Review
Cardiovascular manifestations of mucopolysaccharidosis type VI (Maroteaux–Lamy syndrome),☆☆

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Abstract

The aim of the article is to gather and summarize the published data about the incidence, course of illness, treatment possibilities and complications of cardiovascular disorders in patients with mucopolysaccharidosis type VI (MPS VI) also known as Maroteaux–Lamy syndrome. MPS VI is a lysosomal storage disorder caused by deficient activity of N-acetylogalactosamine-4-sulfatase leading to progressive intracellular accumulation of glycosaminoglycans. The relatively low birth prevalence ranging from 1 in 43,000 to1 in 1.5 million births mirrors the limited descriptions of the cardiovascular disorders in the medical literature. Patients with MPS VI can be specifically treated with enzyme replacement therapy. Extra-cardiac features include growth retardation, coarse facial features, stiff joints, skeletal malformations (dysostosis multiplex), respiratory problems, corneal clouding, and hepatosplenomegaly. The clinical presentation varies considerably, however the development of heart disease and cardiac dysfunction is a serious problem in the majority of patients. The most characteristic cardiac presentation is valvular disease, while other MPS VI patients also develop cardiomyopathy, fibroelastosis, pulmonary hypertension, cardiac conduction system disorders and other complications. There are also reports on acute heart failure. Early cardiovascular manifestation may escape detection since joint stiffness or skeletal malformations limit maximal exercise levels and respiratory system involvement may mask the underlining cardiac insufficiency. A correct and timely diagnosis offers the possibility of disease-specific treatment leading to sustained clinical benefits for cardiac and non-cardiac MPS VI manifestations.

Introduction

Mucopolysaccharidosis type VI (MPS VI; MIM# 253200), or Maroteaux–Lamy syndrome, is an autosomal recessive storage disorder affecting many organs of the human body. The relatively low birth prevalence ranging from 1 in 43,000 [1] to 1 in 1.5 million [2] births mirrors the limited description of the cardiovascular disorders in the medical literature. The aim of this review article is to gather and summarize published data about the incidence, course of illness, treatment possibilities and complications of cardiovascular disorders in patients with Maroteaux–Lamy syndrome. Mucopolysaccharidosis type VI is caused by mutations in the N-acetylogalactosamine-4-sulfatase (arylsulfatase B, ARSB,E.C.3.1.6.12) gene located on chromosome 5 (5q13-5q14) [3]. Pathogenic mutations of this gene result in a reduced or absent activity of ARSB leading to incomplete degradation and accumulation of glycosaminoglycan (GAG) – dermatan sulfate (DS). Another GAG, chondroitin 4-sulfate (CS), is also a substrate for ARSB, but is hydrolyzed by hyaluronidase and β-glucuronidase to trisaccharides and higher oligosaccharides that also accumulate, but are not recognized as "classic storage material" [4].

The clinical presentation of MPS VI varies greatly with respect to age of onset and rate of disease progression [3]. The rate of clinical progression in MPS VI patients differs considerably, generating a wide continuous clinical spectrum from rapidly advancing to relatively attenuated. Compared to the rapidly progressing disease where severe symptoms occur in several systems simultaneously, the slowly progressing disease may have clinically significant symptoms occurring in fewer systems. Despite the utility of illustrating with these descriptive categories, it is important to recognize that the disease manifests symptoms along a continuum. Clinical features include short stature, coarse facial features, stiff joints, skeletal malformations (dysostosis multiplex), respiratory and cardiovascular disorders, corneal clouding, and hepatosplenomegaly. Cardiac impairment representing a serious clinical problem in MPS VI [5], leads to increased morbidity and premature mortality in affected patients [5], [6], [7], [8], [9], [10].

In the pathogenesis of cardiac manifestation in patients with MPS VI two factors are known to play the key roles. The accumulation of GAGs may be the primary pathological defect leading to the dysfunction of heart muscle as well as morphological and biochemical changes in the connective tissue such as altered structure of protein fibers and mononuclear cell infiltrates. The altered mechanical properties of the connective tissue come from the excess of collagen fiber amount, increased and abnormal depositions of GAGs and reduced amount of elastic fibers [11], [12], [13], [14]. Several recent studies have highlighted the reciprocal relationship between elastogenesis and matrix proteoglycan content of tissues [13], [14], [15], [16], [17], [18]. High local concentration of galacto-sugarcontaining GAGs (chondroitin- and dermatan sulfates) interferes with elastic fiber assembly [17]. In the presence of CS or DS, tropoelastin is prematurely released from elastin binding protein leading to decreased assembly of elastic fibers at the cell surface [14], [15]. Cytoplasmic vacuoles containing large concentrations of GAGs are observed in endothelial cells, myocytes and fibroblasts compromising the structure and function of the endocardium, myocardium, valves, coronary arteries, conduction system, great vessels, and lung and systemic vasculature [19]. It is speculated that cardiac lesions are more severe in patients whose enzymatic defect leads to the accumulation of dermatan sulphate (MPS type I, II, VI, or VII), because this GAG prevails naturally in the valves and the blood vessels [7], [20]. The most common cardiovascular lesion, regardless of MPS type (I, II, VII, VII), is thickening of the mitral valve with regurgitation [7]. Accumulation of GAGs in the valve leaflets causes thickening of the valve and the chordae with subsequent dysfunction of the papillary muscle and ultimately regurgitation. The secondary factors of the cardiac manifestation could come from cardiac chamber pressure and/or volume overload mainly in the case of cardiac valve dysfunction and heart rhythm abnormalities. Additionally, in case of MPS VI, patients have a narrow and stiff thoracic cage which decreases the space available for the heart and heart beat movements.

Although dyspnea is a common symptom in patients with MPS VI and may be caused by exacerbation of lung disease, it is also the most common symptom of cardiac failure [6], [12], [21], [22], [23]. The intensity of symptoms may include exertional dyspnoea, orthopnoea and nocturnal dyspnoea [22]. The clinical manifestations described in infants include poor feeding, cyanosis, lethargy and tachycardia [11], [12]. No data on chest pain and cardiac ischemia have been published. On auscultation the great majority of patients with MPS VI present with some murmurs, which are mostly related to mitral valve regurgitation (pansystolic murmur). Dynamic left ventricular outflow tract constriction due to ventricular septum hypertrophy may result in a nonspecified systolic murmur which can also be heard [9].

The 12-lead electrocardiogram (ECG) recording reveals numerous changes in patients with MPS VI. The data obtained in the literature described that approximately half of the patients present with at least one abnormality in the recording. The most common changes were sinus tachycardia and heart axis deviation (left or right). Other abnormalities observed in the literature were typical for atrial enlargement and right, left or both ventricular hypertrophy. The signs of ventricular hypertrophy on ECG recordings may be less common than the hypertrophy diagnosed using echocardiographyin the corresponding patients since the GAGs are electrically less conductive [24]. This electrical conduction impairing property of GAGs together with increased anterior-posterior diameter of the chest may be the cause of low voltage R wave in V6 in MPS VI patients [9]. Other abnormalities like non-specific T-wave abnormalities, precordial inverted T waves, ST depression, premature ventricular extrasystoles and supraventricular tachyarrhythmias (atrial flutter) have also been reported [9], [25], [26]. The affection of the heart conduction system in the patients with MPS VI may cause sinus arrest, permanent or transient atrio-ventricular blocks (permanent or transient) [9], bundle branch blocks or fascicular blocks [8], [9], [10].

The typical cardiac manifestation of MPS VI is progressive valvular disease [22], [27]. The valvular disease is caused by thickened leaflets, chordae tendinae and papillary muscles predominantly due to DS depositions [28]. Both regurgitation and stenoses of valves have been described. The most common is the regurgitation of mitral valve [8], [10]. In addition to the valve disease, left, right or both biventricular dilatation can be found in the echocardiogram recordings [11], [12], [28], [29]. Hypertrophy of the intraventricular septum alone or together with posterior wall have also been described [9], [28]. The ejection fraction of the left ventricle is often normal [7], [28], however, diastolic dysfunction can be impaired [28]. Cases of impaired left ventricle ejection fraction have also been described as have dilatation of the left atrium and thickening of the endocardium [11], [12]. No data on heart imaging using tissue Doppler technique of in patients with MPS VI have been published so far. Information reported in the literature shows, that the echocardiographic changes are more common than the corresponding cardiovascular signs and symptoms. The explanation, therefore, may be the fact that thoracic deformities impede cardiac auscultation and limitation in patients' exercise can be mistakenly qualified as connected to the joints stiffness or respiratory failure [20]. It should be remembered that the progression of MPS VI is variable in nature which also applies to the valvular disease that can vary depending on patient's age as well as phenotype.

Keller et al. provided a pathological description of diseased valves in Maroteaux–Lamy syndrome based on autopsies [30], while Marwick et al., Wilson et al. and Tan et al. were based on specimens obtained during the valve replacement surgery [6], [21], [22]. Keller described mitral and tricuspid involvement; while the aortic and pulmonary valves were only minimally altered by the disease. The mitral and tricuspid valves were strongly deformed and thickened; both – leaflets and chordae tendinae had fibrosis and mucopolysaccharide deposits [30]. Marwick, in his publication, describes the mitral valve as thickened with fibrosis containing foamy cells under the microscope [22]. Tan et al. depicts the excised mitral and aortic valves as diffusely thickened and commissurally fused [21]. The histological examination showed enlarged and foamy appearing fibroblasts surrounded by collagen fibers. In the paper of Wilson et al. the mitral valve, as examined during open heart operation, showed fusion of the anterolateral commissurae, thickened chordae tendinae and multiple nodules covering almost the whole atrial surface of the leaflets [6]. The examination of the excised stenosed aortic valve revealed valve architecture extensively disrupted by fibrosis as well as calcification of both cusp surfaces.

A number of publications report the incidence of valvular disease in MPSVI patients. In a publication by Swiedler et al. [10], the authors presented data on the largest group of MPS VI subjects to date. The majority (96%) of the analyzed 121 patients with MPS VI had signs of functional incompetency in at least one cardiac valve and presented regurgitation, stenosis or both. About 20% of patients had both stenosis and regurgitation in at least one valve, 30% isolated regurgitation and 4% isolated stenosis. The above mentioned study also showed a positive correlation between the patient's age and the severity of valvular disease suggesting its progressive nature. Similar findings were published by Fesslova et al. [27] and Oudit et al. [23]. Echocardiographic data on patients with MPS were also reported by Wippermann et al. [5]. Of all 84 patients with MPS, the author described 8 patients in this manuscript. On the contrary to those previously described he presented measurements semiquanititatively. All subjects analyzed had some kind of valvular disease; 50% of patients had mitral regurgitation described as moderate, 25% as mild and in remaining 25% diagnosed with no regurgitation. Mitral valve stenosis in this set of patients occurred in 25% of subjects and in all cases were reported mild. Aortic valve regurgitation was diagnosed in 50% of subjects and in three of the four cases it was severe; in the remaining patient it was moderate. In the analyzed group no aortic stenosis was diagnosed. The measurements of the thickness of mitral and aortic valve showed, that seven of eight mitral valve leaflets were markedly thickened, whereas the remaining subject had mild thickening of the mitral valve. Mild aortic valve thickening was present in half of the patients, the next 25% had marked thickened aortic valve. Mild mitral stenosis was observed in two patients and none of the eight patients presented with aortic stenosis. Azevedo et al. [8] have summarized echocardiogram findings of 28 patients in the Brazilian population. The data supports previously described observations, that mitral regurgitation is the most common valve disease (96.4%) followed by tricuspid regurgitation (71.4%). Nearly half of the patients had aortic regurgitation (42.8%) while other findings like pulmonary regurgitation and mitral and aortic stenosis were rare (14.3% and 7.1% respectively). The frequency of tricuspid and pulmonary stenoses was not reported.

Performance of ECG can indicate some cardiac rhythm and conduction abnormalities, however, in these three publications only right axis deviation, bifid P waves were seen. The echocardiography with Doppler enables valvular defect assessment with description of leaflets, their movement and coaptation, subvalvular apparatus morphology and valve anulus measurements, valvular tightness and transvalvular gradient together with heart muscle function and cardiac chamber measurement. In the above cited publications, patients presented with palpitations, progressive dyspnoea over time and cardiac murmurs. In case of severe mitral stenosis, typical left atrial enlargement with pulmonary venous congestion could be observed in the chest radiograph.

If severe valvular dysfunction occurs, an indication for cardiac surgical intervention arises. Valve replacement procedures in patients with MPS VI are possible, however, complications should be anticipated [6], [21], [22]. Tan et al. reported that valve replacements with prosthesis were successful in all cases, but were accompanied with obstructions and endotracheal intubation required aid of fiberoptic bronchoscope or transnasal approach [21]. Also an emergency tracheostomy occurred because of acute respiratory distress after extubation with and multiple unsuccessful attempts to intubate the trachea. Further complications in this patient resulted the necessity of a laryngotracheoplasty due to granulation tissue and GAG depositions causing airway narrowing.

Fibroelastosis occurring in patients with MPS VI has been described mainly among infants [11], [31], however fibrotic and thickened endocardium, mostly in the left ventricle, has been described in a middle-aged adult [6] as well as one autopsy report on a 27-year-old MPS VI patient [30]. In three cases of infantile fibroelastosis the patients presented with cardiac failure and hypertrophic and dilated left ventricle with poor contractility. The ECG patterns showed tachycardia, atrial and left ventricular or biventricular hypertrophy with ST depression in V3–V6 leads or T wave inversion over the anterolateral chest leads. The echocardiographic recording revealed biventricular dilatation with poor left ventricular function and a strongly echo dense endocardium in two patients that were siblings [11]. Another case describes a 9 month old male patient with left ventricular dilatation, left atrial enlargement, fibroelastosis and mitral regurgitation. Two of three patients responded to the standard heart failure therapy (diuretics, digoxin, and vasodilator) not only clinically but also in the diagnostic measurements in which echocardiogram showed left ventricular function improvement. An autopsy of a 12-month-old female infant showed hypertrophy of the heart, dilatation of the left ventricle and marked endocardial fibroelastosis. The cardiac valves were normal and no inflammation of the myocardium was present. Upon viewing via electron microscopy, distention of fibroblast with membrane bound vacuoles was found, some of which contained flocculent material and stacks of parallel membranes. Autopsy of an adult presented with a heart with strong fibrosis of the endocardium in both the atria and to a lesser extent in the ventricles and a strong accumulation of AB-PAS positive substances between the collagen fibers and in the fibroblasts [30].

A description of an acute infantile cardiomyopathy in a five-month-old female infant with MPS VI who was hospitalized for acute heart failure was provided by Hayflick et al. [12].On admission, the patient, had diffusely hazy lung fields and cardiomegaly in chest radiography, her ECG showed sinus tachycardia with ST-T wave flattening, left atrial enlargement and left ventricular (LV) hypertrophy. The echocardiogram recording revealed LV dilatation, significant mitral regurgitation, normal LV wall thickness and reduced LV shortening fraction (12%). Endomyocardial biopsy of specimens under the light microscope showed perivascular and interstitial mononuclear cell infiltrates without general necrosis of myocytes. Occasionally foamy macrophages were found. The electron microscopy showed sporadic damage of myocytes with intracellular edema, mild increase of mitochondria and moderate increase of glycogen stores. Numerous interstitial macrophages with prominent secondary lysosomes and lamellar bodies within the lysosomes were also found. The patient was treated with digoxin and captopril, along with a 6-week course of azathioprine and prednisone (for probable myocarditis as MPS VI was the alternate diagnosis that was made based on measurement of ARSB activity at the follow up visit).

Keller et al. described an effect on of the cardiac conduction system in which the pathomorphological changes within the sinus node included a decreased number of parenchyma cells with clumpy and increased number of collagen fibers [30]. The His bundle in description was narrowed with the collagen fiber tracts that extended up into the middle segments. Additionally the bundle showed peripherally accented foamy cell conversion of the fibroblast.

There are very few references describing coronary artery disease in patients with MPS VI. At least two reasonable explanations have been provided for this. The first explanation may be that coronary artery disease develops progressively with age and MPS VI patients have a shorter than normal life expectancy. The second explanation may be that the prevalence of coronary artery disease in the general population of the United States of America in 2006 was 5.9% [32], [33]. However, some pathomorphological data on patients with MPS VI describing vasculature have been published. An autopsy of a 27-year-old patient revealed irregularly pronounced sclerosis of the vascular intima with widened adventitia. Additionally, in all coronary arteries foamy cells between collagen fibers were present [30]. The available literature does not provide any data on symptomatic ischemic disease, however, a pre-operative coronary angiogram in a 43 years old patient showed signs of non-significant stenosis [6]. The same publication supplied extracts from autopsy reports, where in addition to valve disease, heart hypertrophy and endocardial thickening one sibling had coronary artery ostia narrowing (died at age 38) and the second sibling had a total occlusion of the left anterior descending coronary artery (died also at age 38). It can be assumed, that similarly to the general population, the occurrence of coronary heart disease rises with increasing age of MPS VI patients.

So far there have not been any reports about systemic hypertension in patients with MPS VI. Nevertheless, the occurrence of artery stenosis (due to thickening of arterial wall as a result of clumpy collagen deposits in all arterial layers including renal arteries) [30], prolonged life expectancy or obstructive sleep apnea [34] could contribute to the incidence of high systemic pressure. The alteration in upper-airway and decreased pulmonary reserve lead to the obstructive sleep disease in patients with MPS VI [28]. Notably obstructive sleep apnea is associated with coronary heart disease, stroke, peripheral vascular disease, heart failure and arrhythmias [35] however, these observations have not yet been reported in patients with MPS VI.

Pulmonary hypertension occurs in patients with MPS VI [8], [28]. In the pathogenesis of pulmonary hypertension the left heart disease may play a major role, however other factors, like depositions of GAGs in pulmonary vascular bed, thoracic deformities and frequent pneumonias leading to increased pressure in the pulmonary vasculature, cannot be excluded [3], [20]. There is only one reliable report in the literature (during the cardiac catheterization before mitral valve replacement) confirming pulmonary hypertension in an adult female patient with severe mitral stenosis [22]. Most case studies tried to assess pulmonary pressure using Doppler echocardiography. Such measurements, despite having many advantages, do not always provide accurate pressure values and are not suitable for confirming pulmonary hypertension [36]. Azevedo et al. showed that almost half of the patients with MPS VI of mean age of approximately 8 years presented signs of pulmonary hypertension in the echocardiography [8]. In his study 27 out of 28 patients presented with mitral regurgitation. Both reports support the predominant role of the left heart disease in the pathogenesis of pulmonary hypertension in MPS VI. Leal et al. presented similar findings, observing Doppler echocardiographic recordings typical for pulmonary hypertension in 4 out of 5 patients with MPS VI [28].

One report of an extraordinary implantation of a permanent pacemaker in a 15-year-old patient with MPS VI can be found in the literature [26]. The patient presented with a complete AV block, moderate mitral valve and papillary muscle thickening and moderate aortic regurgitation. The procedure described the femoral vein approach to insert the pacing lead. This is an alternative route to the subclavian access, however subclavian access is not typically performed in children [37], [38], [39]. The extraordinary accession route was caused by abnormal anatomy of the subclavian veins [26]. An electrode with an active fixation was placed via the right femoral vein into the right ventricle and good sensing and pacing threshold were obtained. The pulse generator pocket was developed under the rectus abdominalis muscle. The mode of stimulation was set on VVIR. Though lead dislodgement using transfemoral approach is the main complication, the 6-month follow-up revealed intact pacemaker function in this case.

Oudit et al. presented an unusual course of the disease [23]. A 22-year-old man with MPS VI was hospitalized because of persistent dyspnea (NYHA III). The ECG showed normal sinus rhythm with no Q waves, no elevation in serum markers (CK-MB, troponin I) and LDHwere observed. The echocardiogram showed mildly thickened aortic and mitral valve leaflets. Mild aortic and mitral regurgitation was diagnosed as well as impairment of left ventricular systolic function. Upon examination a well-delineated thin-walled apical aneurysm measuring 2.6 × 2.9 cm was visualized. The left ventriculogram confirmed the presence of an aneurysm. The patient was scheduled for an aneurysmectomy via thoracotomy. The resected aneurysmal tissue showed a true aneurysm with areas of significant fibrosis and inflammatory infiltrates (predominantly macrophages). Additionally some percentage of coronary arterioles had lumen loss with proliferation of media with intimal hyperplasia. Electron microscopy revealed degenerated and disorganized muscle fibers with increased amounts of glycogen granules within. Also, marked lysosomal accumulation of pleiomorphic electron-lucent material in the macrophages was observed. Postoperatively moderate improvement in exercise tolerance was observed, however on two year follow-up, both valvular stenoses increased.

Although endocarditis has not been reported so far, it could be a serious problem in patients with MPS VI. The concerns come from abnormal cardiac valves and necessity of implanting the central venous port to provide enzyme replacement therapy (ERT). The infection incidence in hemophiliacs with central venous access port is estimated to be as low as 0.45 per 1000 catheter days [40]. However, in the same study of a mean of 1768 days per patient, 44% of patients were reported to have central venous access device (CVAD) infection [40]. Endocarditis on native or prosthetic valves may be challenging to treat; therefore great attention should be made during administration of ERT through permanent CVADs. The endocarditis prophylaxis is proposed in the management guidelines for MPS VI and includes antibiotics before dental and other surgical procedures [41].

There are currently two forms of treatment of patients with MPS VI – ERT and hematopoietic stem cell transplantation (HSCT).

Section snippets

Transplantation of hematopoietic stem cells

Hematopoietic stem cell transplantation has been reported to prevent cardiovascular disease of MPS VI patients, though the valves were not improved. Influence of HSCT on the heart structure and function was analyzed by Herskowitz et al. [42]. The echocardiography results described in four patients before the HSCT revealed valve involvement in all four cases with MV and TV thickening in all cases and AV and PV thickening in two cases. Minor mitral regurgitation was present in one case and in

Conclusions

The aim of this article was to gather data and updated information about cardiovascular aspects of MPS VI. Since MPS VI is a rare disease with an incidence of about one affected individual per million live births, systematic data on heart disease in MPS VI patients are difficult to obtain. Over time, diagnostics of patients with MPS IV has been changing so it is difficult to uniformly compare data reported from various publications. Cardiovascular disease is a prominent feature of MPS VI and

Acknowledgement

The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [44].

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