Włodzimierz J. Musiał

Oxidative stress and neutrophil activation—the two keystones of ischemia/reperfusion injury

The widespread introduction of fibrinolytics and recently also PTCA in the treatment of myocardial infarction has changed the picture of modern cardiology. But this therapy also raises new problems and challenges. One of them is the occurrence of extensive tissue injury caused by reperfusion. Reinstitution of oxygen to the ischemic tissues initiates various processes leading to generation of reactive oxygen species (ROSs). Acting on the plasma membrane ROS damage its organization and release various proinflammatory agents. Different proteins, including receptors, ionic channels, transporters or components of transduction pathways are substrates of oxidation by ROSs. Their changed structure results in altered functioning and disruption of vital cellular processes. Another key factor of reperfusion injury is activation and infiltration of infarcted area by polymorphonuclear leukocytes (PMNs). Multiple studies identified consecutive stages of PMN activation and substances being involved in it. Main interest lies in cellular adhesion molecules, particularly selectins and beta2 integrins, as their antagonists were repeatedly found to diminish neutrophil activation and infarct size. Nevertheless new publications strike at the foundations of the established order and confront the relation between neutrophil infiltration and infarct size. PMNs are linked by close ties to other cells involved in inflammatory response. Seemingly also in cardiac ischemia-reperfusion injury, the activity of neutrophils is modulated by lymphocytes and macrophages. The article describes mutual interactions between different factors involved in the reperfusion injury that may enable preparing new treatments, hopefully as effective and successful as reperfusion therapy.

Apelin: a novel marker for the patients with first ST-elevation myocardial infarction

To date, only animal studies have been concerned with apelin involvement in acute myocardial ischemia. The aim of this study was to investigate apelin measurements in low-risk patients with first ST-elevation myocardial infarction (STEMI) and to assess if apelin may feature as a marker of left ventricular (LV) injury and prognosis. In 78 consecutive patients (mean age 67 ± 11.5 years, 24 women) with first STEMI treated with primary percutaneous coronary intervention, plasma apelin-36 concentrations were measured twice: on admission and on the 5th day of hospitalization. Left ventricle ejection fraction (LVEF) was applied as marker of LV injury. Composite endpoint (CEP), which included death, stroke, and recurrent ischemic event, was assessed after 1 year follow-up. On the first day, median apelin-36 concentration was 2138.5 pg/ml and on the 5th day was significantly lower, 2008.3 pg/ml (P = 0.002). There were no significant differences found in apelin-36 concentrations between patients with normal and low LVEF. In both groups significant reductions were found in apelin-36 concentrations measured in 5-day intervals (P = 0.04 and P = 0.008, respectively). After a 1-year follow-up, only one patient died and 19 patients (24.3%) had reached CEP. No difference in baseline apelin-36 concentrations were found in the group of patients who reached CEP compared with those without CEP. However, in both groups concentrations significantly decreased after 5 days (P = 0.04 and P = 0.013, respectively). Apelin-36 concentrations are reduced in lowrisk first STEMI patients during the first days regardless of the degree of LV dysfunction and prognosis.

Apelin in acute myocardial infarction and heart failure induced by ischemia.

Apelin is a recently isolated novel endogenous ligand for the angiotensin-like 1 receptor (APJ). Initial experiments in animal models indicate that the cardiovascular system is the main target of the apelin-APJ system. Apelin plays an opposite role to the renin-angiotensin-aldosterone system as a compensatory mechanism. It is reduced in patients with heart failure, also of ischemic origin. However, only animal studies concern the role of the apelin-APJ system in myocardial ischemia. Less is known about the function of this adipokine in an acute phase of myocardial infarction in human. The apelin-APJ system could perhaps be involved in myocardial protection during acute myocardial ischemia. In the current review we have summarized recent data concerning the role of apelin in acute myocardial infarction and heart failure induced by ischemia.

The Role of Different Monocyte Subsets in the Pathogenesis of Atherosclerosis and Acute Coronary Syndromes

The inflammation underlying both atherosclerosis and acute coronary syndromes is strongly related to monocyte‐related actions. However, different monocyte subsets can play differential roles in the formation and destabilization of atherosclerotic plaque as well as healing of damaged myocardial tissue. Monocytes are currently being divided into three functionally distinct subsets with different levels of CD14 (cluster of differentiation 14) and CD16 expression. Thus, there are classical CD14++CD16‐, intermediate CD14++CD16+ and non‐classical CD14+CD16++ monocytes. Here, we summarize the current knowledge on complex activities of different monocyte subsets in atherosclerosis and acute coronary syndromes. Moreover, we discuss which monocyte subsets can serve either as predictive biomarkers of cardiovascular risk or as potential targets used in atherosclerosis and its complications.

Decreased free sphingoid base concentration in the plasma of patients with chronic systolic heart failure

PURPOSE In recent years, the role of sphingolipids in pathophysiology of the heart attracted much attention. Ceramide was found to be involved in the pathogenesis of cardiac dysfunction in animal models of ischemia/reperfusion injury, type 2 diabetes and lipotoxic cardiomyopathy. On the other hand, sphingosine-1-phosphate (S1P), has been shown to possess potent cardioprotective properties. The aim of the present study was to examine plasma concentrations of major sphingolipids in patients with chronic heart failure (HF). MATERIAL AND METHODS The subjects were divided into two major groups: 1) with chronic systolic HF (n=47), and 2) healthy age-matched controls (n=15). Patients in the former group were further divided according to the underlying cause of HF (ischemic heart disease or idiopathic dilated cardiomyopathy, n=29 and 18, respectively). RESULTS Plasma concentrations of S1P, sphinganine-1-phosphate and ceramide observed in both groups of HF patients were very close to these noted in the healthy controls, and no statistically significant differences were found. However, the level of free sphingosine and sphinganine in the plasma of patients with HF decreased by 25 and 27%, respectively, as compared to the control subjects. This effect was independent from the underlying cause of HF as the mean concentrations of these sphingoid bases in patients with ischemic and idiopathic HF were virtually the same. CONCLUSIONS We conclude that chronic heart failure is associated with decreased concentration of free sphingoid bases in the plasma. However, despite lower availability of substrates required for synthesis of cardioprotective sphingoid base-1 phosphates, their plasma level remains stable.

Sustained decrease in plasma sphingosine-1-phosphate concentration and its accumulation in blood cells in acute myocardial infarction.

Sphingosine-1-phosphate (S1P) is a cardioprotective sphingolipid present at high concentration in plasma and blood cells. However, effect of the myocardial infarction on S1P metabolism in blood is poorly recognized. Therefore, we aimed to examine the dynamics of changes in concentration of sphingolipids in blood of patients with acute ST-segment elevation myocardial infarction (STEMI). The study was performed on two groups of subjects: healthy controls (n=32) and patients with STEMI (n=32). In the latter group blood was taken upon admission to intensive heart care unit, and then on the second, fifth and thirtieth day, and approximately two years after admission. STEMI patients showed decreased plasma S1P concentration and accumulation of free sphingoid bases and their 1-phosphates in erythrocytes. This effect was already present upon admission, and was maintained for at least thirty days after the infarction. Interestingly, two years post-infarction plasma S1P level recovered only partially, whereas the content of erythrocyte sphingolipids decreased to the values observed in the control subjects. The most likely reason for the observed reduction in plasma S1P level was its decreased release or increased degradation by vascular endothelial cells, as we did not find any evidence for downregulation of S1P synthesis or release by blood cells. We conclude that patients with STEMI are characterized by marked alterations in sphingolipid metabolism in blood which could be a consequence of the infarction itself, the antiplatelet treatment given or both. Our data suggest that cardioprotective action of S1P may be diminished in patients with acute myocardial infarction.

CCN2 protein is an announcing marker for cardiac remodeling following STZ-induced moderate hyperglycemia in mice

Diabetes causes changes in the myocardium, which are often called diabetic cardiomyopathy. This condition has been extensively investigated in animal models with high glucose levels. Nevertheless, it has not been investigated whether moderate hyperglycemia, in the absence of other features of metabolic syndrome, may also cause similar changes in the heart. The aim of the study was to assess changes in the myocardium in an animal model of mild type 1 diabetes. Moderate hyperglycemia was induced in 8- to 10-week-old male C57BL6J mice by 5 intraperitoneal injections of streptozotocin (40 mg/kg). After 16 weeks, they were sacrificed, and left ventricle (LV) dimensions and extent of cardiac fibrosis were assessed by morphometry. The abundance of CCN proteins in LVsamples was assessed using western blotting, while activity of metalloproteinase 2 was established in zymography. Real time PCR was used to investigate the expression of transforming growth factor beta1 (TGFbeta1) and atrial natriuretic peptide. Mice with moderate hyperglycemia presented comparable cardiac dimensions with fibrosis and hypertrophy parameters as the non-diabetic controls. However, the abundance of profibrotic CCN2 protein was significantly increased in hyperglycemic animals (1.67 +/- 0.28 vs. 1 +/- 0.47, p < 0.05). Interestingly, this change was independent from the TGFbeta1 expression, as its RNA abundance was similar in both groups. Moderate hyperglycemia also caused an increase in the activity of the metalloproteinase 2 (1.21 +/- 0.17 vs. 1 +/- 0.07, p < 0.05). Despite diabetes, no profound changes in cardiac morphology were found. In our animal model, moderate hyperglycemia caused activation of a profibrotic gene expression program, which was counterbalanced by the increase of metalloproteinase activity.

The value of apelin-36 and brain natriuretic peptide measurements in patients with first ST-elevation myocardial infarction☆

BACKGROUND We aimed to assess apelin-novel endogenous ligand for the angiotensin-like 1 receptor in patients with ST-elevation myocardial infarction (STEMI) and to compare its value with B-type natriuretic peptide (BNP). METHODS In 78 consecutive patients with first STEMI treated with primary PCI, plasma apelin-36 (RIA) and BNP (MEIA) concentrations were measured twice: on admission and on the fifth day of hospitalization. Left ventricle ejection fraction (LVEF) was assessed on admission and composite endpoint (CEP)-after 1 year follow-up. RESULTS During the 5-day interval median plasma BNP level significantly increased and median plasma apelin concentration significantly decreased. BNP, but not apelin, correlated with low LVEF (<50%). In ROC analysis only BNP measurements were diagnostic for low LVEF. In ANOVA test, in patients with CEP, a significant decrease in apelin (but not BNP) concentrations measured in 5-day interval was found. ROC analysis identified only second BNP measurement as significant to estimate adverse outcome 0.627 in the prediction of CEP (95% confidence interval=0.507-0.736). CONCLUSION Following STEMI there is a decrease of plasma apelin-36 concentration and an increase of plasma BNP concentration. BNP is better, than apelin diagnostic value for the detection of impaired LVEF. Both BNP and apelin have prognostic value, although both needs further evaluation.

Coronary sinus concentrations of interleukin 6 and its soluble receptors are affected by reperfusion and may portend complications in patients with myocardial infarction

UNLABELLED Interleukin 6 (IL-6) is a pleiotropic cytokine involved in both inflammatory reaction and myocardial response to stress. Its effects largely depend on the concentration of the soluble receptors (sIL-6R and sgp130). We investigated the production of IL-6, sIL-6R and sgp130 by the heart during ischemia and reperfusion. METHODS The levels of IL-6 were determined in blood of 34 patients with first myocardial infarction (STEMI), left anterior descending (LAD) artery occlusion, otherwise normal coronaries, without significant co-morbidities and 16 comparable subjects with stable ischemic heart disease and lesion in LAD. Blood samples from coronary sinus (CS) and aorta (Ao) were drawn before percutaneous intervention (PCI), immediately after and at the end of the procedure. Venous blood from 30 healthy volunteers served as control. RESULTS STEMI patients presented high IL-6 concentrations that increased further after reperfusion when its levels in CS became significantly higher than in Ao. In both groups prior to the PCI there were significantly higher concentrations of sIL-6R in Ao than in CS. This difference disappeared immediately after reperfusion. STEMI patients who experienced cardiovascular complications had higher IL-6 concentration and higher transcardiac sIL-6R gradient than patients with event-free hospitalisation. This association was confirmed in multivariate logistic regression analysis. Myocardial infarction increases concentration of IL-6 that is further elevated by reperfusion. A transcardiac gradient of sIL-6R during ischemia may indicate that large amounts of soluble IL-6 receptors are bound to the infarcted heart and thus affect signal transduction. IL-6 and initial sIL-6R gradient may portend complications in STEMI patients.

Serum levels of CD163 and TWEAK in patients with pulmonary arterial hypertension

BACKGROUND Inflammation may play a pivotal role in the pathogenesis of pulmonary arterial hypertension (PAH). We evaluated the concentrations of serum sTWEAK, its scavenger receptor sCD163 and sTWEAK/sCD163 ratio in patients with PAH. DESIGN The study enrolled 26 stable patients with PAH confirmed by right heart catheterization and 24 healthy volunteers matched for age, sex and body weight. All patients underwent transthoracic echocardiography, cardiopulmonary exercise test, 6-min walk test, measurement of lung diffusing capacity for the carbon monoxide (DLCO) and venous blood tests. Concentrations of sTWEAK and sCD163 were determined using ELISA kits. RESULTS The PAH patients were characterized by significantly higher median serum sCD163 levels (1072 vs 890ng/ml, p=0.04) together with lower serum sTWEAK concentrations (200 vs 278.1pg/ml, p=0.003) comparing to control subjects. sTWEAK/sCD163 ratio was therefore significantly lower in PAH group (0.18 vs 0.33, p=0.0005). No correlation was found between sTWEAK and sCD163 concentrations in both groups. We observed statistically significant inverse correlation between peak VO2 consumption and sCD163 concentrations (r=-0.52, p<0.05) and positive with sTWEAK/sCD163 ratio (r=0.45, p<0.05) in PAH group. Moreover, sTWEAK/sCD163 ratio positively correlated with % of predicted values of DLCO (r=0.42, p<0.05). CONCLUSIONS Patients with PAH present altered serum sTWEAK and sCD163 levels. The sTWEAK/sCD163 ratio appears to be a better indicator of the severity of PAH as compared to sTWEAK or sCD163 alone. The exact role of sCD163 or interaction between CD163 and sTWEAK in the initiation or progression of PAH as well as their potential prognostic significance remains to be established.