Midterm outcomes and durability of sinus segment preservation compared with root replacement for acute type A aortic dissection.

OBJECTIVE: The durability of root repair for acute type A aortic dissection is not well studied in the context of aortic insufficiency and stability of the sinuses of Valsalva. We compared clinical and functional outcomes in patients undergoing root repair and replacement for acute type A aortic dissection. METHODS: Of 716 patients undergoing surgery for acute type A aortic dissection, 585 (81.7%) underwent root repair and 131 (18.3%) underwent root replacement. Survival, cumulative incidence of reoperation, aortic insufficiency, and sinuses of Valsalva dilation were compared between the 2 groups. RESULTS: Survival at 1, 5, and 10 years was 84.1% versus 77.3%, 70.8% versus 69.2%, 57.6% versus 58.0% in the root repair and replacement groups, respectively (P = .69). Cumulative incidence of reoperation at 1, 5, and 10 years was 0.0% versus 0.8%, 1.4% versus 3.8%, and 3.4% versus 8.6% in the root repair and root replacement groups, respectively (P = .011). Multivariable Cox regression identified sinuses of Valsalva diameter 45 mm or more as a risk factor for proximal aortic reoperation (hazard ratio, 9.06; 95% confidence interval, 1.26-65.24). In a repeated-measures, linear, mixed-effects model, root replacement was associated with smaller follow-up of sinuses of Valsalva dimensions (ß = -0.66, P < .001). In an ordinal longitudinal mixed model, root replacement was associated with lower severity of postoperative aortic insufficiency (ß = -3.10, P < .001). CONCLUSIONS: Survival is similar, but the incidence of aortic insufficiency and root dilation may be greater after root repair compared with root replacement for acute type A aortic dissection.

Midterm outcomes of emergency surgery for acute type A aortic dissection in octogenarians.

OBJECTIVE: The incidence of elderly patients with acute type A aortic dissection is increasing. A recent analysis of the International Registry of Acute Aortic Dissection failed to show a mortality benefit with surgery compared with medical management in octogenarians. Therefore, we compared our institutional outcomes of emergency surgery for acute type A aortic dissection in octogenarians versus septuagenarians to understand the outcomes of surgical intervention in elderly patients. METHODS: From 2002 to 2017, 70 octogenarians (aged ≥80 years) and 165 septuagenarians (70-79 years) underwent surgery for acute type A aortic dissection (N = 235, total). Quality of life was assessed by the RAND Short Form-36 quality of life survey. Midterm clinical and functional data were obtained retrospectively. RESULTS: At baseline, septuagenarians had a higher prevalence of diabetes (20.6% vs 5.7%, P = .01). The prevalence of cardiopulmonary resuscitation was 4.8% versus 10.0% (P = .24) in septuagenarians and octogenarians. The prevalence of cardiogenic shock was 18.2% versus 27.1% (P = .17). Thirty-day/in-hospital mortality was 21.2% versus 28.6% (P = .29). Multivariable logistic regression identified cardiogenic shock as an independent risk factor for in-hospital mortality (odds ratio, 10.07; 95% confidence interval, 2.30-44.03) in octogenarians. Survival at 5 years was 49.7% (42.1%-58.6%) versus 34.2% (23.9%-48.8%) in septuagenarians and octogenarians, respectively. Responses to the quality of life survey were no different between septuagenarians and octogenarians across all 8 quality of life categories. CONCLUSIONS: Clinical outcomes after surgery for acute type A aortic dissection are similar in octogenarians and septuagenarians. For discharged survivors, quality of life remains favorable and does not differ between the 2 groups.

Increased Production of Outer Membrane Vesicles by Salmonella Interferes with Complement-Mediated Innate Immune Attack.

Bacterial outer membrane vesicles (OMVs) enriched with bioactive proteins, toxins, and virulence factors play a critical role in host-pathogen and microbial interactions. The two-component system PhoP-PhoQ (PhoPQ) of Salmonella enterica orchestrates the remodeling of outer membrane lipopolysaccharide (LPS) molecules and concomitantly upregulates OMV production. In this study, we document a novel use of nanoparticle tracking analysis to determine bacterial OMV size and number. Among the PhoPQ-activated genes tested, pagC expression had the most significant effect on the upregulation of OMV production. We provide the first evidence that PhoPQ-mediated upregulation of OMV production contributes to bacterial survival by interfering with complement activation. OMVs protected bacteria in a dose-dependent manner, and bacteria were highly susceptible to complement-mediated killing in their absence. OMVs from bacteria expressing PagC bound to complement component C3b in a dose-dependent manner and inactivated it by recruiting complement inhibitor Factor H. As we also found that Factor H binds to PagC, we propose that PagC interferes with complement-mediated killing of Salmonella in the following two steps: first by engaging Factor H, and second, through the production of PagC-enriched OMVs that divert and inactivate the complement away from the bacteria. Since PhoPQ activation occurs intracellularly, the resultant increase in PagC expression and OMV production is suggested to contribute to the local and systemic spread of Salmonella released from dying host cells that supports the infection of new cells. IMPORTANCE Bacterial outer membrane vesicles (OMVs) mediate critical bacterium-bacterium and host-microbial interactions that influence pathogenesis through multiple mechanisms, including the elicitation of inflammatory responses, delivery of virulence factors, and enhancement of biofilm formation. As such, there is a growing interest in understanding the underlying mechanisms of OMV production. Recent studies have revealed that OMV biogenesis is a finely tuned physiological process that requires structural organization and selective sorting of outer membrane components into the vesicles. In Salmonella, outer membrane remodeling and OMV production are tightly regulated by its PhoPQ system. In this study, we demonstrate that PhoPQ-regulated OMV production plays a significant role in defense against host innate immune attack. PhoPQ-activated PagC expression recruits the complement inhibitor Factor H and degrades the active C3 component of complement. Our results provide valuable insight into the combination of tools and environmental signals that Salmonella employs to evade complement-mediated lysis, thereby suggesting a strong evolutionary adaptation of this facultative intracellular pathogen to protect itself during its extracellular stage in the host.

Recurrent aortic insufficiency after emergency surgery for acute type A aortic dissection with aortic root preservation.

OBJECTIVE: Patients with acute type A aortic dissection demonstrate a wide range of aortic insufficiency. Outcomes after valve resuspension and root repair are not well studied in the long term. We evaluated the long-term effects of preoperative aortic insufficiency in patients undergoing emergency root-preserving surgery for acute type A aortic dissection. METHODS: From 2002 to 2017, 558 of 776 patients with acute type A aortic dissection underwent native aortic valve resuspension and root reconstruction. Patients were stratified into 4 groups by preoperative aortic insufficiency grade (n = 539): aortic insufficiency less than 2+ (n = 348), aortic insufficiency = 2+ (n = 72), aortic insufficiency = 3+ (n = 49), and aortic insufficiency = 4+ (n = 70). Multivariable ordinal longitudinal mixed effects and multi-state transition models were used to assess risk factors for recurrent aortic insufficiency. RESULTS: The prevalence of cardiogenic shock in patients presenting with preoperative aortic insufficiency less than 2+, 2+, 3+, and 4+ was 53 of 348 (15.2%), 12 of 72 (16.7%), 10 of 49 (20.4%), and 24 of 70 (34.3%), respectively (P = .002). Postoperatively, 94.0% of patients had aortic insufficiency 1+ or less at discharge. Operative mortality was 34 of 348 (9.8%), 10 of 72 (13.9%), 6 of 49 (12.2%), and 12 of 70 (17.1%) (P = .303). In an ordinal mixed effects model, preoperative aortic insufficiency was associated with more severe postoperative aortic insufficiency. The multi-state transition model demonstrated that severe aortic insufficiency was associated with progression from no to mild aortic insufficiency (hazard ratio, 2.14; 95% confidence interval, 1.35-3.38), and progression from mild to moderate aortic insufficiency (hazard ratio, 5.70; 95% confidence interval, 1.88-17.30). CONCLUSIONS: Preoperative aortic insufficiency is an important predictor of recurrent aortic insufficiency in patients undergoing valve resuspension with root reconstruction for emergency acute type A aortic dissection repair. Increased echocardiographic surveillance for recurrent aortic insufficiency may be warranted in this cohort.

Circulating Donor Heart Exosome Profiling Enables Noninvasive Detection of Antibody-mediated Rejection.

BACKGROUND: Endomyocardial biopsy remains the gold standard for distinguishing types of immunologic injury-acute versus antibody-mediated rejection (AMR). Exosomes are tissue-specific extracellular microvesicles released by many cell types, including transplanted heart. Circulating transplant heart exosomes express donor-specific human leukocyte antigen (HLA) I molecules. As AMR is mediated by antibodies to donor HLAs, we proposed that complement deposition that occurs with AMR at tissue level would also occur on circulating donor heart exosomes. METHODS: Plasma exosomes in 4 patients were isolated by column chromatography and ultracentrifugation. Donor heart exosomes were purified using anti-donor HLA I antibody beads and complement C4d protein expression was assessed in this subset as marker for AMR. RESULTS: Three patients had no rejection episodes. Circulating donor heart exosomes showed troponin protein and mRNA expression at all follow-up time points. One patient developed AMR on day 14 endomyocardial biopsy that was treated with rituximab, IVIG/plasmapheresis. Time-specific detection of C4d protein was seen in donor heart exosome subset in this patient, which resolved with treatment. C4d was not seen in other 3 patients' donor exosomes. CONCLUSIONS: Anti-donor HLA I specificity enables characterization of circulating donor heart exosomes in the clinical setting. Further characterization may open the window to noninvasively diagnose rejection type, such as AMR.

Syncytiotrophoblast extracellular microvesicle profiles in maternal circulation for noninvasive diagnosis of preeclampsia.

Preeclampsia is the most common placental pathology in pregnant females, with increased morbidity and mortality incurred on the mother and the fetus. There is a need for improved biomarkers for diagnosis and monitoring of this condition. Placental syncytiotrophoblasts at the maternal-fetal interface release nanoparticles, including extracellular microvesicles, into the maternal blood during pregnancy. Syncytiotrophoblast extracellular microvesicles (STEVs) are being studied for their diagnostic potential and for their potential physiologic role in preeclampsia. We hypothesized that STEV profiles in maternal circulation would be altered under conditions of preeclampsia compared to normal pregnancy. Extracellular vesicles (EVs) released by BeWo cells in vitro showed high expression of syncytin-1, but no plac1 expression, demonstrating that trophoblast cell EVs express syncytin-1 on their surface. Placental alkaline phosphatase also showed high expression on BeWo EVs, but due to concern for cross reactivity to highly prevalent isoforms of intestinal and bone alkaline phosphatase, we utilized syncytin-1 as a marker for STEVs. In vivo, syncytin-1 protein expression was confirmed in maternal plasma EVs from Control and Preeclampsia subjects by Western blot, and overall, lower expression was noted in samples from patients with preeclampsia (n = 8). By nanoparticle analysis, EV profiles from Control and Preeclampsia groups showed similar total plasma EV quantities (p = 0.313) and size distribution (p = 0.415), but STEV quantitative signal, marked by syncytin-1 specific EVs, was significantly decreased in the Preeclampsia group (p = 2.8 × 10-11). Receiver operating characteristic curve demonstrated that STEV signal threshold cut-off of <0.316 was 95.2% sensitive and 95.6% specific for diagnosis of preeclampsia in this cohort (area under curve = 0.975 ± 0.020). In conclusion, we report that the syncytin-1 expressing EV profiles in maternal plasma might serve as a placental tissue specific biomarker for preeclampsia.

Fate of the Preserved Sinuses of Valsalva After Emergency Repair for Acute Type A Aortic Dissection.

BACKGROUND: Patients with acute type A aortic dissection (ATAAD) present with heterogeneous involvement of the aortic root complex. Despite this variation, the aortic root can usually be preserved the majority of the time by Teflon (WL Gore, Newark, DE) inlay patch reconstruction of the dissected sinuses of Valsalva (SOV). In this study, we report the long term anatomic, functional, and clinical outcomes associated with the preserved SOV after surgery for ATAAD. METHODS: From 2002-2017, of 776 emergency ATAAD operations at a single institution, 558 (71.9%) underwent valve resuspension with SOV preservation. Echocardiography reports were reviewed to obtain postoperative SOV dimensions. Cumulative incidence of SOV dilation ≥ 4 5mm was calculated using the Fine-Gray method with death as a competing risk. Repeated-measures linear mixed effects model was used to determine risk factors for SOV growth over time. RESULTS: During the follow-up period, 62 of 558 (11.1%) patients developed SOV diameter ≥ 45 mm. Cumulative incidence of SOV dilation ≥ 45 mm at 1, 5, and 10 years was 5.5%, 12.4%, and 18.9% respectively. In a multivariable Cox regression model, preoperative SOV diameter ≥ 45 mm was associated with a hazard ratio of 14.11 (95% confidence interval 7.03-31.62) for postoperative SOV dilation ≥ 45 mm. In a repeated-measures linear mixed effects model, preoperative and discharge SOV diameter were significant predictors of SOV dilation. Postoperative time course was also identified as significant indicating growth over time. CONCLUSIONS: The preserved sinuses of Valsalva after surgery for ATAAD may be prone to progressive dilatation over time. Closer echocardiographic surveillance may be warranted in these patients.

Noninvasive diagnosis of recurrent autoimmune type 1 diabetes after islet cell transplantation.

Islet cell transplantation is curative therapy for patients with complicated autoimmune type 1 diabetes (T1D). We report the diagnostic potential of circulating transplant islet-specific exosomes to noninvasively distinguish pancreatic ß cell injury secondary to recurrent autoimmunity vs immunologic rejection. A T1D patient with hypoglycemic unawareness underwent islet transplantation and maintained normoglycemia until posttransplant day 1098 before requiring exogenous insulin. Plasma analysis showed decreased donor islet exosome quantities on day 1001, before hyperglycemia onset. This drop in islet exosome quantity signified islet injury, but did not distinguish injury type. However, analysis of purified transplant islet exosome cargoes showed decrease in insulin-containing exosomes, but not glucagon-containing exosomes, indicating selective destruction of transplanted ß cells secondary to recurrent T1D autoimmunity. Furthermore, donor islet exosome cargo analysis showed time-specific increase in islet autoantigen, glutamic acid decarboxylase 65 (GAD65), implicated in T1D autoimmunity. Time-matched analysis of plasma transplant islet exosomes in 3 control subjects undergoing islet cell transplantation failed to show changes in islet exosome quantities or intraexosomal cargo expression of insulin, glucagon, and GAD65. This is the first report of noninvasive diagnosis of recurrent autoimmunity after islet cell transplantation, suggesting that transplant tissue exosome platform may serve as a biomarker in islet transplant diagnostics.