Distinct enhancers at the Pax3 locus can function redundantly to regulate neural tube and neural crest expressions

AbstractPax3 is a transcription factor expressed in somitic mesoderm, dorsal neural tube and pre-migratory neural crest during embryonic development. We have previously identified cis-acting enhancer elements within the proximal upstream genomic region of Pax3 that are sufficient to direct functional expression of Pax3 in neural crest. These elements direct expression of a reporter gene to pre-migratory neural crest in transgenic mice, and transgenic expression of a Pax3 cDNA using these elements is sufficient to rescue neural crest development in mice otherwise lacking endogenous Pax3. We show here that deletion of these enhancer sequences by homologous recombination is insufficient to abrogate neural crest expression of Pax3 and results in viable mice. We identify a distinct enhancer in the fourth intron that is also capable of mediating neural crest expression in transgenic mice and zebrafish. Our analysis suggests the existence of functionally redundant neural crest enhancer modules for Pax3

Cardiovascular Outcomes in Aortopathy: GenTAC Registry of Genetically Triggered Aortic Aneurysms and Related Conditions.

BACKGROUND: The GenTAC (Genetically Triggered Thoracic Aortic Aneurysm and Cardiovascular Conditions) Registry enrolled patients with genetic aortopathies between 2007 and 2016. OBJECTIVES: The purpose of this study was to compare age distribution and probability of elective surgery for proximal aortic aneurysm, any dissection surgery, and cardiovascular mortality among aortopathy etiologies. METHODS: The GenTAC study had a retrospective/prospective design. Participants with bicuspid aortic valve (BAV) with aneurysm (n = 879), Marfan syndrome (MFS) (n = 861), nonsyndromic heritable thoracic aortic disease (nsHTAD) (n = 378), Turner syndrome (TS) (n = 298), vascular Ehlers-Danlos syndrome (vEDS) (n = 149), and Loeys-Dietz syndrome (LDS) (n = 121) were analyzed. RESULTS: The 25% probability of elective proximal aortic aneurysm surgery was 30 years for LDS (95% CI: 18-37 years), followed by MFS (34 years; 95% CI: 32-36 years), nsHTAD (52 years; 95% CI: 48-56 years), and BAV (55 years; 95% CI: 53-58 years). Any dissection surgery 25% probability was highest in LDS (38 years; 95% CI: 33-53 years) followed by MFS (51 years; 95% CI: 46-57 years) and nsHTAD (54 years; 95% CI: 51-61 years). BAV experienced the largest relative frequency of elective surgery to any dissection surgery (254/33 = 7.7), compared with MFS (273/112 = 2.4), LDS (35/16 = 2.2), or nsHTAD (82/76 = 1.1). With MFS as the reference population, risk of any dissection surgery or cardiovascular mortality was lowest in BAV patients (HR: 0.13; 95% CI: 0.08-0.18; HR: 0.13; 95%: CI: 0.06-0.27, respectively). The greatest risk of mortality was seen in patients with vEDS. CONCLUSIONS: Marfan and LDS cohorts demonstrate age and event profiles congruent with the current understanding of syndromic aortopathies. BAV events weigh toward elective replacement with relatively few dissection surgeries. Nonsyndromic HTAD patients experience near equal probability of dissection vs prophylactic surgery, possibly because of failure of early diagnosis

Abstracts from the 20th International Symposium on Signal Transduction at the Blood-Brain Barriers

https://deepblue.lib.umich.edu/bitstream/2027.42/138963/1/12987_2017_Article_71.pd

One and Five-Year Mortality Risk Prediction in Patients with Moderate and Severe Aortic Stenosis

(1) Background: Our goal was to develop a risk prediction model for mortality in patients with moderate and severe aortic stenosis (AS). (2) Methods: All patients aged 40–95 years, with echocardiographic evidence of moderate and severe AS at a single institution, were studied over a median of 2.8 (1.5–4.8) years, between 2013–2018. Patient characteristics and mortality were compared using Chi-squares, t-tests, and Kaplan–Meier (KM) curves, as appropriate. The risk calculation for mortality was derived using the Cox proportional hazards model. A risk score was calculated for each parameter, and the total sum of scores predicted the individualized risks of 1-and 5-year mortality. (3) Results: A total of 1991 patients with severe and 2212 with moderate AS were included. Severe AS patients were older, had a lower ejection fraction %, were more likely to be Caucasian, and had lower rates of obesity and smoking, but had higher rates of cardiac comorbidities and AVR (49.3% vs. 2.8%, p p = 0.6530, and was not different using KM curves (log rank, p = 0.0853). The models included only patients with complete follow-up (3966 in the 1-year, and 816 in the 5-year model) and included 13 variables related to patient characteristics, degree of AS, and AVR. The C-statistic was 0.75 and 0.72 for the 1-year and the 5-year models, respectively. (4) Conclusions: Patients with moderate and severe AS experience high morbidity and mortality. The usage of a risk prediction model may provide guidance for clinical decision making in complex patients

Living in disadvantaged neighborhoods linked to less intervention for severe aortic stenosis

Abstract To investigate the association between area deprivation index (ADI) and aortic valve replacement (AVR) in patients with severe aortic stenosis (AS). Patients aged 40–95 years with severe AS confirmed by echocardiography were included. The 9-digit zip code of patient residence address was used to identify the ADI ranking, based on which patients were divided into 5 groups (with Group E being most deprived). The rates of AV intervention were compared among 5 groups using competing risks analysis, with death as a competing event. We included 1751 patients with severe AS from 2013 to 2018 followed for a median 2.8 (interquartile range, 1.5–4.8) years. The more distressed ADI groups tended to be younger (P = 0.002), female (P < 0.001), and of African American race (P < 0.001), have higher presentation of sepsis (P = 0.031), arrhythmia (P = 0.022), less likely to have previous diagnosis of AS (P < 0.001); and were less likely to undergo AVR (52.5% vs 46.9% vs 46.1% vs 48.9% vs 39.7%, P = 0.023). Using competing risk analysis, the highest ADI group (E) were the least and the lowest ADI group (A) the most likely to undergo AVR (Gray’s test, P = 0.025). The association between ADI ranking and AVR rates was influenced by sex and race. Within group analysis, there was significant association between race and AVR (Gray’s test, P < 0.001), and between sex and AVR (Gray’s test, P < 0.001). Patients with severe AS living in more deprived neighborhoods were less likely to undergo aortic valve interventions, which was influenced by female gender, and African American race

Screening Tool to Identify Patients with Advanced Aortic Valve Stenosis

(1) Background: The clinical burden of aortic stenosis (AS) remains high in Western countries. Yet, there are no screening algorithms for this condition. We developed a risk prediction model to guide targeted screening for patients with AS. (2) Methods: We performed a cross-sectional analysis of all echocardiographic studies performed between 2013 and 2018 at a tertiary academic care center. We included reports of unique patients aged from 40 to 95 years. A logistic regression model was fitted for the risk of moderate and severe AS, with readily available demographics and comorbidity variables. Model performance was assessed by the C-index, and its calibration was judged by a calibration plot. (3) Results: Among the 38,788 reports yielded by inclusion criteria, there were 4200 (10.8%) patients with &ge;moderate AS. The multivariable model demonstrated multiple variables to be associated with AS, including age, male gender, Caucasian race, Body Mass Index &ge; 30, and cardiovascular comorbidities and medications. C-statistics of the model was 0.77 and was well calibrated according to the calibration plot. An integer point system was developed to calculate the predicted risk of &ge;moderate AS, which ranged from 0.0002 to 0.7711. The lower 20% of risk was approximately 0.15 (corresponds to a score of 252), while the upper 20% of risk was about 0.60 (corresponds to a score of 332 points). (4) Conclusions: We developed a risk prediction model to predict patients&rsquo; risk of having &ge;moderate AS based on demographic and clinical variables from a large population cohort. This tool may guide targeted screening for patients with advanced AS in the general population

Distinct enhancers at the Pax3 locus can function redundantly to regulate neural tube and neural crest expressions

10.1016/j.ydbio.2009.12.030DEVELOPMENTAL BIOLOGY3392519-52