title: Carotid intima-media thickness is increased in patients with treated mucopolysaccharidosis types I and II, and correlates with arterial stiffness.
abstract: BACKGROUND
  Treatments for mucopolysaccharidoses (MPSs) have increased longevity, but coronary artery disease (CAD) and cardiovascular complications cause mortality in a high percentage of patients. Non-invasive measures of sub-clinical atherosclerosis, such as carotid intima-media thickness (cIMT) and arterial stiffness, may be useful for prediction of CAD outcomes in MPS patients.
  
  
  OBJECTIVE
  The aim of the study was to determine if cIMT and arterial stiffness are abnormal in MPS I and II patients compared to healthy controls.
  
  
  METHODS
  MPS patients underwent carotid artery ultrasonography, and electronic wall-tracking software was used to measure cIMT, carotid artery cross-sectional compliance (cCSC), cross-sectional distensibility (cCSD), and incremental elastic modulus (cIEM). Control data from healthy subjects were obtained from a different study that utilized identical testing within the same laboratory.
  
  
  RESULTS
  A total of 406 healthy controls and 25 MPS patients (16 MPS I, 9 MPS II) were studied. All MPS patients had or were receiving treatment: 15 patients (6 MPS I, 9 MPS II) were receiving enzyme replacement therapy (ERT), 9 patients (all MPS I) had received hematopoietic stem cell transplant (HSCT), and 1 patient with MPS I had received HSCT and was receiving enzyme replacement therapy (ERT). MPS patients had significantly higher mean (± SD) cIMT (0.56 ± 0.05 mm) compared to controls (0.44 ± 0.04 mm; adjusted p<0.001). MPS patients also had increased stiffness compared to controls, showing significantly lower cCSC (0.14 ± 0.09 mm(2)/mmHg versus 0.16 ± 0.05 mm(2)/mmHg; adjusted p=0.019), and higher cIEM (1362 ± 877 mmHg versus 942 ± 396 mmHg; adjusted p<0.001). cCSD in MPS patients was lower than that of controls (29.7 ± 16.4% versus 32.0 ± 8.2%) but was not statistically significant; p=0.12. Among MPS patients, cCSD showed a significant association with cIMT (p=0.047), while the association between cIEM and cIMT approached significance (p=0.077). No significant differences were observed in cIMT, cCSD, cCSC, and cIEM between MPS I and MPS II patients.
  
  
  CONCLUSIONS
  Despite treatment, MPS patients had higher cIMT compared to healthy controls, indicating this marker of sub-clinical atherosclerosis may be a useful predictor of CAD outcomes. The association of arterial stiffness measures with cIMT suggests that mechanical and structural changes may occur in concert among MPS patients. Although yet to be confirmed, increased cIMT and arterial stiffness in MPS I and II patients may be a consequence of inflammatory signaling pathways triggered by heparan or dermatan sulfate-derived oligosaccharides. Prospective, longitudinal studies will need to be performed in order to evaluate the usefulness of these carotid measurements as predictors of adverse CAD outcomes in MPS patients.
authors.affiliation: Division of Metabolic Disorders, CHOC Children's Specialists, Orange, CA, USA. Electronic address: rawang@choc.org.
authors.forename: Raymond Y
authors.initials: RY
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Braunlin
authors.affiliation: Division of Biostatistics, University of Minnesota, School of Public Health, Minneapolis, MN, USA.
authors.forename: Kyle D
authors.initials: KD
authors.lastname: Rudser
authors.affiliation: School of Kinesiology, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Donald R
authors.initials: DR
authors.lastname: Dengel
authors.affiliation: Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Metzig
authors.affiliation: Division of Metabolic Disorders, CHOC Children's Specialists, Orange, CA, USA.
authors.forename: Kelly K
authors.initials: KK
authors.lastname: Covault
authors.affiliation: Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: Lynda E
authors.initials: LE
authors.lastname: Polgreen
authors.affiliation: Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: Elsa
authors.initials: E
authors.lastname: Shapiro
authors.affiliation: Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Steinberger
authors.affiliation: Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: Aaron S
authors.initials: AS
authors.lastname: Kelly
mesh_terms: D000293:Adolescent; D002339:Carotid Arteries / Q000000981:diagnostic imaging / Q000473:pathology*; D059168:Carotid Intima-Media Thickness; D016022:Case-Control Studies; D002648:Child; D003324:Coronary Artery Disease / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology* / Q000628:therapy; D003430:Cross-Sectional Studies; D056947:Enzyme Replacement Therapy; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008059:Mucopolysaccharidosis I / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology* / Q000628:therapy; D016532:Mucopolysaccharidosis II / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology* / Q000628:therapy; D011446:Prospective Studies; D011994:Recombinant Proteins / Q000627:therapeutic use; D016896:Treatment Outcome; D059289:Vascular Stiffness
chemical_list: D011994:Recombinant Proteins
keywords: Hunter; Hurler; Intima–media thickness; Marker; Mucopolysaccharidosis; Vascular disease