Human genotyping and an experimental model reveal NPR-C as a possible contributor to morbidity in coarctation of the aorta.

Coarctation of the aorta (CoA) is a common congenital cardiovascular (CV) defect characterized by a stenosis of the descending thoracic aorta. Treatment exists, but many patients develop hypertension (HTN). Identifying the cause of HTN is challenging because of patient variability (e.g., age, follow-up duration, severity) and concurrent CV abnormalities. Our objective was to conduct RNA sequencing of aortic tissue from humans with CoA to identify a candidate gene for mechanistic studies of arterial dysfunction in a rabbit model of CoA devoid of the variability seen with humans. We present the first known evidence of natriuretic peptide receptor C (NPR-C; aka NPR3) downregulation in human aortic sections subjected to high blood pressure (BP) from CoA versus normal BP regions (validated to PCR). These changes in NPR-C, a gene associated with BP and proliferation, were replicated in the rabbit model of CoA. Artery segments from this model were used with human aortic endothelial cells to reveal the functional relevance of altered NPR-C activity. Results showed decreased intracellular calcium ([Ca2+]i) activity to C-type natriuretic peptide (CNP). Normal relaxation induced by CNP and atrial natriuretic peptide was impaired for aortic segments exposed to elevated BP from CoA. Inhibition of NPR-C (M372049) also impaired aortic relaxation and [Ca2+]i activity. Genotyping of NPR-C variants predicted to be damaging revealed that rs146301345 was enriched in our CoA patients, but sample size limited association with HTN. These results may ultimately be used to tailor treatment for CoA based on mechanical stimuli, genotyping, and/or changes in arterial function.

The Impact of Cardiac Motion on Aortic Valve Flow Used in Computational Simulations of the Thoracic Aorta.

Advancements in image-based computational modeling are producing increasingly more realistic representations of vasculature and hemodynamics, but so far have not compensated for cardiac motion when imposing inflow boundary conditions. The effect of cardiac motion on aortic flow is important when assessing sequelae in this region including coarctation of the aorta (CoA) or regurgitant fraction. The objective of this investigation was to develop a method to assess and correct for the influence of cardiac motion on blood flow measurements through the aortic valve (AoV) and to determine its impact on patient-specific local hemodynamics quantified by computational fluid dynamics (CFD). A motion-compensated inflow waveform was imposed into the CFD model of a patient with repaired CoA that accounted for the distance traveled by the basal plane during the cardiac cycle. Time-averaged wall shear stress (TAWSS) and turbulent kinetic energy (TKE) values were compared with CFD results of the same patient using the original waveform. Cardiac motion resulted in underestimation of flow during systole and overestimation during diastole. Influences of inflow waveforms on TAWSS were greatest along the outer wall of the ascending aorta (AscAo) (∼30 dyn/cm2). Differences in TAWSS were more pronounced than those from the model creation or mesh dependence aspects of CFD. TKE was slightly higher for the motion-compensated waveform throughout the aortic arch. These results suggest that accounting for cardiac motion when quantifying blood flow through the AoV can lead to different conclusions for hemodynamic indices, which may be important if these results are ultimately used to predict patient outcomes.

Including aortic valve morphology in computational fluid dynamics simulations: initial findings and application to aortic coarctation.

Computational fluid dynamics (CFD) simulations quantifying thoracic aortic flow patterns have not included disturbances from the aortic valve (AoV). 80% of patients with aortic coarctation (CoA) have a bicuspid aortic valve (BAV) which may cause adverse flow patterns contributing to morbidity. Our objectives were to develop a method to account for the AoV in CFD simulations, and quantify its impact on local hemodynamics. The method developed facilitates segmentation of the AoV, spatiotemporal interpolation of segments, and anatomic positioning of segments at the CFD model inlet. The AoV was included in CFD model examples of a normal (tricuspid AoV) and a post-surgical CoA patient (BAV). Velocity, turbulent kinetic energy (TKE), time-averaged wall shear stress (TAWSS), and oscillatory shear index (OSI) results were compared to equivalent simulations using a plug inlet profile. The plug inlet greatly underestimated TKE for both examples. TAWSS differences extended throughout the thoracic aorta for the CoA BAV, but were limited to the arch for the normal example. OSI differences existed mainly in the ascending aorta for both cases. The impact of AoV can now be included with CFD simulations to identify regions of deleterious hemodynamics thereby advancing simulations of the thoracic aorta one step closer to reality.

Guiding mothers' management of health problems of very low birth-weight infants.

OBJECTIVE: Explore the feasibility, usefulness, and outcomes of a pilot program to support mothers in developing competencies for managing health problems of their very low birth-weight (VLBW) infants in partnership with the primary care clinician (PCC). DESIGN: In a randomized study, mothers who received guided participation (GP) and printed guidelines for managing VLBW infant health problems were compared with mothers who received only the guidelines and standard care (GL group). SAMPLE: All mothers (GP = 20; GL = 11) were at least 18 years old and English speaking. Infants were all VLBW (< or =1,500 g). INTERVENTION: GP began during the infant's neonatal intensive care unit stay and continued with public health nurses (PHNs) and a family service clinician through the infant's first 4 postterm months. MEASUREMENTS: Intervention feasibility and usefulness were assessed with maternal and clinician feedback. Outcomes included maternal and clinician appraisal of mothers' use of clinical resources and mothers' perceptions of primary-care quality and the family-PCC relationship. RESULTS: Intervention feasibility and usefulness were supported. GP and GL groups did not differ significantly on outcomes. CONCLUSIONS: Findings indicate a longer intervention period, GP organized by infant problem episodes, and enhancement of the PHN role in the context of interdisciplinary and interagency collaboration.