B. J. M. Mulder

Mutations in the sarcomere gene MYH7 in Ebstein anomaly

Background—Ebstein anomaly is a rare congenital heart malformation characterized by adherence of the septal and posterior leaflets of the tricuspid valve to the underlying myocardium. An association between Ebstein anomaly with left ventricular noncompaction (LVNC) and mutations in MYH7 encoding &bgr;-myosin heavy chain has been shown; in this report, we have screened for MYH7 mutations in a cohort of probands with Ebstein anomaly in a large population-based study. Methods and Results—Mutational analysis in a cohort of 141 unrelated probands with Ebstein anomaly was performed by next-generation sequencing and direct DNA sequencing of MYH7. Heterozygous mutations were identified in 8 of 141 samples (6%). Seven distinct mutations were found; 5 were novel and 2 were known to cause hypertrophic cardiomyopathy. All mutations except for 1 3-bp deletion were missense mutations; 1 was a de novo change. Mutation-positive probands and family members showed various congenital heart malformations as well as LVNC. Among 8 mutation-positive probands, 6 had LVNC, whereas among 133 mutation-negative probands, none had LVNC. The frequency of MYH7 mutations was significantly different between probands with and without LVNC accompanying Ebstein anomaly (P<0.0001). LVNC segregated with the MYH7 mutation in the pedigrees of 3 of the probands, 1 of which also included another individual with Ebstein anomaly. Conclusions—Ebstein anomaly is a congenital heart malformation that is associated with mutations in MYH7. MYH7 mutations are predominantly found in Ebstein anomaly associated with LVNC and may warrant genetic testing and family evaluation in this subset of patients.

Epidemiology of adult congenital heart disease: demographic variations worldwide

The population of adults with a congenital heart defect (CHD) is increasing, due to improved survival after cardiac surgery. To accommodate the specialised care for these patients, a profound interest in the epidemiology of CHD is required. The exact size of the current population of adults with CHD is unknown, but the best available evidence suggests that currently overall prevalence of CHD in the adult population is about 3000 per million. Regional differences in CHD prevalence have been described, due to both variations in incidence and in mortality. Knowledge of demographic variations of CHD may lead to new aetiological insights and may be useful for preventive therapies. Socioeconomic status, education, urbanisation, climatological factors, ethnicity and patient-related factors, such as comorbidity, lifestyle and healthcare-seeking behaviour, may play a role in CHD incidence and mortality. The higher risk of several major cardiac outcomes in males with CHD might well explain at least partly the increased mortality rate in men. Regional differences in quality of life among CHD patients have been reported and although methodological differences may play a role, sociocultural differences warrant further attention. Socioeconomic outcomes in CHD patients, such as lower education, more unemployment and less relationships, might have a different impact on quality of life in different cultures. To gain more insight into demographic differences around the world large international multicentre studies on the epidemiology of CHD are needed.

The ambiguous role of NKX2-5 mutations in thyroid dysgenesis.

NKX2-5 is a homeodomain-containing transcription factor implied in both heart and thyroid development. Numerous mutations in NKX2-5 have been reported in individuals with congenital heart disease (CHD), but recently a select few have been associated with thyroid dysgenesis, among which the p.A119S variation. We sequenced NKX2-5 in 303 sporadic CHD patients and 38 families with at least two individuals with CHD. The p.A119S variation was identified in two unrelated patients: one was found in the proband of a family with four affected individuals with CHD and the other in a sporadic CHD patient. Clinical evaluation of heart and thyroid showed that the mutation did not segregate with CHD in the familial case, nor did any of the seven mutation carriers have thyroid abnormalities. We tested the functional consequences of the p.A119S variation in a cellular context by performing transactivation assays with promoters relevant for both heart and thyroid development in rat heart derived H10 cells and HELA cells. There was no difference between wildtype NKX2-5 and p.A119S NKX2-5 in activation of the investigated promoters in both cell lines. Additionally, we reviewed the current literature on the topic, showing that there is no clear evidence for a major pathogenic role of NKX2-5 mutations in thyroid dysgenesis. In conclusion, our study demonstrates that p.A119S does not cause CHD or TD and that it is a rare variation that behaves equal to wildtype NKX2-5. Furthermore, given the wealth of published evidence, we suggest that NKX2-5 mutations do not play a major pathogenic role in thyroid dysgenesis, and that genetic testing of NKX2-5 in TD is not warranted.

Ebstein's anomaly may be caused by mutations in the sarcomere protein gene MYH7

Ebstein’s anomaly is a rare congenital heart malformation characterised by adherence of the septal and posterior leaflets of the tricuspid valve to the underlying myocardium. Associated abnormalities of left ventricular morphology and function including left ventricular noncompaction (LVNC) have been observed. An association between Ebstein’s anomaly with LVNC and mutations in the sarcomeric protein gene MYH7, encoding β-myosin heavy chain, has been shown by recent studies. This might represent a specific subtype of Ebstein’s anomaly with a Mendelian inheritance pattern. In this review we discuss the association of MYH7 mutations with Ebstein’s anomaly and LVNC and its implications for the clinical care for patients and their family members.

Adults with congenital heart disease: Patients' knowledge and concerns about inheritance

With recent advances in medical and surgical management, most patients with congenital heart disease (CHD) survive to reproductive age. Current guidelines recommend counseling about inheritance and transmission of CHD to offspring. We evaluated whether adult CHD patients recalled having received information about the inheritance of their CHD, patients knowledge about inheritance and their concerns in this regard. A questionnaire was sent to 486 non‐syndromic CHD patients aged 20–45 years. We received 332 useful questionnaires (response rate 68%). One‐third (33%) of patients recalled receiving information about inheritance of CHD from their cardiologist, and 13% had consulted a clinical geneticist. Eight percent of patients who were considering having children estimated the recurrence risk for their own offspring to be 1% or lower, whereas one‐fourth (25%) estimated it to be higher than 10%. According to our classification, 44% estimated the recurrence risk in a correct range of magnitude. Additional information about inheritance of CHD was desired by 41% of patients. Forty‐two percent of patients considering having children reported concerns about transmitting CHD to offspring. We conclude that a substantial proportion of adult CHD patients lacks knowledge and desires more information about inheritance, indicating a need for better patient education. Current guidelines and/or their implementation do not seem to meet the needs of these patients. A dedicated program of counseling for adults with CHD has to be developed to optimize knowledge and satisfaction with information provision and to reduce or manage concerns regarding inheritance of CHD.

Advanced therapy for pulmonary arterial hypertension due to congenital heart disease: a clinical perspective in a new therapeutic era

IntroductionPulmonary arterial hypertension (PAH) is a progressivedisease with poor survival. PAH is classified by the 2009updated clinical classification of pulmonary hypertensionand a major subgroup is PAH due to congenital heartdisease (CHD) with systemic-to-pulmonary shunt [1]. Thisshunting may lead to extensive histological changes in thedistal pulmonary arteries resulting in an irreversibleincrease in pulmonary vascular resistance (PVR). Theclassification of CHD-PAH includes four categories: (1)Eisenmenger syndrome, (2) PAH associated with systemic-to-pulmonary shunts, (3) PAH with small septal defects,and (4) PAH after corrective cardiac surgery [2]. In thesepatients advanced pharmacological therapy should beconsidered.Three classes of advanced therapy for PAH are currentlyin use: prostanoids such as epoprostenol, endothelin-1receptor antagonists such as bosentan, and phosphodiester-ase 5 inhibitors such as sildenafil [3]. Bosentan has beenshown to improve 6-min walking distance (6MWD) and todecrease PVR in patients with Eisenmenger syndrome [4].Anecdotal experience with the phosphodiesterase type-5inhibitors sildenafil and tadalafil show favourable function-al and haemodynamic results in patients with CHD-PAH[5, 6]. We present three patients treated with advancedpharmacological therapy for CHD-PAH: a patient withEisenmenger syndrome receiving standard care, a patientwith atrial septal defect receiving advanced therapy as abridge to surgery, and a patient with segmental PAH whowas started on advanced therapy empirically.Case 1: an Eisenmenger patientThe first case describes a 38-year-old male patient with adouble inlet left ventricle, hypoplastic aortic arch and patentductus arteriosus. He was deemed ineligible for a Fontancirculation and developed PAH in childhood. He wasseverely symptomatic (NYHA functional class III-IV) andcould only live a sedentary lifestyle. He had been on thewaiting list for combined heart and lung transplantation for2 years. He was cyanotic with a peripheral saturation of80%. His haemoglobin level was 13.4 mmol/L. Onauscultation, normal heart sounds were heard, as well as asystolic murmur grade II/VI. Trans-thoracic echocardiogra-phy (TTE) showed a moderate systolic ventricular function,mild mitral regurgitation, and moderate tricuspid regurgita-

Is cardiac CT a reproducible alternative for cardiac MR in adult patients with a systemic right ventricle

Objective20xa0% of patients with a systemic RV are pacemaker dependent, and unsuitable to undergo cardiac magnetic resonance (CMR). Multidetector row computed tomography (MDCT) could provide a reproducible alternative to CMR in these patients. The aim of this study was to compare variability of MDCT with CMR.MethodsThirty-five patients with systemic RV underwent either MDCT (nu2009=u200915) or CMR (nu2009=u200920). Systemic RV volumes and ejection fraction were obtained, and intra- and interobserver variability for both modalities were assessed and compared.ResultsWe found the intra- and interobserver variability of volumes and function measurements of the systemic RV obtained with MDCT to be higher compared with those obtained with CMR. However, these differences in variability were not significant, the only exception being the interobserver variability of systemic RV stroke volume.ConclusionsMDCT provides a reproducible alternative to CMR for volumes and function assessment in patients with a systemic RV.

The value of the clinical geneticist caring for adults with congenital heart disease: diagnostic yield and patients' perspective

For adult patients with congenital heart disease (CHD), knowledge about the origin and inheritance of their CHD is important. Clinical geneticists may play a significant role in their care. We explored the diagnostic yield of clinical genetic consultation of adult CHD patients, patients motivations for the consultation, implications for reproductive decisions, patients evaluation of the impact of provided information, and satisfaction with counseling. Chart review was performed on all adult patients referred for CHD to our clinical genetics department between 2000 and 2011 (nu2009=u200990). Additionally, a questionnaire was sent to those patients referred between 2005 and 2011 (nu2009=u200964), of which 46 useful questionnaires were returned (72% response). Of patients without an etiological diagnosis at referral (nu2009=u200983), 17 (20%) were eventually diagnosed with syndromic CHD, 6 (7%) with nonsyndromic monogenetic CHD and 45 (54%) with nonsyndromic multifactorial CHD. The diagnosis remained undetermined in 15 (18%) patients. Half of patients who returned the questionnaire had purposefully postponed having children until after genetic consultation and 13% had changed their mind about having children or not after the consultation. Counseling was valued positively. In this study, we showed the added value of clinical genetic consultation in the care for adult CHD patients: it improves diagnostics by establishing an etiological diagnosis and associated recurrence risk in a substantial proportion of patients and leads to more informed reproductive decisions. With new genetic testing technologies an etiological diagnosis may be established in an increasing number of patients in the near future.

Per-operative stent placement in the right pulmonary artery; a hybrid technique for the management of pulmonary artery branch stenosis at the time of pulmonary valve replacement in adult Fallot patients

After having undergone surgical correction at an early age, many patients with tetralogy of Fallot develop long-term complications including progressive pulmonary regurgitation and peripheral pulmonary stenosis. A high percentage of these patients need to undergo a second operation in their adolescence or early adulthood. If simultaneous treatment of both pulmonary regurgitation and peripheral pulmonary stenosis is warranted, a complete surgical approach has several disadvantages. We describe four cases of Fallot patients with severe pulmonary regurgitation and peripheral pulmonary stenosis who were treated using a hybrid approach involving surgical implantation of a pulmonary homograft and peroperative stenting of the pulmonary artery.

Recent progress in treatment of pulmonary arterial hypertension due to congenital heart disease

IntroductionPulmonary arterial hypertension (PAH) is a severe, progres-sive disease, which can present idiopathically or secondary toconditions such as systemic sclerosis or congenital heartdisease(CHD)[1]. In the setting of CHD-PAH a systemic-to-pulmonary shunt and increased volume overload ultimatelylead to adaptations of pulmonary vasculature and endothelialdysfunction. The classification of CHD-PAH has recentlybeen updated to include four categories: (1) Eisenmengersyndrome, (2) PAH associated with systemic-to-pulmonaryshunts, (3) PAH with small septal defects and (4) PAH aftercorrective cardiac surgery or intervention. Three classes ofadvanced therapy for PAH are currently in use: prostanoidssuch as epoprostenol, endothelin-1 receptor antagonists suchas bosentan and phosphodiesterase 5 inhibitors such assildenafil.Eisenmenger syndromeNowadays, all patients with class III Eisenmengersyndrome should be treated according to the currentguidelines, based on a class IC recommendation [2]. Inour nationwide study with a standardised treatment protocolwe observed a prolonged beneficial effect of bosentantreatment on exercise capacity, echocardiographic strokevolume and quality of life in CHD-PAH patients (79%Eisenmenger syndrome) [3]. In Eisenmenger patients withDown syndrome a stabilisation of clinical parameters wasseen.Expanding indicationsIndications for advanced therapy are expanding. In NYHAfunctionalclassIIPAHpatients,short-termefficacyofbosentanhas been demonstrated. Moreover, prevention of clinicaldeteriorationshouldbeconsideredanimportanttreatmentgoal.Some patients with complex CHD have peripheralpulmonary artery stenosis resulting in local variation ofpulmonary artery arterial pressure. Consequently, somesegments of pulmonary tissue have higher pressures thanothers; therefore, the term segmental PAH has beensuggested to describe this situation [4]. Our group hasreported a case series with segmental PAH demonstratingimprovement of NYHA functional class and exercisecapacity after 12 months of bosentan treatment.Surgical patientsPatients with septal defects and severe or irreversible PAHare by convention ineligible for cardiac surgery. However, anumber of these patients can benefit from advanced therapyas a bridge to surgical intervention. In the literature a fewcases have been reported on CHD-PAH patients whobecame eligible for cardiac surgery after bosentan treatment[5].