Do platelets protect the heart against ischemia/reperfusion injury or exacerbate cardiac ischemia/reperfusion injury? The role of PDGF, VEGF, and PAF.

BACKGROUND: Acute myocardial infarction (AMI) is one of the main causes of death. It is quite obvious that there is an urgent need to develop new approaches for treatment of AMI. OBJECTIVE: This review analyzes data on the role of platelets in the regulation of cardiac tolerance to ischemia/reperfusion (I/R). METHODS: It was performed a search of topical articles using PubMed databases. FINDINGS: Platelets activated by a cholesterol-enriched diet, thrombin, and myocardial ischemia exacerbate I/R injury of the heart. The P2Y12 receptor antagonists, remote ischemic postconditioning and conditioning alter the properties of platelets. Platelets acquire the ability to increase cardiac tolerance to I/R. Platelet-derived growth factors (PDGFs) increase tolerance of cardiomyocytes and endothelial cells to I/R. PDGF receptors (PDGFRs) were found in cardiomyocytes and endothelial cells. PDGFs decrease infarct size and partially abrogate adverse postinfarction remodeling. Protein kinase C, phosphoinositide 3-kinase, and Akt involved in the cytoprotective effect of PDGFs. Vascular endothelial growth factor increased cardiac tolerance to I/R and alleviated adverse postinfarction remodeling. The platelet-activating factor (PAF) receptor inhibitors increase cardiac tolerance to I/R in vivo. PAF enhances cardiac tolerance to I/R in vitro. It is possible that PAF receptor inhibitors could protect the heart by blocking PAF receptor localized outside the heart. PAF protects the heart through activation of PAF receptor localized in cardiomyocytes or endothelial cells. Reactive oxygen species and kinases are involved in the cardioprotective effect of PAF. CONCLUSION: Platelets play an important role in the regulation of cardiac tolerance to I/R.

The role of ß-adrenergic receptors in the regulation of cardiac tolerance to ischemia/reperfusion. Why do ß-adrenergic receptor agonists and antagonists protect the heart?

BACKGROUND: Catecholamines and ß-adrenergic receptors (ß-ARs) play an important role in the regulation of cardiac tolerance to the impact of ischemia and reperfusion. This systematic review analyzed the molecular mechanisms of the cardioprotective activity of ß-AR ligands. METHODS: We performed an electronic search of topical articles using PubMed databases from 1966 to 2023. We cited original in vitro and in vivo studies and review articles that documented the cardioprotective properties of ß-AR agonists and antagonists. RESULTS: The infarct-reducing effect of ß-AR antagonists did not depend on a decrease in the heart rate. The target for ß-blockers is not only cardiomyocytes but also neutrophils. ß1-blockers (metoprolol, propranolol, timolol) and the selective ß2-AR agonist arformoterol have an infarct-reducing effect in coronary artery occlusion (CAO) in animals. Antagonists of ß1- and ß2-АR (metoprolol, propranolol, nadolol, carvedilol, bisoprolol, esmolol) are able to prevent reperfusion cardiac injury. All ß-AR ligands that reduced infarct size are the selective or nonselective ß1-blockers. It was hypothesized that ß1-AR blocking promotes an increase in cardiac tolerance to I/R. The activation of ß1-AR, ß2-AR, and ß3-AR can increase cardiac tolerance to I/R. The cardioprotective effect of ß-AR agonists is mediated via the activation of kinases and reactive oxygen species production. CONCLUSIONS: It is unclear why ß-blockers with the similar receptor selectivity have the infarct-sparing effect while other ß-blockers with the same selectivity do not affect infarct size. What is the molecular mechanism of the infarct-reducing effect of ß-blockers in reperfusion? Why did in early studies ß-blockers decrease the mortality rate in patients with acute myocardial infarction (AMI) and without reperfusion and in more recent studies ß-blockers had no effect on the mortality rate in patients with AMI and reperfusion? The creation of more effective ß-AR ligands depends on the answers to these questions.

Ferroptosis, a Regulated Form of Cell Death, as a Target for the Development of Novel Drugs Preventing Ischemia/Reperfusion of Cardiac Injury, Cardiomyopathy and Stress-Induced Cardiac Injury.

The hospital mortality in patients with ST-segment elevation myocardial infarction (STEMI) is about 6% and has not decreased in recent years. The leading cause of death of these patients is ischemia/reperfusion (I/R) cardiac injury. It is quite obvious that there is an urgent need to create new drugs for the treatment of STEMI based on knowledge about the pathogenesis of I/R cardiac injury, in particular, based on knowledge about the molecular mechanism of ferroptosis. In this study, it was demonstrated that ferroptosis is involved in the development of I/R cardiac injury, antitumor drug-induced cardiomyopathy, diabetic cardiomyopathy, septic cardiomyopathy, and inflammation. There is indirect evidence that ferroptosis participates in stress-induced cardiac injury. The activation of AMPK, PKC, ERK1/2, PI3K, and Akt prevents myocardial ferroptosis. The inhibition of HO-1 alleviates myocardial ferroptosis. The roles of GSK-3ß and NOS in the regulation of ferroptosis require further study. The stimulation of Nrf2, STAT3 prevents ferroptosis. The activation of TLR4 and NF-κB promotes ferroptosis of cardiomyocytes. MiR-450b-5p and miR-210-3p can increase the tolerance of cardiomyocytes to hypoxia/reoxygenation through the inhibition of ferroptosis. Circ_0091761 RNA, miR-214-3p, miR-199a-5p, miR-208a/b, miR-375-3p, miR-26b-5p and miR-15a-5p can aggravate myocardial ferroptosis.

SCAI Staging Application for Acute Myocardial Infarction-Related Cardiogenic Shock at a Single-Center Russian Registry.

AIM: To access the features of the course of myocardial infarction (MI) in patients with different stages of MI complicated by cardiogenic shock (MI CS) according to the SCAI scale. METHODS: We retrospectively described the portrait of CS MI (n = 117) at different stages of SCAI from the hospital MI registry (n = 1253). RESULTS: Hospital mortality increased from stage to stage (p ≤ 0.001). Significant differences in biochemical parameters were found both for indicators characterizing intensive care measures, such as the presence of mechanical lung ventilation or an intra-aortic balloon pump, and for indicators of organ hypoperfusion such as lactate level, pHv (7.39 (7.36; 7.44) at stage A-B; 7.14 (7.06; 7.18) at stage E), creatinine, and glomerular filtration rate. Parameters related to MI characteristics, such as instrumental and laboratory data, anamnesis of ischemia, and performed treatment, did not differ between groups. Polynomial logistic regression showed that lactate level, mechanical ventilation, and monocyte count upon admission (1.15 (0.96; 1.23) at stage A-B; 0.78 (0.49; 0.94) at stage E, p = 0.005) correlated with CS severity. CONCLUSION: The characteristics of MI at different stages of SCAI do not have differences and do not determine the severity of shock. We revealed a high discriminatory potential of the pH level in predicting refractory shock. The value of monocytes at admission may be a promising predictor of the severity of MI CS. The question of the causes of heterogeneity of MI CS, taking into account the homogeneity of MI characteristics, remains open and promising.

Pro-Inflammatory Biomarkers and Progression of Atherosclerosis in Patients with Myocardial Infarction with Non-Obstructive Coronary Artery Disease: 1-Year Follow-Up.

The objective of our study was to evaluate the concentrations of pro-inflammatory biomarkers in patients with acute myocardial infarction with non-obstructive coronary arteries (MINOCA) compared to patients with acute myocardial infarction with obstructive coronary arteries (MI-CAD) in the early post-infarction period and after 1 year and to perform a comparative analysis of the relationship between laboratory biomarkers and atherosclerosis progression in patients with MINOCA and MI-CAD. METHODS: Samples of peripheral venous blood were collected upon admission and on days 2, 4, and 7 of hospitalization and after 1 year. An extended multiplex analysis was performed in blood serum. Multidetector-computed tomography coronary angiography was performed on day 7 and 1 year after acute myocardial infarction to assess the progression of atherosclerosis. RESULTS: The level of high-sensitive C-reactive protein (hsCRP) was elevated upon admission in MINOCA patients compared to MI-CAD patients (p = 0.05), but it was comparable in two groups at other time points and did not exceed the reference range after 1 year. Despite comparable levels of cytokines CXCL-6, LIGHT, CCL-8, and endocan-1 in patients in both groups, MINOCA patients had a greater increase in pro-inflammatory cytokines PlGF, oncostatin M, IL-20, and CCL-15 sVCAM-1 in the early post-infarction period and in CCL-21, sVCAM-1, oncostatin M, and PlGF after 1 year. We observed significant differences in the dynamics of the following biomarkers between patients with MI-CAD and MINOCA: the dynamics of concentrations of CCL21 (p = 0.002), LIGHT (p = 0.03), and endocan-1 (p = 0.03) after 1 year compared to day 1 in MI-CAD and MINOCA patients was opposite, while the dynamics of CXCL6 (p = 0.04) and endocan-1 (p = 0.02) differed between groups when evaluated after 1 year compared to day 7 of the early post-infarction period. In the MINOCA group, factors associated with atherosclerosis progression were concentrations of sVCAM-1 and CCL-21, while in the MI-CAD group, concentrations of CCL-8 and CXCL6 were the main determinants of atherosclerosis progression. CONCLUSIONS: This small study showed that MINOCA and MI-CAD patients exhibited differences in a pro-inflammatory biomarker profile in the early post-infarction period and after 1-year follow-up, which implies distinct inflammatory pathways involved in atherogenesis during MINOCA. The key factors that were associated with atherosclerosis progression in MINOCA patients are sVCAM-1 and CCL-21, which may suggest a complex genesis of atherosclerosis progression due to structurally altered plaques and changes in the microcirculatory bed. In MI-CAD patients, CCL-8 and CXCL-6 were the key biomarkers associated with atherosclerosis progression. Further large-scale studies are required to confirm our data.

A historical literature review of coronary microvascular obstruction and intra-myocardial hemorrhage as functional/structural phenomena.

The analysis of experimental data demonstrates that platelets and neutrophils are involved in the no-reflow phenomenon, also known as microvascular obstruction (MVO). However, studies performed in the isolated perfused hearts subjected to ischemia/reperfusion (I/R) do not suggest the involvement of microembolization and microthrombi in this phenomenon. The intracoronary administration of alteplase has been found to have no effect on the occurrence of MVO in patients with acute myocardial infarction. Consequently, the major events preceding the appearance of MVO in coronary arteries are independent of microthrombi, platelets, and neutrophils. Endothelial cells appear to be the target where ischemia can disrupt the endothelium-dependent vasodilation of coronary arteries. However, reperfusion triggers more pronounced damage, possibly mediated by pyroptosis. MVO and intra-myocardial hemorrhage contribute to the adverse post-infarction myocardial remodeling. Therefore, pharmacological agents used to treat MVO should prevent endothelial injury and induce relaxation of smooth muscles. Ischemic conditioning protocols have been shown to prevent MVO, with L-type Ca 2+ channel blockers appearing the most effective in treating MVO.

Potential utility of SPECT/CT with 99mTc-Tektrotyd for imaging of post-myocardial infarction inflammation.

BACKGROUND: There is a need to develop methods for post-myocardial infarction (MI) inflammation monitoring. Scintigraphy with somatostatin receptor targeted radiotracers has potential in this field. The purpose was to study the association of 99mTc-Tektrotyd uptake intensity in MI area with heart contractility indices over 6-month follow-up. METHODS: Fourteen patients with acute ST-segment elevation anterior MI (STEMI) were examined with 99mTc-Tektrotyd SPECT/CT, myocardial perfusion scintigraphy (MPS) at rest, cardiac magnetic resonance imaging (cMRI) and transthoracic echocardiography (TTE). Scintigraphic results were compared with 6-month TTE indices. RESULTS: On the 7th day after a MI onset, cardiac 99mTc-Tektrotyd uptake was found in 7 of 14 patients. Median of 99mTc-Tektrotyd SUVmax was 1.59 (1.38; 2.83), the summed rest score (SRS) was 11 (5; 18), infarct size (by cMRI)-13.15 (3.3; 32.2) %. 99mTc-Tektrotyd SUVmax strongly correlated with 6-month heart contractility indices (r = 0.81, P < 0.05 for the end diastolic volume; r = 0.61 P < 0.05 for Δ end diastolic volume), with SRS (r = 0.85, P < 0.05) and infarct size (by cMRI) (r = 0.79, P < 0.05). CONCLUSION: The intensity (SUVmax) of 99mTc-Tektrotyd uptake in the area of recent MI directly depends on the size of ischemic myocardial injury and correlates with changes of heart contractility indexes over the 6 month follow-up.

The Signaling Mechanism of Remote Postconditioning of the Heart: Prospects of the Use of Remote Postconditioning for the Treatment of Acute Myocardial Infarction.

Acute myocardial infarction (AMI) remains the leading cause of mortality in the world, highlighting an urgent need for the development of novel, more effective approaches for the treatment of AMI. Remote postconditioning (RPost) of the heart could be a useful approach. It was demonstrated that RPost triggers infarct size reduction, improves contractile function of the heart in reperfusion, mitigates apoptosis, and stimulates autophagy in animals with coronary artery occlusion and reperfusion. Endogenous opioid peptides and adenosine could be involved in RPost. It was found that kinases and NO-synthase participate in RPost. KATP channels, MPT pore, and STAT3 could be hypothetical end-effectors of RPost. Metabolic syndrome and old age abolish the cardioprotective effect of RPost in rats. The data on the efficacy of RPost in clinical practice are inconsistent. These data are discussed in the review.

Relationships between indicators of prothrombotic activity and coronary microvascular dysfunction in patients with myocardial infarction with obstructive and non-obstructive coronary artery disease.

The relationship between prothrombotic activity and coronary microvascular dysfunction (MVD) is limited. This study aimed to perform a comparative analysis of the relationship between prothrombotic activity and MVD in patients with myocardial infarction without obstructive coronary artery disease (MINOCA) and myocardial infarction with obstructive coronary artery disease (MI-CAD). MATERIAL AND METHODS: A total of 37 patients were enrolled in the study; the main group included 16 MINOCA patients, and 21 MI-CAD patients were included in the control group. Blood samples for protein C, antithrombin, WF, plasminogen, and homocysteine were performed on the 4th ± 1 day of admission. CZT-SPECT data were used to determine the standard indices of myocardial perfusion dis-orders (SSS, SRS, and SDS), as well as stress and rest myocardial blood flow (MBF), myocardial flow reserve (MFR), and difference flows (DF). MVD was defined as MFR (≤ 1.91 ml/min); coronary slow flow (CSF) was defined as corrected TIMI frame count (21 ± 3). RESULTS: We performed a step-by-step analysis of prothrombotic activity of the hemostasis system in binary logistic regression for MINOCA patients to identify factors associated with MVD (MFR ≤ 1.91 ml/min). A predictive model was developed to estimate the probability of reduced MFR. A low MFR is related to only plasminogen in MINOCA patients, whereas only wall motion score index (WMSI) in MI-CAD group was associated with a low MFR. CONCLUSION: This small-scale study revealed the relationship between indicators of prothrombotic activity and MVD. The key factors that affect MVD in MINOCA patients was plasminogen, whereas, in patients with MI-CAD, WMSI was the key factor. Measurements of MVD may enhance the risk stratification and facilitate future targeting of adjunctive antithrombotic therapies in MINOCA and MI-CAD patients.

Pyroptosis is a drug target for prevention of adverse cardiac remodeling: The crosstalk between pyroptosis, apoptosis, and autophagy.

Acute myocardial infarction (AMI) is one of the main reasons of cardiovascular disease-related death. The introduction of percutaneous coronary intervention to clinical practice dramatically decreased the mortality rate in AMI. Adverse cardiac remodeling is a serious problem in cardiology. An increase in the effectiveness of AMI treatment and prevention of adverse cardiac remodeling is difficult to achieve without understanding the mechanisms of reperfusion cardiac injury and cardiac remodeling. Inhibition of pyroptosis prevents the development of postinfarction and pressure overload-induced cardiac remodeling, and mitigates cardiomyopathy induced by diabetes and metabolic syndrome. Therefore, it is reasonable to hypothesize that the pyroptosis inhibitors may find a role in clinical practice for treatment of AMI and prevention of cardiac remodeling, diabetes and metabolic syndrome-triggered cardiomyopathy. It was demonstrated that pyroptosis interacts closely with apoptosis and autophagy. Pyroptosis could be inhibited by nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 inhibitors, caspase-1 inhibitors, microRNA, angiotensin-converting enzyme inhibitors, angiotensin Ⅱ receptor blockers, and traditional Chinese herbal medicines.

Association of increased oncostatin M with adverse left ventricular remodeling in patients with myocardial infarction.

Background: The study of laboratory biomarkers that reflect the development of adverse cardiovascular events in the postinfarction period is of current relevance. The aim of the present study was evaluation of oncostatin M (OSM) concentration changes in the early and late stages of myocardial infarction and evaluation of the possibility of its use in prediction of adverse left ventricular (LV) remodeling in patients with myocardial infarction with ST-elevated segment (STEMI). Methods: The study involved 31 patients with STEMI admitted in the first 24 hours after the onset of MI and 30 patients with chronic coronary artery disease as a control group. Echocardiographic study was performed on day 3 and in 6 months after STEMI. The serum levels of biomarkers were evaluated on the day of hospital admission and 6 months after MI using multiplex immunoassay. Results: OSM level increased during the first 24 h after the onset of the disease, with the following decrease in 6 months. OSM concentration at admission had correlated with echocardiography parameters and Nt-proBNP, troponin I, CK-MB levels. Our study has demonstrated association of the increased levels of OSM at the early stages of STEMI with development of the adverse LV remodeling in 6 months after the event. Conclusions: Elevation of OSM levels in the first 24 h after STEMI is associated with the development of the adverse LV remodeling in the long-term post-infarction period.

Pharmacological Approaches to Limit Ischemic and Reperfusion Injuries of the Heart: Analysis of Experimental and Clinical Data on P2Y12 Receptor Antagonists.

Ischemic and reperfusion injuries of the heart underlie the pathogenesis of acute myocardial infarction (AMI) and sudden cardiac death. The mortality rate is still high and is 5-7% in patients with ST-segment elevation myocardial infarction. The review is devoted to pharmacological approaches to limitation of ischemic and reperfusion injuries of the heart. The article analyzes experimental evidence and the clinical data on the effects of P2Y12 receptor antagonists on the heart's tolerance to ischemia/reperfusion in animals with coronary artery occlusion and reperfusion and also in patients with AMI. Chronic administration of ticagrelor prevented adverse remodeling of the heart. There is evidence that sphingosine-1-phosphate is the molecule that mediates the infarct-reducing effect of P2Y12 receptor antagonists. It was discussed a role of adenosine in the cardioprotective effect of ticagrelor.

Reperfusion Cardiac Injury: Receptors and the Signaling Mechanisms.

It has been documented that Ca2+ overload and increased production of reactive oxygen species play a significant role in reperfusion injury (RI) of cardiomyocytes. Ischemia/reperfusion induces cell death as a result of necrosis, necroptosis, apoptosis, and possibly autophagy, pyroptosis and ferroptosis. It has also been demonstrated that the NLRP3 inflammasome is involved in RI of the heart. An increase in adrenergic system activity during the restoration of coronary perfusion negatively affected cardiac resistance to RI. Toll-like receptors are involved in RI of the heart. Angiotensin II and endothelin-1 aggravated ischemic/reperfusion injury of the heart. Activation of neutrophils, monocytes, CD4+ T-cells and platelets contributes to cardiac ischemia/reperfusion injury. Our review outlines the role of these factors in reperfusion cardiac injury.

The Role of Pyroptosis in Ischemic and Reperfusion Injury of the Heart.

While ischemia itself can kill heart muscle, much of the infarction after a transient period of coronary artery occlusion has been found to result from injury during reperfusion. Here we review the role of inflammation and possible pyroptosis in myocardial reperfusion injury. Current evidence suggests pyroptosis's contribution to infarction may be considerable. Pyroptosis occurs when inflammasomes activate caspases that in turn cleave off an N-terminal fragment of gasdermin D. This active fragment makes large pores in the cell membrane thus killing the cell. Inhibition of inflammation enhances cardiac tolerance to ischemia and reperfusion injury. Stimulation of the purinergic P2X7 receptor and the ß-adrenergic receptor and activation of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) by toll-like receptor (TLR) agonists are all known to contribute to ischemia/reperfusion (I/R) cardiac injury through inflammation, potentially by pyroptosis. In contrast, stimulation of the cannabinoid CB2 receptor reduces I/R cardiac injury and inhibits this pathway. MicroRNAs, Akt, the phosphate and tension homology deleted on chromosome 10 protein (PTEN), pyruvate dehydrogenase and sirtuin-1 reportedly modulate inflammation in cardiomyocytes during I/R. Cryopyrin and caspase-1/4 inhibitors are reported to increase cardiac tolerance to ischemic and reperfusion cardiac injury, presumably by suppressing inflammasome-dependent inflammation. The ambiguity surrounding the role of pyroptosis in reperfusion injury arises because caspase-1 also activates cytotoxic interleukins and proteolytically degrades a surprisingly large number of cytosolic enzymes in addition to activating gasdermin D.

Application of machine learning and laser optical-acoustic spectroscopy to study the profile of exhaled air volatile markers of acute myocardial infarction.

Conventional acute myocardial infarction (AMI) diagnosis is quite accurate and has proved its effectiveness. However, despite this, discovering more operative methods of this disease detection is underway. From this point of view, the application of exhaled air analysis for a similar diagnosis is valuable. The aim of the paper is to research effective machine learning algorithms for the predictive model for AMI diagnosis constructing, using exhaled air spectral data. The target group included 30 patients with primary myocardial infarction. The control group included 42 healthy volunteers. The 'LaserBreeze' laser gas analyzer (Special Technologies Ltd, Russia), based on the dual-channel resonant photoacoustic detector cell and optical parametric oscillator as the laser source, had been used. The pattern recognition approach was applied in the same manner for the set of extracted concentrations of AMI volatile markers and the set of absorption coefficients in a most informative spectral range 2.900 ± 0.125µm. The created predictive model based on the set of absorption coefficients provided 0.86 of the mean values of both the sensitivity and specificity when linear support vector machine (SVM) combined with principal component analysis was used. The created predictive model based on using six volatile AMI markers (C5H12, N2O, NO2, C2H4, CO, CO2) provided 0.82 and 0.93 of the mean values of the sensitivity and specificity, respectively, when linear SVM was used.

Serum Levels of Bone Morphogenetic Proteins 2 and 4 in Patients with Acute Myocardial Infarction.

BACKGROUND: Bone morphogenetic proteins-2 and -4 (BMPs) have been implicated in left ventricular remodeling (LVR) processes such as an inflammation and fibrogenesis. We hypothesized that this knowledge could be translated into clinics. METHODS: We studied the dynamics of serum levels of BMPs, its correlation with markers of LVR and with parameters of echocardiography in patients (n = 31) during the six-month follow-up period after myocardial infarction (MI). RESULTS: Elevated serum levels of BMPs decreased by the six-month follow-up period. BMP-2 decreased from the first day after MI, and BMP-4 decreased from the Day 14. The elevated level of BMP-2 at Day 1 was associated with a lower level of troponin I, reperfusion time and better left ventricular ejection fraction (LV EF) at the six-month follow-up. Elevated serum level of BMP-4 at Day 1 was associated with a lower level of a soluble isoform of suppression of tumorigenicity 2 (sST2), age and reperfusion time. An elevated level of BMP-2 at the six-month follow-up was associated with higher levels of BMP-4, high-sensitivity C-reactive protein (hCRP) and sST2. High serum level of BMP-2 correlated with high levels of hCRP and matrix metalloproteinase (MMP)-9 on Day 7. High serum level of BMP-4 correlated with low levels of hCRP, MMP-9 at Day 3, sST2 at Day 1 and with decreased LV EF on Day 7. The findings of multivariate analysis support the involvement of BMP-2 in the development of post-infarction LVR. CONCLUSIONS: Our research translates experimental data about the BMPs in the development of adverse LVR into the clinic. Elevated serum levels of BMPs decreased by the end of the six-month period after MI. BMP-2 decreased from the first day and BMP-4 decreased from Day 14. BMP-2 and BMP-4 were associated with the development of LVR. Their correlations with markers of inflammation, degradation of the extracellular matrix, hemodynamic stress and markers of myocardial damage further support our hypothesis. Diagnostic and predictive values of these BMPs at the development of post-infarction LVR in vivo should be investigated further.

Relationships of growth factors, proinflammatory cytokines, and anti-inflammatory cytokines with long-term clinical results of autologous bone marrow mononuclear cell transplantation in STEMI.

AIM: The aim of the study was to test the hypothesis suggesting that the pre-intervention levels of proinflammatory cytokines, anti-inflammatory cytokines, and angiogenic growth factors predict the long-term clinical results of autologous bone marrow-derived mononuclear cell (ABMMC) transplantation in patients with primary ST elevation myocardial infarction (STEMI). METHODS AND RESULTS: From 2003 to 2006, a total of 62 patients with primary STEMI were enrolled in an open randomized study registered under the title ESTABOMA. Patients were randomized into two groups: group 1 included patients treated with percutaneous coronary intervention (PCI) and ABMMC transplantation (n = 28); group 2 comprised patients treated only with PCI (n = 34). Follow-up study was performed 7.96 ± 0.96 years after STEMI and involved physical examination, six-minute walk test, echocardiography, and determination of brain natriuretic peptide (BNP) levels. The total and cardiovascular mortality rates were higher in group 1 compared with group 2: 36% (n = 10) vs. 12% (n = 4) (p = 0.02) and 29% (n = 8) vs. 6% (n = 2) (p = 0.03), respectively. Lower levels of proinflammatory cytokines were observed in group 1 after PCI and ABMMC transplantation. Serum levels of FGF, VEGF, and IL-10, determined before PCI and ABMMC transplantation were prognostically significant long-term indicators of unfavorable course of CAD after STEMI.