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J Thorac Cardiovasc Surg 2003;126:797-805
© 2003 The American Association for Thoracic Surgery
Surgery for acquired cardiovascular disease |
a Division of Cardiac Surgery University of Toronto, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
b Department of Pathology, University of Toronto, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
c Division of Cardiology, University of Toronto, Roy and Ann Foss Research Program, Terrence Donnelly Heart Centre, St Michael’s Hospital, Toronto, Ontario, Canada
Read at the C. Walton Lillehei Resident Forum of the Eighty-second Annual Meeting of The American Association for Thoracic Surgery, Washington, DC, May 5-8, 2002.
Received for publication June 5, 2002; revisions received September 3, 2002; revisions received January 26, 2003; accepted for publication February 11, 2003.
* Address for reprints: Tirone E. David, MD, Division of Cardiac Surgery, Toronto General Hospital, 13EN-219, 200 Elizabeth St, Toronto, Ontario, Canada M5G 2C4
tirone.david{at}uhn.on.ca
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Abstract |
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METHODS: Samples of the pulmonary artery and aorta were obtained from surgical patients with bicuspid aortic valves (n = 21) and tricuspid aortic valves (n = 16).
RESULTS: Fibrillin-1 content was reduced in bicuspid aortic valve aortas compared with that seen in tricuspid aortic valve aortas (P = .001), whereas the associated matrix components, elastin and collagen, were unchanged (P = .51 and P = .21). Reductions of aortic fibrillin-1 content were independent of valve function and patient age. Compared with tricuspid aortic valve aorta, matrix metalloproteinase 2 activity was increased more than 2-fold in bicuspid aortic valve aortas (P = .04) and correlated positively with aortic diameter (r = 0.74, P = .05). Matrix metalloproteinase 9 activity was not significantly different. Fibrillin-1 content was also reduced in the pulmonary arteries of patients with bicuspid aortic valves (P = .06), suggesting a systemic deficiency of fibrillin-1. Promatrix metalloproteinase 2 was increased (P = .04), reflecting an increased production of matrix metalloproteinase 2 in these fibrillin-1–deficient tissues, whereas active matrix metalloproteinase 2 and matrix metalloproteinase 9 species were unchanged, and correspondingly, the pulmonary arteries were not dilated.
CONCLUSIONS: Deficient fibrillin-1 content in the vasculature of patients with bicuspid aortic valves might trigger matrix metalloproteinase production, leading to matrix disruption and dilatation. This process of vascular matrix remodeling in patients with bicuspid aortic valves offers novel therapeutic targets to prevent the aortic degeneration and dilatation characteristic of this disease.
Fibrillin-1 is a fundamental extracellular matrix component of the aortic media.2 The fibrillin-rich microfibrils play a prominent role in regulating tissue development and maintaining tissue elasticity by linking vascular smooth muscle cells to adjacent elastin fibrils.3 Gene defects that alter fibrillin-1 content, as in Marfan syndrome and other disorders, can reduce the structural integrity of the vessel wall, leading to aortic dilatation or dissection.4 In transgenic mouse models targeted underexpression of the fibrillin-1 gene results in aortic aneurysms with increased matrix metalloproteinase (MMP) matrix fragmentation, reducing the structural integrity of the aorta.3 In patients with aortic valve malformations, we and others have documented medial degeneration5 consistent with that seen in experimental models of fibrillin-1 deficiency, suggesting that a similar pathologic process might occur.
In the present study we hypothesized that BAV disease is associated with a fibrillin-1 deficiency and increased MMP activity.
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Immunohistochemistry
Samples were fixed in acetone, cryosectioned at a 4- to 5-µm thickness, and air-dried. To expose elastin-associated fibrillin-1 and remove elastin autofluorescence, which could mask the fluorescence of fibrillin-1, enzymatic digestion of the sections before fibrillin-1 staining was performed by incubating the samples in 0.01% elastase (Worthington Biochemical) in Tris-HCl buffer (67 mmol/L, pH 8.8) for 20 minutes. Sections were stained for fibrillin-1 with mouse anti-fibrillin monoclonal antibody (clone 12A5.18, Neomarkers Inc) at a 1:50 dilution for 1 hour. For elastin staining, samples were air-dried, formalin fixed, and incubated in rabbit polyclonal anti-
-elastin antibody (Neomarkers Inc) at 1:100 dilution for 1 hour. For all sections, goat anti-mouse IgG conjugated to Cy3 (Jackson Immunoresearch Lab, Inc) was used as a secondary antibody. All sections were counterstained for DNA with 4,6 diamino-1-phenylindolel (Sigma Chemical Co). Sections were mounted and examined with a fluorescence microscope. Negative controls were stained, omitting the incubation step with the primary antibody.
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Quantitative fluorescence microscopy |
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The IOD of each image was measured by using a histogram of the cumulative relative percentages of the gray scale score. Gray scale score is a value assigned to each pixel of the image on the basis of its relative brightness level. The nonfluorescence background is zero, and any pixel with a nonzero score represents fluorescence. The IOD is obtained by subtracting the background percentage from 100%. The fluorescence level of each sample (average of 9 different regions), represented by mean IOD, was calculated by subtracting the mean IOD of the negative control from that of the sample labeled with primary antibody. Fibrillin-1 slides were also reanalyzed by using the 20x objective to determine whether the magnification could interfere with results. No difference was observed between results obtained with the 10x or 20x objective. An observer blinded to the groups performed all assessments.
Hydroxyproline determination of collagen and elastin
Collagen and elastin content were also determined by using the method of Strauss and colleagues.7 Samples were digested overnight by using a cyanogen bromide treatment (50 mg/mL in 70% formic acid), which solubilizes all proteins except elastin by cleaving methionine bonds. The supernatant, containing fragments of collagen and other proteins, was dried and hydrolyzed in 6N HCl at 110°C for 24 hours. Because collagen is the only protein in the supernatant fraction containing significant amounts of hydroxyproline, collagen content was measured by determining the total hydroxyproline content of the hydrolysate. The insoluble residue after cyanogen bromide treatment contains essentially pure elastin on the basis of amino acid analysis.8 As such, the dry weight of the residue was taken as the content of total insoluble elastin in the vascular tissue.
Gelatinase zymography
Samples were pulverized in liquid nitrogen and extracted in ice-cold extraction buffer (cacodylic acid, 10 mmol/L; NaCl, 0.15 mol/L; ZnCl2, 20 mmol/L; NaN3, 1.5 mmol/L; and 1% sodium dodecylsulfate, pH 5.0). After 1 hour, the supernatant was separated from any insoluble debris by means of centrifugation (4°C, 10 minutes, 13,000 rpm) and assayed for protein concentration by using the Bio-Rad protein assay kit (Bio-Rad). Samples were placed in aliquots and stored at -80°C until use. Gelatin zymography was performed according to the method of Cruz and colleagues.9 Extracts containing 40 µg of protein were loaded onto a 10% sodium dodecylsulfate–polyacrylamide gel precast with 0.1% gelatin substrate (Criterion Zymogram Gels, Bio-Rad) and electrophoresed at 125 V. After electrophoresis, the gels were washed in 2.5% Triton X-100, incubated overnight at 37°C in Tris buffer (Tris, 50 mmol/L; CaCl2, 15 mmol/L), and then stained with 0.5% Coomassie brilliant blue R-250 (Bio-Rad). After destaining for 4 hours, areas of clearing in the gels indicated the presence of gelatinase activity (MMP-2 and MMP-9). Gels were calibrated with molecular weight markers (Bio-Rad) and positive controls (activated purified MMP-2 and MMP-9). The zymograms were digitized, and MMP activity was determined by means of quantitative image analysis (Scion Image, NIH Software).
Statistical analysis
Unless otherwise specified, all variables are reported as means ± SD. Differences between groups were evaluated by means of 1-way analysis of variance. The post hoc Bonferroni multiple comparison test was used to find differences between groups. Categoric variables were analyzed by using the t test or the Fisher exact test when numbers were small.
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Fibrillin-1 content
The mean IOD for aortic fibrillin-1 content was not different in patients with normal or diseased aortic valves (26.0 ± 5 vs 20.6 ± 9, P = .45). Because values in patients with nondiseased TAVs were not statistically different from those in patients with diseased TAVs, all patients with TAVs were combined for comparison with the BAV group. Patients with BAVs had significantly less fibrillin-1 than patients with TAVs (mean IOD ± SD: 14.1 ± 8 vs 24.5 ± 7, P = .001; Figure 1,
A). This difference was uniform because the mean IOD in the inner, middle, and outer portions of the media was not statistically different. Linear regression analysis did not show a relationship between fibrillin-1 content and either aortic diameter (BAV and TAV: P = .58 and P = .17, respectively) or patient age (BAV and TAV: P = .84 and P = .12, respectively).
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Collagen content, as assessed by means of hydroxyproline determination, was not significantly different between the BAV and TAV groups (203 ± 111 vs 185 ± 97 µg/mg dry weight, P = .21; Figure 1, B).
Mmp activity
Compared with TAV aortas, MMP-2 activity was increased over 2-fold in BAV aortas (mean densitometric units: 20.6 ± 13 vs 7.7 ± 5, P = .04) and correlated positively with aortic diameter (r = 0.74, P = .04, Figure 2).
Pro-MMP-2 and MMP-9 levels were not significantly different (Figure 2, B).
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Discussion |
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Advances in molecular biology offer new insights into the pathogenesis of aortic dilatation resulting from molecular defects in genes that encode for matrix elements. Analysis of varied combinations of normal and mutant fibrillin-1 gene expression points to a threshold phenomenon for the deterioration of the vessel wall that is based on the abundance and integrity of fibrillin-1 microfibrils.12 Mice homozygous for a targeted hypomorphic allele of the fibrillin-1 gene have structurally normal fibrillin-1 protein but at a significantly reduced level. In these mouse models fibrillin-1 protein deficiency resulted in increased MMP matrix fragmentation, reducing the structural integrity of the aorta. Disruption of the aortic media resulted in progressive aortic dilatation.13 Reduced fibrillin-rich microfibrils dissociated smooth muscle cells from elastic laminae and stimulated the cells to increase constitutive MMP activity and undergo apoptotic cell death.14 Premature, medial-layer, smooth muscle cell apoptosis has been associated with aortic valve malformations.15 The pathology of the aorta in these experimental models of fibrillin-1 deficiency resembles that in patients with congenital aortic valve malformations, which encouraged us to explore a similar pathophysiologic mechanism in our patients with BAVs.
The present study outlines a mechanism of vascular matrix remodeling that might contribute to the aortic pathology associated with BAV malformations. We hypothesized that the process of vascular matrix reorganization in patients with BAVs was similar to those identified in experimental models of fibrillin-1 deficiency,10 and as such, we assessed the abundance of key matrix components in the vasculature of these patients. Our data indicates that a subset of patients with congenital BAV disease have significantly reduced fibrillin-1 content in the aortic media (Figure 1, A). These fibrillin-1 reductions occurred without comparable reductions in the matrix components elastin and collagen (Figure 1, B). Fibrillin-1 content was equivalent in the aorta of patients with normal and diseased TAVs, suggesting that reductions of fibrillin-1 are not caused by valve dysfunction and are specific to the presence of a congenital BAV malformation, irrespective of its function. In addition, this novel observation is not typical of diseased aorta; fibrillin-1 content is increased, not reduced, in atherosclerotic aortic dilatation.16
Given that matrix-degrading enzymes do not act on fibrillin-1 independently,17 the fibrillin-1 deficiency might be a result of reduced fibrillin-1 protein production, a failure of compensatory replacement of lost fibrillin-1 in the face of ongoing matrix degradation, or both. Although our observations are suggestive of aberrant gene regulation, it is unclear whether these changes are due to a primary failure in the regulation of the gene, which would occur systemically, or excessive degradation and inadequate replacement of this protein specific to the diseased aorta. To further investigate this mechanism, we assessed matched pulmonary artery samples in patients with TAVs versus BAVs for matrix content. In subsets of patients with BAV malformations, a pathologic deficiency of fibrillin-1 was also observed in the pulmonary artery. These data indicate that fibrillin-1 might be deficient systemically in these patients, which is most consistent with dysregulation of the fibrillin-1 gene. However, our data are limited to the level of the protein and cannot discriminate between a primary defect in expression of the fibrillin-1 gene versus a secondary effect from inadequate processing and deposition of fibrillin-1 into the extracellular space or excessive fibrillin-1 degradation with inadequate compensatory replacement.
In patients with BAV malformations, the possibility of a molecular defect in genes that regulate the production and assembly of microfibrillar proteins, such as fibrillin-1, is intriguing. Mutations in the fibrillin-1 gene itself that result in decreased gene expression have been associated with thoracic aortic aneurysms and dissection in the absence of Marfan syndrome,4,18 although they have yet to be described in families with BAVs. In theory, altered fibrillin-1 gene and protein structure would result in the Marfan syndrome or similar conditions. A reduction in fibrillin-1 abundance, with preserved protein structure, could result in a similar but less severe phenotype restricted to the vasculature. However, the lack of skeletal manifestations in patients with BAVs, like those of patients with Marfan syndrome, argues against an inherited and systemic deficiency of fibrillin-1, whether caused by a primary gene defect or secondary microfibrillar losses. For example, patients with inherited defects that reduce the systemic expression of fibrillin-1, such as the MASS phenotype and familial Marfanoid habitus, characteristically show prominent abnormalities in the skeleton and skin, with only mild aortic disease. On the other hand, the relationship of fibrillin-1 defects and their diverse and variable clinical manifestations is not well understood. Marfan syndrome and its related phenotypes (ie, MASS phenotype) have a highly variable timing of onset, tissue distribution (ie, vascular vs skeletal and proximal vs distal ascending aorta), and severity of clinical manifestations, even in patients with identical fibrillin-1 gene mutations and expression levels.19 Thus the cause of fibrillin-1 deficiency in patients with BAV malformations remains an open question.
It has been suggested that a common genetic defect underlies both the valvular and vascular complications of BAV disease. Is fibrillin-1 the elusive BAV gene? The microfibrillar proteins, such as fibrillin-1, act as scaffolding for embryonic cells and aid in the formation of both the aortic valve and aorta.20,21 In fact, differentiation of cushion mesenchymal cells into mature valve cells correlates with the expression of fibrillin-1.21 Inadequate production or excessive degradation of fibrillin-1 during valvulogenesis might disrupt the formation of the aortic cusps, resulting in a bicuspid valve, as well as a weakened aorta. Yet in multiple clinical states associated with defects in the structure, expression, or both of fibrillin-1, such as the Marfan and MASS phenotypes, there does not appear to be an increased propensity for congenital aortic valve malformations. The possibility of an intact fibrillin-1 gene but aberrant transcriptional elements might explain the inability of previous investigators to link known fibrillin-1 gene defects with BAV disease. Although a mutation in genes that regulate transcription has not been associated with congenital aortic valve malformations to date, they are widely implicated in a number of other congenital cardiac anomalies.22 BAV disease is a complex and heterogeneous phenotype that might result from genes that encode matrix elements, although it probably does not result from a single gene defect alone, such as the fibrillin-1 gene.
Like the fibrillin-1–deficient mouse, we hypothesized that degeneration of the aortic media in patients with congenital aortic valves is the result of MMP-mediated matrix fragmentation. The MMPs are a family of endogenous enzymes that degrade extracellular matrix components. Increased MMP activity plays an essential role in the formation and progression of aortic aneurysms.23-27 Both MMP-2 and MMP-9 are involved in the turnover of elastic matrix components.23 MMP-2 is expressed by smooth muscle cells constitutively and might have a pivotal role in the early formation of aneurysms.24-26 Crowther and coworkers24 established that smooth muscle cells from aneurysmal abdominal aortas produced 3-fold higher levels of MMP-2 than smooth muscle cells from normal aortas. In patients with Marfan syndrome, excessive MMP-2 released from vascular smooth muscle cells is highly localized to areas of matrix fragmentation within the thoracic aortic media, supporting a causative role for MMP-2 in the development of the characteristic vessel wall degeneration.28 The role of MMPs in the vascular disease of patients with BAVs had not been previously assessed.
Our observations support the concept, similar to that previously formulated for both atherosclerotic and Marfan aneurysms,28 that increased MMP activity is involved in the vascular manifestations of congenital BAV disease. Compared with TAV aortas, MMP-2 activity was increased in the aortas of patients with BAVs (Figure 2), perhaps in response to a reduction in fibrillin-1 microfibrils. Increased MMP activity might indeed disrupt vessel wall integrity, given that MMP-2 activity positively correlated with aortic dilatation (Figure 2, C). Although MMPs appear to mediate aneurysms of diverse causes,23 the triggers promoting their production and activation might differ. In BAV disease reduced tethering of fibrillin-1 microfibrils from the underlying protein deficiency might activate smooth muscle cells and increase production of MMP-2. In support, pro-MMP-2 was increased in the pulmonary arteries of patients with BAVs, which were also deficient in fibrillin-1. Shear stresses and inflammation might be important activators of the latent MMP-2 produced in the vessel wall, and active MMPs might lead to dilatation. The lower pressures in the pulmonary circulation might have prevented activation of this latent form given that active MMP-2 was not different from controls in the pulmonary artery, and correspondingly, dilatation did not occur in the pulmonary arteries of the patients with BAVs despite the concomitant deficiency of fibrillin-1. These data also suggest that the reduced fibrillin-1 content in the aorta and pulmonary artery is not predominantly the result of MMP degradation, given that fibrillin-1 was reduced in the pulmonary artery without concurrent increases in active MMP species.
Unlike atherosclerotic aortic aneurysms, MMP-9 was not increased in patients with congenital aortic valves. MMP-9 is a major product of macrophages and might be important in atherosclerotic aneurysm formation after prolonged inflammation, particularly in the intermediate to late stages after substantial dilatation.27 In the present study aortic dilatation, if present, was only mild to moderate in severity.
Study limitations
Because of limitations in sample collection, the study groups were not perfectly matched. In the TAV group, only one patient had significant aortic dilatation, whereas half the patients in the BAV group had significant dilatation. Furthermore, we successfully obtained 6 normal tricuspid valve samples from patients undergoing transplantation; however, all patients in the BAV group had significant valvular disease. Our data must be interpreted in light of these group differences. Second, although fibrillin-1 content was reduced, electron microscopy should be performed in a future study to confirm that fibrillin-1 microfibrils are indeed deficient in the vessel walls of patients with BAVs. Third, the content of other microfibrillar proteins should also be assessed to determine whether bicuspid valve disease is associated with loss of other key microfibrillar matrix components. Fourth, the possibility exists that the pretreatment of tissue samples with elastase led to a nonspecific degradation of fibrillin-1 microfibrils. The disorganized matrix in the BAV group might have allowed the enzyme to more easily penetrate the tissues of patients with BAVs, resulting in an apparent deficiency of fibrillin-1. However, we used a diluted enzyme concentration and a limited duration of exposure to minimize any nonspecific matrix degradation during elastase treatment. Further studies should be performed to confirm these novel observations.
A possible genetic basis for aberrant matrix remodeling in BAV disease
Patients with congenital BAV malformations might have an inherited defect in genes that regulate the processing of microfibrillar proteins into intact stable matrix components in the vessel wall. This might result in a structurally normal protein product but at a significantly reduced amount in the extracellular space. Fibrillin-1 microfibril deficiency might detach smooth muscle cells from the elastic laminae, resulting in matrix degradation and cell death, vessel wall weakening, and progressive aortic dilatation (Figure 4). Aortic aneurysm and dissection might occur when the abundance of fibrillin-rich microfibrils in the media decreases to less than some critical threshold, triggering the release of pathologic MMP species. Although the absence of other associated nonvascular complications is difficult to explain, it might suggest that the clinical phenotype only manifests in areas with high mechanical stress, such as the ascending aorta. As such, under conditions of increased wall stress, a pulmonary autograft in the aortic position in patients with BAV disease might be prone to dilatation given the underlying vascular matrix abnormalities.29 The deficient fibrillin-1 content and increased pro-MMP-2 in the pulmonary artery appears primed for vascular degeneration if subjected to systemic pressures. Secondary events, such as increased wall stress and inflammation, which can activate MMPs that degrade fibrillin-1, could exacerbate the protein deficiency.17 The influence of secondary fibrillin-1 losses over time might explain the phenotypic variability for the aortic dilatation associated with BAVs.
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Discusison |
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Dr Fedak. Thank you, Mr Yacoub. I hope I have not given the impression that we believe that we have proved that aortic root dilatation in patients with BAVs is the result of a specific gene defect. Our data are suggestive, but there are, as you outlined, other possible explanations for our findings. However, in transgenic mouse models a targeted reduction of aortic fibrillin-1 content results in a similar sequence of events that includes excessive MMP activity, medial degeneration, and progressive aortic dilatation. In addition, when vessels are subjected to excessive stretching (ie, balloon angioplasty), the arteries characteristically respond with hyperplasia and wall thickening rather than the matrix degradation and dilatation that we have demonstrated in patients with bicuspid valves. These studies and others indicate that matrix degradation is a cause rather than a consequence of aneurysm formation. Shear stresses likely play an important role in exacerbating and maintaining arterial dilatation once it has occurred but probably do not initiate the process. Increased shear stresses alone could not explain why young patients with normally functioning BAVs and normal aortic shear stresses also have significant root dilatation. Further work should be done to identify whether pathologic matrix degradation and deficient fibrillin-1 are indeed the cause of aortic dilatation and whether this process is the result of a specific gene defect. We believe that we have identified an important molecular process that results in aortic dilatation, but our data do not definitively demonstrate a genetic cause. In light of this, I think your measured perspective on our data is very appropriate. We agree with your comments, and that is why in our abstract title we used the phrase "a possible gene defect." We also revised the title of our article to minimize potential confusion.
Dr Thoralf M. Sundt (Rochester, Minn). I agree with the professor and in fact would argue that your correlation between aortic diameter and MMPs argues exactly this point. What you have observed could well be a secondary biomechanical response to alterations in transmural stress distribution occurring with dilatation rather than a reflection of a primary genetic abnormality.
I would like to note that there is more to the phenotype of ascending aortic aneurysms associated with bicuspid valves than you imply in your presentation. There is not just one phenotype but in fact a number of different kinds of ascending aortic aneurysms associated with bicuspid valves: some aneurysms arise entirely above the sinotubular ridge with normal sinuses and, commonly, aortic stenosis. There is also another configuration that looks for all the world like Marfan syndrome with dilatation of the sinuses, as well as the ascending aorta, and an onion-shaped root with, most often, aortic regurgitation. Do you have any more precise information about the phenotypes of the individuals that you were studying?
Dr Fedak. In my presentation I outlined that some patients with BAVs had normal aortic fibrillin-1 content. Clearly, not every patient with BAV disease is equivalent on a molecular level, and as you outlined, this is also true on a clinical level. Some younger patients with aortic insufficiency manifest aortic dilatation early, and some older patients with stenosis never have significant aortic dilatation. These diverse clinical phenotypes combined with our heterogeneous molecular data suggest that if there are genes involved, and I believe that there are, likely there is more than one involved. I believe that a host of genes, all probably encoding matrix components, are involved in this disease and result in diverse clinical phenotypes. Unfortunately, our small sample size precluded a useful analysis of these important issues.
Dr Frank W. Sellke (Boston, Mass). That was sort of my question. What is known about the genetic regulation of fibrillin-1 expression? And the second point was, if you try to inhibit MMP activity and expression, what kind of consequence might you have? They are so involved in a lot of physiologic processes, such as angiogenesis, tissue remodeling, and things like that.
Dr Fedak. Absolutely, Dr Sellke. The MMPs play a critical role in a number of normal physiologic processes, and that is what has largely hampered efforts in the past to prevent MMP matrix remodeling with use of synthetic inhibitors. In fact, I think in the next talk we will hear more about the use of specific MMP inhibitors in heart failure. In studies that outline pathologic MMP activities, it is important to identify which specific MMPs are involved, because there are more than 20, to develop targeted therapies to specifically prevent their activation.
Therefore, on the basis of our data, if we had a specific inhibitor for MMP-2, its use in patients with BAVs might prevent aortic dilatation. It would be better to specifically target the tissue involved to avoid a systemic effect. Therefore, as I mentioned, using gene therapy with the TIMPs, the tissue inhibitors of MMPs, which are the endogenous biologic inhibitors of MMPs, we might be able to target pathologic MMPs within the tissue compartment of interest while maintaining normal physiologic matrix regulation in the remaining tissues.
Dr Christian Pizarro (Wilmington, Del). Did you have any chance to look at segments of the pulmonary artery in these patients? And truly, if this is a genetic problem that affects any great vessel, it probably would be a consideration against a potential Ross operation if that came into play.
Dr Fedak. Given that the aorta and pulmonary artery have the same embryonic origins, Dr de Sa has studied the pulmonary artery in detail to better understand this complex pathologic process. I do not want to go into detail about his work, but we have identified a similar process of matrix remodeling in the pulmonary arteries of patients with BAVs. The pulmonary artery observations suggest that this pathologic process is systemic and not likely the result of increased shear stresses, which occur only in the aorta. And, again, it is suggestive of a gene defect but certainly not proved.
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J. S. Ikonomidis, J. A. Jones, J. R. Barbour, R. E. Stroud, L. L. Clark, B. S. Kaplan, A. Zeeshan, J. E. Bavaria, J. H. Gorman III, F. G. Spinale, et al. Expression of matrix metalloproteinases and endogenous inhibitors within ascending aortic aneurysms of patients with bicuspid or tricuspid aortic valves J. Thorac. Cardiovasc. Surg., April 1, 2007; 133(4): 1028 - 1036. [Abstract] [Full Text] [PDF]
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S. Goland, L. S.C. Czer, M. A. De Robertis, J. Mirocha, R. M. Kass, G. P. Fontana, W. Chang, and A. Trento Risk Factors Associated With Reoperation and Mortality in 252 Patients After Aortic Valve Replacement for Congenitally Bicuspid Aortic Valve Disease Ann. Thorac. Surg., March 1, 2007; 83(3): 931 - 937. [Abstract] [Full Text] [PDF]
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T. Walker, D. H.L. Bail, M. Gruler, R. Vonthein, V. Steger, and G. Ziemer Unsupported Reduction Ascending Aortoplasty: Fate of Diameter and of Windkessel Function Ann. Thorac. Surg., March 1, 2007; 83(3): 1047 - 1053. [Abstract] [Full Text] [PDF]
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J. D. Schmoker, K. J. McPartland, E. K. Fellinger, J. Boyum, L. Trombley, F. P. Ittleman, C. Terrien III, A. Stanley, and A. Howard Matrix metalloproteinase and tissue inhibitor expression in atherosclerotic and nonatherosclerotic thoracic aortic aneurysms J. Thorac. Cardiovasc. Surg., January 1, 2007; 133(1): 155 - 161. [Abstract] [Full Text] [PDF]
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J. S. Ikonomidis, J. A. Jones, J. R. Barbour, R. E. Stroud, L. L. Clark, B. S. Kaplan, A. Zeeshan, J. E. Bavaria, J. H. Gorman III, F. G. Spinale, et al. Expression of Matrix Metalloproteinases and Endogenous Inhibitors Within Ascending Aortic Aneurysms of Patients With Marfan Syndrome Circulation, July 4, 2006; 114(1_suppl): I-365 - I-370. [Abstract] [Full Text] [PDF]
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E. M. Kirsch, N C. Radu, E. Allaire, and D. Y Loisance Pathobiology of Idiopathic Ascending Aortic Aneurysms Asian Cardiovasc Thorac Ann, June 1, 2006; 14(3): 254 - 260. [Abstract] [Full Text] [PDF]
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P. W.M. Fedak, P. E. Szmitko, R. D. Weisel, S. M. Altamentova, N. Nili, N. Ohno, S. Verma, S. Fazel, B. H. Strauss, and R.-K. Li Cell transplantation preserves matrix homeostasis: A novel paracrine mechanism J. Thorac. Cardiovasc. Surg., November 1, 2005; 130(5): 1430 - 1439. [Abstract] [Full Text] [PDF]
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R. G. Seipelt, C. L. Backer, C. Mavroudis, V. Stellmach, M. Cornwell, I. M. Seipelt, F. A. Schoendube, and S. E. Crawford Local delivery of osteopontin attenuates vascular remodeling by altering matrix metalloproteinase-2 in a rabbit model of aortic injury J. Thorac. Cardiovasc. Surg., August 1, 2005; 130(2): 355 - 362. [Abstract] [Full Text] [PDF]
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M. Cotrufo, A. D. Corte, L. S. De Santo, C. Quarto, M. De Feo, G. Romano, C. Amarelli, M. Scardone, F. Di Meglio, G. Guerra, et al. Different patterns of extracellular matrix protein expression in the convexity and the concavity of the dilated aorta with bicuspid aortic valve: Preliminary results J. Thorac. Cardiovasc. Surg., August 1, 2005; 130(2): 504 - 511. [Abstract] [Full Text] [PDF]
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C. A. Warnes The Adult With Congenital Heart Disease: Born To Be Bad? J. Am. Coll. Cardiol., July 5, 2005; 46(1): 1 - 8. [Abstract] [Full Text] [PDF]
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S. Verma, P. E. Szmitko, P. W. M. Fedak, L. Errett, D. A. Latter, and T. E. David Can statin therapy alter the natural history of bicuspid aortic valves? Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2547 - H2549. [Full Text] [PDF]
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E. M. Isselbacher Thoracic and Abdominal Aortic Aneurysms Circulation, February 15, 2005; 111(6): 816 - 828. [Full Text] [PDF]
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S. H. Rahimtoola The year in valvular heart disease J. Am. Coll. Cardiol., January 4, 2005; 45(1): 111 - 122. [Full Text] [PDF]
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N. D. Desai, O. Merin, G. N. Cohen, J. Herman, S. Mobilos, J. Y. Sever, S. E. Fremes, B. S. Goldman, and G. T. Christakis Long-Term Results of Aortic Valve Replacement With the St. Jude Toronto Stentless Porcine Valve Ann. Thorac. Surg., December 1, 2004; 78(6): 2076 - 2083. [Abstract] [Full Text] [PDF]
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M. A. Borger, M. Preston, J. Ivanov, P. W.M. Fedak, P. Davierwala, S. Armstrong, and T. E. David Should the ascending aorta be replaced more frequently in patients with bicuspid aortic valve disease? J. Thorac. Cardiovasc. Surg., November 1, 2004; 128(5): 677 - 683. [Abstract] [Full Text] [PDF]
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E. Rabkin-Aikawa, M. Aikawa, M. Farber, J. R. Kratz, G. Garcia-Cardena, N. T. Kouchoukos, M. B. Mitchell, R. A. Jonas, and F. J. Schoen Clinical pulmonary autograft valves: Pathologic evidence of adaptive remodeling in the aortic site J. Thorac. Cardiovasc. Surg., October 1, 2004; 128(4): 552 - 561. [Abstract] [Full Text] [PDF]
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M. Massetti, S. Veron, E. Neri, O. Coffin, O. le Page, G. Babatasi, D. Buklas, D. Maiza, J. L. Gerard, and A. Khayat Long-term durability of resection and end-to-end anastomosis for ascending aortic aneurysms J. Thorac. Cardiovasc. Surg., May 1, 2004; 127(5): 1381 - 1387. [Abstract] [Full Text] [PDF]
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J. Boyum, E. K. Fellinger, J. D. Schmoker, L. Trombley, K. McPartland, F. P. Ittleman, and A. B. Howard Matrix metalloproteinase activity in thoracic aortic aneurysms associated with bicuspid and tricuspid aortic valves J. Thorac. Cardiovasc. Surg., March 1, 2004; 127(3): 686 - 691. [Abstract] [Full Text] [PDF]
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