Proteasome Levels and Activity in Pregnancies Complicated by Severe Preeclampsia and Hemolysis, Elevated Liver Enzymes, and Thrombocytopenia (HELLP) Syndrome.

Excessive accumulation of misfolded proteins was recently demonstrated in preeclampsia. We examined levels and activity of circulatory proteasome and immunoproteasome (inflammatory subtype) in preeclampsia and hemolysis, elevated liver enzymes, and thrombocytopenia (HELLP) syndrome. We analyzed samples from women with hypertensive pregnancy disorders (n=115), including preeclampsia with severe features (sPE) and HELLP syndrome, and normotensive controls (n=45). Plasma proteasome and immunoproteasome immunoreactivity were determined by quantifying the α-subunit of the 20S core and ß5i (proteasome subunit beta 8 [PSMB8]), respectively. Plasma proteasome activity was analyzed with fluorogenic substrates. MG132, lactacystin, and ONX0914 were used to inhibit the circulating proteasome and immunoproteasome, respectively. Plasma cytokine profiles were evaluated by multiplex immunoassay. Placental expression of ß5 (constitutive proteasome) and ß5i (immunoproteasome) was interrogated by immunohistochemistry. Women with sPE had increased plasma 20S levels ( P<0.001) and elevated lytic activities (chymotrypsin-like 7-fold, caspase-like 4.2-fold, trypsin-like 2.2-fold; P <0.001 for all) compared with pregnant controls. Women with features of HELLP displayed the highest plasma proteasome levels and activity, which correlated with decreased IFN-γ (interferon-γ), and increased IL (interleukin)-8 and IL-10. In sPE and HELLP, chymotrypsin-like activity was suppressed by proteasome inhibitors including ONX0914. Compared with gestational age-matched controls, sPE placentas harbored increased ß5 and ß5i immunostaining in trophoblasts. ß5i signal was elevated in HELLP with predominant staining in villous core, extravillous trophoblasts in placental islands, and extracellular vesicles in intervillous spaces. Pregnancy represents a state of increased proteostatic stress. sPE and HELLP were characterized by significant upregulation in circulating levels and lytic activity of the proteasome that was partially explained by placental immunoproteasome upregulation.

Transcatheter Occlusion of the Patent Ductus Arteriosus in 747 Infants <6 kg: Insights From the NCDR IMPACT Registry.

OBJECTIVES: The authors sought to identify risk factors associated with major adverse events (MAEs) in infants <6 kg undergoing transcatheter patent ductus arteriosus (PDA) occlusion. BACKGROUND: Transcatheter PDA occlusion is among the safest of interventional cardiac procedures in adults and older children, but use among infants <6 kg has not been characterized adequately. METHODS: Using the IMPACT (IMproving Pediatric and Adult Congenital Treatments) registry, we identified infants <6 kg undergoing transcatheter PDA occlusion (January 1, 2011, to March 1, 2015). Using mixed-effects multivariate regression, the authors assessed characteristics predictive of MAE or composite failure (procedural failure or MAE). Individual safety metrics (e.g., embolization, malposition) were also examined for differences across weight thresholds: extremely low weight (LW) (<2 kg), very LW (2 to <4 kg), and LW (4 to <6 kg). RESULTS: Transcatheter PDA occlusion was attempted in 747 infants <6 kg at 73 hospitals. Rate of procedural success was 94.3%. MAEs were observed in 12.6% of cases; the most common events were acute arterial injury and device embolization in 3.5% and 2.4% of cases, respectively. Younger age (<30 days) was associated with greater risk of a MAE (risk ratio: 3.3; 95% confidence interval: 1.5 to 7.6) and composite failure (risk ratio: 3.0; 95% confidence interval: 1.4 to 6.7). Risk of embolization was higher among extremely LW (10.5%) than very LW or LW infants (1.6% and 2.5%, respectively; p = 0.050). CONCLUSIONS: Among infants <6 kg, transcatheter PDA occlusion is technically feasible, but risks of MAE are noteworthy. These findings may help inform patient selection and procedural approach for transcatheter PDA occlusion and direct targeted research efforts to support the practice of evidence-based medicine.