Gerry Coghlan

Right ventricle in pulmonary arterial hypertension: haemodynamics, structural changes, imaging, and proposal of a study protocol aimed to assess remodelling and treatment effects.

Although right ventricular (RV) failure is the main cause of death in patients with pulmonary arterial hypertension (PAH), there is insufficient data about the effects of PAH treatment on RV geometry and function mainly because the RV assessment has been hampered by its complex crescentic shape, large infundibulum, and its trabecular nature. Echocardiography is a widely available imaging technique particularly suitable for follow-up studies, because of its non-invasive nature, low cost, and lack of ionizing radiation or radioactive agent. Real-time three-dimensional echocardiography (RT3DE) has been shown to be accurate in assessing RV and left ventricular (LV) volumes, stroke volumes, and ejection fractions in comparison with cardiac magnetic resonance imaging. In this review, we describe RV structural and functional changes which occur in patients with PAH and strengths and weaknesses of current non-invasive imaging techniques to assess them. Finally, we describe an ongoing multicentre, prospective observational study involving seven centres expert in treating patients with PAH from four different countries. Investigators will use conventional and advanced echo parameters from RT3DE and speckle-tracking echocardiography to assess the extent of LV and RV remodelling before symptom onset and during pharmacological treatment in patients with PAH. Seventy patients who will survive for at least 1 year will be recruited. All the participating institutions will perform comprehensive standard 2D and Doppler as well as RT3DE examinations with a pre-defined imaging protocol. Measurements will be performed at the core echocardiography laboratory by experienced observers who will be unaware of each patients treatment assignment and whether the examination was a baseline or a follow-up study. Enrolment duration is expected to be 1 year.

Anticoagulation and Survival in Pulmonary Arterial Hypertension

Background— For almost 30 years, anticoagulation has been recommended for patients with idiopathic pulmonary arterial hypertension (IPAH). Supporting evidence, however, is limited, and it is unclear whether this recommendation is still justified in the modern management era and whether it should be extended to patients with other forms of pulmonary arterial hypertension (PAH). Methods and Results— We analyzed data from Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), an ongoing European pulmonary hypertension registry. Survival rates of patients with IPAH and other forms of PAH were compared by the use of anticoagulation. The sample consisted of 1283 consecutively enrolled patients with newly diagnosed PAH. Anticoagulation was used in 66% of 800 patients with IPAH and in 43% of 483 patients with other forms of PAH. In patients with IPAH, there was a significantly better 3-year survival (P=0.006) in patients on anticoagulation compared with patients who never received anticoagulation, albeit the patients in the anticoagulation group had more severe disease at baseline. The survival difference at 3 years remained statistically significant (P=0.017) in a matched-pair analysis of n=336 IPAH patients. The beneficial effect of anticoagulation on survival of IPAH patients was confirmed by Cox multivariable regression analysis (hazard ratio, 0.79; 95% confidence interval, 0.66–0.94). In contrast, the use of anticoagulants was not associated with a survival benefit in patients with other forms of PAH. Conclusions— The present data suggest that the use of anticoagulation is associated with a survival benefit in patients with IPAH, supporting current treatment recommendations. The evidence remains inconclusive for other forms of PAH. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01347216.BACKGROUND: For almost 30 years, anticoagulation has been recommended for patients with idiopathic pulmonary arterial hypertension (IPAH). Supporting evidence, however, is limited, and it is unclear whether this recommendation is still justified in the modern management era and whether it should be extended to patients with other forms of pulmonary arterial hypertension (PAH). METHODS AND RESULTS: We analyzed data from COMPERA, an ongoing European pulmonary hypertension registry. Survival rates of patients with IPAH and other forms of PAH were compared by the use of anticoagulation. The sample consisted of 1,283 consecutively enrolled patients with newly diagnosed PAH. Anticoagulation was used in 66% of 800 patients with IPAH and in 43% of 483 patients with other forms of PAH. In patients with IPAH, there was a significantly better 3-year-survival (p=0.006) in patients on anticoagulation compared to patients who never received anticoagulation, albeit the patients in the anticoagulation group had more severe disease at baseline. The survival difference at 3 years remained statistically significant (p=0.017) in a matched-pair analysis of n=336 IPAH patients. The beneficial effect of anticoagulation on survival of IPAH patients was confirmed by Cox multivariable regression analysis (hazard ratio 0.79, 95% confidence interval 0.66 to 0.94). In contrast, the use of anticoagulants was not associated with a survival benefit in patients with other forms of PAH. CONCLUSIONS: The present data suggest that the use of anticoagulation is associated with a survival benefit in patients with IPAH, supporting current treatment recommendations. The evidence remains inconclusive for other forms of PAH. CLINICAL TRIALS REGISTRATION INFORMATION: www.clinicaltrials.gov. Identifier: NCT01347216.

Dynamic Risk Stratification of Patient Long-Term Outcome After Pulmonary Endarterectomy Results From the United Kingdom 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.

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.

Characterizing the Right Ventricle: Advancing Our Knowledge

Our ability to evaluate the right ventricle (RV) in pulmonary hypertension has traditionally been quite limited: the RVs complex anatomy is not adequately represented by 2-dimensional imaging, and our understanding of what is an adaptive and maladaptive RV response is incomplete. However, measures of RV function appear to be a strong predictor of survival in pulmonary hypertension. This is, therefore, a promising area for future study. To more fully understand the challenges and opportunities in this area, this article provides a review of RV embryology and anatomy, current assessment of the RV function, animal models of RV function, RV-pulmonary artery coupling, and how translating lessons from studies of the left ventricle may increase our knowledge of the RV.

Plasma Metabolomics Implicates Modified Transfer RNAs and Altered Bioenergetics in the Outcomes of Pulmonary Arterial Hypertension.

Background: Pulmonary arterial hypertension (PAH) is a heterogeneous disorder with high mortality. Methods: We conducted a comprehensive study of plasma metabolites using ultraperformance liquid chromatography mass spectrometry to identify patients at high risk of early death, to identify patients who respond well to treatment, and to provide novel molecular insights into disease pathogenesis. Results: Fifty-three circulating metabolites distinguished well-phenotyped patients with idiopathic or heritable PAH (n=365) from healthy control subjects (n=121) after correction for multiple testing (P<7.3e-5) and confounding factors, including drug therapy, and renal and hepatic impairment. A subset of 20 of 53 metabolites also discriminated patients with PAH from disease control subjects (symptomatic patients without pulmonary hypertension, n=139). Sixty-two metabolites were prognostic in PAH, with 36 of 62 independent of established prognostic markers. Increased levels of tRNA-specific modified nucleosides (N2,N2-dimethylguanosine, N1-methylinosine), tricarboxylic acid cycle intermediates (malate, fumarate), glutamate, fatty acid acylcarnitines, tryptophan, and polyamine metabolites and decreased levels of steroids, sphingomyelins, and phosphatidylcholines distinguished patients from control subjects. The largest differences correlated with increased risk of death, and correction of several metabolites over time was associated with a better outcome. Patients who responded to calcium channel blocker therapy had metabolic profiles similar to those of healthy control subjects. Conclusions: Metabolic profiles in PAH are strongly related to survival and should be considered part of the deep phenotypic characterization of this disease. Our results support the investigation of targeted therapeutic strategies that seek to address the alterations in translational regulation and energy metabolism that characterize these patients.

Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension

Background: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. Methods: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource–Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. Results: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (KCO; 33% [interquartile range, 30%–35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23–38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. Conclusions: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low KCO and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation.

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.Pulmonary arterial hypertension (PAH) is a rare lung disorder characterised by narrowing and obliteration of small pulmonary arteries ultimately leading to right heart failure. Here, the authors sequence whole genomes of over 1000 PAH patients and identify likely causal variants in GDF2, ATP13A3, AQP1 and SOX17.

Does left heart disease cause most systemic sclerosis associated pulmonary hypertension

In this issue of the European Respiratory Journal, Fox et al. [1] present data that suggest most pulmonary hypertension (PH) in systemic sclerosis is post-capillary and that many patients are receiving pulmonary vasodilator therapy inappropriately. Of 53 patients identified as having PH, nearly half (24) had elevated wedge pressures, a further five had elevated left ventricular end-diastolic pressure and another six were “exposed” as having occult post-capillary abnormalities in response to a 500-mL fluid challenge administered over 5–10 min. Thus, in total, 35 (67%) out of 53 PH patients did not have pulmonary arterial hypertension (PAH). The number of patients with elevated pulmonary artery occlusion pressures (PAOP) is high when compared with other studies [2, 3] and there is no “threshold” wedge pressure that differentiates normality from cardiac disease during fluid challenge [4, 5], but this misses the bigger point. Their work illustrates the flaws in the accepted diagnostic benchmark. These issues may seem of relevance only to rheumatologists, but as the average age of patients with idiopathic PAH increases [6], requiring diagnosis of PAH in the presence of diastolic dysfunction, and as increased numbers of patients with diastolic heart failure and PH [7] …

Endothelin Receptor Antagonism Role in the Treatment of Pulmonary Arterial Hypertension Related to Scleroderma

Pulmonary arterial hypertension (PAH) is a devastating disease, which is associated with a 1-year survival of about 50% without specific treatment. Pulmonary vascular remodelling, thrombosis and vasoconstriction are thought to be directly involved in increasing pulmonary vascular resistance (PVR), which, left untreated, ultimately leads to right ventricular failure and death. A total of 10–12% of patients with systemic sclerosis (SSc) develop PAH, which is a leading cause of mortality in these patients. Targeted treatment regimens involving oral therapies, in particular endothelin receptor antagonists (ERAs), such as bosentan, sitaxsentan (sitaxentan) and ambrisentan, are now being used and this approach has improved symptoms as well as survival. 1-Year survival has improved to about 80%, while 3-year survival in advanced SSc-PAH has improved from 44% to 65% since the introduction of ERAs. Subanalysis of BREATHE-1, a pilot study and the STRIDE-2X randomized controlled trials has reported improvements in time to clinical worsening, 6-minute walk distance (6mwd) and right heart haemodynamics in SSc-PAH patients given bosentan and sitaxsentan, respectively, compared with placebo. The ARIES studies have also demonstrated a delay in the time to clinical worsening and improvement in 6mwd in connective tissue associated-PAH patients given ambrisentan compared with placebo. Unfortunately, these drugs are expensive and also have the potential for adverse interactions with other PAH and supportive therapies. Mandatory monthly liver function tests are required for safe administration of bosentan, ambrisentan and sitaxsentan, while dose adjustment of warfarin and careful monitoring are required when sitaxsentan is initiated. Earlier diagnosis and treatment of PAH may further improve outcomes with current ERAs. WHO functional class (FC) has traditionally been used to determine which patients with PAH will start therapy. The EARLY study has reported significant reductions in PVR and time to clinical worsening in mildly symptomatic PAH patients treated with bosentan, and many PAH clinicians now believe WHO FC should be used as a monitoring tool once targeted therapies have been initiated and not as a tool for deciding when to start PAH specific therapies.Many pathways are thought to be involved in the pathophysiology of the PAH. There is growing evidence that combination therapies targeting different pathophysiological steps may be necessary to effectively treat SSc-PAH. The COMPASS-1 study has reported an acute haemodynamic benefit in PAH when a single-dose of sildenafil is used in combination with bosentan and COMPASS-2 will investigate whether this acute response translates into long-term benefit. Well designed morbidity and mortality trials in SSc-PAH should help increase our understanding and treatment of this orphan disease.