Influence of injected metoprolol and high-dosage statin therapy on some markers of early myocardial remodeling in acute coronary syndrome

Aim of the study was to evaluate of the effect of intravenous metoprolol tartrate administered before percutaneous coronary intervention (PCI), in combination with long-term use of high-dose atorvastatin, on dynamic changes in biochemical and ultrasound markers, as well as on the outcomes of early myocardial remodeling in patients with ST-segment elevation acute myocardial infarction (MI). 
Material and methods. A prospective randomized clinical trial included 136 patients with MI. The terms of the study were 35 ± 5 (from 30 to 40) days from the moment of admission to the hospital. The first group (control) included patients who received standard interventional and drug treatment at the hospital and outpatient post-infarction stages. The second group (exposure) included individuals who received a single intravenous injection of metoprolol tartrate before PCI, followed by a switch to oral metoprolol succinate on a systemic basis. These patients, as well as in the first group, regularly received all components of the basic drug therapy, including atorvastatin at a dose of 80 mg per day for one month from the onset of MI. On the 1st-2nd day of MI and a month later, plasma levels of biochemical biomarkers were assessed in patients; on the 1st, 10th day and one month later, ultrasound markers were evaluated using echocardiography. Upon the follow-up clinical outcomes of post-infarction myocardial remodeling were analyzed. 
Results. We confirmed that the use of a single intravenous injection of metoprolol tartrate (5–15 mg) in acute myocardial infarction before PCI against the background of high-dose atorvastatin (80 mg/day) for one month from the onset of myocardial infarction demonstrated convincing efficacy in relation to the prevention of early myocardial remodeling, which we assessed by the dynamics of ultrasound markers, as well as by the plasma activity of all three key biochemical markers in comparison with the control group of patients. 
Conclusions. The use of a single intravenous injection of metoprolol tartrate in the acute phase of MI against the background of high-dose atorvastatin for one month from the onset of MI is a highly effective pharmacological method for preventing the formation of early postinfarction myocardial remodeling.

1. Galli A., Lombardi F. Postinfarct left ventricular remodelling: a prevailing cause of heart failure. Cardiol. Res. Pract., 2016: 2579832. doi: 10.1155/2016/2579832

2. Rossello X., Lobo-Gonzalez M., Ibanez B. Editor’s choice – pathophysiology and therapy of myocardial ischaemia/reperfusion syndrome. Eur. Heart J. Acute Cardiovasc. Care, 2019; 8 (5): 443–456. doi: 10.1177/2048872619845283

3. Gabriel-Costa D. The pathophysiology of myocardial infarction-induced heart failure. Pathophysiology, 2018; 25 (4): 277–284. doi: 10.1016/j.pathophys.2018.04.003

4. Davidson S.M., Ferdinandy P., Andreadou I., Botker H.E., Heusch G., Ibanez B., Ovize M., Schulz R., Yellon D.M., Hausenloy D.J., Garcia-Dorado D.; CARDIOPROTECTION COST Action (CA16225). Multitarget strategies to reduce myocardial ischemia/reperfusion injury. J. Am. Coll. Cardiol., 2019; 73 (1): 89–99. doi: 10.1016/j.jacc.2018.09.086

5. Giblett J.P., Bulluck H. Cardioprotection for Acute MI in Light of the CONDI2/ERIC-PPCI Trial: New Targets Needed. Interventional Cardiology Review, 2020; 15: e13. doi: 10.15420/icr.2020.01

6. García-Prieto J., Villena-Gutierrez R., Gomez M., Bernardo E., Pun-García A., García-Lunar I., Crainiciuc G., Fernandez-Jimenez R., Sreeramkumar V., Bourio-Martínez R., García-Ruiz J.M., del Valle A.S., Sanz-Rosa D., Pizarro G., FernandezOrtiz A., Hidalgo A., Fuster V., Ibanez B. Neutrophil stunning by metoprolol reduces infarct size. Nat. Commun., 2017; 8: 14780. doi: 10.1038/ncomms14780

7. Lobo-Gonzalez M., Galán-Arriola C., Rossello X., González-Del-Hoyo M., Vilchez J.P., Higuero-Verdejo M.I., García-Ruiz J.M., López-Martín G.J., Sánchez-González J., Oliver E., Pizarro G., Fuster V., Ibanez B. Metoprolol blunts the time-dependent progression of infarct size. Basic Res. Cardiol., 2020; 115 (5): 55. doi: 10.1007/s00395-020-0812-4

8. Cannon C.P., Braunwald E., McCabe C.H., Rader J.D., Rouleau J.L., Belder R., Joyal S.V., Hill K.A., Pfeffer M.A., Skene A.M. Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N. Engl. J. Med., 2004; 350 (15): 1495–1504. doi: 10.1056/NEJMoa040583

9. Flachskampf F.A., Schmid M., Rost С., Achenbach S., Demaria A.N., Daniel W.G. Cardiac imaging after myocardial infarction. Eur. Heart J., 2011; 32 (3): 272–283. doi: 10.1093/eurheartj/ehq446

10. Ibanez B., James S., Agewall S., Antunes M.J., Bucciarelli-Ducci C., Bueno H., Caforio A.L.P., Crea F., Goudevenos J.A., Halvorsen S., Hindricks G., Kastrati A., Lenzen M.J., Prescott E., Roffi M., Valgimigli M., Varenhorst C., Vranckx P., Widimsky P. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with STsegment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur. Heart J., 2018; 39: 119–177. doi: 10.1093/eurheartj/ehx393

11. Chatterjee S., Chaudhuri D., Vedanthan R., Fuster V., Ibanez B., Bangalore S., Mukherjee D. Early intravenous beta-blockers in patients with acute coronary syndrome - a meta-analysis of randomized trials. Int. J. Cardiol., 2013; 168 (2): 915–921. doi: 10.1016/j.ijcard.2012.10.050

12. Won H., Suh Y., Kim G., Ko Y., Hong M. Clinical impact of beta blockers in patients with myocardial infarction from the Korean National Health Insurance Database. Korean Circ. J., 2020; 50 (6): 499–508. doi: 10.4070/kcj.2019.0231

13. Giannakopoulos G., Noble S. Should we be using upstream beta-blocker therapy for acute myocardial infarction? Curr. Cardiol. Rep., 2021; 23 (6): 66. doi: 10.1007/s11886-021-01494-3

14. Dominguez-Rodriguez A., Abreu-Gonzalez P., Reiter R. Cardioprotection and pharmacological therapies in acute myocardial infarction: Challenges in the current era. World J. Cardiol., 2014; 6 (3): 100–106. doi: 10.4330/wjc.v6.i3.100

15. Ibanez B., Macaya C., Sanchez-Brunete V., Pizarro G., Fernandez-Friera L., Mateos A., Fernandez-Ortiz A., Garcia-Ruiz J.M., Garcia-Alvarez A., Iniguez A., Jimenez-Borreguero J., Lopez-Romero P., Fernandez-Jimenez R., Goicolea J., Ruiz-Mateos B., Bastante T., Arias M., Iglesias-Vazquez J.A., Rodriguez M.D., Escalera N., Acebal C., Cabrera J.A., Valenciano J., Perez de Prado A., Fernandez-Campos M.J., Casado I., Garcia-Rubira J.C., Garcia Prieto J., Sanz-Rosa D., Cuellas C., HernandezAntolin R., Albarran A., Fernandez-Vazquez F., de la Torre-Hernandez J.M., Pocock S., Sanz G., Fuster V. Effect of early metoprolol on infarct size in ST-segment-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: the effect of metoprolol in cardioprotection during an acute myocardial infarction (METOCARDCNIC) trial. Circulation, 2013; 128: 1495–1503. doi: 10.1161/CIRCULATIONAHA.113.003653

16. Roolvink V., Ibanez B., Ottervanger J.P., Pizarro G., van Royen N., Mateos A., Dambrink J.E., Escalera N., Lipsic E., Albarran A., Fernandez-Ortiz A., Fernandez-Aviles F., Goicolea J., Botas J., Remkes W., Hernandez-Jaras V., Kedhi E., Zamorano J.L., Navarro F., Alfonso F., Garcia-Lledo A., Alonso J., van Leeuwen M., Nijveldt R., Postma S., Kolkman E., Gosselink M., de Smet B., Rasoul S., Piek J.J., Fuster V., van Hof A.W.J.; EARLY-BAMI Investigators. Early Intravenous Beta-Blockers in Patients With ST-Segment Elevation Myocardial Infarction Before Primary Percutaneous Coronary Intervention. J. Am. Coll. Cardiol., 2016; 67 (23): 2705–2715. doi: 10.1016/j.jacc.2016.03.522

17. Podlesnikar T., Pizarro G., Fernández-Jiménez R., Montero-Cabezas J., Sánchez-González J., Bucciarelli-Ducci C., Ajmone Marsan N., Fras Z., Bax J., Fuster V., Ibáñez B., Delgado V. Five-year outcomes and prognostic value of feature-tracking cardiovascular magnetic resonance in patients receiving early prereperfusion metoprolol in acute myocardial infarction. Am. J. Cardiol., 2020; 133: 39–47. doi: 10.1016/j.amjcard.2020.07.037

18. Lai Q., Yuan G., Wang H., Liu Z., Kou J., Yu B., Li F. Metabolomic profiling of metoprolol-induced cardioprotection in a murine model of acute myocardial ischemia. Biomed. Pharmacother., 2020; 124: 109820. doi: 10.1016/j.biopha.2020.109820

19. Li D., Li Y., Lin M., Zhang W., Fu G., Chen Z., Jin C., Zhang W. Effects of metoprolol on periprocedural myocardial infarction after percutaneous coronary intervention (type 4a MI): an inverse probability of treatment weighting analysis. Front. Cardiovasc. Med., 2021 23; 8: 746988. doi: 10.3389/fcvm.2021.746988

20. Wu W., Huang L., Zhang J., Gao Y., Yang Y. Highfrequency ultrasound evaluation of effects of early treatment with metoprolol on myocardial inflammatory cytokine expression in rats with acute myocardial infarction. J. Huazhong Univ. Sci. Technolog. Med. Sci., 2012; 32 (5): 774–778. doi: 10.1007/s11596-012-1033-3