Antiproteinase 3 Positive Eosinophilic Granulomatosis with Polyangiitis Presenting with Heart Failure and Intraventricular Thrombosis

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare systemic vasculitis commonly with cardiac complications. We describe a case of anti-PR3 ANCA-positive EGPA complicated by congestive heart failure and intraventricular thrombosis. Interestingly, the thrombus was resolved rapidly with steroid and cyclophosphamide in the setting of interrupted anticoagulation. To the best of our knowledge, we report the first case of anti-PR3 positive EGPA with extensive cardiac involvement. Our patient had overlapping features with previously studied ANCA-positive and ANCA-negative EGPA cases. We also hypothesize that the thrombogenic potential of eosinophils may play a central role in thrombogenesis in EGPA and aggressive immunosuppressive therapy remains the cornerstone of treatment, and the addition of anticoagulation therapy in the setting of thrombus formation and also very high risk of bleeding needs to be considered cautiously

脂肪酸β‐氧化和线粒体融合参与胰高血糖素受体拮抗剂对糖尿病小鼠心脏微血管内皮细胞的保护作用

Abstract Introduction The role of cardiac microvascular endothelial cells (CMECs) in diabetic cardiomyopathy is not fully understood. We aimed to investigate whether a glucagon receptor (GCGR) monoclonal antibody (mAb) ameliorated diabetic cardiomyopathy and clarify whether and how CMECs participated in the process. Research Design and Methods The db/db mice were treated with GCGR mAb or immunoglobulin G (as control) for 4 weeks. Echocardiography was performed to evaluate cardiac function. Immunofluorescent staining was used to determine microvascular density. The proteomic signature in isolated primary CMECs was analyzed by using tandem mass tag‐based quantitative proteomic analysis. Some target proteins were verified by using western blot. Results Compared with db/m mice, cardiac microvascular density and left ventricular diastolic function were significantly reduced in db/db mice, and this reduction was attenuated by GCGR mAb treatment. A total of 199 differentially expressed proteins were upregulated in db/db mice versus db/m mice and downregulated in GCGR mAb‐treated db/db mice versus db/db mice. The enrichment analysis demonstrated that fatty acid β‐oxidation and mitochondrial fusion were the key pathways. The changes of the related proteins carnitine palmitoyltransferase 1B, optic atrophy type 1, and mitofusin‐1 were further verified by using western blot. The levels of these three proteins were upregulated in db/db mice, whereas this upregulation was attenuated by GCGR mAb treatment. Conclusion GCGR antagonism has a protective effect on CMECs and cardiac diastolic function in diabetic mice, and this beneficial effect may be mediated via inhibiting fatty acid β‐oxidation and mitochondrial fusion in CMECs

Trilateral π-conjugation extensions of phenothiazine-based dyes enhance the photovoltaic performance of the dye-sensitized solar cells

Two novel organic dyes TLEP-1 and TLEP-2 based on phenothiazine with trilateral π-conjugation extensions were designed and synthesized for dye-sensitized solar cells, where phenothiazine ring was linked with two phenyl moieties at 7- and 10-positions as the first and second π-conjugation extensions, and with furan or thiophene ring at 3-position as the third π-conjugation extension for TLEP-1 and TLEP-2, respectively. The influence of the π-conjugation extensions on the photovoltaic performance was evaluated. The cell based on TLEP-2 exhibits an impressive short-circuit photocurrent density of 14.87 mA cm-2, which is much higher than the cell based on the reference dye without π-conjugation extension (9.01 mA cm-2), leading to high power conversion efficiency of 7.33% under simulated AM 1.5 G illumination condition. The results indicate that the trilateral π-conjugation extensions are an effective way to improve the photovoltaic performance of the dye-sensitized solar cells

Evidence for a role of immunoproteasomes in regulating cardiac muscle mass in diabetic mice

The ubiquitin-proteasome system plays an important role in regulating muscle mass. Inducible immunoproteasome subunits LMP-2 and LMP-7 are constitutively expressed in the heart; however, their regulation and functions are poorly understood. We here investigated the hypothesis that immunoproteasomes regulate cardiac muscle mass in diabetic mice. Type 1 diabetes was induced in wildtype mice by streptozotocin. After hyperglycemia developed, insulin and the proteasome inhibitor epoxomicin were used to treat diabetic mice for 6. weeks. Isolated mouse hearts were perfused with control or high glucose solution. Catalytic proteasome β-subunits and proteolytic activities were analyzed in the heart by immunoblotting and fluorogenic peptide degradation assays, respectively. Insulin and epoxomicin blocked loss of heart weight and improved cardiac function in diabetic mice. LMP-7 and its corresponding chymotryptic-like proteasome activity were increased in diabetic hearts and high glucose-treated hearts. Myosin heavy chain protein was decreased in diabetic hearts, which was largely reversed by epoxomicin. High glucose decreased LMP-2 protein levels in perfused hearts. In diabetic hearts, LMP-2 expression was downregulated whereas expression of the phosphatase and tensin homologue deleted on chromosome ten (PTEN) and the muscle atrophy F-box were upregulated. Moreover, mice with muscle-specific knockout of PTEN gene demonstrated increased cardiac muscle mass, while mice with LMP-2 deficiency demonstrated PTEN accumulation, muscle mass loss, and contractile impairment in the heart. Therefore, we concluded that high glucose regulates immunoproteasome subunits and modifies proteasome activities in the heart, and that dysregulated immunoproteasome subunits may mediate loss of cardiac muscle mass in experimental diabetic mice.11 page(s

Myeloperoxidase-oxidized high density lipoprotein impairs atherosclerotic plaque stability by inhibiting smooth muscle cell migration

Abstract Background High density lipoprotein (HDL) has been proved to be a protective factor for coronary heart disease. Notably, HDL in atherosclerotic plaques can be nitrated (NO2-oxHDL) and chlorinated (Cl-oxHDL) by myeloperoxidase (MPO), likely compromising its cardiovascular protective effects. Method Here we determined the effects of NO2-oxHDL and Cl-oxHDL on SMC migration using wound healing and transwell assays, proliferation using MTT and BrdU assays, and apoptosis using Annexin-V assay in vitro, as well as on atherosclerotic plaque stability in vivo using a coratid artery collar implantation mice model. Results Our results showed that native HDL promoted SMC proliferation and migration, whereas NO2-oxHDL and Cl-oxHDL inhibited SMC migration and reduced capacity of stimulating SMC proliferation as well as migration, respectively. OxHDL had no significant influence on SMC apoptosis. In addition, we found that ERK1/2-phosphorylation was significantly lower when SMCs were incubated with NO2-oxHDL and Cl-oxHDL. Furthermore, transwell experiments showed that differences between native HDL, NO2-oxHDL and Cl-oxHDL was abolished after PD98059 (MAPK kinase inhibitor) treatment. In aortic SMCs from scavenger receptor BI (SR-BI) deficient mice, differences between migration of native HDL, NO2-oxHDL and Cl-oxHDL treated SMCs vanished, indicating SR-BI’s possible role in HDL-associated SMC migration. Importantly, NO2-oxHDL and Cl-oxHDL induced neointima formation and reduced SMC positive staining cells in atherosclerotic plaque, resulting in elevated vulnerable index of atherosclerotic plaque. Conclusion These findings implicate MPO-catalyzed oxidization of HDL may contribute to atherosclerotic plaque instability by inhibiting SMC proliferation and migration through MAPK-ERK pathway which was dependent on SR-BI

Peri‐operative Takotsubo syndrome after non‐cardiac surgery: a retrospective nested case–control study

Abstract Aims Takotsubo syndrome (TTS) is an acute reversible cardiac dysfunction that may occur during the peri‐operative period and among patients with serious illness. We aimed to evaluate the clinical characteristics, peri‐operative management, and prognosis of peri‐operative TTS (pTTS) and explore the factors associated with pTTS. Methods We conducted a retrospective nested case–control study using the database of patients who underwent in‐hospital non‐cardiac surgeries between January 2017 and December 2020 in Peking University Third hospital. Cases were adult patients diagnosed TTS at discharge who were matched with four controls based on operative types. Multivariable conditional logistic regression was used to identified the factors associated with pTTS. The area under the curve (AUC) was used to evaluate the diagnostic efficacy. Results Among the 128 536 patients underwent non‐cardiac surgery, 20 patients with pTTS and 80 patients without were enrolled in this study. The incidence of pTTS was about 0.016% in our centre. The median age of patients with pTTS was 52.5 (38.25, 76.25) years, although 90% of them were female. Fifty per cent (9 cases) of female patients were pre‐menopausal. Caesarean section has the highest proportion of pTTS (30% of the pTTS cases) with the incidence of caesarean section‐related pTTS of 0.06% in our centre. A high prevalence of non‐apical ballooning pattern of regional wall motion abnormality (seven cases, 35%) and a high mortality (two cases, 10%) were observed. Left ventricular ejection fraction (LVEF) of patients with pTTS was significantly decreased (41.7 ± 8.8%). In the acute phase, supportive treatments aiming to reduce life‐threatening complications were main treatment strategies. After receiving systematic treatment, significant improvements were observed in LVEF (63.1 ± 13.5%), with median recovery time of LVEF of 7.48 days. Leucocyte count [odds ratio (OR): 4.59; 95% confidence interval (CI): 1.10–19.15], haemoglobin (HGB) (OR: 10.52; 95% CI: 1.04–106.36), and the revised cardiac risk index (RCRI) score (OR: 6.30; 95% CI: 1.05–37.88) were the factors significantly associated with pTTS. The RCRI score performed poorly in the prediction of pTTS (AUC: 0.630; 95% CI: 0.525–0.735). After adding leucocyte count and HGB into the RCRI score, the AUC was significantly improved (AUC: 0.768; 95% CI: 0.671–0.865; P = 0.001). Conclusions Patients with pTTS have some differences compared with common TTS, including higher proportion of pre‐menopausal female, higher prevalence during caesarean section, higher prevalence of non‐apical ballooning pattern of regional wall motion abnormality, and higher mortality. The RCRI score performed poorly in the evaluation of pTTS. Adding HGB and leucocyte count into the RCRI score could significantly improve its predictive performance