John Wort

Dynamic risk stratification of patient long-term outcome after pulmonary endarterectomy: results from the UK national cohort

Background— Chronic thromboembolic pulmonary hypertension results from incomplete resolution of pulmonary emboli. Pulmonary endarterectomy (PEA) is potentially curative, but residual pulmonary hypertension following surgery is common and its impact on long-term outcome is poorly understood. We wanted to identify factors correlated with poor long-term outcome after surgery and specifically define clinically relevant residual pulmonary hypertension post-PEA. Methods and Results— Eight hundred eighty consecutive patients (mean age, 57 years) underwent PEA for chronic thromboembolic pulmonary hypertension. Patients routinely underwent detailed reassessment with right heart catheterization and noninvasive testing at 3 to 6 months and annually thereafter with discharge if they were clinically stable at 3 to 5 years and did not require pulmonary vasodilator therapy. Cox regressions were used for survival (time-to-event) analyses. Overall survival was 86%, 84%, 79%, and 72% at 1, 3, 5, and 10 years for the whole cohort and 91% and 90% at 1 and 3 years for the recent half of the cohort. The majority of patient deaths after the perioperative period were not attributable to right ventricular failure (chronic thromboembolic pulmonary hypertension). At reassessment, a mean pulmonary artery pressure of ≥30 mm Hg correlated with the initiation of pulmonary vasodilator therapy post-PEA. A mean pulmonary artery pressure of ≥38 mm Hg and pulmonary vascular resistance ≥425 dynes·s−1·cm−5 at reassessment correlated with worse long-term survival. Conclusions— Our data confirm excellent long-term survival and maintenance of good functional status post-PEA. Hemodynamic assessment 3 to 6 months and 12 months post-PEA allows stratification of patients at higher risk of dying of chronic thromboembolic pulmonary hypertension and identifies a level of residual pulmonary hypertension that may guide the long-term management of patients postsurgery.

The prostacyclin-mimetic cicaprost inhibits endogenous endothelin-1 release from human pulmonary artery smooth muscle cells.

There is increasing evidence supporting a role for endothelin-1 (ET-1) in human pulmonary hypertension. The aim of this study was to determine the relative roles of human pulmonary microvascular endothelial cells (HPMVE) and human pulmonary artery smooth muscle (HPASM) cells to produce ET-1 under inflammatory conditions and to investigate further possible control mechanisms of ET-1 production by HPASM. Although HPMVE cells produced more ET-1 than HPASM when cultured with fetal calf serum (FCS) alone and after treatment with cytokines; HPASM produced significant amounts of ET-1 after stimulation with cytokines. Cytokine-stimulated increase in ET-1 production by HPASM was inhibited by cicaprost, a prostacyclin analogue, and other agents that are known to increase intracellular cyclic AMP. Cicaprost also inhibited proliferation of HPASM in response to FCS lending support to the theory that part of the clinical benefit seen in long-term treatment with prostacyclin in pulmonary hypertension may be a result of inhibition of ET-1 production in these cells.

S71 Influence of age on clinical phenotypes of incident idiopathic pulmonary arterial hypertension. Results from the pulmonary hypertension registry of the UK and Ireland

Introduction and Objectives The age of patients with idiopathic pulmonary arterial hypertension (IPAH) has increased since the NIH registry. It is postulated that older IPAH patients may have a different disease phenotype compared to their younger counterparts. Methods Retrospective observational study of all consecutive incident cases of IPAH, heritable and anorexigen-associated pulmonary arterial hypertension diagnosed in all eight pulmonary hypertension centres in the UK and Ireland between 1st January 2001 and 31st December 2009. Patients were divided into younger and older subgroups by the median age (57 years). Results Of 646 incident cases (mean age=54), 22% were over the age of 70 and 3% over age 80. Younger patients had higher % female (71% vs 56%), shorter duration of symptoms (median 15 months vs 21 months), better functional class (18% in functional class I/II vs 10%), exercise capacity (6-minute walk distance 325 m vs 217 m) and higher % predicted DLCO (65% vs 47%) compared to older patients. Older patients were more likely to present with peripheral oedema (41% vs 28%) whereas younger patients were more likely to complain of syncope (30% vs 10%), presyncope (14% vs 7%) and fatigue (15% vs 9%) at the time of diagnosis. Younger patients had higher mean pulmonary artery pressure (56 mm Hg vs 49 mm Hg) and pulmonary vascular resistance index (24 WU.m2 vs 21 WU.m2) but lower wedge pressure (9 mm Hg vs 10 mm Hg) compared to older patients. Patients in the highest age quartile had the worst survival [Abstract S71 figure 1].Abstract S71 Figure 1 Survival of incident idiopathic, heritable and anorexigen-associated pulmonary arterial hypertension by age quartiles. Conclusion Older incident IPAH patients appear to have a different disease phenotype compared to younger patients. IPAH is no longer a disease that affect predominantly young female only.

P244 Haemoglobin mediated proliferation and il-6 release in human pulmonary artery endothelial cells: a role for cd163 and implications for pulmonary vascular remodelling

Introduction Pulmonary arterial hypertension (PAH) is characterised by vascular remodelling of pulmonary arterioles. Disrupted iron homeostasis as well as subclinical haemolysis are implicated in PAH, although exact mechanisms remain unknown. IL-6, a proinflamatory cytokine and regulator of iron homeostasis is elevated in PAH patients and also been implicated in pulmonary vascular remodelling in murine models. Objectives In this study we explored the influences of free haemoglobin (Hb) on proliferative responses and secondary mediator, IL-6 release in human pulmonary artery endothelial cells (hPAECs). Methods Cells were challenged with Hb (10 uM) and/or IL-6 (1–10 ng/mL). Transcriptional regulation was analysed by RT-PCR, protein expression by immunocytochemistry, secretion by ELISA and proliferation by BrdU incorporation. Results Novel findings demonstrate that Hb and IL-6 individually and in combination increased proliferation of hPAECs (by 32%, 47% and 63% respectively; p < 0.05). CD163, a Hb scavenger receptor, was basally expressed as mRNA and protein (cell surface) on hPAECs and further modulated by Hb or IL-6 exposure. Hb treatment also caused increased transcription (30%; p < 0.05) and release of IL-6 (107%; p < 0.01) from hPAECs. Conclusion This is the first report of Hb-mediated proliferation, CD163 expression and IL-6 release in hPAECs with potential implications for autocrine and paracrine signalling in pulmonary vasculature. Hb uptake may be facilitated via CD163. These studies may provide novel insights regarding mechanisms for haemoglobin driven proliferative and second messenger responses of relevance to PAH. Abstract P244 Figure 1 IL-6 relaese after 24h

S72 Prediction of survival in pulmonary arterial hypertension using survival equations. Results from the pulmonary hypertension registry of the UK and Ireland

Introduction The NIH survival equation1 was developed in the 1980s and used in many clinical trials to show survival benefit. Since then, significant advances had been made in the diagnosis and management of pulmonary arterial hypertension (PAH). Several new equations have been developed to better predict survival in PAH. All these survival equations were derived using prognostic factors identified from a mixed incident and prevalent PAH cohort. However, prevalent patients have better survival compared to incident patients. Objectives To determine applicability of currently available survival equations in incident idiopathic (IPAH), heritable and anorexigen-associated PAH. Methods Retrospective observational study of all incident cases of IPAH, heritable and anorexigen-associated PAH diagnosed in the UK and Ireland between 1st January 2001 and 31st December 2009. Observed survival in the UK and Ireland was estimated using life table analysis and compared with predicted survival in the same patients calculated using the NIH,1 French,2 Pulmonary Hypertension Connection (PHC)3 and REVEAL4 Registry equations. Results Total of 646 patients were diagnosed over the study period. Observed vs predicted survival were compared [Abstract S72 figure 1].Abstract S72 Figure 1 Observed vs predicted survival using the NIH, French, PHC and REVEAL equations. Conclusion Survival equations derived from other mixed incident and prevalent pulmonary hypertension populations may not accurately predict survival of incident pulmonary arterial hypertension from the UK and Ireland. Differences in baseline characteristics, treatment practice and time period between our patients and survival equations derivation populations need to be taken into account when applying these equations in daily clinical practice.

Pulmonary Hypertension in Idiopathic Interstitial Pneumonias

The classification of the idiopathic interstitial pneumonias (IIPs) has recently been updated by the ATS and ERS [1] (Table 6.1). Idiopathic pulmonary fibrosis (IPF) is the most common of the IIPs, and data from existing registries suggest that IPF accounts for 17–37% of all interstitial lung disease (ILD) diagnoses [2, 3]. Although estimates of the true incidence and prevalence of IPF are hampered by different methodologies used in epidemiological studies. IPF is a heterogeneous disease with some patients experiencing slow progressive disease, others a much more rapidly progressive disease and others still experiencing periods of stability punctuated by accelerated decline within acute exacerbations. Median survival is just 2–3 years [4]. It is appreciated that the development of pulmonary hypertension (PH) within IPF is common and its development has a dramatic effect both on morbidity and mortality. The desire to improve prognosis and quality of life in patients with IIP-associated PH (IIP–PH) who unfortunately at present have no clinically proven intervention to do so drives clinical research within this difficult area. The study of PH within IIP has predominantly focused upon IPF or mixed patient groups with IIP (which are predominantly made up of IPF patients). Therefore, this chapter focuses predominantly on PH within the IPF population.

Intravenous prostacyclin for pulmonary hypertension: Patient's perspective on complications

Introduction: Intravenous (IV) prostacyclin therapy in patients with severe pulmonary arterial hypertension can be associated with life-threatening complications. Patient education and confidence in local healthcare services is critical to ensuring prompt treatment of such complications. We evaluated patient9s understanding of potential complications and their attitudes towards local healthcare services. Methods: Patients established on IV prostacyclin therapy were identified. Patients were counselled prior to receiving IV prostacyclin and subsequently completed a questionnaire assessing their level of understanding. Results: Ten patients were identified and agreed to participate; median distance from home to their specialist centre was 35 miles. All patients agreed or strongly agreed that they were confident in managing their pump. 8 patients reported not being aware of how long it was safe to keep their pump disconnected. 3 patients were not aware of the correct course of action to take in the event of pump failure and 3 patients did not know their correct dose. Only 3 patients felt confident in their local emergency department being able to manage any complications. Conclusions: Patients seem to require additional education. Strategies to ensure prompt recognition of complications and enhance patient confidence with local healthcare is necessary. We present a patient information card, which may assist achieving these goals. .

P269 Perioperative outcomes in patients with Pulmonary Hypertension undergoing non-cardiac non-obstetric surgery in a Designated UK Pulmonary Hypertension Centre

Introduction and objectives Patients with pulmonary hypertension (PH) represent an extremely high-risk surgical group, with previous reported mortality 7–18%, and predicting perioperative risk is difficult. The aim of this study was to characterise a current cohort of patients with pulmonary hypertension undergoing surgery in a National UK Designated PH centre and to determine predictors of adverse events. Methods Consecutive patients with PH undergoing non-cardiac, non-obstetric surgery were identified by matching theatre and PH databases between 1st April 2008 and 1st April 2015. Demographics, recent echocardiogram, right heart catheterisation, B-natriuretic peptide (BNP), six-minute walk test (6MWT) and World Health Organisation functional class (WHO-FC) on last clinic visit was recorded. Anaesthetic and perioperative details; post-operative management, short-term morbidity and 28-day outcome were recorded. Data are mean±SD or median (range). Results 37 procedures requiring anaesthesia were identified in 32 patients with PAH (7 idiopathic PAH, 1 PVOD, 24 CHD-PAH, 4 CTD-PAH) and 1 CTEPH. Average age was 44.4 ± 13 years, 27(84%) were female. Baseline preoperative WHO-FC was II (3, 9%), III (28, 88%), IV (1, 3%). Baseline 6MWT distance was 317 ± 68 m; BNP 200 (12–2027) ng/L; RV systolic pressure (RVSP) 85 ± 16 mmHg, tricuspid annular planar systolic excursion (TAPSE) 18 ± 7 mm. Cases including oesophagogastroscopy (n = 4), dental extraction (n = 8) under general anaesthesia (GA) were classified as minor; 6 (16%) including mastectomy, laparotomy and fasciotomy as major surgical procedures. Almost all (95%) were performed under GA; most were elective procedures and were monitored on the high dependency or intensive care unit post-operatively. Cardiovascular perioperative complications occurred in 6 cases (16%) including death in 2 patients (5.4%) in the days following surgery, in both cases related to PH crises, resulting in right ventricular (RV) failure. Baseline parameters of RV function including RVSP, TAPSE and the presence of a pericardial effusion were associated with adverse events. Conclusion Perioperative mortality in patients with PH remains high, even in the current era. If surgery is deemed essential, PH centres with experts in cardiothoracic anaesthesia and ICU should be involved in preoperative planning with the PH multidisciplinary team guiding appropriate selection of patients, considering pulmonary haemodynamics and indices of RV function, as well as surgical factors.