Gene Expression in Experimental Aortic Coarctation and Repair: Candidate Genes for Therapeutic Intervention?

Coarctation of the aorta (CoA) is a constriction of the proximal descending thoracic aorta and is one of the most common congenital cardiovascular defects. Treatments for CoA improve life expectancy, but morbidity persists, particularly due to the development of chronic hypertension (HTN). Identifying the mechanisms of morbidity is difficult in humans due to confounding variables such as age at repair, follow-up duration, coarctation severity and concurrent anomalies. We previously developed an experimental model that replicates aortic pathology in humans with CoA without these confounding variables, and mimics correction at various times using dissolvable suture. Here we present the most comprehensive description of differentially expressed genes (DEGs) to date from the pathology of CoA, which were obtained using this model. Aortic samples (n=4/group) from the ascending aorta that experiences elevated blood pressure (BP) from induction of CoA, and restoration of normal BP after its correction, were analyzed by gene expression microarray, and enriched genes were converted to human orthologues. 51 DEGs with \u3e6 fold-change (FC) were used to determine enriched Gene Ontology terms, altered pathways, and association with National Library of Medicine Medical Subject Headers (MeSH) IDs for HTN, cardiovascular disease (CVD) and CoA. The results generated 18 pathways, 4 of which (cell cycle, immune system, hemostasis and metabolism) were shared with MeSH ID’s for HTN and CVD, and individual genes were associated with the CoA MeSH ID. A thorough literature search further uncovered association with contractile, cytoskeletal and regulatory proteins related to excitation-contraction coupling and metabolism that may explain the structural and functional changes observed in our experimental model, and ultimately help to unravel the mechanisms responsible for persistent morbidity after treatment for CoA

Computational Simulations for Aortic Coarctation: Representative Results From a Sampling of Patients

Treatments for coarctation of the aorta (CoA) can alleviate blood pressure (BP) gradients(D), but long-term morbidity still exists that can be explained by altered indices of hemodynamics and biomechanics. We introduce a technique to increase our understanding of these indices for CoA under resting and nonresting conditions, quantify their contribution to morbidity, and evaluate treatment options. Patient-specific computational fluid dynamics (CFD) models were created from imaging and BP data for one normal and four CoA patients (moderate native CoA: D12 mmHg, severe native CoA: D25 mmHg and postoperative end-to-end and end-to-side patients: D0 mmHg). Simulations incorporated vessel deformation, downstream vascular resistance and compliance. Indices including cyclic strain, time-averaged wall shear stress (TAWSS), and oscillatory shear index (OSI) were quantified. Simulations replicated resting BP and blood flow data. BP during simulated exercise for the normal patient matched reported values. Greatest exercise-induced increases in systolic BP and mean and peak DBP occurred for the moderate native CoA patient (SBP: 115 to 154 mmHg; mean and peak DBP: 31 and 73 mmHg). Cyclic strain was elevated proximal to the coarctation for native CoA patients, but reduced throughout the aorta after treatment. A greater percentage of vessels was exposed to subnormal TAWSS or elevated OSI for CoA patients. Local patterns of these indices reported to correlate with atherosclerosis in normal patients were accentuated by CoA. These results apply CFD to a range of CoA patients for the first time and provide the foundation for future progress in this area

Aortic stenting in the growing sheep causes aortic endothelial dysfunction but not hypertension: Clinical implications for coarctation repair

Stent implantation is the treatment of choice for adolescents and adults with aortic coarctation (CoAo). Despite excellent short-term results, 20%-40% of the patients develop arterial hypertension later in life, which was attributed to inappropriate response of the aortic baroreceptors to increased stiffness of the ascending aorta (ASAO), either congenital or induced by CoAo repair. In particular, it has been hypothesized that stent itself may cause or sustain hypertension. Therefore, we aimed to study the hemodynamic and structural impact following stent implantation in the normal aorta of a growing animal

Treating a 20 mm Hg Gradient Alleviates Myocardial Hypertrophy in Experimental Aortic Coarctation

Background Children with coarctation of the aorta (CoA) can have a hyperdynamic and remodeled left ventricle (LV) from increased afterload. Literature from an experimental model suggests the putative 20 mm Hg blood pressure gradient (BPG) treatment guideline frequently implemented in CoA studies may permit irreversible vascular changes. LV remodeling from pressure overload has been studied, but data are limited following correction and using a clinically representative BPG. Materials and methods Rabbits underwent CoA at 10 weeks to induce a 20 mm Hg BPG using permanent or dissolvable suture thereby replicating untreated and corrected CoA, respectively. Cardiac function was evaluated at 32 weeks by magnetic resonance imaging using a spoiled cine GRE sequence (TR/TE/FA 8/2.9/20), 14 × 14-cm FOV, and 3-mm slice thickness. Images (20 frames/cycle) were acquired in 6-8 short axis views from the apex to the mitral valve annulus. LV volume, ejection fraction (EF), and mass were quantified. Results LV mass was elevated for CoA (5.2 ± 0.55 g) versus control (3.6 ± 0.16 g) and corrected (4.0 ± 0.44 g) rabbits, resulting in increased LV mass/volume ratio for CoA rabbits. A trend toward increased EF and stroke volume was observed but did not reach significance. Elevated EF by volumetric analysis in CoA rabbits was supported by concomitant increases in total aortic flow by phase-contrast magnetic resonance imaging. Conclusions The indices quantified trended toward a persistent hyperdynamic LV despite correction, but differences were not statistically significant versus control rabbits. These findings suggest the current putative 20 mm Hg BPG for treatment may be reasonable from the LV\u27s perspective

Spontaneous subarachnoid haemorrhage due to coarctation of aorta and intraspinal collaterals : a rare presentation

The occurrence of spontaneous subarachnoid haemorrhage (SAH) in association with coarctation of thoracic aorta and absence of intracranial aneurysm is a rare association. In spontaneous SAH, the predominant cause is intracranial aneurysmal rupture. This report describes a case of a 40 year-old male who presented with SAH and was incidentally diagnosed to have coarctation of aorta (CoA) with intraspinal collaterals on further work up. This case demonstrates the importance of detailed evaluation of patients with spontaneous SAH on whom common aetiologies have been ruled out.peer-reviewe

Different patterns of cerebral and muscular tissue oxygenation 10 years after coarctation repair

The purpose of this study was to assess whether the lower exercise tolerance in children after coarctation repair is associated with alterations in peripheral tissue oxygenation during exercise. A total of 16 children after coarctation repair and 20 healthy control subjects performed an incremental ramp exercise test to exhaustion. Cerebral and locomotor muscle oxygenation were measured by means of near infrared spectroscopy. The responses of cerebral and muscle tissue oxygenation index (cTOI, mTOI), oxygenated (O(2)Hb), and deoxygenated hemoglobin (HHb) as a function of work rate were compared. Correlations between residual continuous wave Doppler gradients at rest, arm-leg blood pressure difference and local oxygenation responses were evaluated. Age, length, and weight was similar in both groups. Patients with aortic coarctation had lower peak power output (Ppeak) (72.3 +/- 20.2% vs. 106 +/- 18.7%, P < 0.001), VO(2)peak/kg (37.3 +/- 9.1 vs. 44.2 +/- 7.6 ml/kg, P = 0.019) and %VO(2)peak/kg (85.7 +/- 21.9% vs. 112.1 +/- 15.5%, P < 0.001). Cerebral O(2)Hb and HHb had a lower increase in patients vs. controls during exercise, with significant differences from 60 to 90% Ppeak (O(2)Hb) and 70% to 100% Ppeak (HHb). Muscle TOI was significantly lower in patients from 10 to 70% Ppeak and muscle HHb was significantly higher in patients vs. controls from 20 to 80% Ppeak. Muscle O(2)Hb was not different between both groups. There was a significant correlation between residual resting blood pressure gradient and Delta muscle HHb/Delta P at 10-20W and 20-30W (r = 0.40, P = 0.039 and r = 0.43, P = 0.034). Children after coarctation repair have different oxygenation responses at muscular and cerebral level. This reflects a different balance between O-2 supply to O-2 demand which might contribute to the reduced exercise tolerance in this patient population

Computational simulations demonstrate altered wall shear stress in aortic coarctation patients previously treated by resection with end-to-end anastomosis

Background.  Atherosclerotic plaque in the descending thoracic aorta (dAo) is related to altered wall shear stress (WSS) for normal patients. Resection with end-to-end anastomosis (RWEA) is the gold standard for coarctation of the aorta (CoA) repair, but may lead to altered WSS indices that contribute to morbidity. Methods.  Computational fluid dynamics (CFD) models were created from imaging and blood pressure data for control subjects and age- and gender-matched CoA patients treated by RWEA (four males, two females, 15 ± 8 years). CFD analysis incorporated downstream vascular resistance and compliance to generate blood flow velocity, time-averaged WSS (TAWSS), and oscillatory shear index (OSI) results. These indices were quantified longitudinally and circumferentially in the dAo, and several visualization methods were used to highlight regions of potential hemodynamic susceptibility. Results.  The total dAo area exposed to subnormal TAWSS and OSI was similar between groups, but several statistically significant local differences were revealed. Control subjects experienced left-handed rotating patterns of TAWSS and OSI down the dAo. TAWSS was elevated in CoA patients near the site of residual narrowings and OSI was elevated distally, particularly along the left dAo wall. Differences in WSS indices between groups were negligible more than 5 dAo diameters distal to the aortic arch. Conclusions.  Localized differences in WSS indices within the dAo of CoA patients treated by RWEA suggest that plaque may form in unique locations influenced by the surgical repair. These regions can be visualized in familiar and intuitive ways allowing clinicians to track their contribution to morbidity in longitudinal studies

Palliative balloon dilation of native coarctation of the aorta in a preterm infant

The role of balloon dilation for native coarctation in neonates is controversial, due to the relatively high recurrence rate. Balloon dilation may however provide adequate palliation in preterm infants, by relieving symptoms and allowing somatic growth until definitive surgical repair can be performed. We report successful balloon angioplasty, on 2 occasions, in a preterm neonate with coarctation of the aorta and associated left ventricular cardiomyopathy.peer-reviewe

A Coupled Experimental and Computational Approach to Quantify Deleterious Hemodynamics, Vascular Alterations, and Mechanisms of Long-Term Morbidity in Response to Aortic Coarctati

Introduction Coarctation of the aorta (CoA) is associated with morbidity despite treatment. Although mechanisms remain elusive, abnormal hemodynamics and vascular biomechanics are implicated. We present a novel approach that facilitates quantification of coarctation-induced mechanical alterations and their impact on vascular structure and function, without genetic or confounding factors. Methods Rabbits underwent thoracic CoA at 10 weeks of age (~ 9 human years) to induce a 20 mm Hg blood pressure (BP) gradient using permanent or dissolvable suture thereby replicating untreated and corrected CoA. Computational fluid dynamics (CFD) was performed using imaging and BP data at 32 weeks to quantify velocity, strain and wall shear stress (WSS) for comparison to vascular structure and function as revealed by histology and myograph results. Results Systolic and mean BP was elevated in CoA compared to corrected and control rabbits leading to vascular thickening, disorganization and endothelial dysfunction proximally and distally. Corrected rabbits had less severe medial thickening, endothelial dysfunction, and stiffening limited to the proximal region despite 12 weeks of normal BP (~ 4 human years) after the suture dissolved. WSS was elevated distally for CoA rabbits, but reduced for corrected rabbits. Discussion These findings are consistent with alterations in humans. We are now poised to investigate mechanical contributions to mechanisms of morbidity in CoA using these methods

Aortic Coarctation: Recent Developments in Experimental and Computational Methods to Assess Treatments for this Simple Condition

Coarctation of the aorta (CoA) is often considered a relatively simple disease, but long-term outcomes suggest otherwise as life expectancies are decades less than in the average population and substantial morbidity often exists. What follows is an expanded version of collective work conducted by the authors\u27 and numerous collaborators that was presented at the 1st International Conference on Computational Simulation in Congenital Heart Disease pertaining to recent advances for CoA. The work begins by focusing on what is known about blood flow, pressure and indices of wall shear stress (WSS) in patients with normal vascular anatomy from both clinical imaging and the use of computational fluid dynamics (CFD) techniques. Hemodynamic alterations observed in CFD studies from untreated CoA patients and those undergoing surgical or interventional treatment are subsequently discussed. The impact of surgical approach, stent design and valve morphology are also presented for these patient populations. Finally, recent work from a representative experimental animal model of CoA that may offer insight into proposed mechanisms of long-term morbidity in CoA is presented