J Thorac Cardiovasc Surg 2006;131:254-255
© 2006 The American Association for Thoracic Surgery
Molecular changes occurring with aneurysm formation: Possible impact of sampling error
Stephen H. McKellar, MD,
Sami Takieddine, MD,
Ramanath Majumdar, PhD,
Thoralf M. Sundt, III, MD
Division of Cardiovascular Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905
To the Editor:
We congratulate Cotrufo and colleagues
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for exploring messenger RNA expression and extracellular matrix protein content in the ascending aorta associated with bicuspid aortic valves (BAVs), with particular attention to differences between the inner and outer curvatures. Our laboratory is also exploring the molecular changes occurring with aneurysm formation, and we have been concerned about the potential impact of sampling error on experimental results.
Cotrufo and colleagues
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demonstrated differences in levels of collagens I, III, and IV, as well as fibronectin and laminin protein, by western blot analysis when comparing samples taken from the concave and convex portions of dilated aortas resected from patients with BAV. Additionally, they reported differences between patients with functionally regurgitant versus stenotic valves. Importantly, Cotrufo and colleagues
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also reported significant differences in protein levels between dilated aortas (regardless of functional valve pathology) and normal control aortas. Indeed, these differences were as striking as those observed between concavity and convexity or between stenotic and regurgitant specimens.
We too are intrigued by the observations made on aneurysmal tissues, but we urge caution in interpreting the comparisons made between dilated aortas and the control group. A marked difference in age may have profoundly impacted results. Cotrufo and colleagues
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reported mean ages for the regurgitation, stenosis, and control groups as 56 ± 9, 59 ± 12, and 33 ± 8 years, respectively. The 95% confidence intervals for these groups (from data provided in the article's on-line Table E1
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) were 51.2-61.4, 50.9-66.4, and 24.6-41.4 years, respectively. The difference in collagen expression led Cotrufo and colleagues
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conclude that "collagen degradation by proteinases could prevail over collagen synthesis" and that smooth muscle cells "could react differently to different types and degrees of mechanical stress and could favor, in turn, a predominant production of either ECM [extracellular matrix] proteins or proteolytic enzymes." An alternative hypothesis is that age-related changes explain these differences. A proportional decrease in aortic collagen with advancing age has been previously described.
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In our laboratory, we have looked at messenger RNA expression in dilated aortas with microarray gene chip analysis. Looking at expression of tenascin, for example, we have found similar expressions in tissues from patients with aneurysms and older control subjects (mean ages 63.3 ± 6.4 years, 95% confidence interval 59.8-66.9 years, and 48.8 ± 4.9 years, 95% confidence interval 35.3-62.3 years, respectively). We too have struggled to obtain appropriately age-matched control tissue for obvious reasons; however, appreciation of these age-related changes may be crucial to understanding the pathophysiology and genetic basis of BAV and aortic aneurysms and should not be overlooked.
Again, Cotrufo and colleagues are to be commended for their comparative study of expression of extracellular matrix proteins within dilated aortas among patients with BAV. Their comparisons between regurgitant and stenotic BAV and between the concavity and convexity of dilated aortas are valuable contributions to the field and should be in the foreground of discussions, whereas the comparisons between patients with disease and control subjects should remain in the background.
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References
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- Cotrufo M, Della Corte A, De Santo LS, Quarto C, De Feo M, Romano G, et al. Different patterns of extracellular matrix protein expression in the convexity and concavity of the dilated aorta with bicuspid aortic valve. preliminary results. J Thorac Cardiovasc Surg 2005;130:504-511.[Abstract/Free Full Text]
- Cattell MA, Anderson JC, Hasleton PS. Age-related changes in amounts and concentrations of collagen and elastin in normotensive human thoracic aorta. Clin Chim Acta 1996;245:73-84.[Medline]
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