trial evaluating the efficacy and safety of early intravenous administration of esmolol in patients with acute ST-segment elevation myocardial infarction (MI) and relative contraindications to administration of other intravenous β1-adrenergic blocker (metoprolol etс.). Сomparison group will include patients who have not received intravenous β1-adrenergic blocker. Secondary outcome in this substudy is the degree of microvascular obstruction and infarct size according to MRI with gadolinium delayed enhancement.

Second substudy examines the quantitative parameters of coronary physiology in patients with MI and multivessel disease. Changes of coronary physiology measurements over time ((iFR, Pd/Pa, FFR, delta FFR, gradient FFR per time unit (dFFR(t)/dt), pullback pressure gradient (PPG)) measured in the infarct-related artery and in non-infarct-related arteries with diameter stenosis of 50-85% immediately after the completion of a primary percutaneous coronary intervention and during a second hospitalization (30-45 days after STEMI) will be evaluated. The comparison changes of coronary physiology over time with presence of an MVO and infarct size determined by MRI. The model of calculating coronary flow reserve (CFR) based on tridimensional reconstruction of coronary arteries and coronary physiology parameters as measured during coronary angiography will be developed. The influence of coronary physiology parameters measured after complete myocardial revascularization by PCI, and derived CFR in patients with MI on long-term clinical outcomes will be evaluated, based on prospective data collection.

Primary composite outcome in all substudies will be the sum of adverse cardiac outcomes (congestive heart failure, episodes of recurrent congestive heart failure worsening resulting in hospitalizations, cardiac mortality, MI recurrences, unstable angina, urgent myocardial revascularization) within > 12 months post-infarction.

Secondary composite outcome in all substudies is the degree of microvascular obstruction and infarct size evaluated by MRI with gadolinium delayed enhancement.

Study rationale: to evaluate clinical and prognostic relevance of microvascular dysfunction, coronary flow reserve and cardioprotective effects of iv administration of esmolol in patients with myocardial infarction.

Substudy of early esmolol administration: On admission patients will undergo ECG and echocardiography in an intensive care ward, according to standard clinical practice. Eligible patients having signed the Informed Consent Form will be randomized 1:1 by appropriate software. In the esmolol arm the infusion will begin immediately on admission simultaneously with conventional upfront treatment. Study procedures will be performed in parallel to the patient's preparation for the catheterization lab and transportation for primary PCI, without any delay of time to the catheterization lab. During the hospitalization cardiac MRI will be done with contrast enhancement using an ultraconducting MRI scanner with the magnetic field intensity of 1.5 T (Siemens Avanto). The following elements will be done without contrast enhancement:

• cine imaging MRI in standard views (long axis 2- and 4-chamber views, LV short axis) measuring left ventricle end diastolic volume (LV EDV), left ventricle end systolic volume (LV ESV), LV EF, regional wall motion abnormality across 17 LV segments;
• Т2-weighed images (T2WI) using the same views to assess myocardial edema (signal intensity elevation more than 2-fold compared to the normal myocardium).

For contrast enhancement a gadolinium-based contrast agent will be used (gadobutrol, Bayer) in the dose of 0.15 mmol/kg body weight. The following elements will be done with contrast enhancement:

• early contrast enhancement (2 minutes after intravenous administration of the contrast agent);
• delayed contrast enhancement (10 - 20 minutes after intravenous administration of the contrast agent).

The areas demonstrating with contrast enhancement will be assessed as areas of acute or chronic myocardial injury (during the presence of edema, according to T2WI results).

Substudy investigating coronary physiology. This substudy is expected to include 200 patients with MI and multivessel Coronary Artery Disease who will be found on PCI (performed for the IRA) to have lesions with diameter stenosis of 50-85% in other arteries.

During hospitalization for AMI treatment and diagnostic evaluation of patients will be done according to current clinical practice guidelines. All patients enrolled into the study will undergo PCI with IRA stenting. In the STEMI group, 50 hemodynamically stable patients after primary PCI will undergo invasive measurements of coronary hemodynamical parameters: instantaneous wave-free ratio, Pd/Pa, FFR with papaverine administration both into the IRA and into non-IRA (FFR measurements with papaverine administration will only be performed in patients without contraindications to such administrations [as worded for AMI patients as a separate exclusion criterion]). During the hospitalization those 50 patients will undergo cardiac MRI with IV contrast enhancement to evaluate MVO, beyond routine assessments.

Other 150 patients enrolled into the study (50 with STEMI and 100 with NSTEMI) during their first hospitalization for AMI will only undergo routine assessments and treatment procedures according to clinical practice guidelines. In 30-40 days after the MI patients will be hospitalized again. During their second hospitalization patients will undergo stress SPECT myocardial perfusion imaging or exercise stress echocardiography with physical exertion or ATP infusion, with CFR measurement, unless contraindicated. All patients will undergo a follow-up coronary angiography with invasive measurement of coronary hemodynamical parameters in non-IRA, accompanied by an assessment of IRA stenting outcomes (instantaneous wave-free ratio, Pd/Pa, unless contraindicated - FFR with papaverine administration etc.). If non-IRA stenting is indicated, PCI with subsequent invasive re-assessment of coronary hemodynamical parameters. The CFR value across the coronary artery basins will be calculated based on the tridimensional reconstruction of coronary arteries and intracoronary pressure measurements before and after stenting. In the subgroup of patients who underwent measurements of coronary hemodynamical parameters in the acute setting, follow-up measurements of coronary hemodynamical parameters will be performed. Subsequently relationship will be evaluated between invasive measurements of coronary hemodynamical parameters and the presence of MVO. Also, results of stress tests will be compared to invasive measurements of coronary hemodynamical parameters. Patients demonstrating CFR reduction in a stress echocardiography with ATP infusion will be asked to repeat a stress test within 1 month post-stenting, during a hospitalization, or on an out-patient visit within one month after discharge from the hospital.

Substudy evaluating cardioprotective effects of early iv administration of esmolol

Inclusion Criteria:

• Diagnosed acute ST elevation MI, type 1, within the first 8 hours of disease onset;
• Treating physician's decision not to administer metoprolol intravenously prior to primary PCI due to a high risk of complications (BP < 120/80 mm Hg at baseline examination, moderate evidence of heart failure (Killip 2) or a risk of its development (LV EF ≤ 30%), first degree AV block with PQ ≥ 0.25 ms, history of asthma or severe COPD etc.)
• Signed Informed Consent to participate in the study

Exclusion Criteria:

• severe heart failure (pulmonary edema; SCAI В-Е cardiogenic shock);
• atrioventricular conduction abnormality higher than first degree, without a pacemaker;
• sinus bradycardia with the heart rate of < 60 bpm;
• BP < 100/60 mm Hg.;
• asthma in exacerbation;
• history of a STEMI in the IRA basin;
• clinically significant bleeding or hypovolemia;
• hypersensitivity to esmolol;
• pregnancy or lactation;
• known severe comorbidities independently affecting prognosis (Child Pugh class C liver failure, active malignancies etc.);
• contraindications to MRI (MR-incompatible pacemaker/implanted cardioverter-defibrillator, cochlear implants, clips on brain vessels, foreign metal objects - bullets, intraorbital metal fragments, insulin pumps, body weight above 150 kg, history of allergies to gadolinium, claustrophobia);
• severe dementia;
• known severe comorbidities independently affecting prognosis (chronic renal or liver failure, active malignancies etc.);
• complicated PCI, "no reflow" phenomenon on follow-up coronary angiography;
• thrombolysis for AMI;
• ECG evidence of spontaneous reperfusion on admission;
• patient's refusal from participation in the study.

Substudy investigating coronary physiology

Inclusion Criteria:

• Diagnosed MI, completed PCI for the IRA and multivessel Coronary Artery Disease with diameter stenosis of 50-85% in non-IRA.
• Signed Informed Consent to participate in the study

Exclusion criteria:

• History of coronary artery bypass grafting surgery;
• Non-IRA lesions resulting in diameter stenosis of below 50% and above 85%, main left coronary artery (LCA) stenosis above 50%;
• Chronic kidney disease stage 3b or above (glomerular filtration rate below 45 mL/min/m2 according to the CKD-EPI equation);
• History of a contrast-induced nephropathy (CIN) or a high CIN risk (calculated using the Mehran score);
• History of allergies to iodine-containing medications;
• Pregnancy or lactation;
• Left ventricle ejection fraction ≤ 30%;
• Known severe comorbidities independently affecting prognosis (chronic renal or liver failure, active malignancies etc.);
• Early post-infarction angina;
• Severe dementia;
• Patient's refusal from participation in the study.

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