The Carotid Intima-Media Thickness and Arterial Stiffness of Pediatric Mucopolysaccharidosis Patients Are Increased Compared to Both Pediatric and Adult Controls

Raymond Y Wang, Kyle D Rudser, Donald R Dengel, Elizabeth A Braunlin, Julia Steinberger, David R Jacobs, Alan R Sinaiko, Aaron S Kelly, Raymond Y Wang, Kyle D Rudser, Donald R Dengel, Elizabeth A Braunlin, Julia Steinberger, David R Jacobs, Alan R Sinaiko, Aaron S Kelly

Abstract

Treatments for mucopolysaccharidoses (MPSs) have increased longevity, but cardiovascular disease causes mortality in a significant percentage of survivors. Markers must be developed to predict MPS cardiac risk and monitor efficacy of investigational therapies.MPS patients underwent carotid artery ultrasonography from which carotid intima-media thickness (cIMT) and three measures of arterial stiffness were calculated: carotid artery distensibility (cCSD), compliance (cCSC), and incremental elastic modulus (cIEM). MPS carotid measurements were compared to corresponding data from pediatric and adult healthy cohorts. 33 MPS patients (17 MPS I, 9 MPS II, 4 MPS IIIA, and 3 MPS VI; mean age 12.5 ± 4.7 years), 560 pediatric controls (age 13.1 ± 4.0 years), and 554 adult controls (age 39.2 ± 2.2 years) were studied. Age and sex-adjusted aggregate MPS cIMT (0.56 ± 0.05 mm) was significantly greater than both pediatric (+0.12 mm; 95% CI +0.10 to +0.14 mm) and adult (+0.10 mm; 95% CI +0.06 to +0.14 mm) control cohorts; similar findings were observed for all MPS subtypes. Mean MPS cIMT approximated the 80th percentile of the adult cohort cIMT. MPS patients also demonstrated significantly increased adjusted arterial stiffness measurements, evidenced by reduced cCSD, cCSC, and increased cIEM, compared to pediatric and adult control cohorts. Regardless of treatment, MPS patients demonstrate increased cIMT and arterial stiffness compared to healthy pediatric and adult controls. These data suggest that relatively young MPS patients demonstrate a "structural vascular age" of at least 40 years old.

Keywords: function; intima; lysosomal; media; mucopolysaccharidosis; outcome; stiffness; structure; thickness; treatment; vascular.

Conflict of interest statement

Raymond Y. Wang has received consultancy fees from Biomarin Pharmaceutical, Shire, and Genzyme-Sanofi. None of these entities played any role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. All other co-authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Scatter plots of carotid measurements from MPS cohort (blue stars), pediatric, and adult control cohorts (gray circles) versus age. (A) Carotid intima-media thickness; (B) carotid incremental elastic modulus; (C) carotid cross-sectional distensibility; (D) carotid cross-sectional compliance. The orange lines in each panel denote the 20th (lower) and 80th (upper) percentiles of control cohort measurements.

References

    1. Neufeld E.F., Muenzer J. The Mucopolysaccharidoses. In: Scriver C., Beaudet A.L., Sly W., Valle D., editors. The Metabolic and Molecular Basis of Inherited Disease. McGraw-Hill; New York, NY, USA: 2001. pp. 3421–3452.
    1. Braunlin E.A., Stauffer N.R., Peters C.H., Berry J.M., Bass J.L., Hopwood J.J., Krivit W. Usefulness of bone marrow transplantation in the Hurler syndrome. Am. J. Cardiol. 2003;93:882–886. doi: 10.1016/S0002-9149(03)00909-3.
    1. Lin H.Y., Lin S.P., Chuang C.K., Chen M.R., Chen B.F., Wraith J.E. Mucopolysaccharidosis I under enzyme replacement therapy with laronidase—A mortality case with autopsy report. J. Inherit. Metab. Dis. 2005;28:1146–1148. doi: 10.1007/s10545-005-0211-x.
    1. Yano S., Moseley K., Pavlova Z. Postmortem studies on a patient with mucopolysaccharidosis type I: Histopathological findings after one year of enzyme replacement therapy. J. Inherit. Metab. Dis. 2009;32:S53–S57. doi: 10.1007/s10545-009-1057-4.
    1. Van den Broek L., Backx A.P., Coolen H., Wijburg F.A., Wevers R., Morava E., Neeleman C. Fatal coronary artery disease in an infant with severe mucopolysaccharidosis type I. Pediatrics. 2011;127:1343–1346. doi: 10.1542/peds.2009-2047.
    1. Gupta S., O’Meara A., Wynn R., McDermott M. Fatal and unanticipated cardiorespiratory disease in a two-year-old child with Hurler syndrome following successful stem cell transplant. JIMD Rep. 2013;10:1–5.
    1. Aldenhoven M., Wynn R.F., Orchard P.J., O’Meara A., Veys P., Fischer A., Valayannopoulos V., Neven B., Rovelli A., Prasad VK., et al. Long-term outcome of Hurler syndrome patients after hematopoietic cell transplantation: An international multicenter study. Blood. 2015;125:2164–2172. doi: 10.1182/blood-2014-11-608075.
    1. Lin H.Y., Chuang C.K., Huang Y.H., Tu R.Y., Lin F.J., Lin S.J., Chiu P.C., Niu D.M., Tsai F.J., Hwu W.L., et al. Causes of death and clinical characteristics of 34 patients with Mucopolysaccharidosis II in Taiwan from 1995–2012. Orphanet. J. Rare Dis. 2016;11:1–7. doi: 10.1186/s13023-016-0471-6.
    1. Braunlin E., Orchard P.J., Whitley C.B., Schroeder L., Reed R.C., Manivel J.C. Unexpected coronary artery findings in mucopolysaccharidosis. Report of four cases and literature review. Cardiovasc. Pathol. 2014;23:145–151. doi: 10.1016/j.carpath.2014.01.001.
    1. Wendelhag I., Gustavsson T., Suurküla M., Berglund G., Wikstrand J. Ultrasound measurement of wall thickness in the carotid artery: Fundamental principles and description of a computerized analysing system. Clin. Physiol. 1991;11:565–577. doi: 10.1111/j.1475-097X.1991.tb00676.x.
    1. Wang R.Y., Covault K.K., Halcrow E.M., Gardner A.J., Cao X., Newcomb R.L., Dauben R.D., Chang A.C. Carotid intima-media thickness is increased in patients with mucopolysaccharidoses. Mol. Genet. Metab. 2011;104:592–596. doi: 10.1016/j.ymgme.2011.09.004.
    1. Wang R.Y., Braunlin E.A., Rudser K.D., Dengel D.R., Metzig A.M., Covault K.K., Polgreen L.E., Shapiro E., Steinberger J., Kelly A.S. Carotid intima-media thickness is increased in patients with treated mucopolysaccharidosis types I and II, and correlates with arterial stiffness. Mol. Genet. Metab. 2014;111:128–132. doi: 10.1016/j.ymgme.2013.11.001.
    1. Mitchell J., Berger K.I., Borgo A., Braunlin E.A., Burton B.K., Ghotme K.A., Kircher S.G., Molter D., Orchard P.J., Palmer J., et al. Unique medical issues in adult patients with mucopolysaccharidoses. Eur. J. Intern. Med. 2016 doi: 10.1016/j.ejim.2016.05.017.
    1. Braunlin E., Wang R. Cardiac issues in adults with the mucopolysaccharidoses: Current knowledge and emerging needs. Heart. 2016 doi: 10.1136/heartjnl-2015-309258.
    1. Pignoli P., Tremoli E., Poli A., Oreste P., Paoletti R. Intimal plus medial thickness of the arterial wall: A direct measurement with ultrasound imaging. Circulation. 1986;74:1399–1406. doi: 10.1161/01.CIR.74.6.1399.
    1. Lorenz M.W., Markus H.S., Bots M.L., Rosvall M., Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness. Circulation. 2007;115:459–467. doi: 10.1161/CIRCULATIONAHA.106.628875.
    1. Ylä-Herttuala S., Solakivi T., Hirvonen J., Laaksonen H., Möttönen M., Pesonen E., Raekallio J., Akerblom H.K., Nikkari T. Glycosaminoglycans and apolipoproteins B and A-I in human aortas. Chemical and immunological analysis of lesion-free aortas from children and adults. Arteriosclerosis. 1987;7:333–340. doi: 10.1161/01.ATV.7.4.333.
    1. Funderburgh J.L., Funderburgh M.L., Mann M.M., Conrad G.W. Arterial lumican. Properties of a corneal-type keratan sulfate proteoglycan from bovine aorta. J. Biol. Chem. 1991;266:24773–24777.
    1. Schiattarella G.G., Cerulo G., de Pasquale V., Cocchiaro P., Paciello O., Avallone L., Belfiore M.P., Iacobellis F., di Napoli D., Magliulo F., et al. The murine model of mucopolysaccharidosis IIIB develops cardiopathies over time leading to heart failure. PLoS ONE. 2015;10:e0131662. doi: 10.1371/journal.pone.0131662.
    1. Yasuda E., Fushimi K., Suzuki Y., Shimizu K., Takami T., Zustin J., Patel P., Ruhnke K., Shimada T., Boyce B., et al. Pathogenesis of Morquio A syndrome: An autopsied case reveals systemic storage disorder. Mol. Genet. Metab. 2013;109:301–311. doi: 10.1016/j.ymgme.2013.04.009.
    1. Metcalf J.A., Linders B., Wu S., Bigg P., O’Donnell P., Sleeper M.M., Whyte M.P., Haskins M., Ponder K.P. Upregulation of elastase activity in aorta in mucopolysaccharidosis I and VII dogs may be due to increased cytokine expression. Mol. Genet. Metab. 2010;99:396–407. doi: 10.1016/j.ymgme.2009.12.003.
    1. Lyons J.A., Dickson P.I., Wall J.S., Passage M.B., Ellinwood N.M., Kakkis E.D., McEntee M.F. Arterial pathology in canine mucopolysaccharidosis-I and response to therapy. Lab. Investig. 2011;91:665–674. doi: 10.1038/labinvest.2011.7.
    1. Khalid O., Vera M.U., Gordts P.L., Ellinwood N.M., Schwartz P.H., Dickson P.I., Esko J.D., Wang R.Y. Immune-mediated inflammation may contribute to the pathogenesis of cardiovascular disease in mucopolysaccharidosis type I. PLoS ONE. 2016;11:e0150850. doi: 10.1371/journal.pone.0150850.
    1. Simonaro C.M., Tomatsu S., Sikora T., Kubaski F., Frohbergh M., Guevara J.M., Wang R.Y., Vera M., Kang J.L., Smith L.J., et al. Pentosan polysulfate: Oral versus subcutaneous injection in mucopolysaccharidosis type I dogs. PLoS ONE. 2016;11:e0153136. doi: 10.1371/journal.pone.0153136.
    1. Syeda B., Gottsauner-Wolf M., Denk S., Pichler P., Khorsand A., Glogar D. Arterial compliance: A diagnostic marker for atherosclerotic plaque burden? Am. J. Hypertens. 2003;16:356–362. doi: 10.1016/S0895-7061(03)00037-2.
    1. Kiotsekoglou A., Moggridge J.C., Kapetanakis V., Newey V.R., Kourliouros A., Mullen M.J., Kaski J.C., Nassiri D.K., Camm J., Sutherland G.R., et al. Assessment of carotid compliance using real time vascular ultrasound image analysis in Marfan syndrome. Echocardiography. 2009;26:441–451. doi: 10.1111/j.1540-8175.2008.00813.x.
    1. Hinderer C., Bell P., Gurda B.L., Wang Q., Louboutin J.P., Zhu Y., Bagel J., O’Donnell P., Sikora T., Ruane T., et al. Liver-directed gene therapy corrects cardiovascular lesions in feline mucopolysaccharidosis type I. Proc. Natl. Acad. Sci. USA. 2014;111:14894–14899. doi: 10.1073/pnas.1413645111.
    1. Liu Y., Xu L., Hennig A.K., Kovacs A., Fu A., Chung S., Lee D., Wang B., Herati R.S., Mosinger Ogilvie J., et al. Liver-directed neonatal gene therapy prevents cardiac, bone, ear, and eye disease in mucopolysaccharidosis I mice. Mol. Ther. 2005;11:35–47. doi: 10.1016/j.ymthe.2004.08.027.
    1. Marlatt K.L., Kelly A.S., Steinberger J., Dengel D.R. The influence of gender on carotid artery compliance and distensibility in children and adults. J. Clin. Ultrasound. 2013;41:340–346. doi: 10.1002/jcu.22015.
    1. Steffen L.M., Sinaiko A.R., Zhou X., Moran A., Jacobs D.R., Jr., Korenfeld Y., Dengel D.R., Chow L.S., Steinberger J. Relation of adiposity, television and screen time in offspring to their parents. BMC Pediatr. 2013;13:1–8. doi: 10.1186/1471-2431-13-133.
    1. Halvorsen T., Moran A., Jacobs D.R., Jr., Steffen L.M., Sinaiko A.R., Zhou X., Steinberger J. Relation of cardiometabolic risk factors between parents and children. J. Pediatr. 2015;167:1049–1056. doi: 10.1016/j.jpeds.2015.07.053.
    1. Ryder J.R., Dengel D.R., Jacobs D.R., Jr., Sinaiko A.R., Kelly A.S., Steinberger J. Relations among adiposity and insulin resistance with flow-mediated dilation, carotid intima-media thickness, and arterial stiffness in children. J. Pediatr. 2016;168:205–211. doi: 10.1016/j.jpeds.2015.08.034.
    1. Neocleous T., Portnoy S. Partially linear censored quantile regression. Lifetime Data Anal. 2009;15:357–378. doi: 10.1007/s10985-009-9117-5.
    1. R Core Team . R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing; Vienna, Austria: 2016.

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