Traffic exposures, air pollution and outcomes in pulmonary arterial hypertension: A United Kingdom cohort study analysis

While traffic and air pollution exposure is associated with increased mortality in numerous diseases, its association with disease severity and outcomes in pulmonary arterial hypertension (PAH) remains unknown.Exposure to particulate matter ≤2.5 μm3 (PM2.5), nitrogen dioxide (NO2) and indirect measures of traffic-related air pollution (distance to main road and length of roads within buffer zones surrounding residential addresses) were estimated for 301 patients with idiopathic/heritable PAH recruited in the UK PAH national Cohort study. Associations with transplant-free survival and pulmonary hemodynamic severity at baseline were assessed, adjusting for confounding variables defined a priori.Higher estimated exposure to PM2.5 was associated with higher risk of death or lung transplant (Unadjusted hazard ratio (HR) 2.68; 95% CI 1.11-6.47 per 3 μg·m-3, p=0.028). This association remained similar when adjusted for potential confounding variables (HR 4.38; 95% CI 1.44-13.36 per 3 μg·m-3, p=0.009). No associations were found between NO2 exposure or other traffic pollution indicators and transplant-free survival Conversely, indirect measures of exposure to traffic-related air pollution within the 500-1000 m buffer zones correlated with the ERS/ESC risk categories as well as pulmonary hemodynamics at baseline. This association was strongest for pulmonary vascular resistance.In idiopathic/heritable PAH, indirect measures of exposure to traffic-related air pollution were associated with disease severity at baseline, whereas higher PM2.5 exposure may independently predict shorter transplant-free survival

EmPHasis-10 health-related quality of life score predicts outcomes in patients with idiopathic and connective tissue disease-associated pulmonary arterial hypertension: results from a UK multi-centre study

Health-related quality of life (HRQoL) scores assess symptom burden in pulmonary arterial hypertension (PAH) but data regarding their role in prognostication and risk stratification are limited. We assessed these relationships using the emPHasis-10 HRQoL measure. 1745 patients with idiopathic or connective tissue disease-associated PAH who had completed emPHasis-10 questionnaires between 2014–17 at 6 UK referral centres were identified. Correlations with exercise capacity and WHO functional class (FC) were assessed, and exploratory risk stratification thresholds were tested. Moderate correlations were seen between emPHasis-10 scores and 6-minute walk distance (r=−0.546), incremental shuttle walking distance (r=−0.504) and WHO FC (r=0.497; p all <0.0001). Distribution of emPHasis-10 differed significantly between each WHO FC (p all <0.0001). At multivariate analysis, emPHasis-10, but not WHO FC, was an independent predictor of mortality. In a risk stratification approach, scores of 0–16, 17–33 and 34–50 identified incident patients with one-year mortality of 5%, 10% and 23%, respectively. Survival of patients in WHO FC III could be further stratified using an emPHasis-10 score ≥34 (p<0.01). At follow-up, patients with improved emPHasis-10 had improved exercise capacity (p<0.0001), and patients who transitioned risk groups demonstrated similar survival to patients originally in those risk groups. The emPHasis-10 score is an independent prognostic marker in patients with idiopathic or connective tissue disease-associated PAH. It has utility in risk stratification in addition to currently used parameters. Improvement in emPHasis-10 score is associated with improved exercise capacity

Loss-of-function ABCC8 mutations in pulmonary arterial hypertension

Background: In pulmonary arterial hypertension (PAH), pathological changes in pulmonary arterioles progressively raise pulmonary artery pressure and increase pulmonary vascular resistance, leading to right heart failure and high mortality rates. Recently, the first potassium channelopathy in PAH, because of mutations in KCNK3, was identified as a genetic cause and pharmacological target. Methods: Exome sequencing was performed to identify novel genes in a cohort of 99 pediatric and 134 adult-onset group I PAH patients. Novel rare variants in the gene identified were independently identified in a cohort of 680 adult-onset patients. Variants were expressed in COS cells and function assessed by patch-clamp and rubidium flux analysis. Results: We identified a de novo novel heterozygous predicted deleterious missense variant c.G2873A (p.R958H) in ABCC8 in a child with idiopathic PAH. We then evaluated all individuals in the original and a second cohort for rare or novel variants in ABCC8 and identified 11 additional heterozygous predicted damaging ABCC8 variants. ABCC8 encodes SUR1 (sulfonylurea receptor 1)—a regulatory subunit of the ATP-sensitive potassium channel. We observed loss of ATP-sensitive potassium channel function for all ABCC8 variants evaluated and pharmacological rescue of all channel currents in vitro by the SUR1 activator, diazoxide. Conclusions: Novel and rare missense variants in ABCC8 are associated with PAH. Identified ABCC8 mutations decreased ATP-sensitive potassium channel function, which was pharmacologically recovered

Pulmonary veno-occlusive disease presenting with recurrent pulmonary oedema and the use of nitric oxide to predict response to sildenafil

Pulmonary veno-occlusive disease (PVOD) is a disorder which causes progressive pulmonary hypertension, usually presenting with worsening dyspnoea and right heart failure. Pulmonary oedema induced by pulmonary vasodilator therapy to reduce pulmonary arterial pressure has been well described in PVOD, but here we describe a case of PVOD presenting with recurrent episodes of acute non-cardiogenic pulmonary oedema, in the absence of significant pulmonary hypertension. Concern over the risk of precipitating pulmonary oedema led us to use inhaled nitric oxide to predict the safety and efficacy of sildenafil

Patient descriptions of breathlessness in heart failure

Objective: To explore patient experience of breathlessness in heart failure. Methods: Semi-structured interviews were undertaken with 27 patients with chronic heart failure and were analysed using a constant comparative approach. Results: The patients had a mean age of 69 (range 38–94 years). All had chronic heart failure with a mean left ventricular ejection fraction of 33.1%. The patient narratives suggested three dominant experiences of breathlessness, “everyday”, “worsening” and “uncontrollable”. These descriptions predominantly focused on physical functioning, relating to patients' ability to manage breathlessness on a day to day basis. Patients were able to accommodate everyday breathlessness, using a number of coping strategies. In most cases this experience of breathlessness came to be accepted as “normal”. Worsening breathlessness was a symptom that patients were unable to manage and that prompted a hospital admission, whereas uncontrollable breathlessness was experienced as a symptom that even health care professionals struggled to control. Conclusions: Patients' descriptions of breathlessness are distinct from medical terminology and more clearly relate to physical adaptations to breathlessness. Further research is required to identify whether heart failure patients' descriptions of breathlessness are different to those of cancer patients, and to establish whether the categories generated from this data set are applicable to other heart failure patients in other settings

Cardiopulmonary exercise testing as a guideline indicator for mitral valve intervention

Abstract Background Primary mitral regurgitation (MR) is one of the most common heart valvular pathologies. However, optimum timing of surgery remains controversial. Purpose To describe changes in cardiopulmonary exercise testing (CPET) parameters after surgery for severe primary MR. Methods In a single centre prospective study, patients undergoing surgery under current ESC guidelines for severe primary MR underwent assessment with transthoracic echocardiogram, CPET, cardiac MRI and quality of life questionnaire pre-operatively and at six months after surgery. The primary outcome was a per protocol analysis of impaired post-operative functional capacity (defined as post-operative left ventricular ejection fraction on transthoracic echocardiogram &amp;lt;50% and/or post-operative percentage predicted peak VO2 ≤84%). Results 43 of the 50 patients recruited between February 2017 and October 2018 were included in the per protocol analysis. Thirty five patients (72.9%) had impaired post-operative functional capacity. In the overall cohort (n=43), there was a significant fall post-operatively in percentage predicted peak VO2 (ppVO2) (81.8±15.7% vs. 76.2±16.2%, p&amp;lt;0.01) and anaerobic threshold (AT) (48.0±11.1% vs. 44.3±10.1%, p=0.01). In patients with a class I indication for surgery (n=30), there was no significant change post-operatively in ppVO2 (79.6±15.7% vs. 75.6±16.7%, p=0.09) or AT (49.9±11.4% vs. 46.4±10.2%, p-0.09). However, in patients with a class II indication for surgery (n=13), there was a significant change post-operatively in ppVO2 (86.9±15.1% vs. 77.4±15.9%, p&amp;lt;0.01), but not in AT (43.5±9.6% vs. 39.5±8.3%, p=0.16). In the multivariable analysis, pre-operative left ventricular ejection fraction ≤60% (hazard ratio, 1.69; 95% confidence interval, 1.56 to 480.1, p=0.04) and pre-operative percentage predicted peak VO2 ≤84% (hazard ratio, 1.22; 95% confidence interval, 2.13 to 107.1, p&amp;lt;0.01) were independent predictors for impaired post-operative functional capacity. Conclusions Pre-operative percentage predicted peak VO2 ≤84% is an independent predictor of impaired post-operative functional capacity. Subject to a confirmatory study, this may help to refine current ESC guidelines for intervention for severe primary MR. Change in ppVO2 after surgery Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Rosetrees Trust and Friends of Hammersmith Hospital </jats:sec