Search

Although the invention of right heart catheterisation in the 1950s enabled accurate clinical diagnosis of pulmonary arterial hypertension (PAH), it was not until 2000 when the landmark discovery of the causative role of bone morphogenetic protein receptor type II (BMPR2) mutations shed new light on the pathogenesis of PAH. Since then several genes have been discovered, which now account for around 25% of cases with the clinical diagnosis of idiopathic PAH. Despite the ongoing efforts, in the majority of patients the cause of the disease remains elusive, a phenomenon often referred to as “missing heritability”. In this review, we discuss research approaches to uncover the genetic architecture of PAH starting with forward phenotyping, which in a research setting should focus on stable intermediate phenotypes, forward and reverse genetics, and finally reverse phenotyping. We then discuss potential sources of “missing heritability” and how functional genomics and multi-omics methods are employed to tackle this problem.

Microarrays are increasingly requested as a first-line genetic investigation for chromosome anomalies in the neonatal population. Consent is usually taken by paediatricians, frequently trainees, often without specific training in how to consent for genetic tests. Unlike in the paediatric population,1 there are no consensus guidelines on the indications for neonatal microarray testing. Our local guideline recommends microarray testing in babies with multiple congenital anomalies or ambiguous genitalia. However, studies have also suggested the utility of microarray testing in congenital heart disease2 and intrauterine growth restriction (IUGR) without congenital anomalies.3 Informed genetic consent needs to cover prognostication (most pathogenic copy number variants (CNVs) are associated with a significant risk of learning disability); potential implications for family members; incidental findings and the risk of identifying variants of uncertain significance (VUS). We conducted a retrospective study on …

A 29-year old male with recurrent respiratory and skin infections, anaemia and neutropaenia during childhood required immunoglobulin replacement for antibody deficiency from age 16. He remained relatively well until age 28 when he presented with a two-week history of fatigue, sore throat, fever and productive cough. He was found to have EBV viraemia and splenomegaly and a diagnosis of EBV-driven lymphoproliferative disease was made following bone marrow trephine. Family history was notable with three siblings: a healthy sister and two brothers with anaemia and neutropaenia; one who succumbed to septicaemia secondary to neutropaenic enterocolitis age 5 and another who developed intestinal vasculitis and antibody deficiency and had a successful haemopoetic stem cell transplant. The proband's DNA underwent targeted sequencing of 279 genes associated with immunodeficiency (GRID panel). The best candidates were two ADA2 variants, p.Arg169Gln (R169Q) and p.Asn370Lys (N370K). Sanger sequencing and co-segregation of variants in the parents, unaffected sister and all three affected brothers was fully consistent with compound heterozygous inheritance. Subsequent whole genome sequencing of the proband identified no other potential causal variants. ADA2 activity was consistent with a diagnosis of ADA2 deficiency in affected family members. This is the first description of EBV-driven lymphoproliferative disease in ADA2 deficiency. ADA2 deficiency may cause susceptibility to severe EBV-induced disease and we would recommend that EBV status and viral load is monitored in patients with this diagnosis and allogeneic SCT is considered at an early stage for patients whose ADA2 deficiency is associated with significant complications., Highlights • We report a patient with ADA2 deficiency and EBV-driven lymphoproliferative disease. • ADA2 deficiency may predispose to severe EBV-induced disease. • We would recommend that EBV status and viral load is monitored in patients with ADA2 deficiency.

The spectrum of bicuspid aortic valve (BAV) disease encompasses not only maldevelopment of the aortic valve but also abnormalities of the thoracic aorta, including aortic root and ascending aortic dilatation. Insidious formation of thoracic aortic aneurysm (TAA) can lead to aortic dissection or rupture with necropsy series suggesting a 5–10 times higher risk of aortic dissection in BAV compared to patients with a trileaflet aortic valve.

The thoracic aorta is the second most common site of aneurysm formation after the abdominal aorta. Thoracic aortic aneurysms (TAAs) often result from medial wall degeneration secondary to genetic aberrations. Over recent decades, unprecedented research in the field of connective tissue disease has led to identification of key molecular pathways involved in TAA formation. Prolonged survival of congenital heart disease patients following successful reparative surgery has also led to increased incidence of TAA in this context with extensive investigations of underlying mechanisms. This chapter summarizes breakthrough discoveries in congenital arterial wall remodelling and discusses their potential clinical applications.

Advances in sequencing technology have led to the introduction of panel testing in hereditary breast and ovarian cancer. While direct-to-consumer testing services have become widely available, the clinical validity of many of the genes on panel tests remains contentious and risk management guidelines are often lacking. This article gives an overview of advantages with panel testing as well as important challenges, including clinical translation of test results.

Pulmonary arterial hypertension (PAH) is considered primarily a disease of the distal pulmonary arteries whereas little is known on the effect of long-standing pulmonary hypertension on the larger proximal pulmonary arteries. This study aims to investigate the structural changes in the great arteries of adults who developed PAH in association with congenital heart disease (CHD), with severe cases termed Eisenmenger syndrome.We performed macroscopic and light microscopy analyses on the great arteries of 10 formalin-fixed human hearts from patients with PAH/CHD and compared them to age-matched healthy controls. A detailed histology grading score was used to assess the severity of medial wall abnormalities.Severe atherosclerotic lesions were found macroscopically in the elastic pulmonary arteries of 4 PAH/CHD specimens and organised thrombi in 3; none were present in the controls. Significant medial wall abnormalities were present in the pulmonary trunk (PT), including fibrosis (80%), and atypical elastic pattern (80%). Cyst-like formations were present in less than one third of patients and were severe in a single case leading to wall rupture. The cumulative PT histology grading score was significantly higher in PAH/CHD cases compared to controls (p0.0001) and correlated positively with larger PT diameters (ρ=0.812, p0.0001) and the degree of medial wall hypertrophy (ρ=0.749, p0.0001).Chronic PAH in association with CHD results in marked macroscopic and histological abnormalities in the large pulmonary arteries. These abnormalities are likely to affect haemodynamics and contribute to morbidity and mortality in this cohort.

To evaluate the relationship between socioeconomic status (SES), access to physical activity resources, urban-rural dwelling, levels of pollution and exercise capacity in adult congenital heart disease (ACHD) patients.Exercise intolerance is prevalent in ACHD and the contributing factors are poorly understood.A total of 1268 ACHD patients living in England who underwent cardiopulmonary exercise testing at our center were included. Neighborhood deprivation (English Indices of Deprivation), urban-rural dwelling, availability of green space, distance to the closest gym/fitness center and levels of pollution were estimated based on administrative data.Urban-rural dwelling, availability of green space and levels of pollution were unrelated to exercise capacity. Lower SES was associated with a significantly lower peak oxygen consumption (P0.002) and heart rate reserve (P0.004). This association was non-linear and most pronounced in ACHD patients with cardiac defects of medium complexity living in the most socioeconomically disadvantaged communities. Low SES was associated with higher prevalence of diabetes (P=0.015) and smoking (P=0.01). Coronary artery disease was rare in this young population and low SES was found to be related to exercise capacity independently of the presence of coronary artery disease.Living in poorer areas is associated with exercise intolerance in contemporary ACHD patients. Although low SES is linked to traditional cardiovascular risk factors, the deleterious effects of SES on exercise capacity seem to be only partially mediated via coronary artery disease. Reducing social inequalities in ACHD patients may have a positive effect on quality of life and long-term prognostic implications.

Background Patients with congenitally corrected transposition of the great arteries (ccTGA) have significantly reduced exercise tolerance. Progressive right ventricular (RV) dysfunction with tricuspid regurgitation (TR) and other haemodynamic lesions are common among them. We hypothesised that interaction of these factors may result in increased systemic RV filling pressure, which in turn impact on exercise capacity. Methods Patients with ccTGA in functional class I or II, able to perform treadmill exercise and without resting cyanosis were enrolled. All patients underwent cardiopulmonary exercise testing and transthoracic echocardiographic examination. RV filling pressure was estimated using tissue Doppler imaging (TDI) techniques by measuring early annular diastolic velocity (Ea) and the ratio of the transtricuspid inflow to the early annular diastolic velocity ( E /Ea). Results A total of 27 patients (mean age 41years, 48% female) were assessed, the majority (63%) asymptomatic. Many patients had coexistent haemodynamic lesions including shunts, pulmonary stenosis, TR and systemic ventricular dysfunction. Average percentage predicted peak oxygen consumption, VE/VCO 2 slope and heart rate reserve were abnormal in this population. Patients with moderately/severely impaired exercise capacity (≤60% predicted peak VO 2 ) had significantly higher E /Ea ratios compared to those with normal/mildly impaired exercise capacity (septal E /Ea=17.1±9.7 vs 8.8±1.6 and lateral E /Ea=11.5±5.8 vs 6.6±1.3, p =0.007 and 0.01 respectively). Conclusion Reduced exercise capacity is common in adults with ccTGA even among asymptomatic patients and relates to increased RV filling pressures assessed by TDI. This index could potentially be used to optimize therapy or prognosticate adverse events in ccTGA patients.

Lesions of the semilunar valve and the aortic arch can occur either in isolation or as part of well-described clinical syndromes. The polygenic cause of calcific aortic valve disease will be discussed including the key role of NOTCH1 mutations. In addition, the complex trait of bicuspid aortic valve disease will be outlined, both in sporadic/familial cases and in the context of associated syndromes, such as Alagille, Williams–Beuren, and Kabuki syndromes. Aortic arch abnormalities particularly coarctation of the aorta and interrupted aortic arch, including their association with syndromes such as Turner and 22q11 deletion, respectively, are also discussed. Finally, the genetic basis of congenital pulmonary valve stenosis is summarized, with particular note to Ras-/mitogen-activated protein kinase (Ras/MAPK) pathway syndromes and other less common associations, such as Holt–Oram syndrome.

Heart failure in pregnancy is rare, but usually ascribed to peripartum cardiomyopathy in the absence of other possible diagnoses. However, heart failure can develop solely due to a tachycardia, so-called 'tachycardia-induced cardiomyopathy'. The incidence of tachycardia-induced cardiomyopathy in pregnancy is unknown, but it is a treatable and potentially reversible cause of heart failure. Clinically, tachycardia-induced cardiomyopathy during pregnancy might present in a similar manner, but its management has to be individualized according to the arrhythmic substrate and usually involve multidisciplinary input from specialists in obstetrics, cardiac electrophysiology and heart failure.

A 66-year-old female with obesity and a history of coronary artery bypass graft surgery 35 years ago presented with a 3-month history of chest discomfort, dyspnoea, right hypochondrium pain, and peripheral edema. On physical examination there was a systolic ejection murmur over the left upper sternal border. Chest X-ray revealed a mass abutting the left mediastinal contour (Figure 1A). Echocardiogram showed a large, partially thrombosed extracardiac mass compressing the right ventricular outflow tract (RVOT) and main pulmonary artery, causing significant stenosis with a systolic peak gradient pressure of 74 mm Hg (Figure 1B–1D and Movies I and II in the online-only Data Supplement). Figure 1. A , Chest X-ray revealing a mass abutting the left mediastinal contour. B , Two-dimensional transthoracic echocardiogram picture (short-axis view) showing a large, partially trombosed (white asterisk) extracardiac mass (white arrows) …

Congenital heart disease (CHD) is defined as a cardiovascular defect that is present since birth. Due to substantial medical and surgical advances, the majority of patients with CHD now survive into adulthood and form an exponentially growing population of more than 1,000,000 in the USA. Despite improved survival, it has become apparent that timely interventions are reparative and not curative with significant sequelae and residual hemodynamic lesions in most cases. The complexity of the anatomy and physiology of patients with CHD presents physicians with challenges that are unique to this population. Thus, familiarization with the principles of management of patients with CHD is essential. This book chapter provides an introduction to the most prevalent CHD lesions and summarizes specific issues which are topical to adult patients with CHD.

Ebstein's anomaly of the tricuspid valve often results in biventricular dysfunction and functional deterioration. Little is known about the relation between exercise capacity, disease severity and outcome in adults with Ebstein's anomaly.Data on all patients with Ebstein's anomaly of the tricuspid valve who underwent cardiopulmonary exercise testing in our tertiary center were collected. The relation between exercise parameters, anatomic severity (Glasgow outcome score) and the combined end-point of death, non-elective hospitalization and surgical repair was studied using Cox regression analysis.A total of 51 adult patients fulfilled inclusion criteria (49% male, mean age 37.8±13.6 years). Mean peak oxygen uptake (peak VO2) was 63.2±18.7% of predicted, the slope of ventilation per unit of carbon dioxide output (VE/VCO2 slope) 37.4±11.4, heart rate reserve (HRR) 23.6±22.7 bpm. A significantly lower peak VO2 was found in patients with a higher Glasgow outcome score, higher cardiothoracic ratio and documented atrial shunt. Peak VO2 (HR for value60% of predicted 3.47, 95% CI: 1.28–9.44, p=0.015) and HRR (HR for value25 bpm 3.07, 95% CI: 1.24–7.61, p=0.016) were significant predictors of outcome, the former being the strongest on multivariable analysis.Reduced exercise capacity in patients with Ebstein's anomaly relates to severity of the underlyingdisease and is a strong and independent predictor of outcome. Cardiopulmonary exercise testing should be incorporated in the follow-up and risk stratification of patients with this relatively uncommon and challenging cardiac defect.

Arterial switch Transposition of the great arteries Atrial switch Quality of life Congenital heart disease Exercise capacity