A role for plasma transforming growth factor-beta and matrix metalloproteinases in aortic aneurysm surveillance in Marfan syndrome?
BACKGROUND
We have previously shown that the angiotensin-converting enzyme (ACE) inhibitor perindopril reduced aortic diameter by 3-7mm in Marfan syndrome (MFS) patients. Excessive signalling by the transforming growth factor-beta (TGF-beta) has been implicated in the development of aortic dilatation. We hypothesised that reduction in aortic diameter would correlate with reduction in plasma TGF-beta and matrix metalloproteinase (MMP) levels.


METHODS
17 MFS patients (aged 33+/-5 (mean+/-SD)) on standard beta-blocker therapy were randomised to also receive perindopril (n=10) or placebo (n=7) for 24 weeks in a double blind study. Aortic root diameters were assessed at four sites via transthoracic echocardiography. Venous blood samples were analysed for latent and active TGF-beta, MMP-2 and MMP-3 levels.


RESULTS
Perindopril significantly reduced aortic root diameters relative to placebo in both end-systole and end-diastole (by 1.2-3mm/m(2), p<0.001). In addition, compared to placebo perindopril significantly reduced latent TGF-beta levels by 14.0+/-4.5ng/ml (p=0.01), active TGF-beta levels by 4+/-1ng/ml (p=0.02), MMP-2 levels by 22+/-6ng/ml (p<0.001), and MMP-3 levels by 5+/-1ng/ml (p<0.001). There were moderately strong correlations between the pre/post intervention change in aortic diameters and the change in both latent (r=0.49-0.76, p=0.001-0.04) and active TGF-beta (r=0.59-0.73, p=0.002-0.02), MMP-2 (r=0.63-0.75, p=0.001-0.007), and MMP-3 plasma levels (r=0.81-0.83, p<0.0001).


CONCLUSIONS
Plasma TGF-beta, MMP-2 and MMP-3 should be further explored in longitudinal trials as potential prognostic indicators of progression of aortic dilatation and response to therapy in MFS.
Ahimastos
Anna A
AA
Alfred and Baker Medical Unit, Baker IDI Heart and Diabetes Research Institute, Melbourne, Australia. A.Ahimastos@alfred.org.au
Aggarwal
Anuradha
A
Savarirayan
Ravi
R
Dart
Anthony M
AM
Kingwell
Bronwyn A
BA
D000328:Adult; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D001014:Aortic Aneurysm / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D015415:Biomarkers / Q000097:blood; D005260:Female; D006801:Humans; D008297:Male; D008382:Marfan Syndrome / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D020778:Matrix Metalloproteinase 2 / Q000097:blood*; D019278:Matrix Metalloproteinase 3 / Q000097:blood*; D061965:Matrix Metalloproteinase Inhibitors; D020913:Perindopril / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000097:blood*
D000806:Angiotensin-Converting Enzyme Inhibitors; D015415:Biomarkers; D061965:Matrix Metalloproteinase Inhibitors; D016212:Transforming Growth Factor beta; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020913:Perindopril