Post-procedural and long-term functional outcomes of jailed side branches in stented coronary bifurcation lesions assessed with side branch Murray law–based quantitative flow ratio

IntroductionIn coronary bifurcation lesions treated with percutaneous coronary intervention (PCI) using a 1-stent strategy, the occurrence of side branch (SB) compromise may lead to long-term myocardial ischemia in the SB territory. Murray law–based quantitative flow ratio (μQFR) is a novel angiography-based approach estimating fractional flow reserve from a single angiographic view, and thus is more feasible to assess SB compromise in routine practice. However, its association with long-term SB coronary blood flow remains unknown.MethodsA total of 146 patients with 313 non-left main bifurcation lesions receiving 1-stent strategy with drug-eluting stents was included in this retrospective study. These lesions had post-procedural Thrombolysis in Myocardial Infarction (TIMI) flow grade 3 in SBs, and documented angiographic images of index procedure and 6- to 24-month angiographic follow-up. Post-procedural SB μQFR was calculated. Long-term SB coronary blood flow was quantified with the TIMI grading system using angiograms acquired at angiographic follow-up.ResultsAt follow-up, 8 (2.6%), 16 (5.1%), 61 (19.5%), and 228 (72.8%) SBs had a TIMI flow grade of 0, 1, 2, and 3, respectively. The incidences of long-term SB TIMI flow grade ≤1 and ≤2 both tended to decrease across the tertiles of post-procedural SB μQFR. The receiver operating characteristic curve analyses indicated the post-procedural SB μQFR ≤0.77 was the optimal cut-off value to identify long-term SB TIMI flow grade ≤1 (specificity, 37.50%; sensitivity, 87.20%; area under the curve, 0.6673; P = 0.0064), and it was independently associated with 2.57-fold increased risk (adjusted OR, 2.57; 95% CI, 1.02–7.25; P = 0.045) in long-term SB TIMI flow grade ≤1 after adjustment.DiscussionPost-procedural SB μQFR was independently associated with increased risk in impaired SB TIMI flow at long-term follow-up. Further investigations should focus on whether PCI optimization based on μQFR may contribute to improve SB flow in the long term

Neutrophil Extracellular Traps Promote Inflammatory Responses in Psoriasis via Activating Epidermal TLR4/IL-36R Crosstalk

Epidermal infiltration of neutrophils is a hallmark of psoriasis, where their activation leads to release of neutrophil extracellular traps (NETs). The contribution of NETs to psoriasis pathogenesis has been unclear, but here we demonstrate that NETs drive inflammatory responses in skin through activation of epidermal TLR4/IL-36R crosstalk. This activation is dependent upon NETs formation and integrity, as targeting NETs with DNase I or CI-amidine in vivo improves disease in the imiquimod (IMQ)-induced psoriasis-like mouse model, decreasing IL-17A, lipocalin2 (LCN2), and IL-36G expression. Proinflammatory activity of NETs, and LCN2 induction, is dependent upon activation of TLR4/IL-36R crosstalk and MyD88/nuclear factor-kappa B (NF-κB) down-stream signaling, but independent of TLR7 or TLR9. Notably, both TLR4 inhibition and LCN2 neutralization alleviate psoriasis-like inflammation and NETs formation in both the IMQ model and K14-VEGF transgenic mice. In summary, these results outline the mechanisms for the proinflammatory activity of NETs in skin and identify NETs/TLR4 as novel therapeutic targets in psoriasis

CREB1-driven CXCR4hi neutrophils promote skin inflammation in mouse models and human patients

Abstract Neutrophils have a pathogenic function in inflammation via releasing pro-inflammatory mediators or neutrophil extracellular traps (NETs). However, their heterogeneity and pro-inflammatory mechanisms remain unclear. Here, we demonstrate that CXCR4hi neutrophils accumulate in the blood and inflamed skin in human psoriasis, and correlate with disease severity. Compared to CXCR4lo neutrophils, CXCR4hi neutrophils have enhanced NETs formation, phagocytic function, neutrophil degranulation, and overexpression of pro-inflammatory cytokines and chemokines in vitro. This is accompanied by a metabolic shift in CXCR4hi neutrophils toward glycolysis and lactate release, thereby promoting vascular permeability and remodeling. CXCR4 expression in neutrophils is dependent on CREB1, a transcription factor activated by TNF and CXCL12, and regulated by de novo synthesis. In vivo, CXCR4hi neutrophil infiltration amplifies skin inflammation, whereas blockade of CXCR4hi neutrophils through CXCR4 or CXCL12 inhibition leads to suppression of immune responses. In this work, our study identifies CREB1 as a critical regulator of CXCR4hi neutrophil development and characterizes the contribution of CXCR4hi neutrophils to vascular remodeling and inflammatory responses in skin

Antagonism between ambient ozone increase and urbanization-oriented population migration on Chinese cardiopulmonary mortality

Ever-increasing ambient ozone (O3) pollution in China has been exacerbating cardiopulmonary premature deaths. However, the urban-rural exposure inequity has seldom been explored. Here, we assess population-scale O3 exposure and mortality burdens between 1990 and 2019 based on integrated pollution tracking and epidemiological evidence. We find Chinese population have been suffering from climbing O3 exposure by 4.3 ± 2.8 ppb per decade as a result of rapid urbanization and growing prosperity of socioeconomic activities. Rural residents are broadly exposed to 9.8 ± 4.1 ppb higher ambient O3 than the adjacent urban citizens, and thus urbanization-oriented migration compromises the exposure-associated mortality on total population. Cardiopulmonary excess premature deaths attributable to long-term O3 exposure, 373,500 (95% uncertainty interval [UI]: 240,600–510,900) in 2019, is underestimated in previous studies due to ignorance of cardiovascular causes. Future O3 pollution policy should focus more on rural population who are facing an aggravating threat of mortality risks to ameliorate environmental health injustice