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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

Right ventricular function is impaired in chronic thromboembolic pulmonary hypertension (CTEPH). Tricuspid annular plane systolic excursion (TAPSE) and right ventricular fractional area change (RVFAC) have been shown to help assess right ventricular function in pulmonary hypertension. Our goal was to (1) assess TAPSE and RVFAC before and after PTE, and (2) assess correlation of these variables with right heart catheterization data and PVR.We evaluated 67 consecutive patients with CTEPH for pulmonary thromboendarterectomy (PTE). Of these 67 patients, 48 were deemed surgical candidates. Preoperative right heart catheterization was performed within 1.3±1.2 days of the preoperative echocardiogram. All postoperative right heart catheterizations were performed on the first postoperative day.TAPSE dropped from 18±6 to 10±3 mm after PTE (P.0001). RVFAC remained the same (25%±10% vs 30%±12%). Mean pulmonary artery (mPAP) pressure dropped from 45±12 to 28±6 mm Hg after PTE, and pulmonary vascular resistance (PVR) decreased from 757±406 to 306±147 dyne-s/cmIn patients with CTEPH, TAPSE paradoxically decreased by 50% early after PTE. TAPSE correlated inversely with PVR prior to PTE, but this correlation was lost completely after PTE. Thus, despite the immediate and marked decrease in afterload postoperatively, TAPSE did not improve; thus, TAPSE cannot be used as an early marker for surgical success.

Chronic thromboembolic pulmonary hypertension is a progressive and life-threatening condition that is believed to be related to inadequate dissolution of acute pulmonary thromboemboli, followed by fibrotic organization. Without appropriate treatment, progressive pulmonary hypertension, right ventricular failure, and death may occur. While the disorder was initially described nearly a century ago in autopsy studies, antemortem diagnosis became feasible with the advent of cardiac catheterization and angiography techniques in the 1940s, while surgical thromboendarterectomy was not attempted until the 1960s. However, this procedure initially had high mortality rates until refinements in management and surgical techniques resulted in much improved outcomes starting in the 1980s. Many questions remain about the pathophysiology and epidemiology of this condition, with unclear contributions of genetics and environmental exposures. The optimal approach to diagnosis also continues to evolve, with improvements in preoperative imaging and hemodynamic assessment. Treatment of chronic thromboembolic pulmonary hypertension has not remained static, as surgical techniques continue to improve and newer pharmacological treatments and percutaneous catheter-based interventions may play therapeutic roles in selected patients. This is the introductory article of a series that provides a state-of-the-art review of chronic thromboembolic pulmonary hypertension.

Pulmonary hypertension due to chronic thromboembolic disease is potentially curable with pulmonary thromboendarterectomy surgery. As a result, it is important for clinicians to recognize and appropriately diagnose this form of pulmonary hypertension. Advances in this field with changes in surgical technique, the availability of PH-targeted medical therapy for select patient subgroups, and the development of balloon pulmonary angioplasty have broadened therapeutic options for patients. This review will examine what is known about the epidemiology and medical conditions placing patients at risk of developing this disease, will present an approach to evaluation of patients with suspected chronic thromboembolic disease, and will describe the surgical and non-surgical management of this unique patient population.

Background Post-operative atrial arrhythmias (POAA) after cardiac surgery are common and known to prolong hospital length of stay (LOS), but have been reported grouping atrial fibrillation (POAF), atrial flutters (AFL), and atrial tachycardias (AT). The impact of POAA vs. specifically POAF on intensive care unit time (ICUT) and hospital LOS after pulmonary thromboendarterectomy surgery (PTE) remains unknown. Objective To determine the impact of POAA and POAF on ICUT and hospital LOS after PTE. Method We identified consecutive patients undergoing PTE at our medical center from June 2013 to March 2020. After assessing baseline patient characteristics, we compared ICUT and LOS in patients with and without POAA and POAF after PTE. Results A total of 224 patients underwent PTE. POAA occurred in 31% (n = 68), of which 71% (n = 48) were POAF. Patients who developed POAA were older on average (63.5 vs. 51.5 years, p Conclusion In an adjusted analysis, in patients undergoing PTE, neither development of POAA nor specifically POAF were associated with increased ICUT. However, both POAA and POAF were associated with longer hospital LOS, denoting that POAA and POAF prolong hospitalization outside the ICU.

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.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive pulmonary vascular disease with significant morbidity. It is a result of an alternate natural history in which there is limited resolution of thromboemboli with pulmonary artery obstruction leading to pulmonary hypertension (PH). CTEPH requires a thorough clinical assessment including pulmonary hemodynamics and radiologic evaluation in addition to consultation with an expert center. Surgical intervention remains the optimal management strategy. Select patients may be candidates for catheter-based intervention with balloon pulmonary angioplasty in centers with clinical expertise. Inoperable patients or those with post-intervention PH are treated with pulmonary hypertension-targeted medical therapy.

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.

Reperfusion lung injury is a postoperative complication of pulmonary thromboendarterectomy that can significantly affect morbidity and mortality. Studies in other postoperative patient populations have demonstrated a reduction in acute lung injury with the use of a low-tidal volume (Vt) ventilation strategy. Whether this approach benefits patients undergoing thromboendarterectomy is unknown.We sought to determine if low-Vt ventilation reduces reperfusion lung injury in patients with chronic thromboembolic pulmonary hypertension undergoing thromboendarterectomy.Patients undergoing thromboendarterectomy at one center were randomized to receive either low (6 ml/kg predicted body weight) or usual care Vts (10 ml/kg) from the initiation of mechanical ventilation in the operating room through Postoperative Day 3. The primary endpoint was the onset of reperfusion lung injury. Secondary outcomes included severity of hypoxemia, days on mechanical ventilation, and intensive care unit and hospital lengths of stay.A total of 128 patients were enrolled and included in the analysis; 63 were randomized to the low-Vt group and 65 were randomized to the usual care group. There was no statistically significant difference in the incidence of reperfusion lung injury between groups (32%, n=20 in the low-Vt group vs. 23%, n=15 in the usual care group; P=0.367). Although differences were noted in plateau pressures (17.9 cm H2O vs. 20.1 cm H2O, P0.001) and peak inspiratory pressures (20.4 cm H2O vs. 23.0 cm H2O, P0.001) between the low-Vt and usual care groups, respectively, mean airway pressures, PaO2/FiO2, days on mechanical ventilation, and ICU and hospital lengths of stay were all similar between groups.In patients with chronic thromboembolic pulmonary hypertension undergoing pulmonary thromboendarterectomy, intra- and postoperative ventilation using low Vts (6 mg/kg) compared with usual care Vts (10 mg/kg) does not reduce the incidence of reperfusion lung injury or improve clinical outcomes. Clinical trial registered with www.clinicaltrials.gov (NCT00747045).

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 …

Background Right ventricular (RV) function is significantly impaired in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Two-dimensional speckle tracking RV strain and strain rate are novel methods to assess regional RV systolic function in CTEPH patients before and after pulmonary thromboendarterectomy (PTE). Our goal was to (1) assess baseline longitudinal strain and strain rate of the basal RV free wall in CTEPH and (2) measure early changes in RV strain and strain rate after PTE. Methods We performed echocardiography on 30 consecutive patients with CTEPH referred for PTE with adequate pre- and post-PTE strain imaging. Strain and strain rate were assessed 6.4 ± 4.5 days before and 9.1 ± 3.9 after PTE. Results Basal RV free wall strain and time to peak strain—but not basal RV strain rate and time to peak strain rate—changed significantly after PTE. Unexpectedly, basal RV strain became less negative, from −24.3% to −18.9% after PTE (P = 0.005). Time to peak strain decreased from 356 to 287 msec after PTE (P

Chronic thromboembolic pulmonary hypertension (CTEPH) is a disease with high mortality and few treatment options. This article reviews the epidemiology of CTEPH and identifies risk factors for its development. The pathobiology and the progression from thromboembolic events to chronically increased right-sided pressures are discussed. The diagnosis and assessment of CTEPH requires several modalities and the role of these is detailed. The pre-operative evaluation assesses peri-operative risk and determines the likelihood of benefit from PTE. Pulmonary thromboendarterectomy (PTE) remains the treatment of choice in appropriate patients. Nonsurgical therapies for CTEPH may provide benefit in patients who cannot be offered surgery.

UNLABELLED The ratio of tricuspid regurgitation velocity divided by the velocity-time integral of right ventricular outflow tract pulsed-wave Doppler tracing (TRV/VTI(RVOT) ) has been used to estimate pulmonary vascular resistance (PVR). However, this method has not been validated in chronic thromboembolic pulmonary hypertension (CTEPH). We assessed the utility of TRV/VTI(RVOT) in patients with CTEPH and PVR from 2 to 20 WU. All had right heart catheterization (RHC) within 2 days of echocardiography. TRV/VTI(RVOT) was calculated and RHC-derived pressures, PVR, and cardiac outputs were recorded. Mean pulmonary artery pressure was 47 ± 12 mmHg, cardiac output: 4.2 ± 1.1 L/min, PVR: 9 ± 4 WU, right atrial pressure: 12 ± 6 mmHg. Mean VTI(RVOT) was 13 ± 5 cm; mean TRV was 4.2 ± 0.8 m/s, mean tricuspid regurgitation severity was 2.5 ± 0.8 (1 = trace, 2 = mild, 3 = moderate, 4 = severe). Regression analysis demonstrated a correlation between RHC PVR and TRV/VTI(RVOT) : PVR = 19.4 × (TRV/VTI(RVOT) ) + 2.4 (r = 0.74, P < 0.001). However, Bland-Altman analysis found a poor degree of agreement between echo-derived PVR and RHC PVR. We also studied 28 patients with non-CTEPH pulmonary hypertension. Similar analysis revealed a regression equation of PVR = 20.1 × (TRV/VTIR(RVOT) ) + 0.3 (r = 0.57, P < 0.01). CONCLUSION TRV/VTI(RVOT) is only marginally useful for estimating PVR in CTEPH (r = 0.74). Moreover, the regression equation in CTEPH differs significantly from previous studies in pulmonary hypertension. Reasons for this may include the markedly elevated PVR levels in this population and specific effects on VTI(RVOT) from CTEPH.

Pulmonary hypertension is defined by a mean pulmonary artery pressure greater than 25 mm Hg. Chronic thromboembolic pulmonary hypertension (CTEPH) is defined as pulmonary hypertension in the presence of an organized thrombus within the pulmonary vascular bed that persists at least 3 months after the onset of anticoagulant therapy. Because CTEPH is potentially curable by surgical endarterectomy, correct identification of patients with this form of pulmonary hypertension and an accurate assessment of surgical candidacy are essential to provide optimal care. Patients most commonly present with symptoms of exertional dyspnea and otherwise unexplained decline in exercise capacity. Atypical chest pain, a nonproductive cough, and episodic hemoptysis are observed less frequently. With more advanced disease, patients often develop symptoms suggestive of right ventricular compromise. Physical examination findings are minimal early in the course of this disease, but as pulmonary hypertension progresses, may include nonspecific finding of right ventricular failure, such as a tricuspid regurgitation murmur, pedal edema, and jugular venous distention. Chest radiographs may suggest pulmonary hypertension, but are neither sensitive nor specific for the diagnosis. Radioisotopic ventilation-perfusion scanning is sensitive for detecting CTEPH, making it a valuable screening study. Conventional catheter-based pulmonary angiography retains an important role in establishing the presence and extent of chronic thromboembolic disease. However, computed tomographic and magnetic resonance imaging are playing a growing diagnostic role. Innovative technologies such as dual-energy computed tomography, dynamic contrast-enhanced magnetic resonance imaging, and optical coherence tomography show promise for contributing diagnostic information and assisting in the preoperative characterization of patients with CTEPH.

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.

Chronic thromboembolic pulmonary hypertension is one of the few forms of pulmonary hypertension that is surgically curable. It is likely underdiagnosed and must be considered in every patient presenting with pulmonary hypertension to avoid missing the opportunity to cure these patients. This article discusses the epidemiology, risk factors, natural history, diagnosis, and preoperative evaluation of patients with this disorder. Also covered are putative mechanisms for the conversion of acute emboli into fibrosed thrombembolic residua. Mechanical obstruction of the central pulmonary vasculature is rarely the sole cause of the pulmonary hypertension, and a discussion of the small vessel arteriopathy present in these patients is offered. Technical aspects of pulmonary endartectomy and the data supporting its role are discussed, as are the limited data on pulmonary arterial hypertension specific medical therapies for patients deemed noncandidates for the operation.

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.

Chronic thromboembolic obstruction of the pulmonary vascular bed has been increasingly recognized as a treatable form of pulmonary hypertension, with surgery referred to as a pulmonary endarterectomy. Careful evaluation of patients with pulmonary hypertension and proper selection of those with surgically accessible, chronic thromboembolic disease are critical determinants for a successful outcome from this operation. This article describes the clinical presentation, appropriate evaluation, and an approach to surgical selection for patients with chronic thromboembolic pulmonary hypertension.

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.

Objectives: To determine the femoral-to-radial arterial pressure gradient, as well as the factors associated with them, in patients receiving cardiopulmonary bypass (CPB) with profound hypothermia and circulatory arrest. Design: Retrospective automated hemodynamic record review. Setting: University hospital. Participants: Patients undergoing pulmonary thromboendarterectomy with deep hypothermic circulatory arrest. Measurements and Main Results: The automated hemodynamic records of 54 consecutive patients undergoing pulmonary thromboendarterectomy with deep hypothermic circulatory arrest were reviewed, comparing the femoral and radial arterial pressures throughout the intraoperative period. In 20 of the patients, the hemodynamic data from the first 16 postoperative hours were also studied. Forty-one of 54 (76%) of the patients exhibited a mean arterial gradient of at least 10 mmHg either during or after CPB, femoral being higher. Clinically significant gradients were noted throughout the CPB period and the post-CPB period in these patients. In the 54 patients studied, the systolic blood pressure (SBP) gradient was 32 ± 19 mmHg after CPB (95% confidence limits 28.2 mmHg, 39.0 mmHg), and the mean arterial pressure (MAP) gradient was 6.3 ± 4.9 mmHg (95% confidence limits 5.5 mmHg, 8.6 mmHg). The duration of clinically significant SBP (>10 mmHg) and MAP (>5 mmHg) gradients in the postoperative period were 5.2 ± 5.7 hours and 5.8 ± 7.2 hours, respectively. Advanced age correlated with high post-CPB pressure gradients in this population and was associated with prolonged postoperative resolution of the gradients. Conclusions: The femoral-to-radial arterial pressure gradients, particularly systolic, after CPB, were greater and of longer duration in these patients undergoing deep hypothermic circulatory arrest than gradients previously reported for routine CPB. Central arterial pressure monitoring is recommended for patients undergoing deep hypothermic circulatory arrest, being valuable both for intraoperative and postoperative care.

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.