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Molecular and Cellular Characterization of Cardiac Tissue in Postnatal Development

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ClinicalTrials.gov Identifier: NCT00243776
Recruitment Status : Recruiting
First Posted : October 25, 2005
Last Update Posted : September 21, 2018
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Michael Davis, Emory University

Tracking Information
First Submitted Date October 24, 2005
First Posted Date October 25, 2005
Last Update Posted Date September 21, 2018
Study Start Date April 2005
Estimated Primary Completion Date January 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: September 19, 2018)
  • Calcium Current Measures [ Time Frame: Duration of Study (Up to 13 Years) ]
    Calcium currents including transients and modulation of calcium handling by activation of different pathways in isolated cells from waste tissue obtained at the time of surgical repair for Congenital Heart Disease will be measured for the duration of the study.
  • Change in structural, functional and metabolic maturation of Human pluripotent stem cell derived Cardiomyocytes (hPSC-CMs) [ Time Frame: Duration of Study (Up to 3 Years) ]
    Change in structural, functional and metabolic maturation of Human pluripotent stem cell derived Cardiomyocytes (hPSC-CMs) is achieved using combinations of 3D cardiac spheres with multiple environmental cues to improve mitochondrial fatty acid oxidation (FAO or beta-oxidation) pathway will promote functional and metabolic maturation of hPSC-CMs and generate a more clinically relevant model. The outcome will be measured whether the cells achieved maturation (structural, functional and metabolic maturation) or not after using combinations of 3D cardiac spheres with multiple environmental cues.
Original Primary Outcome Measures Not Provided
Change History Complete list of historical versions of study NCT00243776 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures Not Provided
Original Secondary Outcome Measures Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Molecular and Cellular Characterization of Cardiac Tissue in Postnatal Development
Official Title Molecular and Cellular Characterization of Cardiac Tissue in Postnatal Development
Brief Summary The study team will use small pieces of human hearts which are removed as part of a required surgical procedure to study different objectives. One of the objective is how calcium ions pass through the membrane of heart cells in order to tell the heart cell how much force to contract with when the heart beats. Investigators will also study the proteins and RNA of these pieces to determine how the newborn heart cells control their force of contraction differently from adult heart cells. Investigators hypothesize that infant hearts have different regulation of calcium entry than adult hearts. The study team also wants to study combinations of 3D cardiac spheres with multiple environmental cues that can improve functional and metabolic maturation of Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) and generate a more clinically relevant cell model.
Detailed Description

Extrapolating pharmacological and surgical therapies from adult (AD) studies to infant (INF) patients is problematic because the knowledge of cellular electrophysiology and molecular biology of human INF heart cells is limited. The investigators have studied developmental differences in rabbit ventricular cells and now extend these studies to atrial and ventricular cells isolated from AD, young adult (YAD) or INF patients.

The study aims are as follows:

  1. Developmental differences in transient outward current of atrial cells. Investigators will extend their studies to isolated cells and tissue from YADs (age 14-20). In addition, several other accessory beta-subunits have been found in cardiac myocytes and may interact with Kv channels and regulate the function of these channels. The study team will determine relative amounts of these putative regulators of human atrial Ito to determine which correlate with developmental changes in Ito kinetics.
  2. Developmental differences in amplitude and regulation of calcium current in atrial cells. Investigators hypothesize that INF atrial cells have tonic inhibition of adenylyl cyclase (and thus of ICa) mediated by inhibitory G proteins, possibly related to constitutive activity of the adenosine A1 receptor, and that, compared to AD or YAD cells, have greater sensitivity to inhibitors of phosphatases and phosphodiesterases, and that developmental changes in basal ICa amplitude and beta-sympathetic modulation correlate with inhibitory G protein levels, receptor numbers for M2 and A1 receptors, and constitutive inhibitory activity.
  3. Modulation of atrial cell calcium transients by changes in AP waveform and developmental age. The study team will test the hypothesis that prolongation of the early repolarization phase of the after potential (AP) increases Ca2+ entry and that YAD cells have faster removal of Ca2+ from cytoplasm than INF cells and will determine if the Na- Ca2+ exchange current (INCX) is greater in INF vs. AD or YAD cells.
  4. Developmental differences in Ca current and transients and contractility in ventricular cells. Investigators propose that INF cells and tissue have lower basal ICa, lower potency for Isoproterenol stimulation, higher levels of Gialpha3 and A1 receptors, greater inhibitory potency for adenosine, and tonic inhibition of ICa. We also propose that the YAD cells have lower levels of NCX and lower INCX, higher levels of SERCA and faster removal of Ca2+ from the cytoplasm. Previous animal studies have indicated various developmental changes in cardiac cells. We will specifically study human postnatal developmental changes in Ito, regulation of ICa and intracellular Ca2+ transients.
  5. Structural, Functional and Metabolic Maturation of hPSC-CMs. Investigators propose that combinations of 3D cardiac spheres with multiple environmental cues to improve mitochondrial fatty acid oxidation (FAO or beta-oxidation) pathway will promote functional and metabolic maturation of hPSC-CMs and generate a more clinically relevant model. using tissue engineering combined with pharmacological agents to regulate signals that are involved in FAO metabolism and appropriate growth factor and hormonal signaling that mimic the microenvironment for the maturation of CMs.
Study Type Observational
Study Design Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples Without DNA
Description:
tissue obtained from surgical waste tissue
Sampling Method Probability Sample
Study Population Children undergoing surgery for repair of congenital heart disease
Condition
  • Congenital Heart Disease
  • Tetralogy of Fallot
Intervention Not Provided
Study Groups/Cohorts Not Provided
Publications * Wiegerinck RF, Cojoc A, Zeidenweber CM, Ding G, Shen M, Joyner RW, Fernandez JD, Kanter KR, Kirshbom PM, Kogon BE, Wagner MB. Force frequency relationship of the human ventricle increases during early postnatal development. Pediatr Res. 2009 Apr;65(4):414-9. doi: 10.1203/PDR.0b013e318199093c.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Recruiting
Estimated Enrollment
 (submitted: October 24, 2005)
600
Original Enrollment Same as current
Estimated Study Completion Date January 31, 2020
Estimated Primary Completion Date January 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria:

  • Patients undergoing cardiopulmonary bypass surgery

Exclusion Criteria:

  • Prior cardiac surgery
  • History of atrial fibrillation or other atrial arrhythmias prior to operation
Sex/Gender
Sexes Eligible for Study: All
Ages up to 18 Years   (Child, Adult)
Accepts Healthy Volunteers No
Contacts
Contact: Michael E Davis, PhD 404-727-9858 medavis@emory.edu
Contact: Janet Fernandez, RN 4047851731 janet.fernandez@choa.org
Listed Location Countries United States
Removed Location Countries  
 
Administrative Information
NCT Number NCT00243776
Other Study ID Numbers IRB00005500
R01HL077485 ( U.S. NIH Grant/Contract )
35328 ( Other Grant/Funding Number: American Heart Association )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement Not Provided
Responsible Party Michael Davis, Emory University
Study Sponsor Emory University
Collaborators National Heart, Lung, and Blood Institute (NHLBI)
Investigators
Principal Investigator: Michael E Davis, PhD Emory University
PRS Account Emory University
Verification Date September 2018