Unilateral Chronic Thromboembolic Pulmonary Disease: Do Patients Benefit From Thromboendarterectomy? Case Series From Three CTEPH Centres.

BACKGROUND: Unilateral chronic thromboembolism pulmonary disease (CTEPD) is very rare. There is limited information on the safety and efficacy of pulmonary endarterectomy (PEA) in this population. This study investigated the effectiveness of PEA in this unique disease. METHODS: This multicentre study included patients with unilateral CTEPD from three referral centres in the United States, Turkey, and Iran. The patients' demographic information, 6-minute walk test distance (6MWD), New York Heart Association (NYHA) functional class, and haemodynamics were evaluated. RESULT: Of the 1,031 patients who had undergone PEA, 39 patients (3.7%) had pure unilateral involvement, of whom 28 were female (71.8%). There was a significant improvement in the mean pulmonary artery pressure (mPAP, 26 mmHg vs 21 mmHg; p=0.011) and pulmonary vascular resistance (PVR, 202 vs 136 dynes∗sec1∗cm-5; p=0.014). There was also a significant improvement in NYHA functional class (p<0.001) and 6MWD (360 vs 409 m; p<0.001). In the nine patients with normal haemodynamic parameters at rest, there was no significant change in median 6MWD (448.5 vs 449 m; p=0.208), mPAP (19 mmHg vs 16.5 mmHg; p=0.397), and PVR (129 vs 84.5 dynes∗sec1∗cm-5; p=0.128). The most common postoperative complication was ipsilateral pleural effusion. One patient needed extracorporeal membrane oxygenation support. No patient died within the 1-year follow up. CONCLUSION: Pulmonary endarterectomy is a safe and effective procedure for improving the symptoms and haemodynamic parameters of patients with unilateral CTEPH. Symptomatic patients with unilateral chronic thromboembolic disease are suitable for PEA.

Lessons learned in developing a chronic thromboembolic pulmonary hypertension program.

PURPOSE OF REVIEW: Chronic thromboembolic pulmonary hypertension (CTEPH) is a deadly underdiagnosed form of pulmonary hypertension, traditionally treated with surgical extraction of thrombo-fibrotic lesions via pulmonary thrombendarterectomy (PTE) surgery. More recently, treatment options have expanded to pulmonary vasodilator medical therapy and balloon pulmonary angioplasty (BPA). This has led to increased awareness and detection of CTEPH, as well as growing interest in performing PTE and BPA. This review will describe the steps required to build a successful CTEPH team in the context of the rapidly evolving treatment of CTEPH. RECENT FINDINGS: CTEPH care requires a multidisciplinary team, including a Pulmonologist or Cardiologist expert in Pulmonary Hypertension, a PTE surgeon, a BPA interventionalist, a dedicated radiologist, cardiothoracic anesthesia and Vascular Medicine or Hematology. Careful assessment of precise imaging and hemodynamic data is needed for operability assessment in the context of the experience of the CTEPH team and surgeon. Medical therapy and BPA are indicated for inoperable CTEPH and residual CTEPH after PTE. Increasingly, multimodality approaches, including surgery, BPA and medical therapy are utilized for best outcomes. SUMMARY: An expert CTEPH center requires a multidisciplinary team with dedicated specialists, and time to develop the experience and expertise to achieve high volumes and good outcomes.

Estrogen Signaling and Portopulmonary Hypertension: The Pulmonary Vascular Complications of Liver Disease Study (PVCLD2).

BACKGROUND AND AIMS: Portopulmonary hypertension (POPH) was previously associated with a single-nucleotide polymorphism (SNP) rs7175922 in aromatase (cytochrome P450 family 19 subfamily A member 1 [CYP19A1]). We sought to determine whether genetic variants and metabolites in the estrogen signaling pathway are associated with POPH. APPROACH AND RESULTS: We performed a multicenter case-control study. POPH patients had mean pulmonary artery pressure >25 mm Hg, pulmonary vascular resistance >240 dyn-sec/cm-5 , and pulmonary artery wedge pressure ≤15 mm Hg without another cause of pulmonary hypertension. Controls had advanced liver disease, right ventricular (RV) systolic pressure <40 mm Hg, and normal RV function by echocardiography. We genotyped three SNPs in CYP19A1 and CYP1B1 using TaqMan and imputed SNPs in estrogen receptor 1 using genome-wide markers. Estrogen metabolites were measured in blood and urine samples. There were 37 patients with POPH and 290 controls. Mean age was 57 years, and 36% were female. The risk allele A in rs7175922 (CYP19A1) was significantly associated with higher levels of estradiol (P = 0.02) and an increased risk of POPH (odds ratio [OR], 2.36; 95% confidence interval [CI], 1.12-4.91; P = 0.02) whereas other SNPs were not. Lower urinary 2-hydroxyestrogen/16-α-hydroxyestrone (OR per 1-ln decrease = 2.04; 95% CI, 1.16-3.57; P = 0.01), lower plasma levels of dehydroepiandrosterone-sulfate (OR per 1-ln decrease = 2.38; 95% CI, 1.56-3.85; P < 0.001), and higher plasma levels of 16-α-hydroxyestradiol (OR per 1-ln increase = 2.16; 95% CI, 1.61-2.98; P < 0.001) were associated with POPH. CONCLUSIONS: Genetic variation in aromatase and changes in estrogen metabolites were associated with POPH.

Identifying Patients with Group 3 Pulmonary Hypertension Associated with COPD or ILD Using an Administrative Claims Database.

BACKGROUND: Group 3 pulmonary hypertension (PH) describes a subpopulation of patients with PH due to chronic lung disease and/or hypoxia, with chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) being two large subgroups. Claims database studies provide insights into the real-world treatment patterns and outcomes among these patients. However, claims data do not provide sufficient detail to assign the clinical subtype of PH required for identifying these patients. METHODS: A panel of PH clinical experts and researchers was convened to discuss methodologies to identify patients with Group 3 PH associated with COPD or ILD in retrospective claims databases. To inform the discussion, a literature review was conducted to identify claims-based studies of Group 3 PH associated with COPD or ILD published from 2010 through June 2020. RESULTS: Targeted title and abstract review identified 11 claims-based studies and two conference abstracts (eight based in the United States [US] and five conducted outside the US) that met search criteria. Based on insights from the panel and literature review, the following components were detailed across studies in the identification of Group 3 PH associated with COPD and ILD: (a) COPD or ILD identification, (b) PH identification, (c) defining the sequence between COPD/ILD and PH, and (d) other PH Group and Group 3 PH exclusions. CONCLUSION: This article provides recommended approaches and considerations for identifying and studying patients with Group 3 PH associated with COPD or ILD using administrative claims data that provide the foundation for future validation studies.

Direct oral anticoagulants in chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) represents the later stage consequence of at least one or more unresolved episodes of acute pulmonary embolism; thus, indefinite anticoagulation is strongly recommended by current practice guidelines. Historically, vitamin K antagonists have been widely used in these patients. However, recent data indicate a shift toward direct oral anticoagulants (DOACs), despite lack of data on the safety and efficacy in this patient population. Herein, we briefly discuss the current rationale for oral anticoagulation use in CTEPH, addressing important issues and controversies involved with the use of DOACs, opening a strategy for further clinical research in the field of oral anticoagulation.

Lipids and ketones dominate metabolism at the expense of glucose control in pulmonary arterial hypertension: a hyperglycaemic clamp and metabolomics study.

Individuals with idiopathic pulmonary arterial hypertension (PAH) display reduced oral glucose tolerance. This may involve defects in pancreatic function or insulin sensitivity but this hypothesis has not been tested; moreover, fasting nutrient metabolism remains poorly described in PAH. Thus, we aimed to characterise fasting nutrient metabolism and investigated the metabolic response to hyperglycaemia in PAH.12 participants (six PAH, six controls) were administered a hyperglycaemic clamp, while 52 (21 PAH, 31 controls) underwent plasma metabolomic analysis. Glucose, insulin, C-peptide, free fatty acids and acylcarnitines were assessed from the clamp. Plasma metabolomics was conducted on fasting plasma samples.The clamp verified a reduced insulin response to hyperglycaemia in PAH (-53% versus control), but with similar pancreatic insulin secretion. Skeletal muscle insulin sensitivity was unexpectedly greater in PAH. Hepatic insulin extraction was elevated in PAH (+11% versus control). Plasma metabolomics identified 862 metabolites: 213 elevated, 145 reduced in PAH (p<0.05). In both clamp and metabolomic cohorts, lipid oxidation and ketones were elevated in PAH. Insulin sensitivity, fatty acids, acylcarnitines and ketones correlated with PAH severity, while hepatic extraction and fatty acid:ketone ratio correlated with longer six-min walk distance.Poor glucose control in PAH could not be explained by pancreatic ß-cell function or skeletal muscle insulin sensitivity. Instead, elevated hepatic insulin extraction emerged as an underlying factor. In agreement, nutrient metabolism in PAH favours lipid and ketone metabolism at the expense of glucose control. Future research should investigate the therapeutic potential of reinforcing lipid and ketone metabolism on clinical outcomes in PAH.

Morphologic and Functional Dual-Energy CT Parameters in Patients With Chronic Thromboembolic Pulmonary Hypertension and Chronic Thromboembolic Disease.

OBJECTIVE. The objective of our study was to compare morphologic and functional dual-energy CT (DECT) parameters in patients with chronic thromboembolic disease (CTED) and chronic thromboembolic pulmonary hypertension (CTEPH). MATERIALS AND METHODS. Using the local CTEPH registry, we identified 28 patients with CTED and 72 patients with CTEPH. On each DECT examination, a clot burden score was calculated by assigning the following scores for chronic changes by location: pulmonary trunk, 5; each main pulmonary artery (MPA), 4; each lobar branch, 3; each segmental branch, 2; and each subsegmental branch, 1. The total clot burden score was calculated by adding the individual scores from both lungs. Functional parameters were assessed using perfused blood volume (PBV) maps and included lung enhancement (in Hounsfield units), percentage of PBV, MPA peak enhancement (in Hounsfield units), maximum enhancement corresponding to 100, and the ratio of MPA peak enhancement to lung enhancement. A perfusion defect (PD) score was calculated by assigning 1 point to each segmental PD. Patients with CTED and patients with CTEPH were matched using propensity score matching to account for potential confounders. RESULTS. After matching, the CTEPH group showed a higher PD score than the CTED group and unilateral disease was more common in the CTED group than in the CTEPH group. In the unmatched sample, patients with CTED showed increased percentages of PBV for both lungs (PBV total) and for the right lung as compared with the CTEPH group (adjusted p = 0.040 and 0.028, respectively); after adjustment for clot burden, the difference between groups was still noted but was not statistically significant. No statistically significant differences were noted in the various functional DECT parameters after propensity score matching. CONCLUSION. Patients with CTED show anatomic and functional changes in the pulmonary vasculature and lung parenchyma similar to those seen in patients with CTEPH. Functional DECT parameters support the observation that CTED is an intermediate clinical phenotype in the population with chronic pulmonary embolism.

CT-Based Biomarkers for Prediction of Chronic Thromboembolic Pulmonary Hypertension After an Acute Pulmonary Embolic Event.

OBJECTIVE. The purpose of this study is to assess CT-based markers predictive of the development of chronic thromboembolic pulmonary hypertension (CTEPH) after acute pulmonary embolism. MATERIALS AND METHODS. Identified from a search of local registries, 48 patients who had CTEPH develop were included in the study group, and 113 patients who had complete resolution of acute pulmonary embolism were included in the control group. Baseline CT scans obtained at the time of the initial pulmonary embolism event were evaluated for the degree of clot-induced vessel obstruction, the quantitative Walsh score, the ratio of the right ventricle diameter to the left ventricle diameter, the right atrium diameter, the pulmonary artery diameter, right heart thrombus, pericardial effusion, lung infarction, and mosaic attenuation. Classification and regression tree analysis was used to create a decision tree. The decision tree was externally validated on an anonymized cohort of 50 control subjects and 50 patients with CTEPH. RESULTS. During univariable analysis, an increase in the degree occlusive clot on initial imaging, a decrease in the Walsh score, absence of pericardial effusion, presence of lung infarction, and the presence of mosaic attenuation were associated with an increased probability of CTEPH development. In the final decision tree, the occlusive nature of the clot remained. Two patients in the cohort used for external validation had nondiagnostic findings and were excluded. The decision process correctly classified 33% (16/48) of patients who had CTEPH develop and 86% (43/50) of patients who did not have CTEPH develop, for an odds ratio of 3.1 (95% CI, 1.1-8.3). CONCLUSION. The presence of an occlusive clot on initial imaging is associated with an increased probability of CTEPH development. Presence of mosaic attenuation and lung infarction may also predict CTEPH development, although additional studies are needed.

Inpatient Initiation of Oral Treprostinil in an Academic Medical System.

PURPOSE: Clinicians may transition patients on parenteral or inhaled prostacyclins to oral treprostinil for ease of use or to avoid adverse effects related to parenteral therapy. However, few data are available to guide these transitions in inpatients. The purpose of this analysis is to describe the inpatient initiation of oral treprostinil at an academic medical system. METHODS: This is a retrospective cohort analysis of patients newly initiated on oral treprostinil at Cleveland Clinic Heath System from 2015 to 2017. Demographic information regarding pulmonary arterial hypertension (PAH) history and previous PAH therapies were recorded. Outcomes evaluated included doses of oral treprostinil utilized, adverse effects related to therapy, and measures of clinical and functional status before and after the initiation of oral treprostinil. RESULTS: Overall, 29 patients were prescribed oral treprostinil, of which 15 patients were included in the analysis. Common reasons for initiation of oral treprostinil included disease progression (6, 40%) and patient desire (4, 25%). The median duration of transition/initiation of oral treprostinil was 4 days (range, 3-11 days). Median daily dose of oral treprostinil on day 1 of initiation was 2 mg (0.25-4 mg). By day 7, median daily dose was 15 mg (0.75-27.75 mg). Common adverse effects related to therapy were gastrointestinal (7, 47%) and headache (4, 27%). No patients required discontinuation of oral treprostinil due to adverse effects within 90 days of initiation. CONCLUSION: Inpatient initiation/transition to oral treprostinil was relatively well tolerated. Future studies should evaluate clinical outcomes surrounding the transitioning to oral treprostinil.

Follow-Up Functional Class and 6-Minute Walk Distance Identify Long-Term Survival in Pulmonary Arterial Hypertension.

PURPOSE: Guidelines recommend specific treatment goals for pulmonary arterial hypertension (PAH) patients: functional class I or II, 6-min walk distance (6MWD) ≥ 380 to 440 m, normal natriuretic peptide levels, and normal right-sided invasive hemodynamics. Only observational registry data support this recommendation. Our aim was to test these goals in a large group 1 PAH cohort against long-term survival. METHODS: We analyzed the PHIRST and TRIUMPH populations (n = 563, age 53.5 ± 14.7 years, female sex 79%). The predictor variables were the treatment goals measured at the end of the placebo-controlled phase (16 and 12 weeks, respectively). The primary outcome was all-cause mortality at the end of follow-up during the open-label extension phase. RESULTS: There were 73 deaths during median follow of 1072 days (range 27 to 2177). Patients who achieved a functional class I or II had better survival. Both a 6MWD ≥ 380 m and ≥ 440 m were associated with lower mortality, but survival was better in patients able to walk ≥ 440 m. The best long-term survival was achieved with functional class I or II and 6MWD ≥ 440 m. In a subset of the population, cardiac index > 2.5 L/min/m2 was weakly associated with better survival. CONCLUSION: WHO functional class I or II, 6MWD ≥ 440 m and CI > 2.5 L/min/m2 measured 12-16 weeks after the introduction of PAH-targeted therapy are associated with better long-term survival in PAH. Best survival is observed by reaching both the functional class and the 6MWD goals.

A pulmonary embolism response team (PERT) approach: initial experience from the Cleveland Clinic.

Management of intermediate and high risk acute pulmonary embolism (PE) is challenging. The role of multidisciplinary teams for the care of these patients is emerging. Herein, we report our experience with a pulmonary embolism response team (PERT). We conducted a retrospective chart review on all patients admitted to the Cleveland Clinic main campus who required activation of the (PERT) from October 1, 2014 to September 1, 2016. We extracted data pertaining to clinical presentation, bleeding complications, and pre- and post-discharge imaging. Patients were classified as low, intermediate or high risk PE. Descriptive and continuous variables were collected and analyzed. There were 134 PERT activations. PE was confirmed by CT-PA in 118 patients. Fifteen (13%) patients were classified as low risk, 80 (68%) intermediate risk PE and 23 (19%) high risk PE. Fourteen (12%) patients were treated with catheter directed rtPA, 6 (5%) received full dose (100 mg rtPA), 16 (13%) received systemic half-dose (50 mg rtPA), 6 (5%) underwent a surgical embolectomy and 4 (3%) underwent mechanical thrombectomy. 65 (55%) patients received anticoagulation only, and 8 (7%) patients were managed conservatively without any anticoagulation or advanced therapy. 11 (9%) patients died while during the hospitalization. Fourteen patients had major bleeding events. There were no bleeding events among patients who received systemic low dose or full dose rtPA. A multidisciplinary approach to cases of intermediate risk and high risk PE can be implemented successfully. We saw a relatively low rate of bleeding events with use of rtPA.

Pulmonary embolism response teams.

Pulmonary embolism (PE) is a common thrombotic event that is variable in its presentation. Depending on the patients' risk for mortality, guidelines provide several treatment strategies including thrombolysis, catheter-directed therapies, pulmonary embolectomy, anticoagulation, and inferior vena cava filters. However, there is considerable disagreement between guidelines regarding the optimal treatment strategy for patients, particularly for those with intermediate-risk PE. In order to provide rapid and individualized care, PE response teams (PERT) have been developed. These teams consist of members from different specialties with a particular interest in PE, varying technical skills, and clinical experience, thereby allowing for a multidisciplinary approach. PERT allows for consensus decision making, and for rapid intervention in patients whose conditions worsen. In this review, we provide an overview of treatment guidelines for PE, and of results from recent clinical trials involving patients with submassive PE. In addition, we discuss an outline of our approach and use of PERT.

Healthcare burden of pulmonary hypertension owing to lung disease and/or hypoxia.

BACKGROUND: Group 3 pulmonary hypertension (PH) encompasses PH owing to lung diseases and/or hypoxia. Treatment patterns, healthcare resource use, and economic burden to US payers of Group 3 PH patients were assessed. METHODS: This retrospective observational study extracted data from July 1, 2010 to June 30, 2013 from two Truven Health Analytics MarketScan databases. Adult Group 3 PH patients were identified based on claims for PH (ICD-9-CM 416.0/416.8), a related lung disease, and an echocardiogram or right heart catheterization (RHC). The index date was the date of the first PH claim; data were collected for 12 months pre- and post-index. A difference-in-difference approach using generalized estimating equations was done to account for baseline differences. RESULTS: Group 3 PH patients (n = 2,236) were matched 1:1 to controls on lung disease. PH patients had higher all-cause resource utilization and annual healthcare costs ($44,732 vs. $7,051) than controls. Costs were driven by inpatient admissions (35.4% of total costs), prescriptions (33.0%), and outpatient care (26.5%). Respiratory-related costs accounted for 11.4% of post-index annual costs for PH patients. PH diagnosis was not confirmed in the majority of PH patients (<7% RHC use) but nevertheless, 22% of PH patients post-index had claims for drugs approved for the treatment of pulmonary arterial hypertension (PAH). CONCLUSIONS: Group 3 PH poses a significant clinical and economic burden. Given the low use of RHC and the prevalence of PAH-indicated prescriptions that are not currently approved for Group 3 PH, this study suggests some Group 3 PH patients may not be receiving guideline-recommended treatment.

O-linked ß-N-acetylglucosamine transferase directs cell proliferation in idiopathic pulmonary arterial hypertension.

BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) is a cardiopulmonary disease characterized by cellular proliferation and vascular remodeling. A more recently recognized characteristic of the disease is the dysregulation of glucose metabolism. The primary link between altered glucose metabolism and cell proliferation in IPAH has not been elucidated. We aimed to determine the relationship between glucose metabolism and smooth muscle cell proliferation in IPAH. METHODS AND RESULTS: Human IPAH and control patient lung tissues and pulmonary artery smooth muscle cells (PASMCs) were used to analyze a specific pathway of glucose metabolism, the hexosamine biosynthetic pathway. We measured the levels of O-linked ß-N-acetylglucosamine modification, O-linked ß-N-acetylglucosamine transferase (OGT), and O-linked ß-N-acetylglucosamine hydrolase in control and IPAH cells and tissues. Our data suggest that the activation of the hexosamine biosynthetic pathway directly increased OGT levels and activity, triggering changes in glycosylation and PASMC proliferation. Partial knockdown of OGT in IPAH PASMCs resulted in reduced global O-linked ß-N-acetylglucosamine modification levels and abrogated PASMC proliferation. The increased proliferation observed in IPAH PASMCs was directly impacted by proteolytic activation of the cell cycle regulator, host cell factor-1. CONCLUSIONS: Our data demonstrate that hexosamine biosynthetic pathway flux is increased in IPAH and drives OGT-facilitated PASMC proliferation through specific proteolysis and direct activation of host cell factor-1. These findings establish a novel regulatory role for OGT in IPAH, shed a new light on our understanding of the disease pathobiology, and provide opportunities to design novel therapeutic strategies for IPAH.

Causes and circumstances of death in pulmonary arterial hypertension.

RATIONALE: The causes and circumstances surrounding death are understudied in patients with pulmonary arterial hypertension (PAH). OBJECTIVES: We sought to determine the specific reasons and characteristics surrounding the death of patients with PAH. METHODS: All deaths of patients with pulmonary hypertension (PH) followed in the Cleveland Clinic Pulmonary Vascular Program were prospectively reviewed by the PH team. A total of 84 patients with PAH (age 58 ± 14 yr; 73% females) who died between June 2008 and May 2012 were included. MEASUREMENTS AND MAIN RESULTS: PH was determined to be the direct cause of death (right heart failure or sudden death) in 37 (44%) patients; PH contributed to but did not directly cause death in 37 (44%) patients; and the death was not related to PH in the remaining cases (n = 7; 8.3%). In three (3.6%) patients the final cause of death could not be adequately assessed. Most patients died in a healthcare environment and most received PH-specific therapies. In our cohort, 50% of all patients with PAH and 75.7% of those who died of right heart failure received parenteral prostanoid therapy. Less than half of patients had advanced healthcare directives. CONCLUSIONS: Most patients with PAH in our cohort died of their disease; however, right ventricular failure or sudden death was the sole cause of death in less than half of patients.

Pulmonary endarterectomy for subacute on top of chronic thromboembolic disease.

Our objective is to describe our approach for a case of subacute on top of chronic thromboembolic disease and highlight operative learning points. Prior to incision, appropriate monitoring equipment, including an arterial line, Swan-Ganz catheter, brain saturation monitor and bispectral index monitor, is placed for proper management of haemodynamics. Sternotomy was performed, and the ascending aorta was cannulated, followed by bicaval cannulation for venous drainage. The patient was cooled to deep hypothermia. Once target temperature was achieved, circulatory arrest commenced. The left pulmonary artery was opened and the subacute component was removed without disrupting the plane of the chronic thromboembolic disease. An endarterectomy plane was then created proximally and dissected into the distal segmental/subsegmental branches. Once the endarterectomy was completed, the left pulmonary artery was closed. Circulation was resumed for end-organ perfusion. Once the right pulmonary artery was ready for dissection, circulatory arrest was restarted. Similarly to the left side, the subacute component was removed without disrupting the plane of the chronic thromboembolic disease. An endarterectomy plane was then created proximally and dissected into the distal segmental/subsegmental branches. Circulation was then resumed. Once rewarmed to 35.5°C, the patient was decannulated and the sternum was closed.