Aortic risk according to aortic diameter in patients with thoracic aortic aneurysm associated with pathogenic variants in TGFBR1, TGFBR2, and SMAD3

Background/Introduction

Aortic root surgery can effectively prevent type A aortic dissection but is associated with procedural risk. Accurate estimation of dissection risk according to aortic root diameter is therefore essential to optimize the timing of preventive surgery. However, limited data are available to determine event rates according to aortic root size in patients with rare genetic disorders affecting the TGF-β signaling pathway.

Purpose

To evaluate the risk of aortic events according to aortic root diameter in patients carrying pathogenic variants in TGF-β pathway genes.

Methods

We included consecutive patients carrying pathogenic variants in TGFBR1, TGFBR2, or SMAD3 who were evaluated and followed at our center between 1995 and 2022. Patients who had experienced aortic dissection or undergone aortic root surgery prior to their first visit were excluded. All patients received beta-blocker therapy; angiotensin receptor blockers were added in cases of aortic dilatation or intolerance to beta-blockers.

Patients were evaluated every three years. Aortic events occurring within three years after the last clinical visit were included in the risk analysis. Annual risks of aortic dissection and preventive aortic root surgery were calculated according to aortic root diameter categories (0–39 mm; 40–44 mm; 45–49 mm; 50–54 mm; ≥55 mm).

Results

Among more than 3,000 patients referred for evaluation of aortic disease, 375 carried a pathogenic variant in TGFBR1, TGFBR2, or SMAD3. Of these, 133 had experienced aortic dissection or undergone preventive surgery before their first visit and were excluded; 10 were lost to follow-up.

A total of 232 patients, representing 866 consultations and 1,599.7 patient-years of follow-up. Pathogenic variants were : TGFBR1 (n=66), TGFBR2 (n=82), and SMAD3 (n=84). Mean age at first visit was 29.5±18.2 years, and 48.7% were male.

Three type A aortic dissections occurred during follow-up: in a 27-year-old woman with a TGFBR1 variant at an aortic root diameter of 45 mm (bicuspid aortic valve). Two in patients with TGFBR2 variants: a 34-year-old woman at 59 mm, and a 15-year-old boy (Arg528 variant) at 40 mm (bicuspid aortic valve). No dissections occurred in patients with SMAD3 variants.

The annual risks of aortic dissection and preventive aortic root surgery are presented in Table 1.

Conclusion

Contemporary management of patients with pathogenic variants in TGF-β pathway genes is associated with a low incidence of aortic dissection at diameters below 45-50 mm. However, limited patient numbers preclude reliable risk estimation for diameters ≥50 mm. The rate of preventive aortic root surgery increases substantially with increasing aortic root diameter, reflecting proactive surgical management in this high-risk population.For image description, please refer to the figure legend and surrounding text.