Carotid intima-media thickness is increased in patients with mucopolysaccharidoses

doi:10.1016/j.ymgme.2011.09.004

Molecular Genetics and Metabolism

Volume 104, Issue 4, December 2011, Pages 592-596

https://doi.org/10.1016/j.ymgme.2011.09.004 Get rights and content

Abstract

Background

The feasibility of carotid artery intima-media thickness (C-IMT), an established cardiovascular disease marker, as a cardiac risk marker in mucopolysaccharidosis (MPS) patients was explored.

Objectives

To determine if C-IMT is abnormal in MPS versus unaffected controls, and if C-IMT correlates with coronary artery diameter in MPS.

Material and methods

Measurements of C-IMT via neck ultrasound and echocardiographic parameters, including coronary artery diameters, were obtained from MPS and control patients, and compared.

Results

Sixteen MPS subjects (6 MPS I, 6 MPS II, 2 MPS III, 1 MPS VI, 1 MPS VII) and sixteen age, ethnicity, and gender-matched controls were enrolled. Median MPS and control subject ages were 8.3 ± 4.5 and 8.6 ± 4.3 years, respectively (p = 0.73). Mean MPS and control C-IMTs were 0.54 ± 0.070 and 0.48 ± 0.034 mm (p = 0.0029). No differences in left main, left anterior descending, or right coronary artery diameters were seen between MPS and controls. A significant proportion of MPS subjects had mitral insufficiency (14/16; p = 0.0002), aortic insufficiency (10/16; p = 0.0021), and left ventricular dilatation (7/16, p = 0.037) versus controls. C-IMT did not correlate significantly with age, height, weight, coronary measurements, or duration of treatment.

Conclusion

C-IMT in MPS patients is increased compared to matched controls, likely reflective of arterial intima-medial glycosaminoglycan accumulation. MPS subjects demonstrated a high percentage of left-sided valvular insufficiency and ventricular dilatation. Additional studies should be performed in MPS patients to determine if C-IMT correlates with arterial elasticity, biomarkers of vascular dysfunction, and higher risk of cardiovascular events.

Highlights

► Carotid IMTs of mucopolysaccharidosis patients and matched controls were measured. ► Carotid IMT of mucopolysaccharidosis cohort was significantly greater than controls. ► No correlations seen with carotid IMT and age or duration of treatment. ► Carotid IMT is a viable marker of cardiovascular disease for mucopolysaccharidosis.

Introduction

The mucopolysaccharidoses (MPSs) are a group of seven inborn errors of metabolism linked by a deficiency in lysosomal hydrolases that catalyze the stepwise degradation of glycosaminoglycans (GAGs). As a result of the enzyme deficiency, GAGs that are normally recycled in a healthy individual cannot be degraded in the MPS patient. Specific MPS symptomatology varies according to the missing hydrolase and location of accumulating GAG species, but is usually multisystemic and always progressive without treatment. Somatic symptoms of GAG storage include airway compromise, hearing loss, cardiac valvular dysplasia, coronary stenosis, visceromegaly, spinal cord compression, vertebral dysplasia, and restriction of joint mobility. When present, neurologic symptoms from central nervous system storage manifest as psychomotor stagnation, then steady regression of skills until all developmental milestones have been lost [1].

The advent of intravenous enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT) as treatments for specific types of MPS has dramatically altered the natural history of MPS [2], [3], [4], [5]. Although ERT and HSCT are able to mitigate many symptoms of MPS, it is important to emphasize that they are only treatments and not cures. Certain tissues remain resistant to treatment and continue to manifest GAG storage [3], [5], [6], [7]. In addition, with treatment, more MPS patients are now surviving into adulthood and face a different set of potentially life-threatening disease complications. Worsening valvular disease, cardiac dysfunction, and coronary intimal proliferation with stenosis have been reported in stably treated patients [8], [9], [10], [11]. A review of the Hunter Outcome Survey, a global registry of MPS II patients, showed that 16% of the Hunter syndrome deaths reported to the survey were a result of cardiac complications; this was most pronounced in the patients older than 20 years of age, where cardiac etiologies accounted for 33% of deaths [12]. While complications related to coronary artery stenosis are being recognized as potentially fatal manifestations of MPS [11], [13], [14], there are currently no validated markers of cardiovascular or coronary artery disease in this disease population.

We report the results of a pilot study conducted to explore the feasibility of common carotid intima-media thickness (C-IMT) as a cardiovascular risk marker in MPS patients by comparing them with age, ethnicity, and gender-matched unaffected controls.

Section snippets

Human subjects

Approval from the CHOC Children's Institutional Review Board obtained for this study (Study #090538). Patients were recruited from the Multidisciplinary Lysosomal Program at CHOC Children's. Matched controls included unaffected siblings (n = 2; 1 carrier sibling of MPS I patient and 1 homozygous normal sibling) or unrelated individuals (n = 14). Informed consent was obtained for all patients participating in this study. Anthropomorphic measurements (height, weight, body surface area) were obtained

Human subjects

There were no significant differences in mean age, height, weight, gender distribution, or ethnicity between the MPS and control groups (Table 1). Sixteen patients with MPS were enrolled: six had MPS I, six had MPS II, two had MPS IIIa, and one each with MPS types VI and VII. A summary of their confirmatory testing, type and duration of treatment, and symptoms can be found in Table 2. The four patients with severe MPS I received HSCT at a median age of 1.36 years; none were taking

Discussion

Carotid intima-media thickness (C-IMT) measurement is an ultrasonographic method that has been validated as a noninvasive marker of cardiovascular disease in many conditions, including hypertension, hyperlipidemia, and diabetes mellitus. In adults, each 0.1 mm increase above the mean has been estimated to increase lifetime myocardial infarction and stroke risk by up to 15% and 18%, respectively [15]. Although pediatric C-IMT does vary with height, weight, gender, blood pressure, and other

Conflicts of interest

Raymond Wang has received speaking honoraria from Shire Human Genetic Therapies, plc. unrelated to this study, and had costs of travel and accommodation for Lysosomal Disease Registry meetings unrelated to this report paid by the Genzyme Corporation.

Acknowledgments

This study was funded with support from the CHOC Children's Pediatric Subspecialty Faculty, Shire Human Genetic Therapies, and NIH UL1 RR031985 (UC Irvine, CTSA) from the National Center for Research Resources, a component of the National Institutes of Health (NIH) and the NIH Roadmap for Medical Research. We also wish to express our gratitude to the Commission for Families and Children of Orange County for its support of our clinical work.

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Biomarkers of Glycosaminoglycans (GAG) accumulation in patients with mucopolysaccharidosis type VI—LeukoGAG, Corneal Opacification (COM) and Carotid Intima Media Thickening (CIMT)
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Mucopolysaccharidosis type VI (MPS VI) is an autosomal recessive lysosomal storage disorder characterized by deficient activity of arylsulfatase B enzyme (ASB) resulting in cellular accumulation of dermatan sulfate (DS) and chondroitin sulfate (CS) that leads to cell injury. Urinary glycosaminoglycans (GAG) are often used as a biomarker in MPS diseases for diagnosis and to monitor treatment efficacy. This study evaluated leukocyte GAGs (leukoGAG) and skin GAGs as alternate biomarkers representing intracellular GAG changes in patients with MPS VI and treated with enzyme replacement therapy (ERT). In addition, we evaluated corneal opacification measurements (COM) and carotid intima media thickness (CIMT) as indicators of GAG accumulation and tissue injury. The study was performed in a serial two-step design in a single center. A quantitative method to measure leukoGAG levels in leukocytes was developed in Study 1 to compare the GAG levels between MPS VI patients and a control group and to assess correlations between leukoGAG and urineGAG. Study 2 validated the leukoGAG measurement, assessed the effect of ERT infusion on leukoGAG and ASB activity in leukocytes, identified correlations between leukoGAG and other biomarkers, and assessed differences in GAG accumulation between MPS VI patients and control subjects. In Study 1, leukoCS and leukoDS levels were significantly higher in the MPS VI group than the control group (leukoCS: 37.9 ± 10.2 and 2.9 ± 1.5 μg/μg protein, respectively, p = 0.005; leukoDS: 0.26 ± 0.2 and 0.0 ± 0.0 μg/μg protein, respectively, p = 0.028) with positive correlations between leukoCS and urine CS and leukoDS and urineDS. In Study 2, leukoCS (32.0 ± 11.8 vs 6.9 ± 3.1 μg/mg protein, p = 0.005) and leukoDS (0.4 ± 0.1 and 0.2 ± 0.1 μg/mg protein, p = 0.020) were significantly higher compared with control subjects. Thus, these results highlight the potential of leukoGAG as a new biomarker representing intracellular GAG accumulation in MPS VI patients and may be valuable for patient management.
Natural history of echocardiographic abnormalities in mucopolysaccharidosis III
2018, Molecular Genetics and Metabolism
Citation Excerpt :
Mucopolysaccharidosis (MPS) type III, Sanfilippo Syndrome, is an autosomal recessive lysosomal storage disorder with four described subtypes typically diagnosed in early childhood [1]. Patients with MPS disorders lack one of many enzymes necessary for glycosaminoglycan (GAG) breakdown, and as a result have an accumulation of GAGs in various tissues within the body [2]. The proposed mechanism for cardiac involvement in MPS is accumulation of GAGs within the cardiac valves, coronary arties, great vessels, and cardiac myocytes [3,4].
Mucopolysaccharidosis (MPS) type III, Sanfilippo Syndrome, is an autosomal recessive lysosomal storage disorder. MPS I and II patients often develop cardiac involvement leading to early mortality, however there are limited data in MPS III. The objective of this study is to describe cardiac abnormalities in a large group of MPS III patients followed in a longitudinal natural history study designed to determine outcome measures for gene transfer trials.
A single center study of MPS III patients who were enrolled in the Nationwide Children's Hospital natural history study in 2014. Two cardiologists reviewed all patient echocardiograms for anatomic, valvular, and functional abnormalities. Valve abnormalities were defined as abnormal morphology, trivial mitral regurgitation (MR) with abnormal morphology or at least mild MR, and any aortic regurgitation (AR). Abnormal left ventricular (LV) function was defined as ejection fraction < 50%. Group comparisons were assessed using two-sample t-tests or Wilcoxon rank sum tests for continuous variables and chi-square or Fisher's exact tests for categorical variables.
Twenty-five patients, 15 Type A and 10 Type B MPS III, underwent 45 echocardiograms. Fifteen patients (60%) demonstrated an abnormal echocardiographic finding with age at first abnormal echocardiogram within the study being 6.8 ± 2.8 years. Left-sided valve abnormalities were common over time: 7 mitral valve thickening, 2 mitral valve prolapse, 16 MR (8 mild, 8 trivial), 3 aortic valve thickening, and 9 AR (7 mild, 2 trivial). Two patients had asymmetric LV septal hypertrophy. No valvular stenosis or ventricular function abnormalities were noted. Incidental findings included: mild aortic root dilation (2), bicommissural aortic valve (1), and mild tricuspid regurgitation (3).
Individuals with Sanfilippo A and B demonstrate a natural history of cardiac involvement with valvular abnormalities most common. In short-term follow up, patients demonstrated only mild progression of abnormalities, none requiring intervention. Valvular disease prevalence is similar to MPS I and II, but appears less severe. These findings raise no specific concerns for gene transfer trials in patients in this age range.
Unique medical issues in adult patients with mucopolysaccharidoses
2016, European Journal of Internal Medicine
Citation Excerpt :
Although cardiac manifestations have only been reported occasionally for MPS III [75], severe life-threatening cardiac problems may occur in these patients as well [70]. Evidence suggests pan-arterial storage of GAGs in all MPS types, as confirmed by an increase in carotid intima-media thickness and arterial dysfunction (increased aortic stiffness, poor endothelial function) versus healthy controls [8,76–79]. Because of this phenomenon, which manifests in childhood and, in untreated individuals, worsens with age, MPS patients tend to exhibit an arterial age comparable to that of healthy subjects three times their age and frequently present with increased blood pressure [8,74,78,80].
The mucopolysaccharidoses are a group of inherited metabolic diseases caused by deficiencies in enzymes involved in the sequential degradation of glycosaminoglycans (GAGs) leading to substrate accumulation in various tissues and organs. GAG accumulation can cause growth retardation and progressive damage to respiratory, cardiovascular, musculoskeletal, nervous, gastrointestinal, auditory, and visual systems. In the past, few people with severe phenotypic mucopolysaccharidosis (MPS) reached adulthood. However, better methods for diagnosis, multi-disciplinary care, and new therapies have extended lifespan, leading to an increasing number of patients surviving beyond childhood. The growing number of adult MPS patients poses significant challenges for clinicians who may not be familiar with the clinical manifestations of MPS. In addition, as new interventions have changed the natural history of these disorders, it is difficult to anticipate both the impact on life expectancy and other complications that may occur as these patients age. Because the MPS disorders are multi-organ diseases, their management requires a coordinated multi-disciplinary approach. Here we discuss the unique pattern of medical issues and multi-organ involvement in adult patients with MPS and identify the challenges that are associated with management of MPS. This review is based on information from an expert investigator meeting with MPS specialists held October 2–4, 2014 in Dublin, Ireland, as well as on current literature searches focusing on MPS and adults.
Carotid intima-media thickness is increased in patients with treated mucopolysaccharidosis types I and II, and correlates with arterial stiffness
2014, Molecular Genetics and Metabolism
Citation Excerpt :
Carotid intima–media thickness correlates well with carotid histology [18], has been repeatedly validated as a predictive risk factor for myocardial infarction and cerebrovascular accident [19], and is also used as an end point in interventional studies. The finding of increased cIMT, independent of ERT, prior HSCT-associated corticosteroid exposure, or degree of aortic insufficiency, in a cohort of 12 MPS I and II patients [14] indicated its potential utility as a biomarker for MPS cardiovascular disease. The results from that study suggested that the plaques and GAG storage observed in post-mortem coronary and aortic specimens [4] reflected a pan-arterial process that could be visualized in vivo with non-invasive ultrasound imaging.
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.
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.
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.
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 mm²/mm Hg versus 0.16 ± 0.05 mm²/mm Hg; adjusted p = 0.019), and higher cIEM (1362 ± 877 mm Hg versus 942 ± 396 mm Hg; 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.
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.
Mucopolysaccharidosis type VI: A cardiologist's guide to diagnosis and treatment
2013, International Journal of Cardiology
Citation Excerpt :
It could be assumed, that in the attenuated phenotype with longer life expectancy as well as in MPS VI patients receiving ERT coronary artery disease of common arteriosclerotic origin will develop with progressing age. The elevated cardiovascular risk was proved by Wang et al. on an unselected group of MPS patients [57]. An increase of carotid intima-media thickness in studied patients was found, which had been well validated as a cardiovascular non-invasive marker of cardiovascular risk in many conditions including hypertension, hyperlipidemia and diabetes mellitus [57].
Mucopolysaccharidosis type VI (MPS VI, Maroteaux–Lamy syndrome) is an inborn error of metabolism, with incidences at birth ranging from 1 in 1.5 million to 1 in 43,000 live births. This disorder is rarely considered when evaluating patients with common populational cardiovascular diseases. A significant number of MPS VI patients, however, do present cardiovascular disease and MPS VI should be considered as a potential differential diagnosis for other cardiovascular disorders. This article reviews the clinical features, diagnostic tests and treatment options for MPS VI. Although MPS VI affects many organs and systems of the human body this review focuses on MPS VI diseases of the heart and vessels. The most characteristic cardiac presentation of MPS VI is valvular disease, but heart failure, pulmonary hypertension, cardiomyopathy, fibroelastosis and cardiac conduction system disorders may also occur. Cardiovascular disease in MPS VI patients may emerge silently. An early diagnosis is difficult due to joint stiffness, respiratory system involvement or skeletal malformations that limit exercise capacity and mask the underlining heart failure. This article is supposed to serve as a very practical reference for cardiologists who may come across MPS VI in their daily practices. A greater awareness of cardiovascular manifestations of MPS VI among cardiologists can help to reduce misdiagnosis and promote early detection of this inborn disorder and aid the implementation of adequate therapy at the earliest stage possible which is crucial for its efficacy.
Metabolic Cardiomyopathies and Cardiac Defects in Inherited Disorders of Carbohydrate Metabolism: A Systematic Review
2023, International Journal of Molecular Sciences

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^☆: Financial disclosures: Raymond Wang received research funding for this study from Shire Human Genetic Therapies, plc, who played no role in the design of the study, the analysis or interpretation of the data, the writing of this report, or in the decision to submit this report for publication.

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Carotid intima-media thickness is increased in patients with mucopolysaccharidoses☆

Abstract

Background

Objectives

Material and methods

Results

Conclusion

Highlights

Introduction

Section snippets

Human subjects

Human subjects

Discussion

Conflicts of interest

Acknowledgments

Blood

J. Pediatr.

Mol. Genet. Metab.

Am. J. Cardiol.

Pharmacol. Ther.

Am. J. Cardiol.

Mol. Ther.

Mol. Ther.

Outcome of 27 patients with Hurler's syndrome transplanted from either related or unrelated haematopoietic stem cell sources

Bone Marrow Transplant.

Limitations of enzyme replacement therapy: current and future

J. Inherit. Metab. Dis.

The natural course and the impact of therapies of cardiac involvement in the mucopolysaccharidoses

Cardiol. Young

Postmortem studies on a patient with mucopolysaccharidosis type I: histopathological findings after one year of enzyme replacement therapy

J. Inherit. Metab. Dis.

Echocardiographic study of paediatric patients with mucopolysaccharidosis

Cardiol. Young