Calcium handling remodeling during development and disease

Doctor's Name: 
Dr. Mary Wagner
Hospital/Institution: 
Emory University

Collaboratively awarded through the CHF and AHA Congenital Heart Defect Research Awards
(Total Grant Amount = $178,200; CHF portion = $89,100)

Surgical repair for congenital heart disease (CHD) continues to improve and while surgical repair of some forms of CHD result in normal or near-normal physiology, there are many children who are left with palliated CHD or abnormal hemodynamic loads on their hearts. Many of the treatments for these children were designed for the adult cardiac patient and do not take into account the unique physiology of the early postnatal heart. Furthermore, contractility has been shown to increase with developmental age and may be due, in part, to alterations in calcium handling. Thus, the overall goal of this proposal is to identify alterations of calcium handling in the developing heart and to determine if increased pressure loading of the immature heart alters the development of the calcium handling system. We utilize the developing rabbit heart for these studies but also use our unique collaboration with the cardiovascular surgeons at Children’s Healthcare of Atlanta to obtain ventricular tissue from children undergoing surgical repair for congenital heart defects where part of the repair includes the therapeutic removal of tissue. In our first aim we will systematically examine cytosolic calcium dynamics of the developing rabbit heart and correlate these changes with T-tubule development. We hypothesize that lack of T-tubules in the newborn rabbit alters the spatial distribution and pharmacologic modulation of the calcium transient. We hypothesize that there are developmental changes in the effects of kinases and beta-adrenergic stimulation on calcium movement in the rabbit heart that correspond to T-tubule alterations. In the second aim, we will examine calcium movement in the developing human heart. We will compare cells from patients < 1 week old to those 2-12 months old to determine if the developmental changes we see in the rabbit hold true for human heart development. Our preliminary data suggest that older infants have adverse remodeling that is not seen in the developing rabbit heart. In our third aim, we will determine if pressure overload in an immature rabbit, created by pulmonary artery banding, will induce adverse remodeling of the calcium handling system and thus explain the differences we find in human compared to rabbit development. A better understanding of how the immature heart responds to hemodynamic stress may lead to improved therapies for these young patients

 

Award Date 1: 
2015
Award Amount 1: 
$89,100