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Background Despite major advances, transcatheter aortic valve replacement (TAVR) is associated with procedure-related vascular and bleeding complications, that have a significant impact on mortality. A recently published study has shown that heparin antagonization using protamine resulted in significantly lower rates of serious bleeding events in patients undergoing TAVR as compared to those without heparin reversal. However, the optimal protamine-to-heparin dosing ratio to prevent bleeding complications without increasing ischemic complications in patients undergoing TAVR is unknown. Accordingly, daily clinical practice varies between selective to routine administration of protamine in different dosing ratios. Purpose The aim of this observational multicentre study was to compare the safety and efficacy of two different protamine-to-heparin dosing ratios for the prevention of bleeding complications after TAVR. Methods The study included 1446 patients undergoing TAVR, of whom 623 (43.1%) received partial and 823 (56.9%) full heparin antagonization (0.4–0.6 mg versus 0.9–1.0 mg protamine/100 units of heparin). The indication for partial or full heparin antagonization was left to the discretion of the operator, who made the decision according to the patient's individual thrombotic and bleeding risk. The primary endpoint was a composite of 30-day mortality, life-threatening and major bleeding. Safety endpoints included stroke and myocardial infarction at 30 days. Results The overall study population had a mean age of 81.1±6.0 years; 47.9% were of female gender. The baseline characteristics were well balanced between the two groups. Full antagonization of heparin resulted in significantly lower rates of the primary endpoint as compared to partial heparin reversal (5.6 vs. 10.4%, p<0.01), mainly driven by lower rates of life-threatening (0.5 vs 1.6%, p=0.05) and major bleeding (3.2 vs 7.5%, p<0.01). The incidence of major vascular complications was significantly lower in patients with full heparin reversal (3.5 vs 7.5%, p<0.01), as presented in Figure 1. Accordingly, the post-interventional drop in hemoglobin level and the need for red-blood-cell transfusion was lower in patients receiving full as compared to partial heparin reversal (1.5±1.2 vs 1.7±1.2 g/dl, p<0.01; 10.4 vs 15.9%, p<0.01, respectively). Regarding safety endpoints, no differences were observed in the incidence of stroke and myocardial infarction between the groups (2.2 vs 2.6%, p=0.73 and 0.2 vs 0.4%, p=0.64, respectively). Multivariate regression analyses revealed that full antagonization of heparin (OR: 0.43 [95% CI: 0.24–0.81], p<0.01) was independently associated with the primary end point Conclusion Full heparin antagonization resulted in significantly lower rates of life-threatening and major bleeding after TAVR as compared to partial heparin reversal. The occurrence of stroke and myocardial infarction was low and comparable between both groups. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation).
Background Proliferation and phenotypic modulation of vascular smooth muscle cells (SMCs) significantly contribute to the functionality of the aortic wall. Dysregulation of underlying signal transduction pathways impairs the vessel wall structure and promote the development and progression of abdominal aortic aneurysms (AAA). The PI 3-kinase (PI3K) isoform p110α is activated downstream of receptor tyrosine kinases (RTKs) and represents the most relevant PI3K isoform in SMCs. Aim This project follows the hypothesis that p110α deficiency impairs proliferation and phenotypic modulation of SMCs as well as the structure of the extracellular matrix (ECM) and therefore promotes the development and progression of AAA. It was investigated how p110α deficiency affects the plasticity of SMCs, the production and structure of ECM components, and the formation of AAA. Methods and results Western blot analyses showed that SMCs isolated from smooth muscle specific p110α−/− (sm-p110α−/−) mice were characterized by decreased expression of the differentiation markers sm-α-actin, calponin and sm-MHC. Mechanistically, phosphorylation of key modulators of the SMC phenotype – AKT1, AKT2, FOXO1, -3 and -4 as well as GSK3β – was impaired in p110α−/− SMCs after RTK stimulation. These findings indicate that phenotypic modulation of p110α−/− SMCs is restricted. In addition, protein expression of elastin and fibrillin was reduced in p110α−/− SMCs. In silico analysis (MatLab macro CT-FIRE and Curvalign) of the ECM produced by SMCs in vitro revealed a significantly reduced elastin fiber length and width in p110α−/− SMCs compared to fibers produced by WT SMCs (p<0.05). Consistently, aortas from sm-p110α−/− mice showed a significantly higher number of elastic fiber breaks specifically in the thoracic section than WT controls (289±31 mmm–2 versus 190±9 mmm–2, n=5, p=0.015). Aortic aneurysms in sm-p110α−/− mice and wild-type littermates were analyzed using the established porcine pancreatic elastase (PPE) model. PPE was perfused into the infrarenal aorta to induce AAA formation. Ultrasound examination of the aorta revealed an enlarged aortic diameter in all PPE-treated mice. However, the increase in aortic diameter in sm-p110α−/− mice (70.16±10.82% mm, n=9) was significant more pronounced compared to wild-type animals (42.44±5.99%, n=10) (p<0.05). Three days after PPE perfusion, the number of elastic fiber breaks was significantly increased, and amount of proliferating SMCs were decreased in the infrarenal aorta of sm-p110α−/− mice compared to WT controls. Conclusion p110α deficiency in SMCs impairs aortic wall structure and promotes the development and progression of aortic aneurysms. Mechanistically, p110α activity maintains a differentiated SMC phenotype as well as the expression and assembly of ECM components. These data identify p110α signaling as a modifiable target for preventive and therapeutic strategies for aortic aneurysms. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Deutsche Forschungsgemeinschaft
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