Does Maintenance of Pulmonary Blood Flow Pulsatility at the Time of the Fontan Operation Improve Hemodynamic Outcome in Functionally Univentricular Hearts?

It is unclear whether residual anterograde pulmonary blood flow (APBF) at the time of Fontan is beneficial. Pulsatile pulmonary flow may be important in maintaining a compliant and healthy vascular circuit. We, therefore, wished to ascertain whether there was hemodynamic evidence that residual pulsatile flow at time of Fontan promotes clinical benefit. 106 consecutive children with Fontan completion (1999-2018) were included. Pulmonary artery pulsatility index (PI, (systolic pressure-diastolic pressure)/mean pressure)) was calculated from preoperative cardiac catheterization. Spectral analysis charted PI as a continuum against clinical outcome. The population was subsequently divided into three pulsatility subgroups to facilitate further comparison. Median PI prior to Fontan was 0.236 (range 0-1). 39 had APBF, in whom PI was significantly greater (median: 0.364 vs. 0.177, Mann-Whitney p < 0.0001). There were four early hospital deaths (3.77%), and PI in these patients ranged from 0.214 to 0.423. There was no correlation between PI and standard cardiac surgical outcomes or systemic oxygen saturation at discharge. Median follow-up time was 4.33 years (range 0.0273-19.6), with no late deaths. Increased pulsatility was associated with higher oxygen saturations in the long term, but there was no difference in reported exercise tolerance (Ross), ventricular function, or atrioventricular valve regurgitation at follow-up. PI in those with Fontan-associated complications or the requiring pulmonary vasodilators aligned with the overall population median. Maintenance of pulmonary flow pulsatility did not alter short-term outcomes or long-term prognosis following Fontan although it tended to increase postoperative oxygen saturations, which may be beneficial in later life.

The cardiac proteome in patients with congenital ventricular septal defect: A comparative study between right atria and right ventricles.

Right ventricle (RV) remodelling occurs in neonatal patients born with ventricular septal defect (VSD). The presence of a defect between the two ventricles allows for shunting of blood from the left to right side. The resulting RV hypertrophy leads to molecular remodelling which has thus far been largely investigated using right atrial (RA) tissue. In this study we used proteomic and phosphoproteomic analysis in order to determine any difference between the proteomes for RA and RV. Samples were therefore taken from the RA and RV of five infants (0.34 ±â€¯0.05 years, mean ±â€¯SEM) with VSD who were undergoing cardiac surgery to repair the defect. Significant differences in protein expression between RV and RA were seen. 150 protein accession numbers were identified which were significantly lower in the atria, whereas none were significantly higher in the atria compared to the ventricle. 19 phosphorylation sites (representing 19 phosphoproteins) were also lower in RA. This work has identified differences in the proteome between RA and RV which reflect differences in contractile activity and metabolism. As such, caution should be used when drawing conclusions based on analysis of the RA and extrapolating to the hypertrophied RV. SIGNIFICANCE: RV hypertrophy occurs in neonatal patients born with VSD. Very little is known about how the atria responds to RV hypertrophy, especially at the protein level. Access to tissue from age-matched groups of patients is very rare, and we are in the unique position of being able to get tissue from both the atria and ventricle during reparative surgery of these infants. Our findings will be beneficial to future research into heart chamber malformations in congenital heart defects.

Management dilemmas in pulmonary arterial hypertension associated with congenital heart disease.

There are few randomised controlled data to guide management of patients with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD). In this clinical review, common areas of uncertainty in the management of PAH-CHD are identified, the literature is summarised and discussed and a suggested approach offered for each clinical dilemma.

A pilot randomised controlled trial investigating a mindfulness-based stress reduction (MBSR) intervention in individuals with pulmonary arterial hypertension (PAH): the PATHWAYS study.

BACKGROUND: Pulmonary arterial hypertension (PAH) is an uncommon condition with progressive heart failure and premature death. Treatment costs up to £120,000 per patient per year, and the psychological burden of PAH is substantial. Mindfulness-based stress reduction (MBSR) is an intervention with the potential to reduce this burden, but to date, it has not been applied to people with pulmonary hypertension. We wished to determine whether a trial of MBSR for people with PAH would be feasible. METHODS: A customised gentle MBSR programme of eight sessions was developed for people with physical disability due to PAH, and they were randomised to group-based MBSR or treatment as usual. The completeness of outcome measures including Beck Anxiety Index, Beck Depression Inventory and standard physical assessment at 3 months after randomisation were recorded. Health care utilisation was measured. Attendance at the sessions and the costs involved in delivering the intervention were assessed. Semi-structured interviews were conducted to explore the acceptability of the MBSR intervention and when appropriate the reasons for trial non-participation. RESULTS: Fifty-two patients were recruited, but only 34 were randomised due to patients finding it difficult to travel to sessions. Twenty-two completed all questionnaires and attended all clinics, both routine and additional in order to collect outcomes measures. The MSBR sessions were delivered in Bristol, Cardiff and London, costing, on average, between £2234 (Cardiff) and £4128 (London) per patient to deliver. Attendance at each session averaged between two patients in Bristol and Cardiff and three in London. For those receiving treatment as usual, clinician blinding was achievable. Interviews revealed that people who attended MBSR found it interesting and helpful in managing their symptoms and minimising the psychological component of their disease. CONCLUSIONS: We found that attendance at group MBSR was poor in people with chronic PAH within the context of a trial. Achieving better MBSR intervention attendance or use of an Internet-based programme might maximise the benefit of MBSR.

Early Experience of Macitentan for Pulmonary Arterial Hypertension in Adult Congenital Heart Disease.

BACKGROUND: Endothelin receptor antagonists (ERA) have been recognised as effective therapy for pulmonary arterial hypertension in congenital heart disease (CHD-PH), and Eisenmenger syndrome (ES) since The Bosentan Randomized Trial of Endothelin Antagonist Therapy-5 (Breathe 5) study. A new dual receptor antagonist - Macitentan - is currently undergoing trials to determine its efficacy in simple ES. To date there is little information on this therapy in CHD and we report our first experience, some with more complex diseases. METHODS: Data was collected prospectively from September 2014. Patients with CHD-PH were started on or converted to macitentan if they required therapy with phosphodiesterase 5 inhibitor (PDE5i) or if there was insufficient response or a reaction to bosentan, especially those with trisomy 21. Patients were seen approximately three months after starting therapy to assess echocardiography, six minute walk test, clinical response and tolerability. All patients underwent monthly liver tests initially, but this was reduced to three-monthly in Q4 2015. RESULTS: Fifteen patients with CHD-PH (eight male, seven female) were started on macitentan, median (range) age 38 (23-61) years, and eight patients with Down's syndrome. Eight patients had complex CHD with one having unoperated double inlet left ventricle with ventriculo-arterial discordance, one had double outlet right ventricle and six with complete atrio-ventricular septal defect. Six patients were ERA naïve and nine patients changed from bosentan to macitentan in order to achieve improved drug-drug interaction. Median length of time of treatment with macitentan is 289 (0-694) days to date. One discontinued due to rash and feeling unwell; one was unable to comply with medication due to learning difficulties and one died soon after commencing rescue therapy. This last patient was functional class IV with oxygen saturation of 67% at rest, with right heart failure and was unable to perform a walk test before commencing therapy. All patients who remained on therapy had significant increase in six minute walk test from median 286 (120-426) to 360m (150-450)(p <0.05), most notably in those treatment naïve. Functional class median remained at 3 but the range was reduced (1-3). Resting oxygen saturations improved from median 83 range (77-95%) at rest to 91 (77-96%) and at end walk from 78 (48-90%) to 79 (62-96%). Tricuspid regurgitant peak Doppler derived pressure drop did not change (as expected) at 4.6 (4.3-5.5)m/s. There were no episodes of liver dysfunction. CONCLUSIONS: The introduction of this new therapy has been simple and mostly well tolerated in our sick group of patients. With the usual reservations concerning the open-label nature of our observations, macitentan has good signals regarding oxygen saturations and encouraging signals relating to efficacy.

Sildenafil, pulmonary hypertension and bronchopulmonary dysplasia.

Pulmonary hypertension (PH) secondary to bronchopulmonary dysplasia (BPD) in infants remains a serious concern and continues to cause significant morbidity despite improvements in both quality of life and survival for patients. One of the potential agents that might help is sildenafil citrate, a phosphodiesterase-V inhibitor used a first line therapy for idiopathic PH. However, only limited evidence exists for its use as either monotherapy or part of a combination approach towards the management of PH in BPD. The evidence and current knowledge is presented for sildenafil alone and in combination with other disease modifying agents to treat PH in the presence of BPD. We have previously suggested that sildenafil appears to be safe and possibly effective in this condition. We present the evidence that if continued until PH resolution, there might be reduced mortality in this debilitating disease.

Cellular and molecular basis of RV hypertrophy in congenital heart disease.

RV hypertrophy (RVH) is one of the triggers of RV failure in congenital heart disease (CHD). Therefore, improving our understanding of the cellular and molecular basis of this pathology will help in developing strategic therapeutic interventions to enhance patient benefit in the future. This review describes the potential mechanisms that underlie the transition from RVH to RV failure. In particular, it addresses structural and functional remodelling that encompass contractile dysfunction, metabolic changes, shifts in gene expression and extracellular matrix remodelling. Both ischaemic stress and reactive oxygen species production are implicated in triggering these changes and will be discussed. Finally, RV remodelling in response to various CHDs as well as the potential role of biomarkers will be addressed.

Cardiovascular status after Kawasaki disease in the UK.

OBJECTIVE: Kawasaki disease (KD) is an acute vasculitis that causes coronary artery aneurysms (CAA) in young children. Previous studies have emphasised poor long-term outcomes for those with severe CAA. Little is known about the fate of those without CAA or patients with regressed CAA. We aimed to study long-term cardiovascular status after KD by examining the relationship between coronary artery (CA) status, endothelial injury, systemic inflammatory markers, cardiovascular risk factors (CRF), pulse-wave velocity (PWV) and carotid intima media thickness (cIMT) after KD. METHODS: Circulating endothelial cells (CECs), endothelial microparticles (EMPs), soluble cell-adhesion molecules cytokines, CRF, PWV and cIMT were compared between patients with KD and healthy controls (HC). CA status of the patients with KD was classified as CAA present (CAA+) or absent (CAA-) according to their worst-ever CA status. Data are median (range). RESULTS: Ninety-two KD subjects were studied, aged 11.9 years (4.3-32.2), 8.3 years (1.0-30.7) from KD diagnosis. 54 (59%) were CAA-, and 38 (41%) were CAA+. There were 51 demographically similar HC. Patients with KD had higher CECs than HC (p=0.00003), most evident in the CAA+ group (p=0.00009), but also higher in the CAA- group than HC (p=0.0010). Patients with persistent CAA had the highest CECs, but even those with regressed CAA had higher CECs than HC (p=0.011). CD105 EMPs were also higher in the KD group versus HC (p=0.04), particularly in the CAA+ group (p=0.02), with similar findings for soluble vascular cell adhesion molecule 1 and soluble intercellular adhesion molecule 1. There was no difference in PWV, cIMT, CRF or in markers of systemic inflammation in the patients with KD (CAA+ or CAA-) compared with HC. CONCLUSIONS: Markers of endothelial injury persist for years after KD, including in a subset of patients without CAA.

Lung function in pulmonary hypertension.

Breathlessness is a common symptom in pulmonary hypertension (PH) and an important cause of morbidity. Though this has been attributed to the well described pulmonary vascular abnormalities and subsequent cardiac remodelling, changes in the airways of these patients have also been reported and may contribute to symptoms. Our understanding of these airway abnormalities is poor with conflicting findings in many studies. The present review evaluates these studies for the major PH groups. In addition we describe the role of cardiopulmonary exercise testing in the assessment of pulmonary arterial hypertension (PAH) by evaluating cardiopulmonary interaction during exercise. As yet, the reasons for the abnormalities in lung function are unclear, but potential causes and the possible role of inflammation are discussed. Future research is required to provide a better understanding of this to help improve the management of these patients.

Management of Kawasaki disease.

Kawasaki disease (KD) is an acute self-limiting inflammatory disorder, associated with vasculitis, affecting predominantly medium-sized arteries, particularly the coronary arteries. In developed countries KD is the commonest cause of acquired heart disease in childhood. The aetiology of KD remains unknown, and it is currently believed that one or more as yet unidentified infectious agents induce an intense inflammatory host response in genetically susceptible individuals. Genetic studies have identified several susceptibility genes for KD and its sequelae in different ethnic populations, including FCGR2A, CD40, ITPKC, FAM167A-BLK and CASP3, as well as genes influencing response to intravenous immunoglobulin (IVIG) and aneurysm formation such as FCGR3B, and transforming growth factor (TGF) ß pathway genes. IVIG and aspirin are effective therapeutically, but recent clinical trials and meta-analyses have demonstrated that the addition of corticosteroids to IVIG is beneficial for the prevention of coronary artery aneurysms (CAA) in severe cases with highest risk of IVIG resistance. Outside of Japan, however, clinical scores to predict IVIG resistance perform suboptimally. Furthermore, the evidence base does not provide clear guidance on which corticosteroid regimen is most effective. Other therapies, including anti-TNFα, could also have a role for IVIG-resistant KD. Irrespective of these caveats, it is clear that therapy that reduces inflammation in acute KD, improves outcome. This paper summarises recent advances in the understanding of KD pathogenesis and therapeutics, and provides an approach for managing KD patients in the UK in the light of these advances.

Paediatric pulmonary hypertension and sildenafil: current practice and controversies.

In recent times, paediatric pulmonary arterial hypertension management has been transformed to focus on disease modifying strategies that improve both quality of life and survival, rather than just symptom palliation. Sildenafil, a phosphodiesterase-V inhibitor, has been at the centre of this. Despite controversial beginnings, its success in treating pulmonary arterial hypertension has led to its consideration for related pathologies such as persistent pulmonary hypertension of the newborn and bronchopulmonary dysplasia, as well as the development of a range of alternative formulations. However, this has caused its own controversy and confusion regarding the use of sildenafil in younger patients. In addition, recent data regarding long-term mortality and the repeal of US drugs approval have complicated the issue. Despite such setbacks, sildenafil continues to be a major component of the contemporary care of paediatric pulmonary hypertension in a variety of contexts, and this does not seem likely to change in the foreseeable future.

Management of pulmonary hypertension and Down syndrome.

Down syndrome (DS) is strongly associated with pulmonary hypertension, but there are many causes requiring a multi-disciplinary approach to the problem. Nearly half of children with DS have upper airway obstruction and the same proportion have congenital heart disease, both of which may cause pulmonary hypertension. Additional problems include pulmonary hypoplasia, structural lung disease and gastro-oesophageal reflux. It is no longer acceptable to ignore these symptoms as early treatment may be preventative.

Successful introduction and audit of a step-down oral antibiotic strategy for low risk paediatric febrile neutropaenia in a UK, multicentre, shared care setting.

PURPOSE: Patients with febrile neutropaenia (FN) can be stratified according to their risk of significant complications, allowing reduced intensity therapy for low risk (LR) episodes. Serious events are very rare in low risk episodes making randomised trials difficult. Introduction of new evidence-based guidelines followed by re-auditing of the outcome is an alternative strategy. METHODS: New guidelines for the management of LR FN were implemented in 4 specialist paediatric oncology centres (POCs) and in their associated shared care units (POSCUs). All patients commenced empirical intravenous antibiotic therapy and after 48h those with blood culture negative episodes designated LR were eligible for discharge on oral co-amoxiclav. Prospective data collection on FN episodes in all treatment centres was undertaken over a 1-year period. RESULTS: Seven hundred and sixty two eligible episodes of FN were recorded in 368 patients; 213 episodes were initiated in POCs and 549 episodes were initiated in POSCUs. In 40% of episodes no clinical or microbiological focus of infection was found. At 48h, 212 (27%) episodes were classified as LR and 143 of these (19%) were managed on the LR protocol. There was a low hospital readmission rate (8/143 episodes; 5.6%), no intensive care admissions and no deaths in LR episodes. Almost all LR episodes (209/212) occurred in the shared care setting. CONCLUSIONS: Rapid step-down to oral antibiotics was a feasible and safe management strategy for LR FN in the shared care setting in England.

Kawasaki disease in children.

Kawasaki disease (KD) is an acute self-limiting systemic vasculitis of unknown aetiology. It is the most common cause of acquired heart disease in young children. The intense inflammatory process has a predilection for the coronary arteries, resulting in the development of aneurysmal lesions, arterial thrombotic occlusion or, potentially, sudden death. There is no specific diagnostic test; however, treatment with immunoglobulin and aspirin effectively reduces cardiac complications from 25% to 4.7% in the UK. Inflammation of the myocardium, endocardium or pericardium can occur early in the disease and endothelial dysfunction along with abnormalities of myocardial blood flow may require continuing medication, interventional catheterisation or even cardiac surgery. Several new pharmacological treatments may have important roles to play in managing KD in children and adolescents. This review discusses the history of the disease, the diagnostic challenges, epidemiology, aetiology, pathology, immunopathogenesis, treatment, genetic influences and the long-term cardiovascular sequelae.

Hypocalcaemia and vitamin D deficiency: an important, but preventable, cause of life-threatening infant heart failure.

BACKGROUND: In recent large paediatric cardiomyopathy population studies from North America and Australia, vitamin D deficiency was not identified as a cause of infant heart failure. However, rickets is resurgent in developed countries. OBJECTIVE: To review the prevalence of this cardiomyopathy in paediatric cardiology units of southeast England and determine the prognosis. METHODS AND RESULTS: A retrospective review from 2000 to 2006 in southeast England. Sixteen infants (6 Indian subcontinent, 10 black ethnicity) were identified: median (range) age at presentation was 5.3 months (3 weeks-8 months). All had been breast fed. Ten presented at the end of the British winter (February-May). Median shortening fraction was 10% (range 5-18%) and median left ventricular end diastolic dimension z score was 4.1 (range 3.1-7.0). Six had a cardiac arrest; three infants died. Eight were ventilated, two required mechanical circulatory support and 12 required intravenous inotropic support. Two were referred for cardiac transplantation. Median (range) of biochemical values on admission was: total calcium 1.5 (1.07-1.74) mmol/l; alkaline phosphatase 646 (340-1057) IU/l; 25-hydroxyvitamin D 18.5 (0-46) nmol/l (normal range >35) and parathyroid hormone 34.3 (8.9-102) pmol/l (normal range <6.1). The clinical markers and echocardiographic indices of all survivors have improved. The mean time from diagnosis to achieve normal fractional shortening was 12.4 months. CONCLUSIONS: Vitamin D deficiency and consequent hypocalcaemia are seen in association with severe and life-threatening infant heart failure. That no infant or mother was receiving the recommended vitamin supplementation highlights the need for adequate provision of vitamin D to ethnic minority populations.

Interventional cardiac catheterisation in congenital heart disease.

As a result of recent technological advances, more types of congenital heart disease are amenable to treatment in the cardiac catheter laboratory than ever before.1 Improved imaging techniques allow for better selection of patients, and the development of a wide range of devices specifically for use in children means that many patients can avoid surgery altogether, while those with complex congenital heart disease may require fewer or less complex surgical procedures.2 This allows for a quicker recovery and a shorter hospital stay, and gives many patients an improved quality of life in the short to medium term. However, the long term outcome for many of the newer forms of intervention is still unknown.