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BACKGROUND The United States Chronic Thromboembolic Pulmonary Hypertension Registry (US-CTEPH-R) was designed to characterize the demographic characteristics, evaluation, clinical course, and outcomes of surgical and nonsurgical therapies for patients with chronic thromboembolic pulmonary hypertension. RESEARCH QUESTION What are the differences in baseline characteristics and 1-year outcomes between operated and nonoperated subjects? STUDY DESIGN AND METHODS This study describes a multicenter, prospective, longitudinal, observational registry of patients newly diagnosed (< 6 months) with CTEPH. Inclusion criteria required a mean pulmonary artery pressure ≥ 25 mm Hg documented by right heart catheterization and radiologic confirmation of CTEPH. Between 2015 and 2018, a total of 750 patients were enrolled and followed up biannually until 2019. RESULTS Most patients with CTEPH (87.9%) reported a history of acute pulmonary embolism. CTEPH diagnosis delays were frequent (median, 10 months), and most patients reported World Health Organization functional class 3 status at enrollment with a median mean pulmonary artery pressure of 44 mm Hg. The registry cohort was subdivided into Operable patients undergoing pulmonary thromboendarterectomy (PTE) surgery (n = 566), Operable patients who did not undergo surgery (n = 88), and those who were Inoperable (n = 96). Inoperable patients were older than Operated patients; less likely to be obese; have a DVT history, non-type O blood group, or thrombophilia; and more likely to have COPD or a history of cancer. PTE resulted in a median pulmonary vascular resistance decline from 6.9 to 2.6 Wood units (P < .001) with a 3.9% in-hospital mortality. At 1-year follow-up, Operated patients were less likely treated with oxygen, diuretics, or pulmonary hypertension-targeted therapy compared with Inoperable patients. A larger percentage of Operated patients were World Health Organization functional class 1 or 2 at 1 year (82.9%) compared with the Inoperable (48.2%) and Operable/No Surgery (56%) groups (P < .001). INTERPRETATION Differences exist in the clinical characteristics between patients who exhibited operable CTEPH and those who were inoperable, with the most favorable 1-year outcomes in those who underwent PTE surgery. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov; No.: NCT02429284; URL: www.clinicaltrials.gov.

Objectives The aim of this study was to investigate the incidence of May-Thurner anatomy (MTA) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) and identify its predictors. Background MTA is an anatomical variant characterized by compression of left common iliac vein by the overlying right iliac artery. Over time, this leads to venous intimal scarring, blood flow stasis, and the development of deep vein thrombosis (DVT). DVT is a known risk factor for the development of CTEPH. The prevalence of this anatomical variation in patients with CTEPH is unknown. Methods A retrospective chart review was conducted in patients referred to Temple University Hospital’s cardiac catheterization laboratory for the evaluation of CTEPH between January 2016 and June 2020. Among these patients, those who underwent invasive venography were evaluated for the presence of angiographic MTA. Multivariate regression was used to identify factors associated with presence of MTA. Results A total of 193 patients with CTEPH were referred for pulmonary angiography, of whom 148 patients underwent invasive venography. MTA was identified in 44 patients (29.7%). Factors associated with the presence of MTA were lower extremity DVT (odds ratio: 3.5; 95% confidence interval: 1.58-7.8; P = 0.002), and left lower extremity post-thrombotic syndrome (odds ratio: 2.0; 95% confidence interval: 0.98-4.1; P = 0.05). Patients with MTA were more likely to undergo pulmonary thromboendarterectomy than patients without MTA (79.5% vs 58.7%; P = 0.015). Conclusions MTA is very common in patients with CTEPH. History of lower extremity DVT and or left lower extremity post-thrombotic syndrome was associated with the presence of MTA.

Background At the University of California, San Diego, routine coronary angiography has generally been performed in men 40 years of age and older and women 45 years of age and older before pulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension (CTEPH). The prevalence of significant coronary artery disease (CAD) in this population has not been evaluated, however, and the optimal screening strategy has not been established. This study sought to evaluate whether the current approach may be better optimized on the basis of cardiac risk factors. Methods This study included 462 consecutive patients with CTEPH who were undergoing preoperative coronary angiography for pulmonary thromboendarterectomy. Baseline demographic and medical information was recorded. Major cardiac risk factors included: diabetes, hypertension, hyperlipidemia, body mass index 25 kg/m2 or greater, tobacco use, and family history of CAD. Charts were then reviewed for presence of significant CAD and revascularization. Results Significant CAD was found in 13.4% of patients who underwent routine preoperative coronary angiography; it was present in only 5% of patients younger than 50 years of age, compared with 16% of patients 50 years old and older. No patient younger than 50 years of age without cardiac risk factors was found to have significant CAD. Furthermore, in patients younger than 50 years of age, significant CAD was found only among those with 3 or more major risk factors. Conclusions In patients younger than 50 years of age with CTEPH, the prevalence of significant CAD was low. Omitting preoperative coronary angiography in this subset of patients is reasonable when no coronary risk factors are present. Preoperative coronary angiography is warranted in individuals 50 years of age and older, as well as in those younger than 50 years who have significant risk factors for CAD.

ISHLT members have recognized the importance of a consensus statement on the evaluation and management of patients with chronic thromboembolic pulmonary hypertension. The creation of this document required multiple steps, including the engagement of the ISHLT councils, approval by the Standards and Guidelines Committee, identification and selection of experts in the field, and the development of 6 working groups. Each working group provided a separate section based on an extensive literature search. These sections were then coalesced into a single document that was circulated to all members of the working groups. Key points were summarized at the end of each section. Due to the limited number of comparative trials in this field, the document was written as a literature review with expert opinion rather than based on level of evidence. (C) 2021 International Society for Heart and Lung Transplantation. All rights reserved.

Inflammatory pseudotumor (IPT), also known as plasma cell granuloma, is a rare lesion of unknown etiology that occurs in many organs, especially in the lung. Here we report five cases of IPT arising in pulmonary artery mimicking chronic thromboembolic disease, not previously documented in the literature. Those cases were identified at our institute among over 2500 pulmonary endarterectomy (PEA) specimens acquired from 2000 to 2017. The cohort included three men and two women with a median age of 41 years (range: 23-54). All patients presented with dyspnea and radiologic findings of pulmonary artery thromboembolism, some concerning for intimal sarcoma. The duration between disease onset and PEA ranged from 6 months to approximately 3 years. Histologically, all cases showed proliferation of spindle cells with marked inflammatory infiltrates composed predominantly of plasma cells, histiocytes, and small lymphocytes. Ancillary studies were performed in each case and ruled out other possibilities, such as sarcoma, lymphoma, plasmacytoma, IgG4-related disease, and infection. IPT arising in pulmonary artery presenting clinically as acute or chronic thromboembolic disease is very unusual, in which clinical data, radiographic findings, and histopathologic features have to be integrated for reaching the proper diagnosis.

Perioperative anticoagulation management for patients with heparin-induced thrombocytopenia requiring cardiopulmonary bypass and deep hypothermic circulatory arrest presents a clinical challenge. Alternative anticoagulants have been used but can cause significant postoperative bleeding. We report the successful use of cangrelor and heparin in a 30-year-old patient with severe heparin-induced thrombocytopenia undergoing urgent pulmonary thromboendarterectomy.

To assess the efficacy of ramelteon in preventing delirium, an acute neuropsychiatric condition associated with increased morbidity and mortality, in the perioperative, ICU setting.Parallel-arm, randomized, double-blinded, placebo-controlled trial.Academic medical center in La Jolla, California.Patients greater than or equal to 18 years undergoing elective pulmonary thromboendarterectomy.Ramelteon 8 mg or matching placebo starting the night prior to surgery and for a maximum of six nights while in the ICU.Incident delirium was measured twice daily using the Confusion Assessment Method-ICU. The safety outcome was coma-free days assessed by the Richmond Agitation-Sedation Scale. One-hundred twenty participants were enrolled and analysis completed in 117. Delirium occurred in 22 of 58 patients allocated to placebo versus 19 of 59 allocated to ramelteon (relative risk, 0.8; 95% CI, 0.5-1.4; p = 0.516). Delirium duration, as assessed by the number of delirium-free days was also similar in both groups (placebo median 2 d [interquartile range, 2-3 d] vs ramelteon 3 d [2-5 d]; p = 0.181). Coma-free days was also similar between groups (placebo median 2 d [interquartile range, 1-3 d] vs ramelteon 3 d [2-4 d]; p = 0.210). We found no difference in ICU length of stay (median 4 d [interquartile range, 3-5 d] vs 4 d [3-6 d]; p = 0.349), or in-hospital mortality (four vs three deaths; relative risk ratio, 0.7; 95% CI, 0.2-3.2; p = 0.717), all placebo versus ramelteon, respectively.Ramelteon 8 mg did not prevent postoperative delirium in patients admitted for elective cardiac surgery.

The aim of this study was to investigate the incidence of May-Thurner anatomy (MTA) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) and identify its predictors.MTA is an anatomical variant characterized by compression of left common iliac vein by the overlying right iliac artery. Over time, this leads to venous intimal scarring, blood flow stasis, and the development of deep vein thrombosis (DVT). DVT is a known risk factor for the development of CTEPH. The prevalence of this anatomical variation in patients with CTEPH is unknown.A retrospective chart review was conducted in patients referred to Temple University Hospital's cardiac catheterization laboratory for the evaluation of CTEPH between January 2016 and June 2020. Among these patients, those who underwent invasive venography were evaluated for the presence of angiographic MTA. Multivariate regression was used to identify factors associated with presence of MTA.A total of 193 patients with CTEPH were referred for pulmonary angiography, of whom 148 patients underwent invasive venography. MTA was identified in 44 patients (29.7%). Factors associated with the presence of MTA were lower extremity DVT (odds ratio: 3.5; 95% confidence interval: 1.58-7.8; P = 0.002), and left lower extremity post-thrombotic syndrome (odds ratio: 2.0; 95% confidence interval: 0.98-4.1; P = 0.05). Patients with MTA were more likely to undergo pulmonary thromboendarterectomy than patients without MTA (79.5% vs 58.7%; P = 0.015).MTA is very common in patients with CTEPH. History of lower extremity DVT and or left lower extremity post-thrombotic syndrome was associated with the presence of MTA.

Background Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare sequela of acute pulmonary embolism that is treatable when recognized. Awareness of this disease has increased with recent advancements in therapeutic options, but delays in diagnosis remain common, and diagnostic and treatment guidelines are often not followed. Data gathered from international registries have improved our understanding of CTEPH, but these data may not be applicable to the US population owing to differences in demographics and medical practice patterns. Objective The US CTEPH Registry (US-CTEPH-R) was developed to provide essential information to better understand the demographics, risk factors, evaluation, and treatment of CTEPH in the United States, as well as the short- and long-term outcomes of surgical and nonsurgical therapies in the modern treatment era. Methods Thirty sites throughout the United States enrolled 750 subjects in this prospective, longitudinal, observational registry of patients newly diagnosed with CTEPH. Enrollment criteria included a mean pulmonary artery pressure ≥25 mmHg by right heart catheterization and radiologic confirmation of CTEPH by a multidisciplinary adjudication committee. Following enrollment, subjects were followed biannually until the conclusion of the study. Quality of life surveys were administered at enrollment and biannually, and all other testing was at the discretion of the treating clinician. Details regarding surgical therapy, balloon pulmonary angioplasty, and medical therapy were collected at enrollment and at follow-up, as well as information related to health care utilization and survival. Results Data from this registry will improve understanding of the demographics, risk factors, and treatment patterns of patients with CTEPH, and the longitudinal impact of therapies on quality of life, health care utilization, and survival. Conclusions This manuscript details the methodology and design of the first large, prospective, longitudinal registry of patients with CTEPH in the United States. Trial Registration ClinicalTrials.gov NCT02429284; https://www.clinicaltrials.gov/ct2/show/NCT02429284 International Registered Report Identifier (IRRID) DERR1-10.2196/25397

BACKGROUND Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare sequela of acute pulmonary embolism that is treatable when recognized. Awareness of this disease has increased with recent advancements in therapeutic options, but delays in diagnosis remain common, and diagnostic and treatment guidelines are often not followed. Data gathered from international registries have improved our understanding of CTEPH, but these data may not be applicable to the US population owing to differences in demographics and medical practice patterns. OBJECTIVE The US CTEPH Registry (US-CTEPH-R) was developed to provide essential information to better understand the demographics, risk factors, evaluation, and treatment of CTEPH in the United States, as well as the short- and long-term outcomes of surgical and nonsurgical therapies in the modern treatment era. METHODS Thirty sites throughout the United States enrolled 750 subjects in this prospective, longitudinal, observational registry of patients newly diagnosed with CTEPH. Enrollment criteria included a mean pulmonary artery pressure ≥25 mmHg by right heart catheterization and radiologic confirmation of CTEPH by a multidisciplinary adjudication committee. Following enrollment, subjects were followed biannually until the conclusion of the study. Quality of life surveys were administered at enrollment and biannually, and all other testing was at the discretion of the treating clinician. Details regarding surgical therapy, balloon pulmonary angioplasty, and medical therapy were collected at enrollment and at follow-up, as well as information related to health care utilization and survival. RESULTS Data from this registry will improve understanding of the demographics, risk factors, and treatment patterns of patients with CTEPH, and the longitudinal impact of therapies on quality of life, health care utilization, and survival. CONCLUSIONS This manuscript details the methodology and design of the first large, prospective, longitudinal registry of patients with CTEPH in the United States. CLINICALTRIAL ClinicalTrials.gov NCT02429284; https://www.clinicaltrials.gov/ct2/show/NCT02429284 INTERNATIONAL REGISTERED REPORT DERR1-10.2196/25397

Background Hypodense filling defects within the pulmonary veins on computed tomography described as pulmonary vein sign (PVS) have been noted in acute pulmonary embolism and shown to be associated with poor prognosis. We evaluated venous flow abnormalities in chronic thromboembolic pulmonary hypertension (CTEPH) to determine its usefulness in the computed tomography assessment of CTEPH. Methods and Results Blinded retrospective computed tomography analysis of 50 proximal CTEPH cases and 3 control groups—50 acute pulmonary embolism, 50 nonthromboembolic cohort, and 50 pulmonary arterial hypertension. Venous flow reduction was assessed by the following: (1) presence of a filling defect of at least 2 cm in a pulmonary vein draining into the left atrium, and (2) left atrium attenuation (>160 Hounsfield units). PVS was most prevalent in CTEPH. Compared with all controls, sensitivity and specificity of PVS for CTEPH is 78.0% and 85.3% (95% CI, 64.0–88.5 and 78.6–90.6, respectively) versus 34.0% and 70.7% (95% CI, 21.2−48.8 and 62.7–77.8) in acute pulmonary embolism, 8.0% and 62% (95% CI, 2.2–19.2 and 53.7–69.8) in nonthromboembolic and 2.0% and 60% (95% CI, 0.1−10.7 and 51.7−67.9) in pulmonary arterial hypertension. In CTEPH, lobar and segmental arterial occlusive disease was most commonly associated with corresponding absent venous flow. PVS detection was highly reproducible (Kappa=0.96, 95% CI, 0.90–1.01, P Conclusions PVS is easy to detect with higher sensitivity and specificity in CTEPH compared with acute pulmonary embolism and is not a feature of pulmonary arterial hypertension. Asymmetric enhancement of pulmonary veins may serve as an additional parameter in the computed tomography assessment of CTEPH and can be used to differentiate CTEPH from pulmonary arterial hypertension.

Uterine fibroids have been described as an associate to acute venous thromboembolism (VTE), with case reports showing an association between large uterine fibroids, acute deep venous thrombosis (DVT), and acute pulmonary embolism (PE). However, there is little known about the association or causation between uterine fibroids, chronic thromboembolic disease (CTED), and chronic thromboembolic pulmonary hypertension (CTEPH). We report on six women with uterine fibroids and CTEPH, as well as one woman with CTED, all of whom presented with exertional dyspnea, lower extremity swelling, and in the cases of CTEPH, clinical, echocardiographic, and hemodynamic evidence of pulmonary hypertension and right heart failure. Compression of the pelvic veins by fibroids was directly observed with invasive venography or contrast-enhanced computed tomography in five cases. All seven women underwent pulmonary thromboendarterectomy (PTE) followed by marked improvement in functional, clinical, and hemodynamic status.

Background: Left ventricular dyssynchrony has been studied extensively, but this is not the case with right ventricular (RV) dyssynchrony. Our aim was to investigate RV dyssynchrony through 2D speckle strain imaging in patients with chronic thromboembolic pulmonary hypertension (CTEPH) before and after pulmonary thromboendarterectomy (PTE).Methods: We measured 2D peak RV strain (%) of the RV free-wall and time to peak strain (ms) of its three freewall segments (base, mid, and apex) in 127 consecutive CTEPH patients (51 ± 14 years, 59% female) with adequate images pre- and post-PTE. RV strain was calculated using Epsilon Imaging EchoInsight® software. RV dyssynchrony was measured using two methods: the standard deviation of peak systolic strain and the standard deviation of time (ms) to peak strain (RVDT) between the three RV free-wall segments.Results: Mean RV free wall strain did not change significantly after PTE (−11.4 ± 5.7 to −11.2 ± 5.6%, p = 0.67). However, RV dyssynchrony improved dramatic...

Chronic thromboembolic pulmonary hypertension (CTEPH) is an important consequence of pulmonary embolism that is associated with abnormalities in haemostasis. We investigated the ADAMTS13–von Willebrand factor (VWF) axis in CTEPH, including its relationship with disease severity, inflammation, ABO groups and ADAMTS13 genetic variants. ADAMTS13 and VWF plasma antigen levels were measured in patients with CTEPH (n=208), chronic thromboembolic disease without pulmonary hypertension (CTED) (n=35), resolved pulmonary embolism (n=28), idiopathic pulmonary arterial hypertension (n=30) and healthy controls (n=68). CTEPH genetic ABO associations and protein quantitative trait loci were investigated. ADAMTS13–VWF axis abnormalities were assessed in CTEPH and healthy control subsets by measuring ADAMTS13 activity, D-dimers and VWF multimeric size. Patients with CTEPH had decreased ADAMTS13 (adjusted β −23.4%, 95% CI −30.9– −15.1%, p, The ADAMTS-13–VWF axis is dysregulated in chronic thromboembolism with and without pulmonary hypertension and is implicated in the pathogenesis http://ow.ly/J9SC30nh5T0

This study aimed to validate an algorithm developed to identify chronic thromboembolic pulmonary hypertension (CTEPH) among patients with a history of pulmonary embolism. Validation was halted because too few patients had gold-standard evidence of CTEPH in the administrative claims/electronic health records database, suggesting that CTEPH is underdiagnosed.

Objectives This study aimed to identify the prevalence of cardiac implantable electronic devices (CIEDs) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) and to describe the associated disease burden. Background CTEPH is a debilitating disease, now potentially curable with pulmonary thromboendarterectomy (PTE). The contribution of CIEDs to thrombosis in this patient population has not been previously studied. Methods The charts of 982 CTEPH patients, who underwent PTE between January 1, 2009, and December 31, 2015 at University of California-San Diego (UCSD) Medical Center, were reviewed for pacemakers or implantable cardioverter defibrillators (ICDs) implanted before surgery. Results Among 982 CTEPH patients who underwent PTE, 14 had pacemakers and 3 had ICDs, giving 17 CIEDs and a prevalence of 1.7%. Of these 17 CIEDs, 6 devices were extracted intraoperatively, and 5 of 6 devices were replaced with epicardial leads. Furthermore, of the 950 patients classified by intraoperative UCSD level, 12 of 17 (70.6%) patients with CIEDs had distal disease versus 241 of 933 (25.8%) patients without CIEDs (p = 0.0002). The prevalence of known venous thromboembolism (VTE) was 50% in CIED patients compared with 78.6% in patients without CIEDs (p = 0.018). Conclusions At 1.7%, the prevalence of CIEDs in the PTE population was higher than previously reported values, which estimated CIED prevalence between 0.16% and 0.47% in the general population. Moreover, CTEPH patients with CIEDs were more strongly associated with distal disease burden and less likely to have had previous VTE, which suggested that CIEDs may be a nidus for small clots that embolize distally in the pulmonary vasculature.

This study sought to determine the prevalence of coronary artery-pulmonary artery collaterals in patients with chronic thromboembolic pulmonary hypertension (CTEPH) and to correlate their presence with the degree of clot burden. CTEPH is a treatable cause of severe pulmonary hypertension and right heart failure. Bronchopulmonary collateral vessels have been used as a supplementary diagnostic and prognostic tool for this disease. Coronary artery-pulmonary artery collaterals in this population have not been described. The coronary angiograms of 300 consecutive patients with CTEPH evaluated for pulmonary thromboendarterectomy (PTE) between January 1, 2007, and May 1, 2014, were examined. Of these patients, 259 (50% male; mean age, 58.3 ± 10.6 years) had cineangiographic images deemed adequate to definitively assess for the presence of coronary artery-pulmonary artery collaterals and were included in the final analyses. Pulmonary angiogram reports were reviewed for extent of pulmonary artery obstruction. The coronary angiograms of 259 age- and sex-matched control patients were also examined. Among 259 CTEPH patients with definitive imaging, 34 coronary artery-pulmonary artery collaterals were found in 28 patients (10.8%), versus 1 coronary artery-pulmonary artery collateral among control subjects (0.4%; P < 0.001). Compared with CTEPH patients without collaterals, patients with collaterals had a significantly higher prevalence of total occlusion of their right or left main pulmonary artery (P < 0.001) or lobar arteries (P < 0.001). In conclusion, the prevalence of coronary artery-pulmonary artery collaterals in CTEPH patients undergoing coronary angiography for possible PTE is approximately 11%. These vessels are associated with more severe pulmonary artery occlusion.

Chronic thromboembolic pulmonary hypertension (CTEPH), a rare consequence of an acute pulmonary embolism, is a disease that is underdiagnosed, and surgical pulmonary thromboendarterectomy (PTE) remains the preferred therapy. However, determination of operability is multifactorial and can be challenging. There is growing excitement for the percutaneous treatment of inoperable CTEPH with data from multiple centers around the world showing the clinical feasibility of balloon pulmonary angioplasty. Riociguat remains the only approved medical therapy for CTEPH patients deemed inoperable or with persistent pulmonary hypertension after PTE. We recommend that expert multidisciplinary CTEPH teams be developed at individual institutions. Additionally, optimal and standardized techniques for balloon pulmonary angioplasty need to be developed along with dedicated interventional equipment and appropriate training standards. In the meantime, the percutaneous revascularization option is appropriate for patients deemed inoperable in combination with targeted medical therapy, or those who have failed to benefit from surgery.

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.

Although there are several iterations of the same theme, Albert Einstein once proclaimed, “The more I learn, the more I realize how much I don’t know.” An interpretation of this notion is that each step forward in discovery simply leads to more questions to answer. The expanding experience with balloon pulmonary angioplasty worldwide in the treatment of chronic thromboembolic pulmonary hypertension (CTEPH) is reminiscent of Einstein’s assertion. In this month’s issue of Circulation: Cardiovascular Quality and Outcomes , Ogawa et al1 report the combined outcomes from 7 institutions in Japan performing balloon pulmonary angioplasty on patients with inoperable CTEPH. And although the information provided in this article is of considerable value, many unanswered questions remain. See Article by Ogawa et al The aggregate data presented in this multicenter Japanese balloon pulmonary angioplasty (BPA) registry provides a clearer characterization of patients undergoing this intervention—80% were female, medical conditions previously reported to be associated with CTEPH were uncommon, thrombophilic disorders were seen in 8.8% of patients, only 15.3% of patients had a prior episode of acute pulmonary embolism, and 34.7% were with a deep venous thrombosis history. This patient phenotype is distinctly different from that reported in large series of CTEPH patients where the male to female ratio is nearly even and a much higher percentage of patients having been identified as experiencing a previous pulmonary embolic event.2 This raises the issue as to whether the patient type is distinct in this series and, as a consequence, whether the reported outcomes are transferable to other BPA-experienced centers. It might be argued that the patient characteristics in the Japanese Registry may be reflective of those at risk for developing inoperable chronic thromboembolic disease. However, published information from several European BPA centers are more …

Background Obesity is a common comorbidity of patients with chronic thromboembolic pulmonary hypertension referred for pulmonary thromboendarterectomy, yet the effect of obesity on pulmonary thromboendarterectomy outcomes has not been well described. Methods We conducted a retrospective cohort study in which 476 consecutive operations over a 3.5-year period were examined to determine the effects of obesity on outcomes. Patients were grouped into four categories based on body mass index (BMI): less than 22 kg/m 2 , 22 to 30 kg/m 2 , 30 to 40 kg/m 2 , and more than 40 kg/m 2 . Results There were important differences in baseline pulmonary hemodynamics, with obese patients having significantly lower pulmonary vascular resistances than nonobese patients. All patients achieved a significant reduction in pulmonary vascular resistance, although the improvement was greatest in the lower BMI groups. The overall in-hospital mortality was 0.8%, and there were no differences in risk among BMI groups. Among the BMI groups, there were no differences in incidence of postoperative complications, including atrial fibrillation (overall 24.8%), reperfusion lung injury (overall 23.1%), and surgical site infection (overall 4.4%) or in median lengths of stay (including ventilator days, intensive care unit days, and postoperative length of stay). Conclusions Pulmonary thromboendarterectomy outcomes have continued to improve, and this surgery can safely be completed in obese patients, previously deemed to be at high risk for poor outcomes.

Bronchopulmonary collateral vasculature is a significant source of systemic blood flow in patients with chronic thromboembolic pulmonary hypertension (CTEPH).1 We present 2 cases of coronary artery-to-pulmonary artery (PA) collateral vessels, which have not been previously described in patients with CTEPH. A 40-year-old man with a history of deep venous thrombosis after parotidectomy for a benign lesion, recurrent strokes, and right-sided pulmonary embolism was evaluated for 5 years of progressive exertional dyspnea and suspected CTEPH. He had no known hereditary thrombophilia. Preoperative ventilation–perfusion scintigraphy demonstrated absent perfusion to the right lung and small defects in the left lower lobe (Figure 1). Pulmonary angiography confirmed occlusion of the proximal right PA with no distal flow (Figure 2; Movie I in the Data Supplement). His mean PA pressure was 35 mm Hg, pulmonary vascular resistance was 511 dyne/s per cm5, and cardiac index was 2.3 L/min per m2. Coronary angiography revealed a 4.6-mm diameter corkscrew vessel arising from the left circumflex artery and traveling to the right lung (Figure 3; Movie II in the Data Supplement). He had no significant coronary artery disease. The patient underwent bilateral pulmonary thromboendarterectomy (PTE; Figure 4), during which a small atrial septal defect was found and repaired. Collaterals were noted throughout the mediastinum, particularly around the aorta traversing toward the right lung and directly penetrating the right main PA. Final mean PA …

Chronic thromboembolic pulmonary hypertension (CTEPH) is a potentially curable disease when treated with pulmonary thromboendarterectomy (PTE). However, even at experienced surgical centers, nearly one-third of patients with CTEPH will be deemed inoperable for reasons including distal disease, comorbidities, or out-of-proportion pulmonary hypertension. It is in these patients with inoperable CTEPH that pulmonary hypertension (PH)-targeted medical therapy and balloon pulmonary angioplasty have potential therapeutic value. Previous unblinded cohort trials have assessed PH-targeted medical therapy in various subpopulations of CTEPH patients using epoprostenol, treprostinil, sildenafil, bosentan, and iloprost, each demonstrating measurable pulmonary hemodynamic effects. However, riociguat, a soluble guanylate cyclase stimulator, is the first FDA-approved therapy for inoperable CTEPH to demonstrate both an improvement in functional capabilities (6-minute walk time) as well as significant gains in secondary pulmonary hemodynamic end points in a large placebo-controlled trial. Balloon pulmonary angioplasty is an interventional procedure using telescoping catheters placed in the pulmonary arteries, through which wires and balloons are used to mechanically disrupt chronic clot material and relieve pulmonary vascular obstruction. Contemporary case series from multiple centers worldwide have demonstrated pulmonary hemodynamic improvement with this approach. As a result of these advances, patients with inoperable CTEPH who had few options as recently as 5 years ago now have alternatives with emerging evidence of therapeutic efficacy.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a known sequela of acute pulmonary embolic disease and yet remains underdiagnosed. Although nonsurgical options for patients with CTEPH have become increasingly available, including pulmonary artery hypertensive medical therapy, surgical endarterectomy provides the most appropriate intervention as a potential cure for this debilitating disorder. This article summarizes the most recent outcomes of pulmonary endarterectomy at a single institution over the past 12 years, with emphasis on the surgical approach to segmental-level chronic thromboembolic disease.More than 2,700 pulmonary endarterectomy operations have been performed at the University of California, San Diego Medical Center. Because of recent changes in the patient population and in surgical results, 1,500 patients with symptomatic chronic thromboembolic disease who underwent pulmonary endarterectomy between March 1999 and December 2010 were analyzed. The outcomes for the more recent 500 patients, compared with the previous 1,000 were studied.In-hospital mortality for the cohort of 1,000 patients (group 1) was 5.2% compared with 2.2% for the last 500 operations (group 2) (p0.01). There was no mortality in the last 260 consecutive patients undergoing isolated pulmonary endarterectomy. More patients presented with segmental type III disease in the more recent 500 patients (21.4% versus 13.1%; p0.001). Between the 2 patient groups, there was a comparable decline in pulmonary vascular resistance (PVR) (group 1: 861.2 ± 446.2 to 94.8 ± 204.2 dynes/sec/cm(-5); group 2: 719.0 ± 383.2 to 253.4 ± 148.6 dynes/sec/cm(-5)) and mean pulmonary artery (PA) pressures (group 1: 46.1 ± 11.4 to 28.7 ± 10.1 mm Hg; group 2: 45.5 ± 11.6 to 26.0 ± 8.4 mm Hg) after endarterectomy.Despite a patient population with more distal disease, results continue to improve. Pulmonary endarterectomy for patients with CTEPH results in significant pulmonary hemodynamic improvement, with favorable outcomes achievable even in patients with distal segmental-level chronic thromboembolic disease.

Pulmonary hypertension as a result of chronic thromboembolic disease (CTEPH) is potentially curable with pulmonary endarterectomy surgery. Consequently, correctly diagnosing patients with this type of pulmonary hypertension and evaluating these patients with the goal of establishing their candidacy for surgical intervention is of utmost importance. And as advancements in surgical techniques have allowed successful resection of segmental-level chronic thromboembolic disease, the number of CTEPH patients that are deemed suitable surgical candidates has expanded, making it even more important that the evaluation be conducted with greater precision. This article will review a diagnostic approach to patients with suspected chronic thromboembolic disease with an emphasis on the criteria considered in selecting patients for pulmonary endarterectomy surgery.

Over the past 4 decades, chronic thromboembolic pulmonary hypertension has evolved from an autopsy curiosity to a potentially correctable form of pulmonary hypertension. Advances in surgical techniques along with the introduction of pulmonary hypertension disease-modifying therapies provide a therapeutic option for the majority of patients afflicted with the disease. Approximately 5,000 thromboendarterectomy procedures have now been performed worldwide with mortality rates reported by established programs experienced in the management of this disease process falling to a range of 4 to 7%. A mortality rate of 1.3% has been reported in patients at low risk based on their preoperative hemodynamic profile. After a successful pulmonary thromboendarterectomy, substantial improvement and often normalization can be achieved in right ventricular function, gas exchange, exercise capacity, and quality of life. For patients not candidates for thromboendarterectomy, or for those with persistent post-thromboendarterectomy pulmonary hypertension, disease-modifying medical therapies have been demonstrated to stabilize and improve pulmonary hemodynamics, albeit not to the same extent as primary thromboendarterectomy. The current review focuses on the diagnostic approach to chronic thromboembolic pulmonary hypertension and the available surgical and medical therapeutic options. Additional research is necessary to more accurately predict postoperative hemodynamic outcome and to define the optimal therapeutic approach, especially in patients with involvement of the distal vasculature.

Pulmonary vascular remodeling occurs in patients with chronic thromboembolic pulmonary hypertension (CTEPH). One factor contributing to this vascular wall thickening is the proliferation of pulmonary artery smooth muscle cells (PASMC). Store-operated Ca2+ entry (SOCE) and cytosolic free Ca2+ concentration ([Ca2+]cyt) in PASMC are known to be important in cell proliferation and vascular remodeling in pulmonary hypertension. Rapamycin is widely known for its antiproliferative effects in injured coronary arteries. Although several reports have suggested favorable effects of rapamycin in animal models of pulmonary hypertension, no reports have been published to date in human tissues. Here we report that rapamycin has an inhibitory effect on SOCE and an antiproliferative effect on PASMC derived from endarterectomized tissues of CTEPH patients. Cells were isolated from endarterectomized tissues obtained from patients undergoing pulmonary thromboendarterectomy (PTE). Immunohistochemical analysis indicated high deposition of platelet-derived growth factor (PDGF) in tissue sections from PTE tissues and increased PDGF receptor expression. PDGF transiently phosphorylated Akt, mammalian target of rapamycin (mTOR), and p70S6 kinase in CTEPH cells from CTEPH patients. Acute treatment (30 min) with rapamycin (10 nM) slightly increased cyclopiazonic acid (10 μM)-induced Ca2+ mobilization and significantly reduced SOCE. Chronic treatment (24 h) with rapamycin reduced Ca2+ mobilization and markedly inhibited SOCE. The inhibitory effects of rapamycin on SOCE were less prominent in control cells. Rapamycin also significantly reduced PDGF-stimulated cell proliferation. In conclusion, the data from this study indicate the importance of the mTOR pathway in the development of pulmonary vascular remodeling in CTEPH and suggest a potential therapeutic benefit of rapamycin (or inhibition of mTOR) in these patients.

Chronic thromboembolic disease (CTED) remains an impor- tant exclusion in patients presenting with pulmonary hyper- tension. As illustrated by this case, however, exclusion must be rigorous with or without a suggestive history. Although it is a surgically treated disease, not all patients may be can- didates for or elect surgery, leaving medical management as the only remaining option.

Objectives The purpose of this study was to investigate the cause of abnormal left ventricular (LV) Doppler diastolic filling characteristics in chronic thromboembolic pulmonary hypertension (CTEPH). Background In CTEPH, LV diastolic function often appears abnormal. It is unclear whether this “impaired relaxation” (E Methods We studied 61 patients with an E Results After PTE, mitral E velocity increased (from 54 ± 16 cm/s to 81 ± 20 cm/s, p m ) did not change after PTE (8.0 ± 3.1 cm/s to 8.1 ± 2.0 cm/s, p = ns), whereas the velocity of the lateral mitral annulus increased (9.3 ± 3.2 cm/s to 11.8 ± 3.1 cm/s, p Conclusions The results of this study strongly suggest that the impaired relaxation pattern observed in patients with CTEPH is not solely the result of geometric effects of RV enlargement and LV chamber distortion but is caused in large part by low LV preload and relative underfilling.

Patients with chronic thromboembolic pulmonary hypertension (CTEPH) often have substantial right ventricular dysfunction. The resulting low cardiac index might predispose to sleep disordered breathing (SDB) by increasing ventilatory instability. The prevalence of SDB and potential association with impaired cardiac index was examined in patients with CTEPH. Patients referred for evaluation for pulmonary thromboendarterectomy surgery were recruited. Subjects underwent a sleep study, unless already using positive airway pressure therapy. Hemodynamic data were obtained from contemporaneous right-sided cardiac catheterization. A total of 49 subjects were included. SDB-defined as ongoing positive airway pressure use or apnea-hypopnea index (AHI) ≥5/h-was found in 57% of subjects. SDB was generally mild in severity, with respiratory events mainly consisting of hypopneas. Cardiac index was found to be significantly lower in subjects with SDB than those without (2.19 vs 2.55L/min/m(2); p= 0.024), whereas no differences were observed in other characteristics. Additionally, cardiac index was independently predictive of AHI. In a subgroup of subjects with an elevated percentage of central events, both cardiac index and lung to finger circulation time correlated with AHI. In conclusion, SDB is prevalent in patients with CTEPH and might decrease with treatments that improve cardiac index.

Background Pulmonary endarterectomy is the accepted therapy for thromboembolic pulmonary hypertension. A recognized complication of this surgery is the postoperative development of reperfusion edema, a potentially fatal cause of respiratory failure. Because reperfusion edema can be a reversible process, temporizing support measures may be life saving. Methods We retrospectively reviewed our experience with venovenous extracorporeal life support (V-V ECLS) from July 1990 to February 2006, in 20 adult patients (mean age 50.5 ± 14.5 years) presenting with potentially reversible respiratory failure after pulmonary endarterectomy. This subset of patients comprised 1.12% of our total pulmonary endarterectomy experience during that time (1,790 cases). Results Overall in-hospital survival was 30.0% for patients requiring ECLS support after pulmonary endarterectomy versus 94.2% for patients who underwent pulmonary endarterectomy alone during the same timeframe. V-V ECLS was instituted at a mean of 86.8 hours after surgery. The mean duration of V-V ECLS was 123.4 ± 71.3 hours. The most common cause of death in ECLS patients after pulmonary endarterectomy was pulmonary hemorrhage. Survival was greater in patients cannulated within 120 hours of surgery (46.2% survival; 6 of 13 patients) compared with those cannulated after 120 hours (0 of 7 patients). Multiple logistic regression identified long duration of mechanical ventilation pre-ECLS and severity of preoperative pulmonary hypertension together as predictors of mortality. Conclusions A small subset of patients undergoing pulmonary endarterectomy develop temporary life-threatening respiratory failure secondary to severe reperfusion edema. In those patients with satisfactory hemodynamic outcome, V-V ECLS is a therapeutic option when all other conventional strategies have been exhausted.

Although acute pulmonary embolism is epidemiologically associated with chronic thromboembolic pulmonary hypertension, the factors responsible for resistance to thrombolysis and a shift toward vascular remodeling within the pulmonary arteries of patients with chronic thromboembolic pulmonary hypertension are unknown.Determine whether fibrin from patients is more resistant to plasmin-mediated lysis than fibrin from healthy control subjects.Fibrinogen purified from patients and control subjects was used to prepare fibrin clots, which were subsequently digested with plasmin for various periods of time. The degradation of the alpha-, beta-, and gamma-chains of fibrin and the appearance of peptide fragments over time were assessed by polyacrylamide gel electrophoresis and Western blotting.Densitometry of Coomassie-stained gels revealed significantly slower cleavage of all three polypeptide chains of fibrin from patients compared with control subjects (p0.05). In particular, release of N-terminal fragments from the beta-chain of fibrin, which promote cell signaling, cell migration, and angiogenesis, was retarded in patients compared with control subjects (p0.01).The relative resistance of patient fibrin to plasmin-mediated lysis may be due to alterations in fibrin(ogen) structure affecting accessibility to plasmin cleavage sites. The persistence of structural motifs of fibrin, such as the beta-chain N-terminus, within the pulmonary vasculature could promote the transition from acute thromboemboli into chronic obstructive vascular scars.

Pathophysiological findings in chronic thromboembolic pulmonary hypertension (CTEPH) have suggested that a secondary small vessel arteriopathy may contribute to the haemodynamic impairment observed in these patients. It was hypothesised that this element of the elevated vascular resistance may be responsive to continuous intravenous epoprostenol therapy. Retrospectively, the clinical and haemodynamic responses to continuous intravenous epoprostenol were evaluated in nine CTEPH patients who subsequently underwent pulmonary thromboendarterectomy (PTE). Cardiopulmonary haemodyamics were determined prior to the initiation of epoprostenol, while on epoprostenol, prior to PTE, and after PTE. Six patients, treated for 2-26 months prior to PTE, experienced either clinical stability or improvement that was associated with a mean reduction in pulmonary vascular resistance (PVR) of 28% (median 33%,,, range 0-46%). Three patients, treated for 3-9 months, experienced clinical deterioration during epoprostenol administration, with a significant increase in PVR in two patients. Subsequent PTE resulted in a highly significant improvement of cardiac index, mean pulmonary artery pressure and total pulmonary resistance. To conclude, selected patients with chronic thromboembolic pulmonary hypertension may benefit clinically and haemodynamically from continuous intravenous epoprostenol treatment prior to pulmonary thromboendarterectomy. Factors predictive of a beneficial response, and whether this intervention influences either morbidity or mortality associated with pulmonary thromboendarterectomy, remain to be established

Background The incidence of pulmonary hypertension resulting from chronic thrombotic occlusion of the pulmonary arteries is significantly underestimated. Although medical therapy for the condition is supportive only, surgical therapy is curative. Our pulmonary endarterectomy program was begun in 1970, and 188 patients were operated on in the subsequent 20 years. With the increased recognition of the disease and the success of operative therapy, however, more than 1,400 operations have been done since 1990 at our center. Methods The safety and efficacy of the operation was assessed with changes made through increased experience. We examined in detail the results of our last 500 consecutive patients. Results Median sternotomy, cardiopulmonary bypass, profound hypothermia, and circulatory arrest were found to be essential to the success of the operation. All occluding material could be removed at operation. We currently believe that there is no degree of embolic occlusion within the pulmonary vascular tree that is inaccessible and no degree of right ventricular impairment or any level of pulmonary vascular resistance that is inoperable. With shorter cardiac arrest periods and the use of a cooling jacket to the head, cerebral impairment has been eliminated. The pulmonary artery pressures and pulmonary vascular resistance in a recent cohort of 500 patients is examined. The mortality rate for the operation has been reduced steadily, and was 22 of the last 500 patients operated on (4.4%). Conclusions The operation is considered curative and therefore greatly superior to transplantation for this condition. Current techniques of operation make the procedure relatively safe.

Chronic thromboembolic obstruction of the major pulmonary arteries is an underrecognized sequela of acute pulmonary embolism. Depending on the burden and location of thrombus, as well as on the duration of vessel obstruction, chronic thromboembolic disease may lead to pulmonary hypertension and cor pulmonale. Chronic thromboembolic disease affects an estimated 500 to 2500 patients each year in the United States, roughly 0.1 to 0.5 percent of patients who survive acute pulmonary embolism. Consequently, while this disease is uncommon, chronic thromboembolic pulmonary hypertension (CTEPH) is not rare, and should be considered in patients with unexplained dyspnea, as it is potentially correctible with pulmonary thromboendarterectomy.1

Five physicians addressed important issues in the diagnosis and management of patients with pulmonary thromboembolic disease. The roundtable discussion was moderated by Victor F. Tapson, MD, Associate Professor of Medicine, Division of Pulmonary and Critical Care Medicine, Duke University Medical Center, Durham, North Carolina, and included William Auger, MD, Professor of Clinical Medicine, University of California, San Diego, Medical Center, San Diego, California; Peter Fedullo, MD, Clinical Professor of Medicine, University of California, San Diego, Medical Center; Eckhard Mayer, MD, Professor of Thoracic Surgery, Department of Cardio-Thoracic Surgery, University Hospital, Mainz, Germany; and Christopher McGregor, MD, Professor of Surgery, Consultant in Cardio-Thoracic Surgery, and Director of the Mayo Clinic William J von Liebig Transplant Center, Rochester, Minnesota.

In their 1993 report, Moser and Bloor [1] described an array of microvascular “pulmonary hypertensive” lesions in patients with operable chronic thromboembolic disease. Although it was concluded that these findings in any one patient did not “preclude a positive haemodynamic and clinical result”, these early observations became the foundation of our current understanding of the evolution of pulmonary hypertension and right heart failure, following the establishment of proximal vessel, occlusive organised thromboembolic disease [2, 3]. Despite the significance and role of the microcirculation in chronic thromboembolic pulmonary hypertension (CTEPH), our understanding of the histopathology remains rather rudimentary [4] and previously confined to descriptions of the precapillary pulmonary …