Pharmaceutical beta-catenin inhibitors can modulate the nuclear localization of beta-catenin and reduce cell viability of HB cells in vitro. These promising effects might optimize the outcome of high-risk HB. The orthotopic HB model is a suitable basis for further in vivo studies.

Rationale: Calcific Aortic Valve Disease (CAVD) affects more than 5.2 million people in the US. The only effective treatment is surgery and this comes with complications and no guarantee of long-term success. Objective: Outcomes from pharmacological initiatives remain unsubstantiated and therefore the aim of this study is to determine if repurposing a selective XPO1 inhibitor drug (KPT-330) is beneficial in the treatment of CAVD. Methods and Results: We show that KPT-330 prevents, attenuates and mitigates calcific nodule formation in heart valve interstitial cells (VICs) in vitro, and prevents CAVD in Klotho -/- mice. Using RNA-sequencing and Mass Spectrometry we show that KPT-330's beneficial effect is mediated by inhibiting nuclear export of the transcription factor C/EBPβ in VICs, leading to repression of canonical Wnt signaling, in part through activation of the Wnt antagonist Axin1, and a subsequent decrease in pro-osteogenic markers and cell viability. Conclusions: Our findings have met a critical need to discover alterative, pharmacological-based therapies in the treatment of CAVD.

Heart valves are organized connective tissues of high mechanical demand. They open and close over 100,000 times a day to preserve unidirectional blood flow by maintaining structure-function relationships throughout life. In affected individuals, structural failure compromises function and often leads to regurgitant blood flow and progressive heart failure. This is most common in degenerative valve disease due to age-related wear and tear, or congenital malformations. At present, the only effective treatment of valve disease is surgical repair or replacement and this is often impermanent and requires anti-coagulation therapy throughout life. Therefore, there is a critical need to discover new alternatives. A promising therapeutic area is tissue regeneration and in non-valvular tissues this requires a tightly regulated genetic “growth program” involving cell proliferation. To explore this in heart valves, we performed RNA-seq analysis to compare transcriptional profiles of aortic valve tissue isolated from mice during stages of growth (postnatal day (PND) 2) and adult maintenance (4 months). Data analysis reveals distinct mRNA profiles at each time point and pathway ontology identifies associated changes in biological functions. The PND2 aortic valve is characterized by extensive cell proliferation and expression of mRNAs related to the extracellular matrix (ECM). At 4 months, proliferation is not significant and a differential set of ECM-related genes are expressed. Interestingly there is enrichment of the defense response biological process at this later time point. Together, these data highlight the unique transcriptome of the postnatal valve during stages of growth and maturation, as well as biological functions associated with adult homeostatic valves. These studies create a platform for future work exploring the molecular programs altered in the onset of heart valve disease after birth and provide insights for the development of mechanistic-based therapies.

Objective: To compare prevalence of e-cigarette and cigarette use and to determine predictors of dual use. Design, Setting, and Participants: Using a countywide random digit dial telephone health survey conducted during January 2018 to March 2019, we analyzed data from a random sample of 6966 adults. Bivariate analyses described vaping, cigarette use, and sociodemographics. A multivariable logistic regression model examined dual use. Results: Young adults 18 to 24 years of age had the highest prevalence of e-cigarette-only use (11.5%), the second-highest prevalence of dual use (3.9%), and the lowest prevalence of cigarette-only use (5.8%). Males were more likely than females to use e-cigarettes (5.1% vs 2.7%), traditional cigarettes (11.1% vs 6.9%), or be dual users (3.6% vs 1.1%). Of those who used e-cigarettes or both, approximately half had also used marijuana in the past 30 days. Conclusions: E-cigarette use among young adults is concerning because it could lead to eventual dual use of e-cigarettes and traditional cigarettes.

In the original article, there was a mistake in the table listing the qRT-PCR primers, in the Materials and Methods as published. The forward and reverse primers were duplicated for Mki67. The corrected qRT-PCR primer table appears below.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.