Author + information
- aDepartment of Cardiology, Ghent University Hospital, Ghent, Belgium
- bCenter for Medical Genetics, Ghent University Hospital, Ghent, Belgium
- ↵∗Address for correspondence:
Dr. Julie De Backer, Center for Medical Genetics, Ghent University Hospital, C. Heymanslaan 10, B-9000 Ghent, Belgium.
Of all hereditary connective tissue diseases, vascular Ehlers-Danlos Syndrome (vEDS) is pre-eminently the most feared—mainly due to the unpredictability in the occurrence of potentially serious/fatal vascular events such as arterial dissection or rupture. This rare condition is caused by pathogenic variants in the COL3A1 gene and affects the digestive system, the uterus, the skin, and the pulmonary system in addition to the vascular system (1).
The median life expectancy—based on several previous large-scale studies—is 48 to 51 years (2,3). The age of onset of vascular events shows a large variability, but a majority of the initial events occur in the second to third decade of life (4); however, especially in men, increased mortality in adolescence has been noted (3).
Heterozygosity for COL3A1 null alleles leading to haplo-insufficiency (which accounts for <5% of recognized pathogenic variants) may be associated with the onset of complications later in life (4).
The unpredictability of arterial events—which often occur in previously normal-sized blood vessels—has always called into question the usefulness of surveillance. Consequently, the approach across programs and institutions varies, ranging from no scheduled evaluations other than routine examination according to medical needs to regular follow-up with extended vascular imaging at fixed intervals. Equally related to the unpredictability, the criteria for acute or prophylactic intervention in vEDS have not been well established. Moreover, the outcome of surgery and vascular interventions performed in the acute setting in this fragile population is not good, and elective procedures have a higher complication rate than those without vEDS. This all results—whether or not justified—in a reluctance to intervene in these patients.
Finally, pharmacological intervention studies in this patient population are particularly scarce. One important study in this respect is the BBEST (Beta-Blockers in Ehlers-Danlos Syndrome Treatment) trial, (5) a multicenter, open-label, randomized study that suggested that treatment of individuals with vascular EDS with celiprolol extends the time to vascular complications compared with those not treated. Celiprolol is available in most European countries, but not in the United States or Canada. Whether the presumably beneficial effect of celiprolol in vEDS can be extrapolated to other beta-blockers is uncertain.
Beta-adrenoceptor antagonists (beta-blockers) overall have similar therapeutic effects. However, each particular β-adrenoceptor antagonist has a different specific pharmacokinetic profile related to its aromatic ring structure. Celiprolol is indicated for the management of mild to moderate hypertension and angina pectoris. It belongs to the third-generation β1-adrenoceptor antagonists having vasodilatory properties and neutral metabolic (lipid and carbohydrate metabolism) effects.
Celiprolol has a unique pharmacologic profile (6): it is a hydrophilic selective β1-adrenoceptor antagonist (reduced sympathoadrenal activity), a β2-adrenoceptor partial agonist (vasodilation), and a weak α2-adrenoceptor antagonist (increase of adrenergic, dopaminergic, and serotonergic neurotransmitters, and insulin secretion). Additionally, celiprolol may also exert β3-adrenoceptor agonistic activity (coronary vasorelaxation and stimulation of nitric oxide release). Celiprolol reduces systolic and diastolic blood pressure and mean arterial pressure. It gives less heart rate reduction compared with some other beta-blockers. There is no documented increased peripheral resistance and no depression of left ventricular function, or pulmonary function. The exact mechanism of the (purported) beneficial effect in vEDS is not fully understood—interaction via transforming growth factor beta inhibition or endothelial nitric oxide synthase activation has been postulated.
The BBEST study was subjected to criticism such as the open-label design, the insufficient sample size, and the fact it was prematurely terminated due to significant benefit with celiprolol in reducing arterial events in patients with this condition. However, the most important limitation of the BBEST study was that 30% of the patient population had no molecularly confirmed diagnosis, and this undermines the conclusion of this study.
The unpredictability of this genetic disease, questionable outcome of surveillance and interventions, and lack of large clinical studies inherent to vEDS put the disease in contrast with other hereditary connective tissue disorders such as Marfan syndrome. In Marfan syndrome, aortic diameter has an important predictive value toward dissection, and the outcome of elective surgery is good. Several large drug trials also took place, indicating a decrease in aortic growth rate in patients treated with beta-blockers and with losartan. This all resulted in the development of clear recommendations for (prophylactic) treatment and management of Marfan syndrome, which has led to a significant increase in life expectancy in the past 4 decades (7).
Although such a prospect for vEDS patients seems to be unlikely for the time being, a study in this issue of the Journal by Parisian researchers may provide a spark of hope (8). In their study, 144 patients (median age 34.5 years, 91 probands) were systematically monitored and treated in 1 of the largest reference centers for this disorder worldwide. Patients underwent regular controls with vascular imaging and the majority (90.3%) were also treated with celiprolol during follow-up. After a median follow-up of 5.3 years, the authors note a relatively high survival rate of 71.6%. Although the study design does not allow us to conclude that celiprolol influenced this outcome positively, the comparison between the treated and untreated group does show a significant difference in survival. This result must be interpreted cautiously, as the study design does not allow comparison, the group of patients who did not receive celiprolol was very small and heterogeneous, and we really do not know why these patients were not taking celiprolol because every patient was offered treatment with this drug. Also, a comparison of the number of hospitalizations for acute arterial events before and after 2011 (introduction of the organized follow-up and treatment protocol) shows a significant decrease. Again, the exact role of celiprolol in these findings is not known.
Additional interesting findings are that patients harboring variants leading to haplo insufficiency have a better prognosis, confirming earlier reports, and that there is a trend for higher mortality in younger men. A potential bias in this study is the fact that young patients (age <18 years) are not included, possibly indicating that early male deaths might not have been appreciated. The statement in this regard made by the authors—that there was a slight female predominance (60.4%), which was partly due to a nonsignificant excess of male deaths in the vEDS families—indicates that some extra caution and surveillance in the young male group may be warranted.
In comparison with the previous reports on prognosis in vEDS, this study also reflects the further evolution in diagnostics for this condition in which genetic testing plays a prominent role. Systematic cascade screening in first-degree relatives is now strongly recommended. In this sense, this cohort also has evolved (the cohort included 44.2% family members at the end vs. 25.9% before 2011) to better represent the current reality and potentially shows that the prognosis is not equally unfavorable for all patients.
We appreciate this report very much, especially because its main message is that patients with this rare disorder do benefit from a structured multidisciplinary follow-up in a strong reference center. Whether the systematic treatment with celiprolol has an additional genuine pharmacological beneficial effect or helps ensure better follow-up cannot be answered with this study. The only way to determine if it is celiprolol contributing to the better outcome is to conduct a randomized prospective trial comparing celiprolol to another beta-blocker in patients with molecularly confirmed vEDS.
Organizing this high-level multidisciplinary follow-up is challenging, and the French national plan for rare diseases should be praised and strongly considered as a model for all nations in which rare diseases are on the agenda for the organization of health care.
The selection of the patients and the uniform protocol in which all individuals were monitored by the same team also make this a very homogeneous population, resulting in limited bias regarding referral and interpretation of underlying results. The database built up with this research is of inestimable value and certainly deserves further support. Looking forward, we hope that expansion at the international level will be possible; in this respect, we are hopeful that the European Reference Network structure that has been set up will facilitate this.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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