Congenital Heart Disease Characterization and Functionality of Cardiac Progenitor Cells in Congenital Heart Patients

Background—Human cardiac progenitor cells (hCPCs) may promote myocardial regeneration in adult ischemic myocardium. The regenerative capacity of hCPCs in young patients with nonischemic congenital heart defects for potential use in congenital heart defect repair warrants exploration. Methods and Results—Human right atrial specimens were obtained during routine congenital cardiac surgery across 3 groups: neonates (age, Ͻ30 days), infants (age, 1 month to 2 years), and children (age, Ͼ2 to Յ13 years). C-kit ϩ hCPCs were 3-fold higher in neonates than in children Ͼ2 years of age. hCPC proliferation was greatest during the neonatal period as evidenced by c-kit ϩ Ki67 ϩ expression but decreased with age. hCPC differentiation capacity was also greatest in neonatal right atrium as evidenced by c-kit ϩ , NKX2–5 ϩ , NOTCH1 ϩ , and NUMB ϩ expression. Despite the age-dependent decline in resident hCPCs, we isolated and expanded right atrium– derived CPCs from all patients (nϭ103) across all ages and diagnoses using the cardiosphere method. Intact cardiospheres contained a mix of heart-derived cell subpopulations that included cardiac progenitor cells expressing c-kit ϩ , Islet-1, and supporting cells. The number of c-kit ϩ – expressing cells was highest in human cardiosphere-derived cells (hCDCs) grown from neonatal and infant right atrium. Furthermore, hCDCs could differentiate into diverse cardiovascular lineages by in vitro differentiation assays. Transplanted hCDCs promoted greater myocardial regeneration and functional improvement in infarcted myocardium than transplanted cardiac fibroblasts. Conclusions—Resident hCPCs are most abundant in the neonatal period and rapidly decrease over time. hCDCs can be reproducibly isolated and expanded from young human myocardial samples regardless of age or diagnosis. hCPCs are functional and have potential in congenital cardiac repair. T he exact prevalence of pediatric heart failure is largely unknown but is growing because new treatments have increased the life expectancy of these patients. The number of congenital heart patients living presently outnumbers new congenital cardiac diagnoses, occurring in 35 000 to 40 000 infants per year in the United States. 1 Whereas adult heart failure is often ischemic in origin, the origin of pediatric heart failure is more varied, including a spectrum of cardiomyop-athies, congenital heart defects (CHDs), and arrhythmias. 2 A novel emerging treatment for pediatric heart failure is cellular cardiomyoplasty whereby stem cells are delivered to the dysfunctional myocardium, an approach attempted thus far only in adults. 3– 6 Most human studies have addressed the adult diseased myocardium, which is confounded by the …