Celiprolol Treatment in Patients with Vascular Ehlers-Danlos Syndrome

Abstract

WHAT THIS PAPER ADDS The French/Belgian Beta blockers in Ehlers-Danlos Syndrome Treatment (BBEST) trial reported in 2010 that the number of serious/fatal vascular events could be halved by treating patients with vascular Ehlers-Danlos syndrome with celiprolol. Prior to that publication, no evidence based treatment could be offered to patients or their relatives carrying the same pathogenic variant of the procollagen 3A1 gene. This disease is rare, explaining why this is the second largest cohort published on celiprolol treatment. Although treatment is well tolerated in most cases, it is important to know more about the side effects, to enable the treatment of the highest number of patients, if possible, with the full dosage (400 mg daily). Objective: Vascular Ehlers-Danlos syndrome (vEDS) is a rare monogenetic disease caused by pathogenic variants in procollagen 3A1. Arterial rupture is the most serious clinical manifestation. A randomised controlled trial, the Beta-Blockers in Ehlers-Danlos Syndrome Treatment (BBEST) trial, reported a significant protective effect of the beta blocker celiprolol. The aim was to study the outcome of celiprolol treatment in a cohort of Swedish patients with vEDS. Methods: Uppsala is a national referral centre for patients with vEDS. They are assessed by vascular surgeons, angiologists, and clinical geneticists. Family history, previous and future clinical events, medication, and side effects are registered. Celiprolol was administered twice daily and titrated up to a maximum dose of 400 mg daily. Logistic regression was used to analyse predictors of vascular events. Results: Forty patients with pathogenic sequence variants in COL3A1 were offered treatment with celiprolol in the period 2011e2019. The median follow up was 22 months (range 1e98 months); total follow up was 106 patient years. In two patients, uptitration of the dose is ongoing. Of the remaining 38, 26 (65%) patients reached the target dose of 400 mg daily. Dose uptitration was unsuccessful in six patients because of side effects; one died before reaching the maximum dose, and five terminated the treatment. Five major vascular events occurred; four were fatal (ruptured ascending aorta; aortic rupture after type B dissection; ruptured cerebral aneurysm; and ruptured pulmonary artery). One bled from a branch of the internal iliac artery, which was successfully coiled endovascularly. The annual risk of a major vascular event was 4.7% (n ¼ 5/106), similar to the treatment arm of the BBEST trial (5%) and lower than in the control arm of the same trial (12%). No significant predictor of vascular events was identified. Conclusion: Treatment with celiprolol is tolerated in most patients with vEDS. Despite fatal vascular events, these observations suggest that celiprolol may have a protective effect in vEDS.

Comparative therapeutic strategies for preventing aortic rupture in a mouse model of vascular Ehlers-Danlos syndrome

“…Patients suffering from vEDS have a life expectancy mainly reduced by the occurrence of unpredictable arterial rupture in young adulthood. Despite randomized open clinical trial [ 10 ] and cohorts surveys [ 11 , 27 ] data, there is no consensus on a continuous medical therapy that could prevent that risk [ 2 , 28 ]. In such a rare disease, the development of pre-clinical models is particularly useful to test different therapies and better understand the consequences of the disease at the cellular and tissue levels.…”

“…In vEDS, only celiprolol has been rigorously tested [37] showing a significant benefit on cardiovascular mortality and morbidity on a limited number of molecularly-proven patients [10]. Its good tolerance and beneficial effects were also shown in a French cohort with long-term survey (9 years) [11], and a 2-year follow-up of 40 Swedish patients [27]. The significance of these results being disputed, we tested both propranolol, the oldest non-selective βblocker generally used in experimental studies, and celiprolol (at therapeutic plasma concentration).…”

Spontaneous Coronary Artery Dissection and Papillary Muscle Rupture in Patient With Undiagnosed Vascular Ehler-Danlos Syndrome

“…There is no established medical treatment in vEDS, but studies have suggested that treatment with celiprolol, a cardioselective β1 blocker with a vasodilatory effect, may reduce the frequency of arterial events. 5 The patient had no relatives with known vEDS, but approximately 50% of all patients have a de novo mutation, making it possible that she was the first in her family with vEDS.…”

Comparative therapeutic strategies for preventing aortic rupture in a mouse model of vascular Ehlers Danlos syndrome

“…Patients suffering from vEDS have a life expectancy mainly reduced by the occurrence of unpredictable arterial rupture in young adulthood. Despite randomized open clinical trial (9) and cohorts surveys (11,27) data, there is no consensus on a continuous medical therapy that could prevent that risk (2) (28). In such a rare disease, the development of pre-clinical models is particularly useful to test different therapies and better understand the consequences of the disease at the cellular and tissue levels.…”

“…Its good tolerance and beneficial effects were also shown in a French cohort with long-term survey (9 years) (10), and a 2-year follow-up of 40 Swedish patients. (27) The significance of these results being disputed, we tested both propranolol, the oldest non-selective β-blocker generally used in experimental studies, and celiprolol (at therapeutic plasma concentration). Both β-blockers had no beneficial effect on Col3a1 +/G182R mice survival.…”