Management of Adults With Congenital Heart Disease and Pulmonary Arterial Hypertension in the UK:Survey of Current Practice, Unmet Needs and Expert Commentary

BACKGROUND: Pulmonary arterial hypertension (PAH) is a well-recognised complication of adult congenital heart disease (CHD). However, management is not currently standardised between centres and specific guidelines are lacking. In order to identify and understand the unmet needs related to PAH associated with CHD (PAH-CHD), a survey of physicians was performed. METHODS: An electronic survey was sent to two physician groups: (1) cardiologists registered in a UK cardiology directory; (2) specialist pulmonary hypertension (PH) physicians known to manage patients with adult PAH-CHD. The questions related to referral pathways, screening, therapy and palliative care. RESULTS: 821 surveys were distributed and 106 were returned. Respondents included a broad mix of specialist physicians with many patients along with general cardiologists managing only a small number of PAH-CHD patients. Although 97% of respondents have access to a specialist PH centre, patients are still being managed in non-specialist settings. Shared care arrangements are widespread but only 41% have formal shared care protocols. Palliative care services are limited and general cardiologists rarely perform 6-minute walk tests (6MWT) or quality of life assessments. People with PAH-CHD are often undertreated, with 39% of respondents reporting that fewer than 25% of these patients were receiving PAH-specific therapies. CONCLUSIONS: The survey revealed gaps and inconsistencies in the management of patients with PAH-CHD therefore patient-specific guidance is needed for many of these aspects

The use of Macitentan in Fontan circulation: a case report.

BACKGROUND: The Fontan circulation, a result of a palliative procedure in patients with single systemic ventricles, is defined by chronically elevated pulmonary vascular resistance. When traditional heart failure therapies fail, pharmacological agents that reduce pulmonary artery pressures may be used. These include endothelial-receptor antagonists, prostanoids and phosphodiesterase type 5 inhibitors. We report the first use of macitentan, an endothelin-receptor antagonist, in a patient with a Fontan circulation. CASE PRESENTATION: We describe the case of a 50 year old female with tricuspid atresia and transposition of the great arteries. Following complex surgery as a child, she subsequently underwent a fenestrated modified atrial pulmonary Fontan operation which was later converted to a total cavopulmonary anastomosis Fontan circulation. Due to failure of various medications to relieve her worsening symptoms, she was commenced on macitentan in April 2016. Few months later, she demonstrated a significant symptomatic improvement and associated increase in her incremental shuttle walking test distance. CONCLUSIONS: Macitentan has slower receptor dissociation kinetics compared to other endothelin-receptor antagonists, leading to enhanced pharmacological activity with promising effects in patients with pulmonary arterial hypertension. The patient we report has shown considerable improvement in exercise capacity following introduction of this medication and thus we suggest further randomised trials to establish the role of different endothelin-receptor antagonists in the management of the Fontan circulation

Pathways for outpatient management of venous thromboembolism in a UK centre.

It has become widely recognised that outpatient treatment may be suitable for many patients with venous thromboembolism. In addition, non-vitamin K antagonist oral anticoagulants that have been approved over the last few years have the potential to be an integral component of the outpatient care pathway, owing to their oral route of administration, lack of requirement for routine anticoagulation monitoring and simple dosing regimens. A robust pathway for outpatient care is also vital; one such pathway has been developed at Sheffield Teaching Hospitals in the UK. This paper describes the pathway and the arguments in its favour as an example of best practice and value offered to patients with venous thromboembolism. The pathway has two branches (one for deep vein thrombosis and one for pulmonary embolism), each with the same five-step process for outpatient treatment. Both begin from the point that the patient presents (in the Emergency Department, Thrombosis Clinic or general practitioner's office), followed by diagnosis, risk stratification, treatment choice and, finally, follow-up. The advantages of these pathways are that they offer clear, evidence-based guidance for the identification, diagnosis and treatment of patients who can safely be treated in the outpatient setting, and provide a detailed, stepwise process that can be easily adapted to suit the needs of other institutions. The approach is likely to result in both healthcare and economic benefits, including increased patient satisfaction and shorter hospital stays

Pulmonary Artery Denervation Reduces Pulmonary Artery Pressure and Induces Histological Changes in an Acute Porcine Model of Pulmonary Hypertension

Background—Pulmonary arterial hypertension is a devastating disease with high morbidity and mortality and limited treatment options. Recent studies have shown that pulmonary artery denervation improves pulmonary hemodynamics in an experimental model and in an early clinical trial. We aimed to evaluate the nerve distribution around the pulmonary artery, to determine the effect of radiofrequency pulmonary artery denervation on acute pulmonary hypertension induced by vasoconstriction, and to demonstrate denervation of the pulmonary artery at a histological level. Methods and Results—Histological evaluation identified a circumferential distribution of nerves around the proximal pulmonary arteries. Nerves were smaller in diameter, greater in number, and located in closer proximity to the luminal aspect of the pulmonary arterial wall beyond the pulmonary artery bifurcation. To determine the effect of pulmonary arterial denervation acute pulmonary hypertension was induced in 8 pigs by intravenous infusion of thromboxane A2 analogue. Animals were assigned to either pulmonary artery denervation, using a prototype radiofrequency catheter and generator, or a sham procedure. Pulmonary artery denervation resulted in reduced mean pulmonary artery pressure and pulmonary vascular resistance and increased cardiac output. Ablation lesions on the luminal surface of the pulmonary artery were accompanied by histological and biochemical alteration in adventitial nerves and correlated with improved hemodynamic parameters. Conclusions—Pulmonary artery denervation offers the possibility of a new treatment option for patients with pulmonary arterial hypertension. Further work is required to determine the long-term efficacy and safety

A machine learning cardiac magnetic resonance approach to extract disease features and automate pulmonary arterial hypertension diagnosis

Aims: Pulmonary arterial hypertension (PAH) is a progressive condition with high mortality. Quantitative cardiovascular magnetic resonance (CMR) imaging metrics in PAH target individual cardiac structures and have diagnostic and prognostic utility but are challenging to acquire. The primary aim of this study was to develop and test a tensor-based machine learning approach to holistically identify diagnostic features in PAH using CMR, and secondarily, visualize and interpret key discriminative features associated with PAH. Methods and results: Consecutive treatment naive patients with PAH or no evidence of pulmonary hypertension (PH), undergoing CMR and right heart catheterization within 48 h, were identified from the ASPIRE registry. A tensor-based machine learning approach, multilinear subspace learning, was developed and the diagnostic accuracy of this approach was compared with standard CMR measurements. Two hundred and twenty patients were identified: 150 with PAH and 70 with no PH. The diagnostic accuracy of the approach was high as assessed by area under the curve at receiver operating characteristic analysis (P < 0.001): 0.92 for PAH, slightly higher than standard CMR metrics. Moreover, establishing the diagnosis using the approach was less time-consuming, being achieved within 10 s. Learnt features were visualized in feature maps with correspondence to cardiac phases, confirming known and also identifying potentially new diagnostic features in PAH. Conclusion: A tensor-based machine learning approach has been developed and applied to CMR. High diagnostic accuracy has been shown for PAH diagnosis and new learnt features were visualized with diagnostic potential

Homozygous GDF2 nonsense mutations result in a loss of circulating BMP9 and BMP10 and are associated with either PAH or an "HHT-like" syndrome in children.

BACKGROUND: Disrupted endothelial BMP9/10 signaling may contribute to the pathophysiology of both hereditary hemorrhagic telangiectasia (HHT) and pulmonary arterial hypertension (PAH), yet loss of circulating BMP9 has not been confirmed in individuals with ultra-rare homozygous GDF2 (BMP9 gene) nonsense mutations. We studied two pediatric patients homozygous for GDF2 (BMP9 gene) nonsense mutations: one with PAH (c.[76C>T];[76C>T] or p.[Gln26Ter];[Gln26Ter] and a new individual with pulmonary arteriovenous malformations (PAVMs; c.[835G>T];[835G>T] or p.[Glu279Ter];[Glu279Ter]); both with facial telangiectases. METHODS: Plasma samples were assayed for BMP9 and BMP10 by ELISA. In parallel, serum BMP activity was assayed using an endothelial BRE-luciferase reporter cell line (HMEC1-BRE). Proteins were expressed for assessment of secretion and processing. RESULTS: Plasma levels of both BMP9 and BMP10 were undetectable in the two homozygous index cases and this corresponded to low serum-derived endothelial BMP activity in the patients. Measured BMP9 and BMP10 levels were reduced in the asymptomatic heterozygous p.[Glu279Ter] parents, but serum activity was normal. Although expression studies suggested alternate translation can be initiated at Met57 in the p.[Gln26Ter] mutant, this does not result in secretion of functional BMP9. CONCLUSION: Collectively, these data show that homozygous GDF2 mutations, leading to a loss of circulating BMP9 and BMP10, can cause either pediatric PAH and/or "HHT-like" telangiectases and PAVMs. Although patients reported to date have manifestations that overlap with those of HHT, none meet the Curaçao criteria for HHT and seem distinct from HHT in terms of the location and appearance of telangiectases, and a tendency for tiny, diffuse PAVMs

Diagnosis of pulmonary hypertension with cardiac MRI: Derivation and validation of regression models

Purpose: To derive and test multiparametric cardiac MRI models for the diagnosis of pulmonary hypertension (PH). Materials and Methods: Images and patient data from consecutive patients suspected of having PH who underwent cardiac MRI and right-sided heart catheterization (RHC) between 2012 and 2016 were retrospectively reviewed. Of 2437 MR images identified, 603 fit the inclusion criteria. The mean patient age was 61 years (range, 18-88 years; mean age of women, 60 years [range, 18-84 years]; mean age of men, 62 years [range, 22-88 years]). In the first 300 patients (derivation cohort), cardiac MRI metrics that showed correlation with mean pulmonary arterial pressure (mPAP) were used to create a regression algorithm. The performance of the model was assessed in the 303-patient validation cohort by using receiver operating characteristic (ROC) and x² analysis. Results: In the derivation cohort, cardiac MRI mPAP model 1 (right ventricle and black blood) was defined as follows: 2179 + loge interventricular septal angle × 42.7 + log10 ventricular mass index (right ventricular mass/left ventricular mass) × 7.57 + black blood slow flow score × 3.39. In the validation cohort, cardiac MRI mPAP model 1 had strong agreement with RHC-measured mPAP, an intraclass coefficient of 0.78, and high diagnostic accuracy (area under the ROC curve = 0.95; 95% confidence interval [CI]: 0.93, 0.98). The threshold of at least 25 mm Hg had a sensitivity of 93% (95% CI: 89%, 96%), specificity of 79% (95% CI: 65%, 89%), positive predictive value of 96% (95% CI: 93%, 98%), and negative predictive value of 67% (95% CI: 53%, 78%) in the validation cohort. A second model, cardiac MRI mPAP model 2 (right ventricle pulmonary artery), which excludes the black blood flow score, had equivalent diagnostic accuracy (ROC difference: P = .24). Conclusion: Multiparametric cardiac MRI models have high diagnostic accuracy in patients suspected of having pulmonary hypertension