Expression of Matrix Metalloproteinases and Endogenous Inhibitors Within Ascending Aortic Aneurysms of Patients With Marfan Syndrome

Q: What are the key findings of this study?

Ascending thoracic aortic aneurysms in Marfan syndrome exhibited distinct matrix remodeling profiles and increased TGFBR2 expression (193% vs 95%, P<0.05) compared with non-Marfan patients.

Q: What is the clinical evidence from this study?

Study design: Observational. Population: Ascending thoracic aortic aneurysms in Marfan syndrome (n=45). Intervention: Marfan syndrome vs. Non-Marfan syndrome patients and controls without aneurysms. Primary outcome: MMP, TIMP, and TGF-beta receptor expression levels (p=<0.05).

Q: What does this research mean for the field?

Ascending thoracic aortic aneurysms in Marfan syndrome exhibit distinct matrix remodeling profiles and elevated TGFBR2 expression compared with non-Marfan aneurysms. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

To evaluate and compare matrix metalloproteinase, tissue inhibitor of metalloproteinase, and TGF-beta signaling profiles in ascending thoracic aortic aneurysms between patients with and without Marfan syndrome.

John S. Ikonomidis; Jeffrey A. Jones; John Richard Barbour; Robert E. Stroud; Leslie L. Clark; Brooke S. Kaplan; Ahmed Zeeshan; Joseph E. Bavaria; Joseph H. Gorman; Francis G. Spinale; Robert C. Gorman

doi:10.1161/circulationaha.105.000810

July 4, 2006Circulation

Expression of Matrix Metalloproteinases and Endogenous Inhibitors Within Ascending Aortic Aneurysms of Patients With Marfan Syndrome

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Key result

Marfan thoracic aortic aneurysms show distinct matrix remodeling with ~2-fold higher TGFBR2 expression vs non-Marfan.

P<0.05
n=45

Why the study?

Whether and to what degree MMP, TIMP, and TGF-beta signaling profiles are altered in ascending thoracic aortic aneurysms in Marfan syndrome compared with non-Marfan patients remains unknown.

Key Points

To evaluate and compare matrix metalloproteinase, tissue inhibitor of metalloproteinase, and TGF-beta signaling profiles in ascending thoracic aortic aneurysms between patients with and without Marfan syndrome.
Obtained ascending thoracic aortic aneurysm specimens during surgical aortic replacement from age-matched patients with Marfan syndrome (n=9) and without Marfan syndrome (n=18).
Measured tissue expression of representative matrix metalloproteinases (MMPs), all four tissue inhibitors of metalloproteinases (TIMPs), and type 2 TGF-beta receptors (TGFBR2), normalized as a percentage of non-aneurysmal control tissues (n=18).
Marfan syndrome aneurysms demonstrated increased MT1-MMP (248±64% vs 91±21% in non-Marfan and controls; P<0.05), increased MMP-12 (161±27% vs control; P<0.05), reduced MMP-2 (76±7% vs control; P<0.05), reduced TIMP-3 (74±23% vs control; P<0.05), and elevated TIMP-2 (128±31% vs 73±19% in non-Marfan; P<0.05).
Non-Marfan aneurysms showed significant decreases relative to controls in MMP-1 (70±16%), MMP-3 (77±18%), MMP-8 (75±11%), MMP-9 (69±14%), MMP-12 (85±15%), and TIMPs 1 through 3 (all P<0.05).
TGFBR2 expression was significantly elevated in Marfan syndrome aneurysms (193±32%) compared to non-Marfan aneurysms (95±16%) and healthy controls (P<0.05).

Study Design

Type

Observational (n=45)

Structured PICO

P

Population

45 patients, including 9 with Marfan syndrome and 18 non-Marfan patients with ascending thoracic aortic aneurysms undergoing aortic replacement, plus 18 reference controls.

O

Outcome

Expression levels of representative subtypes of all Matrix Metalloproteinase (MMP) classes, all 4 known Tissue Inhibitors of Metalloproteinases (TIMPs), and type 2 TGF-beta receptors (TGFBR2)surrogate

Main Result

p-value: p=<0.05

Aneurysms in patients with Marfan syndrome display a unique molecular profile of extracellular matrix remodeling markers and TGF-beta signaling compared to non-Marfan patients.

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Implication

Marfan aneurysms show distinct MMP/TIMP/TGFBR2 profiles; hypothesis-generating for syndrome-specific mechanisms, does not yet inform management.

Abstract

BACKGROUND: Marfan syndrome (MFS) is known to cause ascending thoracic aortic aneurysms (ATAAs). Transforming growth factor beta (TGF-beta) has recently been implicated in this process. Imbalances between the matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) have also been shown to contribute to aneurysm formation. Whether and to what degree MMP, TIMP, and TGF-beta signaling profiles are altered in ATAAs in MFS compared with non-MFS patients remains unknown. METHODS AND RESULTS: ATAA samples taken during aortic replacement from age-matched MFS (n=9) and non-MFS (n=18) patients were assessed for representative subtypes of all MMP classes, all 4 known TIMPs, and type 2 TGF-beta receptors (TGFBR2). Results were expressed as a percentage (mean+/-SEM) of reference control samples (100%; n=18) obtained from patients without ATAA. In MFS, decreased MMP-2 (76+/-7; P<0.05 versus control), increased MMP-12 (161+/-27% versus control; P<0.05), and increased MT1-MMP (248+/-64% versus 91+/-21 non-MFS and control; P<0.05) were observed. TIMP-3 (74+/-23%) was reduced compared with control values (P<0.05) and TIMP-2 was elevated (128+/-31%) compared with non-MFS (73+/-19%; P<0.05). In non-MFS samples, MMP-1 (70+/-16%), MMP-3 (77+/-18%), MMP-8 (75+/-11%), MMP-9 (69+/-14%), and MMP-12 (85+/-15%) were decreased compared with control (P<0.05). TIMPs 1 to 3 were reduced in non-MFS compared with control values (P<0.05). TGFBR2 were increased in MFS (193+/-32%) compared with non-MFS (95+/-16%) and controls (P<0.05). CONCLUSIONS: A unique MMP and TIMP portfolio was observed in ATAAs from MFS compared with non-MFS patients. In addition, MFS samples showed evidence of increased TGF-beta signaling. These differences suggest disparate mechanisms of extracellular matrix remodeling between these 2 groups of patients.

Discussion

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Cite This Study

Ikonomidis et al. (2006) conducted an observational in Ascending thoracic aortic aneurysms in Marfan syndrome (n=45). Marfan syndrome vs. Non-Marfan syndrome patients and controls without aneurysms was evaluated on MMP, TIMP, and TGF-beta receptor expression levels (p=<0.05). Ascending thoracic aortic aneurysms in Marfan syndrome exhibited distinct matrix remodeling profiles and increased TGFBR2 expression (193% vs 95%, P<0.05) compared with non-Marfan patients.

synapsesocial.com/papers/6acf14fde9cf455829e373c5 https://doi.org/10.1161/circulationaha.105.000810

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Expression of Matrix Metalloproteinases and Endogenous Inhibitors Within Ascending Aortic Aneurysms of Patients With Marfan Syndrome

Key Points

Study Design

Structured PICO

Main Result

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Expression of Matrix Metalloproteinases and Endogenous Inhibitors Within Ascending Aortic Aneurysms of Patients With Marfan Syndrome

Key Points

Study Design

Structured PICO

Main Result

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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