Myokines and Resistance Training: A Narrative Review.

In the last few years, the muscular system has gained attention due to the discovery of the muscle-secretome and its high potency for retaining or regaining health. These cytokines, described as myokines, released by the working muscle, are involved in anti-inflammatory, metabolic and immunological processes. These are able to influence human health in a positive way and are a target of research in metabolic diseases, cancer, neurological diseases, and other non-communicable diseases. Therefore, different types of exercise training were investigated in the last few years to find associations between exercise, myokines and their effects on human health. Particularly, resistance training turned out to be a powerful stimulus to enhance myokine release. As there are different types of resistance training, different myokines are stimulated, depending on the mode of training. This narrative review gives an overview about resistance training and how it can be utilized to stimulate myokine production in order to gain a certain health effect. Finally, the question of why resistance training is an important key regulator in human health will be discussed.

Physiological factors which influence the performance potential of athletes: analysis of sports medicine performance testing in Nordic combined.

BACKGROUND: The sports medicine performance diagnostics include investigative procedures that supply information on the performance capacity and stamina of an athlete. This creates a foundation for a personalised training plan and enables optimised control of the training process. METHODOLOGY: The study population consisted of 24 male Nordic combined athletes from the national German squad. They were monitored using sports medicine over a period of five winter seasons. The test speeds on the treadmill in m/s are determined at lactate values of 2, 3 and 4 mmol/l in the peripheral blood values to calculate the lactate curve. RESULTS: The higher the test performance expressed as a percentage, the more likely it was that a top position could be achieved. The individual anaerobic threshold and the maximal oxygen uptake increased significantly with an increase in test performance expressed as a percentage. The older the athlete, the better they performed in the overall world cup. When age increased, the test speed [m/s] at lactate values of 2, 3 and 4 mmol/l also increased, along with the test performance expressed as a percentage, the maximal oxygen uptake and the individual anaerobic threshold. A higher BMI proved advantageous in terms of placement in the individual competitions. CONCLUSION: In this study the test speed at a lactate concentration of 4 mmol/l can be recommended as a robuster, more independent from mathematical models and physiologically more valid parameter for performance diagnostics in professional athletes.

Evaluation of Myocardial Gene Expression Profiling for Superior Diagnosis of Idiopathic Giant-Cell Myocarditis and Clinical Feasibility in a Large Cohort of Patients with Acute Cardiac Decompensation.

AIMS: The diagnostic approach to idiopathic giant-cell myocarditis (IGCM) is based on identifying various patterns of inflammatory cell infiltration and multinucleated giant cells (GCs) in histologic sections taken from endomyocardial biopsies (EMBs). The sampling error for detecting focally located GCs by histopathology is high, however. The aim of this study was to demonstrate the feasibility of gene profiling as a new diagnostic method in clinical practice, namely in a large cohort of patients suffering from acute cardiac decompensation. Methods and Results: In this retrospective multicenter study, EMBs taken from n = 427 patients with clinically acute cardiac decompensation and suspected acute myocarditis were screened (mean age: 47.03 ± 15.69 years). In each patient, the EMBs were analyzed on the basis of histology, immunohistology, molecular virology, and gene-expression profiling. Out of the total of n = 427 patient samples examined, GCs could be detected in 26 cases (6.1%) by histology. An established myocardial gene profile consisting of 27 genes was revealed; this was narrowed down to a specified profile of five genes (CPT1, CCL20, CCR5, CCR6, TLR8) which serve to identify histologically proven IGCM with high specificity in 25 of the 26 patients (96.2%). Once this newly established profiling approach was applied to the remaining patient samples, an additional n = 31 patients (7.3%) could be identified as having IGCM without any histologic proof of myocardial GCs. In a subgroup analysis, patients diagnosed with IGCM using this gene profiling respond in a similar fashion to immunosuppressive therapy as patients diagnosed with IGCM by conventional histology alone. Conclusions: Myocardial gene-expression profiling is a promising new method in clinical practice, one which can predict IGCM even in the absence of any direct histologic proof of GCs in EMB sections. Gene profiling is of great clinical relevance in terms of a) overcoming the sampling error associated with purely histologic examinations and b) monitoring the effectiveness of therapy.

C-reactive protein levels predict systolic heart failure and outcome in patients with first ST-elevation myocardial infarction treated with coronary angioplasty.

INTRODUCTION: There is growing evidence that inflammation plays a pivotal role in the etiology and progression of atherosclerosis. High C-reactive protein (CRP) levels have been associated with high mortality in patients with acute myocardial infarction (AMI). Furthermore, in animal models CRP has been found to significantly increase infarct size. So there is growing evidence that CRP is not only a marker for cardiovascular disease but also might be pathogenic. The aim of our study was to test the hypothesis that peak CRP levels could predict heart failure (HF) in ST-elevation myocardial infarction (STEMI) patients. MATERIAL AND METHODS: Eighty-one consecutive patients with STEMI were prospectively enrolled in the study. C-reactive protein concentrations were measured on admission and after 6, 12, 24, 30, 48, 72 and 96 h. We assessed the association between the elevation of CRP, heart failure and cardiovascular mortality following the first 12 months after STEMI. RESULTS: C-reactive protein levels reached a peak after 48 h. Patients with STEMI and signs of HF showed significantly higher peak CRP levels. We found a positive correlation between maximum CK levels and peak CRP and a negative correlation between left ventricular ejection fraction (EF) and peak CRP. One year total mortality and HF mortality rates were found to be higher in patients with peak CRP > 47.5 mg/l than in those with CRP below that level (p < 0.001). CONCLUSIONS: Peak CRP levels in STEMI patients predict emergence of HF. Peak CRP is also a strong predictor of global and cardiovascular mortality during the following year after STEMI.

Plasma levels of sRANKL and OPG are associated with atherogenic cytokines in patients with intermediate cardiovascular risk.

Osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL) are regulators of bone remodeling, but are also considered to play important roles in coronary artery disease (CAD). This study evaluated potential associations of soluble (s) RANKL and OPG with atherosclerosis-relevant cytokines. Blood was collected from 414 individuals who presented to our hospital with intermediate likelihood for CAD for further examination. Plasma concentrations of total sRANKL, OPG, and 20 cytokines were measured using sandwich-type enzyme-linked immunoassays (ELISAs; OPG and sRANKL) and Luminex laser-based fluorescence analysis and correlated with each other. The plasma levels of interferon-γ (IFN-γ) and the T-helper cell 2 cytokines interleukin-4 (IL-4) and IL-13 showed a positive correlation with sRANKL. The association with sRANKL levels was negative for IFN-γ-induced protein-10 (IP-10) and monocyte chemotactic protein-1 (MCP-1). The strongest independent association with sRANKL in multivariable analyses was found for IFN-γ (positive) and IP-10 (negative), while IL-13 showed a positive and independent association with OPG plasma levels. OPG and sRANKL plasma levels correlate strongly and independently with specific circulating atherosclerosis-related cytokines in patients with intermediate cardiovascular risk.

Impact of Ivabradine on Inflammatory Markers in Chronic Heart Failure.

Background. Inflammation plays a crucial role in the progression of chronic heart failure (CHF). Ivabradine is known to reduce the morbidity and mortality of patients with CHF under certain conditions. Beyond the reduction of heart rate, only limited knowledge exists about potential anti-inflammatory effects of ivabradine that might contribute to its benefit in CHF. Thus, the present study aimed to investigate the effect of ivabradine on systemic inflammation. Methods. In the present study, 33 patients with CHF due to dilated, ischemic, and hypertensive cardiomyopathy were treated with ivabradine according to the guidelines of the European Society of Cardiology (ESC). A number of circulating dendritic cells as well as inflammatory mediators were investigated using FACS analysis and ELISA, respectively, before and during ivabradine therapy. Results. Treatment with ivabradine resulted in a significant improvement of CHF symptoms as well as an increase in left ventricular ejection fraction. Moreover, ivabradine treatment led to a significant reduction of TNF-alpha (TNF-α) serum levels and a reconstitution of circulating dendritic cells which are known to be reduced in patients with CHF. Conclusion. We show that treatment with ivabradine in patients with CHF resulted in an improvement of HF symptoms and ejection fraction as well as a normalization of inflammatory mediators.

Platelet CD40 contributes to enhanced monocyte chemoattractant protein 1 levels in patients with resistant hypertension.

BACKGROUND: Growing evidence shows that inflammation plays a pivotal role in the pathophysiology of essential hypertension (EH). Although it is acknowledged that target organ damage involves an inflammatory response, most work has focused on the role of macrophages. However, recently, platelets were identified as inducing inflammation partly by releasing cytokines. The goal of our study was to evaluate the role of platelets as inflammatory cells in the pathogenesis of EH. METHODS: Thirty-nine patients with EH and 30 healthy normotensive controls have been examined. Expression of platelet CD40 was measured by flow cytometry. Serum levels of monocyte chemoattractant protein 1 (MCP-1) and sCD40L were measured via a multiplexing assay. In in vitro experiments, activated platelets were cocultured with human umbilical vein endothelial cells (HUVEC) in the presence and absence of anti-CD154 antibodies. MCP-1 in the supernatants was measured by EIA. RESULTS: Essential hypertension patients showed significantly enhanced MCP-1 levels with highest levels in EH patients with microalbuminuria. EH patients showed increased expression of platelet CD40. In the cell coculture model, activated platelets were able to significantly induce MCP-1 release from HUVEC in a CD40L-dependent manner. EH patients showed elevated sCD40L levels with a positive correlation with MCP-1 levels. CONCLUSIONS: Platelets can contribute to enhanced MCP-1 levels in EH. MCP-1 is markedly elevated in serum of EH patients with highest levels in patients with microalbuminuria, one early sign of renal target organ damage. Further studies are required to test whether MCP-1 blocking or antiplatelet strategies may represent new therapeutic options in preventing hypertensive target organ damage.

Left atrial remodeling, early repolarization pattern, and inflammatory cytokines in professional soccer players.

OBJECTIVES: Although regular physical exercise clearly reduces cardiovascular morbidity risk, long-term endurance sports practice has been recognized as a risk factor for atrial fibrillation (AF). However, the mechanisms how endurance sports can lead to AF are not yet clear. The aim of our present study was to investigate the influence of long-term endurance training on vagal tone, atrial size, and inflammatory profile in professional elite soccer players. METHODS: A total of 25 professional major league soccer players (mean age 24±4 years) and 20 sedentary controls (mean age 26±3 years) were included in the study and consecutively examined. All subjects underwent a sports cardiology check-up with physical examination, electrocardiography, echocardiography, exercise testing on a bicycle ergometer, and laboratory analysis [standard laboratory and cytokine profile: interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-8, IL-10]. RESULTS: Athletes were divided into two groups according to presence or absence of an early repolarization (ER) pattern, defined as a ST-segment elevation at the J-point (STE) ≥0.1mm in 2 leads. Athletes with an ER pattern showed significantly lower heart rate and an increased E/e' ratio compared to athletes without an ER pattern. STE significantly correlated with E/e' ratio as well as with left atrial (LA) volume. The pro-inflammatory cytokines IL-6, IL-8, TNF-α as well as the anti-inflammatory cytokine IL-10 were significantly elevated in all soccer players. However, athletes with an ER pattern had significantly higher IL-6 plasma levels than athletes without ER pattern. Furthermore, athletes with "high" level IL-6 had significantly larger LA volumes than players with "low" level IL-6. CONCLUSIONS: Athletes with an ER pattern had significantly higher E/e' ratios, reflecting higher atrial filling pressures, higher LA volume, and higher IL-6 plasma levels. All these factors may contribute to atrial remodeling over time and thus increase the risk of AF in long-term endurance sports.

Suppression of proatherogenic leukocyte interactions by MCS-18--Impact on advanced atherosclerosis in ApoE-deficient mice.

OBJECTIVE: Atherosclerosis is associated with chronic inflammatory responses of the arterial blood vessels. The previously observed protective effect of the MCS-18 substance against the initiation of atherosclerosis in a murine model was explained by its pronounced anti-inflammatory activity. Here, we investigated its impact on murine plaque progression in advanced atherosclerosis and on proatherogenic processes. APPROACH & RESULTS: ApoE-deficient mice were fed a high-fat diet for 12 weeks to induce atherosclerosis, followed by normal chow and intraperitoneal injections of either MCS-18 (500 µg, n = 10) or saline (n = 10) twice a week for another 12 weeks. Plaque size was reduced in MCS-18 treated mice compared to controls (p = 0.001), which was associated with a reduced size of the lipid core (p = 0.01). There was a decrease in apoptotic cells (p = 0.02), endothelial ICAM-1 expression (p < 0.001), and macrophage density (p = 0.01) in the MCS-18 group. In addition, human and murine dendritic cells (DCs) and human umbilical vein endothelial cells (HUVECs) were treated with MCS-18 (50-200 µg/ml) to analyze cell migration and adhesion under flow conditions. MCS-18 reduced human (p = 0.01) and murine (p = 0.006) DC migration. Furthermore, adhesion of MCS-18-treated DCs to a HUVEC monolayer was decreased (p < 0.001). Compared to controls, CD209 (p < 0.001) and CCR7 (p = 0.003) expression was decreased in MCS-18-treated DCs, while in HUVECs lower levels of ICAM-1 (p < 0.001) and of phosphorylated NF-κB-p65 (p = 0.002) were observed. Blocking of ICAM-1 reduced DC adhesion (p < 0.001). CONCLUSIONS: MCS-18 exhibits interesting therapeutic effects when applied in advanced murine atherosclerosis. Its antiatherogenic impact might be associated with a suppressed adhesion to the endothelium due to down-regulation of endothelial ICAM-1 expression.

Relation of functional echocardiographic parameters to infarct scar transmurality by magnetic resonance imaging.

BACKGROUND: Identification of viable but dysfunctional myocardium after myocardial infarction is important for management, including the decision for revascularization. Assessment of infarct transmurality (TRM) by late contrast enhancement on magnetic resonance imaging (MRI) is frequently used for this task but has several limitations, particularly its availability. The goal of this study was to compare the value of several simple echocardiographic parameters measured at rest at the bedside for the identification of three degrees of infarct TRM, with contrast-enhanced MRI as the gold standard. METHODS: In a prospective, single-center study, 41 patients (33 men; mean age, 62 ± 10 years; 32 with ST-segment elevation infarctions) underwent resting echocardiography and contrast-enhanced MRI <5 days after infarction. Wall motion score, preejection velocity by tissue Doppler, and longitudinal, circumferential, and radial peak systolic strain by speckle-tracking-based strain imaging were assessed, and the findings were compared with infarct TRM stratified by contrast-enhanced MRI (no scar, 0% TRM; nontransmural scar, 1%-50% TRM; and transmural scar, 51%-100% TRM). RESULTS: Four hundred segments showed no scar, 125 showed nontransmural scar, and 213 showed transmural scar on contrast-enhanced MRI. The sensitivity and specificity of visual wall motion scoring to detect any scar versus no scar were 71% and 81%, respectively, similar to values for circumferential strain (sensitivity and specificity both 81% with a cutoff of -14.5%). Longitudinal and radial strain performed less well, and the presence of preejection velocity performed distinctly worse (45% and 90%, respectively). The sensitivity and specificity for identifying nontransmural versus transmural infarction was better for circumferential strain (78% and 75%, respectively, with a cutoff of -10.5%) than for the other strain types, preejection velocity (52% and 67%, respectively), or visual wall motion scoring (50% and 81%, respectively, for a score > 2). CONCLUSION: Visual wall motion analysis alone is able to detect infarcted myocardium but cannot differentiate sufficiently between transmural and nontransmural infarction. This is best achieved at the bedside using speckle-tracking-based circumferential strain.

The proinflammatory effect of C-reactive protein on human endothelial cells depends on the FcγRIIa genotype.

INTRODUCTION: The stimulatory effects of CRP (C-reactive protein) on endothelial cells are mainly mediated via FcγRIIa. This receptor exists in two different allotypes bearing either arginine (R131) or histidine (H131) at the extracellular amino acid position 131 of the mature protein, but only FcγRIIa-R131 displays high avidity for CRP. This study investigated the role of the FcγRIIa genotype in CRP-stimulated endothelial cells. MATERIALS AND METHODS: We tested the effects of CRP on expression of the adhesion molecules ICAM-1, VCAM-1, and E-selectin, as well as the endothelial release of pro-inflammatory molecules as a function of the FcγRIIa-genotype (FcγRIIa-H/H131, FcγRIIa-H/R131, FcγRIIa-R/R131) in HUVEC (Human Umbilical Vein Endothelial Cells). HUVEC were grouped according to their FcγRIIa status by genotyping with an allele specific nested-PCR. The expression of ICAM-1, VCAM-1, and E-selectin on HUVEC was detected by flow cytometry. The release of soluble markers (sCD40L, IL-6, IL-8, MCP-1, tPA, sP-selectin, and sVCAM-1) was measured using a multiplex assay for flow cytometry. RESULTS AND CONCLUSIONS: CRP-stimulated expression of ICAM-1 and E-selectin was dependent on the specific FcγRIIa-genotype, with most pronounced induction in HUVEC with the FcγRIIa-R/R genotype, followed by H/R and H/H. In accordance with this finding, the supernatants of stimulated HUVEC with the R/R genotype showed significantly higher levels of tPA, MCP-1, and IL-6. Our data show that CRP stimulates the expression of adhesion molecules and the release of soluble markers by HUVEC as a function of the FcγRIIa-genotype. These findings could be relevant in the context of risk stratification in patients with cardiovascular disease.

Anti-inflammatory effects of danshen on human vascular endothelial cells in culture.

Inflammation plays a crucial role in the pathophysiology of atherosclerosis. Besides cytokines, chemokines and cell adhesion molecules, CD40 and P-selectin play important roles as key regulators of the inflammatory process in atherosclerosis. Danshen (DS) is commonly used in traditional Chinese medicine for therapy of cardiovascular diseases such as coronary artery disease. The aim of the present study was to evaluate the protective effects of DS with respect to possible anti-inflammatory effects. Human umbilical vein endothelial cells as well as platelets were incubated with an extract of DS or one of its major ingredients salvianolic acid B (Sal B), tanshinone IIA (Tansh) and protocatechuic acid (Protoc) under tumor necrosis factor (TNF)-α or ADP stimulation. Expression of CD40 and cellular adhesion molecules (VCAM-1/ICAM-1) were assessed via flow cytometry. Levels of interleukin (IL)-6, IL-8, monocyte-chemoattractant-protein (MCP)-1 as well as soluble VCAM1 and ICAM-1 in the supernatants were examined via luminex based analysis. Treatment with DS attenuated TNF-α induced expression of CD40. Furthermore, the expression of VCAM-1 and ICAM-1 as well as the release of soluble VCAM-1 and ICAM-1 were downregulated. In the cell supernatants we also observed a significant reduction of IL-6, IL8 and MCP-1. DS and its major ingredients, Sal B and Protoc, significantly inhibited TNF-induced expression and release of adhesion molecules, cytokines and chemokines as well as ADP-induced expression of platelet P-selectin. Because of the key roles of inflammatory mediators in the etiology of atherosclerosis, this work provides useful insight in understanding the pharmacological efficacy of Chinese herbal medicine.

Out-of-hospital cardiac arrest and percutaneous coronary intervention for ST-elevation myocardial infarction: long-term survival and neurological outcome.

BACKGROUND: Predictors of long-term outcome after ST-elevation myocardial infarction (STEMI) complicated by out-of-hospital cardiac arrest (OHCA) are incompletely understood, including the influence of successful coronary reperfusion. METHODS: We analysed clinical and procedural data as well as 1-year outcome of 72 consecutive patients who underwent primary coronary intervention (PCI) after witnessed OHCA and STEMI and compared the results with 695 patients with STEMI and PCI, but without OHCA. Neurological recovery after OHCA was assessed using the Cerebral Performance Category (CPC) scale. RESULTS: PCI was successful in 83.3% after OHCA vs. 84.3% in the non-OHCA group (p=0.87). One-year mortality was 34.7% vs. 9.5% (p<0.001). 58.3% of the OHCA-patients showed complete neurological recovery (CPC 1) or moderate neurological disability (CPC 2). Another 6.9% showed severe cerebral disability (CPC 3) or permanent vegetative status (CPC 4). Delay from collapse until start of Advanced Cardiopulmonary Life Support (ACLS) was shorter for survivors with CPC status ≤2 (median 1 min, range 0-11 min) compared to non-survivors or survivors with CPC status >2 (median 8 min, range 0-13 min), p<0.0001. Age-adjusted multivariate analysis identified 'unsuccessful PCI', 'vasopressors on admission' and 'start of ACLS after >6 min' as independent predictors of negative long-term outcome (death or CPC >2). CONCLUSIONS: Mortality is high in patients with STEMI complicated by OHCA - even though PCI was performed with the same success rate as in patients without OHCA. The majority of survivors had favourable neurological outcomes at 1 year, especially if advanced life support had been started within ≤6 min and PCI was successful.

Association of systemic inflammation markers with the presence and extent of coronary artery calcification.

BACKGROUND: Coronary artery calcification (CAC) is a marker for the presence and extent of coronary atherosclerotic plaques and can be detected non-invasively by multi-detector row CT (MDCT). Well known predictors of CAC are age, gender, and the classical atherogenic risk factors. CAC is associated with atherosclerotic plaque burden, but it is still elusive if atherosclerosis-relevant cytokines and chemokines are also associated with CAC. METHODS: We conducted a clinical study among 455 consecutive individuals who underwent coronary calcium assessment performed by MDCT. Before MDCT, blood was drawn and subsequently analyzed for 20 different atherosclerosis-relevant cytokines and chemokines using a Luminex-laser-based fluorescence analysis. RESULTS: Using univariate analyses, CAC patients revealed significantly higher levels of the chemokines IP-10 (P=0.047) and eotaxin (P=0.031) as compared to non-CAC patients. In multivariate analyses using common thresholds for calcium burden, the three cytokines interleukin-6 (P=0.028), interleukin-8 (P=0.009), and interleukin-13 (P=0.024) were associated with high coronary calcium levels after adjustment for classical variables and risk factors. CONCLUSIONS: In a large group of individuals with atypical chest pain and a low to intermediate likelihood for coronary artery disease elevated plasma levels of IL-6 and reduced levels of IL-8 and IL-13 were predictive for distinct coronary artery calcification. These findings support a specific role of these cytokines in coronary calcification.

Serum levels of the Th1 chemoattractant interferon-gamma-inducible protein (IP) 10 are elevated in patients with essential hypertension.

Growing evidence shows that inflammation has a pivotal role in the pathophysiology of essential hypertension (EH). Although it has been acknowledged that target organ damage involves an inflammatory response, most work has focused on the role of macrophages, but T lymphocytes have recently become the center of interest. The goal of our study was to evaluate the role of T-cell-specific cytokines in the pathogenesis of EH. The study examined 39 patients with EH (57.7±6.8 years, systolic blood pressure (SBP) 157.5±11.8 mm Hg, diastolic blood pressure 92.2±12.9 mm Hg, mean arterial pressure 113.9±12.6 mm Hg) and 30 healthy, normotensive controls (55.2±4.9 years). Blood was drawn from a peripheral vein, and serum levels of interferon-inducible protein (IP)-10 and interleukins (IL)-4, -7 and -13 were measured by a multiplexing assay. Hypertensive patients had significantly higher levels of IP-10, IL-4, IL-7 and IL-13 than control subjects. When the patients were classified into tertiles according to their serum IP-10 levels (T1: 41.2-94.1 pg ml(-1); T2: 103.4-162.5 pg ml(-1); T3: 171.7-443.5 pgml(-1)), the patients classified into the highest tertile also had the highest blood pressure. In a correlation analysis, plasma IP-10 concentration was significantly associated with SBP (r=0.59, P<0.001). Furthermore, hypertensives with microalbuminuria, an early sign of hypertensive target organ damage, had the highest IP-10 levels. A stepwise multivariate regression analysis revealed IP-10 as the strongest independent predictor of SBP (P=0.01). In conclusion, our study provides new insights into the pathophysiological mechanisms in EH linking inflammation and IP-10. However, these preliminary results need to be confirmed in larger trials.

Emergence of dendritic cells in the myocardium after acute myocardial infarction - implications for inflammatory myocardial damage.

Dendritic cells (DC) are crucial for T cell mediated immune responses. Recently, we observed a significant decrease in circulating myeloid DC precursors in patients with acute myocardial infarction (AMI). The aim of the present study was to investigate whether myeloid DC are present in infarcted myocardium. Myocardial specimens of 10 patients with AMI and 7 accident victims (controls) were collected after autopsy. In immunostainings the presence of DC (CD209(+), fascin(+)), T cells (CD3(+)), macrophages (CD68(+)), and HLA-DR expression was analyzed. Significantly higher numbers of CD209(+)-DC (97 vs. 44 cells/0.25 mm(2), p=0.03), fascin(+)-DC (54 vs. 8 cells/0.25 mm(2), p=0.02), T cells (27 vs. 6 cells/0.25 mm(2), p=0.02), and macrophages (44 vs. 6 cells/0.25 mm(2), p=0.01) associated with high HLA-DR expression were detected in infarcted myocardium. Frequent colocalizations of DC and T cells were observed. In occluded coronary arteries numerous DC, T cells, macrophages and high HLA-DR expression were found. We show that DC are present in infarcted myocardium after AMI. High HLA-DR expression and the colocalization with T cells suggest that they might trigger an immune response leading to further myocardial damage.

Transient decrease in circulating dendritic cell precursors after acute stroke: potential recruitment into the brain.

The role of DCs (dendritic cells) as potent mediators of inflammation has not been sufficiently investigated in stroke. Therefore, in the present study, circulating mDCPs (myeloid DC precursors), pDCPs (plasmacytoid DCPs) and tDCPs (total DCPs) were analysed by flow cytometry in (i) healthy controls (n=29), (ii) patients with ACI-S (asymptomatic cerebral infarction stenosis; n=46), (iii) patients with TIA (transient ischaemic attack; n=39), (iv) patients with AIS (acute ischaemic stroke; n=73), and (v) patients with AHS (acute haemorrhagic stroke; n=31). The NIHSS (National Institutes of Health Stroke Scale) and infarction size on a CT (computer tomography) scan were evaluated after stroke. In a patient subgroup, post-mortem immunohistochemical brain analyses were performed to detect mDCs (CD209), pDCs (CD123), T-cells (CD3) and HLA-DR. In AIS and AHS, the numbers of circulating mDCPs (P<0.005), pDCPs (P<0.005) and tDCPs (P<0.001) were significantly reduced. A significant inverse correlation was found between the NIHSS and circulating DCPs (P<0.02), as well as between hsCRP (high-sensitivity C-reactive protein) and circulating DCPs (P<0.001). Patients with large stroke sizes on a CT scan had significantly lower numbers of mDCPs (P=0.007), pDCPs (P=0.05) and tDCPs (P=0.01) than those with smaller stroke sizes. Follow-up analysis showed a significant recovery of circulating DCPs in the first few days after stroke. In the infarcted brain, a dense infiltration of mDCs co-localized with T-cells, single pDCs and high HLA-DR expression were observed. In conclusion, acute stroke leads to a decrease in circulating DCPs. Potentially, circulating DCPs are recruited from the blood into the infarcted brain and probably trigger cerebral immune reactions there.

Predictive value of the decrease in circulating dendritic cell precursors in stable coronary artery disease.

DCs (dendritic cells) are present in atherosclerotic lesions leading to vascular inflammation, and the number of vascular DCs increases during atherosclerosis. Previously, we have shown that the levels of circulating DCPs (DC precursors) are reduced in acute coronary syndromes through vascular recruitment. In the present study, we have investigated whether DCP levels are also reduced in stable CAD (coronary artery disease). The levels of circulating mDCPs (myeloid DCPs), pDCPs (plasmacytoid DCPs) and tDCP (total DCPs) were investigated using flow cytometry in 290 patients with suspected stable CAD. A coronary angiogram was used to evaluate a CAD score for each patient as follows: (i) CAD excluded (n=57); (ii) early CAD (n=63); (iii) moderate CAD (n=85); and (iv) advanced CAD (n=85). Compared with controls, patients with advanced stable CAD had lower HDL (high-density lipoprotein)-cholesterol (P=0.03) and higher creatinine (P=0.003). In advanced CAD, a significant decrease in circulating mDCPs, pDCPs and tDCPs was observed (each P<0.001). A significant inverse correlation was observed between the CAD score and mDCPs, pDCPs or tDCPs (each P<0.001). Patients who required percutaneous coronary intervention or coronary artery bypass grafting had less circulating mDCPs, pDCPs and tDCPs than controls (each P<0.001). Multiple stepwise logistic regression analysis suggested mDCPs, pDCPs and tDCPs as independent predictors of CAD. In conclusion, we have shown that patients with stable CAD have significantly lower levels of circulating DCPs than healthy individuals. Their decrease appears to be an independent predictor of the presence of, and subsequent therapeutic procedure in, stable CAD.

Atorvastatin enhances interleukin-10 levels and improves cardiac function in rats after acute myocardial infarction.

LV (left ventricular) remodelling is the basic mechanism of HF (heart failure) following MI (myocardial infarction). Although there is evidence that pro-inflammatory cytokines [including TNF-alpha (tumour necrosis factor-alpha) and IL-6 (interleukin-6)] are involved in the remodelling process, only little is known about the role of anti-inflammatory cytokines, such as IL-10. As accumulating evidence has revealed that statins possess anti-inflammatory properties, the aim of the present study was to elucidate the effect of atorvastatin on the modulation of the anti-inflammatory cytokine IL-10 and its effect on LV function in rats with HF subsequent to MI. Rats with MI, induced by permanent LAD (left anterior descending) branch coronary artery ligation, were treated for 4 weeks with atorvastatin (10 mg x kg(-1) of body weight x day(-1) via oral gavage) starting on the first day after induction of MI. Cardiac function was assessed by echocardiography and cardiac catheterization 4 weeks after MI induction. Membrane-bound and soluble fractions of TNF-alpha, IL-6 and IL-10 protein, the TNF-alpha/IL-10 ratio, serum levels of MCP-1 (monocyte chemoattractant protein-1) as well as myocardial macrophage infiltration were analysed. Treatment with atorvastatin significantly improved post-MI LV function (fractional shortening, +120%; dP/dt(max), +147%; and LV end-diastolic pressure, -27%). Furthermore atorvastatin treatment markedly decreased the levels of TNF-alpha, IL-6 and MCP-1, reduced myocardial infiltration of macrophages and significantly increased myocardial and serum levels of the anti-inflammatory cytokine IL-10. Thus the balance between pro-inflammatory and anti-inflammatory cytokines was shifted in the anti-inflammatory direction, as shown by a significantly decreased TNF-alpha/IL-10 ratio. Atorvastatin ameliorated early LV remodelling and improved LV function in rats with HF subsequent to MI. Our study suggests that the modulation of the balance between pro- and anti-inflammatory cytokines towards the anti-inflammatory cytokine IL-10 is one salutary mechanism underlying how atorvastatin influences post-MI remodelling and thus improves LV function.