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1.
J Cardiovasc Dev Dis ; 10(7)2023 Jul 11.
Article in English | MEDLINE | ID: mdl-37504550

ABSTRACT

BACKGROUND: Left ventricular global longitudinal strain (LV GLS) is a superior predictor of adverse cardiac events in patients with myocardial infarction and heart failure. We investigated the ability of morphological features of infarcted myocardium to detect acute left ventricular (LV) dysfunction and predict LV functional recovery after three months in patients with acute ST-segment elevation myocardial infarction (STEMI). METHODS: Sixty-six STEMI patients were included in the C-reactive protein (CRP) apheresis in Acute Myocardial Infarction Study (CAMI-1). LV ejection fraction (LVEF), LV GLS, LV global circumferential strain (LV GCS), infarct size (IS), area-at-risk (AAR), and myocardial salvage index (MSI) were assessed by CMR 5 ± 3 days (baseline) and 12 ± 2 weeks after (follow-up) the diagnosis of first acute STEMI. RESULTS: Significant changes in myocardial injury parameters were identified after 12 weeks of STEMI diagnosis. IS decreased from 23.59 ± 11.69% at baseline to 18.29 ± 8.32% at follow-up (p < 0.001). AAR and MVO also significantly reduced after 12 weeks. At baseline, there were reasonably moderate correlations between IS and LVEF (r = -0.479, p < 0.001), LV GLS (r = 0.441, p < 0.001) and LV GCS (r = 0.396, p = 0.001) as well as between AAR and LVEF (r = -0.430, p = 0.003), LV GLS (r = 0.501, p < 0.001) and weak with LV GCS (r = 0.342, p = 0.020). At follow-up, only MSI and change in LV GCS over time showed a weak but significant correlation (r = -0.347, p = 0.021). Patients with larger AAR at baseline improved more in LVEF (p = 0.019) and LV GLS (p = 0.020) but not in LV GCS. CONCLUSION: The CMR tissue characteristics of myocardial injury correlate with the magnitude of LV dysfunction during the acute stage of STEMI. AAR predicts improvement in LVEF and LV GLS, while MSI is a sensitive marker of LV GCS recovery at three months follow-up after STEMI.

2.
J Clin Med ; 11(21)2022 Oct 31.
Article in English | MEDLINE | ID: mdl-36362673

ABSTRACT

In the multicenter, non-randomized, exploratory C-reactive protein (CRP) Apheresis in Myocardial Infarction (CAMI-1) study, CRP apheresis after ST-Elevation Myocardial Infarction (STEMI) significantly decreased blood CRP concentrations in humans. Cardiac damage was assessed by Cardiac Magnetic Resonance (CMR1) 3−9 d after onset of STEMI symptoms and quantified by myocardial infarct size (IS; %), left ventricular ejection fraction (LVEF; %), circumferential strain (CS) and longitudinal strain (LS). Compared with the control group (n = 34), cardiac damage was significantly lower in the apheresis group (n = 32). These findings suggested improved wound healing due to CRP apheresis already within few days after the STEMI event. In the current supplementary data analysis of CAMI-1, we have tested by a follow-up CMR (CMR2) after an average of 88 (65−177) d whether the effect of CRP apheresis is clinically maintained. After this time period, wound healing in STEMI is considered complete. Whereas patients with low CRP production and a CRP gradient cut off of <0.6 mg/L/h in the hours after STEMI (9 of 32 patients in the CRP apheresis group) did not significantly benefit from CRP apheresis in CMR2, patients with high CRP production and a CRP gradient cut off of >0.6 mg/L/h (23 of 32 patients in the CRP apheresis group) showed significant treatment benefit. In the latter patients, CMR2 revealed a lower IS (−5.4%; p = 0.05), a better LVEF (+6.4%; p = 0.03), and an improved CS (−6.1%; p = 0.005). No significant improvement, however, was observed for LS (−2.9%; p = 0.1). These data suggest a sustained positive effect of CRP apheresis on heart physiology in STEMI patients with high CRP production well beyond the period of its application. The data demonstrate the sustainability of the CRP removal from plasma which is associated with less scar tissue.

3.
J Clin Med ; 11(7)2022 Mar 23.
Article in English | MEDLINE | ID: mdl-35407379

ABSTRACT

C-reactive protein (CRP), the prototype human acute phase protein, may be causally involved in various human diseases. As CRP has appeared much earlier in evolution than antibodies and nonetheless partly utilizes the same biological structures, it is likely that CRP has been the first antibody-like molecule in the evolution of the immune system. Like antibodies, CRP may cause autoimmune reactions in a variety of human pathologies. Consequently, therapeutic targeting of CRP may be of utmost interest in human medicine. Over the past two decades, however, pharmacological targeting of CRP has turned out to be extremely difficult. Currently, the easiest, most effective and clinically safest method to target CRP in humans may be the specific extracorporeal removal of CRP by selective apheresis. The latter has recently shown promising therapeutic effects, especially in acute myocardial infarction and COVID-19 pneumonia. This review summarizes the pros and cons of applying this novel technology to patients suffering from various diseases, with a focus on its use in cardiovascular medicine.

4.
Med Klin Intensivmed Notfmed ; 117(3): 191-199, 2022 Apr.
Article in German | MEDLINE | ID: mdl-35333926

ABSTRACT

C­reactive protein (CRP) is the best-known acute phase protein. In humans, inflammation and infection are usually accompanied by an increase in CRP levels in the blood, which is why CRP is an important biomarker in daily clinical routine. CRP can mediate the initiation of phagocytosis by labeling damaged cells. This labeling leads to activation of the classical complement pathway (up to C4) and ends in the elimination of pathogens or reversibly damaged or dead cells. This seems to make sense in case of an external wound of the body. However, in the case of "internal wounds" (e.g., myocardial infarction, stroke), CRP induces tissue damage to potentially regenerable tissue by cell labeling, which has corresponding deleterious effects on cardiac and brain tissue or function. The described labeling of ischemic but potentially regenerable cells by CRP apparently also occurs in coronavirus disease 2019 (COVID-19). Parts of the lung become ischemic due to intra-alveolar edema and hemorrhage, and this is accompanied by a dramatic increase in CRP. Use of selective immunoadsorption of CRP from blood plasma ("CRP apheresis") to rapidly and efficiently lower the fulminant CRP load in the body fills this pharmacotherapeutic gap. With CRP apheresis, it is possible for the first time to remove this pathological molecule quickly and efficiently in clinical practice.


Subject(s)
Blood Component Removal , COVID-19 , Myocardial Infarction , Biomarkers , C-Reactive Protein , COVID-19/therapy , Humans , Myocardial Infarction/therapy
5.
Front Cardiovasc Med ; 8: 591714, 2021.
Article in English | MEDLINE | ID: mdl-33778017

ABSTRACT

Background: C-reactive protein (CRP) is a well-known marker of inflammation. It is less known that CRP mediates tissue damage in acute myocardial infarction (AMI) thus potentially worsening prognosis. A newly developed specific CRP adsorber allows efficient lowering of CRP levels and may improve survival. Objectives: Aim of this multi-center, controlled, non-randomized first-in-man CRP apheresis in Acute Myocardial Infarction study (CAMI-1) was to investigate the relationship between CRP levels (CRP gradient), myocardial infarct size and function as well as safety and efficacy of CRP apheresis in the setting of acute ST-segment Elevation Myocardial Infarction (STEMI) in humans. Methods: Eighty-three patients (45 apheresis, 38 controls) were recruited. CRP apheresis was performed 24 ± 12, 48 ± 12, and optionally 72 ± 12 h after onset of symptoms. First aphereses were performed at a median CRP concentration of 23.0 mg/L (range 9-279). In each apheresis session, 5,900 ± 400 mL plasma was processed via peripheral venous access. Primary study endpoint was a reduction in myocardial infarct size after STEMI as determined by cardiovascular magnetic resonance (CMR). Results: In controls, the CRP concentration significantly correlated with infarct size (p = 0.002) and decreased myocardial function (p ≤ 0.001). The CRP concentration in apheresis patients did not correlate with infarct size (p = 0.66) or left ventricular (LV) function (p = 0.79) and global strains and therefore significantly differed from controls (p = 0.03 and p = 0.002). Three major adverse cardiac events occurred in the control group after 12 months, none occurred in the apheresis group. Mean CRP depletion achieved over all apheresis procedures was 53.0 ± 15.1%. Apheresis sessions were well-tolerated. Reduced infarct size in the apheresis group compared to the control group (primary endpoint) was not achieved according to the original statistical analysis plan. Taking into account the individual CRP levels, however, revealed significant results. Modifications of the analysis plan were introduced in order to recruit a sufficient number of patients. Conclusions: This pilot study in humans reveals a correlation between CRP concentration and myocardial infarct size. CRP concentrations in STEMI can effectively be reduced by CRP apheresis without relevant side effects. CRP apheresis has the potential to interfere with deleterious aspects of STEMI. By lowering CRP levels, it resulted in the loss of correlation of CRP concentrations with myocardial infarct sizes as well as LV function. These results encourage a larger, randomized clinical trial. Clinical Trial Registration: https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00008988, DRKS00008988.

6.
Ther Apher Dial ; 23(6): 570-574, 2019 Dec.
Article in English | MEDLINE | ID: mdl-30924312

ABSTRACT

C-reactive protein (CRP), the prototype human acute-phase protein, is a well-known marker of inflammation. However, CRP may also mediate tissue damage in various human diseases like atherosclerosis, acute myocardial infarction, dilated cardiomyopathy, stroke, and potentially autoimmune disease. Therefore, CRP elimination from human plasma may indeed be a widely usable therapeutic approach. Recently, a first-in-man case report of selective CRP-apheresis in a patient with acute ST-segment elevation myocardial infarction (STEMI) has been published. Here, the method is further elucidated by detailed description of 13 patients receiving CRP-apheresis at two study centers. Thirteen patients received two sequential CRP-apheresis treatments with the PentraSorb CRP adsorber starting 24 ± 12 h after STEMI and successful percutaneous coronary intervention (PCI). CRP was measured immediately before and after each treatment, and additionally twice a day for a period of 96 h after symptom onset. Compared to the initial (before-treatment) CRP plasma concentration, CRP-apheresis resulted in an average 53.4% ± 11.9% CRP depletion. First apheresis was performed 27.5 ± 4.6 h after symptom onset at a mean CRP concentration of 25.1 ± 11.1 mg/L. Mean CRP concentration after the first treatment was 12.1 ± 6.4 mg/L. Second apheresis started 47.9 ± 5.4 h after symptom onset at a mean CRP concentration of 30.2 ± 21.4 mg/L. After the second treatment, mean CRP concentration was reduced to 13.9 ± 10.9 mg/L. No severe apheresis-associated side effects were observed. Patients tolerated selective CRP-apheresis without any side effects. The new method is feasible and safe and significantly reduces CRP plasma concentration in humans.


Subject(s)
Blood Component Removal/methods , C-Reactive Protein/metabolism , Percutaneous Coronary Intervention , ST Elevation Myocardial Infarction/therapy , Aged , Female , Humans , Male , Middle Aged , Treatment Outcome
7.
Case Rep Cardiol ; 2018: 4767105, 2018.
Article in English | MEDLINE | ID: mdl-30533227

ABSTRACT

C-reactive protein (CRP) may be causative in cardiovascular disease. As yet, no specific CRP inhibitor for human application has been described. A 69-year-old male was referred with ST segment elevation myocardial infarction (STEMI). Typical symptoms of chest pain started at 10.00 p.m. The patient was admitted to the hospital at 1.30 a.m. the next day. As ECG showed anterior wall myocardial infarction, the patient was immediately transferred to successful emergency angioplasty/drug-eluting- (DE-) stenting of the subtotally occluded left anterior descending artery. Consecutively, the hemodynamically stable patient was monitored at the chest pain unit. C-reactive protein (CRP) apheresis using the CRP adsorber (PentraSorb® CRP) within CAMI-1 trial was performed 34 h and 58 h after the onset of symptoms. In each apheresis session, 6000 ml plasma was treated via peripheral venous access. Plasma CRP levels decreased from 28.77 mg/l to 12.58 mg/l during the first apheresis session and from 24.17 mg/l to 11.55 mg/l during the second session, respectively. No side effects were observed. This is the first report of selective CRP apheresis in a man. The technology offers multiple opportunities to clarify the immunological/pathogenic role of CRP in health and disease.

8.
Arch Med Sci ; 13(5): 1086-1093, 2017 Aug.
Article in English | MEDLINE | ID: mdl-28883850

ABSTRACT

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.

9.
Heart Vessels ; 32(11): 1304-1313, 2017 Nov.
Article in English | MEDLINE | ID: mdl-28567553

ABSTRACT

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.


Subject(s)
Atherosclerosis/blood , Coronary Artery Disease/blood , Cytokines/blood , Osteoprotegerin/blood , RANK Ligand/blood , Risk Assessment , Adult , Aged , Aged, 80 and over , Atherosclerosis/epidemiology , Biomarkers/blood , Coronary Artery Disease/epidemiology , Enzyme-Linked Immunosorbent Assay , Female , Germany/epidemiology , Humans , Male , Middle Aged , Morbidity/trends , Risk Factors , Young Adult
10.
Eur J Clin Invest ; 46(6): 564-71, 2016 Jun.
Article in English | MEDLINE | ID: mdl-27090943

ABSTRACT

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.


Subject(s)
Albuminuria/metabolism , Blood Platelets/metabolism , CD40 Antigens/metabolism , CD40 Ligand/metabolism , Chemokine CCL2/metabolism , Hypertension/metabolism , Albuminuria/etiology , Case-Control Studies , Coculture Techniques , Essential Hypertension , Female , Flow Cytometry , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Hypertension/complications , In Vitro Techniques , Inflammation , Male , Middle Aged
11.
J Control Release ; 229: 23-36, 2016 05 10.
Article in English | MEDLINE | ID: mdl-26988601

ABSTRACT

Cardiovascular diseases, including ischemic heart disease and stroke, are responsible for nearly 25% of all deaths worldwide. Globally, their prevalence continues to increase, in spite of enormous progress in cardiovascular diagnostics and therapy. For therapeutic and regenerative purposes, biomaterials promise solutions with multiple advantages over synthetic materials. Furthermore, their easy availability as nanoformulations recommends their application as drug carriers or protective nanoshells improving the biocompatibility of imaging agents. In this work, we review the most promising and clinically meaningful scientific reports with regard to (nano)biomaterials with particular focus on potential improvements of existing, and development of novel constructs for cardiovascular applications.


Subject(s)
Biocompatible Materials/therapeutic use , Cardiovascular Diseases/therapy , Nanostructures/therapeutic use , Animals , Blood Vessel Prosthesis , Cardiovascular Diseases/diagnostic imaging , Humans , Regeneration , Stents , Tissue Engineering
12.
PLoS One ; 10(10): e0141336, 2015.
Article in English | MEDLINE | ID: mdl-26501774

ABSTRACT

OBJECTIVE: Na+ can be stored in muscle and skin without commensurate water accumulation. The aim of this study was to assess Na+ and H2O in muscle and skin with MRI in acute heart failure patients before and after diuretic treatment and in a healthy cohort. METHODS: Nine patients (mean age 78 years; range 58-87) and nine age and gender-matched controls were studied. They underwent 23Na/1H-MRI at the calf with a custom-made knee coil. Patients were studied before and after diuretic therapy. 23Na-MRI gray-scale measurements of Na+-phantoms served to quantify Na+-concentrations. A fat-suppressed inversion recovery sequence was used to quantify H2O content. RESULTS: Plasma Na+-levels did not change during therapy. Mean Na+-concentrations in muscle and skin decreased after furosemide therapy (before therapy: 30.7±6.4 and 43.5±14.5 mmol/L; after therapy: 24.2±6.1 and 32.2±12.0 mmol/L; p˂0.05 and p˂0.01). Water content measurements did not differ significantly before and after furosemide therapy in muscle (p = 0.17) and only tended to be reduced in skin (p = 0.06). Na+-concentrations in calf muscle and skin of patients before and after diuretic therapy were significantly higher than in healthy subjects (18.3±2.5 and 21.1±2.3 mmol/L). CONCLUSIONS: 23Na-MRI shows accumulation of Na+ in muscle and skin in patients with acute heart failure. Diuretic treatment can mobilize this Na+-deposition; however, contrary to expectations, water and Na+-mobilization are poorly correlated.


Subject(s)
Diuretics/therapeutic use , Heart Failure/etiology , Heart Failure/metabolism , Leg/pathology , Magnetic Resonance Imaging/methods , Aged , Aged, 80 and over , Case-Control Studies , Diuretics/adverse effects , Female , Humans , Male , Middle Aged , Muscle, Skeletal/metabolism , Prospective Studies , Skin/metabolism , Sodium/metabolism , Water/metabolism
13.
Inflamm Res ; 64(5): 313-9, 2015 May.
Article in English | MEDLINE | ID: mdl-25763815

ABSTRACT

BACKGROUND: Increased epicardial fat volume (EFV) has been shown to be associated with coronary atherosclerosis. While it is postulated to be an independent risk factor, a possible mechanism is local or systemic inflammation. We analyzed the relationship between coronary atherosclerosis, quantified by coronary calcium in CT, epicardial fat volume and systemic inflammation. METHODS: Using non-enhanced dual-source CT, we quantified epicardial fat volume (EFV) and coronary artery calcium (CAC) in 391 patients who underwent coronary computed tomography for suspected coronary artery disease. In addition to traditional risk factors, serum markers of systemic inflammation were measured (IL-1α, IL-2, IL-4, IL-6, IL-7, IL-8, IL-10,IL-12, IL-13, IL-15, IL-17, IFN-γ, TNF-α, hs-CRP, GM-CS, G-CSF, MCP-1, MIP-1, Eotaxin and IP-10). In 94 patients follow-up data were obtained after 1.9 ± 0.5 years. RESULTS: The 391 patients had a mean age of 60 ± 10 years, and 69 % were males. Mean EFV was 116 ± 50 mL. Median CAC was 12 (IQR 0; 152). CAC and EFV showed a significant correlation (ρ = 0.37; P < 0.001). EFV and CAC were significantly correlated with the traditional risk factors like age, male gender, diabetes, smoking and hypertension. With regard to biomarkers, CAC was significantly associated (negatively) to G-CSF and IL-13. EFV (median binned) was significantly associated (positively) with IP-10 (P = 0.002) and MCP-1 (ρ = 0.037). In follow-up, EFV showed a mean annualized progression of 6 mL (IQR 3; 9) (P < 0.001); CAC progressed by a mean of six Agatston Units (IQR 0; 30). The progression of CAC was significantly correlated with the extent of EFV (P < 0.001) while there was no significant correlation between progression of EFV or CAC with systemic inflammation markers. CONCLUSION: Epicardial fat volume and the baseline extent as well as progression of coronary atherosclerosis-measured by the calcium score-are significantly correlated. While both baseline EFV and CAC displayed significant correlations with systemic inflammation markers, biomarkers were not predictive of the progression of CAC or EFV.


Subject(s)
Adipose Tissue/pathology , Calcinosis/pathology , Coronary Artery Disease/pathology , Inflammation/pathology , Pericardium/pathology , Adipose Tissue/metabolism , Aged , Aging/metabolism , Biomarkers/blood , Calcinosis/metabolism , Coronary Artery Disease/metabolism , Cytokines/blood , Disease Progression , Female , Humans , Male , Middle Aged , Pericardium/metabolism , Risk Factors
14.
Clin Hemorheol Microcirc ; 59(3): 219-33, 2015.
Article in English | MEDLINE | ID: mdl-24787629

ABSTRACT

BACKGROUND: In coronary artery disease, highly stenosed arteries are frequently treated by stent implantation, which thereafter necessitates a dual-antiplatelet therapy (DAPT) in order to prevent stent-thrombosis. We hypothesized that specific patterns of microstructures on stents can accelerate endothelialisation thereby reducing their thrombogenicity and the DAPT duration. METHODS: Differently designed, 2-5 µm high elevations or hollows were lithographically etched on silicon plates, subsequently coated with silicon carbide. Smooth silicon plates and bare metal substrates were used as controls. To assess attachment and growth of human umbilical vein endothelial cells under static or flow conditions, actin cytoskeleton was visualised with green phalloidin. Endothelial migration was assessed in a modified barrier assay. To investigate surface thrombogenicity, platelets were incubated on the structured surfaces in static and flow conditions, and visualised with fluorescein-conjugated P-selectin antibody. Images were taken with incident-light fluorescent microscope for non-transparent objects. RESULTS: Compared to smooth surface, flat cubic elevations (5 µm edge length) improved endothelial cell attachment and growth under static and dynamic conditions, whereas smaller, spiky structures (2 µm edge length) had a negative influence on endothelialisation. Endothelial cell migration was fastest on flat cubic elevations, hollows, and smooth surfaces, whereas spiky structures and bare metal had a negative effect on endothelial migration. Thrombogenicity assays under static and flow conditions showed that platelet adhesion was reduced on the flat elevations and the smooth surface, as compared to the spiky structures, the hollow design and the bare metal substrates. CONCLUSION: Surface microstructures strongly influence endothelialisation of substrates. Designing stents with surface topography which accelerates endothelialisation and reduces thrombogenicity may be of clinical benefit by improving the safety profile of coronary interventions.


Subject(s)
Atherosclerosis/drug therapy , Coronary Artery Disease/drug therapy , Stents/standards , Humans
15.
Atherosclerosis ; 235(2): 263-72, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24887015

ABSTRACT

INTRODUCTION: Inflammation accelerates both plaque progression and instability in the pathogenesis of atherosclerosis. The inhibition of dendritic cell (DC) maturation is a promising approach to suppress excessive inflammatory immune responses and has been shown to be protective in several autoimmune models. The aim of this study was to investigate the immune modulatory effects of the natural substance MCS-18, an inhibitor of DC maturation, regarding the progression of atherosclerosis in ApoE-deficient mice. MATERIALS AND METHODS: ApoE-deficient mice were fed for twelve weeks with a Western-type diet (n = 32) or normal chow (control group; n = 16). Animals receiving high-fat diet were treated with MCS-18 (500 µg/kg body weight, n = 16) or saline (n = 16) twice a week. After 12 weeks, animals were transcardially perfused and sacrificed. The percentage of mature DCs (CD3(-)/CD19(-)/CD14(-)/NK1.1(-)/CD11c(+)/MHCII(+)/CD83(+)/CD86(+)) and T cell subpopulations (CD4(+)/CD25(+)/Foxp3(+), CD3/CD4/CD8) was analyzed in peripheral blood and in the spleen using flow cytometry. Plaque size was determined in the aortic root and the thoracoabdominal aorta using en-face staining. Immunohistochemical stainings served to detect inflammatory cells in the aortic root. Several cytokines and chemokines were determined in serum using multiplex assays. RESULTS: In splenic cells derived from saline-treated atherosclerotic mice an increased DC maturation, reflected by the upregulation of CD83 and CD86 expression, was observed. The enhanced expression of both maturation markers was absent in MCS-18 treated atherosclerotic mice. While the percentage of splenic Foxp3 expressing Treg was increased in animals receiving MCS-18 compared to saline-treated atherosclerotic mice, cytotoxic T cells were reduced in the spleen and in atherosclerotic lesions of the aortic root. Furthermore, proatherogenic cytokines (e.g. IL-6 and IFN-γ) and chemokines (e.g. MIP-1ß) were decreased in serum of MCS-18-treated animals when compared to saline-treated atherosclerotic mice. Also plaque size in the aortic root and the thoracoabdominal aorta was significantly lower following administration of MCS-18. CONCLUSION: This study provides for the first time evidence that MCS-18 is able to prevent the onset of atherosclerosis in ApoE-deficient mice. The observed anti-atherogenic effect is associated with the suppression of DC maturation and an inhibited migration and proliferation of cytotoxic T cells.


Subject(s)
Atherosclerosis/prevention & control , Biological Products/therapeutic use , Dendritic Cells/drug effects , Plaque, Atherosclerotic/prevention & control , Animals , Anti-Inflammatory Agents , Apolipoproteins E/deficiency , Atherosclerosis/pathology , Dendritic Cells/immunology , Diet, High-Fat , Disease Progression , Inflammation/metabolism , Male , Mice, Inbred C57BL , Mice, Knockout
16.
Thromb Res ; 133(3): 426-32, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24440139

ABSTRACT

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.


Subject(s)
C-Reactive Protein/metabolism , Coronary Artery Disease/metabolism , Human Umbilical Vein Endothelial Cells/metabolism , Inflammation/metabolism , Receptors, IgG/genetics , Coronary Artery Disease/genetics , Genotype , Humans , Inflammation/blood , Polymorphism, Genetic , Receptors, IgG/metabolism , Vascular Cell Adhesion Molecule-1/metabolism
17.
Immunol Lett ; 158(1-2): 95-100, 2014.
Article in English | MEDLINE | ID: mdl-24333341

ABSTRACT

BACKGROUND: Cerebral ischemia is associated with infectious complications due to immunosuppression and decreased T lymphocyte activity. G-CSF, which has neuroprotective properties, is known to modulate inflammatory processes after induced stroke. The aim of our study was to investigate the impact of G-CSF in experimental stroke and to compare two different modes of treatment, focusing on circulating T lymphocytes. METHODS: Cerebral ischemia was induced in Wistar rats by occlusion of the middle cerebral artery, followed by reperfusion after 1h. G-CSF was applied either as a single dose 30 min after occlusion, or daily for seven days. Silver staining was used to determine infarct size. T lymphocytes in the peripheral blood were measured before and 7 days after induced cerebral ischemia by flow cytometry. In addition, migration of CD3-expressing T lymphocytes into the brain was investigated by immunohistochemistry. RESULTS: Both single dose and daily treatment with G-CSF significantly reduced infarct size. A significant improvement of neurological outcome was only observed after single application of G-CSF. While a decrease in peripheral T lymphocytes was detected seven days after induced stroke, no reduction was observed in the G-CSF-treated groups. Apart from that, G-CSF significantly reduced the number of brain migrated T lymphocytes in both treatment settings as compared to vehicle. CONCLUSION: A single dose of G-CSF exerted neuroprotective effects in ischemic stroke, which were less pronounced after daily G-CSF application. Both treatment strategies inhibited stroke-induced reduction of T lymphocytes in peripheral blood, which may have contributed to the reduction of infarct size.


Subject(s)
Brain Ischemia/therapy , Brain/immunology , Granulocyte Colony-Stimulating Factor/administration & dosage , Immunotherapy/methods , Neuroprotective Agents/administration & dosage , Stroke/therapy , T-Lymphocytes/immunology , Animals , Blood Circulation , Brain/pathology , Brain Ischemia/immunology , Cell Movement , Clinical Protocols , Disease Models, Animal , Granulocyte Colony-Stimulating Factor/immunology , Humans , Immunity, Cellular , Male , Middle Cerebral Artery , Neuroprotective Agents/immunology , Rats , Rats, Wistar , Reperfusion , Stroke/immunology
18.
Am J Chin Med ; 41(5): 1065-77, 2013.
Article in English | MEDLINE | ID: mdl-24117069

ABSTRACT

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.


Subject(s)
Abietanes/pharmacology , Anti-Inflammatory Agents , Benzofurans/pharmacology , Drugs, Chinese Herbal/pharmacology , Human Umbilical Vein Endothelial Cells/metabolism , Hydroxybenzoates/pharmacology , Inflammation Mediators/metabolism , Adenosine Diphosphate/pharmacology , Atherosclerosis/etiology , Blood Platelets/metabolism , CD40 Antigens/metabolism , Cells, Cultured , Chemokine CCL2/metabolism , Down-Regulation/drug effects , Humans , Intercellular Adhesion Molecule-1/metabolism , Interleukin-6/metabolism , Interleukin-8/metabolism , P-Selectin/metabolism , Salvia miltiorrhiza , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/pharmacology , Vascular Cell Adhesion Molecule-1/metabolism
19.
Atherosclerosis ; 230(1): 92-9, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23958259

ABSTRACT

PURPOSE: Mature dendritic cells (DCs) play a crucial role in the inflammatory process within atherosclerotic lesions by stimulation of effector T cells, which can contribute to plaque instability. Interactions between DCs and regulatory T cells (Treg), which regulate immune response by attenuating acute inflammation, are postulated to be involved in the pathogenesis of autoimmune diseases. We investigated a possible correlation between infiltrated DCs and Treg in human atherosclerotic plaques. METHODS: Cross-sections of 40 human carotid endarterectomy specimens were classified into groups of stable and vulnerable plaques using Trichrome staining. Immunohistochemical staining of plaques was used to detect infiltrated total (S100) and mature DCs (fascin, DC-LAMP, CD83), Treg (CD3, Foxp3), and to analyze the inflammatory state of the plaques (CD3, COX-2, CD68). In addition, RNA was isolated from plaque specimens and quantitative real-time PCR was performed to analyze transcription rates of DC markers (CD11c, CD209, HLA-DR), maturation markers (CD80, CD83, CD86), Treg-associated genes (CTLA-4, Foxp3) and of pro- and anti-inflammatory cytokines (TGFß-family, IL-10, IFN-γ, IL-17α, IL-6). Migration assays and adhesion experiments were performed, to investigate the effects of Treg on mature DCs in vitro. RESULTS: As compared with stable plaques, vulnerable lesions were characterized by increased numbers of COX-2-expressing cells and T lymphocytes, indicating an enhanced inflammatory process. In vulnerable plaques, numbers of total and mature DCs were significantly higher in the inflammatory plaque shoulder, whereas the numbers of Treg were decreased compared to stable plaques. This inverse correlation and the association of the observed infiltration rates with plaque stability, were confirmed by PCR analyses, showing increased transcription levels of DC-specific markers, decreased mRNA expression of Treg-associated genes and decreased anti-inflammatory cytokines in vulnerable atherosclerotic plaques. In vitro, pre-incubation of mature DCs with Treg resulted in decreased DC migration and inhibited the adhesion of DCs to endothelial cells under non-uniform shear stress. CONCLUSIONS: The results of our study provide novel insights in the direct interaction of mature DCs and Treg in plaque inflammation and stability.


Subject(s)
Atherosclerosis/metabolism , Carotid Stenosis/metabolism , Dendritic Cells/cytology , T-Lymphocytes, Regulatory/cytology , Aged , Carotid Arteries/pathology , Carotid Stenosis/surgery , Cell Adhesion , Chemotaxis , Cytokines/metabolism , Dendritic Cells/metabolism , Endarterectomy, Carotid , Female , Gene Expression Regulation , Humans , Immunohistochemistry , Inflammation , Male , Middle Aged , T-Lymphocytes, Regulatory/metabolism , Transcription, Genetic
20.
Cytokine ; 62(2): 290-6, 2013 May.
Article in English | MEDLINE | ID: mdl-23541900

ABSTRACT

BACKGROUND: Hypertension is one of the most prominent risk factors for coronary artery disease (CAD). Treatment of hypertension is therefore important for reducing cardiovascular events and the progression of atherosclerosis. Several treatment strategies are common in clinical practice for example the use of ACE-blockers or angiotensin receptor II blockers (ARBs), so called sartans. Telmisartan, belonging to the class of ARBs, was shown to exert anti-inflammatory effects besides the blood pressure lowering. METHODS: In this work, two separate substudy groups of hypertensives were compared. 16 patients with arterial hypertension have been treated with telmisartan (initial 40 mg Kinzalmono®) for 7.3 ± 4.4 months. The telmisartan group was compared to a matched control group including 31 hypertensive patients without telmisartan treatment with a follow up period of 1.9 ± 0.5 years. Serum samples from the beginning and the end of follow up were analyzed with Luminex® technology for 26 cytokines and chemokines. The baseline scores of coronary artery calcification (CAC) were gathered by multislice detector computer tomography. RESULTS: After 7 months of telmisartan treatment and 2 years in control patients most of the measured analytes did not change significantly. MCP-1 (P=0.001; P<0.001) was increased significantly in both telmisartan and control group. The relative decrease in IP-10 and TNF-α levels was observed in telmisartan group, as opposed to the increase in control (telmisartan vs. control P=0.048; P=0.01). No linear rank-correlation between measured analytes and the initial CAC was found. CONCLUSION: Telmisartan reduced blood pressure in patients with atherosclerosis and arterial hypertension within a short time period, whereas the inflammatory status of these patients remained largely unchanged. An involvement of telmisartan in the regulation of inflammatory and anti-inflammatory mediators in the context of CAD and CAC is possible, but cannot clearly be assumed based on the present findings.


Subject(s)
Benzimidazoles/therapeutic use , Benzoates/therapeutic use , Chemokine CCL2/blood , Chemokine CXCL10/blood , Coronary Artery Disease/drug therapy , Tumor Necrosis Factor-alpha/blood , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Atherosclerosis/drug therapy , Blood Pressure/drug effects , Female , Humans , Hypertension/drug therapy , Inflammation/drug therapy , Interleukin-6/blood , Male , Middle Aged , Telmisartan
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