(III-3B.2) Dynamic progression of aortic stenosis in the patient with Fabry disease despite enzyme replacement therapy during 4.5-year follow-up Petkow-Dimitrow P. MD, PhD, Dziedzic H. MD, Miszalski-Jamka T. MD, PhD

Keywords: aortic stenosis, Fabry disease

Background
Fabry disease is a rare X-linked lysosomal storage disorder leading to an accumulation of glycosphingolipids in all tissues and organs including the heart. Currently available data suggest that valve abnormalities are observed frequently in Fabry patients.
Recently, a systematic evaluation of the severity of valve abnormalities was performed in a impressive series of Fabry patients in a reference German center. Accordingly, 111 patients with genetically proven Fabry disease were systematically monitored by echocardiography for abnormalities of the valves in the left (aortic and mitral valve) and right heart (pulmonary and tricuspid valve). 60 patients were followed up by echocardiography for 2.7±1.5 years. Both valve stenosis and regurgitation were classified as mild, moderate or severe. Importantly, no patient had severe heart valve abnormalities. The most frequent findings were mild aortic, mitral and tricuspid valve regurgitation. Only two patients showed mild aortic valve stenosis. Moderate aortic, mitral or tricuspid regurgitation were incidentally detected. All Fabry patients in advanced stages had only mild mitral regurgitation and one of them had mild aortic and mitral regurgitation, moderate tricuspid regurgitation and mild aortic stenosis. There was no significant change in heart valve abnormalities during follow-up.

Case description
This 43-year-old male patient presented with very low activity of alpha-galactosidase A in blood leukocytes (0.12 nmol/mg per hour (normal value 7.2 ±1.3). We performed a 4.5-year echocardiographic follow-up during continued enzyme replacement therapy.
We observed:
• distinct diminution of severe leg acroparaesthesia and better heat tolerance
• reduction of proteinuria, stabilization of creatinine clearance and appearance of perspiration
• angiokeratoma remained unchanged
Echocardiography at the onset of follow-up (before enzyme substitution at age 43) revealed mild aortic valve abnormalities with low transvalvular gradient 7 mmHg. At the end of follow-up, echocardiography revealed a significant trans-stenotic gradient of 50 mmHg with the stenotic morphology of the aortic valve.

Conclusion:
Despite enzyme replacement therapy dynamic aortic stenosis was found in storage Fabry disease. We observed an „aggressive valvular storage” variant with gradient progression ~ 10 mmHg/year.

Guidelines
Recommended enzyme replacement therapy
Continuous echocardiographic monitoring of cardiac function

References
1. Weidemann F, Strotmann JM, Niemann M, et al. Heart valve involvement in Fabry cardiomyopathy. Ultrasound Med Biol. 2009 May;35(5):730-5.
2. Linhart A, Palecek T, Bultas J, et al. New insights in cardiac structural changes in patients with Fabry’s disease. Am Heart J. 2000 Jun;139(6):1101-8.
3. Spinelli L, Pisani A, Sabbatini M, et al. Enzyme replacement therapy with agalsidase beta improves cardiac involvement in Fabry’s disease. Clin Genet 2004; 66: 158–165.
4. Beer M, Weidemann F, Breunig F, et al. Impact of enzyme replacement therapy on cardiac morphology and function and late enhancement in Fabry’s cardiomyopathy. Am J Cardiol 2006; 97: 1515–1518.
5. Hughes DA, Elliott PM, Shah J, et al. Effects of enzyme replacement therapy on the cardiomyopathy of Anderson-Fabry disease: a randomised, double-blind, placebo-controlled clinical trial of agalsidase alfa. Heart 2008; 94: 153–158.
6. Kovacevic-Preradovic T, Zuber M, Jost CH, et al. Anderson-Fabry disease: long-term echocardiographic follow-up under enzyme replacement therapy. Eur J Echocardiogr 2008; 9: 729–735.
7. Weidemann F, Niemann M, Breunig F, et al. Long-term effects of enzyme replacement therapy on Fabry cardiomyopathy: evidence for a better outcome with early treatment. Circulation 2009; 119: 524–529.

Experts’ conclusions:
ESC guidelines on valvular heart diseases should be followed.

Conclusions:

Authors:
Petkow-Dimitrow P. MD, PhD², Dziedzic H. MD¹, Miszalski-Jamka T. MD, PhD³

Experts:
Prof. Hetzer R.⁴, Kopec G.MD, PhD¹, Staszecka-Prokop A.MD, PhD⁵, Bederski K.MD⁶, Prof. Podolec P.MD, PhD¹, Marchel M.MD, PhD⁷, Rubiś MD, PhD¹

¹ Department of Cardiac and Vascular Diseases, Jagiellonian University College of Medicine, John Paul II Hospital, Krakow, Poland
² Second Department of Cardiology, CMUJ, Krakow, Poland
³ Center for Diagnosis, Prevention and Telemedicine,, John Paul II Hospital, Krakow, Poland
⁴ Medical Director and Chair of the Executive Management Board, Deutsches Herzzentrum, Berlin, Germany
⁵ Department of Pulmonology in John Paul II Hospital, Krakow
⁶ Department of Thoracic Surgery in John Paul II Hospital, Krakow
⁷ Department of Cardiac Surgery and Clinic of Cardiology, Medical University of Warsaw