Cardiac Challenges in Patients with Fabry Disease

ARTICLE IN PRESS IJCA-12216; No of Pages 8 International Journal of Cardiology xxx (2009) xxx–xxx

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International Journal of Cardiology

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Review Cardiac challenges in patients with Fabry disease

F. Weidemann a,⁎, A. Linhart b, L. Monserrat c, J. Strotmann a a Department of Medicine I, Center of Cardiovascular Medicine, Würzburg, Germany b Second Department of Internal Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic c Instituto de Investigación Biomédica de A Coruña (INIBIC), CHU Juan Canalejo, Coruña, Spain article info abstract

Article history: Fabry disease, an X-linked lysosomal storage disorder affecting both men and women, is a relatively Received 20 March 2009 prevalent cause of hypertrophic cardiomyopathy (HCM) and is associated with significant morbidity and Received in revised form 15 June 2009 early death due to heart failure or ventricular arrhythmias. Fabry cardiomyopathy results from progressive Accepted 11 August 2009 build-up of glycosphingolipids in cardiac structures, but the underlying complex pathophysiologic Available online xxxx mechanisms remain poorly understood. Disease-specific enzyme replacement therapy (ERT) is available for Fabry disease and, therefore, attention should be focused on early diagnosis of this progressive, life- Keywords: Fabry disease threatening disease. Selected cardiology patients at high risk for Fabry disease can be tested using simple Cardiomyopathy enzymatic assays, and diagnosis is confirmed by demonstration of a Fabry mutation. Testing cardiology Cardiac fibrosis patients with HCM of unknown etiology may identify previously unrecognized Fabry patients and allow genetic mapping to be carried out to identify other affected family members at a relatively early stage of the disease. Timely intervention early on in the disease is a key, as the best responses to ERT are seen in patients with the lowest degree of cardiac hypertrophy and fibrosis at the start of treatment. © 2009 Published by Elsevier Ireland Ltd.

1. Introduction EOW [4–11]. To optimize the benefits of therapy, ERT should be initiated early, before irreversible organ damage may occur [12,13]. Fabry disease is an X-linked, recessive lysosomal storage disorder Therefore, it is of critical importance to test cardiology patients with expressed as a deficiency in the enzyme α-galactosidase A (α-Gal A). hypertrophic cardiomyopathy (HCM) for Fabry disease and make This deficiency causes progressive accumulation of globotriaosylcer- an early diagnosis in these patients, as well as in affected family amide (GL-3) and related glycosphingolipids in cardiac, renal, neural, members. vascular, ocular, and skin tissues [1]. In cardiac tissues, progressive GL- This review is based on the Proceedings of the 6th International 3 accumulation in cardiomyocytes, conduction system cells, vascular Expert Panel on Fabry Cardiomyopathy held in Munich, Germany on 30 endothelial and smooth muscle cells, and valvular fibrocytes initiates August 2008 and is supported by published clinical evidence identified secondary pathologic processes that eventually lead to irreversible in a literature review up to October 2008. Three clinical challenges are cardiac damage. Males are primarily affected by Fabry disease, but discussed: the pathophysiology associated with progression of Fabry female heterozygotes may also display symptoms ranging in severity, cardiomyopathy; how to identify and test at-risk cardiology patients for depending on the skewed X-chromosome inactivation [2]. Fabry disease; and how to improve treatment of Fabry-related Cardiac Fabry disease manifests with a broad spectrum of signs cardiomyopathy. and symptoms, including left-ventricular hypertrophy (LVH), This manuscript only focuses on cardiac aspects of Fabry disease. arrhythmias, coronary artery disease (mainly small-vessel disease), and heart failure [1,3]. In some patients, cardiac symptoms predomi- 2. Clinical course and pathophysiology of Fabry-related HCM nate over other typical symptoms such as skin signs, pain crises, and renal impairment. Although cardiac involvement of Fabry disease begins early, the Disease-specific treatment for Fabry disease is available in the average age for clinically overt cardiac symptoms (e.g. dyspnea, form of enzyme replacement therapy (ERT) with either agalsidase alfa reduced exercise tolerance, angina, chest pain, palpitations, ventricu- 0.2 mg/kg every other week (EOW) or agalsidase beta 1.0 mg/kg lar arrhythmias, syncope, transient ischemic attacks, stroke, and heart failure [14–16]) to manifest has been reported to be 32 years in men and 40 years in women [3]. HCM, mainly characterized by LVH and ⁎ Corresponding author. Medical Clinic I, Department of Cardiology, University Hospital Würzburg, Josef-Schneider Str. 2, D 20, 97080 Würzburg, Germany. conduction abnormalities, may in fact be the major presenting feature E-mail address: [email protected] (F. Weidemann). of the disease [17–22]. Nearly all male and female patients with Fabry

Please cite this article as: Weidemann F, et al, Cardiac challenges in patients with Fabry disease, Int J Cardiol (2009), doi:10.1016/j. ijcard.2009.08.002 ARTICLE IN PRESS

2 F. Weidemann et al. / International Journal of Cardiology xxx (2009) xxx–xxx disease will develop LVH, the extent of which increases with age and Table 1 is accompanied by a progressive reduction in regional left-ventricular Non-cardiac symptoms of Fabry disease. function (LVF) [15,23]. The serious cardiac complications cause Symptom Description substantial morbidity and contribute to the reduced life expectancy Neuropathic pain Usually burning or tingling in hands of affected male and also female patients [3]. and feet. Occasionally, bouts of severe Many questions on the pathophysiology of Fabry-related HCM still pain can last for minutes to days remain unanswered. Early accumulation of GL-3 in cardiomyocytes is Cerebrovascular White–gray matter lesions, stroke, TIA thought to initiate a series of pathologic processes – through largely manifestations – Neurologic Hearing loss, tinnitus unknown mechanisms leading to HCM. While GL-3 accumulation manifestations does increase heart mass, studies have shown that GL-3 is only GI manifestations GI symptoms (postprandial bloating responsible for 1–3% of the mass of enlarged hearts [20,22], indicating and pain, diarrhea and nausea) that LVH does not arise solely as a direct consequence of GL-3 Decreased Overheating, frequent fevers and ability to sweat sensitivity to hot weather infiltration. It has recently been suggested that an increase in trophic Skin manifestation A reddish–purplish angioma mainly factors, such as the deacylated GL-3 metabolite lyso-Gb3, may have a on the buttocks, groin and upper causative role in the development of LVH in the hearts of patients with thighs, around the belly button and Fabry disease [24,25]. Other mechanisms may also be operative; for sometimes on elbows and knees example, Shen et al. [26] reported that excess intracellular GL-3 Corneal pattern A starburst pattern occurring on the cornea. The pattern (cornea induces oxidative stress and upregulates the expression of cellular verticillata) can be adhesion molecules in vascular endothelial cells in Fabry disease found by a simple eye examination patients, which might induce small-vessel coronary heart disease. by an ophthalmologist and normally Another hypothesis is that GL-3 accumulation in Fabry disease disrupts does not affect vision mitochondrial energy metabolism [27]. Jung et al. [28] reported Renal symptoms (Micro)albuminuria, impaired concentration ability, tubular alterations in mitochondrial metabolism in the LV wall of patients with function abnormalities, proteinuria, asymptomatic sarcomeric HCM. Similar findings have been reported in decreased glomerular filtration rate skin fibroblasts from patients with Fabry disease [29], suggesting that progressing to end-stage renal disease GL-3 deposits may cause disturbances in respiratory-chain enzyme GI: gastrointestinal; TIA: transient ischemic attack. activity, leading to reduced levels of creatinine phosphate, ADP, and ATP. Further basic clinical research is needed to elucidate the pathophysiology of Fabry disease. diagnosis of affected family members. Family testing is very effective for early identification of Fabry disease. It has been shown that each 3. Testing for Fabry disease ‘index’ patient identified in a testing program may lead to the identification of a further 3 [34,35] to 5 [36] family members with Testing patients at risk of, or suspected of having, Fabry disease Fabry disease (see ‘3.4. Family testing’). Affected family members can meets the criteria recommended for genetic testing programs [30]: then benefit from genetic counselling and early treatment when Fabry disease testing is relevant for public health, early diagnosis required. significantly improves prognosis, and testing can be done rapidly and Although cardiologists commonly see patients with end-stage inexpensively with high sensitivity and specificity without risk to Fabry disease, testing at-risk cardiac patients is important for patients. However, there are a number of important questions to diagnosis, determination of an appropriate treatment regime, consider when planning a Fabry disease testing program in cardiac addressing problems in other organs, and diagnosis of affected family patients. Why test for Fabry disease among cardiac patients? Which members. Testing programs in selected cardiac patients increase the cardiac patients should be tested? How should testing for Fabry awareness of Fabry disease among cardiologists. disease be carried out and what protocols are required to facilitate family testing for the disease? 3.2. Selection of cardiac patients to test for Fabry disease

3.1. Rationale for testing for Fabry disease in at-risk cardiac patients 3.2.1. Screening among patient populations HCM is one of the most prevalent cardiac signs of Fabry disease Signs of Fabry cardiomyopathy can be observed in younger patients, and predominantly involves a progressive concentric thickening of in particular LVH and mild-to-moderate reductions in regional LVF the LV wall, leading to LVH [37]. The Fabry Outcome Survey reported [2,3,15,31,32]. Atrioventricular (AV) conduction abnormalities can also that 54% of untreated and 43% of treated patients had LVH upon entry be detected at younger ages, typically with a shortened PR interval [33],in to the survey [3]. Patients with HCM therefore represent the primary contrast to the prolonged PR interval and AV blocks seen in older patients. target group for Fabry disease testing. Recognizing the early cardiac and non-cardiac signs and symptoms Sarcomeric mutations are responsible for up to 60% of cases of as manifestations of Fabry disease is challenging, as they can be broad- HCM [38,39]. Conditions that mimic HCM include systemic hyper- ranging and non-specific(Table 1). Substantial delays in diagnosis tension, aortic valvular stenosis, and severe aortic valve regurgitation have been reported [31,32]. For example, the Fabry Registry recently [38]. In patient populations with HCM, prevalence rates of Fabry reported that early symptoms appear at an average age of 9 years in disease ranging from 0 to 12% have been reported, depending on the males and 13 years in females, but there is an average delay of 14 years patient selection criteria used (Table 2) [17–19,34,39,40]. No Fabry in men and 19 years in women between symptoms and diagnosis [31]. patients were found in a study of highly selected HCM patients with With the advent of ERT, the benefits of early diagnosis are particularly severely symptomatic, obstructive, asymmetrical basal, septal hyper- compelling, as initiation of ERT early in the disease course can optimize trophy (n=100), suggesting that Fabry disease is unlikely in these the response to treatment [8,12,13]. ERT has been shown to reduce HCM patients [40]. The study with the largest number of patients accumulated intracellular GL-3, which, as we discussed above (see ‘2. included (n=508) reported a 1% prevalence of Fabry disease in Clinical course and pathophysiology of Fabry-related HCM’), is thought otherwise unselected patients with LVH [34]. to be the trigger for a series of pathologic processes leading to As Fabry disease is an X-linked recessive genetic disorder, it has irreversible fibrotic organ damage [26]. Another important reason for long been viewed as a disease that primarily affects men. However, testing for Fabry disease in at-risk cardiac patients is that it allows symptomatic women have been described since the late 1960s [41]

Please cite this article as: Weidemann F, et al, Cardiac challenges in patients with Fabry disease, Int J Cardiol (2009), doi:10.1016/j. ijcard.2009.08.002 ARTICLE IN PRESS

F. Weidemann et al. / International Journal of Cardiology xxx (2009) xxx–xxx 3 and recent studies have shown that cardiac symptoms develop in both 3.3. Laboratory assays for Fabry disease men and women [2,32,34,37]. In women with Fabry disease, LVH typically develops 6–12 years later than in men [15]. Thus, women A number of laboratory assays are available for testing patients for should be included in screening programs. Fabry disease. These assays are based on α-Gal A enzyme activity in leukocytes, plasma, or dried blood spots (DBS); molecular genetic 3.2.2. Testing of individuals analysis; or measuring accumulated GL-3 in urine. Clinical suspicion of Fabry disease should be raised when additional cardiac signs are present, such as premature conduction abnormalities, pre-excitation [38], or reduced regional LVF [15]. 3.3.1. Diagnostic assays α Fabry-disease-specific electrocardiogram (ECG) signs can be identi- Measuring -Gal A enzyme activity in leukocytes using the fl α fied, typified by tall broad QRS complexes and shortened PR intervals uorogenic substrate 4-methylumbelliferyl- -D-glucopyranoside in younger patients [33], progressing to prolonged PR intervals, AV (4MUGal) has become the gold standard for diagnosing Fabry disease blocks, and malignant ventricular arrhythmias with age. in males [43]. The use of plasma samples is associated with a higher Fabry disease should be considered in a differential diagnostic percentage of false-negative results [2,43]. The diagnosis of Fabry disease fi α algorithm for HCM. However, it is important to be aware that other in some women can be con rmed by measuring -Gal A enzyme activity α conditions, including systematic hypertension and aortic valvular stenosis, in leukocytes; however, normal -Gal A enzyme activity does not can mimic HCM [38]. Clinical suspicion of Fabry disease in patients with exclude Fabry disease in female heterozygotes. In these females, fi HCM should be raised in case of other clinical Fabry symptoms, such as diagnosis requires GLA mutation analysis [44].Theidenti cation of a fi acute or chronic peripheral neuropathic pain during adolescence, GLA mutation con rmsthediagnosisinmales[45] and females [46]. decreased ability to sweat, albuminuria/proteinuria, eye abnormalities Moreover, it facilitates the diagnosis of family members and genetic α (cornea verticillata), angiokeratoma, gastrointestinal complaints, and counselling. Not all individuals with low -Gal A enzyme activity have α fi early stroke [1,12]. In this respect there is an educational need to raise Fabry disease; low -Gal A levels can be caused by pseudo-de ciencies awareness among cardiologists of the wider range of symptoms of Fabry such as the D313Y coding sequence variant [47]. disease (Table 1). The cardiologist can identify such clinical symptoms by fi asking speci c additional questions on the patient's medical history. 3.3.2. Screening assays However, some Fabry disease patients may predominantly show cardiac α-Gal A enzyme activity assays using DBS on filter paper samples – symptoms [18,20 22,42], in which case reliance on the presence of other were found to be as accurate as assays using leukocyte samples [48,49]. clinical symptoms may miss a diagnosis of Fabry disease. DBS samples are easy to transport and are stable at room temperature for at least 20 days, making them suitable for screening patients at risk Testing for Fabry disease in cardiac patients for Fabry disease [50]. Leukocyte α-Gal A enzyme activity assays can be • Include Fabry disease systematically in a differential diagnostic algorithm of HCM used to confirm positive DBS results and verify negative results in • Patient selection for testing for Fabry disease: patients with a clinical suspicion of Fabry disease [43]. Urinary GL-3 ▪ ≥ patients with unexplained LVH (detected by a wall thickness 15 mm as levels can be measured reliably by using tandem mass spectrometry. measured by echocardiography) ▪ patients with LVH who do not demonstrate the typical autosomal dominant Urine samples from 28 males with classic Fabry disease had elevated HCM inheritance pattern (exclude those who have another confirmed cause for levels of GL-3 and could readily be distinguished from normal controls, HCM in their family) but 3 of 6 male patients with the N215S mutation had normal urine • Clinical suspicion of Fabry disease should be raised in patients with LVH wall levels and the other 3 had marginally elevated levels in their urine [51]. thickness≥13 mm: In 37 females without the N215S mutation, 97% had elevated urinary ▪ who show Fabry-specific ECG signs (tall broad QRS complexes and shortened PR intervals) [33] GL-3 [51]. The 4 heterozygotes with the N215S mutation had normal ▪ or who demonstrate 1–2 clinical factors associated with Fabry disease (e.g. urinary GL-3 [51]. GL-3 can also be measured in urine on filter paper peripheral neuropathic pain, hypohidrosis, albuminuria/proteinuria, eye [52]. Costs for molecular genetic analysis are decreasing and large abnormality, angiokeratoma, gastrointestinal complaints [1,12], family history Fabry disease screening programs in selected at-risk patients are of premature death) becoming feasible.

Table 2 Prevalence of Fabry disease in patients with hypertrophic cardiomyopathy.

Study n Prevalence, % Patient characteristics LVH selection criteria

Age [range, average±SD], Male, % Location Deﬁnition thickness Other years (mm)

Nakao et al. 1995 [18] 230 3 16–87, 62±13 100 Ventricular-septum ≥13 Otherwise unselected LVH and/or posterior-wall Sachdev et al. 2002 [17] 79 6.3 40–71, 52.9±7.7 100 Ventricular wall ≥13 Apparently unexplained LVH 74 1.4 8–39, 25.9±9.2 Ventricular wall ≥13 Apparently unexplained LVH Chimenti et al. 2004 [19] 34 12 50±13.6 0 Ventricular-septum ≥13 Unexplained LVH (LVH without and/or posterior-wall systemic hypertension, aortic valvular stenosis, or severe aortic valve regurgitation) Monserrat et al. 2007 [34] 508 1 58±16 64.4 Any location ≥15 Otherwise unselected LVH Ommen et al. 2003 [40] 100 0 51±16 44 Not defined Not defined Symptomatic asymmetrical hypertrophy causing severe outflow obstruction Arad et al. 2005 [39] 75 0 12–75 60 Ventricular wall ≥13 Unexplained LVH 20 0 9–58 NA Ventricular wall ≥30 Unexplained massive LVH 24 0 8–42 NA Ventricular wall ≥13 Ventricular pre-excitation

LVH: left-ventricular hypertrophy; NA: not available; SD: standard deviation.

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3.4. Family testing We have only limited data comparing both approved ERT drugs with each other. One head-to-head comparison trial of agalsidase alfa Proactive and early identification of individuals with Fabry disease and agalsidase beta used a dose of 0.2 mg/kg for both drugs [64], can be done using pedigree analysis in families of a patient with a which is the approved dose for agalsidase alfa and one-fifth of the confirmed diagnosis [34–36,53]. For example, Monserrat et al. [34] approved dose for agalsidase beta. ERT treatment failure was noted confirmed the diagnosis of Fabry disease in 5 patients, which led to with both agalsidase alfa (5 of 18 patients) and agalsidase beta (3 of the identification of 15 family members with Fabry disease (3 per 16 patients) [64]. Renal function and pain did not improve, LV mass proband). In the United States, a review of the pedigrees of 74 Fabry was not significantly reduced, and no normalization of plasma and disease patients resulted in detecting 357 affected family members (5 urine GL-3 could be achieved [64]. The development of neutralizing per proband) [36]. In Argentina, pedigree analysis in 6 Fabry disease IgG antibodies to agalsidase has been hypothesized as a reason for an patients from unrelated families resulted in the diagnosis of 64 impaired clinical response in some Fabry patients. Antibodies towards additional patients with Fabry disease (10 per proband) [53]. the enzyme preparations can develop especially in male patients, who Supportive tools, such as the “Fabry Indicator®” software (distributed often do not express residual enzyme activity. More recently, a direct without charge by Genzyme Corp., Cambridge, MA, USA) and the clinical comparison of agalsidase beta (1.0 mg/kg EOW or 0.2 mg/kg “Fabry Pedigree Facilitator” (distributed without charge by TKT EOW) and agalsidase alfa (0.2 mg/kg EOW) showed that 1.0 mg/kg Europe - 5S AB), have been developed to facilitate pedigree analysis. agalsidase beta results in a more robust decline of GL-3, reduction in heart size, and stabilization of renal function than the 0.2 mg/kg 4. Treatment of Fabry-related cardiomyopathy regimen of either agalsidase alfa or beta, suggesting that the neutralizing effect of antibodies can be overcome by a higher dose ERT can reduce neuropathic pain, stabilize kidney function, and of ERT [65,66]. delay progression to major late events (i.e. major renal, cerebrovascular, and cardiac events) [4,5,7–9]. ERT is therefore becoming the 4.2. Early initiation of ERT cornerstone of disease-specific treatment for Fabry patients. A number of questions can be raised specific to the treatment of In patients with Fabry cardiomyopathy, end-stage disease pro- cardiomyopathy due to Fabry disease. Can ERT improve cardiac gression is characterized by severe functional abnormalities due to outcomes? What are the characteristics of patients who benefit most myocardial fibrosis co-existing with LVH and reduced LVF [14,67–69]. from ERT? How can treatment of Fabry-related cardiomyopathy be Patients with end-stage Fabry disease commonly die as a result of improved further in addition to using ERT? heart failure related to severe fibrosis and cardiac arrhythmias [70]. Myocardial fibrosis is indicated by late enhancement on MRI; thus 4.1. Effect of ERT on cardiac morphology and function MRI has an important role in detecting fibrosis and monitoring ERT in these patients. Early studies on subclinical markers of Fabry disease demonstrated Early initiation of treatment, before fibrosis develops, seems a normalization of GL-3 levels in myocardial endothelial cells after ERT consequent strategy to prevent the progression of cardiac dysfunction. with agalsidase beta 1.0 mg/kg EOW [4–7,54]. In a randomized Even though there are no randomized studies including major cardiac controlled trial (RCT) of 29 patients, the mean histologic score for GL- endpoints, some studies have shown that the efficacy of ERT in 3 content in the heart was reduced from 0.9±0.4 at baseline to 0.3± improving cardiac outcomes may depend on the degree of cardiac 0.5 after 20 weeks of treatment with agalsidase beta 1.0 mg/kg EOW, hypertrophy and the level of functional impairment present at the start compared to scores of 0.9±0.5 at baseline and 1.2±0.6 after of ERT using surrogate markers such as LVH [61,71,72]. In a recent study 20 weeks of placebo (p<0.001) [4]. A prospective, observational (n=32), agalsidase beta 1.0 mg/kg EOW was used over a period of study in 16 patients with Fabry disease reported a significant 3 years and patients were grouped according to the extent of fibrosis reduction in myocardial mass from 201±18 g at baseline to 180± [13]. At baseline, 9 patients demonstrated at least 2 fibrotic LV segments 21 g after treatment with agalsidase beta 1.0 mg/kg EOW for (=severe myocardial fibrosis), 11 had 1 LV segment affected (=mild 12 months (p<0.05) [55]. In addition, agalsidase beta treatment fibrosis), and 12 patients were without fibrosis [13]. In all patient was associated with an improvement in regional myocardial function groups, ERT resulted in a significant reduction of LV mass [13]. However, as measured by radial peak systolic strain rate (2.8±0.2 s− 1 at only in those patients without LV fibrosis improvement of regional baseline vs. 3.7±0.3 s− 1 after treatment, p<0.05) and longitudinal radial function and exercise capacity was demonstrated [13].These systolic strain (13.4±0.7% at baseline vs. 17.2±0.6% after treatment, findings are consistent with those of studies that have reported better p<0.05) (see Table 3 in ref. [55]). A recent study using magnetic response rates to treatment for Fabry nephropathy in those patients resonance imaging (MRI) demonstrated reduced LV mass and LV wall with better renal function at the start of treatment [8,60]. thickness as well as a reduction in myocardial T2 relaxation times in How can the cardiac manifestations of Fabry disease be detected at 11 Fabry patients after 45 months of treatment with agalsidase beta an earlier stage? Several recent studies have shown that tissue 1.0 mg/kg EOW [56]. A study of agalsidase alfa 0.2 mg/kg EOW Doppler imaging (TDI) and strain rate imaging can reliably detect treatment (n=14) reported a decrease in LV mass of 6.4 g/m2 by significant abnormalities in myocardial contraction and relaxation week 13 (vs. a 12 g/m2 increase in the placebo control group, that exist before LVH develops [73–75]. Currently these methods are p=0.02) [57]. Such findings are supported by the results of a number not widespread available but they can be used to detect preclinical of other studies (summarized in Table 3) that have reported improved changes in patients with Fabry disease. This information will allow cardiac outcomes with ERT in patients with Fabry cardiomyopathy optimization of management before and during ERT, increasing the [4,5,7–9,54–64]. One placebo-controlled RCT of agalsidase beta likelihood of long-term improvements in cardiac outcomes. 1.0 mg/kg EOW in 82 patients with advanced Fabry disease looked at a composite endpoint of renal, cardiac, and cerebrovascular 4.3. Concomitant therapy in the management of Fabry cardiomyopathy complications and death. The rate of first clinical events favoured treatment with agalsidase beta (27%) over placebo (42%) (hazard ERT might be the cornerstone of disease-specific treatment for ratio 0.47, 95% confidence interval 0.21–1.03, p=0.06). The clinical Fabry patients. However, in patients with advanced Fabry cardiomy- events included cardiac events (arrhythmia, angina, and myocardial opathy, additional treatment to manage cardiac symptoms such as infarction) in 3/51 patients treated with agalsidase beta and 4/31 heart failure or tachycardia should be considered [12]. Assessing the patients treated with placebo [8]. stage of Fabry cardiomyopathy in individual patients is important to

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Table 3 Cardiac outcomes of enzyme replacement therapy.

Study Duration Outcome Study Treatment [vs. comparator] (months) type Baseline Endpoint p

Agalsidase beta Eng et al. 2001a [4] 5 Mean histologic score RCT 0.9±0.4 0.3 (0.5) <0.001 for GL-3 content in CCE [vs. 0.9±0.5] [vs. 1.2±0.6] Banikazemi et al. 2007 [8] 35 Cardiac events (arrhythmia, RCT 3/51 0.42 angina, myocardial infarction) [vs. 4/31]

Bierer et al. 2006 [58] 18 VO2 max, l/min RCT 1.680±0.670 2.139 ±0.676 ns [vs. 1.462±0.691] [vs. 1.346 ±0.250]

VO2/HR 10.8±3.4 +1.71 ns [vs. 8.7±3.4] [vs. +0.025] Stroke volume, ml/beat 67 (49–90) 77 (60–96) ns [vs. 54 (39–69)] [vs. 54 (47–61)] HR reserve, beats/ min 33.8±13.1 16.8±20.6 ns [vs. 12.5±13.4] [vs. 21±1.4] Eng et al. 2001b [5] 5 doses GL-3, ng/mg tissue Open-label 21400±7420 18300±7780 NG Mean histologic score for GL-3 1.75±0.89 0.57±0.79 NG content in CCE Weidemann et al. 12a Deceleration time, ms Open-label 242±11 258±12 NG 2003 [55] Isovolumetric relaxation time, ms 121±4 118±3 NG Ejection fraction, % 62±1 64±1 NG End-diastolic thickness LV 13.8±0.6 11.8±0.6 <0.05 posterior wall, mm Myocardial mass, g 201±18 180±21 <0.05 Radial peak systolic strain rate, s− 1 2.8±0.2 3.7 ±0.3 <0.05 Radial systolic strain, % 34±3 45±4 <0.05 Longitudinal peak systolic 1.1±0.1 1.4 ±0.1 <0.05 strain rate, s− 1 Longitudinal systolic strain, % 13.4±0.7 17.2±0.6 <0.05 Weidemann et al. 36 No fibrosis patients (n=12) Open-label 2009 [13] LV end-diastolic diameter (mm) 48 (4) 49 (4) 0.89 PWT (mm) 13 (1.2) 11.5 (1.6) <0.01 Septum (mm) 13.5 (1.4) 12.0 (1.4) <0.01 LV mass, g 238 (42) 202 (46) <0.01 Mild fibrosis patients (n=11) LV end-diastolic diameter (mm) 49 (5) 48 (6) 0.99 PWT (mm) 14.4 (2.2) 12.9 (1.8) 0.21 Septum (mm) 14.4 (1.8) 13.4 (1.4) 0.20 LV mass, g 275 (62) 244 (65) 0.31 Severe fibrosis patients (n=9) LV end-diastolic diameter (mm) 51 (12) 49 (6) 0.69 PWT (mm) 14.7 (2.7) 12 (1.4) 0.17 Septum (mm) 14.9 (3) 14.1 (2) 0.01 LV mass, g 303 (84) 247 (45) 0.24 Pisani et al. 2005 [59] 24 LVMI, % increase per 2 years Open-label +6% +3% NG Spinelli et al. 2004 [54] 6 and 12 HR, ms Open-label 1033 ±108 1001 ±103 ns (12=endpoint) LV ejection fraction, % 56±4 59±4.5 ns LV posterior wall thickness, mm 13.3±1.6 12.4±1.5 ns LVMI Decreaseb Significant Relative wall thickness Decreaseb Significant Interventricular septum thickness Decreaseb Significant Imbriaco et al. 2009 [56] 45 LV mass, g Open-label 188±60 153±47 <0.05 LV wall thickness (mm) 16±4 14±4 <0.05 Myocardial T2 relaxation times (ms) - Interventricular septum 80±5 66±8 <0.05 - Apex 79±10 64±10 <0.05 - Lateral wall 80±8 65±16 <0.05 Breunig et al. 2006 [60] 23 LV end-diastolic posterior wall Open-label GFR>90 ml/ 10.7±0.7 0.017 thickness, mm min: 11.7±1.0 GFR<90 ml/ 13.4±2.3 0.22 min: 14.0±2.1 Kalliokoski et al. 12 Ejection fraction, % Open-label 69±17 68±17 0.86 2006 [61] Stroke volume, ml 94±11 95±12 0.91 LVM, g 275±28 292±35 0.27 LVMI, g/m2 151±12 156±14 0.37 Myocardial perfusion, ml/min/g NG NG ns Germain et al. 2007 [7] 54 GL-3 clearance from CCE, histologic Open-label NG 32/40 (80%) NG score of 0

Agalsidase alfa Schiffmann et al. 2001 [9] 6 QRS complex, ms RCT 94.1±4.85 91.7±2.14 0.047 [vs. 94.0±3.39] [vs. 97.6±3.37]

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TableTable 3 ((continued)continued) Study Duration Outcome Study Treatment [vs. comparator] (months) type Baseline Endpoint p

Agalsidase alfa Elliott et al. 2006 [62]a 10 Coronary ﬂow reserve Open-label 1.41±0.39 1.6±0.37 ns [vs. 3.03±0.85] [vs. 1.74±0.28] Hughes et al. 2008 [57] 6 GL-3, nmol/µg RCT 0.71±0.18 0.58±0.18 ns [vs. 0.58±0.08] [vs. 0.63±0.13] LVMI, g/m2 NG −6.4 vs. +12 0.02 QRS complex, ms NG −12.9±11.8 0.8 vs. +4 Beck et al. 2004 [63] 12 and 24 MWT, >11 mm Open-label Decreaseb <0.05 LVM, >50 gm− 2.7 Decreaseb <0.05

Agalsidase beta vs. agalsidase alfa Vedder et al. 2007 [64] 24 Change LVM, g Open-label 316 (213 to 517) −46 (−226 to ns vs. 288 (177 to 479) 131) vs. −23 (−167 to 136)

CCE: cardiac capillary endothelial; GFR: glomerular filtration rate; GL-3: globotriaosylceramide; HR: heart rate; LV: left ventricular; LVM: left-ventricular mass; LVMI: left-ventricular mass index; MWT: maximal wall thickness; NG: not given; ns: not significant; RCT: randomized controlled trial. aNon-patient control group. bPrecise values not reported. identify those in whom concomitant therapy is warranted, and to myocardial function and reduce LVH. However, treatment cannot determine the type of supportive therapy required. Such additional reverse extensive fibrotic damage to myocardial tissue, underscoring therapy might include an angiotensin-converting enzyme (ACE) the need for early diagnosis and treatment. Testing high-risk cardiology inhibitor or an angiotensin-receptor blocker to reduce afterload in patients with HCM for Fabry disease is therefore warranted, both to patients with Fabry cardiomyopathy, and beta-blockers to control facilitate early diagnosis and identify affected family members. Once hypertension and tachycardia (Table 4). However, before using beta- Fabry disease is diagnosed, the best treatment course of ERT and blockers, bradycardia has to be excluded. A pacemaker may be ancillary treatment with other cardiology medications needs to be required to manage symptomatic bradycardia in patients with established based on the severity of cardiac involvement. significant AV blocks or an implantable cardioverter–defibrillator (ICD) needed in case of malignant ventricular arrhythmia. However, Disclosures clinical studies evaluating the efficacy and safety profile of concomitant medical therapy in patients with Fabry disease are urgently This review is based on a discussion of available evidence by an needed. The FAACET trial is currently underway to investigate the international panel of experts who met at the 6th International Expert effects of treatment with ACE inhibitors or angiotensin-receptor Panel on Fabry Cardiomyopathy in Munich, Germany, in August 2008 blockers in addition to ERT in Fabry disease (http://clinicaltrials.gov/ organized by Genzyme Europe BV (see Appendix for the list of ct2/show/NCT00446862?term=faacet&rank=1). participants). The authors received writing/editorial support in preparation of this manuscript, funded by Genzyme Europe BV. 5. Conclusions Potential conflict of interests Fabry disease is a relatively prevalent cause of HCM and associated with significant morbidity and early death due to heart failure or Dr. Linhart has received speaker's honoraria from Genzyme. ventricular arrhythmias. Cardiologists therefore have a pivotal role in Dr. Monserrat reports that he has a contract with Health in Code SL, the timely diagnosis and optimal management of patients with Fabry and also has shares in the same company. Dr. Strotmann and cardiomyopathy. Potentially effective, disease-specific ERT is available Dr. Weidemann have received speaker's honoraria and research for Fabry disease and should be considered the cornerstone of treatment grants from Genzyme. for these patients. Clinical studies have shown that ERT can improve Acknowledgments

Table 4 Options for concomitant therapy in patients treated with enzyme replacement therapy The authors would like to thank Dr Bundgaard and Dr McKeown for Fabry cardiomyopathy. for critically reviewing the content of the paper and their valuable contributions. The authors of this manuscript have certiﬁed that they Therapy Indication Comments comply with the Principles of Ethical Publishing in the International ACE LVH Care needed to avoid Journal of Cardiology [76]. inhibitor hypotension Beta-blocker Hypertension and Need to monitor patients tachycardia to avoid worsening of existing Appendix: Participants in the 6th International Expert Panel on bradycardia Fabry Cardiomyopathy, held in Munich, Germany on 30 August Pacemaker Symptomatic Check for malignant 2008 bradycardia ventricular arrhythmia before pacemaker implantation ICD Malignant ventricular If necessary, add beta-blocker A. Anastasakis, Greece; M. Becker, Germany; H. Bundgaard, Denmark; arrhythmia after implantation F. Cecchi, Italy; C. Chimenti, Italy; A. Cokan Vujkovac, Slovenia; ACE: angiotensin-converting enzyme; ICD: implantable cardioverter–deﬁbrillator; M. Frenneaux, United Kingdom; A. Frustaci, Italy; A. Hagège, France; LVH: left-ventricular hypertrophy. A. Linhart, Czech Republic; T.F. Lüsher, Switzerland; P. McKeown, United

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