A complex network of different cytokines and chemokines modulates atherosclerosis, a chronic inflammatory disease. Interleukin-17A (IL-17A) is expressed by different leukocyte subsets such as ...CD4+IL-17+ T cells (Th17), γδ T cells, natural killer cells, natural killer T cells, and neutrophils. IL-17A plays an important role in host defense and is involved in the pathology of different autoimmune and inflammatory diseases. Recent studies demonstrate an association of IL-17A with atherosclerosis. IL-17A seems to have primarily pro-inflammatory effects in atherogenesis, although there are partially controversial results in the literature. In the murine system, several studies indicate a pro-atherogenic role of IL-17A mediated by increased migration of leukocytes (especially macrophages) into atherosclerotic lesions, increased expression of pro-inflammatory cytokines and chemokines as well as plaque destabilizing matrix-metalloproteinases using Apoe-/- and LDLr-/- mice. In contrast, three studies show atheroprotective effects of IL-17A mediated by downregulation of aortic VCAM-1 expression on endothelial cells and increased collagen production by vascular smooth muscle cells (VSMCs) in LDLr-/- mice. In humans, expression of IL-17A was associated with increased inflammation and plaque vulnerability in human atherosclerotic lesions. Moreover, IL-17A induced a pro-inflammatory, pro-thrombotic, plaque-destabilizing, and cell-attracting response of the inflammatory milieu of human plaque tissue samples. Notably, a recently published study challenged these findings by showing a worse outcome of patients with acute myocardial infarction with low serum levels of IL-17A. In the following review, we will focus on the recent progress of functional studies of IL-17A in atherosclerosis and will try to collect explanations for the controversial data.
Atherosclerosis is a chronic inflammatory disease. Lesion progression is primarily mediated by cells of the monocyte/macrophage lineage. IL-17A is a proinflammatory cytokine, which modulates immune ...cell trafficking and is involved inflammation in (auto)immune and infectious diseases. But the role of IL-17A still remains controversial. In the current study, we investigated effects of IL-17A on advanced murine and human atherosclerosis, the common disease phenotype in clinical care. The 26-wk-old apolipoprotein E-deficient mice were fed a standard chow diet and treated either with IL-17A mAb (n = 15) or irrelevant Ig (n = 10) for 16 wk. Furthermore, essential mechanisms of IL-17A in atherogenesis were studied in vitro. Inhibition of IL-17A markedly prevented atherosclerotic lesion progression (p = 0.001) by reducing inflammatory burden and cellular infiltration (p = 0.01) and improved lesion stability (p = 0.01). In vitro experiments showed that IL-17A plays a role in chemoattractance, monocyte adhesion, and sensitization of APCs toward pathogen-derived TLR4 ligands. Also, IL-17A induced a unique transcriptome pattern in monocyte-derived macrophages distinct from known macrophage types. Stimulation of human carotid plaque tissue ex vivo with IL-17A induced a proinflammatory milieu and upregulation of molecules expressed by the IL-17A-induced macrophage subtype. In this study, we show that functional blockade of IL-17A prevents atherosclerotic lesion progression and induces plaque stabilization in advanced lesions in apolipoprotein E-deficient mice. The underlying mechanisms involve reduced inflammation and distinct effects of IL-17A on monocyte/macrophage lineage. In addition, translational experiments underline the relevance for the human system.
In the 12‐month, open‐label MANDELA study, patients were randomized at month 6 after heart transplantation to (1) convert to calcineurin inhibitor (CNI)‐free immunosuppression with everolimus (EVR), ...mycophenolic acid and steroids (CNI‐free, n = 71), or to (2) continue reduced‐exposure CNI, with EVR and steroids (EVR/redCNI, n = 74). Tacrolimus was administered in 48.8% of EVR/redCNI patients and 52.6% of CNI‐free patients at randomization. Both strategies improved and stabilized renal function based on the primary endpoint (estimated GFR at month 18 posttransplant postrandomization) with superiority of the CNI‐free group vs EVR/redCNI: mean 64.1 mL/min/1.73 m2 vs 52.9 mL/min/1.73 m2; difference + 11.3 mL/min/1.73 m2 (P < .001). By month 18, estimated GFR had increased by ≥ 10 mL/min/1.73 m2 in 31.8% and 55.2% of EVR/redCNI and CNI‐free patients, respectively, and by ≥ 25 mL/min/1.73 m2 in 4.5% and 20.9%. Rates of biopsy‐proven acute rejection (BPAR) were 6.8% and 21.1%; all cases were without hemodynamic compromise. BPAR was less frequent with EVR/redCNI vs the CNI‐free regimen (P = .015); 6 of 15 episodes in CNI‐free patients occurred with EVR concentration < 5 ng/mL. Rates of adverse events and associated discontinuations were comparable. EVR/redCNI from month 6 achieved stable renal function with infrequent BPAR. One‐year renal function can be improved by early conversion to EVR‐based CNI‐free therapy but requires close EVR monitoring. Clinical trials registry: ClinicalTrials.gov NCT00862979.
The 12‐month, randomized, open‐label MANDELA study shows that switching patients at 6 months after heart transplantation from standard immunosuppression to everolimus, mycophenolic acid, and steroids or to reduced‐exposure calcineurin inhibitor, everolimus, and steroids improves renal function in either case, but the enhanced renal benefit seen in the calcineurin inhibitor–free group requires close monitoring of everolimus exposure to avoid an increased risk of biopsy‐proven acute rejection. Tsay and Eisen comment in their editorial on page 2967.
Abstract Background and aims Galectin-3 binding protein (Gal-3BP) has been associated with inflammation and cancer, however, its role for coronary artery disease (CAD) and cardiovascular outcome ...remains unclear. Methods Gal-3BP plasma levels were measured by ELISA in 2922 individuals from the LURIC study (62.7 ± 10.6 years, 62.7% male). All-cause and cardiovascular mortality was assessed by Kaplan-Meier analysis and Cox proportional hazards regression. Causal involvement of Gal-3BP was tested for by Mendelian randomization. Gal-3BP effects on human monocyte-derived macrophages were assessed in vitro. Results During 8.8 ± 3.0 years, 866 individuals died, 654 of cardiovascular causes. There was a significant increase of all-cause and cardiovascular mortality with increasing Gal-3BP quintiles. After thorough adjustment, all-cause mortality remained significantly increased in the fifth Gal-3BP quintile (HRQ5 1.292 (1.030–1.620), p = 0.027); cardiovascular mortality remained increased in Gal-3BP quintiles two to five (HRQ5 1.433 (1.061–1.935, p = 0.019). Gal-3BP levels were not associated with diagnosis and extent of coronary artery disease. In addition, Mendelian randomization did not show a direct causal relationship between Gal-3BP levels and mortality. Gal-3BP levels were, however, independently associated with markers of metabolic and inflammatory distress. In vitro , Gal-3BP induced a pro-inflammatory response in human monocyte-derived macrophages. Adding Gal-3BP levels to the ESC score improved risk assessment in patients with ESC SCORE-based risk >5% ( p = 0.010). Conclusions In a large clinical cohort of CAD patients, Gal-3BP levels are independently associated with all-cause and cardiovascular mortality. The underlying mechanisms may likely involve metabolic and inflammatory distress. To further evaluate the potential clinical value of Gal-3BP, prospective studies are needed.
Abstract Objectives This study sought to evaluate myocardial perfusion reserve index (MPRI) and diastolic strain rate, both assessed by cardiac magnetic resonance (CMR) as a noninvasive tool for the ...detection of microvasculopathy. Background Long-term survival of cardiac allograft recipients is limited primarily by cancer and cardiac allograft vasculopathy (CAV). Besides epicardial CAV, diagnosed by coronary angiography, stenotic microvasculopathy was found to be an additional independent risk factor for survival after heart transplantation. Methods Sixty-three consecutive heart transplant recipients who underwent CMR, coronary angiography, and myocardial biopsy were enrolled. Stenotic vasculopathy in microvessels was considered in myocardial biopsies by immunohistochemistry and CAV was graded during coronary angiography according to International Society of Heart and Lung Transplantation criteria. In addition, by CMR microvasculopathy was assessed by myocardial perfusion reserve during pharmacologic hyperemia with adenosine and strain-encoded magnetic resonance using a modified spatial modulation of magnetization tagging pulse sequence in all patients. Results Decreasing MPRI and diastolic strain rates were observed in patients with decreasing microvessel luminal radius to wall thickness ratio and decreasing capillary density ( r = 0.45 and r = 0.61 for MPRI and r = 0.50 and r = 0.38 for diastolic strain rate, respectively; p < 0.005 for all). Using multivariable analysis, both MPRI and diastolic strain rate were robust predictors of stenotic microvasculopathy, independent of age, organ age, and CAV by International Society of Heart and Lung Transplantation criteria (hazard ratio: 0.07, p = 0.006 for MPRI; hazard ratio: 0.91, p = 0.002 for diastolic strain rate). Patients without stenotic microvasculopathy in the presence of no or mild CAV (n = 36) exhibited significantly higher median survival free of events, compared with patients with stenotic microvasculopathy in the presence of no or mild CAV (n = 18; p = 0.04 by log rank). Conclusions CMR represents a valuable noninvasive diagnostic tool, which may be used for the early detection of transplant microvasculopathy before the manifestation of CAV during surveillance coronary angiographic procedures.
CXCL4 is a platelet chemokine released at micromolar concentrations upon platelet activation. CXCL4 has been shown to promote atherogenesis by various mechanisms. However, data on CXCL4 plasma levels ...in patients with coronary artery disease are largely inconclusive. Computed coronary artery angiography (CCTA) represents an excellent tool to quantify and characterize coronary atherosclerotic plaques. We hypothesized that increased CXCL4 plasma levels may be associated with features of plaque instability resulting in adverse cardiovascular events. Specifically, we sought to determine whether CXCL4 levels are correlated with specific features of coronary artery disease including (1) plaque volume, (2) calcium score, (3) degree of stenosis, or (4) vascular remodeling.
CXCL4 plasma levels were measured by ELISA in 217 patients undergoing CCTA for suspected CAD (mean age 64.2 ± 9.4 years, 107 (49.3%) male). Mean CXCL4 plasma levels were 12.5 ± 4.6 ng/mL. There was no significant correlation between CXCL4 levels and any clinical or demographic parameters including cardiovascular risk factors. CXCL4 plasma levels did not differ between patient with or without coronary artery disease (CAD: 12.5 ± 4.5 ng/ml, no CAD: 12.5 ± 4.8 ng/ml). Neither univariate nor multivariate analysis showed an association between CXCL4 levels and plaque volume, total calcium score, degree of stenosis, or vascular remodeling. Subgroup analysis of patients with CAD as confirmed by CCTA did not show any association of CXCL4 levels with the extent of CAD.
While CXCL4 may be present and active within the arterial wall, local increase of CXCL4 may not translate into systemically elevated CXCL4 levels. Further studies will have to test whether CXCL4 may still represent a suitable therapeutic target in human atherosclerosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Atherosclerosis is a chronic inflammatory disease of the arterial wall. Adjacent to lamina intima lesion progression, a cellular compound develops in the lamina adventitia, defined as tertiary ...lymphoid organs (TLO) in mice. But in human system, it remains unknown whether these adventitial cellular accumulations represent these highly organized immunological structures.
In this study, we investigated whether the adventitial cellular compounds represent TLOs in 72 human coronary artery samples by immunoenzyme staining.
The study showed that the adventitial cellular compound partly represented TLOs in human coronary arteries affected by atherogenesis in patients suffering from ischemic heart disease (56%) or a fatal myocardial infarction (100%), but not dilated cardiomyopathy. In addition, we established a classification for human TLOs, stage I–III, and showed that all stages were present in diseased coronary arteries. The stage of TLOs highly correlated with lesion size as well as plaque instability and rupture, and all patients with a myocardial infarction had stage III. Additionally, there were cellular infiltration and destruction of the lamina media, which were restricted to TLOs next to ruptured plaques in patients with a fatal myocardial infarction.
TLOs are present in patients with a coronary artery disease and highly correlated with lesion size, plaque instability, and rupture. Further studies are needed to investigate whether TLOs might be a specific diagnostic and drug target to modify plaque instability/rupture.
•Since only part of the adventitial inflammatory aggregate represented a TLO, the current analysis of the study is not comparable to previous publications, which investigated all adventitial cellular compounds.•Stage classification of human TLOs in atherosclerosis.•Correlation of TLO stage classification with lesion size, plaque instability, and rupture.
Abstract Background The platelet chemokine CXCL4 induces monocyte differentiation resulting in a macrophage phenotype called “M4”, which co-expresses CD68, MMP7, and S100A8. We hypothesized that M4 ...macrophages are associated with plaque destabilization. Methods Atherosclerotic arteries were obtained from explanted hearts of patients with severe coronary artery disease (CAD, n = 32) and of patients with dilated cardiomyopathy and no or mild CAD (controls, n = 19). Coronary arteries were stained with H&E, and immuno-fluorescence was performed against CD68, MMP7, and S100A8. Results Both CD68+ macrophages representing the entire macrophage population and MMP7+ S100A8+ CD68+ M4 macrophages could be reproducibly identified within all arterial layers. The average proportion of the M4 macrophage phenotype amongst all CD68+ macrophages was 31.7 ± 16.2%. The highest number of M4 macrophages was found in the adventitia, followed by the intima. CD68+ and M4 macrophage numbers were significantly higher in patients with severe CAD. The presence of M4 macrophages within the intima and the media was significantly associated with plaque instability as determined by Stary class. Multivariate analysis showed a highly significant contribution of cardiovascular risk factors (P = 0.008) to plaque instability, while only trends were observed for age (P = 0.060) and intimal prevalence of M4 macrophages (P = 0.098). Conclusions We demonstrate for the first time that M4 macrophages can be reproducibly found in coronary artery plaques. The prevalence of M4 macrophages is associated with indexes of plaque instability, most likely representing a surrogate marker of inflammatory activity. These findings suggest a pathogenetic role of M4 macrophages in vulnerable atherosclerotic plaques.
COPD is associated with reduced physical activity, an increased risk for pulmonary infections, and impaired survival in nontransplant patients. The aim of this study was to investigate the influence ...of COPD in patients after heart transplantation (HTX).
We performed an observational retrospective single-center study of 259 patients receiving HTX at Heidelberg University Hospital between 2003 and 2012. Patients were stratified by the Tiffeneau index (forced expiratory volume in 1 second/forced vital capacity FEV1/FVC) <0.70 before HTX. The analysis included demographics, posttransplant medication, length of the initial hospital stay after HTX, early posttransplant atrial fibrillation (AF), mortality, and causes of death.
In total, 63 (24.3%) patients had an FEV1/FVC <0.70. These patients showed a prolonged hospital stay after HTX (52.0 days vs 43.4 days, mean difference (MD) = 8.6 days, 95% CI: 0.2, 17.0 days), a higher rate of early posttransplant AF (19.0% vs 8.2%, MD = 10.8%, 95% CI: 0.4%, 21.2%), and an increased 30-day mortality (9.5% vs 2.6%, HR = 3.79, 95% CI: 1.16, 12.40). Kaplan- Meier analysis showed a significant inferior 5-year survival in patients with an FEV1/FVC <0.70, along with a higher percentage of death due to transplant failure and infection/sepsis. In addition, a multivariate analysis for mortality within 5 years after HTX indicated an FEV1/FVC <0.70 as a significant risk factor for impaired 5-year posttransplant survival (HR =4.77, 95% CI: 2.76, 8.22).
COPD in patients after HTX is associated with a prolonged hospital stay, early posttransplant AF, and impaired posttransplant survival.
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