Arterial complications in classical Ehlers-Danlos syndrome: a case series.

BACKGROUND: The Ehlers-Danlos syndromes (EDS) are a group of connective tissue disorders with several recognised types. Patients with a type of EDS have connective tissue abnormalities resulting in a varying degree of joint hypermobility, skin and vascular fragility and generalised tissue friability. Classical EDS (cEDS) typically occurs as a result of dominant pathogenic variants in COL5A1 or COL5A2. The cardinal features of cEDS are hyperextensible skin, atrophic scarring and joint hypermobility. Arterial complications are more characteristically a feature of vascular EDS although individual cases of arterial events in cEDS have been reported. METHODS: A cohort of 154 patients with a clinical diagnosis of cEDS from the UK was analysed. RESULTS: Seven patients (4.5%) with a diagnosis of cEDS (four pathogenic, one likely pathogenic and two variants of uncertain significance in COL5A1) who had experienced arterial complications were identified. Arterial complications mostly involved medium-sized vessels and also two abdominal aortic aneurysms. No unique clinical features were identified in this group of patients. CONCLUSION: There is a possible increased risk of arterial complications in patients with cEDS, although not well-defined. Clinicians need to be aware of this possibility when presented with a patient with an arterial complication and features of cEDS. Long-term management in families with cEDS and a vascular complication should be individually tailored to the patient's history and their family's history of vascular events.

Atypical COL3A1 variants (glutamic acid to lysine) cause vascular Ehlers-Danlos syndrome with a consistent phenotype of tissue fragility and skin hyperextensibility.

PURPOSE: The Ehlers-Danlos syndromes (EDS) are a group of rare inherited connective tissue disorders. Vascular EDS (vEDS) is caused by pathogenic variants in COL3A1, most frequently glycine substitutions. We describe the phenotype of the largest series of vEDS patients with glutamic acid to lysine substitutions (Glu>Lys) in COL3A1, which were all previously considered to be variants of unknown significance. METHODS: Clinical and molecular data for seven families with three different Glu>Lys substitutions in COL3A1 were analyzed. RESULTS: These Glu>Lys variants were reclassified from variants of unknown significance to either pathogenic or likely pathogenic in accordance with American College of Medical Genetics and Genomics guidelines. All individuals with these atypical variants exhibited skin hyperextensibility as seen in individuals with classical EDS and classical-like EDS and evidence of tissue fragility as seen in individuals with vEDS. CONCLUSION: The clinical data demonstrate the overlap between the different EDS subtypes and underline the importance of next-generation sequencing gene panel analysis. The three different Glu>Lys variants point toward a new variant type in COL3A1 causative of vEDS, which has consistent clinical features. This is important knowledge for COL3A1 variant interpretation. Further follow-up data are required to establish the severity of tissue fragility complications compared with patients with other recognized molecular causes of vEDS.

Use of Pulmonary Arterial Hypertension Therapies in Patients with a Fontan Circulation: Current Practice Across the United Kingdom.

Background The Fontan circulation is a successful operative strategy for abolishing cyanosis and chronic volume overload in patients with congenital heart disease with single ventricle physiology. "Fontan failure" is a major cause of poor quality of life and mortality in these patients. We assessed the number and clinical characteristics of adult patients with Fontan physiology receiving pulmonary arterial hypertension (PAH) therapies across specialist centers in the United Kingdom. Methods and Results We identified all adult patients with a Fontan-type circulation under active follow-up in 10 specialist congenital heart disease centers in England and Scotland between 2009 and 2019. Patients taking PAH therapies were matched to untreated patients. A survey of experts was also performed. Of 1538 patients with Fontan followed in specialist centers, only 76 (4.9%) received PAH therapies during follow-up. The vast majority (90.8%) were treated with a phosphodiesterase-5 inhibitor. In 33% of patients, PAH therapies were started after surgery or during hospital admission. In the matched cohort, treated patients were more likely to be significantly limited, have ascites, have a history of protein-losing enteropathy, or receive loop diuretics (P<0.0001 for all), also reflecting survey responses indicating that failing Fontan is an important treatment target. After a median of 12 months (11-15 months), functional class was more likely to improve in the treated group (P=0.01), with no other changes in clinical parameters or safety issues. Conclusions PAH therapies are used in adult patients with Fontan circulation followed in specialist centers, targeting individuals with advanced disease or complications. Follow-up suggests stabilization of the clinical status after 12 months of therapy.

Use of high intensity adjusted dose low molecular weight heparin in women with mechanical heart valves during pregnancy: a single-center experience.

The use of standard dose low molecular weight heparin (LMWH) to anticoagulate women with mechanical valves in pregnancy is associated with morbidity and mortality. We conducted a prospective audit of the use of adjusted dose high intensity LMWH in 12 pregnancies in 11 women with prosthetic heart valves. LMWH +/- low-dose aspirin was started at therapeutic-dose with monitoring of anti-Xa levels to achieve a target level of 1.0-1.2 IU/mL (0.8-1.2 in the first 3/12 pregnancies). This necessitated a mean increase in the dose of LMWH of 54.4% (SD+/-33.2) over initial dose. Eleven of 12 pregnancies resulted in live births, with one intrauterine fetal death at 37 weeks. One non-fatal valve thrombosis occurred at 26 weeks gestation associated with subtherapeutic anti-Xa levels. Three patients experienced major bleeding. This regime provides a therapeutic option for women with mechanical heart valves during pregnancy, provided anti-Xa levels are kept within the target range. These patients require close surveillance for bleeding and thrombotic complications within a multi-disciplinary setting.

Echocardiographic Screening for Pulmonary Hypertension in Congenital Heart Disease: JACC Review Topic of the Week.

Echocardiography is the mainstay in screening for pulmonary hypertension (PH). International guidelines suggest echocardiographic parameters for suspecting PH, but these may not apply to many adults with congenital heart disease (ACHD). PH is relatively common in ACHD patients and can significantly affect their exercise capacity, quality of life, and prognosis. Identification of patients who have developed PH and who may benefit from further investigations (including cardiac catheterization) and treatment is thus extremely important. A systematic review and survey of experts from the United Kingdom and Ireland were performed to assess current knowledge and practice on echocardiographic screening for PH in ACHD. This paper presents the findings of the review and expert statements on the optimal approaches when using echocardiography to assess ACHD patients for PH, with particular focus on major subgroups: patients with right ventricular outflow tract obstruction, patients with systemic right ventricles, patients with unrepaired univentricular circulation, and patients with tetralogy of Fallot with pulmonary atresia.

Why is post-partum haemorrhage more common in women with congenital heart disease?

OBJECTIVE: To identify the factors associated with an increased post-partum blood loss in women with congenital heart disease (CHD). METHODS: The study was a retrospective cohort study, which included 366 nulliparous women with CHD and a singleton pregnancy cared for in a single tertiary centre (Chelsea and Westminster Hospital) between 1994 and 2014. The women were classified into one of 12 different functional groups and univariate and multivariate regression analysis were used to identify factors associated with increased blood loss at delivery. RESULTS: The average volume of blood loss in women with CHD was twice that expected. Univariate analysis showed that White European women had the lowest blood loss. Women who had been on anticoagulants, had a forceps delivery, emergency Caesarean section or general anaesthesia lost more blood than those having a spontaneous vaginal birth under regional analgesia. Higher CARPREG scores were associated strongly with increased blood loss. Women with a Fontan circulation had the highest blood loss and the difference remained significant after correcting for other significant variables. CONCLUSIONS: Women with CHD are at increased risk of PPH. We have identified several potentially modifiable risk factors that may be targeted to reduce this risk. In addition, women with a Fontan circulation were most prone to PPH, independent of other risk factors, suggesting the existence of lesion-specific abnormalities and the need for extra vigilance in this group of women at the time of birth.

The management of the second stage of labour in women with cardiac: A mixed methods study.

OBJECTIVE: To examine the duration of the passive and active parts of the second stage (SS) of labour in women with cardiac disease (CD) and to assess the adherence to antenatal care plans regarding timing of assisted delivery. Cardiac parameters were measured in a subset of women to investigate any differences between the passive and active SS of labour. STUDY DESIGN: Cohort study of 73 women with CD, classified into mWHO Class Groups I-IV. Women were matched with an equal number of women controlling for gestational age, maternal age (+/- five years), parity, use of regional anaesthesia, and spontaneous versus assisted delivery. 12 of the 73 women with cardiac disease had cardiac parameters and oxygen saturations measured in the active and passive SS of labours. RESULTS: Length of passive SS was longer and the active component of the SS was significantly shorter in women with CD, because of a policy of elective assisted delivery. However, thirty four percent pushed for longer than was recommended. No adverse cardiac events were reported. Analysis of Holters showed no evidence of maternal arrhythmia in the active SS. Maternal heart rate increased at a modest but significant rate in the active SS. CONCLUSION: Compliance with antenatal recommendations was poor; prolonged pushing was not associated with an increase in cardiac events. A restrictive policy for the duration of the active SS of labour in women with CD is currently based entirely on expert opinion and more prospective studies are needed justify this policy. ETHICS APPROVAL: West London Regional Ethics Committee REC reference: 13/LO/0042.

A cohort study of women with a Fontan circulation undergoing preconception counselling.

OBJECTIVE: To describe outcomes for women with a Fontan circulation attending preconception counselling (PCC). Exploring (1) impact of counselling on decision to become pregnant; (2) pregnancy rates in those opting for pregnancy and (3) short-term and long-term outcome of those who succeeded in becoming pregnant. METHODS: Retrospective review of women aged 16-45 years with a Fontan circulation from 1994 to 2014. RESULTS: 58 women were offered PCC, 3 declined and 55 received PCC. Following PCC, 15 opted against conception, 16 decided to delay pregnancy, 19 attempted pregnancy and 5 were lost to follow-up. Of the 19 women, 14 succeeded, becoming pregnant a total of 43 times (median 1, range 1-9). Of these, 6 miscarried all pregnancies. 8 carried 14 pregnancies to viability. Baseline hypoxaemia and cardiac disease in pregnancy (CARPREG) score was similar in those opting for and against pregnancy, but CARPREG score was better in those delaying conception. Women exclusively miscarrying or unable to conceive were more likely to have baseline hypoxaemia and greater CARPREG score. Cardiac complications included arrhythmia requiring treatment (n = 4) and one thromboembolism. Obstetric complications were greater in women with a Fontan circulation, 10 preterm births (< 37 weeks) and 8 small for gestational age babies (< 10th centile). There was one neonatal death. At follow-up, there was no deterioration in clinical status as determined by echo. CONCLUSIONS: Most women accept PCC and decided to pursue pregnancy; in some cases, this was despite being advised of a poor prognosis. Pregnancy outcome was related to baseline hypoxia and CARPREG scores.