Aortic Dissection: New Frontiers in Diagnosis and Management Part I: From Etiology to Diagnostic Strategies Christoph A. Nienaber, MD; Kim A. Eagle, MD C ardiovascular disease is the leading cause of death in most Western societies and is increasing steadily in many developing countries. Aortic diseases constitute an emerging share of the burden. New diagnostic imaging modalities, longer life expectancy in general, longer exposure to elevated blood pressure, and the proliferation of modern noninvasive imaging modalities have all contributed to the growing awareness of acute and chronic aortic syndromes. Despite recent progress in recognition of both the epidemio- logical problem and diagnostic and therapeutic advances, the cardiology community and the medical community in general are far from comfortable in understanding the spectrum of aortic syndromes and defining an optimal pathway to manage aortic diseases. 1–13 This comprehensive review is organized in two parts, with a focus on the etiology, natural history, and classification (with vascular staging) of aortic wall disease in Part I and emphasis on therapeutic management and follow-up in Part II. Both parts may help to better integrate the complexities of acute aortic syndromes. I. Etiology of Aortic Dissection All mechanisms weakening the aorta’s media layers via micro apoplexy of the vessel wall lead to higher wall stress, which can induce aortic dilatation and aneurysm formation, eventually resulting in intramural hemorrhage, aortic dissec- tion, or rupture (Table 1). Three major inherited connective tissue disorders are currently known to affect the arterial walls: (1) Marfan’s syndrome, (2) Ehlers-Danlos syndrome, and (3) familial forms of thoracic aneurysm and dissection. Marfan’s Syndrome Among hereditary diseases, Marfan’s syndrome (MFS) is the most prevalent connective tissue disorder, with an estimated incidence of 1 in 7000 and an autosomal dominant inheri- tance with variable penetrance. More than 100 mutations on the fibrillin-1 gene have been identified as encoding for a defective fibrillin in the extracellular matrix, which may affect the ocular, cardiovascular, skeletal, and pulmonary systems, as well as the skin and dura mater. The diagnosis of MFS is currently based on revised clinical criteria of the “Gent nosology.” 9 The Gent criteria pay particular attention to genetic information like MFS in kindreds of an unequiv- ocally affected individual. Moreover, both skeletal and car- diovascular features are major (eg, diagnostic) criteria if 4 of 8 typical manifestations are present. Considering, however, borderline manifestations such as the mitral-aortic-skin- skeletal (MASS) phenotype or subtle phenotypic features (“forme fruste”), the molecular analysis of suspected MFS and the delineation of criteria for differentiating other inher- ited conditions (genotypes) from a Marfan phenotype are attracting interest. 14 –20 The clinical variety of the MFS is only partially explained by the number of mutations on the fibrillin-1 gene. Genetic heterogeneity and the involvement of a second gene (MFS2) may further add to the broad spectrum of symptoms. 20 A common denominator of all phenotypic forms of aortic wall disease is the dedifferentiation of vascular smooth muscle cells, not only with classic progression of atherosclerosis and aneu- rysm formation, but also from enhanced elastolysis of aortic wall components 21 —as shown in a fibrillin-q– deficient animal mod- el. 22 Moreover, enhanced expression of metalloproteinases in vascular smooth muscle cells of the Marfan aorta may promote both fragmentation of medial elastic layers and elastolysis, thus initiating an activated phenotype of smooth muscle cells. 23 In parallel, expression of peroxisome proliferator–activated receptor- is upregulated both in smooth muscle cells of MFS aorta and in the presence of cystic medial degeneration and correlates with clinical severity, whereas vascular smooth mus- cle cell apoptosis is likely to be related to progression of aortic dilatation. Thus, peroxisome proliferator–activated receptor- expression might reflect the pathogenesis of cystic medial degeneration and disease progression in the aorta of MFS and non-MFS individuals without any vascular inflammatory response. 24 Ehlers-Danlos Syndrome Ehlers-Danlos syndrome (EDS) is a heterogeneous group of hereditable connective tissue disorders characterized by ar- From the Division of Cardiology at the University Hospital Rostock (C.A.N.), Rostock School of Medicine, Rostock, Germany, and the Division of Cardiology at the University of Michigan (K.A.E.), Ann Arbor, Mich. This is Part I of a 2-part article. Part II will appear in the August 12, 2003, issue of Circulation. Correspondence to Christoph A. Nienaber, MD, FACC, Division of Cardiology, University Hospital Rostock, Rostock School of Medicine, Ernst-Heydemann-Str. 6, 18057 Rostock, Germany. E-mail christoph.nienaber@med.uni-rostock.de (Circulation. 2003;108:628-635.) © 2003 American Heart Association, Inc. Circulation is available at http://www.circulationaha.org DOI: 10.1161/01.CIR.0000087009.16755.E4 628 Review: Clinical Cardiology: New Frontiers by guest on April 22, 2016 http://circ.ahajournals.org/ Downloaded from