—  SPECIALTY CONFERENCE  —

Cardiovascular Pathology

Case 2 - The Heart in Fabry's Disease

Mary Sheppard
Royal Brompton Heart Hospital
London, England


Click on each slide thumbnail image for an enlarged view
Clinical History
  • DOB: 09-02-1949.

  • Patient aged 53 originally presented from a family screening program. His mother presented with hypertrophic cardiomyopathy (aged 65 years) and he was subsequently also found to have the condition. At the time his only cardiac symptom was that of palpitations. Echocardiography demonstrated concentric left ventricular hypertrophy (maximal wall thickness 20mm). He was also found to have asthma and was treated with inhalers and intermittent courses of oral steroids. He progressed over 5 years to heart failure and presented to hospital with severe chest pain and difficulty breathing. He suffered cardiac arrest shortly after admission from which he was not able to be resuscitated.
AUTOPSY
  • The weight of the heart is 879g. On examination, there is left ventricular hypertrophy particularly noted in the anteroseptal and posteroseptal wall of the left ventricle. The thickness of the postero-septal wall is 21mm whereas the anterior and posterior appear to be 16mm. The lateral free wall of the left ventricle appears of normal thickness at 15mm. There is hypertrophy of the trabeculae which appear quite prominent in the left ventricle.

  • In the postero-lateral wall of the left ventricle there is a slightly sunken area in the inner one third of the subendocardium. Elsewhere, the muscle appears prominent with some swirling but no other macroscopic areas of fibrosis.

  • The right ventricle appears normal in the anterior and lateral wall with overlying epicardial fat, but there is hypertrophy of the posterior wall which is approximately 6mm.

  • There is nodular calcification of the aortic valve leaflets which extends onto the anterior mitral leaflet with calcification extending onto the chordae of the mitral valve. The aortic leaflets are slightly thickened but there is no significant stenosis of the valve leaflets which move freely. There is extensive nodular calcification of the anterior leaflet of the mitral valve which involves both the annulus and the body of the mitral leaflet. At the edge of the anterior leaflet, there is slight ballooning and thickening between the chordae. The tricuspid valve also appears slightly thickened and ballooned between the chordae. Pulmonary valve appears macroscopically normal. There are no congenital defects seen in the heart. The coronary arteries appear normal with no narrowing macroscopically.



Case 2 - Figure 1 -
Shows a transverse short axis view of the heart with left ventricular hypertrophy. Note slight thinning of the posterolateral wall. There is also mild right ventricular hypertrophy in the posterobasal area.
Case 2 - Figure 2 -
Mitral valve shows extensive annular calcification with mild thickening of valve leaflets
Case 2 - Figure 3 -
Aortic valve and anterior leaflet of mitral valve shows extensive annular calcification extending onto the aortic valve. Note the mild thickening of the aortic valve leaflets.



Case 2 - Figure 4 -
Tricuspid valve shows thickening and ballooning between the chordae.
Case 2 - Figure 5 -
Transverse sections of the coronary arteries showing eccentric intimal proliferation and vacuolization of medial smooth muscle cells. Haematoxylin and Eosin stain.
Case 2 - Figure 6 -
Sections of the myocardium showing myocyte hypertrophy, vacuolization of the cytoplasm and interstitial fibrosis. Haematoxylin and Eosin stain.



Case 2 - Figure 7 -
Sections of the myocardium showing myocyte hypertrophy, vacuolization of the cytoplasm and interstitial fibrosis. Note also the foamy macrophages surrounding degenerating myocytes . Haematoxylin and Eosin stain.
Case 2 - Figure 8 -
Electron microscopic section of myocyte showing the typical lamellar bodies within the cytoplasm.
Case 2 - Figure 9 -
Shows fibrosis ( red stain) replacing myocardium and surrounding individual myocytes (yellow). Picro Sirius red staining.



Case 2 - Figure 10 -
Shows mitral valve with diffuse thickening and calcification . Haematoxylin and Eosin stain.
Case 2 - Figure 11 -
Shows aorta with vacuoles within the smooth muscle cells highlighted by the van Gieson Trichrome staining.
Case 2 - Figure 12 -
Shows aorta with vacuoles within the smooth muscle cells (Haematoxylin and Eosin stain)
Fabry disease (FD) is a genetic disorder caused by the deficiency of α-galactosidase A, resulting in the lysosomal accumulation of glycosphingolipids. Symptoms of Fabry disease include cardiac, cerebral and renal complications. Cardiac abnormalities in patients with Fabry's disease were first described in the 1960s. In the 1990s a form of Fabry disease confined to the heart was reported; however, this variant is extremely rare and a more appropriate concept is a cardiac predominance of the disease in some patients. Up to 60% of males with classic Fabry disease have cardiac abnormalities, including left ventricular hypertrophy (LVH) valvular dysfunction and conduction abnormalities. Cardiac manifestations of Fabry's disease were described over 30 years ago [1, 2], yet their significance in the natural history of this disease is still the subject of much research. The increased awareness of the condition amongst cardiologists has resulted in the emergence of new data on the prevalence and spectrum of disease in the heart. There is an improved understanding of the disorder, but uncertainty about some of the long-accepted truths concerning cardiovascular involvement in Fabry disease. The prospect of enzyme replacement therapy (ERT) has opened up new therapeutic options in this condition. Recent data suggest that left ventricular mass and systolic function in patients with Fabry disease improve after 12 months of enzyme replacement therapy (ERT).

Key words: Cardiovascular disease, enzyme replacement therapy, Fabry disease, left ventricular hypertrophy, conduction abnormalities, valve abnormalities, regurgitation

Epidemiology of Fabry disease
Published estimates for the prevalence of Fabry disease range from 0.02 to 0.09 per 10 000 of the population [3, 4, 5]. However, these values are extrapolations from data obtained from reference laboratories around the world and, as a result, do not take into account asymptomatic heterozygotes or misdiagnosed cases. Patients with Fabry disease can present with non-specific symptoms, resulting in a delay in diagnosis. Recent data from FOS – the Fabry Outcome Survey – suggest that there is a delay of 13.7 years for males and 16.3 years for females from the onset of symptoms to diagnosis [6]. Overall, 25% of patients in FOS have reported a previous misdiagnosis.

Recent screening programs of patients with end-stage renal disease receiving haemodialysis suggest that the prevalence of Fabry disease in this cohort ranges from 1.2 to 3.5% [7, 8]. Similarly, the prevalence of Fabry disease in adult males with unexplained left ventricular hypertrophy (LVH) has been reported to be 3% or more [9, 10]. FD has been recognized as the cause of left ventricular hypertrophy in 6% of men with clinical late-onset hypertrophic cardiomyopathy FD may account for up to 12% of females with late-onset LVH [11]. Together , these data suggest that Fabry disease is much more common than previously thought

Frequency of cardiac disease in Fabry disease
Up to 60% of males with classic Fabry disease have cardiac abnormalities, including left ventricular hypertrophy , valvular dysfunction and conduction abnormalities [12, 13, 14]. Females are also affected, but generally present at a later age than men. In the FOS registry, over 60% of patients have reported angina, dyspnoea or palpitations, with no gender difference in the prevalence of these symptoms. Kampmann et al. [15] reported that all female patients over the age of 45 years had evidence of LVH

The 'cardiac variant' of Fabry disease
In the early 1990s there were several reports of a form of Fabry disease confined to the heart. Patients with this 'cardiac variant' had residual enzyme activity (approximately 1–5% of normal values) and presented in the fifth and sixth decades of life with LVH and conduction disease without classic manifestations such as angiokeratoma, acroparaesthesia, hypohidrosis and characteristic ophthalmological changes. These patients occasionally had proteinuria, but did not progress to end-stage renal disease [9, 16, 17]. Histologically, patients with the cardiac variant were said to differ from those with classic Fabry disease in that there was an absence of vascular endothelial glycosphingolipid deposits [9, 16, 17]. In clinical practice, this cardiac variant seems to be extremely rare, as detailed evaluation usually identifies some manifestations of the classic form of the disease. A more appropriate concept therefore may be that there is a cardiac predominance of the disease in some patients, rather than a purely cardiac variant. The prevalence of Fabry disease with predominantly cardiac features was thought to be low, until a Japanese study of 1603 males undergoing routine echocardiography found that seven (3%) of 230 patients with LVH had Fabry disease that had not been suspected clinically [9]. Another study performed in a referral clinic for patients with hypertrophic cardiomyopathy in the UK reported a prevalence of Fabry disease of 4% in men with otherwise unexplained hypertrophy. This value increased to 6% in those first diagnosed over 40 years of age [10].

Cardiac Fabry disease
The dominant cardiac manifestations include myocardial hypertrophy of the left ventricle, which mimics hypertrophic cardiomypathy. Left ventricular systolic function is usually preserved, while mild to moderate diastolic dysfunction is regularly detected. Valvular abnormalities are frequently noted but hemodynamically significant lesions are rare. Conduction system involvement leads initially to the shortening of atrioventricular conduction, in later stages, with a progression of the disease, antrioventricular blocks and various forms of supraventricular and ventricular arrhythmias appear. Myocardial ischemia in Fabry disease has in most cases a functional origin due to endothelial dysfunction of coronary arteries and also due to the increase oxygen demand of hypertrophied myocardium [18].

In females there is a strong correlation between age and the severity of LVH and all patients older than 45 years had LVH. With increasing LVM, there was a significant age-independent decrease in systolic and diastolic LV function. Mild thickening of the aortic valve leaflets is present in 25.5% of patients, with the same percentage demonstrating mild thickening of the mitral valve leaflets. Mild mitral valve prolapse was documented in 10.9% of patients [15]. RV involvement is common in Fabry disease and ultimately progresses to severe systolic and diastolic RV dysfunction [19].

Pathology of Cardiac involvement in Fabry's Disease
Pathological case reports of cardiac involvement describe cardiomegaly, left ventricular hypertrophy and mitral and aortic regurgitation.. Valvular structural abnormalities are frequent due to valvular infiltration. Hypertrophy of papillary muscles and/or systolic anterior motion of the mitral leaflets associated with LV outflow obstruction may aggravate the mitral valve dysfunction. Valvular regurgitation is usually non-significant [21].

Sudden death in heterozygous elderly females have been described [22, 23].

As well as hypertrophy localized thinning of the basal posterior wall of the left ventricle has been described in those who die of heart failure [24].

The most prominent feature of cardiac disease in patients with Fabry disease is the presence of lipid storage. This is seen in all cell types within the heart, including myocytes, specialized conduction tissues, valves and endothelium [12]. Endomyocardial biopsy shows myocytes cytoplasmic vacuolization by light microscopy, and electron-dense deposits consisting of parallel or concentric lamellae with periodic spacing [25]. These deposits are thought to be the pathological basis for cardiac disease in this condition; however, glycosphingolipid accumulation accounts only for approximately 1% of the myocardial mass in patients with Fabry disease cardiomyopathy. This suggests that other histological features, such as hypertrophy and fibrosis, are also important [26]. Patients develop progressive systolic dysfunction and myocardial fibrosis. which could be secondary to coronary microvascular dysfunction [27]. Histologically there is vacuolar cytoplasmic change in myocytes with lamellar bodies on electron microscopic examination. A definite biochemical diagnosis of Fabry's disease will demonstrates a large amount of trihexosylceramide in the myocardium, kidney, and liver [20].

VASCULAR CHANGES
The arterial wall in large muscular arteries (coronary, renal and intrarenal) show arteriopathy with pronounced involvement of the smooth muscle cells in the media. Arteriopathy starts with storage, followed by cell degeneration and breakdown, extracellular matrix deposition and, often, calcification (confined to the muscular layer). Smooth muscle cells occasionally exhibited shrinkage-type necrosis, with dispersion of the stored lipid into the dense cytoplasmic mass. Intimal and mitral valve fibroblasts exhibited variable storage, which was associated with cell loss and necrosis [14].

Progression to Heart failure
Although there are isolated case reports of heart failure in Fabry disease, its importance in the natural history of Fabry disease is unknown. In a recent retrospective analysis of a cohort of patients with Fabry disease cardiomyopathy followed for at least 1 year, there is a progressive deterioration in fractional shortening (an echocardiographic measure of left ventricular contractile function) of approximately 2.6% per year [28] This change in left ventricular contractile function may be due to progressive glycosphingolipid accumulation, but recent studies by us using magnetic resonance imaging of the heart have identified a unique pattern of myocardial gadolinium hyperenhancement [29] This hyperenhancement is thought to represent fibrosis and scarring, and may be a marker of end-stage heart disease.

Role of ERT in the treatment of Fabry cardiomyopathy
Until recently, Fabry's disease management consisted of symptomatic and palliative treatment, but this has changed with the availability of the recombinant human alpha-Gal A enzyme, agalsidase. Two different agalsidase formulations have been obtained: one from human fibroblast (agalsidase alpha), and one from Chinese hamster ovary (CHO) cells (agalsidase beta). Both preparations have undergone clinical trials that documented the feasibility, efficacy and safety of the treatment. Several clinical observations have proved that agalsidase reduces the storage of the substrate from several organs and tissues and, consequently, improves signs and symptoms of Fabry's disease [30]. There is improvement in renal function [31], but its role in improving and attenuating the progression of cardiac symptoms is still under investigation.

Improvements in cardiac function were suggested during clinical trials with a significant improvement in cardiac conduction being reported in patients treated with ERT for 6 months [32]. It is also interesting to note that administration of galactose (1g/kg, given over a 4-hour period every other day), which enhances residual α -galactosidase A activity, results in improvement in cardiac contractility, a moderate reduction in ventricular wall thickness and a 20% decrease in cardiac mass after 3 months in a single patient [33]

More recent studies have specifically investigated the effects of ERT on cardiac structure and function An improvement in left ventricular mass has been observed and reduction in QRS duration [34] in patients as early as 6 months after the initiation of ERT .Other studies show a modest reduction in left ventricular mass and stiffness [35, 36, 37, 38], 12 months of ERT. Results of 2 years of treatment with alpha-Gal A in nine patients with Fabry disease showed that the mean slope of left ventricular mass index progression decreased [36]. Agalsidase alfa (Replagal) administered to male patients with Fabry disease showed significant decrease in left ventricular mass and a significant reduction in QRS durations [34].

The results of these randomized, double-blind, placebo-controlled clinical trials and open-label extensions have shown that replacement of the deficient enzyme stabilizes renal function and produces significant improvements in myocardial mass and function [39]. However, many of the patients studied are relatively young and have mild cardiac abnormalities, and more research into the efficacy of ERT in older patients is necessary. There are several critical features of ERT that require attention . Among these are the development of severity-score indices that can be used to explicitly quantify the benefit of ERT. Detection of early cardiac disease and the role of ERT in prevention or progression / development of disease also needs exploring. Postmortem findings in a 47-year-old man with Fabry disease, on enzyme replacement therapy for more than 2 years showedwidespread atherosclerotic coronary artery disease and Fabry cardiomyopathy. With the exception of vascular endothelial cells, extensive glycolipid storage deposits were seen in all vascular and nonvascular cells and organ systems. ERT over a prolonged period did not appreciably clear storage material in cells other than vascular endothelial cells [40]. Thus the role and timing of ERT is still under investigation in dealing with the prevention and amelioration of the cardiac complications of Fabry's disease.

In conclusion, cardiac manifestations of Fabry disease are common and much more frequent than previously thought. Enzyme replacement therapy offers an exciting new and expensive treatment option but more ongoing studies are needed to determine the efficacy of ERT for improving and preventing cardiac symptoms in patients with Fabry's disease.

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