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Cryptogenic Ventricular Arrhythmias and Sudden Death by
Fabry Disease: Prominent Infiltration of Cardiac
Conduction Tissue
Andrea Frustaci, MD; Cristina Chimenti, MD, PhD;
A
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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 mm Hg).
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 alphagalactosidase A activity in the peripheral leukocytes
(25.4⫾8.5 nmol 䡠 h⫺1 䡠 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 cardioverterdefibrillator implantation.
Sources of Funding
This study was supported by the Telethon Foundation Grant
GGP05264 (Rome, Italy).
Disclosures
None.
References
1. Desnick RJ, Ioannou YA, Eng CM. Alpha-galactosidase A deficiency:
Fabry disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Kinzler KE,
Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited
Disease. New York: McGraw-Hill; 2001:3733–3774.
2. Shah JS, Hughes DA, Sachdev B, Tome M, Ward D, Lee P, Metha AB,
Elliott PM. Prevalence and clinical significance of cardiac arrhythmia in
Anderson-Fabry disease. Am J Cardiol. 2005;96:842– 846.
3. Igawa O, Miake J, Hisatome I. Ventricular tachycardias and dilated
cardiomyopathy caused by Fabry disease. Pacing Clin Electrophysiol.
2005;28:1142–1143.
From the Heart and Great Vessels “Attilio Reale” Department, La Sapienza University, Molecular and Cellular Cardiology Laboratory, National
Institute for Infectious Diseases “Lazzaro Spallanzani,” Rome, Italy.
Correspondence to Andrea Frustaci, MD, Heart and Great Vessels Department “Attilio Reale,” La Sapienza University, viale del Policlinico 155, 00100
Rome, Italy. E-mail [email protected]
(Circulation. 2007;116:e350-e351.)
© 2007 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.107.723387
e350
Frustaci and Chimenti
Cryptogenic Ventricular Arrhythmias and Sudden Death
A
B
C
D
e351
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A, Resting ECG showing frequent ventricular ectopic beats with normal QRS voltages and repolarization. B, Cardiac magnetic resonance imaging showing normal thickness of the ventricular walls and the absence of late-enhancement signals after gadolinium infusion. C, Left ventricular endomyocardial biopsy showing a fragment of conduction tissue (CT) in which almost the entire cell area is
occupied by large vacuoles (arrows), whereas in the working myocardium only small perinuclear vacuoles are evident. D, Transmission
electronmicroscopy showing the vacuoles to consist of single membrane-bound myelin bodies containing concentric lamellar figures
suggestive of Fabry disease.
Cryptogenic Ventricular Arrhythmias and Sudden Death by Fabry Disease: Prominent
Infiltration of Cardiac Conduction Tissue
Andrea Frustaci and Cristina Chimenti
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
Circulation. 2007;116:e350-e351
doi: 10.1161/CIRCULATIONAHA.107.723387
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