Dolores Taboada

Outcome of pulmonary endarterectomy in symptomatic chronic thromboembolic disease

Chronic thromboembolic disease is characterised by persistent pulmonary thromboembolic occlusions without pulmonary hypertension. Early surgical treatment with pulmonary endarterectomy may improve symptoms and prevent disease progression. We sought to assess the outcome of pulmonary endarterectomy in symptomatic patients with chronic thromboembolic disease. Patients with symptomatic chronic thromboembolic disease and a mean pulmonary artery pressure <25 mmHg at baseline with right heart catheterisation and treated with pulmonary endarterectomy between January 2000 and July 2013 were identified. Patients were reassessed at 6 months and at 1 year following surgery. A total of 42 patients underwent surgery and the median length of stay in hospital was 11 days. There was no in-hospital mortality but complications occurred in 40% of patients. At 1 year, following surgery, 95% of the patients remained alive. There was a significant symptomatic improvement with 95% of patients in the New York Heart Association functional classes I or II at 6 months. There was a significant improvement in quality of life assessed by the Cambridge pulmonary hypertension outcome review questionnaire. In this carefully selected cohort of chronic thromboembolic disease patients, pulmonary endarterectomy resulted in significant improvement in symptoms and quality of life. Appropriate patient selection is paramount given the known surgical morbidity and mortality, and surgery should only be performed in expert centres. Pulmonary endarterectomy improves symptoms and quality of life in patients with chronic thromboembolic disease http://ow.ly/AeECt

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.

Right ventricular dysfunction in chronic thromboembolic obstruction of the pulmonary artery: a pressure-volume study using the conductance catheter

Pressure-volume loops describe dynamic ventricular performance, relevant to patients with and at risk of pulmonary hypertension. We used conductance catheter-derived pressure-volume loops to measure right ventricular (RV) mechanics in patients with chronic thromboembolic pulmonary arterial obstruction at different stages of pathological adaptation. Resting conductance catheterization was performed in 24 patients: 10 with chronic thromboembolic pulmonary hypertension (CTEPH), 7 with chronic thromboembolic disease without pulmonary hypertension (CTED), and 7 controls. To assess the validity of conductance measurements, RV volumes were compared in a subset of 8 patients with contemporaneous cardiac magnetic resonance (CMR). Control, CTED, and CTEPH groups showed different pressure-volume loop morphology, most notable during systolic ejection. Prolonged diastolic relaxation was seen in patients with CTED and CTEPH [tau = 56.2 ± 6.7 (controls) vs. 69.7 ± 10.0 (CTED) vs. 67.9 ± 6.2 ms (CTEPH), P = 0.02]. Control and CTED groups had lower afterload (Ea) and contractility (Ees) compared with the CTEPH group (Ea = 0.30 ± 0.10 vs. 0.52 ± 0.24 vs. 1.92 ± 0.70 mmHg/ml, respectively, P < 0.001) (Ees = 0.44 ± 0.20 vs. 0.59 ± 0.15 vs. 1.13 ± 0.43 mmHg/ml, P < 0.01) with more efficient ventriculoarterial coupling (Ees/Ea = 1.46 ± 0.30 vs. 1.27 ± 0.36 vs. 0.60 ± 0.18, respectively, P < 0.001). Stroke volume assessed by CMR and conductance showed closest agreement (mean bias +9 ml, 95% CI -1 to +19 ml) compared with end-diastolic volume (+48 ml, -16 to 111 ml) and end-systolic volume (+37 ml, -21 to 94 ml). RV conductance catheterization detects novel alteration in pressure-volume loop morphology and delayed RV relaxation in CTED, which distinguish this group from controls. The observed agreement in stroke volume assessed by CMR and conductance suggests RV mechanics are usefully measured by conductance catheter in chronic thromboembolic obstruction.

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.

Pulmonary hypertension and its management in patients undergoing non‐cardiac surgery

Pulmonary hypertension is a complex disorder of the pulmonary vasculature that leads to increased peri‐operative morbidity and mortality. Non‐cardiac surgery constitutes a significant risk in patients with pulmonary hypertension. The management of right ventricular failure is inherently challenging and fraught with life‐threatening consequences. A thorough understanding of the pathophysiology, the severity of the disease and its treatment modalities is required to deliver optimal peri‐operative care. This review provides an evidence‐based overview of the definition, classification, pathophysiology, diagnosis and treatment of pulmonary hypertension and focuses on the peri‐operative management and treatment of pulmonary hypertensive crises in a non‐cardiac setting.

Maximal cardiac output determines 6 minutes walking distance in pulmonary hypertension

Purpose The 6 minutes walk test (6MWT) is often shown to be the best predictor of mortality in pulmonary hypertension (PH) probably because it challenges the failing heart to deliver adequate cardiac output. We hypothesised that the 6MWT elicits maximal cardiac output as measured during a maximal cardiopulmonary exercise testing (CPET). Methods 18 patients with chronic thromboembolic pulmonary hypertension (n = 12) or pulmonary arterial hypertension (n = 6) and 10 healthy subjects performed a 6MWT and CPET with measurements of cardiac output (non invasive rebreathing device) before and directly after exercise. Heart rate was measured during 6MWT with a cardiofrequence meter. Results Cardiac output and heart rate measured at the end of the 6MWT were linearly related to 6MW distance (mean±SD: 490±87 m). Patients with a high NT-pro-BNP achieve a maximum cardiac output during the 6MWT, while in normal subjects and in patients with a low-normal NT-proBNP, cardiac output at the end of a 6MWT was lower than achieved at maximum exercise during a CPET. In both cases, heart rate is the major determinant of exercise-induced increase in cardiac output. However, stroke volume increased during CPET in healthy subjects, not in PH patients. Conclusion Maximal cardiac output is elicited by 6MWT in PH patients with failing right ventricle. Cardiac output increase is dependent on chronotropic response in patients with PH.

Prognostic value of transthoracic echocardiography in hemodynamically stable patients with acute symptomatic pulmonary embolism

OBJECTIVE To determine the prognostic value of transthoracic echocardiography in hemodynamically stable patients diagnosed with acute symptomatic pulmonary embolism. PATIENTS AND METHODS Hemodynamically stable outpatients diagnosed with acute symptomatic pulmonary embolism at a tertiary university hospital were prospectively included in the study. All patients underwent transthoracic echocardiography within 48 hours of diagnosis. The primary endpoint was all-cause mortality at 1 month. RESULTS Right ventricular dysfunction was documented by echocardiography in 86 of the 214 patients (40%) in our series. In the first month of follow-up, 7 patients died--4 with positive echocardiographic findings and 3 with negative findings (odds ratio, 2.0; 95% confidence interval, 0.4-9.3; P=.41). For the primary endpoint, the negative predictive value of transthoracic echocardiography was 98%, the positive predictive value was 5%, and the negative likelihood ratio was 0.7. The negative predictive value was 100% and the positive predictive value was 3% when we analyzed death due to pulmonary embolism only. CONCLUSIONS In our setting, transthoracic echocardiography is not useful for prognostic stratification of hemodynamically stable patients with pulmonary embolism.

Estimación de la severidad de la insuficiencia mitral según un método simplificado basado en el flujo de convergencia proximal

Introduction and objectives. Calculation of the effective regurgitant orifice (ERO) is regarded as the most accurate way of assessing the severity of mitral regurgitation (MR), but the technique’s complexity limits its use. Our objective was to modify and validate a previously published semiquantitative method of assessment based on measurement of the proximal isovelocity surface area (PISA) in order to adapt it to recent recommendations from American and European cardiology societies. Methods. In the PISA method, maximum regurgitant flow (MRF) is a function of the radius and aliasing velocity (AV). Using this relationship, it is possible to construct a nomogram formed by lines of different MRF value, which can be easily derived by looking for radius values on the graph and observing where they cross with AV values. The MR severity limits on the nomogram were set to reflect the different severity grades and limits recommended for use with ERO measurements by American and European cardiology societies. Results. We studied 76 patients with MR using Doppler echocardiography. There was an excellent correlation between MRF and ERO (r=0.98, P<.001). Estimates of MR severity made using the new nomogram were in good agreement with those derived from the ERO: for a scale with three severity grades, kappa was 0.951 and the standard error was 0.11; for four grades, kappa was 0.969 and the standard error, 0.11. Conclusions. Estimates of MR severity derived semiquantitatively from MRF using the nomogram proposed here were in excellent agreement with quantitative estimates obtained using the ERO, and the method was faster and easier to use.

S108 Genome-wide association study in chronic thromboembolic pulmonary hypertension reveals new insights into aetiology

Introduction Chronic thromboembolic pulmonary hypertension (CTEPH) is an infrequent but important complication of acute pulmonary embolism (PE). Thrombophilias and non-O blood groups are genetic risk factors for venous thromboembolism (VTE), however they are not independently associated with CTEPH. Identifying genetic risk factors for CTEPH would provide important insights into pathobiology and might allow risk-stratification following PE. We undertook a genome-wide association study (GWAS) in CTEPH to identify novel disease loci. Methods To date, 1457 Caucasian CTEPH patients were enrolled from 10 European and US Centres and compared to 1536 healthy Caucasian controls from the Wellcome Trust Case Control Consortium. Genotyping was performed using the HumanOmniExpressExome-8 array. Quality control criteria and statistical analysis are summarised in figure 1. Results 1250 CTEPH cases, 1492 controls and 7 million single-nucleotide polymorphisms (SNPs) were included after quality control exclusions. Two loci, in chromosomes 4 and 9 were significantly associated with CTEPH (figure 1). The lead SNP in chr9 (rs532436, OR=2.38, p=4.6x10-32) is highly correlated with the tagging SNP for the A1 blood group (rs507666, R2=0.99). Reconstructing genetic ABO groups confirmed an over-representation of the A1A1 group in CTEPH compared to controls (7% vs. 2.9%, OR 4.5). Additionally, there were 11 significant SNPs in the chr9 ADAMTS13 gene locus that is moderately correlated with ABO (R2=0.33). The lead SNP in chr4 (rs13130318, OR=1.4, p=5.6x10-8) is highly correlated with a missense variant in FGG (rs6050, R2=0.89) associated with decreased fibrinogen protein and increased resistance to fibrinolysis in CTEPH. There were no associations at the F5 locus, which is highly significant in VTE. Conclusions We report the first GWAS in CTEPH, identifying at least 2 genetic loci associated with the disease. The ABO association is driven by the A1 blood group and represents the largest population attributable genetic risk factor for CTEPH, which is higher than previously reported for VTE. The potential ADAMTS13 association is a plausible biological candidate, and further work will establish whether it is independent from ABO. The lack of associations with other loci found in VTE suggests that ABO might have a pathobiological role in CTEPH in addition to its contribution to VTE. Abstract S108 Figure 1 Manhattan plot of significant loci in chromosome 4 and 9 associated with CTEPH. Quality control exclusion thresholds and chromosome 9 regional association plot shown within figure. Dotted line represents a Genome-wide significance threshold of p=5x10-8 (Bonferroni). Imputaton was performed from the HapIotype Reference Consortium (Sanger imputation service). An additive model of association was applied using logistic regression with gender and 1 principal component as covariates. HWE (Hardy-Weinberg equilibrium), IBD (iderity by descent), MAF (minor allele frequency), PCA (principal component analysis), SNP (single nucleotide polymorphism).

S109 Adamts13 protein levels are decreased in chronic thromboembolic pulmonary hypertension and implicated in its pathobiology

Introduction Chronic thromboembolic pulmonary hypertension (CTEPH) Results from failure of thrombus resolution following acute pulmonary embolism. Abnormalities in haemostasis are implicated in the pathobiology, including elevated levels of von Willebrand factor (VWF), which is normally regulated by ADAMTS13. Interim analysis of a genome-wide association study (GWAS) identified a significant association in CTEPH with the ADAMTS13 and ABO gene loci. We aimed to determine if ADAMTS13 protein levels are altered in CTEPH. Methods ADAMTS13 and VWF plasma antigen levels were measured by ELISA in 208 individuals with CTEPH and compared to 68 healthy controls. Levels were also measured in subjects with chronic thromboembolic disease but without pulmonary hypertension (CTED), and other disease comparator groups summarised in figure 1. In 22 CTEPH individuals ADAMTS13 and VWF levels were measured pre-operatively and at least 3 months post-pulmonary endarterectomy (PEA). Results ADAMTS13 levels were decreased in CTEPH (median ±IQR: 0.88±0.40 µg/ml; p=5.7x10-09) and CTED (0.83±0.22 µg/ml; p=2.1x10-06) patients compared to healthy controls (1.15±0.30 µg/ml) (figure 1). ADAMTS13 levels remained low in CTEPH patients following PEA (pre: 0.78±0.27 µg/ml vs. post: 0.83±0.29 µg/ml; p=0.92) even in those with normalised mean pulmonary arterial pressures (<25 mmHg) after PEA. Furthermore, ADAMTS13 levels were lowest in the CTEPH and CTED groups when covariates (age, gender and batch) were included in multivariate rank regression models. VWF levels were increased in CTEPH (16.7±15.2 µg/ml; p=4.0x10-12) and CTED (17.0±10.1 µg/ml; p=3.9x10-06) compared to healthy controls (8.5±8.8 µg/ml). There was no change post-PEA (pre: 22.2±17.3 µg/ml vs. post: 19.6±14.2 µg/ml; p=0.24). Conclusions Plasma ADAMTS13 antigen levels are markedly decreased in CTEPH. This is not secondary to pulmonary hypertension, as demonstrated by the similarly low levels in CTED, and individuals with normal pulmonary artery pressures post-PEA. Thus, the VWF/ADAMTS13 axis is implicated in the underlying disease pathophysiology. Ongoing work will clarify if there is a causal link by defining whether genetic variation at the ADAMTS13 locus contributes to reduced ADAMTS13 protein levels and CTEPH. Abstract S109 Figure 1 ADAMTSI3 protein levels and diagnostic group. Log transformed ADAMTS13 antigen levels. Table of pairwise p-values displayed within figure (Dunns test). CTEPH, chronic thromboembolic pulmonary hypertension; CTED, chronic thromboembolic disease; IPAH, idiopathic pulmonary arterial hypertension; PE, pulmonary embolism.