Mechanistic analysis of mechanical alterations to improve therapeutic interventions for aortic coarctation

Doctor's Name: 
Dr. John LaDisa,
Hospital/Institution: 
Marquette University

Collaboratively awarded through the CHF and AHA Congenital Heart Defect Research Awards
(Total Request = $154,241;  CHF portion = $77,121)

Coarctation of the aorta (CoA) is a constriction of the thoracic aorta and is one of the most common congenital cardiovascular (CV) defects. Treatment by surgical correction has saved the lives of thousands of children, but they still have a reduced lifespan from CV morbidity, mostly due to refractory hypertension. Identifying associated mechanisms is difficult in humans due to confounding variables (e.g. severity of CoA at correction, time to follow-up, concurrent anomalies). Thus, in spite of surgical repair being available for >70 years, the causes of morbidity after correction for CoA remain elusive. This proposal to the AHA/Children’s Heart Foundation (CHF) partnership addresses long-term morbidity after correction for CoA using an innovative animal model devoid of these confounding variables. Our model mimics the pathology of CoA in humans, and permits correction at different times using dissolvable suture. This model is used with computational fluid dynamics to quantify detailed mechanical alterations from the coarctation that we hypothesize are responsible for vascular remodeling, endothelial dysfunction, and eventually lead to long-term morbidity after correction. Mechanical alterations are compared to structural, functional, and mechanistic vascular changes using histology, myography, and protein analysis, respectively. Our preliminary data revealed adverse vascular changes resulting solely from CoA, and indicates these changes may be permanent. Microarray analysis revealed differentially expressed genes after correction of CoA in our model, including decreased expression of SERCA (sarco/endoplasmic reticulum calcium ATPase). This proposal builds on the preliminary data with 2 aims. Aim 1 will determine the minimum mechanical stimuli for persistent vascular remodeling with endothelial and smooth muscle cell dysfunction by varying the severity and duration of CoA within clinical ranges. Aim 2 will correlate down-regulation of the SERCA message with protein expression, and the persistence of pathological changes after correction for CoA. Results from these aims have the potential for clinical translation by proposing a fresh criteria for when correction of CoA should be performed, and identifying potential targets for monitoring persistent vascular alterations. Our goal of translating results to enhance health, reduce morbidity, and allow individuals treated for CoA to live longer healthier lives is aligned with the goals of the AHA/CHF partnership.

 

 

 

Award Date 1: 
2015
Award Amount 1: 
$77,121