Cryptogenic Ventricular Arrhythmias and Sudden Death by Fabry Disease: Prominent Infiltration of Cardiac Conduction Tissue
A 22-year-old man, whose mother died at 40 years because of sudden death, came to our observation complaining of palpitations. Physical examination was unremarkable except for an irregular cardiac rhythm, and his clinical history was otherwise uneventful. ECG showed frequent ventricular ectopic beats with normal QRS voltages and repolarization (Figure, A). Holter monitoring registered 7.800 polymorphic ventricular ectopic beats frequently occurring in couplets and triplets. Two-dimensional echocardiography showed normal parameters including thickness of cardiac walls, valvular pattern, and left ventricular ejection fraction (68%), and tissue Doppler imaging registered reduced relaxation and contraction velocities, suggesting some myocardial abnormality. Cardiac magnetic resonance imaging failed to show areas of thickened or dysfunctional cardiac wall as well as late-enhancement signals after gadolinium infusion (Figure, B). Because of abnormal tissue Doppler imaging and the family history of sudden death, an invasive cardiac study including a cardiac catheterization with coronary angiography and left ventricular endomyocardial biopsy was performed. Coronary arteries were normal and cardiac catheterization showed an increase in left ventricular end-diastolic pressure (18 mmHg).
Histology revealed mild hypertrophy of cardiomyocytes containing small perinuclear vacuoles. Remarkably, a fragment of conduction tissue included in the biopsy samples showed almost the entire cell area occupied by large vacuoles (Figure, C).
At transmission electronmicroscopy the vacuoles appeared to consist of membrane-bound myelin bodies (Figure, D) suggesting a Fabry disease cardiomyopathy with prominent involvement of cardiac conduction tissue. The diagnosis was confirmed by the detection of a very low level of alpha-galactosidase A activity in the peripheral leukocytes (25.4±8.5 nmol · h−1 · mg−1, 3% of normal controls) and by the presence of the causal alpha-galactosidase A mutation (C946delG).
The patient received enzyme replacement therapy (Replagal, 0.2 mg/kg every other week) and at three months Holter registration, a reduction of ventricular extrasystoles to 600/24 hour with disappearance of repetitive phenomena was observed.
Cryptogenic ventricular arrhythmias and sudden death can be the first manifestation of several cardiac disorders, but the structural changes leading to such events are rarely recognizable.
Fabry disease is an X-linked lysosomal storage disorder caused by deficiency of the enzyme alpha-galactosidase A and characterized by a progressive left ventricular hypertrophy mimicking the clinical phenotype of hypertrophic cardiomyopathy.1 Supraventricular and ventricular arrhythmias are commonly observed in older patients with cardiac hypertrophy and in the advanced stage of the disease.2–3 The present report shows that ventricular arrhythmias in Fabry disease are caused by infiltration of cardiac conduction tissue that can be privileged with respect to working cardiomyocytes giving rise to occult ventricular arrhythmias and sudden death even in young people.
The reasons for such pathological discrepancy are unclear, although a contrast between high metabolic activity and reduced energy reserve may lead cells of conduction tissue to a lower availability of alpha-galactosidase A and then a prominent glycosphingolipid accumulation.
Clinical implications are that an early recognition and treatment of this entity with enzyme replacement therapy may avoid fatal outcomes and even the use of potentially ineffective or harmful antiarrhythmic drugs and/or cardioverter-defibrillator implantation.
Sources of Funding
This study was supported by the Telethon Foundation Grant GGP05264 (Rome, Italy).