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.

NF-κB inhibition prevents acute shear stress-induced inflammation in the saphenous vein graft endothelium.

The long saphenous vein (LSV) is commonly used as a conduit in coronary artery bypass grafting. However, long term patency remains limited by the development of vascular inflammation, intimal hyperplasia and accelerated atherosclerosis. The impact of acute exposure of venous endothelial cells (ECs) to acute arterial wall shear stress (WSS) in the arterial circulation, and the subsequent activation of inflammatory pathways, remain poorly defined. Here, we tested the hypothesis that acute exposure of venous ECs to high shear stress is associated with inflammatory responses that are regulated by NF-κB both in-vitro and ex-vivo. Analysis of the LSV endothelium revealed that activation of NF-κB occurred within 30 min after exposure to arterial rates of shear stress. Activation of NF-κB was associated with increased levels of CCL2 production and enhanced binding of monocytes in LSVECs exposed to 6 h acute arterial WSS. Consistent with this, ex vivo exposure of LSVs to acute arterial WSS promoted monocyte interactions with the vessel lumen. Inhibition of the NF-κB pathway prevented acute arterial WSS-induced CCL2 production and reduced monocyte adhesion, both in vitro and in human LSV ex vivo, demonstrating that this pathway is necessary for the induction of the acute arterial WSS-induced pro-inflammatory response. We have identified NF-κB as a critical regulator of acute endothelial inflammation in saphenous vein in response to acute arterial WSS. Localised endothelial-specific inhibition of the NF-κB pathway may be beneficial to prevent vein graft inflammation and consequent failure.

Outcomes following aortic valve procedures in 201 complex congenital heart disease cases-results from the UK National Audit.

OBJECTIVES: Some patients with complex congenital heart disease (cCHD) also require aortic valve (AoV) procedures. These cases are considered high risk but their outcome has not been well characterized. We aim to describe these scenarios in the current practice, and provide outcome data for counselling and decision-making. METHODS: This was a retrospective study using the UK National Congenital Heart Disease Audit data on cCHD patients undergoing aortic valve replacement, balloon dilation (balloon aortic valvuloplasty) or surgical repair (surgical aortic valve repair) between 2000 and 2012. Coarsened exact matching was used to pair cCHD with patients undergoing AoV procedures for isolated valve disease. RESULTS: A total of 201 patients with a varied spectrum of cCHD undergoing 242 procedures were included, median age 9.4 years (1 day-65 years). Procedure types were: balloon aortic valvuloplasty (n = 31, 13%), surgical aortic valve repair (n = 57, 24%) and aortic valve replacement (n = 154, 63%). Mortality at 30 days was higher in neonates (21.8% vs 5.3%, P = 0.02). Survival at 10 years was 83.1%, freedom from aortic valve replacement 83.8% and freedom from balloon aortic valvuloplasty/surgical aortic valve repair 86.3%. Neonatal age (P < 0.001), single ventricle (P = 0.08), concomitant Fontan/Glenn (P = 0.002) or aortic arch procedures (0.02) were associated with higher mortality. cCHD patients had lower survival at 30 days (93% vs 100%, P = 0.003) and at 10 years (86.4% vs 96.1%, P = 0.005) compared to matched isolated AoV disease patients. CONCLUSIONS: AoV procedures in cCHD can be performed with good results outside infancy, but with higher mortality than in isolated AoV disease. Neonates and patients with single ventricle defects, especially those undergoing concomitant Fontan/Glenn, have worse outcomes.

Age over 35 years is associated with increased mortality after pulmonary valve replacement in repaired tetralogy of Fallot: results from the UK National Congenital Heart Disease Audit database.

OBJECTIVES: Many adults with repaired tetralogy of Fallot will require a pulmonary valve replacement (PVR), but there is no consensus on the best timing. In this study, we aim to evaluate the impact of age at PVR on outcomes. METHODS: This is a national multicentre retrospective study including all patients >15 years of age with repaired tetralogy of Fallot who underwent their first PVR between 2000 and 2013. The optimal age cut-off was identified using Cox regression and classification and regression tree analysis. RESULTS: A total of 707 patients were included, median age 26 (15-72) years. The mortality rate at 10 years after PVR was 4.2%, and the second PVR rate of 6.8%. Age at PVR of 35 years was identified as the optimal cut-off in relation to late mortality. Patients above 35 years of age had a 5.6 fold risk of death at 10 years compared with those with PVR under 35 years (10.4% vs 1.3%, P < 0.001), more concomitant tricuspid valve repair/replacement (15.1% vs 5.7%, P < 0.001) and surgical arrhythmia treatment (18.4% vs 5.9%, P < 0.001). In those under 50 years, there was an 8.7 fold risk of late death compared with the general population, higher for those with PVR after 35 than those with PVR below 35 years (hazard ratio 9.9 vs 7.4). CONCLUSIONS: Patients above 35 years of age with repaired tetralogy of Fallot have significantly worse mortality after PVR, compared with younger patients and a higher burden of mortality relative to the general population. This suggests that there are still cases where the timing of initial PVR is not optimal, warranting a re-evaluation of criteria for intervention.

Lifetime cardiovascular management of patients with previous Kawasaki disease.

Kawasaki disease (KD) is an inflammatory disorder of young children, associated with vasculitis of the coronary arteries with subsequent aneurysm formation in up to one-third of untreated patients. Those who develop aneurysms are at life-long risk of coronary thrombosis or the development of stenotic lesions, which may lead to myocardial ischaemia, infarction or death. The incidence of KD is increasing worldwide, and in more economically developed countries, KD is now the most common cause of acquired heart disease in children. However, many clinicians in the UK are unaware of the disorder and its long-term cardiac complications, potentially leading to late diagnosis, delayed treatment and poorer outcomes. Increasing numbers of patients who suffered KD in childhood are transitioning to the care of adult services where there is significantly less awareness and experience of the condition than in paediatric services. The aim of this document is to provide guidance on the long-term management of patients who have vascular complications of KD and guidance on the emergency management of acute coronary complications. Guidance on the management of acute KD is published elsewhere.

Recommendations from the Association for European Paediatric and Congenital Cardiology for training in pulmonary hypertension.

Pulmonary hypertension is a complex and progressive condition that is either idiopathic or heritable, or associated with one or multiple health conditions, with or without congenital or acquired cardiovascular disease. Recent developments have tremendously increased the armamentarium of diagnostic and therapeutic approaches in children and young adults with pulmonary hypertension that is still associated with a high morbidity and mortality. These modalities include non-invasive imaging, pharmacotherapy, interventional and surgical procedures, and supportive measures. The optimal, tailored diagnostic and therapeutic strategies for pulmonary hypertension in the young are rapidly evolving but still face enormous challenges: Healthcare providers need to take the patient's age, development, disease state, and family concerns into account when initiating advanced diagnostics and treatment. Therefore, there is a need for guidance on core and advanced medical training in paediatric pulmonary hypertension. The Association for European Paediatric and Congenital Cardiology working group "pulmonary hypertension, heart failure and transplantation" has produced this document as an expert consensus statement; however, all recommendations must be considered and applied in the context of the local and national infrastructure and legal regulations.

2019 updated consensus statement on the diagnosis and treatment of pediatric pulmonary hypertension: The European Pediatric Pulmonary Vascular Disease Network (EPPVDN), endorsed by AEPC, ESPR and ISHLT.

The European Pediatric Pulmonary Vascular Disease Network is a registered, non-profit organization that strives to define and develop effective, innovative diagnostic methods and treatment options in all forms of pediatric pulmonary hypertensive vascular disease, including pulmonary hypertension (PH) associated with bronchopulmonary dysplasia, PH associated with congenital heart disease (CHD), persistent PH of the newborn, and related cardiac dysfunction. The executive writing group members conducted searches of the PubMed/MEDLINE bibliographic database (1990-2018) and held face-to-face and web-based meetings. Ten section task forces voted on the updated recommendations, based on the 2016 executive summary. Clinical trials, meta-analyses, guidelines, and other articles that include pediatric data were searched using the term "pulmonary hypertension" and other keywords. Class of recommendation (COR) and level of evidence (LOE) were assigned based on European Society of Cardiology/American Heart Association definitions and on pediatric data only, or on adult studies that included >10% children or studies that enrolled adults with CHD. New definitions by the World Symposium on Pulmonary Hypertension 2018 were included. We generated 10 tables with graded recommendations (COR/LOE). The topics include diagnosis/monitoring, genetics/biomarkers, cardiac catheterization, echocardiography, cardiac magnetic resonance/chest computed tomography, associated forms of PH, intensive care unit/lung transplantation, and treatment of pediatric PH. For the first time, a set of specific recommendations on the management of PH in middle- and low-income regions was developed. Taken together, these executive, up-to-date guidelines provide a specific, comprehensive, detailed but practical framework for the optimal clinical care of children and young adults with PH.

Surgical Repair of Tetralogy of Fallot With Absent Pulmonary Valve: Favorable Long-Term Results.

Tetralogy of Fallot with absent pulmonary valve syndrome (ToF-APVS) is a rare variant of tetralogy, associated with severe pulmonary valve regurgitation and aneurysmal dilation of the pulmonary arteries (PAs). Reported outcomes after surgical corrections are limited to single center, older series and might not reflect the current outcome. We aim to use data from a national registry to evaluate short- and long-term outcomes after surgical repair of ToF-APVS, to serve for counselling and planning. All children undergoing ToF-APVS repair in the UK between 2002 and 2013 were included. Survival and freedom from reintervention were estimated using the Kaplan-Meier method, and univariable analysis was done using the Weibull regression model. A total of 98 children, 45% male, 10% with DiGeorge syndrome, median age of 213 days (1 day to 13 years) were included. Mortality at 30 days was 3.3%, higher for neonates (6.7% vs 2.7%, P = 0.4) and those on preoperative mechanical ventilatory support (16.7% vs 1.3%, P = 0.04). Survival was 92.1% and freedom from pulmonary valve or conduit replacement (PVR) 73.2% at 10 years. Neonates had worse survival (hazard ratio [HR] 6.2, P = 0.02), freedom from PVR (HR 4.5, P = 0.01), freedom from PAs arterioplasty (HR 6.6, P = 0.001), and overall freedom from any reintervention (HR 5.3, P < 0.001). Low weight at repair was associated with worse freedom from PVR (P = 0.02) and from PAs arterioplasty (P = 0.009), preoperative ventilatory support with increased mortality (P = 0.009), the presence of DiGeorge syndrome was associated with worse freedom from PVR (HR 4, P = 0.02). Surgical repair of ToF-APVS can be performed with low early and late mortality, with improving results even in those with preoperative mechanical ventilatory support. The need for right ventricular outflow tract reintervention, including on the PAs, is an expected issue in the long term for the majority of patients.

Assessment of Myocardial Function in Kenyan Children With Severe, Acute Malnutrition: The Cardiac Physiology in Malnutrition (CAPMAL) Study.

Importance: Mortality among African children hospitalized with severe malnutrition remains high, with sudden, unexpected deaths leading to speculation about potential cardiac causes. Malnutrition is considered high risk for cardiac failure, but evidence is limited. Objective: To investigate the role of cardiovascular dysfunction in African children with severe, acute malnutrition (SAM). Design, Setting, and Participants: A prospective, matched case-control study, the Cardiac Physiology in Malnutrition (CAPMAL) study, of 88 children with SAM (exposed) vs 22 severity-matched patients without SAM (unexposed) was conducted between March 7, 2011, and February 20, 2012; data analysis was performed from October 1, 2012, to March 1, 2016. Exposures: Echocardiographic and electrocardiographic (ECG) recordings (including 7-day Holter monitoring) at admission, day 7, and day 28. Main Outcomes and Measures: Findings in children with (cases) and without (controls) SAM and in marasmus and kwashiorkor phenotypes were compared. Results: Eighty-eight children (52 with marasmus and 36 with kwashiorkor) of the 418 admitted with SAM and 22 severity-matched controls were studied. A total of 63 children (57%) were boys; median age at admission was 19 months (range, 12-39 months). On admission, abnormalities more common in cases vs controls included severe hypokalemia (potassium <2.5 mEq/L) (18 of 81 [22%] vs 0%), hypoalbuminemia (albumin level <3.4 g/dL) (66 of 88 [75%] vs 4 of 22 [18%]), and hypothyroidism (free thyroxine level <0.70 ng/dL or thyrotropin level >4.2 mU/L) (18 of 74 [24%] vs 1 of 21 [5%]) and were associated with typical electrocardiographic changes (T-wave inversion: odds ratio, 7.3; 95% CI, 1.9-28.0; P = .001), which corrected as potassium levels improved. Fourteen children with SAM (16%) but no controls died. Myocardial mass was lower in cases on admission but not by day 7. Results of the Tei Index, a measure of global cardiac function, were within the reference range and similar in cases (median, 0.37; interquartile range [IQR], 0.26-0.45) and controls (median, 0.36; IQR, 0.28-0.42). Echocardiography detected no evidence of cardiac failure among children with SAM, including those receiving intravenous fluids to correct hypovolemia. Cardiac dysfunction was generally associated with comorbidity and typical of hypovolemia, with low cardiac index (median, 4.9 L/min/m2; IQR, 3.9-6.1 L/min/m2), high systemic vascular resistance index (median, 1333 dyne seconds/cm5/m2; IQR, 1133-1752 dyne seconds/cm5/m2), and with few differences between the marasmus and kwashiorkor manifestations of malnutrition. Seven-day continuous ECG Holter monitoring during the high-risk initial refeeding period demonstrated self-limiting significant ventricular arrhythmias in 33 of 55 cases (60%) and 6 of 18 controls (33%) (P = .049); none were temporally related to adverse events, including fatalities. Conclusions and Relevance: There is little evidence that African children with SAM are at greater risk of cardiac dysfunction or clinically significant arrhythmias than those without SAM or that marasmus and kwashiorkor differed in cardiovascular profile. These findings should prompt a review of current guidelines.

Kawasaki disease: a prospective population survey in the UK and Ireland from 2013 to 2015.

OBJECTIVE: Kawasaki disease (KD) is an increasingly common vasculitis with risk of coronary artery aneurysms (CAAs). The last UK survey was in 1990, whereas current epidemiology, treatment patterns and complication rates are unknown. The aim of this study was to address this knowledge gap. METHODS: A British Paediatric Surveillance Unit survey in the UK and Ireland from 1 January 2013 to 28 February 2015 ascertained demographics, ethnicity, seasonal incidence, treatment and complication rates. RESULTS: 553 cases were notified: 389 had complete KD, 46 had atypical KD and 116 had incomplete KD; 2 were diagnosed at postmortem with an incidence of 4.55/100 000 children under 5 years, with a male to female ratio of 1.5:1 and a median age of 2.7 years (2.5 months-15 years). Presentation was highest in January and in rural areas. Most were white (64%), and Chinese and Japanese Asians were over-represented as were black African or African mixed-race children. 94% received intravenous immunoglobulin (IVIG). The overall CAA rate was 19%, and all-cardiac complications affected 28%. Those with CAA received IVIG later than in those without (median 10 days vs 7 days). Those under 1 year had fewer symptoms, but the highest CAA rate (39%). Overall 8 of 512 cases (1.6%) had giant CAA, and 4 of 86 cases (5%) under 1 year of age developed giant CAA. Mortality from KD was 0.36%. CONCLUSIONS: The UK and Ireland incidence of KD has increased and is more frequently seen in winter and rural areas. Delayed IVIG treatment is associated with CAA, suggesting earlier and adjunctive primary treatment might reduce complications to prevent CAA, particularly in the very young.

ERS statement on exercise training and rehabilitation in patients with severe chronic pulmonary hypertension.

Objectives of this European Respiratory Society task force were to summarise current studies, to develop strategies for future research and to increase availability and awareness of exercise training for pulmonary hypertension (PH) patients.An evidence-based approach with clinical expertise of the task force members, based on both literature search and face-to-face meetings was conducted. The statement summarises current knowledge and open questions regarding clinical effects of exercise training in PH, training modalities, implementation strategies and pathophysiological mechanisms.In studies (784 PH patients in total, including six randomised controlled trials, three controlled trials, 10 prospective cohort studies and four meta-analyses), exercise training has been shown to improve exercise capacity, muscular function, quality of life and possibly right ventricular function and pulmonary haemodynamics. Nevertheless, further studies are needed to confirm these data, to investigate the impact on risk profiles and to identify the most advantageous training methodology and underlying pathophysiological mechanisms.As exercise training appears to be effective, cost-efficient and safe, but is scarcely reimbursed, support from healthcare institutions, commissioners of healthcare and research funding institutions is greatly needed. There is a strong need to establish specialised rehabilitation programmes for PH patients to enhance patient access to this treatment intervention.

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.

Respiratory virus prophylaxis in congenital heart disease.

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections and causes up to 200,000 infant deaths a year worldwide. The average rate of hospitalization for severe RSV infection is 5 per 1000 children, and the rate is three-times higher in those with congenital heart disease (CHD). Palivizumab, a monoclonal antibody, reduces hospitalization rates and intensive care admissions. It is used prophylactically and is administered as monthly doses during the RSV season. Hemodynamically unstable CHD is the most susceptible CHD to a severe episode of RSV infection. This review explores current evidence surrounding therapies, patterns of infection and identifies groups which may still be vulnerable to severe RSV infection.

Primary repair versus surgical and transcatheter palliation in infants with tetralogy of Fallot.

OBJECTIVES: Treatment of infants with tetralogy of Fallot (ToF) has evolved in the last two decades with increasing use of primary surgical repair (PrR) and transcatheter right ventricular outflow tract palliation (RVOTd), and fewer systemic-to-pulmonary shunts (SPS). We aim to report contemporary results using these treatment options in a comparative study. METHODS: This a retrospective study using data from the UK National Congenital Heart Disease Audit. All infants (n=1662, median age 181 days) with ToF and no other complex defects undergoing repair or palliation between 2000 and 2013 were considered. Matching algorithms were used to minimise confounding due to lower age and weight in those palliated. RESULTS: Patients underwent PrR (n=1244), SPS (n=311) or RVOTd (n=107). Mortality at 12 years was higher when repair or palliation was performed before the age of 60 days rather than after, most significantly for primary repair (18.7% vs 2.2%, P<0.001), less so for RVOTd (10.8% vs 0%, P=0.06) or SPS (12.4% vs 8.3%, P=0.2). In the matched groups of patients, RVOTd was associated with more right ventricular outflow tract (RVOT) reinterventions (HR=2.3, P=0.05 vs PrR, HR=7.2, P=0.001 vs SPS) and fewer pulmonary valve replacements (PVR) (HR=0.3 vs PrR, P=0.05) at 12 years, with lower mortality after complete repair (HR=0.2 versus PrR, P=0.09). CONCLUSIONS: We found that RVOTd was associated with more RVOT reinterventions, fewer PVR and fewer deaths when compared with PrR in comparable, young infants, especially so in those under 60 days at the time of the first procedure.

Lung Function, Inflammation, and Endothelin-1 in Congenital Heart Disease-Associated Pulmonary Arterial Hypertension.

BACKGROUND: Breathlessness is the most common symptom in people with pulmonary arterial hypertension and congenital heart disease (CHD-APAH), previously thought to be caused by worsening PAH, but perhaps also by inflammation and abnormalities of lung function. We studied lung function and airway inflammation in patients with CHD-APAH and compared the results with controls. METHODS AND RESULTS: Sixty people were recruited into the study: 20 CHD-APAH, 20 CHD controls, and 20 healthy controls. Spirometry, gas transfer, whole body plethysmography and lung clearance index, 6-minute walk distance, and medical research council dyspnea scoring were performed. Inflammatory markers and endothelin-1 levels were determined in blood and induced sputum. The CHD-APAH group had abnormal lung function with lung restriction, airway obstruction, and ventilation heterogeneity. Inverse correlations were shown for CHD-APAH between medical research council dyspnea score and percent predicted peak expiratory flow (r=-0.5383, P=0.0174), percent predicted forced expiratory flow rate at 50% of forced vital capacity (r=-0.5316, P=0.0192), as well as for percent predicted forced expiratory volume in 1 s (r=-0.6662, P=0.0018) and percent predicted forced vital capacity (r=-0.5536, P=0.0186). The CHD-APAH patients were more breathless with lower 6-minute walk distance (360 m versus 558 m versus 622 m, P=0.00001). Endothelin-1, interleukin (IL)-ß, IL-6, IL-8, tumor necrosis factor α, and vascular endothelial growth factor were significantly higher in CHD-APAH than controls. Serum endothelin-1 for CHD-APAH correlated with airflow obstruction with significant negative correlations with percent predicted forced expiratory flow rate at 75% of forced vital capacity (r=-0.5858, P=0.0135). CONCLUSIONS: Raised biomarkers for inflammation were found in CHD-APAH. Significant abnormalities in airway physiology may contribute to the dyspnea but are not driven by inflammation as assessed by circulating and sputum cytokines. A relationship between increased serum endothelin-1 and airway dysfunction may relate to its bronchoconstrictive properties.

Changes in contractile protein expression are linked to ventricular stiffness in infants with pulmonary hypertension or right ventricular hypertrophy due to congenital heart disease.

Background: The right ventricle (RV) is not designed to sustain high pressure leading to failure. There are no current medications to help RV contraction, so further information is required on adaption of the RV to such hypertension. Methods: The Right Ventricle in Children (RVENCH) study assessed infants with congenital heart disease undergoing cardiac surgery with hypertensive RV. Clinical and echocardiographic data were recorded, and samples of RV were taken from matched infants, analysed for proteomics and compared between pathologies and with clinical and echocardiographic outcome data. Results: Those with tetralogy of Fallot (TOF) were significantly more cyanosed than those with ventricular septal defect (median oxygen saturation 83% vs 98%, P=0.0038), had significantly stiffer RV (tricuspid E wave/A wave ratio 1.95 vs 0.84, P=0.009) and had most had restrictive physiology. Gene ontology in TOF, with enrichment analysis, demonstrated significant increase in proteins of contractile mechanisms and those of calmodulin, actin binding and others associated with contractility than inventricular septal defect. Structural proteins were also found to be higher in association with sarcomeric function: Z-disc, M-Band and thin-filament proteins. Remaining proteins associated with actin binding, calcium signalling and myocyte cytoskeletal development. Phosphopeptide enrichment led to higher levels of calcium signalling proteins in TOF. Conclusion: This is the first demonstration that those with an RV, which is stiff and hypertensive in TOF, have a range of altered proteins, often in calcium signalling pathways. Information about these alterations might guide treatment options both in terms of individualised therapy or inotropic support for the Right ventricle when hypertensive due to pulmoanry hypertension or congenital heart disease.

Retrospective study of the impact of unrecognised Kawasaki disease, coronary aneurysm and ectasia.

BACKGROUND: Coronary artery aneurysms resulting from unrecognised or untreated Kawasaki Disease (KD) have thrombotic and stenotic potential leading to myocardial infarction. We aimed to characterise the prevalence and outcomes of patients presenting to a UK-based adult tertiary cardiology service with angiographic evidence of aneurysm or ectasia. METHODS: Retrospective review was undertaken of reports and original coronary angiograms in all patients under 50years old undergoing coronary angiography between 2011 and 2015. Aneurysm/ectasia were defined by calibre discrepancy >1.5× and the number of segments involved. Aneurysms were categorised as being probable, or unlikely to represent unrecognised KD. RESULTS: Aneurysm or ectasia was observed in 49 of 1578 patients (3.7%). Eleven patients had angiographic findings consistent with probable antecedent KD (0.8%), a further 18 patients had evidence of coronary artery aneurysm (1.4%) and ectasia was observed in 20 patients (1.5%). The commonest mode of presentation was ST elevation myocardial infarction, observed in 71.4% of patients. Review of angiogram written reports demonstrated a spurious application of the terms aneurysm and ectasia, with a sensitivity of 10.3% & 55.0%, and a positive predictive value of reporting of 50.0% & 52.4%, respectively. CONCLUSIONS: As the first UK study to characterise the angiographic prevalence of Kawasaki Disease, both aneurysm and ectasia were observed with a relatively low frequency. However, their presence is associated with high-risk acute ischaemic presentations. Furthermore, we demonstrated a poor level of reporting of coronary abnormalities and advocate an increased awareness of Kawasaki disease and coronary aneurysm/ectasia amongst adult cardiologists.

CHD and respiratory syncytial virus: global expert exchange recommendations.

BACKGROUND: Palivizumab is the standard immunoprophylaxis against serious disease due to respiratory syncytial virus infection. Current evidence-based prophylaxis guidelines may not address certain children with CHD within specific high-risk groups or clinical/management settings. METHODS: An international steering committee of clinicians with expertise in paediatric heart disease identified key questions concerning palivizumab administration; in collaboration with an additional international expert faculty, evidence-based recommendations were formulated using a quasi-Delphi consensus methodology. RESULTS: Palivizumab prophylaxis was recommended for children with the following conditions: <2 years with unoperated haemodynamically significant CHD, who are cyanotic, who have pulmonary hypertension, or symptomatic airway abnormalities; <1 year with cardiomyopathies requiring treatment; in the 1st year of life with surgically operated CHD with haemodynamically significant residual problems or aged 1-2 years up to 6 months postoperatively; and on heart transplant waiting lists or in their 1st year after heart transplant. Unanimous consensus was not reached for use of immunoprophylaxis in children with asymptomatic CHD and other co-morbid factors such as arrhythmias, Down syndrome, or immunodeficiency, or during a nosocomial outbreak. Challenges to effective immunoprophylaxis included the following: multidisciplinary variations in identifying candidates with CHD and prophylaxis compliance; limited awareness of severe disease risks/burden; and limited knowledge of respiratory syncytial virus seasonal patterns in subtropical/tropical regions. CONCLUSION: Evidence-based immunoprophylaxis recommendations were formulated for subgroups of children with CHD, but more data are needed to guide use in tropical/subtropical countries and in children with certain co-morbidities.

Guanylate cyclase stimulators for pulmonary hypertension.

BACKGROUND: Pulmonary hypertension is a condition of complex aetiology that culminates in right heart failure and early death. Soluble guanylate cyclase (sGC) stimulators are a promising class of agents that have recently gained approval for use. OBJECTIVES: To evaluate the efficacy of sGC stimulators in pulmonary hypertension. SEARCH METHODS: We searched CENTRAL (Cochrane Central Register of Controlled Trials), MEDLINE, EMBASE and the reference lists of articles. Searches are current as of 12 February 2016. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) involving participants with pulmonary hypertension of all ages, severities and durations of treatment. DATA COLLECTION AND ANALYSIS: AW, MS and RW independently selected studies, assessed evidence quality and extracted data. This process was overseen by RT and SG. All included studies were sponsored by the drug manufacturer. MAIN RESULTS: Five trials involving 962 participants are included in this review. All trials were of relatively short duration (< 16 weeks). Due to the heterogenous aetiology of pulmonary hypertension in participants, results are best considered according to each pulmonary hypertension subtype.Pooled analysis shows a mean difference (MD) increase in six-minute walking distance (6MWD) of 30.13 metres (95% CI 5.29 to 54.96; participants = 659; studies = 3). On subgroup analysis, for pulmonary arterial hypertension (PAH) there was no effect noted (6MWD; MD 11.91 metres, 95% CI -44.92 to 68.75; participants = 398; studies = 2), and in chronic thromboembolic pulmonary hypertension (CTEPH) sGC stimulators improved 6MWD by an MD of 45 metres (95% CI 23.87 to 66.13; participants = 261; studies = 1). Data for left heart disease-associated PH was not available for pooling. Importantly, when participants receiving phosphodiesterase inhibitors were excluded, sGC stimulators increased 6MWD by a MD of 36 metres in PAH. The second primary outcome, mortality, showed no change on pooled analysis against placebo (Peto odds ratio (OR) 0.57, 95% CI 0.18 to 1.80).Pooled secondary outcomes include an increase in World Health Organization (WHO) functional class (OR 1.53, 95% CI 0.87 to 2.72; participants = 858; studies = 4), no effect on clinical worsening (OR 0.45, 95% CI 0.17 to 1.14; participants = 842; studies = 3), and a reduction in mean pulmonary artery pressure (MD -2.77 mmHg, 95% CI -4.96 to -0.58; participants = 744; studies = 5). There was no significant difference in serious adverse events on pooled analysis (OR 1.12, 95% CI 0.66 to 1.90; participants = 818; studies = 5) or when analysed at PAH (MD -3.50, 95% CI -5.54 to -1.46; participants = 344; studies = 1), left heart disease associated subgroups (OR 1.56, 95% CI 0.78 to 3.13; participants = 159; studies = 2) or CTEPH subgroups (OR 1.29, 95% CI 0.65 to 2.56; participants = 261; studies = 1).It is important to consider the results for PAH in the context of a person who is not also receiving a phosphodiesterase-V inhibitor, a contra-indication to sGC stimulator use. It should also be noted that CTEPH results are applicable to inoperable or recurrent CTEPH only.Evidence was rated according to the GRADE scoring system. One outcome was considered high quality, two were moderate, and eight were of low or very low quality, meaning that for many of the outcomes the true effect could differ substantially from our estimate. There were only minor concerns regarding the risk of bias in these trials, all being RCTs largely following the original protocol. Most trials employed an intention-to-treat analysis. AUTHORS' CONCLUSIONS: sGC stimulators improve pulmonary artery pressures in people with PAH (who are treatment naive or receiving a prostanoid or endothelin antagonist) or those with recurrent or inoperable CTEPH. In these settings this can be achieved without notable complication. However, sGC stimulators should not be taken by people also receiving phosphodiestase-V inhibitors or nitrates due to the risks of hypotension, and there is currently no evidence supporting their use in pulmonary hypertension associated with left heart disease. There is no evidence supporting their use in children. These conclusions are based on data with limitations, including unavailable data from two of the trials.