Fabry disease (cardiac manifestations)

Fabry disease or Anderson-Fabry disease is the most frequent X-linked lysosomal disorder with cardiac involvement and the isolated ‘cardiac variant’ is next in frequency after the ‘classic phenotype’. Diagnosis of cardiac involvement is important because of the potentially adverse outcome otherwise.

This article focuses on cardiac manifestations. For a general discussion refer to the article on Fabry disease.

Epidemiology

Fabry disease has a prevalence of 0.5-1% in patients with hypertrophic cardiomyopathy and is observed in up to 75% of all patients with Fabry disease. Isolated involvement of the heart is more common in males than in females with a frequency of 40% and 28% respectively ^1,2.

The occurrence of cardiac involvement increases with age.

Clinical presentation

Patients may present with symptoms of heart failure as dyspnea on exertion as well as angina, palpitations, arrhythmias or syncope ³.

ECG might show short PR intervals on ECG, sinus bradycardia with chronotropic incompetence and/or atrioventricular conduction abnormalities ^1,3.

Suspected Fabry disease should be confirmed with biochemical (reduced leukocyte α-GalA activity) and genetic testing ².

Complications

Particularly cardiac involvement can lead to the following potentially life-threatening conditions and are the leading cause of death in Fabry disease ^1-4:

• arrhythmias including bradyarrhythmias, atrial fibrillation and ventricular tachycardia

• myocardial infarction/MINOCA

• valvular heart disease

• heart failure

Pathology

Cardiac involvement is characterized by an accumulation of glycosphingolipids (Gb₃) within the cells of the cardiac tissue specifically within the cardiomyocytes, valvular fibroblasts endothelial cells and cardiac conduction system leading to left ventricular hypertrophy, chronic inflammation with focal myocardial edema and myocardial fibrosis classically in the basal inferolateral wall ^1,4.

Etiology

Fabry disease is an X-linked lysosomal disorder (Xq22.1) leading to a shortage or absence of the enzyme α-galactosidase ^1-4.

Radiographic features

Echocardiography

Echocardiography acts as a first-line imaging modality and has a role in monitoring therapy ^2,3.

It might reveal the following characteristics ^1-4:

• left ventricular hypertrophy concentric or eccentric

• variably right ventricular hypertrophy

• thickening of the papillary muscles

• a hyperechoic region in the left ventricular myocardium, known as ‘binary sign’ 

• thinning of the left basal inferolateral wall

• diastolic dysfunction

• reduced ejection fraction as an adverse prognostic indicator

• valvular thickening

• reduced longitudinal and circumferential strain in particular in the basal inferolateral region

MRI

Cardiac MRI can aid in the differentiation of left ventricular hypertrophy and can analyze the tissue properties of the myocardium employing cardiac tissue characterization ^1,2. In addition to aiding in the diagnosis, it can be used for prognosis, the initiation, and potentially monitoring of enzyme replacement therapy ^3,4. Characteristic features of cardiac involvement in Fabry disease are ^1-5:

• cine SSFP

  • left ventricular hypertrophy

  • increased left ventricular mass

  • increased papillary mass

• IRGRE/PSIR: focal midmyocardial late gadolinium enhancement indicating myocardial inflammation and myocardial fibrosis classically occurring in a basal inferolateral location

• T1 mapping

  • decreased T1 [ms] in remote areas due to intracellular accumulation of glycosphingolipids

  • increased in areas of myocardial inflammation and myocardial fibrosis

  • might be normal in areas where both features are present (pseudonormalization)

• T2 mapping

  • normal in remote areas

  • increased in areas of chronic inflammation

• ECV

  • normal in remote areas

  • increased in areas of chronic inflammation

Radiology report

The radiological report should include a description of the following:

• left ventricular volumes and measurements including left ventricular mass and papillary mass

• cardiac wall motion abnormalities

• low native T1 values

• areas of chronic inflammation and myocardial fibrosis

Treatment and prognosis

Patients with Fabry disease benefit from enzyme replacement therapy (ERT) and chaperone therapy with migalastat ^1-3.

Other management recommendations include the control of cardiovascular risk factors as hypertension, diabetes and dyslipidemia as well as smoking cessation and increased aerobic exercise.

Symptomatic bradyarrhythmias, supraventricular and ventricular arrhythmias might require consideration of pacing or prophylactic ICD implantation ³.

Differential diagnosis

Conditions that can mimic the presentation and/or the appearance of the ‘cardiac variant’ Fabry disease include:

• hypertensive heart disease

• aortic stenosis

• cardiac amyloidosis

  • increased native T1

  • subendocardial late gadolinium enhancement in a non-coronary distribution

• hypertrophic cardiomyopathy

  • usually eccentric hypertrophy

  • reduced strain in the area of maximum hypertrophy

  • late gadolinium enhancement at the right ventricular junction points (hinge points)

• Danon disease

• cardiac sarcoidosis

• Chagas disease

• anti-malarial induced cardiomyopathy (AMIC) ⁶