Left Atrial Volume Index Is Associated with Cardioembolic Stroke and Atrial Fibrillation Detection after Embolic Stroke of Undetermined Source

Background and Purpose-Left atrial enlargement has been shown to be associated with ischemic stroke, but the association with embolic stroke mechanisms remains unknown. We aim to study the associations between left atrial volume index (LAVI) and embolic stroke subtypes and atrial fibrillation (AF) detection on cardiac event monitoring in patients with embolic stroke of unknown source. Methods-Data were collected from a prospective cohort of consecutive patients with ischemic stroke admitted to a comprehensive stroke center over 18 months. Stroke subtype was classified into cardioembolic stroke, noncardioembolic stroke of determined mechanism (NCE), or embolic stroke of undetermined source (ESUS). Univariate and prespecified multivariable analyses were performed to assess associations between LAVI and stroke subtype and AF detection in patients with ESUS. Results-Of 1224 consecutive patients identified during the study period, 1020 (82.6%) underwent transthoracic echocardiography and had LAVI measurements. LAVI was greater in patients with cardioembolic stroke than NCE (41.4 mL/m2±18.0 versus 28.6 mL/m2±12.2; P<0.001) but not in ESUS versus NCE (28.9 mL/m2±12.6 versus 28.6 mL/m2±12.2; P=0.61). In multivariable logistic regression models, LAVI was greater in cardioembolic stroke versus NCE (adjusted odds ratio per mL/m2, 1.07; 95% CI, 1.05-1.09; P<0.001) but not in ESUS versus NCE (adjusted odds ratio per mL/m2, 1.00; 95% CI, 0.99-1.02; P=0.720). Among 99 patients with ESUS who underwent cardiac monitoring, 18.2% had AF detected; LAVI was independently associated with AF detection in ESUS (adjusted odds ratio per mL/m2, 1.09; 95% CI, 1.02-1.15; P=0.007). Conclusions-LAVI is associated with cardioembolic stroke as well as AF detection in patients with ESUS, 2 subsets of ischemic stroke that benefit from anticoagulation therapy. Patients with increased LAVI may be a subgroup where anticoagulation may be tested for stroke prevention. © 2019 American Heart Association, Inc

Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy.

Immunotherapy is revolutionizing cancer treatment but is often restricted by toxicities. What distinguishes adverse events from concomitant antitumor reactions is poorly understood. Here, using anti-CD40 treatment in mice as a model of T <sub>H</sub> 1-promoting immunotherapy, we showed that liver macrophages promoted local immune-related adverse events. Mechanistically, tissue-resident Kupffer cells mediated liver toxicity by sensing lymphocyte-derived IFN-γ and subsequently producing IL-12. Conversely, dendritic cells were dispensable for toxicity but drove tumor control. IL-12 and IFN-γ were not toxic themselves but prompted a neutrophil response that determined the severity of tissue damage. We observed activation of similar inflammatory pathways after anti-PD-1 and anti-CTLA-4 immunotherapies in mice and humans. These findings implicated macrophages and neutrophils as mediators and effectors of aberrant inflammation in T <sub>H</sub> 1-promoting immunotherapy, suggesting distinct mechanisms of toxicity and antitumor immunity