Fabry disease: Cardiovascular disease

INTRODUCTION — Fabry disease (MIM 300644, also known as angiokeratoma corporis diffusum, ceramide trihexosidosis, or Anderson-Fabry disease) is an X-linked glycolipid storage disease [1,2]. It is caused by deficient activity of the lysosomal enzyme alpha-galactosidase A, resulting in the accumulation of globotriaosylceramide in lysosomes in multiple cell types throughout the body.

While males are more severely diseased, most heterozygous females are also affected, though usually at a later age [3-6].

Clinical manifestations are variable and include cutaneous, corneal, cardiac, renal, and neurologic manifestations. The typical presentation occurs in children who suffer from peripheral neuropathy of the hands and feet, nausea, and abdominal pain. However, diagnosis is frequently missed due to the rarity of the disease. Other characteristic features include reduced sweating and the cutaneous lesions of angiokeratoma corporis (picture 1 and picture 2), which are vascular papules typically distributed in the inguinal, hip, and periumbilical areas. These become more prominent with age. Manifestations of renal disease include proteinuria and progressive renal insufficiency, which sometimes result in end-stage kidney disease. In adults, there is progressive cardiac, renal, and cerebral involvement (transient ischemic attacks and strokes), which are the major causes of death associated with Fabry disease. (See "Fabry disease: Clinical features and diagnosis".)

The cardiac features of Fabry disease and the incidence of unexpected Fabry disease in patients with otherwise unexplained left ventricular hypertrophy will be reviewed here. The general clinical manifestations and treatment of Fabry disease are discussed separately. (See "Fabry disease: Clinical features and diagnosis" and "Fabry disease: Treatment and prognosis".)

CARDIOVASCULAR MANIFESTATIONS

Clinical features — Cardiovascular manifestations of Fabry disease include left ventricular hypertrophy (LVH), aortic and mitral regurgitation, conduction defects, coronary artery disease, hypertension, and aortic root dilation [6-11]. The right ventricle is also often hypertrophied [12]. Many patients with cardiac involvement are asymptomatic, whereas others present with angina, dyspnea, palpitations, or syncope. Rare patients have advanced heart failure symptoms in the setting of unexplained LVH and generally normal LV ejection fraction (LVEF).

Although LVH has been detected in some children, cardiovascular signs and symptoms are not usually evident until the third or fourth decade or later in males and approximately a decade later in females [6,13]. While males are more severely diseased, most heterozygous females are also affected, though usually at a later age [3-6]. Life expectancy is reduced by approximately 20 years in untreated males and by approximately 15 years in females compared with the general population [9,14]. It has been hypothesized that females are affected due to inactivation of the normal X-chromosome, though the frequency of disease in females is greater than expected due to X-inactivation alone [6].

Cardiac manifestations typically accompany other findings of Fabry disease, but they can occasionally occur as the sole manifestation of the disease in patients with the "cardiac variant." As an example, in a series of 139 patients with Fabry disease, while 60 percent have cardiovascular signs and symptoms, only two patients had cardiovascular manifestations without any other signs of Fabry disease [15]. Among patients with Fabry disease, females are more likely to present with the cardiac variant of disease [16].

Ventricular hypertrophy — Unexplained LVH is the hallmark of cardiac disease and is more common and more severe in males [7,8,15,17-19]. Several patterns of LVH and remodeling occur, including concentric, asymmetric, and eccentric hypertrophy (figure 1) [13]. Early concentric remodeling progresses to concentric hypertrophy, which is the most common pattern seen [13,20]. Asymmetric septal hypertrophy occurs in approximately 5 percent of cases [20]. In some cases of severe cardiac disease, the septum may appear asymmetrically hypertrophied because the basal posterior wall is thinned due to fibrosis. Dynamic LV outflow tract obstruction is rare (occurring in <1 percent) but has been reported [17,18].

LVH is likely due to both myocyte hypertrophy and glycolipid deposition. The extent of hypertrophy increases with age and is inversely correlated with renal function and alpha-galactosidase A activity [15].

LVH is generally diagnosed by echocardiography and is frequently suggested by electrocardiography (ECG). Echocardiography also enables detection of alterations in systolic and diastolic myocardial function that may accompany LVH. Cardiovascular magnetic resonance imaging (CMR) is also helpful in identifying LVH and other features of Fabry heart disease. (See 'Cardiac tests' below.)

Right ventricular hypertrophy and impaired right ventricular function (as assessed by strain rate imaging) are also common [12]. Patients with late gadolinium enhancement of the left ventricle had the most impaired right ventricular function.

Myocardial fibrosis — Interstitial and replacement myocardial fibrosis (particularly around severely narrowed intraluminal coronary arteries) has been observed on endomyocardial biopsy in patients with cardiac Fabry disease with angina [21]. The distribution of myocardial fibrosis can be identified by late gadolinium enhancement on CMR imaging. (See 'Cardiovascular magnetic resonance' below.)

Valve disease — Patients with Fabry disease frequently have mild thickening of mitral and/or aortic valves [5,19]. Aortic, mitral, and tricuspid regurgitation are common [5,19,22]. However, these are usually mild lesions and patients usually do not need valve surgery.

Coronary artery disease — Angina occurs frequently in both males and females with Fabry disease and appears to be typically caused by coronary small vessel disease, although epicardial coronary artery disease can occur [6,23]. (See 'Myocardial perfusion imaging' below and 'Coronary angiography' below.)

Examination of intramural coronary arteries on endomyocardial biopsy reveals luminal narrowing due to hypertrophy and proliferation of smooth muscle and endothelial cells with glycosphingolipid deposits [21,23]. Severely narrowed intramural coronary arteries are often surrounded by myocardial replacement fibrosis.

Arrhythmias and conduction abnormalities — Atrial and ventricular arrhythmias occur in patients with Fabry disease [24]. Atrial arrhythmias, including atrial fibrillation, are more common and appear related to age. Non-sustained ventricular tachycardia may be related to LV wall thickness. Conduction abnormalities may be caused glycolipid deposition in the atrioventricular (AV) node, His bundle, and bundle branches [25,26]. The PR interval may be short due to accelerated atrioventricular conduction, particularly in younger patients [27]. Older patients may develop PR prolongation (first degree AV block) [25,28] and bundle branch abnormalities and may progress to advanced AV block, though progression to requiring a pacemaker is uncommon [24,29].

Aortic dilation — Fabry disease may also cause aortic dilation, particularly in males. In a study of 52 males and 54 females (mean age 42 years) with Fabry disease, aortic dilation at the sinus of Valsalva was identified in 33 percent of males and 6 percent of females [30]. Ascending aortic aneurysms (>1.5 x 21 mm/m² x body surface area) were present in 10 percent of males and 2 percent of females. In females, the diameter of the sinus of Valsalva correlated with systolic blood pressure, but in males, there was no correlation between aortic diameter and systolic or diastolic blood pressure. (See 'Echocardiogram' below and 'Cardiovascular magnetic resonance' below.)

Hypertension — Hypertension is common in patients with Fabry disease with over one-half developing increased blood pressure after the onset of chronic kidney disease. (See "Fabry disease: Kidney manifestations", section on 'Hypertension'.)

Hypertension is a risk factor for cardiovascular events in Fabry disease patients. (See 'Heart failure and other cardiovascular events' below.)

Heart failure and other cardiovascular events — Cardiovascular events in Fabry disease include heart failure, myocardial infarction, and cardiac death. Among 2869 Fabry Registry patients (1424 males and 1445 females) not treated with enzyme replacement therapy, 5.8 percent of males and 3.7 percent of females experienced cardiovascular events at mean ages of 45 and 54 years, respectively [10]. Heart failure was the most common first cardiovascular event. Hypertension and LVH were risk factors for cardiovascular events. Possible causes of sudden death in Fabry disease include ventricular arrhythmias and bradyarrhythmias [24]. (See 'Arrhythmias and conduction abnormalities' above.)

Cardiac tests

Electrocardiogram — In patients with Fabry disease, the ECG frequently shows LVH by voltage criteria and/or repolarization abnormalities and the QRS is frequently prolonged, particularly in patients with LV remodeling or LVH by echocardiography [6,11,31]. ST segment and Q wave abnormalities have been reported in the absence of myocardial infarction [26,32]. Conduction abnormalities and arrhythmias may occur as described above. (See 'Arrhythmias and conduction abnormalities' above.)

Cardiac biomarkers — Limited data are available on the prevalence of troponin elevations in patients with Fabry disease. In one series, troponin I was elevated in 6 of 13 patients with Fabry disease and angina and in none of 25 patients with Fabry disease without angina [23].

A study of 117 patients with Fabry disease found that plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) was frequently elevated, particularly in patients with echocardiographic and/or ECG abnormalities [33]. Age, creatinine, left atrial volume index, the ratio of transmitral peak E velocity to the peak Ea velocity of the lateral wall (E/Ea), and presence of ECG findings were independently associated with log NT-proBNP.

Echocardiogram — Echocardiography is the most common test to assess cardiac morphology, valve function, and ascending aorta diameter, although there are no pathognomonic echocardiographic features in Fabry disease [6]. Concentric LVH is the most frequent pattern of LV remodeling seen with this disease. The LVEF is usually normal. In contrast, speckle tracking and tissue Doppler measures of systolic and diastolic function are frequently abnormal in patients with Fabry disease [34]. Greater wall thicknesses correlate with lower tissue Doppler imaging velocities [35]. Since speckle tracking and tissue Doppler abnormalities also frequently occur in patients with Fabry disease without LVH, they may aid in detection of patients with early cardiac involvement [34,36].

Some patients with Fabry disease with advanced cardiac involvement have a thinned basal inferolateral wall with focal hypokinesis and regional reductions in longitudinal strain [37]. The presence of a thinned basal inferolateral LV wall or increased LV Tei index are predictors of increased risk of heart failure and cardiac death [38].

In one series, 51 patients with Fabry disease and 25 controls underwent tissue Doppler echocardiography to measure peak systolic strain rates (SR) [39]. Patients with Fabry disease without LVH had reduced longitudinal SR but normal radial SR while patients with LVH had reduced longitudinal and radial SR. Patients with LVH who had late gadolinium enhancement on CMR imaging had severely reduced radial and longitudinal function.

An echocardiographic binary appearance of the myocardium (a thickened hyperechogenic endocardial layer subtended by a hypoechogenic layer) was proposed as a marker of Fabry disease reflecting endomyocardial glycosphingolipids compartmentalization (figure 2) [40]. However, subsequent studies found that the binary sign had limited sensitivity (15 to 35 percent) and specificity (73 to 80 percent) for Fabry disease [41-43]. The likelihood of a binary sign is associated with the degree of septal hypertrophy [43].

Cardiovascular magnetic resonance — CMR imaging can identify and quantify LVH (by wall thickness and three-dimensional measurement of LV mass) and ascending aorta size if echocardiographic images are suboptimal or nondiagnostic.

CMR also enables identification of fibrosis by late gadolinium enhancement (LGE), which is frequently observed in patients with Fabry disease [37,44-46]. Among males with Fabry disease, myocardial fibrosis generally occurs only in those with LVH [47]. In contrast, among females with Fabry disease, myocardial fibrosis can occur without LVH. In Fabry disease, LGE characteristically involves the basal and mid segments of the anterolateral and inferolateral walls and in severe cases may involve the basal third of other LV walls. LGE in Fabry disease usually spares the subendocardium, which helps distinguish it from the pattern seen with myocardial infarction [48]. Focal basal lateral replacement fibrosis detected by CMR is associated with regional impaired longitudinal strain on echocardiography (eg, by speckle-tracking) [37]. (See "Clinical utility of cardiovascular magnetic resonance imaging", section on 'Late gadolinium enhancement'.)

Myocardial perfusion imaging — Stress myocardial perfusion imaging in patients with Fabry disease and angina reveals reversible defects consistent with ischemia, often accompanied by fixed defects [23]. These findings generally occur without significant obstructive coronary disease and appear to be due to small coronary vessel disease with replacement fibrosis surrounding severely stenosed intramural arteries. (See 'Coronary artery disease' above.)

Coronary angiography — Coronary angiography in patients with Fabry disease generally shows no epicardial luminal abnormalities with diffuse slow flow likely caused by small vessel disease [23,49]. (See 'Coronary artery disease' above.)

DIAGNOSIS

When to suspect cardiac Fabry disease — Given the availability of enzyme replacement therapy, which may favorably alter the course of the disease as well as the potential risk of progressing to irreversible disease [50-52], it is important to diagnose patients afflicted with Fabry disease as early as possible. Fabry disease should be considered in the differential diagnosis of unexplained left ventricular hypertrophy (LVH; ie, absence of causes such as hypertension and aortic stenosis) or cardiomyopathy, particularly hypertrophic cardiomyopathy (HCM) or restrictive cardiomyopathy, though it can rarely present as a dilated cardiomyopathy (table 1 and table 2) [10,11,53-57] (see "Definition and classification of the cardiomyopathies", section on 'Anatomic and physiologic classification'). Exclusion of Fabry disease is an important step in the evaluation of patients with HCM, as approximately 0.3 to 5 percent have Fabry disease [18,53,58]. The 2009 Heart Failure Society of America practice guideline on genetic evaluation of cardiomyopathy recommended screening for Fabry disease in all males with sporadic or nonautosomal dominant (no male-to-male) transmission of unexplained cardiac hypertrophy [57]. (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation", section on 'Differential diagnosis'.)

Although cardiac Fabry disease is generally accompanied by other manifestations of Fabry disease, a cardiac variant of the disease rarely presents with LVH without other obvious disease manifestations [7,17,18,53]. Among patients with Fabry disease, the cardiac variant is more common among females than males. (See "Fabry disease: Clinical features and diagnosis".)

Differential diagnosis — The differential diagnosis of cardiac Fabry disease includes other causes of LVH, HCM, restrictive cardiomyopathy, or dilated cardiomyopathy (table 1 and table 2). Other causes of LVH include aortic stenosis, hypertension, athlete’s heart, and obesity. HCM is defined to include a variety of conditions with increased ventricular wall thickness or mass not caused by pathologic loading conditions. Restrictive cardiomyopathy is characterized by nondilated nonhypertrophied ventricles with impaired filling. Dilated cardiomyopathy is characterized by dilated ventricles and impaired systolic function of one or both ventricles. (See "Definition and classification of the cardiomyopathies" and "Causes of dilated cardiomyopathy" and "Restrictive cardiomyopathies" and "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation" and "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation", section on 'Differential diagnosis' and "Echocardiographic recognition of cardiomyopathies".)

Cardiac amyloidosis is a cause of HCM or restrictive cardiomyopathy that should be distinguished from cardiac Fabry disease. A preliminary report found that a septal apical to basal longitudinal peak systolic strain ration >2.1 differentiated cardiac amyloidosis from other causes of LVH, including Fabry disease [59].

Confirmatory testing — In males with suspected Fabry disease, the diagnosis is generally confirmed by measurement of leukocyte alpha-Gal A activity. However, this assay will identify less than 50 percent of female heterozygotes. In females with suspected Fabry disease (and males with marginal levels of alpha-Gal A activity), genetic testing is recommended. (See "Fabry disease: Clinical features and diagnosis", section on 'Establishing the diagnosis'.)

In patients with the cardiac variant of Fabry disease, plasma, or leukocyte alpha-galactosidase A activity is usually low but detectable [17,18], in contrast to patients with the classic Fabry phenotype who may have undetectable activity [1]. The presence of some alpha-galactosidase A activity may prevent the microvascular accumulation of globotriaosylceramide that is responsible for the classic extracardiac manifestations of the disease [1].

Endomyocardial biopsy is generally not required but can be helpful in confirming that LVH is associated with glycosphingolipid deposition if the diagnosis is uncertain. Histologic findings include perinuclear vacuoles that stain with periodic acid-Schiff stain and Sudan-Black [21]. Electron microscopy reveals myelin bodies that are single membrane bound vesicles containing concentric lamellar figures. Arterial endothelial and smooth muscle cells and interstitial capillary endothelial cells also contain glycosphingolipid deposits [21,60]. Histologic findings are not pathognomonic since similar histologic findings are seen with chloroquine or amiodarone toxicity [11,61]. (See "Endomyocardial biopsy", section on 'Restrictive cardiomyopathy'.)

Screening family members — Screening is suggested for family members of patients diagnosed with Fabry disease, as discussed separately. Early diagnosis of Fabry disease is advocated since enzyme replacement therapy may favorably alter the course of the disease. (See "Fabry disease: Clinical features and diagnosis", section on 'Screening family members'.)

MANAGEMENT — Patients with Fabry disease with cardiac manifestations should generally receive standard therapies for heart disease, including antianginal medication for angina, standard antiarrhythmic therapy, and guideline-directed therapy for heart failure. In addition, we suggest initiating enzyme replacement therapy (ERT) in patients with Fabry disease with cardiac manifestations, although the impact on cardiovascular outcomes is not known. (See "Fabry disease: Treatment and prognosis", section on 'Fabry-specific therapy'.)

Cardiovascular effects

Angina — Patients with Fabry disease frequently complain of angina. Antianginal medications are indicated in patients with angina caused by small vessel disease. Evaluation with stress testing and coronary angiography is indicated in some patients to identify concurrent epicardial coronary artery disease [6]. (See "Chronic coronary syndrome: Overview of care" and "Overview of the nonacute management of unstable angina and non-ST-elevation myocardial infarction".)

Arrhythmia and conduction disease — Patients with Fabry disease should receive standard therapy for atrial and ventricular arrhythmias. Depending on the frequency of any symptoms, a 48-hour Holter recorder or an event recorder [62] may be considered to detect possible arrhythmias. Permanent pacemaker implantation is occasionally required to treat symptomatic bradycardia and/or advanced conduction system disease. Some patients with advanced cardiomyopathy may require implantable cardioverter-defibrillator placement to prevent sudden cardiac death. (See "Permanent cardiac pacing: Overview of devices and indications" and "Atrial fibrillation: Overview and management of new-onset atrial fibrillation" and "Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management" and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".)

Asymptomatic left ventricular systolic dysfunction — Patients without symptoms with reduced left ventricular ejection fraction should receive an angiotensin converting enzyme inhibitor. A beta blocker is also suggested in such patients, though supporting evidence is limited. (See "Management and prognosis of asymptomatic left ventricular systolic dysfunction".)

Hypertension — Treatment of hypertension in patients with Fabry disease is discussed separately. (See "Fabry disease: Treatment and prognosis", section on 'Fabry-specific therapy'.)

Heart failure — Patients with Fabry disease with heart failure should receive conventional evidence-based and guideline-directed medical therapy [63-65]. Successful heart transplantation for advanced Fabry cardiac disease has been performed without development of Fabry disease in the graft, likely due to enzyme activity in the graft [66]. (See "Treatment and prognosis of heart failure with preserved ejection fraction" and "Overview of the management of heart failure with reduced ejection fraction in adults".)

Aortic dilation — Given the risk of development of ascending aortic aneurysm described above, patients with Fabry disease should be monitored for progressive ascending aortic dilation, as described separately. In patients with Fabry disease with aortic dilation, we generally follow general guidelines for degenerative thoracic aortic aneurysm surveillance and prophylactic repair. There is scant evidence available to guide management of aortic aneurysm in patients with Fabry disease. (See 'Aortic dilation' above and "Management of thoracic aortic aneurysm in adults", section on 'Aneurysm surveillance' and "Management of thoracic aortic aneurysm in adults", section on 'Degenerative TAA'.)

Enzyme replacement therapy — Enzyme replacement therapy (ERT) can reduce the deposition of globotriaosylceramide in the myocardium and may reduce LV hypertrophy and improve symptoms. The use of ERT depends on factors that include sex, circulating levels of alpha-Gal-A, and the severity of disease. The indications for treatment and effects of treatment are discussed elsewhere. (See "Fabry disease: Treatment and prognosis", section on 'Fabry-specific therapy'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Fabry disease" and "Society guideline links: Heart failure in adults" and "Society guideline links: Cardiomyopathy".)

SUMMARY AND RECOMMENDATIONS

●Clinical features – Cardiovascular manifestations of Fabry disease include left ventricular hypertrophy (LVH), right ventricular hypertrophy, aortic and mitral regurgitation, arrhythmias, conduction defects, coronary artery disease, hypertension, and aortic root dilation. Many patients with cardiac involvement are asymptomatic, whereas others present with angina, dyspnea, palpitations, syncope, or heart failure. (See 'Clinical features' above.)

●Manifestations

•Ventricular hypertrophy – Unexplained LVH is the hallmark of Fabry cardiac disease and is more common and more severe in males. (See 'Ventricular hypertrophy' above.)

LVH is generally diagnosed by echocardiogram and may be suspected on ECG. Cardiovascular magnetic resonance (CMR) imaging can confirm LVH and also enables identification of myocardial fibrosis. (See 'Cardiac tests' above.)

Fabry disease should be considered in the differential diagnosis of unexplained LVH, particularly hypertrophic cardiomyopathy or restrictive cardiomyopathy, though it can rarely present as a dilated cardiomyopathy (table 1 and table 2). (See 'When to suspect cardiac Fabry disease' above.)

•Coronary artery disease – Angina occurs frequently in both males and females with Fabry disease and appears to be typically caused by coronary small vessel disease, though epicardial coronary artery disease can occur. (See 'Coronary artery disease' above.)

●Diagnosis

•Males – In males with suspected Fabry disease, the diagnosis is generally confirmed by measurement of leukocyte alpha-Gal A activity. However, this assay will identify less than 50 percent of female heterozygotes. (See 'Confirmatory testing' above.)

•Females – In females with suspected Fabry disease (and males with marginal levels of alpha-Gal A activity), genetic testing is recommended. (See 'Confirmatory testing' above and "Fabry disease: Clinical features and diagnosis", section on 'Establishing the diagnosis'.)

•Role of endomyocardial biopsy – Endomyocardial biopsy is generally not required to diagnose Fabry disease but can be helpful in confirming that LVH is associated with glycosphingolipid deposition if the diagnosis is uncertain. (See 'Confirmatory testing' above.)

●Management

•Treatment of cardiac complications – Patients with Fabry disease with cardiac manifestations should generally receive standard therapy to treat heart failure, arrhythmias, and angina. (See 'Cardiovascular effects' above.)

•Enzyme replacement therapy – Enzyme replacement therapy (ERT) can reduce the deposition of globotriaosylceramide in the myocardium and may reduce LV hypertrophy and improve symptoms. The use of ERT depends on factors that include sex, circulating levels of alpha-Gal-A, and the severity of disease. The indications for treatment, agents available for use, and effects of treatment are discussed elsewhere. (See "Fabry disease: Treatment and prognosis", section on 'Fabry-specific therapy'.)