Ehlers-Danlos syndrome arises from defects in type III collagen, causing skin hyperelasticity and fragility and joint hypermobility. Fatal complications, which occur at a median age of 40–50, can include mitral valve prolapse and spontaneous rupture of large- and medium-sized arteries. Although propranolol is known to lower rates of aortic dilatation and death in Marfan syndrome, the preventive role of beta-blockers in Ehlers-Danlos syndrome is unknown. Celiprolol, a β₁-adrenoceptor antagonist with partial β₂-adrenoceptor agonist action, has been used for hypertension in various countries since 1989 but is currently unavailable in the U.S. In an open-label trial with blinded assessment of clinical events, investigators in France and Belgium randomized 53 patients with clinical vascular Ehlers-Danlos syndrome (33 of whom had mutations of COL3A1) to celiprolol (uptitrated by 100 mg every 6 months to a maximum of 400 mg twice daily) or no beta-blocker treatment for 5 years. Most patients were normotensive at baseline. All but two celiprolol recipients achieved the maximum dosage.

After a mean follow-up of 47 months, the trial was stopped early because the rate of the primary endpoint, arterial rupture or dissection, was significantly lower in celiprolol recipients than in controls (20% vs. 50%; hazard ratio, 0.36; 95% confidence interval, 0.15–0.88). Blood pressure levels and heart rates did not differ significantly between the two groups. Only one patient discontinued celiprolol because of fatigue.

Comment: These findings suggest that celiprolol can prevent life-threatening complications of vascular Ehlers-Danlos syndrome. Although more data are needed to elucidate how celiprolol exerts its therapeutic effect independently of a hemodynamic effect, an editorialist notes that beta-blockers seem to suppress transforming growth factor β (TGFβ) expression, which might decrease matrix turnover and stabilize aneurysms in these patients. The possible role of other drugs that block TGFβ (e.g., angiotensin-receptor blockers) in vascular Ehlers-Danlos syndrome remains to be determined.

Published in Journal Watch Cardiology September 29, 2010