Cardiac involvement is common in Fabry disease, both in hemizygous men and heterozygous women, and is one of the three major causes of morbidity and mortality. Storage of globotriaosylceramide occurs in various cells of the heart, including cardiomyocytes, conduction system cells, valvular fibroblasts, endothelial cells within all types of vessels, and vascular smooth muscle cells. Cardiac hypertrophy associated with depressed contractility and diastolic filling impairment is common. In addition, coronary insufficiency, atrioventricular conduction disturbances, arrhythmias and valvular involvement may be present. In patients with the atypical 'cardiac variant', the disease manifestations may be limited to the heart. Enzyme replacement therapy is now the treatment of choice for patients with Fabry disease, and preliminary results indicate promising effects not only on the renal and neurological manifestations of the disease but also on the cardiac manifestations.

Introduction

Cardiac involvement is one of the three major causes of morbidity and mortality in Fabry disease, together with end-stage renal disease and cerebrovascular events (Figure 1) [1, 2]. Lysosomal storage occurs within almost all cardiac tissues and leads to clinically important symptoms, including dyspnoea, chest pain, palpitations and syncope. These symptoms relate mainly to the development of progressive cardiac hypertrophy, conduction abnormalities and arrhythmias.

Figure 1

The relative frequency of causes of death among 113 relatives of patients with Fabry disease in FOS – the Fabry Outcome Survey.

Pathogenesis of the cardiac involvement

Storage of globotriaosylceramide (Gb₃) is found in various cells of the heart, including cardiomyocytes, conduction system cells, valvular fibroblasts, endothelial cells within all types of vessels, and vascular smooth muscle cells [3]. In women, a mosaic pattern caused by random X-chromosome inactivation is observed [4]. Gb₃ storage by itself, however, is unable to explain the observed level of cardiac hypertrophy, conduction abnormalities and other cardiac manifestations. Autopsy of an individual with Fabry disease who had an extremely hypertrophied heart revealed a relatively limited contribution (1–2%) of the stored material to the enormous increase in cardiac mass [5]. It appears that storage induces progressive lysosomal and cellular malfunctioning that, in turn, activates common signalling pathways leading to hypertrophy, apoptosis, necrosis and fibrosis (Figure 2). Energy depletion was recently proposed as the common denominator in multiple metabolic and even sarcomeric hypertrophic cardiomyopathies [6]. Energy depletion may also occur in Fabry disease, as suggested by the impairment in energy handling seen in skin fibroblasts [7]. This might be further supported by the observation of a decreased ratio of ATP to inorganic orthophosphate, as has been shown by magnetic resonance imaging (MRI) studies in patients with sarcomeric hypertrophic cardiomyopathies [8].

Figure 2

Schematic showing the possible pathways between lysosomal storage and signs and symptoms of Fabry disease. VSMC, vascular smooth muscle cells; AV, atrioventricular.

In summary, the natural history of Fabry disease is characterized by progressive hypertrophy of the cardiac muscle, with increasing interstitial and fibrotic changes. This is consistent with observations of relatively mild diastolic dysfunction in early stages of the disease and with the late appearance of signs and symptoms that might be observed in patients with restrictive cardiomyopathy [9]. The disease process is potentiated by absolute or relative ischaemia, occurring even in the absence of significant epicardial coronary artery disease. This might be mainly due to the increased oxygen demand of the hypertrophied muscle, decreased capillary density, increased diastolic filling pressures that impair blood flow throughout the subendocardial layers in diastole, and to the infiltration of small arterioles and capillaries within endothelial cells and the smooth muscle layer [3, 10].

A similar pattern of progressive involvement is observed in the conduction system of the heart. Early stages of the disease are associated with accelerated conduction, and late stages are characterized by progressive bradycardia and atrioventricular conduction defects, frequently necessitating pacemaker implantation [11].

Cardiac hypertrophy

Left ventricular (LV) hypertrophy is the predominant finding, detected both by imaging techniques (echocardiography, MRI) (Figures 3 and 4) and by electrocardiography (ECG) (LV hypertrophy voltage criteria) (Figure 5) [9, 12, 13]. Histologically, hypertrophy is characterized by the absence of myofibrillar disarray, lysosomal inclusions within myofibrils and vascular structures, and a variable degree of fibrosis depending on the stage of the disease [5, 14]. Although the absolute amount of Gb₃ within cardiomyocytes is low, the heart contains the highest quantity of glycosphin-golipid compared with other organs (kidney, liver, skin) [5, 15].

Figure 3

Echocardiographic M-mode recording in a patient with Fabry disease, showing the concentric character of left ventricular hypertrophy with both diastolic interventricular septum (IVSd) and posterior wall (PWd) thickness exceeding 19 mm (normal values should (more...)

Figure 4

Magnetic resonance imaging of a patient with Fabry disease, showing marked diffuse hypertrophy of the left ventricle (LV). LA, left atrium; RV, right ventricle.

Figure 5

Typical electrocardiogram tracing from a patient with Fabry disease, showing short PR intervals, marked electric left ventricular hypertrophy, and prominent ST depressions and T-wave inversions.

The hypertrophy is progressive and occurs earlier in men than in women. Early stages are characterized by concentric remodelling, progressing later to overt hypertrophy. In a large majority of patients, the hypertrophy is symmetrical; however, asymmetric septal hypertrophy, indistinguishable from that considered typical for sarcomeric cardiomyopathies, may be present in about 5% of all cases [9, 16]. Asymmetric hypertrophy may be associated with marked LV outflow obstruction. In these patients, treatment by alcohol ablation may bring substantial relief and stabilization, in spite of the progressive nature of the hypertrophy [17].

Although early autopsy reports indicated important disease-related organ involvement in females heterozygous for Fabry disease, for a long time women were considered as carriers [18]. Due to random X-chromosome inactivation and the inability of cells expressing the wild-type allele to cross-correct the metabolic defect, affected women may express symptoms that are similar to those of hemizygous males [19, 20]. Cardiac involvement in women has recently been confirmed. However, symptoms are often milder, the onset delayed and disease progression slower than in men [21]. These observations have been confirmed by analysis of data from FOS – the Fabry Outcome Survey – in untreated patients (Figure 6), which shows the delayed onset of hypertrophy in females.

Figure 6

Age at diagnosis of left ventricular hypertrophy among untreated men and women with Fabry disease in FOS – the Fabry Outcome Survey – showing a later onset and lower cumulative prevalence in women. Sixty-two out of 121 untreated males (more...)

Magnetic resonance studies using gadolinium have provided new insights into the development of Fabry cardiomyopathy. In patients with LV hypertrophy, such studies have demonstrated late enhancement areas, corresponding to myocardial fibrosis, occurring frequently within the midwall of the posterolateral basal segments [22]. It appears that this finding characterizes late stages of LV involvement and is associated with decreased regional functioning, as assessed by strain and strain-rate imaging [23].

The right ventricle also appears to be affected by storage and hypertrophy. However, the functional impact of right ventricular infiltration and hypertrophy is low, and right ventricular failure almost never complicates the course of the disease [24].

LV function

LV systolic function, measured by traditional parameters such as ejection fraction or fractional shortening, is seldom decreased [9, 25]. However, studies using tissue Doppler imaging and contractility assessment by strain-rate imaging documented a substantial decrease in contractile performance, occurring earlier in the longitudinal than in the radial dimension [23, 26]. FOS data show a progressive decline in midwall fractional shortening with age (Figure 7). This parameter reflects the contractility impairment that may be masked by the geometrical structural changes and may be undetectable by the measurement of ejection fraction or fractional shortening.

Figure 7

Correlation of midwall fractional shortening with age in patients with Fabry disease in FOS – the Fabry Outcome Survey. Females n = 189, males n = 159.

Diastolic dysfunction is a common feature of Fabry disease. In contrast to genuine restrictive cardiomyopathies, however, restrictive pathophysiology is found only rarely, mostly in extremely advanced stages of the disease that are associated with pronounced fibrosis. End-stage cardiac involvement may then present with restrictive pathophysiology [14, 27].

Ischaemia and coronary events

Traditional descriptions of Fabry disease report a high frequency of ischaemic events and myocardial infarctions. Data from the FOS database, however, suggest a low incidence of proven myocardial infarctions. By October 2005, the FOS database included 752 patients (393 heterozygous women and 359 hemizygous men). Only 13 myocardial infarctions were reported, representing a prevalence of less than 2%. On the other hand, angina and chest pain are frequent, being reported in FOS by almost 23% of females and 22% of males. This, together with frequently disturbed ECG patterns (Figure 5), including ST segment depressions and T-wave inversions, might be the cause of mis-diagnosis of either acute or subacute myocardial infarction [28]. In addition, anginal pain and ECG changes are more frequent in patients with LV hypertrophy, in whom minor increases in markers of cardiac necrosis are possible. Epicardial coronary arteries, however, are only rarely occluded.

As shown by Kalliokoski and Elliott, patients with Fabry disease have a significantly reduced coronary flow reserve [29, 30]. This might be due to endothelial infiltration and dysfunction, potentiated by the increased oxygen demand of the hypertrophied ventricle and further aggravated by elevated diastolic filling pressures. In some cases, vasospasms may contribute to the anginal symptoms [31]. Most patients with Fabry disease who are investigated for chest pain have patent large coronary arteries. A history of revascularization due to the presence of stenotic lesions was reported in the FOS database in only five cases, representing a prevalence of less than 1%. However, as underlined by the recent case report by Schiffmann and co-workers, the risk of death due to coronary artery disease should not be underestimated [32].

In addition to the infiltrative changes within the endothelial and muscular layers of arteries, patients with Fabry disease often accumulate a large number of risk factors for atherosclerosis, including high levels of blood lipids, hypertension and renal insufficiency. Another aggravating factor might be the prothrombotic state associated with the endothelial dysfunction caused by the disease [33]. However, it remains unclear to what extent these lesions are due to atherosclerosis or to infiltrative changes [3].

Electrophysiological abnormalities and arrhythmias

In most patients with Fabry disease, resting ECG patterns are perturbed. Besides high voltage and repolarization changes, a short PR interval is frequently found (Figure 5) [12]. The shortening is due to accelerated atrioventricular (AV) conduction [34]. However, as in other lysosomal and glycogen storage diseases, pre-excitation with accessory pathways may also be present in patients with Fabry disease [35, 36]. With disease progression, conduction system dysfunction occurs, leading to bundle branch and AV blocks of varying degrees, requiring pacemaker implantation. In some patients, a pacemaker is needed due to symptomatic bradycardia, as progressive sinus node dysfunction is relatively frequent [11].

Palpitations and arrhythmias are common complaints in patients with Fabry disease. The most frequently encountered rhythm abnormalities include supraventricular tachycardias, atrial fibrillation and flutter. Non-sustained ventricular tachycardias (NSVT), however, were detected by 24-hour Holter monitoring, and cases of fatal malignant arrhythmias resistant to an implantable cardioverter defibrillator have been reported [37, 38]. Ventricular arrhythmias were found mostly in very advanced stages of the disease. Studies showing the high incidence of NSVT on Holter monitoring support the regular use of this method to identify high-risk individuals who may benefit from cardioverter defibrillator implantation.

Valvular involvement

Valvular disease in patients with Fabry disease is due, in part, to infiltrative changes within valvular fibroblasts. Although pulmonary valvular involvement has been reported, valvular changes are found almost exclusively in the left heart valves, probably due to the higher haemodynamic stresses in the left side of the heart [39, 40]. This results in valvular thickening and deformation (Figure 8). In original reports, the prevalence of mitral valve prolapse was overestimated, probably due to the different diagnostic criteria used [41]. Subsequent reports confirmed the existence of mitral valve prolapse, but with a lower prevalence [9, 12]. Valvular regurgitant lesions are usually mild to moderate (Figure 9) and only rarely require surgical correction (3 cases out of 752 patients in FOS). At the level of the aortic valve, root dilation may contribute to valvular dysfunction and has been reported repeatedly, particularly in advanced stages of the disease [9, 25].

Figure 8

Echocardiogram showing mild thickening of the mitral valve leaflets (arrows) in a patient with Fabry disease. Marked thickening of the interventricular septum is also present. Ao, Aorta; LA, left atrium; LV, left ventricle.

Figure 9

Colour Doppler recording, illustrating mild to moderate mitral regurgitation (MR), in a patient with Fabry disease. In addition, bilateral atrial dilation can be seen and a pacemaker electrode (E) is visible. LA, left atrium; LV, left ventricle; RA, right (more...)

Cardiac variant

Early studies suggested that cardiac hypertrophy might be the sole or predominant manifestation of Fabry disease in a small number of male hemizygotes. Histopathological studies revealed Gb₃ storage located almost exclusively in the heart [5, 15, 42]. These cases, described as cardiac variants, were distinguished by relatively high residual α-galactosidase A activity. In addition, some mutations have been shown to be associated almost exclusively with this type of involvement [43].

Several studies have attempted to identify Fabry disease among patients with cardiac hypertrophy [36, 44–47]. An early study by Nakao and co-workers identified seven unrelated patients with Fabry disease (3%) among 230 men with unexplained LV hypertrophy. A particularly important observation was made by Sachdev and co-workers, indicating that special attention should be paid to patients in whom unexplained LV hypertrophy is diagnosed after 40 years of age [44]. At this age, most male patients with Fabry disease have at least LV hypertrophy, which is not necessarily present in younger patients [9]. The negative findings of Ommen and coworkers is an understandable result of population selection [46]. As stated above, only about 5% of patients with Fabry disease have asymmetric septal hypertrophy, and even fewer have LV tract obstruction [16]. Therefore, the probability that patients with Fabry disease would be identified when investigating individuals referred for septal myectomy was a priori extremely low. The fact that diagnosing Fabry disease among individuals with LV hypertrophy may be subject to chance is documented by the strikingly high prevalence of Fabry disease among women with unexplained LV hypertrophy observed by Chimenti and colleagues, which contrasts with the negative result within the series explored by Arad and colleagues [36, 47].

Clinical symptoms

The predominant symptoms of cardiovascular involvement include dyspnoea and chest pain. In most patients, both symptoms are related to LV hypertrophy. The dyspnoea is mainly caused by diastolic dysfunction, although valvular regurgitation and/or systolic LV dysfunction may be the cause in some cases.

Anginal pain usually occurs even in the absence of stenotic coronary lesions, due to an increase in oxygen consumption and a decrease in coronary flow reserve. Coronary angiography should, however, be performed in patients with relevant anginal symptoms, as coronary stenosis may be encountered.

The third most frequent complaint includes palpitations and proven arrhythmias. The high frequency of life-threatening ventricular tachycardia, and the potential benefits of implantable cardioverter defibrillators should encourage the investigation of symptomatic patients by 24-hour Holter monitoring.

Finally, syncope may occur in patients with Fabry disease. Cardiac causes of syncope include high degrees of AV blockade or, more rarely, severe dynamic obstruction of the LV outflow tract.

Analysis of FOS data has confirmed the high prevalence of cardiovascular symptoms among women. However, the age of onset was delayed compared with that in hemizygous men (Figure 10).

Figure 10

The age of onset of symptoms among women and men with Fabry disease in FOS – the Fabry Outcome Survey – demonstrating the later onset of symptoms in women. Values are means ± SD.

Treatment issues

Although we have no formal proof of efficacy and prognostic improvement, all the usual measures for reducing cardiovascular risk are used in patients with Fabry disease, including statin therapy to lower lipid levels and antihypertensive treatment.

Patients should be treated according to the signs and symptoms they experience. Anti-anginal treatment should be given with care, as β-blockers may aggravate the tendency for symptomatic bradycardia and AV conduction impairment in some patients. Based on our experience, dihydropyridine calcium channel blockers are relatively effective and safe. Anti-aggregation therapy should be offered to all symptomatic patients.

Treatment for heart failure should be given to all symptomatic patients. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers should also be considered in asymptomatic individuals with LV hypertrophy. In addition, the potential nephroprotective effects of such treatment should be considered. Patients with advanced stages of heart disease, such as congestive heart failure, may be candidates for heart transplantation, as the intrinsic enzyme production within the graft should prevent its rapid deterioration [27].

Anticoagulant treatment should be initiated immediately in patients with supraventricular rhythm disturbances. In individuals with symptomatic bradycardia and/or AV conduction abnormalities, pacemaker implantation is frequently required. Patients with proven malignant arrhythmias may benefit from an implantable cardioverter defibrillator.

Septal alcohol ablation may be effective in patients with LV outflow tract obstruction. Other treatment modalities (surgical myectomy, mitral valve replacement) should be considered in individuals with unsuitable septal branch anatomy [17].

Enzyme replacement therapy (ERT) has recently been introduced in clinical practice. Agalsidase alfa, produced in human fibroblasts, is given at a dose of 0.2 mg/kg body weight every 2 weeks; agalsidase beta, produced in Chinese hamster ovary cells, is administered every 2 weeks at a dose of 1 mg/kg.

Several trials have been completed using both treatments, and have demonstrated the efficacy of ERT on neurological and renal manifestations of the disease and on quality of life [48–51]. None of these trials was designed specifically to demonstrate an improvement in cardiac structure and function. However, a phase III trial of agalsidase alfa has shown an improvement in the duration of the QRS complex, and bundle branch block was resolved in one patient [48]. In addition, results of cardiac biopsies performed during a phase III trial with agalsidase beta have shown that Gb₃ is cleared from endothelial cells within the myocardial capillaries [49]. Case reports and observational studies have also repeatedly suggested a significant improvement in LV structure and function with both treatments [52–55]. Furthermore, analysis of the FOS database has demonstrated long-term benefits of agalsidase alfa treatment on LV structure and function (see Chapter 37).

A case report has been published that describes an improvement in cardiac function after large doses of galactose – a competitive inhibitor of α-galactosidase A – in a patient with the cardiac variant of Fabry disease [56]. The clinical applicability of such therapy, however, remains unclear. The potential of other, more effective, small molecules, used as chaperones or as substrate deprivation mediators, is under investigation. Correction of the inherent genetic defect would represent the ultimate cure, and promising experimental studies are in progress. [57]

Conclusions

Cardiac involvement is a frequent finding in Fabry disease, both in hemizygous men and heterozygous women. Cardiac hypertrophy associated with depressed contractility and diastolic filling impairment is common, and coronary insufficiency, AV conduction disturbances, arrhythmias and valvular involvement may be present. Cardiac mortality appears to be a major problem in patients with Fabry disease. In those with the atypical 'cardiac variant', the disease manifestations may be limited to the heart. ERT is now the treatment of choice, and preliminary results indicate promising effects not only on the renal and neurological manifestations of the disease but also on the cardiac manifestations.

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