Konstantinos A. Polyzos

Risk factors for cardiac implantable electronic device infection: a systematic review and meta-analysis

Infectious complications after cardiac implantable electronic device (CIED) implantation are increasing over time and are associated with substantial mortality and healthcare costs. The aim of this study was to systematically summarize the literature on risk factors for infection after pacemaker, implantable cardioverter-defibrillator, and cardiac resynchronization therapy device implantation. Electronic searches (up to January 2014) were performed in PubMed, Scopus, and Web of Science databases. Sixty studies (21 prospective, 9 case-control, and 30 retrospective cohort studies) met the inclusion criteria. The average device infection rate was 1-1.3%. In the meta-analysis, significant host-related risk factors for infection included diabetes mellitus (odds ratio (OR) [95% confidence interval] = 2.08 [1.62-2.67]), end-stage renal disease (OR = 8.73 [3.42-22.31]), chronic obstructive pulmonary disease (OR = 2.95 [1.78-4.90]), corticosteroid use (OR = 3.44 [1.62-7.32]), history of the previous device infection (OR = 7.84 [1.94-31.60]), renal insufficiency (OR = 3.02 [1.38-6.64]), malignancy (OR = 2.23 [1.26-3.95]), heart failure (OR = 1.65 [1.14-2.39]), pre-procedural fever (OR = 4.27 [1.13-16.12]), anticoagulant drug use (OR = 1.59 [1.01-2.48]), and skin disorders (OR = 2.46 [1.04-5.80]). Regarding procedure-related factors, post-operative haematoma (OR = 8.46 [4.01-17.86]), reintervention for lead dislodgement (OR = 6.37 [2.93-13.82]), device replacement/revision (OR = 1.98 [1.46-2.70]), lack of antibiotic prophylaxis (OR = 0.32 [0.18-0.55]), temporary pacing (OR = 2.31 [1.36-3.92]), inexperienced operator (OR = 2.85 [1.23-6.58]), and procedure duration (weighted mean difference = 9.89 [0.52-19.25]) were all predictors of CIED infection. Among device-related characteristics, abdominal pocket (OR = 4.01 [2.48-6.49]), epicardial leads (OR = 8.09 [3.46-18.92]), positioning of two or more leads (OR = 2.02 [1.11-3.69]), and dual-chamber systems (OR = 1.45 [1.02-2.05]) predisposed to device infection. This systematic review on risk factors for CIED infection may contribute to developing better infection control strategies for high-risk patients and can also help risk assessment in the management of device revisions.

Antimicrobial-impregnated and -coated shunt catheters for prevention of infections in patients with hydrocephalus: a systematic review and meta-analysis

OBJECT The aim of this study was to evaluate the effectiveness of antimicrobial-impregnated and -coated shunt catheters (antimicrobial catheters) in reducing the risk of infection in patients undergoing CSF shunting or ventricular drainage. METHODS The PubMed and Scopus databases were searched. Catheter implantation was classified as either shunting (mainly ventriculoperitoneal shunting) or ventricular drainage (mainly external [EVD]). Studies evaluating antibioticimpregnated catheters (AICs), silver-coated catheters (SCCs), and hydrogel-coated catheters (HCCs) were included. A random effects model meta-analysis was performed. RESULTS Thirty-six studies (7 randomized and 29 nonrandomized, 16,796 procedures) were included. The majority of data derive from studies on the effectiveness of AICs, followed by studies on the effectiveness of SCCs. Statistical heterogeneity was observed in several analyses. Antimicrobial shunt catheters (AICs, SCCs) were associated with lower risk for CSF catheter-associated infections than conventional catheters (CCs) (RR 0.44, 95% CI 0.35-0.56). Fewer infections developed in the patients treated with antimicrobial catheters regardless of randomization, number of participating centers, funding, shunting or ventricular drainage, definition of infections, de novo implantation, and rate of infections in the study. There was no difference regarding gram-positive bacteria, all staphylococci, coagulase-negative streptococci, and Staphylococcus aureus, when analyzed separately. On the contrary, the risk for methicillin-resistant S. aureus (MRSA, RR 2.64, 95% CI 1.26-5.51), nonstaphylococcal (RR 1.75, 95% CI 1.22-2.52), and gram-negative bacterial (RR 2.13, 95% CI 1.33-3.43) infections increased with antimicrobial shunt catheters. CONCLUSIONS Based on data mainly from nonrandomized studies, AICs and SCCs reduce the risk for infection in patients undergoing CSF shunting. Future studies should evaluate the higher risk for MRSA and gram-negative infections. Additional trials are needed to investigate the comparative effectiveness of the different types of antimicrobial catheters.

Inhibition of indoleamine 2,3-dioxygenase promotes vascular inflammation and increases atherosclerosis in Apoe-/- mice.

AIMS Atherosclerosis is a chronic inflammatory disease that is initiated by the retention and accumulation of low-density lipoprotein in the artery, leading to maladaptive response of cells from the immune system and vessel wall. Strong evidence implicates indoleamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme of the kynurenine pathway of tryptophan (Trp) degradation, with immune regulation and anti-inflammatory mechanisms in different diseases. However, the role of IDO and the endogenous degradation of Trp have never been directly examined in atherosclerosis development. We used the IDO inhibitor 1-methyl-Trp (1-MT) to determine the role of IDO-mediated Trp metabolism in vascular inflammation and atherosclerosis. METHODS AND RESULTS Apoe(-/-) mice were treated with 1-MT in drinking water for 8 weeks. Systemic IDO inhibition led to a significant increase in atherosclerotic lesions that were ∼58 and 54% larger in the aortic arch and root, respectively. 1-MT treatment enhanced vascular inflammation, up-regulated VCAM-1 and CCL2, and increased CD68 macrophage accumulation into the plaque. Notably, the rise in VCAM-1 expression was not limited to the plaque but also found in smooth muscle cells (SMCs) of the tunica media. Furthermore, we found that IDO-dependent Trp metabolism by SMCs regulates VCAM-1 expression, and that 1-MT-induced acceleration of atherosclerosis and vascular inflammation can be reversed by exogenous administration of the Trp metabolite 3-hydroxyanthranilic acid (3-HAA). CONCLUSION IDO-mediated Trp metabolism regulates vascular inflammation and plaque formation in hypercholesterolaemic Apoe(-/-) mice. Our data establish that this pathway plays a major role in the pathological process of atherogenesis.

Maternal Influenza Vaccination and Risk for Congenital Malformations: A Systematic Review and Meta-analysis.

OBJECTIVE: To systematically summarize the literature on maternal influenza vaccination and the risk for congenital malformations using the methodology of meta-analysis. DATA SOURCES: PubMed, Scopus, and Embase databases (up to December 2014) as well as ClinicalTrials.gov (May 2015) and references of relevant articles were searched. The search strategy included combinations of the terms “influenza,” “vaccin*,” “pregnan*,” “safe*,” “adverse,” “congenital,” “malformation,” “defect,” and “anomal*.” METHODS OF STUDY SELECTION: Eligible studies examined the association between antepartum or preconceptional maternal immunization with inactivated influenza vaccines (seasonal trivalent or monovalent H1N1) and the risk for congenital malformations. Studies with no or inappropriate control group (comparison with population background rates or other vaccine types) were excluded. TABULATION, INTEGRATION, AND RESULTS: The risk for congenital anomalies after influenza vaccination was examined in 15 studies: 14 cohorts (events per vaccinated compared with unvaccinated: 859/32,774 [2.6%] compared with 7,644/245,314 [3.1%]) and one case–control study (vaccinated per cases compared with controls: 1,351/3,618 [37.3%] compared with 511/1,225 [41.7%]). Eight studies reported on first-trimester immunization (events per vaccinated compared with unvaccinated: 258/4,733 [5.4%] compared with 6,470/196,054 [3.3%]). No association was found between congenital defects and influenza vaccination at any trimester of pregnancy (odds ratio [OR] 0.96, 95% confidence interval 0.86–1.07; 15 studies; I2=36) or at the first trimester (OR 1.03, 0.91–1.18; eight studies; I2=0). When assessing only major malformations, no increased risk was detected after immunization at any trimester (OR 0.99, 0.88–1.11; 12 studies; I2=31.5) or at the first trimester (OR 0.98, 0.83–1.16; seven studies; I2=0). Neither adjuvanted (OR 1.06, 0.95–1.20; five studies; I2=18.8) nor unadjuvanted vaccines (OR 0.89, 0.75–1.04; seven studies; I2=22.6) were associated with an increased risk for congenital defects. CONCLUSION: This systematic review did not indicate an increased risk for congenital anomalies after maternal influenza immunization adding to the evidence base on the safety of influenza vaccination in pregnancy.

The role of the kynurenine pathway of tryptophan metabolism in cardiovascular disease. An emerging field.

Coronary heart disease and stroke, the deadliest forms of cardiovascular disease (CVD), are mainly caused by atherosclerosis, a chronic inflammatory disease of the artery wall driven by maladaptive immune responses in the vessel wall. Various risk factors for CVD influence this pathogenic process, including diabetes mellitus, hypertension, dyslipidaemia, and obesity. Indoleamine 2,3-dioxygenase (IDO), an enzyme catalyzing the rate-limiting step in the kynurenine pathway of tryptophan degradation, is strongly induced by inflammation in several tissues, including the artery wall. An increasing body of evidence indicates that IDO promotes immune tolerance, decreases inflammation, and functions as a homeostatic mechanism against excessive immune reactions. This review provides an overview of the emerging field of the kynurenine pathway of tryptophan degradation in CVD, emphasizing the role of IDO-mediated tryptophan metabolism and its metabolites in the modulation of ‘classical’ cardiovascular risk factors, such as hypertension, obesity, lipid metabolism, diabetes mellitus, and in the development of atherosclerotic CVD. In diesem Review geben wir einen Uberblick uber das neue Forschungsgebiet zum Kynurenin-Stoffwechselweg des Tryptophanabbaus bei CVD, mit Schwerpunkt auf der Rolle des IDO-vermittelten Stoffwechsels von Tryptophan und seiner Abbauprodukte bei der Modulation „klassischer“ kardiovaskularer Risikofaktoren wie Hypertonie, Adipositas, Lipidstoffwechsel oder Diabetes mellitus, und bei der Entwicklung einer atherosklerotischen CVD.

The role of the kynurenine pathway of tryptophan metabolism in cardiovascular disease

Coronary heart disease and stroke, the deadliest forms of cardiovascular disease (CVD), are mainly caused by atherosclerosis, a chronic inflammatory disease of the artery wall driven by maladaptive immune responses in the vessel wall. Various risk factors for CVD influence this pathogenic process, including diabetes mellitus, hypertension, dyslipidaemia, and obesity. Indoleamine 2,3-dioxygenase (IDO), an enzyme catalyzing the rate-limiting step in the kynurenine pathway of tryptophan degradation, is strongly induced by inflammation in several tissues, including the artery wall. An increasing body of evidence indicates that IDO promotes immune tolerance, decreases inflammation, and functions as a homeostatic mechanism against excessive immune reactions. This review provides an overview of the emerging field of the kynurenine pathway of tryptophan degradation in CVD, emphasizing the role of IDO-mediated tryptophan metabolism and its metabolites in the modulation of ‘classical’ cardiovascular risk factors, such as hypertension, obesity, lipid metabolism, diabetes mellitus, and in the development of atherosclerotic CVD. In diesem Review geben wir einen Uberblick uber das neue Forschungsgebiet zum Kynurenin-Stoffwechselweg des Tryptophanabbaus bei CVD, mit Schwerpunkt auf der Rolle des IDO-vermittelten Stoffwechsels von Tryptophan und seiner Abbauprodukte bei der Modulation „klassischer“ kardiovaskularer Risikofaktoren wie Hypertonie, Adipositas, Lipidstoffwechsel oder Diabetes mellitus, und bei der Entwicklung einer atherosklerotischen CVD.

Atherosclerosis Susceptibility in Mice Is Independent of the V1 Immunoglobulin Heavy Chain Gene

Objective— The V1 (V H S107.1.42) immunoglobulin heavy chain gene is thought to be critical in producing IgM natural antibodies of the T15-idiotype that protect against both atherosclerosis and infection from Streptococcus pneumoniae. Our aim was to determine whether genetic loss of the V1 gene increased atherosclerotic plaque burden in vivo because of a reduction in the T15-idiotype or other atheroprotective antibodies. Approach and Results— We crossed V H S107.1.42-deficient mice with the atherosclerosis-prone Apoe −/− and Ldlr −/− strains. Although these double knockout strains manifested no defects in B-cell development, we did observe a substantial reduction in early immune responses against phosphocholine after immunization. However, the titers of plasma antibodies reacting against defined atherosclerotic antigens such as oxidized low-density lipoprotein, as well as the T15-idiotype, were unaffected by loss of the V H S107.1.42 gene in hypercholesterolemic mice. Furthermore, we observed no increase in atherosclerotic lesion formation, either within the aortic arch or aortic root. Robust deposition of IgM within atherosclerotic plaques could also be readily observed in both control and experimental mice. Conclusions— Our data indicate that IgM-dependent protection against atherosclerosis is unlikely to be dependent on antibodies that use the V H S107.1.42 gene, in contrast to the acute immune response conferred by this heavy chain in the response to phosphocholine and in providing resistance against lethal S pneumoniae infection.

Hypercholesterolemia Induces Differentiation of Regulatory T Cells in the Liver

Rationale: The liver is the central organ that responds to dietary cholesterol intake and facilitates the release and clearance of lipoprotein particles. Persistent hypercholesterolemia leads to immune responses against lipoprotein particles that drive atherosclerosis. However, the effect of hypercholesterolemia on hepatic T-cell differentiation remains unknown. Objective: To investigate hepatic T-cell subsets upon hypercholesterolemia. Methods and Results: We observed that hypercholesterolemia elevated the intrahepatic regulatory T (Treg) cell population and increased the expression of transforming growth factor-&bgr;1 in the liver. Adoptive transfer experiments revealed that intrahepatically differentiated Treg cells relocated to the inflamed aorta in atherosclerosis-prone low-density lipoprotein receptor deficient (Ldlr−/−) mice. Moreover, hypercholesterolemia induced the differentiation of intrahepatic, but not intrasplenic, Th17 cells in wild-type mice, whereas the disrupted liver homeostasis in hypercholesterolemic Ldlr−/− mice led to intrahepatic Th1 cell differentiation and CD11b+CD11c+ leukocyte accumulation. Conclusions: Our results elucidate a new mechanism that controls intrahepatic T-cell differentiation during atherosclerosis development and indicates that intrahepatically differentiated T cells contribute to the CD4+ T-cell pool in the atherosclerotic aorta.

Hypercholesterolemia Enhances T Cell Receptor Signaling and Increases the Regulatory T Cell Population

Hypercholesterolemia promotes the inflammation against lipoproteins in atherosclerosis. Development of atherosclerosis is affected by the balance between pro-inflammatory effector T cells and anti-inflammatory regulatory T (Treg) cells. However, phenotype and function of T cell subpopulations in hypercholesterolemia remain to be investigated. Here, we found that cholesterol-containing diet increased the expression of the Treg cell lineage-defining transcription factor FoxP3 among thymocytes and splenocytes. Hypercholesterolemia elevated the FoxP3 expression level and population size of peripheral Treg cells, but did not prevent enhanced proliferation of stimulated T cells. Moreover, cholesterol supplementation in diet as well as in cell culture medium promoted T cell antigen receptor (TCR) signaling in CD4+ T cells. Our results demonstrate that hypercholesterolemia enhances TCR stimulation, Treg cell development as well as T cell proliferation. Thus, our findings may help to understand why hypercholesterolemia correlates with altered CD4+ T cell responses.

LDL-Reactive T Cells Regulate Plasma Cholesterol Levels and Development of Atherosclerosis in Humanized Hypercholesterolemic Mice

Background: Atherosclerotic cardiovascular disease is a chronic inflammatory process initiated when cholesterol-carrying low-density lipoprotein (LDL) is retained in the arterial wall. CD4+ T cells, some of which recognize peptide components of LDL as antigen, are recruited to the forming lesion, resulting in T-cell activation. Although these T cells are thought to be proatherogenic, LDL immunization reduces disease in experimental animals. These seemingly contradictory findings have hampered the development of immune-based cardiovascular therapy. The present study was designed to clarify how activation of LDL-reactive T cells impacts on metabolism and vascular pathobiology. Methods: We have developed a T-cell receptor–transgenic mouse model to characterize the effects of immune reactions against LDL. Through adoptive cell transfers and cross-breeding to hypercholesterolemic mice expressing the antigenic human LDL protein apolipoprotein B-100, we evaluate the effects on atherosclerosis. Results: A subpopulation of LDL-reactive T cells survived clonal selection in the thymus, developed into T follicular helper cells in lymphoid tissues on antigen recognition, and promoted B-cell activation. This led to production of anti-LDL immunoglobulin G antibodies that enhanced LDL clearance through immune complex formation. Furthermore, the cellular immune response to LDL was associated with increased cholesterol excretion in feces and with reduced vascular inflammation. Conclusions: These data show that anti-LDL immunoreactivity evokes 3 atheroprotective mechanisms: antibody-dependent LDL clearance, increased cholesterol excretion, and reduced vascular inflammation.