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

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

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

Imaging and Risk Stratification in Pulmonary Arterial Hypertension: Time to Include Right Ventricular Assessment

Background: Current European Society of Cardiology and European Respiratory Society guidelines recommend regular risk stratification with an aim of treating patients with pulmonary arterial hypertension (PAH) to improve or maintain low-risk status (<5% 1-year mortality). Methods: Consecutive patients with PAH who underwent cardiac magnetic resonance imaging (cMRI) were identified from the Assessing the Spectrum of Pulmonary hypertension Identified at a Referral centre (ASPIRE) registry. Kaplan–Meier survival curves, locally weighted scatterplot smoothing regression and multi-variable logistic regression analysis were performed. Results: In 311 consecutive, treatment-naïve patients with PAH undergoing cMRI including 121 undergoing follow-up cMRI, measures of right ventricular (RV) function including right ventricular ejection fraction (RVEF) and RV end systolic volume and right atrial (RA) area had prognostic value. However, only RV metrics were able to identify a low-risk status. Age (p < 0.01) and RVEF (p < 0.01) but not RA area were independent predictors of 1-year mortality. Conclusion: This study highlights the need for guidelines to include measures of RV function rather than RA area alone to aid the risk stratification of patients with PAH

Genetic counselling and testing in pulmonary arterial hypertension:a consensus statement on behalf of the International Consortium for Genetic Studies in PAH

Pulmonary arterial hypertension (PAH) is a rare disease that can be caused by (likely) pathogenic germline genomic variants. In addition to the most prevalent disease gene, BMPR2 (bone morphogenetic protein receptor 2), several genes, some belonging to distinct functional classes, are also now known to predispose to the development of PAH. As a consequence, specialist and non-specialist clinicians and healthcare professionals are increasingly faced with a range of questions regarding the need for, approaches to and benefits/risks of genetic testing for PAH patients and/or related family members. We provide a consensus-based approach to recommendations for genetic counselling and assessment of current best practice for disease gene testing. We provide a framework and the type of information to be provided to patients and relatives through the process of genetic counselling, and describe the presently known disease causal genes to be analysed. Benefits of including molecular genetic testing within the management protocol of patients with PAH include the identification of individuals misclassified by other diagnostic approaches, the optimisation of phenotypic characterisation for aggregation of outcome data, including in clinical trials, and importantly through cascade screening, the detection of healthy causal variant carriers, to whom regular assessment should be offered.</p

Non-invasive detection of severe PH in lung disease using magnetic resonance imaging

IntroductionSevere pulmonary hypertension (mean pulmonary artery pressure ≥35 mmHg) in chronic lung disease (PH-CLD) is associated with high mortality and morbidity. Data suggesting potential response to vasodilator therapy in patients with PH-CLD is emerging. The current diagnostic strategy utilises transthoracic Echocardiography (TTE), which can be technically challenging in some patients with advanced CLD. The aim of this study was to evaluate the diagnostic role of MRI models to diagnose severe PH in CLD.Methods167 patients with CLD referred for suspected PH who underwent baseline cardiac MRI, pulmonary function tests and right heart catheterisation were identified. In a derivation cohort (n = 67) a bi-logistic regression model was developed to identify severe PH and compared to a previously published multiparameter model (Whitfield model), which is based on interventricular septal angle, ventricular mass index and diastolic pulmonary artery area. The model was evaluated in a test cohort.ResultsThe CLD-PH MRI model [= (−13.104) + (13.059 * VMI)—(0.237 * PA RAC) + (0.083 * Systolic Septal Angle)], had high accuracy in the test cohort (area under the ROC curve (0.91) (p &lt; 0.0001), sensitivity 92.3%, specificity 70.2%, PPV 77.4%, and NPV 89.2%. The Whitfield model also had high accuracy in the test cohort (area under the ROC curve (0.92) (p &lt; 0.0001), sensitivity 80.8%, specificity 87.2%, PPV 87.5%, and NPV 80.4%.ConclusionThe CLD-PH MRI model and Whitfield model have high accuracy to detect severe PH in CLD, and have strong prognostic value

NBEAL2 is required for neutrophil and NK cell function and pathogen defense.

Mutations in the human NBEAL2 gene cause gray platelet syndrome (GPS), a bleeding diathesis characterized by a lack of α granules in platelets. The functions of the NBEAL2 protein have not been explored outside platelet biology, but there are reports of increased frequency of infection and abnormal neutrophil morphology in patients with GPS. We therefore investigated the role of NBEAL2 in immunity by analyzing the phenotype of Nbeal2-deficient mice. We found profound abnormalities in the Nbeal2-deficient immune system, particularly in the function of neutrophils and NK cells. Phenotyping of Nbeal2-deficient neutrophils showed a severe reduction in granule contents across all granule subsets. Despite this, Nbeal2-deficient neutrophils had an enhanced phagocyte respiratory burst relative to Nbeal2-expressing neutrophils. This respiratory burst was associated with increased expression of cytosolic components of the NADPH oxidase complex. Nbeal2-deficient NK cells were also dysfunctional and showed reduced degranulation. These abnormalities were associated with increased susceptibility to both bacterial (Staphylococcus aureus) and viral (murine CMV) infection in vivo. These results define an essential role for NBEAL2 in mammalian immunity

Identification of rare sequence variation underlying heritable pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-β pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlies most heritable forms of PAH. To identify the missing heritability we perform whole-genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses reveal significant overrepresentation of rare variants in ATP13A3, AQP1 and SOX17, and provide independent validation of a critical role for GDF2 in PAH. We demonstrate familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2, encoding a BMPR2 ligand, lead to reduced secretion from transfected cells. In addition, we identify pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings contribute new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention