title: Cardiac disease in mucopolysaccharidosis type I attributed to catecholaminergic and hemodynamic deficiencies.
abstract: Cardiac dysfunction is a common cause of death among pediatric patients with mutations in the lysosomal hydrolase α-l-iduronidase (IDUA) gene, which causes mucopolysaccharidosis type I (MPS-I). The purpose of this study was to analyze adrenergic regulation of cardiac hemodynamic function in MPS-I. An analysis of murine heart function was performed using conductance micromanometry to assess in vivo cardiac hemodynamics. Although MPS-I (IDUA(-/-)) mice were able to maintain normal cardiac output and ejection fraction at baseline, this cohort had significantly compromised systolic and diastolic function compared with IDUA(+/-) control mice. During dobutamine infusion MPS-I mice did not significantly increase cardiac output from baseline, indicative of blunted cardiac reserve. Autonomic tone, measured functionally by β-blockade, indicated that MPS-I mice required catecholaminergic stimulation to maintain baseline hemodynamics. Survival analysis showed mortality only among MPS-I mice. Linear regression analysis revealed that heightened end-systolic volume in the resting heart is significantly correlated with susceptibility to mortality in MPS-I hearts. This study reveals that cardiac remodeling in the pathology of MPS-I involves heightened adrenergic tone at the expense of cardiac reserve with cardiac decompensation predicted on the basis of increased baseline systolic volumes.
authors.affiliation: Department of Integrative Biology and Physiology, University of Minnesota Medical School, University of Minnesota Academic Health Center, Minneapolis, Minnesota 55455, USA.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Palpant
authors.forename: Fikru B
authors.initials: FB
authors.lastname: Bedada
authors.forename: Brandon
authors.initials: B
authors.lastname: Peacock
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Metzger
authors.forename: Jakub
authors.initials: J
authors.lastname: Tolar
mesh_terms: D058665:Adrenergic beta-1 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D000873:Anthracenes; D015153:Blotting, Western; D004280:Dobutamine / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006331:Heart Diseases / Q000378:metabolism* / Q000503:physiopathology*; D006439:Hemodynamics; D016014:Linear Models; D051379:Mice; D018345:Mice, Knockout; D008059:Mucopolysaccharidosis I / Q000378:metabolism* / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism*; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D058665:Adrenergic beta-1 Receptor Agonists; C546739:AnOV compound; D000873:Anthracenes; D004280:Dobutamine