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.

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.

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.

Clinical Study of Acute Vasoreactivity Testing in Patients with Chronic Thromboembolic Pulmonary Hypertension

Background： The clinical significance of acute vasoreactivity testing （AVT） in patients with chronic thromboembolic pulmonary hypertension （CTEPH） remains unclear. We analyzed changes in hemodynamics and oxygenation dynamics indices after AVT in patients with CTEPH using patients with pulmonary arterial hypertension （PAH） as controls. Methods： We analyzed retrospectively the results of AVT in 80 patients with PAH and 175 patients with CTEPH registered in the research database of Beijing Chao-Yang Hospital between October 2005 and August 2014. Demographic variables, cardiopulmonary indicators, and laboratory findings were compared in these two subgroups. A long-term follow-up was conducted in patients with CTEPH. Between-group comparisons were performed using the independent-sample t-test or the rank sum test, within-group comparisons were conducted using the paired t-test or the Wilcoxon signed-rank test, and count data were analyzed using the Chi-squared test. Survival was estimated using the Kaplan-Meier method and log-rank test. Results： The rates of positive response to AVT were similar in the CTEPH （25/175, 14.3%） and PAH （9/80, 11.3%） groups （P 〉 0.05）. Factors significantly associated a positive response to AVT in the CTEPH group were level of N-terminal pro-brain natriuretic peptide （〈1131.000 ng/L）, mean pulmonary arterial pressure （mPAE ≤44.500 mmHg）, pulmonary vascular resistance （PVR, 〈846.500 dyn＇s-1·m-5）, cardiac output （CO,≥3.475 L/rain）, and mixed venous oxygen partial pressure （PvO2, ≥35.150 mmHg）. Inhalation of iloprost resulted in similar changes in mean blood pressure, mPAE PVR, systemic vascular resistance, CO, arterial oxygen saturation （SaO2）, mixed venous oxygen saturation, partial pressure of oxygen in arterial blood （PaO2）, PvO2, and intrapulmonary shunt （Qs/Qt） in the PAH and CTEPH groups （all P 〉 0.05）. The survival time in patients with CTEPH with a negative response to AVT was somewhat shorter than that in AVT-responders although the difference was not statistically significant （X2= 3,613, P = 0.057）. The survival time of patients with CTEPH who received calcium channel blockers （CCBs） was longer than that in the group with only basic treatment and not shorter than that of patients who receiving targeted drugs or underwent pulmonary endarterectomy （PEA） although there was no significant difference between the four different treatment regimens （X2 = 3.069, P = 0.381 ）. Conclusions： The rates of positive response to AVT were similar in the CTEPH and PAH groups, and iloprost inhalation induced similar changes in hemodynamics and oxygenation dynamics indices. A positive response to AVT in the CTEPH group was significantly correlated with milder disease and better survival. Patients with CTEPH who cannot undergo PEA or receive targeted therapy but have a positive response to AVT might benefit from CCB treatment.

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.

Pulmonary oligemia maneuver can alleviate pulmonary artery injury during pulmonary thromboendarterectomy procedure

Background Pulmonary thromboendarterectomy （PTE） has evolved as a treatment of choice for chronic thromboembolic pulmonary hypertension （CTEPH）. This study aimed to characterize if pulmonary oligemia maneuver （POM） can alleviate pulmonary artery injury during PTE procedure. Methods A total of 112 cases of CTEPH admitted to Beijing Anzhen Hospital from March 2002 to August 2011 received PTE procedure. They were retrospectively classified as non-POM group （group A, n=55） or POM group （group B, n=57）. Members from group B received POM during rewarming period, whereas members from group A did not. Results There were three （5.45%） early deaths in group A, no death in group B （0） （Fisher＇s exact test, P=0.118）. Six patients in group A needed extracorporeal membrane oxygenation （ECMO） as life support after the PTE procedure, no patients in group B needed ECMO （Fisher＇s exact test, P=0.013）. The patients in group B had a shorter intubation and ICU stay, lower mean pulmonary arterial pressure （mPAP） and pulmonary vascular resistance （PVR）, higher partial pressure of oxygen in artery （PaO2） and arterial oxygen saturation （SaO2） and less medical expenditure than patients in group A. With a mean follow-up time of （58.3 ± 30.6） months, two patients in group A and one patient in group B died. The difference of the actuarial survival after the procedure between the two groups did not reach statistical significance. Three months post the PTE procedure, the difference of residual occluded pulmonary segment between the two groups did not reach statistical significance （P=0.393）. Conclusion POM can alleviate pulmonary artery injury, shorten ICU stay and intubation time, and lower down the rate of ECMO after PTE procedure.

Pulmonary artery injury management during pulmonary thromboendarterectomy

Pulmonary thromboendarterectomy （PEA） is the recommended treatment for chronic thromboembolic pulmonary hypertension （CTEPH）.1 Pulmonary artery injury is a major risk factor during PEA performed at less experienced surgical centers and is associated with adverse short-term consequences.In-hospital mortality may be as high as 15% in some PEA case series,with pulmonary artery injury and persistent pulmonary hypertension as the principal etiologies.2 Many techniques have been used to prevent pulmonary artery injury during PEA,but once the injury occurs,the prognosis is poor and may even result in death.Out of 202 PEA procedures performed at our surgical center,we successfully managed two cases of severe pulmonary artery injury and report our experience in the present case series.Keywords：chronic thromboembolic pulmonary hypertension; pulmonary thromboendarterectomy; pulmonary artery injury