Treatment and Clinical Management of Chronic Thromboembolic Pulmonary Hypertension:An Update of Literature Review

Chronic thromboembolic pulmonary hypertension(CTEPH)is a chronic,progressive,debilitating,and life-threa-tening complication of pulmonary embolism(PE).Recent technological advances have permitted various treat-ment options for the treatment of CTEPH,including surgery,angioplasty,and medical treatment,depending on the location and characteristics of lesions.Pulmonary endarterectomy(PEA)is the treatment of choice for CTEPH,as it offers excellent long-term outcomes and a high probability of recovery.Moreover,various medical and interventional therapies are currently being developed for patients with inoperable CTEPH.This review mainly summarizes the current treatment approaches of CTEPH,offering more options for specialist physicians to,thus,better manage chronic thromboembolic syndromes.

Pulmonary endarterectomy in chronic thromboembolic pulmonary hypertension: How can patients be better selected?

Chronic thromboembolic pulmonary hypertension (CTEPH) comprises organizing thrombotic obstructions in the pulmonary arteries by nonresolving thromboemboli, formation of fibrosis and remodeling of pulmonary blood vessels. Surgical pulmonary endarterectomy (PEA) is the therapy of choice for patients with surgically accessible CTEPH, which leads to a profound improvement in hemodynamics, functional class and survival. Select- ing the candidates that will benefit from surgery is still a challenging task. Criteria for surgical suitability have been described but the decision-making for or against surgical intervention remains still subjective. The optimal characterization of the reciprocal contribution of large vessel and small vessel disease in the elevation of pulmonary vascular resistance is crucial for the indication and outcome of PEA. Recently, Toshner et al intended to validate the partition resistance into small and large vessels compartments (upstream resistance:Rup) by the occlusion technique in the preoperative assessment of PEA. We discuss the advantages and disadvantages of Rup and compare it with other hemodynamic predictor to evaluate operative risk in CTEPH patients.

Balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension:State of the art

Chronic thromboembolic pulmonary hypertension(CTEPH)is a complex chronic disease in which pulmonary artery stenosis or obstruction caused by organized thrombus can lead to increased pulmonary artery pressure and pulmonary vascular resistance,ultimately triggering progressive right heart failure and death.Currently,its exact mechanism is not fully understood.Pulmonary endarterectomy(PEA)has immediate effects with low perioperative mortality and satisfactory prognosis in experienced expert centers for CTEPH patients with proximal lesions.Nevertheless,37%of patients are deemed unsuitable for PEA surgery due to comorbidities and other factors,and nearly half of the operated patients have residual or recurrent pulmonary hypertension.Riociguat is the only approved drug for CTEPH,although its effect is limited.Balloon pulmonary angioplasty(BPA)is a promising alternative treatment for patients with CTEPH.After more than 30 years of development and refinements,emerging evidence has confirmed its role in patients with inoperable CTEPH or residual/recurrent pulmonary hypertension,with acceptable complications and comparable longterm prognosis to PEA.This review summarizes the pathophysiology of CTEPH,BPA history and development,therapeutic principles,indications and contraindications,interventional procedures,imaging modalities,efficacy and prognosis,complications and management,bridging and hybrid therapies,ongoing clinical trials and future prospects.

Chronic thromboembolic pulmonary hypertension(CTEPH):outcomes of surgical effect in patients with unilateral main pulmonary artery occlusion

Objective To summarize the clinical characteristics and the effect of pulmonary endarterectomy(PEA)in CTEPH patients with unilateral main pulmonary artery occlusion.Methods Of 160 CTEPH patients operated between January2004 and March 2018 at our center,13(8.1%)had complete main pulmonary artery occlusion.Patients were included if the ventilation/perfusion(V/Q)scan revealed nonperfusion of an entire lung and the pathological examination showed chronic thromboembolic.

Mortality-Related Risk Factors in Patients with Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension. The Importance of Response to Treatment

Background: Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are serious diseases with similar pathophysiologic aspects. The prognosis of patients with these conditions is highly uncertain, particularly incident cases. Methods: A Cox proportional hazards model was applied to a group of 85 patients (81% women, mean age 52 (18 - 82) years) with PAH (80%) and non-surgical CTEPH (20%) to evaluate risk factors for mortality. The following variables were included in the model: age, etiology, baseline 6-minute walk test (6 mWT), cardiac index, and improvement in the 6 mWT following initiation of first medical treatment. Results: In the multivariate analysis, the response to treatment, assessed by an improvement on the 6 mWT, was the most relevant prognostic factor in these patients (RR, 4.832 (95% CI, 1.888 - 12.364);p = 0.001). The remaining variables studied in this model had less influence on the prognosis: age > 50 years (RR, 0.744 (95% CI, 0.26 - 2.133);p = 0.582);etiology of connective tissue disease-associated PAH (RR, 3.145 (95% CI, 0.995-9.946);p = 0.051) or CTEPH (RR, 0.654 (95% CI, 0.179 - 2.387);p = 0.521) with respect to idiopathic PAH;baseline 6 mWT (RR, 1.173 (95% CI, 0.599 - 4.895);p = 0.315);or cardiac index (RR, 2.295 (95% CI, 0.793 - 6.642);p = 0.125). Conclusions: There is a high degree of uncer-tainty regarding the prognosis of PAH and CTEPH at the start of appropriate treatment. Our results support the idea that the initial treatment response is of paramount importance as prognostic factor in these patients.

Risk of Major Hemorrhage in Bilateral Lung Transplantation for Chronic Thromboembolic Pulmonary Hypertension: A Case Report

Chronic thromboembolic pulmonary hypertension (CTEPH) is one of the indications for lung transplantation. When patients with CTEPH undergo transplantation, massive bleeding can occur because of severe pleural adhesions and collateral vessels that develop from the thoracic wall to the lungs. However, there has been no previous case report that has discussed the bleeding risk in detail. We report the case of a patient having CTEPH who underwent bilateral lung transplantation with massive blood loss (11,730 mL) in the first operation and required repeat operations for hemostasis. The patient underwent left upper lobectomy because compromised blood flew to the left upper lobe. He recovered from the operations by postoperative day 9;however, he died from pyothorax from an intractable air leak 56 days after transplantation.

Chronic thromboembolic pulmonary hypertension related to hemangiolymphangioma

Hemangiolymphangioma (HL) is a congenital anomaly and histologically benign tumor, which was composed of both the lymphatic and the blood vessels. We report an adult case of HL complicated by chronic thromboembolic pulmonary hypertension (CTEPH) in a 20-year-old female. Gastrointestinal bleeding scintigraphy and operative findings elucidate a close relationship between CTEPH and residual HL. This case indicates that HL survivors with remaining left-to-right shunt might lead to CTEPH during the long-term follow-up.

Post splenectomy related pulmonary hypertension

Splenectomy predisposes patients to a slew of infectious and non-infectious complications including pulmonary vascular disease. Patients are at increased risk for venous thromboembolic events due to various mechanisms that may lead to chronic thromboembolic pulmonary hypertension(CTEPH). The development of CTEPH and pulmonary vasculopathy after splenectomy involves complex pathophysiologic mechanisms, some of which remain unclear. This review attempts to congregate the current evidence behind our understanding about the etio-pathogenesis of pulmonary vascular disease related to splenectomy and highlight the controversies that surround its management.

THROMBOENDARTERECTOMY FOR CHRONIC PULMONARY THROMBOEMBOLISM

Objective To evaluate the improving reliability and safety of thromboendarterectomy and perioperative management for chronic pulmonary thromboembolism. Methods The clinical data of 12 cases with chronic pulmonary thromboembolism, who underwent thromboendarterec- tomy assisted by low flow or circulation arrest with deep hypothermia, were reviewed retrospectively. Results Pulmonary artery pressure decreased 20 to 40 mmHg immediately after surgical procedures in 9 cases. The postoperative pulmonary edema at various degrees happened in 12 cases, among them, 1 died of severe lung infection and pulmonary re-embolism at 19 days postoperation. Computed tomography pulmonary angiography and angiography of 11 cases indicated that the original obstruction of pulmonary artery disappeared. During the follow-up period of 2 months to 5 years, the clinical symptoms and activity was improved. Conclusion Thromboendarterectomy is an effective treatment for chronic pulmonary thromboembolism. The outcome of the surgical procedure needs to be further investigated and followed up regularly according to an evaluative system, because it might be influenced by multiple factors.

Role of pulmonary perfusion magnetic resonance imaging for the diagnosis of pulmonary hypertension:A review

Among five types of pulmonary hypertension,chronic thromboembolic pulmonary hypertension(CTEPH)is the only curable form,but prompt and accurate diagnosis can be challenging.Computed tomography and nuclear medicine-based techniques are standard imaging modalities to non-invasively diagnose CTEPH,however these are limited by radiation exposure,subjective qualitative bias,and lack of cardiac functional assessment.This review aims to assess the methodology,diagnostic accuracy of pulmonary perfusion imaging in the current literature and discuss its advantages,limitations and future research scope.

Pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension： preliminary exploration in China

Background Pulmonary endarterectomy is safe and effective surgical treatment for chronic thromboembolic pulmonary hypertension. This study aimed to evaluate the efficacy of pulmonary endarterectomy in treatment of thromboembolic pulmonary hypertension. Methods A retrospective study of 15 patients who underwent pulmonary endarterectomy in Beijing Chaoyang Hospital was performed. Obvious pulmonary hypertension and hypoxemia were observed in all patients. Bilateral pulmonary endarterectomy was performed under cardiopulmonary bypass with profound hypothermic circulatory arrest. Results Two patients （2/15） died of residual postoperative pulmonary hypertension and bleeding complication. The other 13 cases had significant decrease in systolic pulmonary artery pressure （（92.8＋_27.4） mmHg vs. （49.3＋18.6） mmHg） and pulmonary vascular resistance （（938.7±464.1） dynes.s.cm5 vs. （316.8±153.3） dynes＇s.cm5）, great improvement in cardiac index （（2.31：LK）.69） L.min-l.m2 vs. （3.85±1.21） L.min-l.m2）, arterial oxygen saturation （0.67±O.11 vs. 0.96±0.22） and mixed venous 02 saturation （0.52±0.12 vs. 0.74±0.16） postoperatively compared to preoperative data. Mid-term follow-up showed that the cardiac function of all cases returned to NYHA class I or II, with great improvement in 6-minute walking distance （（138±36） m） and quality of life. Conclusions Bilateral pulmonary endarterectomy using cardiopulmonary bypass with the aid of deep hypothermia and circulatory arrest can effectively reduce pulmonary hypertension and provide good mid-term hemodynamic and symptomatic results with low surgical mortality rate and few complications.

Serum Bilirubin and 6-min Walk Distance as Prognostic Predictors for Inoperable Chronic Thromboembolic Pulmonary Hypertension： A Prospective Cohort Study

Background： Inoperable chronic thromboembolic pulmonary hypertension （CTEPH） is a severe clinical syndrome characterized by right cardiac failure and possibly subsequent liver dysfunction. However, whether serum markers of liver dysfunction can predict prognosis in inoperable CTEPH patients has not been determined. Our study aimed to evaluate the potential role of liver function markers （such as serum levels of transaminase, bilirubin, and gamma-glutamyl transpeptidase [GGT]） combined with 6-min walk test in the prediction of prognosis in patients with inoperable CTEPH. Methods： From June 2005 to May 2013, 77 consecutive patients with inoperable CTEPH without confounding co-morbidities were recruited for this prospective cohort study. Baseline clinical characteristics and 6-min walk distance （6MWD） results were collected. Serum biomarkers of liver function, including levels of aspartate aminotransferase, alanine aminotransferase, GGT, uric acid, and serum bilirubin, were also determined at enrollment. All-cause mortality was recorded during the follow-up period. Results： During the follow-up, 22 patients （29%） died. Cox regression analyses demonstrated that increased serum concentration of total bilirubin （hazard ratio [HR] = 7.755, P 〈 0.001）, elevated N-terminal of the prohormone brain natriuretic peptide （HR = 1.001, P = 0.001）, decreased 6MWD （HR = 0.990, P 〈 0.001）, increased central venous pressure （HR = 1.074, P = 0.040）, and higher pulmonary vascular resistance （HR = 1.001, P = 0.018） were associated with an increased risk of mortality. Serum concentrations of total bilirubin （HR = 4.755, P = 0.007） and 6MWD （HR = 0.994, P = 0.017） were independent prognostic predictors for CTEPH patients. Patients with hyperbilirubinemia （≥23.7 μmol/L） had markedly worse survival than those with normobilirubinemia. Conclusion： Elevated serum bilirubin and decreased 6MWD are potential predictors for poor prognosis in inoperable CTEPH.

A male with chronic thromboembolic pulmonary hypertension caused by isolated noncompaction of ventricular myocardium

Noncompaction of the ventricular myocardium （NVM） is a rare disease of endomyocardialmorphogenesis characterized by numerous, prominent trabeculations and deep intertrabecular recesses. It is commonly associated with congenital heart disease. Isolated noncompaction of the ventricular myocardium （INVM） is thought to be caused by arrest of normal embryogenesis of the endocardium and myocardimn. A significant amount of data on INVM are available for the left ventricle but right ventricular involvement is rare.

The clinical characteristics of antiphospholipid syndrome associated with chronic thromboembolic pulmonary hypertension

Objective To analyze the clinical characteristics ofantiphospholipid syndrome (APS) patients with chronicthromboembolic pulmonary hypertension ( CTEPH ).Methods A total of 22 APS patients with CTEPH wereenrolled in our study,who were admitted in PekingUnion Medical College Hospital from January 2012 toAugust 2018. Diagnoses were confirmed by computed to-mographic pulmonary angiography (CTPA),or pulmonaryangiography. Demographic characteristics, clinicalmanifestations,laboratory tests,therapy,World HealthOrganization (WHO) functional class were retrospectivelycollected. Results There were 15 females and 7 maleswith a median age of 29-year-old. Chest pain (6 cases),dyspnea on exertion (22 cases),cough (6 cases) andhemoptysis ( 9 cases) were the most common clinicalmanifestations. Lupus anticoagulant ( LA),anticardiolipin(ACL) antibodies and anti-beta 2 glycoprotein Ⅰ(anti-β2 GPⅠ) antibodies were all positive in 12 patients,two of three antibodies positive in 5 patients,onlyone positive in 5 patients.

中西医治疗慢性血栓栓塞性肺动脉高压的研究进展

慢性血栓栓塞性肺动脉高压是一种相对较少见的肺部疾病,患者早期症状和体征并不明显,随着病情发展,患者可能会经历一系列较为典型的症状,如活动后出现的呼吸困难和胸痛,这些症状反映了心脏负荷增加和血液循环受阻的情况。中医对慢性血栓栓塞性肺动脉高压的诊疗主要通过平衡身体阴阳,调理气血,改善体质,以达到治疗和预防疾病的目的。中医提倡中药调理,穴位、推拿,艾灸疗法等,通过促进血液循环,调节免疫系统,缓解炎症反应等手段,来解决栓塞和高血压带来的问题。中西医结合治疗可以针对不同患者的个体差异和病情特点,精准制定治疗方案,最大限度地提高治疗效果。中西医结合治疗既可以发挥传统西医疗法的快速见效和明显疗效,也能充分利用中医调理体质、预防复发的优势,全面提升患者的生活质量和预后。本综述对近年来中西医治疗慢性血栓栓塞性肺动脉高压的治疗方法进行综合分析,为临床的诊疗工作提供参考和借鉴依据。

Pulmonary artery stent thrombosis and symptomatic pulmonary hypertension following COVID-19 infection in Alagille patient:A case report

BACKGROUND Alagille syndrome is a multisystem disease that results in various vascular anomalies,commonly involving the cardiac and pulmonary systems.To the best of our knowledge,there is no literature regarding the cardiovascular outcomes of these patients in association with coronavirus disease 2019(COVID-19).CASE SUMMARY A 34-year-old woman with a history of Alagille syndrome who underwent successful atrial septal defect with partial anomalous pulmonary veins and patent ductus arteriosus repair,as well as left pulmonary artery catheterization and stenting in childhood due to pulmonary stenosis.The patient was without any respiratory symptoms and was a dancer prior to contracting COVID-19.Several weeks after her COVID-19 infection,she developed left pulmonary artery stent thrombosis and subsequent symptomatic pulmonary hypertension.A treatment strategy of anticoagulation alongside pharmacological agents for pulmonary hypertension for 3 months followed by balloon pulmonary artery angioplasty to reopen the stenosis was unsuccessful.CONCLUSION In the era of COVID-19,patients with pulmonary vascular malformations and endovascular stents are at an increased risk for chronic thromboembolic disease.Patients may benefit from prophylactic antiplatelet or anticoagulation therapy.Stent thrombosis is a devastating phenomenon and should be treated urgently and aggressively with balloon pulmonary angioplasty,and/or a thrombolytic agent.

慢性血栓栓塞性肺动脉高压的治疗进展

球囊肺血管成形术和药物是无法手术的慢性血栓栓塞性肺动脉高压(CTEPH)患者的主要治疗方案。在临床实践中,药物治疗是否比球囊肺血管成形术具有更好的获益-风险比,以及二者联用是否可增加临床疗效或改善安全性尚存争议。本文将系统阐述CTEPH的治疗进展,以指导临床管理。

对比肺通气/灌注显像和CT肺动脉造影对急性肺栓塞患者发生慢性血栓栓塞性肺动脉高压的预测价值

目的:比较肺通气/灌注(ventilation/perfusion,V/Q)显像和CT肺动脉造影(pulmonary angiography,PA)预测急性肺栓塞(acute pulmonary embolism,APE)后慢性血栓栓塞性肺动脉高压(chronic thromboembolic pulmonary hypertension,CTEPH)发生的价值。方法:回顾性收集了2012年1月至2020年8月,确诊为APE患者的资料,所有患者经至少3个月规范化抗凝后复查肺V/Q显像和CTPA。分别评估并计算肺V/Q显像和CTPA图像中的残余肺栓塞,并分别记录为肺灌注缺损百分比(percentage of pulmonary defect scores,PPDs%)和CT肺动脉阻塞指数(pulmonary artery obstruction index,PAOI)。评价PPDs%和CTPAOI预测CTEPH发生的一致性。绘制受试者工作特征(ROC)曲线,评估PPDs%和CTPAOI对APE后CTEPH发生的预测效能。结果:共纳入224例APE患者,1年内随访,共有26例进展为CTEPH。Bland-Altman图示两检查评估APE治疗后残余肺栓塞的一致性较好。ROC分析示PPDs%的AUC>CTPAOI(0.958 vs.0.868,P=0.03);预测CTEPH发生的阈值分别为20.5%和15.0%,相应的敏感性和特异性分别为92.3%、88.9%和76.9%、89.4%,差异均无统计学意义(敏感性:P=0.13;特异性:P>0.999)。结论:肺V/Q显像预测APE后CTEPH发生率比CT PA更敏感,但特异性略低。

球囊肺动脉扩张成形术治疗慢性血栓栓塞性肺动脉高压的研究进展

慢性血栓栓塞性肺动脉高压是一类由于肺动脉血栓反复栓塞或治疗不及时导致肺血管狭窄或闭塞,肺血管阻力增加,最终导致右心衰竭的疾病。目前该疾病首选治疗方式是肺动脉血栓内膜剥脱术,但不能手术的患者亦不在少数。随着球囊肺动脉扩张成形术更深入的发展,其疗效及安全性得到提高和证实,并在全世界范围内受到广泛关注,成为慢性血栓栓塞性肺动脉高压患者治疗的新选择。文章就球囊肺动脉扩张成形术的发展、适应证、治疗效果及其并发症进行综述。

球囊肺动脉成形术对不能手术的慢性血栓栓塞性肺动脉高压夜间低氧的影响

目的研究球囊肺动脉成形术(balloon pulmonary angioplasty,BPA)对不能手术的慢性血栓栓塞性肺动脉高压(chronic thromboembolic pulmonary hypertension,CTEPH)夜间低氧的影响。方法2020年7月-2022年10月在同济大学附属上海市肺科医院肺循环科确诊为CTEPH患者(n=60)纳入研究,随机分组为利奥西呱联合(n=36)或不联合(n=24)BPA进行干预,检测两组患者临床干预前后夜间低氧情况,明确BPA对CTEPH夜间低氧影响。结果BPA可明显改善CTEPH患者呼吸暂停低通气指数、夜间平均脉搏血氧饱和度(arterial oxygen saturation,SpO_(2))、夜间SpO_(2)低于90%的时间占总监测时间的百分比(T90%)及夜间最低SpO_(2),差异均有统计学意义(均P<0.05)。临床治疗干预后,BPA联合利奥西呱组T90%较利奥西呱组更低,差异有统计学意义(P=0.047);干预后,BPA联合利奥西呱组平均肺动脉压力(mean pulmonary artery pressure,mPAP)及肺血管阻力较药物组更低(均P<0.05);经双变量直线相关分析,BPA联合利奥西呱干预后,ΔMean SpO_(2)及ΔT90%均与ΔmPAP存在相关性(均P<0.05)。结论BPA可明显改善CTEPH患者夜间低氧,可能与血流动力学改善相关。