Current Evidence and Future Perspectives in the Medical Management of Vascular Ehlers-Danlos Syndrome: Focus on Vascular Prevention.

Vascular Ehlers-Danlos syndrome (vEDS) is a rare autosomal dominant connective tissue disease resulting from pathogenic variants in the collagen type III alpha 1 chain (COL3A1) gene, encoding type III procollagen. Patients with vEDS present with severe tissue fragility that can result in arterial aneurysm, dissection, or rupture, especially of medium-caliber vessels. Although early reports have indicated a very high mortality rate in affected patients, with an estimated median survival of around 50 years, recent times have seen a remarkable improvement in outcomes in this population. This shift could be related to greater awareness of the disease among patients and physicians, with improved management both in terms of follow-up and treatment of complications. Increasing use of drugs acting on the cardiovascular system may also have contributed to this improvement. In particular, celiprolol, a ß1 cardio-selective blocker with a ß2-agonist vasodilator effect, has been shown to reduce rates of vascular events in patients with vEDS. However, the evidence on the true benefits and possible mechanisms responsible for the protective effect of celiprolol in this specific setting remains limited. Drugs targeting the extracellular matrix organization and autophagy-lysosome pathways are currently under investigation and could play a role in the future. This narrative review aims to summarize current evidence and future perspectives on vEDS medical treatment, with a specific focus on vascular prevention.

Despite celiprolol therapy, patients with vascular Ehlers-Danlos syndrome remain at risk of vascular events: A 12-year experience in an Italian referral center.

BACKGROUND: Vascular Ehlers-Danlos syndrome (vEDS) is an inherited connective tissue disorder characterized by arterial fragility. Celiprolol has been suggested to significantly reduce rates of vascular events in this setting, though real-world evidence is limited. The aim of this study was to report our experience with celiprolol therapy in vEDS management. METHODS: Patients with a genetically confirmed diagnosis of vEDS who were referred for outpatient consultation at the Brescia University Hospital between January 2011 and July 2023 were included. At each visit, patients' medical history, results of vascular imaging, and office blood pressure measurements were recorded. Celiprolol therapy was progressively titrated to the maximum tolerated dose of up to 400 mg daily, according to the patients' tolerance. RESULTS: Overall, 26 patients were included. Female sex was prevalent (62%). Mean (SD) age was 37 (16) years. Follow-up duration was 72 (41) months. At the last follow-up visit, all patients were on celiprolol therapy, 80% of whom were taking the maximum recommended dose. The yearly risk of symptomatic vascular events was 8.8%, the majority of which occurred after reaching the maximum recommended dose of celiprolol. No significant predictor of symptomatic vascular events was identified among patients' clinical characteristics. CONCLUSION: In our cohort, rates of celiprolol use were high and the drug was well tolerated overall. Nonetheless, the risk of symptomatic vascular events remained nonnegligible. Future studies should identify reliable predictors of major adverse events and explore additional therapeutic strategies that could further lower the risk of life-threatening events in this population.

Improvement in Quality of Life Following Celiprolol Hydrochloride Administration in a Patient with Vascular Ehlers-Danlos Syndrome: A Case Report.

A 40-year-old female, who underwent transcatheter arterial embolization due to acute bleeding from an iliolumbar artery, was subsequently genetically diagnosed with vascular Ehlers-Danlos syndrome. She experienced chronic anemia for many years due to the easy bruising of her whole body. The bruising improved with oral administration of celiprolol hydrochloride. There were no cardiac or vascular events during the 7 years following the transcatheter arterial embolization. Vascular Ehlers-Danlos syndrome requires specialized treatment that is scientifically proven to prevent a major vascular event. Proactive genetic diagnosis is recommended in patients suspected of having vascular Ehlers-Danlos syndrome after careful patient interview.

Cardiovascular manifestations of type IV Ehlers-Danlos syndrome - A case report.

Type IV Ehlers-Danlos syndrome (vascular) is a rare connective tissue disease caused by COL3A1 gene mutation on type III collagen. Clinical presentation is related to vascular fragility and risk of rupture of the arterial wall. Definite diagnosis is given by genetic study and the approach to these patients requires a multidisciplinary team and effective blood pressure control. There is currently only one medication with potential benefit in prevention of cardiovascular events: celiprolol. This article describes the case of a 41-year-old female patient, diagnosed with vascular Ehlers-Danlos syndrome after multiple major cardiovascular events: aortic, coronary and carotid dissections and venous and arterial thrombosis. These required multiple surgical interventions and long-term admission in intensive care units leading to complete functional recovery. This case report seeks to stress the need for an early diagnosis to prevent the severe cardiovascular complications of this rare syndrome.

Characterization of degradation products of celiprolol hydrochloride using hyphenated mass and NMR techniques.

Stress degradation studies were carried out on celiprolol hydrochloride under the ICH prescribed hydrolysis (acidic, basic and neutral), photolytic, oxidative and thermal conditions. Maximum degradation was observed upon hydrolysis, especially in the basic condition. In oxidative condition, the drug degraded only upon severe exposure to H2O2, but it remained stable when challenged with AIBN. It also degraded significantly under photolytic conditions. However, the drug was stable to thermal stress. A total of seven degradation products were formed, whose separation was successfully achieved on an Inertsil ODS-3V C-18 HPLC column employing a gradient mobile phase. A comprehensive mass fragmentation pattern of the drug was initially established through the support of high resolution mass spectrometry (HR-MS), multi-stage tandem mass spectrometry (MSn) and on-line H/D exchange MS data. The same approach was then extended to characterization of the degradation products. Additionally, two degradation products were isolated and subjected to 1D/2D NMR studies for their structural confirmation. One of the degradation products showed instability during isolation, therefore, it was subjected to LC-NMR studies for its structural confirmation.

Celiprolol Treatment in Patients with Vascular Ehlers-Danlos Syndrome.

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 2011-2019. The median follow up was 22 months (range 1-98 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 = 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.

An old drug for a rare disease: The example of celiprolol for vascular Ehlers-Danlos syndrome.

Vascular Ehlers-Danlos syndrome (OMIM 130050, 1/150,000 birth) is caused by mutations in collagen 3A1 gene. It is associated with severe phenotype associating early arterial dissection and rupture, digestive and uterine perforations, and skin and joints fragility. Until recently, no treatment was available. Celiprolol, a beta1 antagonist with beta2 partial antagonist properties betablocker was tested in a randomized, controlled trial. We could show that this compound was associated with a 3-fold decrease in major events related to the disease. This effect was similar in molecular-proven patients. Administration of celiprolol in a cohort of patients followed routinely in France was accompanied to similar benefit. Celiprolol is unavailable in the USA. The ACER Therapeutics company applied for new drug application (NDA) to the Food and Drug Administration.

Vascular Ehlers-Danlos Syndrome: Long-Term Observational Study.

BACKGROUND: Vascular Ehlers-Danlos syndrome (vEDS) is a rare genetic connective tissue disorder secondary to pathogenic variants within the COL3A1 gene, resulting in exceptional arterial and organ fragility and premature death. The only published clinical trial to date demonstrated the benefit of celiprolol on arterial morbimortality. OBJECTIVES: The authors herein describe the outcomes of a large cohort of vEDS patients followed ≤17 years in a single national referral center. METHODS: All patients with molecularly confirmed vEDS were included in a retrospective cohort study. After an initial work-up, patients were treated or recommended for treatment with celiprolol (≤400 mg/day) in addition to usual care and scheduled for yearly follow-up. vEDS-related events and deaths were collected and recorded for each patient. RESULTS: Between 2000 and 2017, 144 patients (median age at diagnosis 34.5 years, 91 probands) were included in this study. After a median follow-up of 5.3 years, overall patient survival was high (71.6%; 95% confidence interval: 50% to 90%) and dependent on the type of COL3A1 variant, age at diagnosis, and medical treatment. At the end of the study period, almost all patients (90.3%) were treated with celiprolol alone or in combination. More than two-thirds of patients remained clinically silent, despite a large number (51%) with previous arterial events or arterial lesions at molecular diagnosis. Patients treated with celiprolol had a better survival than others (p = 0.0004). The observed reduction in mortality was dose-dependent: the best protection was observed at the dose of 400 mg/day versus <400 mg/day (p = 0.003). During the period surveyed, the authors observed a statistically significant difference in the ratio of hospitalizations for acute arterial events/hospitalizations for regular follow-up before and after 2011. CONCLUSIONS: In this long-term survey, vEDS patients exhibited a low annual occurrence of arterial complications and a high survival rate, on which the overall medical care seems to have a positive influence.

[Rare syndromes in intensive care medicine : Presentation of two cases]. / Seltene Syndrome auf der Intensivstation : Vorstellung zweier Fälle.

This article presents two cases of young women with spontaneous life-threatening bleeding events. Both had a history of gastrointestinal rupture or arterial dissection. Based on their medical history and genetic testing, Ehlers-Danlos syndrome (EDS) IV (vascular type) was diagnosed. In this very rare disorder which accounts for only 5 % of all EDS cases, fibroblasts synthesize reduced and abnormal procollagen type III. This is caused by mutations in the COL3A1 gene coding for type III procollagen. Life expectancy in these patients is significantly reduced. In many cases spontaneous arterial ruptures or dissections and organ ruptures are the first manifestations of this disease. More than 80 % of patients with EDS IV suffer from a severe complication before 40 years of age. Treatment options are very limited. Most important is to avoid invasive procedures (open surgery as well as endovascular interventions) because of its high morbidity and mortality. Celiprolol, a cardioselective ß­blocker, seems to have a beneficial effect by reducing the incidence of vascular complications.

New Insight into Effects of ß-Blockers on Arterial Functions.

The effects of ß-blockers on arterial properties are not well investigated. In our recent study, we compared the effects of the two ß-blockers celiprolol and bisoprolol on blood pressure, baroreflex sensitivity (BRS), flow-mediated vasodilatation, and vascular stiffness. We found that bisoprolol achieved a greater reduction in the pulse rate and improved BRS and vascular stiffness, whereas celiprolol reduced the central blood pressure level. In this review, the mechanisms of different types of ß-blockers and their effects on arteries are discussed, and the appropriate use of ß-blockers in hypertensive subjects will be proposed.

Effects of Celiprolol and Bisoprolol on Blood Pressure, Vascular Stiffness, and Baroreflex Sensitivity.

BACKGROUND: We tested the hypothesis that celiprolol and bisoprolol have differential effects on blood pressure (BP), flow-mediated dilation (FMD), and vascular stiffness. METHODS: We analyzed 102 hypertensives (mean age: 59±14 years) who were being treated other than beta-blockers. They were randomized to receive add-on treatment with either celiprolol 100-200mg (C group) or bisoprolol 2.5-5mg (B group), and followed up for 3 months. In addition to clinic, home, and ambulatory BP monitoring, the FMD, radial augmentation index (AI), brachial-ankle pulse wave velocity (baPWV), urine albumin-to-creatinine ratio, and baroreflex sensitivity (BRS) were measured at baseline and at the end of the study. RESULTS: Compared to the baseline values, home and 24-hour BP were significantly lowered in the third month in both groups (all Ps < 0.05). Pulse rate (PR) and baPWV were reduced (P < 0.001), and BRS was increased significantly only in the B group (P = 0.02). Radial AI was unchanged in the C group but was significantly increased in the B group (P < 0.001). Central BP was significantly reduced in the C group (P = 0.003) but was unchanged in the B group. FMD was significantly increased in both groups (both P < 0.01). CONCLUSION: Bisoprolol achieved the greater reduction of PR and improved BRS and vascular stiffness, whereas, celiprolol reduced the central BP level. In treated hypertensive patients, add-on use of celiprolol may be favorable in uncomplicated stage of hypertension. On the other hand, bisoprolol may be useful in hypertensives with cardiac or vascular diseases who have advanced atherosclerotic changes and sympathetic nervous system activation.

The effects of celiprolol on serum concentrations of proinflammatory cytokines in hypertensive (SHR) and normotensive (WKY) rats.

BACKGROUND: A growing body of evidence suggests that some cardiovascular drugs could modulate the level of proinflammatory cytokines. Therefore, the aim of the present study was to investigate whether celiprolol, a third generation ß-adrenoceptor blocker, affects lipopolysaccharide (LPS)-induced serum concentrations of TNF-α, IL-1ß, IL-6 in normotensive (WKY) and spontaneously hypertensive (SHR) rats. METHODS: Celiprolol (150 mgkg(-1)) or vehicle was administered by gavage once daily for 21 days. Arterial blood pressure was measured in conscious rats, using the tail-cuff method. Serum concentrations of proinflammatory cytokines were measured with enzyme-linked immunosorbent assay kits. Additionally, plasma concentrations of total cholesterol, HDL-cholesterol and triglycerides were evaluated. RESULTS: In normotensive WKY rats celiprolol did not affect heart rate, blood pressure, or the serum concentrations of triglycerides, total cholesterol or HDL-cholesterol. In hypertensive animals the drug decreased lipid parameters, increased diastolic and mean blood pressure after the first week of administration, and produced a small but significant decrease in heart rate after the first two weeks of the treatment. In both groups of animals, celiprolol decreased LPS-stimulated serum concentration of IL-6 but did not affect levels of TNF-α and IL-1ß. CONCLUSIONS: It is suggested that the IL-6-modulating properties of celiprolol could provide additional value to the therapeutic effectiveness of the drug in the treatment of hypertension.