Sritharen, Yoginee

Background While recent work from our laboratory showed that DNA (cytosine‐5)‐methyltransferase 3 beta (DNMT3b) is significantly increased in tissue from humans with calcific aortic valve stenosis and is associated with increases in global genomic methylation, it is unknown whether the net effects of these changes are protective or deleterious. The objective of this study was to test the hypothesis that genetic reduction of DNMT3b allows for increased anti‐osteogenic gene expression, and consequently results in suppression of osteogenic signaling and slower progression of valvular stenosis. Methods We used Ldlr −/− /ApoB 100/100 (LA) mice that were wild‐type for DNMT3b (LA‐DNMT3b +/+ ) or deficient in DNMT3b (LA‐DNMT3b +/− ) and fed a western diet for six months. Results Using quantitative real‐time RT‐PCR, we confirmed that expression of DNMT3b was reduced by ~50% in valves from haploinsufficient mice. In line with our hypothesis, reductions in DNMT3b were associated with increases in expression of FABP4 (which opposes osteogenesis) and Smad6 (which opposes canonical BMP signaling). Similarly, expression of the osteogenic genes Msx2 and Spp1 were substantially reduced in DNMT3b‐deficient mice. Critically, aortic valve cusp separation distance was significantly greater in DNMT3b‐deficient mice, demonstrating slower progression of valvular dysfunction. No other gross abnormalities were noted in the mice. Conclusions Collectively, these data suggest that selectively reducing DNMT3b activity may be a viable therapeutic approach to slowing progression of calcific aortic valve stenosis in humans. Support or Funding Information Grant Funding Source: Supported by NHLBI

AbstractBackgroundTube thoracostomy (TT) is a commonly performed procedure which is associated with significant complication rates. Currently, there is no validated taxonomy to classify and compare TT complications across different populations. This study aims to validate such TT complication taxonomy in a cohort of South African trauma patients.MethodsPost hoc analysis of a prospectively collected trauma database from Pietermaritzburg Metropolitan Trauma Service (PMTS) in South Africa was performed for the period January 2010 to December 2013. Baseline demographics, mechanism of injury and complications were collected and categorized according to published classification protocols. All patients requiring bedside TT were included in the study. Patients who necessitated operatively placed or image‐guided TT insertion were excluded. Summary and univariate analyses were performed.ResultsA total of 1010 patients underwent TT. The mean age was (±SD) of 26 ± 8 years. Unilateral TTs were inserted in n = 966 (96%) and bilateral in n = 44 (4%). Complications developed in 162 (16%) patients. Penetrating injury was associated with lower complication rate (11%) than blunt injury (26%), p = 0.0001. Higher complication rate was seen in TT placed by interns (17%) compared to TT placed by residents (7%), p = 0.0001. Complications were classified as: insertional (38%), positional (44%), removal (9%), infective/immunologic (9%), and instructional, educational or equipment related (0%).ConclusionsDespite being developed in the USA, this classification system is robust and was able to comprehensively assign and categorize all the complications of TT in this South African trauma cohort. A universal standardized definition and classification system permits equitable comparisons of complication rates. The use of this classification taxonomy may help develop strategies to improve TT placement techniques and reduce the complications associated with the procedure.Level of evidenceV.Study typeSingle Institution Retrospective review.

Our understanding of the fundamental biology and identification of efficacious therapeutic targets in aortic valve stenosis has lagged far behind the fields of atherosclerosis and heart failure. In this review, we highlight the most clinically relevant problems facing men and women with fibrocalcific aortic valve stenosis, discuss the fundamental biology underlying valve calcification and fibrosis, and identify key molecular points of intersection with sex hormone signaling.