What factor's overexpression contributes to aortic dilation in Marfan syndrome?

Transforming Growth Factor-β (TGF-β) Overexpression is the Primary Factor Contributing to Aortic Dilation in Marfan Syndrome

The dysregulation and overexpression of transforming growth factor-β (TGF-β) is the primary factor contributing to aortic dilation in Marfan syndrome, leading to progressive aortic enlargement and increased risk of dissection. 1, 2

Pathophysiological Mechanism

• Marfan syndrome is caused by mutations in the FBN1 gene on chromosome 15q21, which encodes fibrillin-1, a glycoprotein in the extracellular matrix 3
• Deficiency of fibrillin-1 leads to weakening of supportive tissues and dysregulation of TGF-β signaling 3
• This fibrillin deficiency affects microfibrils found at the periphery of elastic fibers, particularly in the medial layer of the ascending aorta 3
• The abnormal fibrillin-1 protein fails to properly sequester TGF-β, leading to its excessive activation and signaling 1, 4

Evidence for TGF-β's Role

• Higher plasma TGF-β levels in Marfan patients correlate with larger aortic root dimensions (r=0.26, p=0.027) and faster aortic root growth rates (r=0.42, p<0.001) 2
• Patients with TGF-β levels above 140 pg/ml have a 6.5 times higher risk of experiencing aortic complications compared to those with lower levels 2
• TGF-β levels are significantly higher in Marfan patients with aortic root dilatation (124 pg/ml) compared to those with normal aorta (10 pg/ml; p=8×10^-6) 5
• Mouse models of Marfan syndrome demonstrate that aortic root enlargement is caused by excessive TGF-β signaling 6

Therapeutic Implications

• Angiotensin II receptor blockers (ARBs) like losartan inhibit TGF-β activity and have shown promise in slowing aortic growth 6
• In a small cohort study, ARB therapy significantly reduced the rate of aortic root enlargement from 3.54±2.87 mm per year to 0.46±0.62 mm per year (p<0.001) 6
• Beta-blockers are recommended for all patients with aortic root dilation to reduce hemodynamic stress on the aortic wall, and may also reduce TGF-β activation 1, 4
• Clinical trials like the COMPARE study are investigating whether losartan treatment leads to clinically relevant decreases in aortic dilatation in adult Marfan patients 7

Clinical Monitoring

• Echocardiographic assessment should include measurements at the ring, sinus, sinotubular junction, and distal ascending aortic levels 3
• Annual echocardiograms are recommended for Marfan syndrome patients with stable aortic dimensions 1
• More frequent imaging (every 6 months) is recommended when aortic root exceeds 4.5 cm, growth rate exceeds 0.5 cm/year, or significant aortic regurgitation is present 1
• Complete imaging of the entire aorta every 2-3 years is necessary as other parts of the aorta may also become dilated 3, 1

Inflammatory Component

• Recent evidence suggests inflammation may also play a modifying role in Marfan syndrome progression 5
• Increased expression of inflammatory genes is associated with severity of aortic root dilatation 5
• Higher levels of Macrophage Colony Stimulating Factor (M-CSF) are found in patients with progressive aortic disease 5
• Increased numbers of CD4+ T-cells in the media (p=0.02) and CD8+ T-cells in the adventitia (p=0.003) are found in Marfan syndrome aortic tissue 5

Important Considerations

• While TGF-β is the primary factor, the rate of aortic dilation is heterogeneous and unpredictable among patients 3
• The risk of type A dissection increases with increasing aortic root diameter, but dissection may occasionally occur even with only mild aortic dilation 3
• Prophylactic aortic repair should be considered when diameter reaches 5.0-5.5 cm, or at smaller diameters (4.0 cm) for women contemplating pregnancy 1
• Earlier intervention is recommended for patients with rapid growth (approaching 1 cm/year) or progressive aortic regurgitation 1