Background Guidelines provide extensive recommendations regarding implantable cardioverter‐defibrillator (ICD) implantation. However, ICD replacement at the time of battery depletion is rarely studied. Hypothesis Our objectives were to identify patients at high‐risk of death after ICD replacement, with a reassessment of changes in risk factors and comorbidities at the time of replacement, and to determine predictors for subsequent mortality. Methods Patients undergoing ICD replacement for regular battery depletion were selected from a prospective single‐center ICD registry. Both at implant and replacement, 3 demographic parameters, 9 cardiovascular parameters, 5 comorbidities, and 4 laboratory parameters were collected. Cox proportional hazard analyses were used. Results We included 308 patients who were predominantly male (86%) with a median age at ICD replacement of 66 years. Replacement was performed 65 months (interquartile range, 52–91) after implantation. Median follow‐up after replacement was 41 months, during which 82 patients (27%) died. Multivariable analysis revealed 4 independent predictors of mortality after ICD replacement: age/year (hazard ratio [HR]: 1.05, 95% confidence interval [CI]: 1.03‐1.08, P = 0.01), worsening heart failure by 1 class (HR: 1.53, 95% CI: 1.15‐2.03, P = 0.003), presence of left bundle branch block (HR: 1.98, 95% CI: 1.22‐3.23, P = 0.006), and ICD therapy prior to replacement (HR: 2.22, 95% CI: 1.37‐3.58, P = 0.001). Incorporated into a dichotomous score, they strongly correlated with mortality at 5 years after replacement (5% with 0 parameters, 15% with 1 parameter, and 30%–55% with >2 parameters). Conclusions Focused reassessment of selected patient characteristics at the time of ICD replacement correlates with subsequent mortality and can impact decision making at this point in time.

The pattern recognition receptor RIG I is essential for the recognition of viral dsRNA and the activation of a cell autonomous antiviral response. Upon stimulation, RIG I triggers a signaling cascade leading to the expression of cytokines, most prominently type I and III interferons (IFNs). IFNs are secreted and signal in an auto and paracrine manner to trigger the expression of a large variety of IFN stimulated genes, which in concert establish an antiviral state of the cell. While the topology of this pathway has been studied quite intensively, the dynamics, particularly of the RIG I mediated IFN induction, is much less understood. Here, we employed electroporation based transfection to synchronously activate the RIG I signaling pathway, enabling us to characterize the kinetics and dynamics of cell intrinsic innate immune signaling to virus infections. By employing an A549 IFNAR1/IFNLR deficient cell line, we could analyze the difference between the primary RIG I signaling phase and the secondary signaling phase downstream of the IFN receptors. We further used our quantitative data to set up and calibrate a comprehensive dynamic mathematical model of the RIG I and IFN signaling pathways. This model accurately predicts the kinetics of signaling events downstream of dsRNA recognition by RIG I as well as the feedback and signal amplification by secreted IFN and JAK/STAT signaling. We have furthermore investigated the impact of various viral immune antagonists on the signaling dynamics experimentally, and we utilized the here described modelling approach to simulate and in silico study these critical virus-host interactions. Our work provides a comprehensive insight into the signaling events occurring early upon virus infection and opens up new avenues to study and disentangle the complexity of the host-virus interface.

Properly responding to DNA damage is vital for eukaryotic cells, including the induction of DNA repair, growth arrest and, as a last resort to prevent neoplastic transformation, cell death. Besides being crucial for ensuring homeostasis, the same pathways and mechanisms are at the basis of chemoradiotherapy in cancer treatment, which involves therapeutic induction of DNA damage by chemical or physical (radiological) measures. Apart from typical DNA damage response mediators, the relevance of cell-intrinsic antiviral signaling pathways in response to DNA breaks has recently emerged. Originally known for combatting viruses via expression of antiviral factors including interferons (IFNs) and establishing of an antiviral state, retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) were found to be critical for adequate induction of cell death upon the introduction of DNA double-strand breaks. We here show that presence of IRF3 is crucial in this process, most likely through direct activation of pro-apoptotic factors rather than transcriptional induction of canonical downstream components, such as IFNs. Investigating genes reported to be involved in both DNA damage response and antiviral signaling, we demonstrate that IRF1 is an obligatory factor for DNA damage-induced cell death. Interestingly, its regulation does not require activation of RLR signaling, but rather sensing of DNA double strand breaks by ATM and ATR. Hence, even though independently regulated, both RLR signaling and IRF1 are essential for proper induction/execution of intrinsic apoptosis. Our results not only support more broadly developing IRF1 as a biomarker predictive for the effectiveness of chemoradiotherapy, but also suggest investigating a combined pharmacological stimulation of RLR and IRF1 signaling as a potential adjuvant regimen in tumor therapy.