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.

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.

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.

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.

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.

Acute myocardial infarction as a cause of death in palliated hypoplastic left heart syndrome.

A 20 month old child with hypoplastic left heart syndrome died suddenly from a massive myocardial infarction 15 months after a hemi-Fontan operation. This was confirmed at postmortem examination and histological examinations. The sites of surgical reconstruction were all in good condition, there were no gross anatomical coronary abnormalities, and the coronary ostia were unobstructed. On microscopy the internal coronary arteries had notable intimal and medial thickening with narrowing of the lumen, although no thrombotic occlusion was seen. To the authors' knowledge, this is the first published report of arteriosclerosis of the coronary arteries in hypoplastic left heart syndrome. It raises the question as to whether there may be a primary histological abnormality in some children with this condition or whether some mechanism of accelerated arteriosclerosis is at work.

Coronary artery changes in patients with Kawasaki disease.

Kawasaki disease (KD) is an acute, self-limiting, systemic vasculitis of unknown aetiology, which most commonly occurs in children aged 6 mo to 5 y, with a peak incidence at 9-11 mo. The inflammatory process preferentially involves the coronary arteries, potentially resulting in coronary arteritis, aneurysmal lesions, arterial thrombotic occlusion and sudden death. Kawasaki disease is the most common cause of acquired coronary vessel abnormalities in children. The cause of KD is not known, but evidence is presented for an inflammatory response and a genetic predisposition. The diagnostic tests are not yet defined, but treatment with immunoglobulin and aspirin is effective at reducing the risk of cardiac complications from 25% to 4.7% in the UK. Sequelae may occur, either acutely with myocardial, endocardial or pericardial inflammation, or many years after the original illness. There may be abnormalities of myocardial blood flow as assessed by MRI, radio-nucleide studies or echo Doppler. Such abnormalities of coronary arteries may require ongoing medication, interventional catheterization or even cardiac surgery. In the future, we hope to have more accurate diagnostic tests or prophylaxis against the disease, in addition to improved means of determining the susceptibility to or presence of long-term complications.

Percutaneous retrieval of central venous catheter fragments.

Children with indwelling central venous catheters are at risk of embolisation of catheter fragments. Often their underlying condition means that they are poor candidates for surgical removal. We describe six children who underwent uncomplicated percutaneous transcatheter retrieval (and one who underwent percutaneous line tip repositioning), and suggest that this approach should be the treatment of choice.

Coil occlusion of systemic venous collaterals in hypoplastic left heart syndrome.

OBJECTIVE: To assess the frequency of systemic venous collaterals to the atria, which may cause desaturation, after stage II reconstructive surgery for hypoplastic left heart syndrome (HLHS) and to determine whether coil occlusion prevents the need for surgical ligation. DESIGN: Prospective interventional study. SETTING: Tertiary referral centre. PATIENTS: 27 children with HLHS undergoing cardiac catheterisation between October 1996 and February 2001. INTERVENTIONS: 19 children were catheterised prestage II, 1 poststage II, and 17 prestage III. Aortic oxygen saturation (SaAo) and pulmonary artery pressure (pPA) were recorded. Angiography was performed into the left internal jugular vein to look for venous collaterals. If present, they were occluded with Cook MReye coils. Angiography was repeated to confirm occlusion, and SaAo and pPA were remeasured. RESULTS: Collaterals were found in 7 of 27 children: 1 poststage II and 6 prestage III. These were occluded with 1-3 coils without complication. Mean (SE) SaAo before occlusion was 80.2 (2.1)% in those with collaterals compared with 88.7 (1.0)% in those without (p = 0.007). There was no difference in mean pPA between the two groups. After coil occlusion mean SaAo rose to 83.8 (1.8)% (p = 0.007) and mean pPA rose from 12.5 (1.5) to 14.5 (1.8) mm Hg (p = 0.02). None required surgical ligation. CONCLUSION: Angiography should be performed at catheterisation before stage II and III surgery for HLHS to exclude systemic venous collaterals. If present, they may be safely and effectively occluded with coils to improve saturation and prevent the need for subsequent surgical ligation.

Retrospective prenatal diagnosis of scimitar syndrome aided by three-dimensional power Doppler imaging.

Scimitar syndrome is a rare malformation of the arterial supply and venous drainage of the lung. We report the case of a fetus that presented with cardiac asymmetry and malposition of the fetal heart. Postnatally, scimitar syndrome was confirmed at cardiac catheterization. Retrospective reconstruction of three-dimensional power Doppler volumes, obtained during fetal life, allowed direct visualization of the abnormal aortopulmonary collateral vessel. This had not been seen on conventional scans. This case demonstrates many of the strengths of three-dimensional sonographic techniques for the delineation of complex vascular anatomy. It confirms that a prospective diagnosis of scimitar syndrome should be possible during fetal life.

Coronary arterial origins in transposition of the great arteries: factors that affect outcome. A morphological and clinical study.

OBJECTIVE: Transfer of the coronary arteries is crucial during the arterial switch operation for transposition, but little attention has been paid to the position of their orifices relative to the valvar sinuses. The objective of this study was to determine the factors which are important for effective transfer and to determine potential surgical significance. DESIGN: Morphological and clinical study. SETTING: Two national centres for neonatal cardiac surgery. PATIENTS: 277 patients with transposition of the great arteries. One group comprised 88 necropsy specimens (ages ranging from 17 weeks of fetal life to 17 years old), and the other comprised 189 children undergoing surgery. The coronary artery orifices were inspected relative to the depth of the aortic sinuses (vertical origin), relative to the commissures between the valvar leaflets (radial origin), and their angle of exit from the aortic wall (angle of origin). The data were compared with the surgical results. RESULTS: In the necropsy specimens, the vertical origin of the arteries was at, or above, the sinutubular junction in 20%, the radial origin was paracommissural in 3%, and the angle of origin was not orthogonal in 7%. Those with high take off and paracommissural origin were all intramural. In the clinical cases, those children with high take off, paracommissural origin or tangential origin had an increased risk at surgery. CONCLUSIONS: In 20% of hearts, high take off, paracommissural orifice, or tangential origin of coronary arteries is found. This may be recognised preoperatively by echocardiography and may cause technical difficulty in transfer during the arterial switch procedure.

Role of NO in recovery from neonatal hypoxic pulmonary hypertension.

BACKGROUND: The management of sick newborn infants who have sustained a hypoxic insult is a common clinical problem but relatively little is known about the recovery process. The aim of this study was to investigate this process in newborn piglets. METHODS: Thirty five newborn piglets were exposed to chronic hypobaric hypoxia for three days, either from birth, three or 14 days of age, and were allowed to recover for one, three, or six days. Control animals of relevant age were also studied. The heart weight ratio and pulmonary arterial muscularity were measured. Endothelial dependent and independent relaxation of the isolated intrapulmonary conduit arteries was determined in classical organ chamber studies, together with measurement of basal and stimulated cGMP accumulation. RESULTS: After six days of recovery the hypoxia induced right ventricular hypertrophy and pulmonary arterial medial hypertrophy had decreased in all animals but values were still abnormal in the two younger age groups. Relaxation was still impaired during the first three days of recovery in all groups, had normalised by six days in the two youngest groups, but relaxation (both endothelium dependent and independent) remained impaired in older animals. In these older animals basal nitric oxide (NO) production and basal and stimulated cGMP accumulation was normal. CONCLUSIONS: The recovery of the smooth muscle cells lags behind that of the endothelial cells. A normal stimulated increase in cGMP with reduced relaxation suggests an altered threshold for cGMP effected relaxation. These findings help to explain why some hypoxic infants require protracted NO therapy.

A wandering nasal prong-a thing of risks and problems.

We describe an unusual complication of nasal continuous positive airway pressure (nCPAP) ventilation in a preterm low birth weight neonate being weaned from respiratory support. The tube used to administer nasal CPAP became dislodged from its metal connector whilst in the nasopharynx and slipped into the stomach. After waiting eight days the tube showed no signs of passing spontaneously through the gastrointestinal tract and retrieval was then successfully achieved by means of a 3.5 mm paediatric fibreoptic bronchoscope without complication.