Postnatal changes in the mammalian heart make it difficult to extrapolate pharmacological and surgical therapies from adults to infants. Excitation-contraction coupling is the method by which the electrical activity of the heart is translated into the contraction of the heart, with regulation of intracellular calcium playing an integral role. In this study, we will examine the postnatal changes in excitation contraction coupling in the human ventricle. As part of surgical repair of congenital heart defects, ventricular tissue may be removed. We will compare properties of biopsies removed at less than one week of age (newborns) from children with hypoplastic left heart syndrome to ventricular biopsies removed at 3-12 months (infants) of age from children with Tetralogy of Fallot. A better understanding of contraction regulation in infants may suggest therapies that are more appropriate for the pediatric population. SA1: Increasing the strength of contraction is important for treatment of children with heart defects. We show that newborn ventricle, compared to infant, has a blunted response to increases in pacing frequency as well as a diminished response to sympathetic stimulation. We will determine the mechanism of these differences by comparing molecular targets involved in regulation of contraction and examining the contraction with different pharmacological treatments. SA2: We hypothesize that intracellular calcium transients are inhomogeneous in the newborn and become more homogeneous in the first year of life and these changes correlate with the morphology of single ventricular cells. SA3: We will determine if the source of calcium required for contraction is primarily through influx of calcium from the extracellular space or if it is from the intracellular stores, and if this source changes with developmental age. SA4: We will examine other pathways involved in excitation-contraction coupling by testing the hypothesis that sodium-calcium exchange is largest in the newborn human ventricle and decreases with age, thus contributing more to the calcium transient. Furthermore, we hypothesize that the transformation to being more dependent on calcium current (ICa) as a trigger for contraction occurs during the first year of life. SA5: We hypothesize that newborn ventricular cells have smaller ICa and are less sensitive to isoproterenol than infant cells and propose these developmental changes correlate with inhibitory G protein levels. These findings will help to clarify if there are postnatal changes in human ventricle in terms of excitation-contraction coupling and may suggest more appropriate therapies for pediatric patients. This study examines how contraction of the heart changes after birth by comparing properties of heart tissue from patients less than one week old to those 3-12 months old. While heart development has been studied in animal models, very little is known in the human. This study may result in improved therapies for children with heart problems.
|Naqvi, Nawazish; Li, Ming; Calvert, John W et al. (2014) A proliferative burst during preadolescence establishes the final cardiomyocyte number. Cell 157:795-807|
|Ban, Kiwon; Wile, Brian; Kim, Sangsung et al. (2013) Purification of cardiomyocytes from differentiating pluripotent stem cells using molecular beacons that target cardiomyocyte-specific mRNA. Circulation 128:1897-909|
|Wiegerinck, Rob F; Cojoc, Anca; Zeidenweber, Carlo M et al. (2009) Force frequency relationship of the human ventricle increases during early postnatal development. Pediatr Res 65:414-9|
|Wang, Yanggan; Joyner, Ronald W; Wagner, Mary B et al. (2009) Stretch-activated channel activation promotes early afterdepolarizations in rat ventricular myocytes under oxidative stress. Am J Physiol Heart Circ Physiol 296:H1227-35|