{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:09:50Z","timestamp":1790698190619,"version":"4.1.0"},"reference-count":56,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T00:00:00Z","timestamp":1632700800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Fabry disease (FD) is a lysosomal storage disorder characterised by a deficiency in the enzyme \u03b1-galactosidase A resulting in sphingolipid deposition which causes progressive cardiac, renal, and cerebral manifestations. The case illustrates a patient with FD who died suddenly, and medical examination demonstrated myocardial scarring and prior infarction. Angina is a frequent symptom in FD. Our own data are consistent with registry data indicating a high prevalence of risk factors for coronary artery disease (CAD) in FD that may accelerate conventional atherosclerosis. Patients with FD also have a higher high-density lipoprotein (HDL)\/total cholesterol (T-Chol) ratio which may further accelerate atherosclerosis through expression of early atherosclerotic markers. Patients with FD may develop CAD both via classical atherosclerosis and through formation of thickened fibrocellular intima containing fibroblasts with storage of sphingolipids. Both mechanisms occurring together may accelerate coronary stenosis, as well as alter myocardial blood flow. Our data supports limited data that, although coronary flow may be reduced, the prevalence of epicardial coronary stenosis is low in FD. Microvascular dysfunction and arterial wall stress from sphingolipid deposition may form reactive oxygen species (ROS) and myeloperoxidase (MPO), key atherosclerotic mediators. Reduced myocardial blood flow in FD has also been demonstrated using numerous imaging modalities suggesting perfusion mismatch. This review describes the above mechanisms in detail, highlighting the importance of modifying cardiovascular risk factors in FD patients who likely develop accelerated atherosclerosis compared to the general population.<\/jats:p>","DOI":"10.3390\/jcm10194422","type":"journal-article","created":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T10:39:20Z","timestamp":1632739160000},"page":"4422","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Atherosclerosis in Fabry Disease\u2014A Contemporary Review"],"prefix":"10.3390","volume":"10","author":[{"given":"Ashwin","family":"Roy","sequence":"first","affiliation":[{"name":"University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TT, UK"},{"name":"Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamza","family":"Umar","sequence":"additional","affiliation":[{"name":"University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TT, UK"},{"name":"University of Birmingham Medical School, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0406-1436","authenticated-orcid":false,"given":"Antonio","family":"Ochoa-Ferraro","sequence":"additional","affiliation":[{"name":"University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian","family":"Warfield","sequence":"additional","affiliation":[{"name":"University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigel","family":"Lewis","sequence":"additional","affiliation":[{"name":"Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tarekegn","family":"Geberhiwot","sequence":"additional","affiliation":[{"name":"University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TT, UK"},{"name":"Institute of Metabolism and System Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5687-2535","authenticated-orcid":false,"given":"Richard","family":"Steeds","sequence":"additional","affiliation":[{"name":"University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TT, UK"},{"name":"Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"338","DOI":"10.7326\/0003-4819-138-4-200302180-00014","article-title":"Fabry disease, an under-recognized multisystemic disorder: Expert recommendations for diagnosis, management, and enzyme replacement therapy","volume":"138","author":"Desnick","year":"2003","journal-title":"Ann. Intern. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3148","DOI":"10.1016\/S0021-9258(18)51888-3","article-title":"Fabry\u2019s Disease: Classification as a sphingolipidosis and partial characterization of a novel glycolipid","volume":"238","author":"Sweeley","year":"1963","journal-title":"J. Biol. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1093\/qjmed\/hcq117","article-title":"Fabry disease: A review of current management strategies","volume":"103","author":"Mehta","year":"2010","journal-title":"QJM"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1136\/jmg.2008.065904","article-title":"Natural course of Fabry disease: Changing pattern of causes of death in FOS-Fabry Outcome Survey","volume":"46","author":"Mehta","year":"2009","journal-title":"J. Med. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1097\/GIM.0b013e3181bb05bb","article-title":"Life expectancy and cause of death in males and females with Fabry disease: Findings from the Fabry Registry","volume":"11","author":"Waldek","year":"2009","journal-title":"Genet. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1136\/jmedgenet-2014-102797","article-title":"Ten-year outcome of enzyme replacement therapy with agalsidase beta in patients with Fabry disease","volume":"52","author":"Germain","year":"2015","journal-title":"J. Med. Genet."},{"key":"ref_7","first-page":"21","article-title":"Long-term effectiveness of agalsidase alfa enzyme replacement in Fabry disease: A Fabry Outcome Survey analysis","volume":"3","author":"Beck","year":"2015","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1023\/A:1012428009627","article-title":"Cardiac manifestations in Fabry disease","volume":"24","author":"Linhart","year":"2001","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1093\/eurheartj\/ehm153","article-title":"Cardiac manifestations of Anderson-Fabry disease: Results from the international Fabry outcome survey","volume":"28","author":"Linhart","year":"2007","journal-title":"Eur. Heart J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1186\/s13023-015-0338-2","article-title":"Effectiveness of agalsidase alfa enzyme replacement in Fabry disease: Cardiac outcomes after 10 years\u2019 treatment","volume":"10","author":"Kampmann","year":"2015","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1093\/eurheartj\/ehz660","article-title":"Long-term outcomes of chronic coronary syndrome worldwide: Insights from the international CLARIFY registry","volume":"41","author":"Sorbets","year":"2020","journal-title":"Eur. Heart J."},{"key":"ref_12","unstructured":"NICE (2021, July 28). Stable Angina: Management. Available online: www.nice.org.uk\/guidance\/CG126."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1002\/ejhf.1960","article-title":"An expert consensus document on the management of cardiovascular manifestations of Fabry disease","volume":"22","author":"Linhart","year":"2020","journal-title":"Eur. J. Heart Fail."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"216","DOI":"10.3389\/fgene.2017.00216","article-title":"The Aging Risk and Atherosclerosis: A Fresh Look at Arterial Homeostasis","volume":"8","author":"Head","year":"2017","journal-title":"Front. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1161\/CIRCRESAHA.115.307611","article-title":"Epidemiology of Atherosclerosis and the Potential to Reduce the Global Burden of Atherothrombotic Disease","volume":"118","author":"Herrington","year":"2016","journal-title":"Circ. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1016\/j.amjhyper.2006.01.011","article-title":"Prevalence of uncontrolled hypertension in patients with Fabry disease","volume":"19","author":"Kleinert","year":"2006","journal-title":"Am. J. Hypertens."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1016\/j.jacc.2010.11.018","article-title":"Cardiovascular events in patients with fabry disease natural history data from the fabry registry","volume":"57","author":"Patel","year":"2011","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_18","first-page":"41","article-title":"Prevalence of chronic kidney disease in fabry disease patients: Multicenter cross sectional study in Argentina","volume":"12","author":"Jaurretche","year":"2017","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1111\/j.1365-2362.2004.01309.x","article-title":"Fabry disease defined: Baseline clinical manifestations of 366 patients in the Fabry Outcome Survey","volume":"34","author":"Mehta","year":"2004","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1023\/B:BOLI.0000045841.27968.06","article-title":"Raised HDL cholesterol in Fabry disease: Response to enzyme replacement therapy","volume":"27","author":"Cartwright","year":"2004","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_21","first-page":"3","article-title":"Lipid profile in adult patients with Fabry disease-Ten-year follow up","volume":"13","author":"Stepien","year":"2017","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/S0002-9149(02)02436-0","article-title":"The role of high-density lipoprotein (HDL) cholesterol in the prevention and treatment of coronary heart disease: Expert group recommendations","volume":"90","author":"Sacks","year":"2002","journal-title":"Am. J. Cardiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3058","DOI":"10.1253\/circj.CJ-18-0378","article-title":"Correlations Between Serum Cholesterol and Vascular Lesions in Fabry Disease Patients","volume":"82","author":"Katsuta","year":"2018","journal-title":"Circ. J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1042\/CS20040307","article-title":"Plasma vascular endothelial growth factor as a marker for early vascular damage in hypertension","volume":"109","author":"Tsai","year":"2005","journal-title":"Clin. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/S0021-9150(01)00587-1","article-title":"Involvement of ICAM-1 in the progression of atherosclerosis in APOE-knockout mice","volume":"160","author":"Kitagawa","year":"2002","journal-title":"Atherosclerosis"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1093\/cvr\/cvq333","article-title":"Globotriaosylceramide leads to K(Ca)3.1 channel dysfunction: A new insight into endothelial dysfunction in Fabry disease","volume":"89","author":"Park","year":"2011","journal-title":"Cardiovasc. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1161\/01.STR.32.7.1559","article-title":"Enhanced endothelium-dependent vasodilation in Fabry disease","volume":"32","author":"Altarescu","year":"2001","journal-title":"Stroke"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1161\/CIRCHEARTFAILURE.108.769729","article-title":"Angina in fabry disease reflects coronary small vessel disease","volume":"1","author":"Chimenti","year":"2008","journal-title":"Circ. Heart Fail."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2539","DOI":"10.1161\/CIRCULATIONAHA.109.861534","article-title":"Evaluation of recombinant alpha-galactosidase A therapy for amelioration of the cardiovascular manifestations of Fabry disease: An important role for endomyocardial biopsy","volume":"119","author":"Buja","year":"2009","journal-title":"Circulation"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2561","DOI":"10.1161\/CIRCULATIONAHA.108.841494","article-title":"Cardiac microvascular pathology in Fabry disease: Evaluation of endomyocardial biopsies before and after enzyme replacement therapy","volume":"119","author":"Thurberg","year":"2009","journal-title":"Circulation"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1007\/s00428-005-0089-x","article-title":"Pathological findings in a patient with Fabry disease who died after 2.5 years of enzyme replacement","volume":"448","author":"Schiffmann","year":"2006","journal-title":"Virchows Arch."},{"key":"ref_32","first-page":"15","article-title":"Fabry disease. A case report","volume":"14","author":"Kotnik","year":"2005","journal-title":"Acta Derm. Alp. Pannonica Adriat."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"221","DOI":"10.7326\/0003-4819-117-3-221","article-title":"Fabry disease: An unusual cause of severe coronary disease in a young man","volume":"117","author":"Fisher","year":"1992","journal-title":"Ann. Intern. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1136\/hrt.2004.054015","article-title":"Coronary microvascular dysfunction in male patients with Anderson-Fabry disease and the effect of treatment with alpha galactosidase A","volume":"92","author":"Elliott","year":"2006","journal-title":"Heart"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Case records of the Massachusetts General Hospital (1984). Weekly clinicopathological exercises. Case 2-1984. A 47-year-old man with coronary-artery disease and variable neurologic abnormalities. N. Engl. J. Med., 310, 106\u2013114.","DOI":"10.1056\/NEJM198401123100208"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3741","DOI":"10.1007\/s00415-020-10044-w","article-title":"Oxidative stress biomarkers in Fabry disease: Is there a room for them?","volume":"267","author":"Simoncini","year":"2020","journal-title":"J. Neurol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1161\/01.RES.74.4.700","article-title":"Vascular free radical release. Ex vivo and in vivo evidence for a flow-dependent endothelial mechanism","volume":"74","author":"Laurindo","year":"1994","journal-title":"Circ. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3311","DOI":"10.1093\/eurheartj\/ehy501","article-title":"Targeting myeloperoxidase in inflammatory atherosclerosis","volume":"39","author":"Senders","year":"2018","journal-title":"Eur. Heart J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2045","DOI":"10.1212\/01.wnl.0000247278.88077.09","article-title":"Myeloperoxidase predicts risk of vasculopathic events in hemizgygous males with Fabry disease","volume":"67","author":"Kaneski","year":"2006","journal-title":"Neurology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1161\/01.CIR.0000154550.15963.80","article-title":"Alpha-galactosidase A deficiency accelerates atherosclerosis in mice with apolipoprotein E deficiency","volume":"111","author":"Bodary","year":"2005","journal-title":"Circulation"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.jns.2007.01.053","article-title":"The cerebral vasculopathy of Fabry disease","volume":"257","author":"Moore","year":"2007","journal-title":"J. Neurol. Sci."},{"key":"ref_42","first-page":"615218","article-title":"Fabry disease and early stroke","volume":"2011","year":"2011","journal-title":"Stroke Res. Treat."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1681\/ASN.2007030308","article-title":"Chronic kidney disease increases risk for venous thromboembolism","volume":"19","author":"Wattanakit","year":"2008","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1212\/WNL.0000000000001333","article-title":"Thromboembolic events in Fabry disease and the impact of factor V Leiden","volume":"84","author":"Lenders","year":"2015","journal-title":"Neurology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1161\/CIRCULATIONAHA.114.012636","article-title":"Invasive evaluation of patients with angina in the absence of obstructive coronary artery disease","volume":"131","author":"Lee","year":"2015","journal-title":"Circulation"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1161\/01.CIR.89.1.45","article-title":"Constrictor and dilator responses to intracoronary acetylcholine in adjacent segments of the same coronary artery in patients with coronary artery disease. Endothelial function revisited","volume":"89","author":"Mansour","year":"1994","journal-title":"Circulation"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/0002-8703(75)90010-1","article-title":"Mechanism of the effect of coronary artery stenosis on coronary flow in the dog","volume":"89","author":"Lipscomb","year":"1975","journal-title":"Am. Heart J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1093\/cvr\/17.4.200","article-title":"Asynchronous transmural perfusion during coronary reactive hyperaemia","volume":"17","author":"Downey","year":"1983","journal-title":"Cardiovasc Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1159\/000063121","article-title":"The coronary slow flow phenomenon\u2014A new coronary microvascular disorder","volume":"97","author":"Beltrame","year":"2002","journal-title":"Cardiology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1016\/0735-1097(91)90869-B","article-title":"Coronary vasodilation is impaired in both hypertrophied and nonhypertrophied myocardium of patients with hypertrophic cardiomyopathy: A study with nitrogen-13 ammonia and positron emission tomography","volume":"17","author":"Camici","year":"1991","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/S0735-1097(86)80181-4","article-title":"Intramural (\u201csmall vessel\u201d) coronary artery disease in hypertrophic cardiomyopathy","volume":"8","author":"Maron","year":"1986","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1007\/s10545-006-0221-3","article-title":"The effect of 12-month enzyme replacement therapy on myocardial perfusion in patients with Fabry disease","volume":"29","author":"Kalliokoski","year":"2006","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e008872","DOI":"10.1161\/CIRCIMAGING.119.008872","article-title":"Quantitative Myocardial Perfusion in Fabry Disease","volume":"12","author":"Knott","year":"2019","journal-title":"Circ. Cardiovasc. Imaging"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1038\/s41598-018-37320-0","article-title":"Predictors of objective cognitive impairment and subjective cognitive complaints in patients with Fabry disease","volume":"9","author":"Geurtsen","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1093\/qjmed\/hcy120","article-title":"Diagnosis and treatment of the cardiovascular consequences of Fabry disease","volume":"112","author":"Baig","year":"2019","journal-title":"QJM"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Kr\u00e4mer, J., Bijnens, B., St\u00f6rk, S., Ritter, C.O., Liu, D., Ertl, G., Wanner, C., and Weidemann, F. (2015). Left Ventricular Geometry and Blood Pressure as Predictors of Adverse Progression of Fabry Cardiomyopathy. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0140627"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/19\/4422\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:05:35Z","timestamp":1760166335000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/19\/4422"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,27]]},"references-count":56,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["jcm10194422"],"URL":"https:\/\/doi.org\/10.3390\/jcm10194422","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,27]]}}}