Extracellular ATP induces P2X7 receptor activation in mouse Kupffer cells, leading to release of IL-1ß, HMGB1, and PGE2, decreased MHC class I expression and necrotic cell death.

Kupffer cells, which are resident macrophages in liver, can produce various cytokines and chemokines that induce hepatitis and liver fibrosis. It is suggested that extracellular ATP-induced activation of macrophage P2X7 receptor plays an important role in inflammation via release of pro-inflammatory mediators, but the role of P2X7 receptor in Kupffer cells remains unclear. Here, we show that activation of P2X7 receptor in Kupffer cells causes multiple inflammatory responses, using the clonal mouse Kupffer cell line (KUP5) that we previously established. Treatment of LPS-primed Kupffer cells with 3 mM ATP induced Ca(2+) influx, non-selective large pore formation, activation of MAPK, cell lysis, IL-1ß release, prostaglandin E2 (PGE2) release, high mobility group box1 (HMGB1) release, and major histocompatibility complex (MHC) class I shedding. These events were significantly suppressed by pretreatment with P2X7 antagonist A438079, indicating involvement of P2X7 receptor activation in these inflammatory responses. Our results suggest that extracellular ATP-induced activation of P2X7 receptor of Kupffer cells plays multiple roles in the inflammatory response in liver. P2X7 receptor might be a new therapeutic target for treatment of liver diseases.

Transcatheter aortic valve replacement in patients with severe aortic stenosis reduced the frequency of intradialytic hypotension.

Intradialytic hypotension (IDH) is a common complication during hemodialysis that increases cardiovascular morbidity and mortality. Aortic stenosis (AS) is a cause of IDH. Transcatheter aortic valve replacement (TAVR) has become an established treatment for patients with severe AS. However, whether TAVR reduce the frequency of IDH has not been investigated. This study aims to verify the efficacy of TAVR for reduction of the frequency of IDH. Consecutive hemodialysis patients who underwent TAVR at Sendai Kosei Hospital from February 2021 to November 2021 with available records 1 month before and 3 months after TAVR were included in the study. IDH was defined as a decrease in systolic blood pressure by 20 mmHg or a decrease in the mean blood pressure by 10 mmHg associated with hypotensive symptoms or requiring intervention. Patients with ≥ 3 episodes of IDH in ten hemodialysis sessions comprised the IDH group. Overall, 18/41 (43.9%) patients were classified into the IDH group. In ten hemodialysis sessions, IDH events were observed 2.1, 4.3, and 0.4 times in the overall cohort, IDH group, and non-IDH group, respectively. After TAVR, the incidence of IDH decreased from 43.2 to 10.3% (p < 0.0001) and IDH improved significantly in 15 patients in the IDH group. The result suggested that severe AS was the major cause of IDH in this cohort, and TAVR may be an effective treatment option for reduction of the frequency of IDH in patients with severe AS.

Detection of left coronary ostial obstruction during transcatheter aortic valve replacement by coronary flow velocity measurement in the left main trunk by intraoperative transesophageal echocardiography.

BACKGROUND: Coronary obstruction is a rare but catastrophic complication of transcatheter aortic valve replacement (TAVR) and occurs mostly at the left coronary artery (LCA) ostium. However, some patients do not show any clinical findings, and thus, its detection is sometimes difficult. The peak diastolic flow velocity in left main coronary artery (LM) was reportedly increased in significant stenosis lesions. We evaluated the effectiveness of measuring blood flow velocities in LM by transesophageal echocardiography (TEE) for the detection of LCA ostial obstruction during a TAVR procedure. METHODS: A total of 1105 consecutive patients who underwent TAVR in Sendai Kousei Hospital between September 2014 and December 2020 were enrolled. The LM blood flow velocity was measured at pre- and post-valve implantation. RESULTS: Among the 1105 patients, 9 had LCA ostial obstruction. The peak LM blood flow velocity at post-TAVR [0.90 (0.39-1.15) vs. 0.37 (0.28-0.50) m/s; p = 0.0046) was significantly higher in 9 patients who had LCA ostial obstruction, compared with the remaining 1096 patients who had not (controls), although no significant difference was observed before the TAVR procedures between the two groups. The post- to pre-TAVR LM flow velocity ratio [2.26 (1.31-3.42) vs. 1.06 (0.82-1.36); p = 0.0030] was also significantly higher in patients with LCA obstruction, compared to the controls. Furthermore, the post- to pre-TAVR LM blood flow velocity ratio was >2.0 in all six hemodynamically stable patients with LCA obstruction, whereas <2.0 in all three patients with LCA obstruction who showed hemodynamic collapse at post-TAVR procedure. CONCLUSION: Coronary blood flow velocity in LM significantly increased in hemodynamically stable LCA obstruction patients. The intraprocedural TEE measurement of the LM flow velocities would be potentially useful to detect asymptomatic and hemodynamically stable LCA ostial obstruction.

Delivery balloon volume positively correlates with the diameter and effective orifice area of implanted SAPIEN 3.

BACKGROUND: In transcatheter aortic valve replacement (TAVR) using SAPIEN 3 (S3) (Edwards Lifesciences, Irvine, CA, USA), some clinicians decrease or increase the delivery balloon volume (VOL) when deploying S3 or conducting post-dilatation. However, the effects of controlling VOL on transcatheter heart valve diameter (THVD) and valve function remain unclear. We assessed associations among VOL, THVD, and effective orifice area (EOA) of S3. METHODS: We enrolled patients undergoing TAVR using 23- and 26-mm S3 in Sendai Kousei Hospital between 2017 and 2019. VOL was controlled based on preprocedural computed tomography and intraprocedural transesophageal echocardiography (TEE). THVD were defined as the diameters of transcatheter heart valve at mid-level measured by TEE. RESULTS: In enrolled 332 patients (23-mm, n = 188; 26-mm, n = 144), one (0.3%) and two (0.6%) developed annulus rupture and moderate/severe paravalvular leak, respectively. VOL at deployment was positively correlated with THVD on deployment (23-mm, r = 0.44, p < 0.001; 26-mm, r = 0.57, p < 0.001) and EOA (23-mm, r = 0.23, p = 0.0019; 26-mm, r = 0.22, p = 0.0094). In multiple regression analyses, VOL and post-dilatation were significant determinants of THVD, although aortic annulus area, calcium volume, and pre-dilatation were not. The areas under the receiver operating characteristic curve that were used to evaluate the accuracy of the index obtained by dividing THVD by body surface area (indexed THVD) to predict patient-prosthesis mismatch (PPM) were 0.744 and 0.811 in the 23- and 26-mm cohorts, respectively. A cut-off indexed THVD of ≤11.5 and 12.1 mm/m2 well predicted PPM (23-mm, odds ratio, 5.20; 95% confidence interval, 1.33-20.3; 26-mm, odds ratio 14.1, 95% confidence interval 2.40-81.0). CONCLUSION: VOL was positively correlated with THVD and EOA. Smaller indexed THVD was associated with a higher incidence of PPM. Controlling VOL under on-site THVD evaluation may be useful in reducing the PPM incidence.