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(Circulation. 1995;91:1272-1274.)
© 1995 American Heart Association, Inc.
Articles |
Ultrasonic Characterization of the Aortic Architecture in Marfan Patients
From the Department of Internal Medicine, University of Texas–Houston Medical School, Houston, Tex.
Correspondence to Dianna M. Milewicz, MD, PhD, University of Texas–Houston Medical School, MSB 1.614, 6431 Fannin, Houston, TX, 77030.
Key Words: Editorials • ultrasonics • aorta
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Introduction |
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 Top Introduction References |
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Components found within the media of the aortic wall allow the aorta to withstand the mechanical stresses it is subjected to throughout life. Elastic fibers and collagen found in the aortic media form the stress-distributing and stress-bearing systems, respectively, whereas smooth muscle cells provide an active contractile component. These structural components are arranged in a highly ordered manner within the media, with circumferential smooth muscle cell layers alternating with interposing elastic laminae.1 2 3
Elastic fibers consist of two morphologically distinct components: an amorphous core of elastin and a peripheral mantle of microfibrils.4 Elastin is the predominant protein component of the core of the elastic fiber and endows the fiber with the characteristic property of elastic recoil. Microfibrils are fine extracellular filaments that are visible only by electron microscopy. The microfibrils in the elastic fiber are typically 10 to 12 nm in diameter and are composed primarily of fibrillin proteins. These proteins are coded for by two closely related genes, FBN1 and FBN2, and are characterized by a repeated domain structure.5 6 7 The molecular interactions involved in the polymerization of fibrillin to form the microscopically visible microfibrils remain to be defined. All the proteins involved in the formation of microfibrils have not yet been identified, nor is it known how these proteins interact at the molecular level to form microfibrils. It appears that fibrillin-containing microfibrils are crucial for proper elastic fiber system development. Studies of the developing aorta show that microfibrils appear initially in the aortic media, followed by the deposition of elastin within the microfibril bundles.3 These observations suggest that microfibrils serve as the scaffold for elastin deposition and appear to direct and orient elastin in the developing aorta.
Extensive research in the past few years has established that mutations in one of the genes for fibrillin, the FBN1 gene, are the cause of Marfan syndrome.8 9 Many mutations in the FBN1 gene have been identified in Marfan patients, the majority of which are missense mutations that alter the coding of just one of the 2871 amino acids found in the fibrillin protein.10 11 Although mutations in the FBN1 gene can affect various aspects of the cellular metabolism of fibrillin, the ultimate result of a mutation is that less fibrillin is incorporated in the extracellular matrix in the form of microfibrils.12 13 Fibrillin is produced from both the normal and mutated FBN1 gene, but because fibrillin molecules interact and multimerize to form microfibrils, fibrillin produced from a mutated gene can profoundly disrupt the amount and structural integrity of the microfibrils produced. This has been termed a "dominant negative" effect of FBN1 gene mutations on microfibril formation.11 14 Recent studies have confirmed this effect on microfibrils by demonstrating the formation of greatly reduced amounts of structurally abnormal microfibrils by dermal fibroblasts from Marfan patients.15
In this issue of Circulation, Recchia et al16 use acoustic tissue characterization methods to study the three-dimensional organization of aortic tissue obtained from Marfan patients undergoing prophylactic repair of aortic aneurysms.16 They studied aortic tissue from 11 Marfan patients and 8 unaffected individuals. Additionally, biochemical and histological studies were done on the tissues. Biochemical studies on the aortic tissue showed no difference in the amount of collagen between the Marfan and control aortas. The histological studies revealed a decrease in the amount of elastin present and extensive deposits of mucopolysaccharides. This loss of the highly organized elastic lamellar system in the aortic wall reduced ultrasound backscatter and anisotropy in the media of aortic tissue from Marfan patients when compared with control aortic tissues. Since there is a linear correlation between integrated backscatter and the amount of both elastin and collagen in the aortic tissue, the authors conclude that the ultrasound findings in the Marfan aortic tissues is due at least in part to a decrease in the elastin content of the Marfan tissue.
So why does altering a single amino acid in the fibrillin protein result in such profound disruption of the structure of the elastic fibers in the aortic media? We know that the abnormal fibrillin produced due to an FBN1 mutation decreases the amount and alters the structure of microfibrils made. During development, the formation of microfibrils appears to be important for subsequent elastin deposition and orientation in tissues. Theoretically, the lack of proper deposition of fibrillin-containing microfibrils results secondarily in abnormal elastin deposition and therefore an aortic wall that is not able to withstand the mechanical stresses placed on it throughout life. Because the microfibril-dependent deposition of elastin in the aortic media occurs during development, the structure of the elastic fiber system may be abnormal from birth in Marfan patients.
Additional studies are needed to determine the potential clinical significance of the findings reported by Recchia and colleagues. First, can this technique be adapted to give reliable in vivo results in patients? Is this phenomenon specific for aneurysms caused by the Marfan syndrome, or is the finding common to all aneurysms no matter the pathogenesis? More than likely, these ultrasonic changes will be present in the aortic tissue of non-Marfan aneurysm patients with cystic medial necrosis present in the aortic wall since the pathological changes are similar. Because this study was done on aortic tissues obtained from Marfan patients at the time of prophylactic aortic aneurysm repair, a critical clinical question is whether abnormal architecture can be detected in nondilated Marfan aortas. If this technique does allow for noninvasive assessment of early changes in the aortic wall structure and composition in Marfan patients, it has the potential to significantly affect the assessment and management of these patients in a number of ways.
First, the ability to assess the structure of the aortic wall could significantly aid the clinician in assessing patients with possible Marfan syndrome. In the clinic, accurate and timely diagnosis of Marfan syndrome remains a problem despite the advances in our understanding of the underlying gene defect. Many individuals referred for evaluation have the skeletal features of the disorder with or without nonspecific findings of the syndrome, such as myopia or mitral valve prolapse. In the absence of findings specific for Marfan syndrome, such as aortic root dilation, lens dislocation, or a family history of the disorder, the diagnosis cannot be made.17 Although these individuals do not meet the diagnostic criteria for Marfan syndrome, often the diagnosis cannot be excluded with absolute certainty, especially if the patient is young. It is in these cases that it would be useful to have another diagnostic tool available that could specifically assess whether there is an alteration in the structure or composition of the aortic wall.
Another potential use for this ultrasonic tissue characterization method is to identify Marfan patients who are prone to dissection of the aorta before dilation. Although the aortas of most Marfan patients can be monitored routinely and prophylactic surgery can be recommended in a timely manner, the aortas of some Marfan patients dissect when the aorta is not significantly enlarged. Ultrasonic studies of the structure of the aortic media may differentiate Marfan patients prone to dissection, perhaps by demonstrating more severe disruption of the architecture of the nondilated aortic wall. If these patients can be identified, they may benefit from prophylactic repair of their aorta before dilation. Such therapy will not only prevent aortic dissection but also may decrease the incidence of subsequent aortic repairs at other sites.18
Acoustic characterization to monitor aortic structure could be used to gauge the efficacy of medical therapy. Recently published studies have demonstrated that ß-adrenergic blockade can slow the rate of aortic root dilation in Marfan patients.19 It has been suggested that the earlier this therapy is instituted, the greater the potential benefit. Currently, assessment of the effect of such therapy is based on the rate of enlargement of the aortic root. The ability to determine the effect of therapy on changes in the macromolecular architecture of the aorta may provide a new, more sensitive parameter to determine the efficacy of therapy.
For numerous reasons, the identification of the genetic defect causing Marfan syndrome has not affected these clinical management problems. Almost every mutation in the FBN1 gene causing Marfan syndrome has been different, thus limiting the use of direct mutational analysis for presymptomatic diagnosis. The use of FBN1 mutational analysis as a diagnostic test for Marfan syndrome is also complicated by the fact that FBN1 gene mutations can cause isolated features of Marfan syndrome, such as ocular or skeletal manifestations, in the absence of life-threatening cardiovascular problems.10 20 Linkage analysis using intragenic polymorphic markers recently has been shown to be useful in identifying affected individuals within families, but this analysis is limited to families with a sufficient number of participating family members to determine which allele is segregating with the disease.21 This is often not the case either because of small families or other family members not willing to participate or because the individual being evaluated does not have a family history of Marfan syndrome. Characterization of mutations in the FBN1 gene in Marfan syndrome have not led to a complete understanding of the relation between a particular type or location of a FBN1 mutation and the resulting clinical manifestations of the disorder. In other words, we cannot use molecular genetic analysis to predict the severity of the complications associated with Marfan syndrome (with the possible exception of mutations involving exons 24 through 26 of the FBN1 gene10 ).
The ability to assess the aortic architecture in Marfan patients has the potential of significantly affecting the clinical assessment of these patients. The discovery of the genetic defect causing Marfan syndrome has not solved all the problems that clinicians have in managing these patients, and further clinical tools are needed. Just as surgery remains the mainstay of treating the life-threatening cardiovascular complications despite our understanding of the molecular basis of the disease, we may depend on more macroscopic assessment of the effect of FBN1 gene mutations on tissue architecture as a diagnostic and prognostic tool for these patients in the future.
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Acknowledgments |
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Dr Milewicz is supported in part by a Pfizer Scholars Award, an American Heart Association Grant-in-Aid, and the Joel E. Smilow Fund from the National Marfan Foundation.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
Received January 4, 1995; accepted January 5, 1995.
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References |
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