Redo Thoracoabdominal Aortic Aneurysm Repair: A Single-Center Experience Over 25 Years.

BACKGROUND: Aortic disease is a lifelong, progressive illness that may require repeated intervention over time. We reviewed our 25-year experience with open redo thoracoabdominal aortic aneurysm (TAAA) and descending thoracic aortic aneurysm (DTAA) repair. Our objectives were to determine patient outcomes after redo repair of DTAA/TAAA and compare them with nonredo repair. We also attempted to identify the risk factors for poor outcome. METHODS: We reviewed all open redo TAAA and DTAA repairs between 1991 and 2014. Patient characteristics, preoperative, intraoperative variables, and postoperative outcomes were gathered. Data were analyzed by contingency table and by multiple logistic regression. RESULTS: We performed 1,900 open DTAA/TAAA repairs, with 266 (14%) being redos. Redos were associated with younger age (62 ± 16.4 years vs 64.5 ± 13.4 years, p < 0.02). Reasons for redo DTAA/TAAA were extension of the disease (86.8%), intercostal patch expansion (6.8%), visceral patch expansion (10.9%), infection (4.5%), anastomotic pseudoaneurysm (8.3%), and previous endovascular aortic repair complications (6.4%). Extent IV TAAA was predominantly involved in redos (42.8% redo vs 14.6% nonredo, p < 0.0001). The early mortality rate was significantly higher in redo (61 of 266 [23%]). Long-term survival was significantly lower among redo compared with nonredo DTAA/TAAAs. A multivariable analysis using the significant risk factors for early death from the risk factors on univariate analysis found four preoperative variables were significant (age >70 years, glomerular filtration rate <48 mL/min per 1.73m2, extent III TAAA, and emergency presentation) for predicting early death. In the presence of all four risk factors in a redo patient, a maximal risk of 82% for early death was predicted. CONCLUSIONS: The need for a redo operation in DTAA/TAAA repair is common and most often presents as an extension of the disease into an adjacent segment. A hybrid or completely endovascular treatment should be considered in high-risk patients.

Protein kinase Gin4 negatively regulates flippase function and controls plasma membrane asymmetry.

Plasma membrane function requires distinct leaflet lipid compositions. Two of the P-type ATPases (flippases) in yeast, Dnf1 and Dnf2, translocate aminoglycerophospholipids from the outer to the inner leaflet, stimulated via phosphorylation by cortically localized protein kinase Fpk1. By monitoring Fpk1 activity in vivo, we found that Fpk1 was hyperactive in cells lacking Gin4, a protein kinase previously implicated in septin collar assembly. Gin4 colocalized with Fpk1 at the cortical site of future bud emergence and phosphorylated Fpk1 at multiple sites, which we mapped. As judged by biochemical and phenotypic criteria, a mutant (Fpk1(11A)), in which 11 sites were mutated to Ala, was hyperactive, causing increased inward transport of phosphatidylethanolamine. Thus, Gin4 is a negative regulator of Fpk1 and therefore an indirect negative regulator of flippase function. Moreover, we found that decreasing flippase function rescued the growth deficiency of four different cytokinesis mutants, which suggests that the primary function of Gin4 is highly localized control of membrane lipid asymmetry and is necessary for optimal cytokinesis.

A protein kinase network regulates the function of aminophospholipid flippases.

Limited exposure of aminophospholipids on the outer leaflet of the plasma membrane is a fundamental feature of eukaryotic cells and is maintained by the action of inward-directed P-type ATPases ("flippases"). Yeast S. cerevisiae has five flippases (Dnf1, Dnf2, Dnf3, Drs2, and Neo1), but their regulation is poorly understood. Two paralogous plasma membrane-associated protein kinases, Pkh1 and Pkh2 (orthologs of mammalian PDK1), are required for viability of S. cerevisiae cells because they activate several essential downstream protein kinases by phosphorylating a critical Thr in their activation loops. Two such targets are related protein kinases Ypk1 and Ypk2 (orthologs of mammalian SGK1), which have been implicated in multiple processes, including endocytosis and coupling of membrane expansion to cell wall remodeling, but the downstream effector(s) of these kinases have been elusive. Here we show that a physiologically relevant substrate of Ypk1 is another protein kinase, Fpk1, a known flippase activator. We show that Ypk1 phosphorylates and thereby down-regulates Fpk1, and further that a complex sphingolipid counteracts the down-regulation of Fpk1 by Ypk1. Our findings delineate a unique regulatory mechanism for imposing a balance between sphingolipid content and aminophospholipid asymmetry in eukaryotic plasma membranes.