title: Dysregulation of cardiolipin biosynthesis in pediatric heart failure.
abstract: Cardiolipin, a unique phospholipid in the inner mitochondrial membrane, is critical for optimal mitochondrial function. CL abnormalities have been demonstrated in the failing rodent and adult human heart. The aim of this study was to determine whether abnormalities in CL content and the CL biosynthesis and remodeling pathways are present in pediatric idiopathic dilated cardiomyopathy (IDC). A cross-sectional analysis of myocardial tissue from 119 IDC and non-failing (NF) control samples was performed. Electrospray ionizing mass spectrometry was used to measure total CL and CL species content in LV tissue. RT-PCR was employed to measure gene expression of the enzymes in the CL biosynthesis and remodeling pathways in both the adult and pediatric heart. Significantly lower total and (18:2)4CL (the beneficial species) content was demonstrated in myocardium from pediatric patients with IDC compared to NF controls. Analysis of mitochondrial gene transcripts was used to demonstrate that there is no decrease in mitochondrial content. Expression of two biosynthesis enzymes and one remodeling enzyme was significantly lower in pediatric IDC compared to NF controls. Expression of two phospholipases involved in CL degradation were also altered, one up- and one down-regulated. Except for one remodeling enzyme, these changes are unique from those in the failing adult heart. Similar to what has been seen in adults and in a rat model of IDC, total and (18:2)4CL are lower in pediatric IDC. Unique CL species profiles are seen in heart tissue from children with IDC compared to adults. Differences in CL biosynthesis and remodeling enzyme expression likely explain the differences in CL profiles observed in IDC and implicate unique age-related mechanisms of disease.
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, CO, USA. Electronic address: kathryn.chatfield@ucdenver.edu.
authors.forename: Kathryn C
authors.initials: KC
authors.lastname: Chatfield
authors.affiliation: Department of Integrative Physiology, University of Colorado, Boulder, CO, USA.
authors.forename: Genevieve C
authors.initials: GC
authors.lastname: Sparagna
authors.affiliation: Department of Medicine/Division of Cardiology, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Carmen C
authors.initials: CC
authors.lastname: Sucharov
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, CO, USA.
authors.forename: Shelley D
authors.initials: SD
authors.lastname: Miyamoto
authors.affiliation: University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Grudis
authors.affiliation: Department of Medicine/Division of Cardiology, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Rebecca D
authors.initials: RD
authors.lastname: Sobus
authors.affiliation: Department of Medicine/Division of Cardiology, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Jamie
authors.initials: J
authors.lastname: Hijmans
authors.affiliation: Department of Medicine/Division of Cardiology, University of Colorado School of Medicine, Aurora, CO, USA; Department of Integrative Physiology, University of Colorado, Boulder, CO, USA; Division of Cardiology, Denver Health Medical Center, Denver, CO, USA.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Stauffer
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D002308:Cardiolipins / Q000096:biosynthesis* / Q000737:chemistry; D002311:Cardiomyopathy, Dilated / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D002648:Child; D002675:Child, Preschool; D005260:Female; D015870:Gene Expression; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D016027:Heart Transplantation; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology
chemical_list: D002308:Cardiolipins; D024101:Mitochondrial Proteins
keywords: Cardiolipin; Dilated cardiomyopathy; Heart failure; Mitochondria; Pediatric