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Evaluating Enzyme Replacement Therapy in Fabry Disease

Evaluating Enzyme Replacement Therapy in Fabry Disease Blum and colleagues1 reported a case of reversal of first-degree atrioventricular (AV) block and restrictive left ventricular filling in a 34-year-old patient with Fabry disease after receiving enzyme replacement therapy (ERT) for a couple of years. However, a recent study has shown normal PR intervals in patients with Fabry disease.2 There is no evidence supporting that PR interval reflects a cardiac manifestation of Fabry disease or has an association with glycosphingolipid accumulation or α-galactosidase activity. In a larger patient series, PR interval did not change significantly during ERT.3 Moreover, 24-hour electrocardiographic recordings have shown considerable PR interval variation in healthy volunteers, and even first-degree AV blocks existing at sleep are not considered meaningful enough to be reported. In the general population, PR interval does not have prognostic value predicting mortality, making it an unpractical end point for evaluating the effect of ERT, which costs US $300 000 per year. In the case reported by Blum et al,1 the patient probably never fulfilled the criteria for first-degree AV block (the patient's PR interval was 0.2 seconds; the criteria is >200 milliseconds [ms] and age-adjusted reference value is 117-212 ms [notice the overlap]).4 Approximately 3% of healthy volunteers have first-degree AV block. Their patient also did not have a restrictive left ventricular filling physiologic pattern on echocardiography (E/A ratio, 2.0 [reference range, 0.73-2.33]; E-wave deceleration time, 160 ms [reference range, 138-194 ms]; and isovolumic relaxation [IVRT], 50 ms [reference range, 51-83 ms]).5 The reference value of IVRT for a younger age group (2-20 years) is 32 to 68 ms, which may explain supranormal IVRT. The patient's heart rate was also closer to the average heart rate for a younger age group. Aging may mimic reversal of restrictive filling, as E/A ratio decreases and deceleration time increases. Left ventricular filling parameters should always be compared with age-adjusted reference values and interpreted carefully, especially when parameters are contradictory to each other or the patient is asymptomatic. These facts make us question whether the conclusion by Blum et al1 was justified or if they were only inclined to see beneficial effects of early ERT in Fabry disease. Correspondence: Dr Koskenvuo, Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Kiinamyllynkatu 4, 20520 Turku, Finland (juhkos@utu.fi). References 1. Blum APodovitzky OSheiman JKhasin M Reversal of first-degree atrioventricular block in Fabry disease. Arch Intern Med 2009;169 (20) 1925- 1926PubMedGoogle ScholarCrossref 2. Shah JSHughes DASachdev B et al. Prevalence and clinical significance of cardiac arrhythmia in Anderson-Fabry disease. Am J Cardiol 2005;96 (6) 842- 846PubMedGoogle ScholarCrossref 3. Koskenvuo JWHartiala JJNuutila P et al. Twenty-four-month a-galactosidase A replacement therapy in Fabry disease has only minimal effects on symptoms and cardiovascular parameters. J Inherit Metab Dis 2008;31 (3) 432- 441PubMedGoogle ScholarCrossref 4. Mansi IANash IS Ethnic differences in electrocardiographic intervals and axes. J Electrocardiol 2001;34 (4) 303- 307PubMedGoogle ScholarCrossref 5. Oh JKSeward JBTajik AJ The Echo Manual. 3rd ed. Philadelphia, PA Lippincott Williams & Wilkins2006; http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Internal Medicine American Medical Association

Evaluating Enzyme Replacement Therapy in Fabry Disease

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Publisher
American Medical Association
Copyright
Copyright © 2010 American Medical Association. All Rights Reserved.
ISSN
0003-9926
eISSN
1538-3679
DOI
10.1001/archinternmed.2010.42
Publisher site
See Article on Publisher Site

Abstract

Blum and colleagues1 reported a case of reversal of first-degree atrioventricular (AV) block and restrictive left ventricular filling in a 34-year-old patient with Fabry disease after receiving enzyme replacement therapy (ERT) for a couple of years. However, a recent study has shown normal PR intervals in patients with Fabry disease.2 There is no evidence supporting that PR interval reflects a cardiac manifestation of Fabry disease or has an association with glycosphingolipid accumulation or α-galactosidase activity. In a larger patient series, PR interval did not change significantly during ERT.3 Moreover, 24-hour electrocardiographic recordings have shown considerable PR interval variation in healthy volunteers, and even first-degree AV blocks existing at sleep are not considered meaningful enough to be reported. In the general population, PR interval does not have prognostic value predicting mortality, making it an unpractical end point for evaluating the effect of ERT, which costs US $300 000 per year. In the case reported by Blum et al,1 the patient probably never fulfilled the criteria for first-degree AV block (the patient's PR interval was 0.2 seconds; the criteria is >200 milliseconds [ms] and age-adjusted reference value is 117-212 ms [notice the overlap]).4 Approximately 3% of healthy volunteers have first-degree AV block. Their patient also did not have a restrictive left ventricular filling physiologic pattern on echocardiography (E/A ratio, 2.0 [reference range, 0.73-2.33]; E-wave deceleration time, 160 ms [reference range, 138-194 ms]; and isovolumic relaxation [IVRT], 50 ms [reference range, 51-83 ms]).5 The reference value of IVRT for a younger age group (2-20 years) is 32 to 68 ms, which may explain supranormal IVRT. The patient's heart rate was also closer to the average heart rate for a younger age group. Aging may mimic reversal of restrictive filling, as E/A ratio decreases and deceleration time increases. Left ventricular filling parameters should always be compared with age-adjusted reference values and interpreted carefully, especially when parameters are contradictory to each other or the patient is asymptomatic. These facts make us question whether the conclusion by Blum et al1 was justified or if they were only inclined to see beneficial effects of early ERT in Fabry disease. Correspondence: Dr Koskenvuo, Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Kiinamyllynkatu 4, 20520 Turku, Finland (juhkos@utu.fi). References 1. Blum APodovitzky OSheiman JKhasin M Reversal of first-degree atrioventricular block in Fabry disease. Arch Intern Med 2009;169 (20) 1925- 1926PubMedGoogle ScholarCrossref 2. Shah JSHughes DASachdev B et al. Prevalence and clinical significance of cardiac arrhythmia in Anderson-Fabry disease. Am J Cardiol 2005;96 (6) 842- 846PubMedGoogle ScholarCrossref 3. Koskenvuo JWHartiala JJNuutila P et al. Twenty-four-month a-galactosidase A replacement therapy in Fabry disease has only minimal effects on symptoms and cardiovascular parameters. J Inherit Metab Dis 2008;31 (3) 432- 441PubMedGoogle ScholarCrossref 4. Mansi IANash IS Ethnic differences in electrocardiographic intervals and axes. J Electrocardiol 2001;34 (4) 303- 307PubMedGoogle ScholarCrossref 5. Oh JKSeward JBTajik AJ The Echo Manual. 3rd ed. Philadelphia, PA Lippincott Williams & Wilkins2006;

Journal

Archives of Internal MedicineAmerican Medical Association

Published: Mar 22, 2010

Keywords: fabry disease,enzyme replacement therapy

References