The human inflammatory caspases, including caspase-1, -4, -5 and -12, are considered as key regulators of innate immunity protecting from sepsis and numerous inflammatory diseases. Caspase-1 is activated by proximity-induced dimerization following recruitment to inflammasomes but the roles of the remaining inflammatory caspases in inflammasome assembly are unclear. Here, we use caspase bimolecular fluorescence complementation to visualize the assembly of inflammasomes and dimerization of inflammatory caspases in single cells. We observed caspase-1 dimerization induced by the coexpression of a range of inflammasome proteins and by lipospolysaccharide (LPS) treatment in primary macrophages. Caspase-4 and -5 were only dimerized by select inflammasome proteins, whereas caspase-12 dimerization was not detected by any investigated treatment. Strikingly, we determined that certain inflammasome proteins could induce heterodimerization of caspase-1 with caspase-4 or -5. Caspase-5 homodimerization and caspase-1/-5 heterodimerization was also detected in LPS-primed primary macrophages in response to cholera toxin subunit B. The subcellular localization and organization of the inflammasome complexes varied markedly depending on the upstream trigger and on which caspase or combination of caspases were recruited. Three-dimensional imaging of the ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain)/caspase-1 complexes revealed a large spherical complex of ASC with caspase-1 dimerized on the outer surface. In contrast, NALP1 (NACHT leucine-rich repeat protein 1)/caspase-1 complexes formed large filamentous structures. These results argue that caspase-1, -4 or -5 can be recruited to inflammasomes under specific circumstances, often leading to distinctly organized and localized complexes that may impact the functions of these proteases.
Transcatheter aortic valve replacement (TAVR) has developed substantially since its inception. Improvements in valve design, valve deployment technologies, preprocedural imaging and increased operator experience have led to a gradual decline in length of hospitalisation after TAVR. Despite these advances, the need for permanent pacemaker implantation for post-TAVR high-degree atrioventricular block (HAVB) has persisted and has well-established risk factors which can be used to identify patients who are at high risk and advise them accordingly. While most HAVB occurs within 48 hours of the procedure, there is a growing number of patients developing HAVB after initial hospitalisation for TAVR due to the trend for early discharge from hospital. Several observation and management strategies have been proposed. This article reviews major known risk factors for HAVB after TAVR, discusses trends in the timing of HAVB after TAVR and reviews some management strategies for observing transient HAVB after TAVR.
Objectives
To identify associations with either early or late permanent pacemaker (PPM) implantation after transcatheter aortic valve replacement (TAVR) in order to develop an easily interpretable management algorithm.
Background
Injury to the conduction system after TAVR occasionally requires PPM. There is limited data on how to identify which patients will require PPM, particularly after discharge from index hospitalization after TAVR.
Methods
All patients having undergone TAVR at the University of North Carolina through August 2019 were identified and records were manually reviewed. Multivariable analyses were performed to identify associations with post‐TAVR PPM due to high‐degree atrioventricular block (HAVB). Comparisons were made between patients with no PPM (n = 304) and PPM required, stratified into early (during index hospitalization, n = 32) and late (during subsequent hospitalization, n = 11) PPM cohorts.
Results
Of the 347 patents included for analysis, 43 (12.4%) underwent post‐TAVR PPM. In multivariable regression models, early PPM was associated with baseline bifascicular block (OR: 42.16; p < .001), requiring any pacing on first post‐TAVR electrocardiogram (ECG) (OR: 31.55; p < .001), and valve oversizing >15% (OR: 3.61; p < .05). Late PPM was associated with baseline right bundle branch block (RBBB) (OR 12.62; p < .001) and history of atrial fibrillation/flutter (OR 4.83; p < .05).
Conclusions
Bifascicular block, any pacing on first post‐TAVR ECG, and >15% valve oversizing are associated with early PPM, while RBBB and history of atrial fibrillation/flutter are associated with late PPM. We suggest a management strategy for post‐TAVR surveillance and management of HAVB.
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