Prognostic markers of all-cause mortality in patients with atrial fibrillation: data from the prospective long-term registry of the German Atrial Fibrillation NETwork (AFNET).

AIMS: Atrial fibrillation (AF) is associated with a high risk of cardiovascular and non-cardiovascular death, even on anticoagulation. It is controversial, which conditions-including concomitant diseases and AF itself-contribute to this mortality. To further clarify these questions, major determinants of long-term mortality and their contribution to death were quantified in an unselected cohort of AF patients. METHODS AND RESULTS: We established a large nationwide registry comprising 8833 AF-patients with a median follow-up of 6.5 years (45 345 patient-years) and central adjudication of adverse events. Baseline characteristics of the patients were evaluated as predictors of mortality using Cox regression and C-indices for determination of predictive power. Annualized mortality was highest in the first year (6.2%) and remained high thereafter (5.2% in men and 5.5% in women). Thirty-eight percent of all deaths were cardiovascular, mainly due to heart failure or sudden death. Sex-specific age was the strongest predictor of mortality, followed by concomitant cardiovascular and non-cardiovascular conditions. These factors accounted for 25% of the total mortality beyond age and sex and for 84% of the mortality differences between AF types. Thus, the electrical phenotype of the disease at baseline contributed only marginally to prediction of mortality. CONCLUSION: Mortality is high in AF patients and arises primarily from heart failure, peripheral artery disease, chronic obstructive lung disease, chronic kidney disease, and diabetes mellitus, which, therefore, should be targeted to lower mortality. Parameters related to the electrical manifestation of AF did not have an independent impact on long-term mortality in our representative cohort.

Integrating new approaches to atrial fibrillation management: the 6th AFNET/EHRA Consensus Conference.

There are major challenges ahead for clinicians treating patients with atrial fibrillation (AF). The population with AF is expected to expand considerably and yet, apart from anticoagulation, therapies used in AF have not been shown to consistently impact on mortality or reduce adverse cardiovascular events. New approaches to AF management, including the use of novel technologies and structured, integrated care, have the potential to enhance clinical phenotyping or result in better treatment selection and stratified therapy. Here, we report the outcomes of the 6th Consensus Conference of the Atrial Fibrillation Network (AFNET) and the European Heart Rhythm Association (EHRA), held at the European Society of Cardiology Heart House in Sophia Antipolis, France, 17-19 January 2017. Sixty-two global specialists in AF and 13 industry partners met to develop innovative solutions based on new approaches to screening and diagnosis, enhancing integration of AF care, developing clinical pathways for treating complex patients, improving stroke prevention strategies, and better patient selection for heart rate and rhythm control. Ultimately, these approaches can lead to better outcomes for patients with AF.

A roadmap to improve the quality of atrial fibrillation management: proceedings from the fifth Atrial Fibrillation Network/European Heart Rhythm Association consensus conference.

At least 30 million people worldwide carry a diagnosis of atrial fibrillation (AF), and many more suffer from undiagnosed, subclinical, or 'silent' AF. Atrial fibrillation-related cardiovascular mortality and morbidity, including cardiovascular deaths, heart failure, stroke, and hospitalizations, remain unacceptably high, even when evidence-based therapies such as anticoagulation and rate control are used. Furthermore, it is still necessary to define how best to prevent AF, largely due to a lack of clinical measures that would allow identification of treatable causes of AF in any given patient. Hence, there are important unmet clinical and research needs in the evaluation and management of AF patients. The ensuing needs and opportunities for improving the quality of AF care were discussed during the fifth Atrial Fibrillation Network/European Heart Rhythm Association consensus conference in Nice, France, on 22 and 23 January 2015. Here, we report the outcome of this conference, with a focus on (i) learning from our 'neighbours' to improve AF care, (ii) patient-centred approaches to AF management, (iii) structured care of AF patients, (iv) improving the quality of AF treatment, and (v) personalization of AF management. This report ends with a list of priorities for research in AF patients.

Use of vitamin K antagonists for secondary stroke prevention depends on the treating healthcare provider in Germany - results from the German AFNET registry.

BACKGROUND: Anticoagulation using vitamin K antagonists (VKAs) significantly reduces the risk of recurrent stroke in stroke patients with atrial fibrillation (AF) and is recommended by guidelines. METHODS: The German Competence NETwork on Atrial Fibrillation established a nationwide prospective registry including 9,574 AF patients, providing the opportunity to analyse AF management according to German healthcare providers. RESULTS: On enrolment, 896 (9.4 %) patients reported a prior ischaemic stroke or transient ischaemic attack. Stroke patients were significantly older, more likely to be female, had a higher rate of cardiovascular risk factors, and more frequently received anticoagulation (almost exclusively VKA) than patients without prior stroke history. Following enrolment, 76.4 % of all stroke patients without VKA contraindications received anticoagulation, which inversely associated with age (OR 0.95 per year; 95 % CI 0.92-0.97). General practitioners/internists (OR 0.40; 95 % CI 0.21-0.77) and physicians working in regional hospitals (OR 0.47; 95 % CI 0.29-0.77) prescribed anticoagulation for secondary stroke prevention less frequently than physicians working at university hospitals (reference) and office-based cardiologists (OR 1.40; 95 % CI 0.76-2.60). The impact of the treating healthcare provider was less evident in registry patients without prior stroke. CONCLUSIONS: In the AFNET registry, anticoagulation for secondary stroke prevention was prescribed in roughly three-quarters of AF patients, a significantly higher rate than in primary prevention. We identified two factors associated with withholding oral anticoagulation in stroke survivors, namely higher age and-most prominently-treatment by a general practitioner/internist or physicians working at regional hospitals.

Morbidity and treatment in patients with atrial fibrillation and chronic kidney disease.

Chronic kidney disease (CKD) is associated with increased cardiovascular morbidity and mortality but there are few studies available about atrial fibrillation, the most frequent arrhythmia in CKD, and the applied treatment. Based on the prospective German Competence NETwork on Atrial Fibrillation, data of 3138 patients with atrial fibrillation were analyzed and categorized by their estimated glomerular filtration rate (stages 1-3 and 4 plus 5). With advanced CKD, significantly more patients suffered from a more severe form of atrial fibrillation. Despite significantly higher CHADS2 scores in advanced CKD, oral anticoagulation was not prescribed more frequently while antiarrhythmic drugs and catheter ablations were used significantly less often, in contrast to more pacemaker implantations. However, in multivariate hierarchical logistic regression analyses of in-hospital treatments and complications, only hemorrhages and pacemaker implantations turned out to be independently and significantly associated with higher CKD stages. This nationwide study shows that patients with CKD and atrial fibrillation suffer from a markedly higher comorbidity. Thus, while CKD patients have received cardioversions, ablations, antiarrhythmic, or anticoagulation drugs significantly less often in their history, current treatments were not different if adjusted for multiple comorbidities. This might indicate an improvement in the often reported therapeutic nihilism in CKD.

Personalized management of atrial fibrillation: Proceedings from the fourth Atrial Fibrillation competence NETwork/European Heart Rhythm Association consensus conference.

The management of atrial fibrillation (AF) has seen marked changes in past years, with the introduction of new oral anticoagulants, new antiarrhythmic drugs, and the emergence of catheter ablation as a common intervention for rhythm control. Furthermore, new technologies enhance our ability to detect AF. Most clinical management decisions in AF patients can be based on validated parameters that encompass type of presentation, clinical factors, electrocardiogram analysis, and cardiac imaging. Despite these advances, patients with AF are still at increased risk for death, stroke, heart failure, and hospitalizations. During the fourth Atrial Fibrillation competence NETwork/European Heart Rhythm Association (AFNET/EHRA) consensus conference, we identified the following opportunities to personalize management of AF in a better manner with a view to improve outcomes by integrating atrial morphology and damage, brain imaging, information on genetic predisposition, systemic or local inflammation, and markers for cardiac strain. Each of these promising avenues requires validation in the context of existing risk factors in patients. More importantly, a new taxonomy of AF may be needed based on the pathophysiological type of AF to allow personalized management of AF to come to full fruition. Continued translational research efforts are needed to personalize management of this prevalent disease in a better manner. All the efforts are expected to improve the management of patients with AF based on personalized therapy.

The Registry of the German Competence NETwork on Atrial Fibrillation: patient characteristics and initial management.

AIMS: The aim of this study was to describe the characteristics of patients with atrial fibrillation (AF) enrolled in the Central Registry of the German Competence NETwork on Atrial Fibrillation (AFNET) and to assess current medical practice in patients treated at various levels of medical care in Germany. METHODS AND RESULTS: From February 2004 to March 2006, 9582 ambulatory and hospitalized patients with ECG-documented AF were enrolled by 194 participating study centres from all levels of medical care in Germany. Clinical type of AF was reported as paroxysmal in 2893, persistent in 1873, and permanent in 3134 patients or classified as a first episode in 1035 patients. Predisposing conditions were common and present in 87.6% of the patients. Most patients were symptomatic with AF (75.1%). Rhythm control in persistent AF was provided to 53.4% of the symptomatic patients and to 47.8% of the patients without symptoms. Anticoagulation for stroke prevention was given to 71.4% of the patients considered eligible by applicable guidelines and to 48.4% of patients with low risk where guidelines do not recommend anticoagulation. CONCLUSION: This registry provides insight into current medical care of patients with AF in Germany. The use of oral anticoagulation in eligible patients was among the highest reported, whereas decisions on rate and rhythm control often do not follow current recommendations.

Regulation of IFN-gamma production by B effector 1 cells: essential roles for T-bet and the IFN-gamma receptor.

This manuscript systematically identifies the molecular mechanisms that regulate the ability of B cells to produce the critical type 1 cytokine, IFN-gamma. B cells produce IFN-gamma in response to IL-12 and IL-18 and when primed by Th1 cells. We show that development of IFN-gamma-producing B cells by either Th1 cells or IL-12/IL-18 is absolutely dependent on expression of the IFN-gammaR and the T-box transcription factor, T-bet. Interestingly, although T-bet up-regulation in developing B effector 1 (Be1) cells is controlled by IFN-gammaR-mediated signals, STAT1-deficient B cells up-regulate T-bet and produce IFN-gamma, indicating that additional transcriptional activators must be coupled to the IFN-gammaR in B cells. Finally, we show that although IL-12/IL-18 or IFN-gamma-producing Th1 cells are required to initiate transcription of the IFN-gamma gene in B cells, sustained expression of IFN-gamma and T-bet by B cells is dependent on an IFN-gamma/IFN-gammaR/T-bet autocrine feedback loop. These findings have significant implications, because they suggest that IFN-gamma-producing B cells not only amplify Th1 responses, but also imprint a type 1 phenotype on B cells themselves. In the case of immune responses to bacterial or viral pathogens, this B cell-driven autocrine feedback loop is likely to be beneficial; however, in the case of B cell responses to autoantigens, it may result in amplification of the autoimmune loop and increased pathology.

SH2D1A regulates T-dependent humoral autoimmunity.

The signaling lymphocytic activation molecule (SLAM)/CD150 family includes a family of chromosome 1-encoded cell surface molecules with costimulatory functions mediated in part by the adaptor protein SH2D1A (SLAM-associated protein, SAP). Deficiency in SH2D1A protects mice from an experimental model of lupus, including the development of hypergammaglobulinemia, autoantibodies including anti-double stranded DNA, and renal disease. This protection did not reflect grossly defective T or B cell function per se because SH2D1A-deficient mice were susceptible to experimental autoimmune encephalomyelitis, a T cell-dependent disease, and they were capable of mounting normal T-independent antigen-specific immunoglobulin responses. Instead, T-dependent antibody responses were impaired in SH2D1A-deficient mice, reflecting defective germinal center formation. These findings demonstrate a specific role for the SLAM-SH2D1A system in the regulation of T-dependent humoral immune responses, implicating members of the CD150-SH2D1A family as targets in the pathogenesis and therapy of antibody-mediated autoimmune and allergic diseases.

Active inhibition of plasma cell development in resting B cells by microphthalmia-associated transcription factor.

B cell terminal differentiation involves development into an antibody-secreting plasma cell, reflecting the concerted activation of proplasma cell transcriptional regulators, such as Blimp-1, IRF-4, and Xbp-1. Here, we show that the microphthalmia-associated transcription factor (Mitf) is highly expressed in naive B cells, where it antagonizes the process of terminal differentiation through the repression of IRF-4. Defective Mitf activity results in spontaneous B cell activation, antibody secretion, and autoantibody production. Conversely, ectopic Mitf expression suppresses the expression of IRF-4, the plasma cell marker CD138, and antibody secretion. Thus, Mitf regulates B cell homeostasis by suppressing the antibody-secreting fate.

An innate cell-mediated, murine ulcerative colitis-like syndrome in the absence of nuclear factor of activated T cells.

BACKGROUND & AIMS: Nuclear factor of activated T cells transcription factors plays a central role in immunity by regulating the expression of multiple cytokines and other regulatory molecules, many of which have been heavily implicated in the pathogenesis of inflammatory bowel disease. However, few studies have directly investigated the nuclear factor of activated T cells proteins in inflammatory bowel disease. We describe here a specific role for nuclear factor of activated T cells c2 in the pathogenesis of murine inflammatory bowel disease. METHODS: Mice deficient for nuclear factor of activated T cells c2, recombinase activating gene-2, or both and transgenic or nontransgenic for an anti-ovalbumin T-cell receptor or an anti-hen egg lysozyme B-cell receptor were studied. Adoptive transfers were performed of T or B cells or both from nuclear factor of activated T cells c2-deficient mice into nuclear factor of activated T cells c2-deficient recombinase activating gene-deficient animals, in the presence or absence of antibodies that neutralize interleukin-10 activity. RESULTS: Nuclear factor of activated T cells c2-deficient, recombinase activating gene-deficient animals spontaneously developed a severe inflammatory bowel syndrome that resembled ulcerative colitis but was composed entirely of nonlymphocytes. The disease was suppressed by the adoptive transfer of polyclonal B-cell populations, even on neutralization of interleukin-10, but not by the presence of monoclonal T or B cells. CONCLUSIONS: Nuclear factor of activated T cells plays a critical role in the regulation of bowel inflammation by nonlymphoid immune cells, and B cells suppress bowel inflammation by innate immune cells. Such findings indicate a novel, interleukin-10-independent role for nuclear factor of activated T cells in the regulation of innate immunity and in intestinal immune tolerance.

CpG DNA redirects class-switching towards "Th1-like" Ig isotype production via TLR9 and MyD88.

Unmethylated CpG-containing DNA plays a critical role in immunity via the augmentation of Th1 but suppression of Th2 T cell responses. We describe here that CpG motifs also redirect isotype production by murine B cells to "Th1-like" Ig isotypes (IgG2a, IgG2b, and IgG3) while suppressing Th2 isotypes (IgG1 and IgE). Using genetically mutant B cells, we find that the IgG2a, IgG2b and IgG3 isotypes are transcriptionally regulated via the promotion of class-switching, in a manner critically dependent upon TLR9 and MyD88. Thus, CpG DNA redirects Ig isotype production by regulating the specificity of class-switch recombination.

Susceptibility of mast cell-deficient W/Wv mice to pristane-induced experimental lupus nephritis.

In many models of organ-specific autoimmune diseases, mast cells provide a critical cellular link between autoantibodies and end-organ inflammation, both initiating and propagating disease. However, their role in systemic autoimmunity remains speculative. We therefore examined the role of mast cells in a murine model of systemic immune complex-related autoimmune disease, lupus nephritis, expecting to observe the development of humoral autoimmunity in the absence of end-organ disease. Surprisingly, not only did mast cell-deficient animals develop characteristic humoral features of lupus, including hypergammaglobulinemia and autoantibodies, they also developed immune complex glomerulonephritis, as evidenced by renal immune deposits, glomerular disease, and proteinuria. These findings implicate the presence of distinct effector pathways to end-organ damage in humoral autoimmune diseases: one involving the interaction between autoantibodies and mast cells to recruit inflammation in organ-specific autoimmunity, and another involving a more direct--mast cell-independent--interaction between autoantibodies and circulating inflammatory mediators in systemic autoimmunity.

Modulation of Th1 activation and inflammation by the NF-kappaB repressor Foxj1.

Forkhead transcription factors play key roles in the regulation of immune responses. Here, we identify a role for one member of this family, Foxj1, in the regulation of T cell activation and autoreactivity. Foxj1 deficiency resulted in multiorgan systemic inflammation, exaggerated Th1 cytokine production, and T cell proliferation in autologous mixed lymphocyte reactions. Foxj1 suppressed NF-kappaB transcription activity in vitro, and Foxj1-deficient T cells possessed increased NF-kappaB activity in vivo, correlating with the ability of Foxj1 to regulate IkappaB proteins, particularly IkappaBbeta. Thus, Foxj1 likely modulates inflammatory reactions and prevents autoimmunity by antagonizing proinflammatory transcriptional activities. These results suggest a potentially general role for forkhead genes in the enforcement of lymphocyte quiescence.

T-bet regulates T-independent IgG2a class switching.

The IgG2a Ig subclass plays a critical role in the pathogenesis of humoral autoimmunity and protection against pathogens. The T-box transcription factor T-bet has been implicated as a critical mediator of class-switch recombination (CSR) to IgG2a, but its relative importance to this process in various immune contexts remains incompletely defined. We report here that, surprisingly, T-bet is selectively required for IgG2a class switching in response to T-independent, but not T-dependent, stimuli. Specifically, T-dependent signaling through CD40, in contrast to T-independent signaling via lipopolysaccharide, can bypass a requirement for T-bet in IgG2a germline transcription and subsequent isotype switching. In contrast, T-bet-deficient B cells undergo class switching to other IgG isotypes at least as well as wild-type counterparts. Thus, T-bet is a class-specific regulator of IgG CSR and represents a unique regulator of B cell differentiation by participating in a T-independent, but not a T-dependent, activation pathway. T-bet-deficient B cells therefore represent a novel paradigm by which to investigate the regulation of humoral immune responses.

Transvenous defibrillation leads: high incidence of failure during long-term follow-up.

INTRODUCTION: Patients with implantable cardioverter defibrillators (ICD) critically depend on correct functioning of their system. The aim of this study was to determine the incidence and clinical presentation of transvenous ICD lead failures during long-term follow-up. METHODS AND RESULTS: The study group consisted of 261 consecutive patients who received Medtronic right ventricular polyurethane transvenous leads (models 6884, 6966, 6936) between 1990 and 1998 as part of an abdominal (n = 70) or pectoral (n = 191) ICD system. During mean follow-up of 4.0 +/- 2.6 years, 31 patients (12%) developed a lead-related sensing failure with oversensing of artifacts. All failures except two were compatible with an insulation defect and occurred late after ICD placement (6.0 +/- 1.8 years after implant). Lead survival decreased from 98% at 4-year follow-up to only 62% at 8-year follow-up. Lead survival was not related to patient age, sex, venous lead implantation route, or device implantation site. In 26 (87%) of 31 patients, a sensing defect resulted in inappropriate detection of ventricular fibrillation and subsequent delivery of 3 +/- 3 (range 1-11) inappropriate shocks in 19 (61%) of 31 patients. Device interrogation showed artifacts classified as nonsustained ventricular tachycardia in 21 patients, 40 +/- 43 days before clinically relevant failure of the system. One patient with a subclavian crush syndrome required resuscitation because of undersensing of true ventricular fibrillation. CONCLUSION: Transvenous polyurethane ICD leads showed a high rate of lead insulation failure late after implantation with frequent inappropriate shock deliveries. Close follow-up is mandatory in patients with these leads. Automated device control features with patient alert function integrated into new devices may contribute to early detection of lead failure.

Further analysis of the T-cell subsets and pathways of murine cardiac allograft rejection.

The present study examined the role of CD4+ and CD8+ T cells in cardiac allograft rejection when either the direct or indirect pathway was eliminated for the CD4+ portion of the response. To study the pathways in vivo, we used genetically altered mouse strains that lack class II antigens as either the donors or recipients for cardiac transplantation. In contrast to earlier published studies, which used different strain combinations, we found that either CD4- or CD8-depletion prolonged cardiac allograft survival moderately, but not indefinitely, in an MHC-mismatched, minor-matched combination. When the CD4+ indirect pathway was eliminated, rapid graft rejection occurred when both T-cell subsets were present and when either CD4+ or CD8+ T cells were depleted. When the CD4+ direct pathway was eliminated, rapid graft rejection occurred when both T-cell subsets were present, there was slow rejection when CD4+ T cells were eliminated, and no rejection was seen for more than 100 days when CD8+ T cells were eliminated. However, the long-surviving allografts on the recipients with only CD4+ cells and an indirect pathway did show evidence of chronic vasculopathy. Thus, either CD4+ or CD8+ T cells can mediate acute cardiac allograft rejection in these experiments when both pathways are available. In addition, CD4+ T cells can provide help for acute rejection through either the direct or indirect pathway. Finally, recipients who have only CD4+ cells and an indirect pathway do not demonstrate acute rejection, but do show evidence of chronic rejection.