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Abstract Rationale Incident pulmonary arterial hypertension was underrepresented in most pulmonary hypertension registries and may have a different disease profile to prevalent disease. Objectives To determine the characteristics and outcome of a purely incident, treatment-naive cohort of idiopathic, heritable, and anorexigen-associated pulmonary arterial hypertension and to determine the changes in presentations and survival over the past decade in the United Kingdom and Ireland. Methods All consecutive newly diagnosed patients from 2001 to 2009 were identified prospectively. Measurements and Main Results A total of 482 patients (93% idiopathic, 5% heritable, and 2% anorexigen-associated pulmonary arterial hypertension) were diagnosed, giving rise to an estimated incidence of 1.1 cases per million per year and prevalence of 6.6 cases per million in 2009. Younger patients (age ≤ 50 yrs) had shorter duration of symptoms, fewer comorbidities, better functional and exercise capacity, higher percent diffusing capacity of carbon monoxide, more severe hemodynamic impairment, but better survival compared with older patients. In comparison with the earlier cohorts, patients diagnosed in 2007–2009 were older, more obese, had lower percent diffusing capacity of carbon monoxide,, and more comorbidities, but better survival. Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) equation, REVEAL risk score, and Pulmonary Hypertension Connection Registry survival equation accurately predicted survival of our incident cohort at 1 year. Conclusions This study highlights the influence of age on phenotypes of incident pulmonary arterial hypertension and has shown the changes in demographics and epidemiology over the past decade in a national setting. The results suggest that there may be two subtypes of patients: the younger subtype with more severe hemodynamic impairment but better survival, compared with the older subtype who has more comorbidities.

Motion analysis is used in computer vision to understand the behaviour of moving objects in sequences of images. Optimizing the interpretation of dynamic biological systems requires accurate and precise motion tracking as well as efficient representations of high-dimensional motion trajectories so that these can be used for prediction tasks. Here we use image sequences of the heart, acquired using cardiac magnetic resonance imaging, to create time-resolved three-dimensional segmentations using a fully convolutional network trained on anatomical shape priors. This dense motion model formed the input to a supervised denoising autoencoder (4Dsurvival), which is a hybrid network consisting of an autoencoder that learns a task-specific latent code representation trained on observed outcome data, yielding a latent representation optimized for survival prediction. To handle right-censored survival outcomes, our network used a Cox partial likelihood loss function. In a study of 302 patients, the predictive accuracy (quantified by Harrell’s C -index) was significantly higher ( P  = 0.0012) for our model C  = 0.75 (95% CI: 0.70–0.79) than the human benchmark of C  = 0.59 (95% CI: 0.53–0.65). This work demonstrates how a complex computer vision task using high-dimensional medical image data can efficiently predict human survival. A fully convolutional neural network is used to create time-resolved three-dimensional dense segmentations of heart images. This dense motion model forms the input to a supervised system called 4Dsurvival that can efficiently predict human survival.

Abstract Rationale Pulmonary arterial hypertension in association with connective tissue disease (CTD-PAH) has historically had a poor prognosis, with a 1-year survival rate among patients with systemic sclerosis–associated pulmonary arterial hypertension (SSc-PAH) of 45%. However, more therapies have become available. Objectives To investigate the survival and characteristics of all patients diagnosed with CTD-PAH in the U.K. pulmonary hypertension service. Methods National registry of all incident cases of CTD-PAH diagnosed consecutively between January 2001 and June 2006. Measurements and Main Results Patients with CTD-PAH (429; 73% SSc-PAH) were diagnosed by a catheter-based approach. One- and 3-year survival rates were 78 and 47% for patients with isolated SSc-PAH. Survival was worse for those with respiratory disease–associated SSc-PAH (3-yr survival, 28%; P = 0.005) whereas survival among patients with exercise-induced SSc-PAH was superior (3-yr survival, 86%; P = < 0.001). Age, sex, mixed venous oxygen saturation, and World Health Organization functional class were independent predictors of survival in isolated SSc-PAH. Nineteen percent of patients with exercise-induced SSc-PAH and 39% of patients with isolated SSc-PAH who were in functional classes I and II had evidence of disease progression. The prevalence of diagnosed SSc-PAH is 2.93 per 1 million. The 3-year survival rate of 75% for those with pulmonary arterial hypertension associated with systemic lupus erythematosus (SLE-PAH) was significantly better than that for patients with SSc-PAH (P = 0.01). Conclusions Survival of patients with SSc-PAH in the modern treatment era is better than in historical series. A significant proportion of patients with mild functional impairment or exercise-induced SSc-PAH have evidence of disease progression. Survival of patients with respiratory disease–associated pulmonary hypertension is inferior. SLE-PAH has a better prognosis than SSc-PAH.

Pulmonary hypertension (PH) is a common finding in patients with chronic fibrosing idiopathic interstitial pneumonias (IIP). Little is known about the response to pulmonary vasodilator therapy in this patient population. COMPERA is an international registry that prospectively captures data from patients with various forms of PH receiving pulmonary vasodilator therapies. We retrieved data from COMPERA to compare patient characteristics, treatment patterns, response to therapy and survival in newly diagnosed patients with idiopathic pulmonary arterial hypertension (IPAH) and PH associated with IIP (PH-IIP). Compared to patients with IPAH (n = 798), patients with PH-IIP (n = 151) were older and predominantly males. Patients with PH-IIP were treated predominantly with phosphodiesterase-5 inhibitors (88% at entry, 87% after 1 year). From baseline to the first follow-up visit, the median improvement in 6MWD was 30 m in patients with IPAH and 24.5 m in patients with PH-IIP (p = 0.457 for the difference between both groups). Improvements in NYHA functional class were observed in 22.4% and 29.5% of these patients, respectively (p = 0.179 for the difference between both groups). Survival rates were significantly worse in PH-IIP than in IPAH (3-year survival 34.0 versus 68.6%; p<0.001). Total lung capacity, NYHA class IV, and mixed-venous oxygen saturation were independent predictors of survival in patients with PH-IIP. Patients with PH-IIP have a dismal prognosis. Our results suggest that pulmonary vasodilator therapy may be associated with short-term functional improvement in some of these patients but it is unclear whether this treatment affects survival. clinicaltrials.gov NCT01347216.

BackgroundIn addition to N-terminal pro-brain natriuretic peptide (NT-proBNP), red cell distribution width (RDW), growth differentiation factor (GDF)-15, interleukin (IL)-6 and creatinine are all potential circulating prognostic biomarkers in pulmonary arterial hypertension (PAH).ObjectiveTo establish the relative prognostic utility of these biomarkers in patients with idiopathic PAH (IPAH) and to identify independent prognostic markers in this disease.Main outcome measuresCirculating RDW, GDF-15, IL-6, creatinine and NT-proBNP levels were determined in 139 patients with IPAH (mean follow-up 4.0±2.4 years) and 40 age- and sex-matched healthy volunteers. Coincident clinical data and baseline haemodynamic measurements were also analysed.ResultsAll the biomarkers except creatinine correlated with a 6 min walk distance (6MWD; p<0.05), and all but NT-proBNP correlated with WHO functional class (p<0.01). GDF-15, creatinine and NT-proBNP correlated with mean right atrial pressures and cardiac index. RDW outperformed other biomarkers in receiver operating characteristic (ROC) analysis (area under the curve 0.820). Sensitive (>80%) ROC-derived cut-off points of RDW (15.7%, p=0.001), GDF-15 (779 pg/ml, p<0.001), IL-6 (2.5 pg/ml, p=0.019), creatinine (80.5 μmol/l, p=0.010) and NT-proBNP (491 fmol/ml, p<0.001), all predicted survival in patients with IPAH over time. All the plasma biomarkers analysed predicted survival in Cox regression analysis, as did clinical and haemodynamic parameters. However, only RDW predicted survival independently of NT-proBNP and 6MWD.ConclusionsCirculating RDW, GDF-15, IL-6, creatinine and NT-proBNP levels are all related to disease severity and may be used to predict survival in patients with IPAH. RDW added significant prognostic value to measurements of NT-proBNP and exercise capacity and may prove valuable in a multiple biomarker approach to disease stratification.

Abstract Rationale The management of chronic thromboembolic pulmonary hypertension (CTEPH) has changed over recent years with the growth of pulmonary endarterectomy surgery and the availability of disease-modifying therapies. Objectives To investigate the prognosis of CTEPH in a national setting during recent years. Methods All incident cases diagnosed in one of the five pulmonary hypertension centers in the United Kingdom between January 2001 and June 2006 were identified prospectively. Information regarding baseline characteristics, treatment, and follow-up was subsequently collected from hospital records. Measurements and Main Results A total of 469 patients received a diagnosis, of whom 148 (32%) had distal, nonsurgical disease. One- and three-year survival from diagnosis was 82 and 70% for patients with nonsurgical disease and 88 and 76% for those treated surgically (P = 0.023). Initial functional improvement in patients with nonsurgical disease was noted but did not persist at 2 years. Significant functional and hemodynamic improvements were seen in surgically treated patients with an increase in six-minute-walk distance of 105 m (P < 0.001) at 3 months. Five-year survival from surgery in the 35% of patients who survived to 3 months but had persistent pulmonary hypertension was 94%. Conclusions The prognosis in nonsurgical disease has improved. We have confirmed the previously described good outcome in surgically treated disease. However, we have also demonstrated that the long-term prognosis for patients who have persistent pulmonary hypertension at 3 months after surgery is good. The observed improvements in outcome during the modern treatment era reinforce the importance of identifying patients with this increasingly treatable condition.

Pulmonary hypertension represents a group of conditions characterized by higher than normal pulmonary artery pressures. Despite improved treatments, outcomes in many instances remain poor. In recent years, there has been growing interest in the use of Cardiovascular Magnetic Resonance (CMR) in patients with pulmonary hypertension. This technique offers certain advantages over other imaging modalities since it is well suited to the assessment of the right ventricle and the proximal pulmonary arteries. Reflecting the relatively sparse evidence supporting its use, CMR is not routinely recommended for patients with pulmonary hypertension. However, it is particularly useful in patient with pulmonary arterial hypertension associated with congenital heart disease. Furthermore, it has proven informative in a number of ways; illustrating how right ventricular remodeling is favorably reversed by drug therapies and providing explicit confirmation of the importance of the right ventricle to clinical outcome. This review will discuss these aspects and practical considerations before speculating on future applications.

Abstract Rationale: Phosphodiesterase type 5 (PDE5) inhibition has been proposed for the treatment for pulmonary arterial hypertension (PAH). Objective: This study compared adding sildenafil, a PDE5 inhibitor, to conventional treatment with the current practice of adding bosentan, an endothelin receptor antagonist. Methods: Twenty-six patients with PAH, idiopathic or associated with connective tissue disease, World Health Organization (WHO) functional class III, were randomized in a double-blind fashion to receive sildenafil (50 mg twice daily for 4 weeks, then 50 mg three times daily) or bosentan (62.5 mg twice daily for 4 weeks, then 125 mg twice daily) over 16 weeks. Measurements: Changes in right ventricular (RV) mass (using cardiovascular magnetic resonance), 6-minute walk distance, cardiac function, brain natriuretic peptide, and Borg dyspnea index. Main Results: When analyzed by intention to treat, there were no significant differences between the two treatment groups. One patient on sildenafil died suddenly. Patients on sildenafil who completed the protocol showed significant changes from baseline, namely, reductions in RV mass (−8.8 g; 95% confidence interval [CI], −2, −16; n = 13, p = 0.015) and plasma brain natriuretic peptide levels (−19.4 fmol · ml−1; 95% CI, −5, −34; p = 0.014) and improvements in 6-minute walk distance (114 m; 95% CI, 67, 160; p = 0.0002), cardiac index (0.3 L · min−1 · m−2; 95% CI, 0.1, 0.4; p = 0.008), and systolic left ventricular eccentricity index (−0.2; 95% CI, −0.02, −0.37; p = 0.031). Bosentan improved 6-minute walk distance (59 m; 95% CI, 29, 89; n = 12, p = 0.001) and cardiac index (0.3; 95% CI, 0.1, 0.4; p = 0.008). Conclusions: Sildenafil added to conventional treatment reduces RV mass and improves cardiac function and exercise capacity in patients with PAH, WHO functional class III. Safety monitoring is important until more experience is obtained.

Abstract Rationale Growth-differentiation factor (GDF)-15 is a stress-responsive, transforming growth factor-β–related cytokine. Circulating levels of GDF-15 provide independent prognostic information in patients with acute pulmonary embolism and chronic left-sided heart failure. Objectives To assess the prognostic value of GDF-15 in idiopathic pulmonary arterial hypertension. Methods GDF-15 levels were determined in 76 treatment-naive patients at the time of baseline right heart catheterization. Patients were monitored for a median (range) of 48 (0–101) months (first cohort). Twenty-two additional patients were studied at baseline and 3 to 6 months after initiation of therapy (second cohort). Measurements and Main Results Fifty-five percent of the patients in the first cohort presented with GDF-15 levels above 1,200 ng/L, the previously defined upper reference limit. The risk of death or transplantation at 3 years was 15 and 44% in patients with GDF-15 levels below or above 1,200 ng/L, respectively (P = 0.006). Elevated levels of GDF-15 were associated with increased mean right atrial and pulmonary capillary wedge pressures, a lower mixed venous oxygen saturation (SvO2), and higher levels of uric acid and N-terminal pro-brain natriuretic peptide (NT-proBNP). After adjustment for hemodynamic and biochemical variables, GDF-15 remained an independent predictor of adverse outcomes (P = 0.002). GDF-15 provided prognostic information in clinically relevant patient subgroups, and added prognostic information to hemodynamic variables and NT-proBNP. Changes in GDF-15 over time in the second cohort were related to changes in NT-proBNP (P = 0.031) and inversely related to changes in SvO2 (P < 0.001). Conclusions GDF-15 is a promising new biomarker in idiopathic pulmonary arterial hypertension.

Among adults with pulmonary arterial hypertension who had received the diagnosis less than 1 year earlier, the addition of sotatercept to background therapy resulted in a lower risk of clinical worsening than placebo.