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Abstract Background Sodium-glucose cotransporter 2 inhibitors (SGLT-2i) are glucose-lowering agents used for the treatment of type 2 diabetes mellitus, which also improve heart failure and decrease the risk of cardiovascular complications. Epicardial adipose tissue (EAT) dysfunction was suggested to contribute to the development of heart failure. We aimed to elucidate a possible role of changes in EAT metabolic and inflammatory profile in the beneficial cardioprotective effects of SGLT-2i in subjects with severe heart failure. Methods 26 subjects with severe heart failure, with reduced ejection fraction, treated with SGLT-2i versus 26 subjects without treatment, matched for age (54.0 ± 2.1 vs. 55.3 ± 2.1 years, n.s.), body mass index (27.8 ± 0.9 vs. 28.8 ± 1.0 kg/m2, n.s.) and left ventricular ejection fraction (20.7 ± 0.5 vs. 23.2 ± 1.7%, n.s.), who were scheduled for heart transplantation or mechanical support implantation, were included in the study. A complex metabolomic and gene expression analysis of EAT obtained during surgery was performed. Results SGLT-2i ameliorated inflammation, as evidenced by the improved gene expression profile of pro-inflammatory genes in adipose tissue and decreased infiltration of immune cells into EAT. Enrichment of ether lipids with oleic acid noted on metabolomic analysis suggests a reduced disposition to ferroptosis, potentially further contributing to decreased oxidative stress in EAT of SGLT-2i treated subjects. Conclusions Our results show decreased inflammation in EAT of patients with severe heart failure treated by SGLT-2i, as compared to patients with heart failure without this therapy. Modulation of EAT inflammatory and metabolic status could represent a novel mechanism behind SGLT-2i-associated cardioprotective effects in patients with heart failure.

Summary: The Par3 polarity protein is critical for subcellular compartmentalization in different developmental processes. Variants of PARD3, encoding PAR3, are associated with intelligence and neurodevelopmental disorders. However, the role of Par3 in glutamatergic synapse formation and cognitive functions in vivo remains unknown. Here, we show that forebrain-specific Par3 conditional knockout leads to increased long, thin dendritic spines in vivo. In addition, we observed a decrease in the amplitude of miniature excitatory postsynaptic currents. Surprisingly, loss of Par3 enhances hippocampal-dependent spatial learning and memory and repetitive behavior. Phosphoproteomic analysis revealed proteins regulating cytoskeletal dynamics are significantly dysregulated downstream of Par3. Mechanistically, we found Par3 deletion causes increased Rac1 activation and dysregulated microtubule dynamics through CAMSAP2. Together, our data reveal an unexpected role for Par3 as a molecular gatekeeper in regulating the pool of immature dendritic spines, a rate-limiting step of learning and memory, through modulating Rac1 activation and microtubule dynamics in vivo.

Abstract Aims Recipients of left ventricular assist devices (LVAD) are exposed to increased risk of adverse clinical events. One of the potential contributing factors is non‐pulsatile flow generated by LVAD. We evaluated the association of flow patterns in carotid arteries and of increased arterial stiffness with death and cerebrovascular events in LVAD recipients. Methods and results We analysed data from 83 patients [mean age 54 ± 15 years; 12 women; HeartMate II (HMII), n = 34; HeartMate 3 (HM3), n = 49]. Pulsatile and resistive indexes, atherosclerotic changes in carotid arteries (measured by duplex ultrasound), and arterial stiffness [measured by Endo‐PAT 2000 as the augmentation index standardized for heart rate (AI@75)] were evaluated 3 and 6 months after LVAD implantation. Sixteen patients died during follow‐up (27.3 months; interquartile range 15.7–44.3). After adjusting for the main variables examined, the pulsatility index measured at 3 months was positively associated with increased hazard ratios (HR) for death and cerebrovascular events [HR 9.8, 95% confidence interval (CI) 1.62–59.42], with HR increasing after adding AI@75 to the model (HR 18.8, 95% CI 2.44–145.50). In HM3 recipients, HR was significantly lower than in HMII recipients (HR 0.31, 95% CI 0.11–0.91), but the significance disappeared after adding AI@75 to the model (HR 0.33, 95% CI 0.09–1.18). Conclusions The risk of death and cerebrovascular events in LVAD recipients is associated with increased pulsatility index in carotid arteries and potentiated by increased arterial stiffness. The same risk is attenuated by HM3 LVAD implantation, but this effect is weakened by increased arterial stiffness.

Abstract Background Acute Stanford type A aortic dissection (TAAD) is a life-threatening condition. Surgery is usually performed as a salvage procedure and is associated with significant postoperative early mortality and morbidity. Understanding the patient’s conditions and treatment strategies which are associated with these adverse events is essential for an appropriate management of acute TAAD. Methods Nineteen centers of cardiac surgery from seven European countries have collaborated to create a multicentre observational registry (ERTAAD), which will enroll consecutive patients who underwent surgery for acute TAAD from January 2005 to March 2021. Analysis of the impact of patient’s comorbidities, conditions at referral, surgical strategies and perioperative treatment on the early and late adverse events will be performed. The investigators have developed a classification of the urgency of the procedure based on the severity of preoperative hemodynamic conditions and malperfusion secondary to acute TAAD. The primary clinical outcomes will be in-hospital mortality, late mortality and reoperations on the aorta. Secondary outcomes will be stroke, acute kidney injury, surgical site infection, reoperation for bleeding, blood transfusion and length of stay in the intensive care unit. Discussion The analysis of this multicentre registry will allow conclusive results on the prognostic importance of critical preoperative conditions and the value of different treatment strategies to reduce the risk of early adverse events after surgery for acute TAAD. This registry is expected to provide insights into the long-term durability of different strategies of surgical repair for TAAD. Trial registration ClinicalTrials.gov Identifier: NCT04831073 .

Aims: One of the proposed limitations of left ventricular assist device (LVAD) therapy is high degree of sensitization. Apart from human leukocyte antigen (HLA), antibodies against Angiotensin II Type 1 Receptor (AT1R) have been associated with adverse outcomes. The purpose of this study was to compare complications and survival of anti - AT1R positive versus negative Heart Mate II (HMII) recipients. Methods: Altogether 96 patients received HMII at our institution between 2008 and 2012. These were stratified into three groups: antibody positive before implantation (AT1R+), antibody conversion during support (AT1R-/+) and patients who remained antibody negative (AT1R-). Survival, major on-device adverse events and post-transplant rejections were assessed with Kaplan-Meier and log-rank tests. Results: Two year on-device and overall survival was 78 ± 12% and 75 ± 10% in AT1R-, 60 ± 23% and 60 ± 15% in AT1R+ and 92 ± 6% and 87 ± 5% in AT1R-/+ group (P = 0.409, P = 0.185). Freedom from major adverse event at two years for AT1R-, AT1R+ and AT1R-/+ was 49 ± 14%, 53 ± 16% and 41 ± 11% (P = 0.875). Freedom from rejection was 63 ± 17% in patients who were both anti-AT1R and HLA negative and 65 ± 13% in those who were antibody positive (P = 0.788). Conclusion: Patients who were anti-AT1R antibody positive had similar on-device survival and rate of complications in comparison to those who were antibody negative. In transplanted patients, there were no differences in the overall survival and rejection between the groups.

Aims. One of the proposed limitations of left ventricular assist device (LVAD) therapy is high degree of sensitization. Apart from human leukocyte antigen (HLA), antibodies against Angiotensin II Type 1 Receptor (AT1R) have been associated with adverse outcomes. The purpose of this study was to compare complications and survival of anti - AT1R positive versus negative Heart Mate II (HMII) recipients. Methods. Altogether 96 patients received HMII at our institution between 2008 and 2012. These were stratified into three groups: antibody positive before implantation (AT1R+), antibody conversion during support (AT1R-/+) and patients who remained antibody negative (AT1R-). Survival, major on-device adverse events and post-transplant rejections were assessed with Kaplan-Meier and log-rank tests. Results. Two year on-device and overall survival was 78 ± 12% and 75 ± 10% in AT1R-, 60 ± 23% and 60 ± 15% in AT1R+ and 92 ± 6% and 87 ± 5% in AT1R-/+ group (P = 0.409, P = 0.185). Freedom from major adverse event at two years for AT1R-, AT1R+ and AT1R-/+ was 49 ± 14%, 53 ± 16% and 41 ± 11% (P = 0.875). Freedom from rejection was 63 ± 17% in patients who were both anti-AT1R and HLA negative and 65 ± 13% in those who were antibody positive (P = 0.788). Conclusion. Patients who were anti-AT1R antibody positive had similar on-device survival and rate of complications in comparison to those who were antibody negative. In transplanted patients, there were no differences in the overall survival and rejection between the groups. [ABSTRACT FROM AUTHOR]