Angina in Fabry Disease Reflects Coronary SmallVessel DiseaseCristina Chimenti, MD, PhD; Emanuela Morgante, PhD; Gaetano Tanzilli, MD; Enrico Mangieri, MD;Giuseppe Critelli, MD; Carlo Gaudio, MD; Matteo A. Russo, MD; Andrea Frustaci, MDBackground—Chest pain is frequently reported in Fabry disease (FD). However, its mechanism and clinical relevance areunclear.Methods and Results—Basal troponin I level, exercise stress test, single-photon emission computed tomography imagingwith99m Tc sestamibi, coronary angiography with thrombolysis in myocardial infarction (TIMI) frame count and leftventricular angiography and endomyocardial biopsy were obtained in 13 patients with FD with angina. Ratio of external tolumen diameter of intramural arteries (E/L ratio), myocyte diameter, and extent of fibrosis were morphometrically evaluatedby using tissue sections. Controls for coronary angiography and histology were 25 patients with FD without angina and 20mitral stenosis patients with normal left ventricular function. Troponin I level was elevated in 6 of the 13 patients. Exercisestress test showed evidence of myocardial ischemia, and single-photon emission computed tomography was positive forstress-induced perfusion defects in all patients with FD with angina. Epicardial coronaries were structurally normal butshowed slow flow in all and were associated with aneurisms of posterior left ventricular wall in 3 cases. Histology showedremarkable lumen narrowing of most intramural arteries (mean E/L ratio?3.5?1.2; P?0.001 versus both control groups),because of hypertrophy and proliferation of smooth muscle and endothelial cells, both engulfed by glycosphingolipids.Replacement fibrosis exceeded that of both controls (P?0.001). Small vessel disease correlated with coronary slow flow andextent of fibrosis, but did not with patients’ age, sex, and degree of left ventricular hypertrophy.Conclusions— patients with FD with angina have perfusion defects, slow coronary flow, and luminal narrowing ofintramural arteries. Small vessel disease may contribute to symptomatic limitation and progressive myocardialdysfunction. (Circ Heart Fail. 2008;1:161-169.)Key Words: angina ? cardiomyopathy ? Fabry disease ? ischemia ? microcirculationFabry disease (FD) is an X-linked disorder caused bydeficiency of the lysosomal enzyme ? -galactosidase A,resulting in progressive intracellular accumulation of glo-botriaosylceramide (GB3) and related neutral glycosphingo-lipids in different tissues, including skin, kidney, central andperipheral nervous system and the heart. 1In the vasculature, glycosphingolipids accumulate in theendothelial and smooth muscle cells, causing structural ab-normalities and progressive vascular dysfunction.In the heart, glycosphingolipids deposition causes progres-sive left ventricular (LV) hypertrophy that mimics the mor-phological and clinical picture of hypertrophic cardiomyop-athy, 2 with dispnea on effort, palpitation, and angina as thetypical symptoms.A higher incidence of coronary heart disease, as a conse-quence of epicardial coronary endothelial and smooth musclecells involvement, has been suggested to explain the frequentoccurrence of angina, reported in up to 60% of patients. 3Indeed, in contrast with positron emission tomography imag-ing suggesting an impaired myocardial perfusion reserve, 3,4coronary angiography frequently showed normal vesselspointing toward a compromise of coronary microcirculation.However, the mechanisms of microvascular dysfunction arestill unclear and may include increased myocardial oxygendemand, increased LV end-diastolic pressure, decreased cap-illary density, and small vessel disease.Editorial see p 150The purpose of the present study was to investigate thecoronary anatomy, flow and reserve and the histological andultrastructural findings of LV intramural vessels in a populationof patients with FD reporting of angina in comparison withpatients with FD without angina and with normal controls.Received May 5, 2007; accepted July 23, 2008.From the Heart and Great Vessels “Attilio Reale” Department (C.C., G.T., E.M., G.C., C.G., A.F.) and Pathology and Experimental MedicineDepartment (E.M., M.A.R.), La Sapienza University, Rome, Italy; Molecular and Cellular Cardiology Laboratory, National Institute for Infectious Disease“L. Spallanzani” (C.C., A.F.), Rome, Italy; and IRCCS San Raffaele La Pisana (C.C., M.A.R.), Rome, Italy.The online Data Supplement can be found with this article at http://circahajournals.org/cgi/content/full/CIRCHEARTFAILURE.108.769729/DC1.Correspondence to Andrea Frustaci, MD, Heart and Great Vessels “Attilio Reale” Department, La Sapienza University, viale del Policlinico 155, 00100Rome, Italy. E-mail: biocard@inmi.it© 2008 American Heart Association, Inc.Circ Heart Fail is available at http://circheartfailure.ahajournals.org DOI: 10.1161/CIRCHEARTFAILURE.108.769729161 by guest on March 31, 2016 http://circheartfailure.ahajournals.org/ Downloaded from
