Operability assessment in CTEPH: Lessons from the CHEST-1 study.

Pulmonary endarterectomy is the gold standard treatment for chronic thromboembolic pulmonary hypertension and is potentially curative, although some patients are unsuitable for pulmonary endarterectomy and require alternative management. Lack of standardized assessment of pulmonary endarterectomy eligibility risks suboptimal treatment in some patients. We discuss the implications for future clinical trials and practice of a unique operability assessment in patients who have chronic thromboembolic pulmonary hypertension and were initially screened for inclusion in the CHEST-1 (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase Stimulator Trial-1) study. The CHEST-1 study evaluated riociguat for the treatment of inoperable chronic thromboembolic pulmonary hypertension (CTEPH) or persistent/recurrent pulmonary hypertension after pulmonary endarterectomy. Screened patients who were initially considered "inoperable" underwent central independent adjudication by a committee of experienced surgeons, or local adjudication in collaboration with an experienced surgeon. Operability decisions were based on accessibility of thrombi and the association between pulmonary vascular resistance (PVR) and the extent of obstruction, using pulmonary angiography/computed tomography with ventilation/perfusion scintigraphy as the minimum diagnostic tests. Of 446 patients screened for CHEST-1, a total of 188 and 124 underwent central and local adjudication, respectively, after being initially considered to be "inoperable." After a second assessment by an experienced surgeon, 69 of these 312 "inoperable" patients were deemed operable. Rigorous measures in CHEST-1 guaranteed that only technically inoperable patients, or patients who had persistent/recurrent pulmonary hypertension, were enrolled, thus ensuring that only patients for whom surgery was not an option were enrolled. This study design sets new standards for future clinical trials and practice in CTEPH, helping to ensure that patients who have CTEPH receive optimal treatment.

Post-conditioning through lower limb ischemia-reperfusion can alleviate lung ischemia-reperfusion injury.

OBJECTIVE: Operation on the infrarenal aorta could cause ischemic-reperfusion (IR) injury in local tissues and remote organs (e.g. the lung). We aim to explore the method of reducing lung ischemia-reperfusion damage after lower limb IR with post conditioning (LIPC). METHODS: Bilateral lower limb ischemia was performed in Sprague-Dawley (SD) rats, and then animals were divided into 4 groups: IR-Sham-operated, IR, post conditioned-IR (LIPC) and bilateral lower limb ischemia (LIR). The serum free radical, histological changes, Wet/Dry (W/D) ratio, levels of TNF-α, IL-6, cytokines and chemokines were tested and compared. RESULTS: Post-conditioning could ameliorate histological injuries in the lung when compared to IR group. The serum free radical is significantly lower in LIPC group than IR groups. W/D ratio in LIPC groups is significantly lower. LIPC also could reduce the expression of cytokines and chemokines. CONCLUSION: post conditioning could reduce long-term damages of the lung after lower limb ischemic-reperfusion injury.

Preoperative transcatheter occlusion of bronchopulmonary collateral artery reduces reperfusion pulmonary edema and improves early hemodynamic function after pulmonary thromboendarterectomy.

OBJECTIVE: The present study assessed the effectiveness of preoperative transcatheter occlusion of the bronchopulmonary collateral artery (PTOBPCA) in reducing reperfusion pulmonary edema after pulmonary thromboendarterectomy (PEA). METHODS: The data from 155 patients with chronic thromboembolic pulmonary hypertension at Anzhen Hospital, treated from January 2007 to August 2013, with PEA were retrospectively reviewed. The patients were classified into a control (group A, n = 87) and treated (group B, underwent PTOBPCA, n = 68) group. The reperfusion pulmonary edema incidence, mechanical ventilation and intensive care unit hospitalization duration, and hemodynamic function were compared between the 2 groups. RESULTS: Of the 87 patients in group A, 5 died in-hospital (5.7% mortality); no patient in group B died (0% mortality; P = .035). In group A, 9 patients (10.3%) required extracorporeal membrane oxygenation (ECMO) after PEA; 1 patient (1.5%) in group B required ECMO (chi-square test, P = .026, χ(2) = 4.980). Group B had shorter intubation and intensive care unit hospitalization times, lower mean pulmonary artery pressures and pulmonary vascular resistance, higher partial pressures of oxygen in arterial blood and oxygen saturation, and decreased medical expenditure compared with group A. During a mean 37.1 ± 21.4 months of follow-up, 3 patients in group A and 2 in group B died; however, the difference in the actuarial survival at 3 years postoperatively between the 2 groups was not statistically significant. CONCLUSIONS: PTOBPCA can reduce the incidence of reperfusion pulmonary edema, shorten intensive care unit hospitalization and intubation duration, improve early hemodynamic function, and reduce ECMO usage after PEA.

Patients with congenital systemic-to-pulmonary shunts and increased pulmonary vascular resistance: what predicts postoperative survival?

BACKGROUND: We carried out a retrospective data review of patients with systemic to pulmonary shunts that underwent surgical repair between February 1990 and February 2012 in order to assess preoperative pulmonary vascular dynamic risk factors for predicting early and late deaths due presumably to pulmonary vascular disease. METHODS AND RESULTS: A total of 1024 cases of congenital systemic-to-pulmonary shunt and advanced pulmonary vascular disease beyond infancy and early childhood were closed surgically. The mean follow up duration was 8.5±5.5 (range 0.7 to 20) years. Sixty-one in-hospital deaths (5.96%, 61/1024) occurred after the shunt closure procedure and there were 46 late deaths, yielding 107 total deaths. We analyzed preoperative pulmonary vascular resistance index (PVRI), pulmonary vascular resistance index on pure oxygen challenge (PVRIO), difference between PVRI and PVRIO (PVRID), Qp∶Qs, and Rp∶Rs as individual risk predictors. The results showed that these individual factors all predicted in-hospital death and total death with PVRIO showing better performance than other risk factors. A multivariable Cox regression model was built,and suggested that PVRID and Qp∶Qs were informative factors for predicting survival time from late death and closure of congenital septal defects was safe with a PVRIO<10.3 WU.m(2) and PVRID>7.3 WU.m(2) on 100% oxygen. CONCLUSIONS: All 4 variables, PVRI, PVRIO, PVRID and Qp∶Qs, should be considered in deciding surgical closure of congenital septal defects and a PVRIO<10.3 WU.m(2) and PVRID>7.3 WU.m(2) on 100% oxygen are associated with a favorable risk benefit profile for the procedure.

The distinguishing cellular features of pulmonary artery smooth muscle cells from chronic thromboembolic pulmonary hypertension patients.

In chronic thromboembolic pulmonary hypertension (CTEPH), central thrombi are the most likely disease initiators, and progressive pulmonary vascular remodeling, which is characterized by marked proliferation of pulmonary artery smooth muscle cells (PASMCs), may also contribute to the long-term progression of CTEPH. This study was designed to investigate the cellular characteristics of PASMCs isolated from the organized thrombotic tissues of CTEPH. In the present study, analysis of PASMCs isolated from five CTEPH patients and three control subjects showed that cells from CTEPH patients had certain characteristics that distinguished them from control cells, including inferior or no cell-cell contact inhibition growth, increased sensitivity to hypoxia-induced proliferation, resistance to serum starvation-induced apoptosis, and mitochondrial metabolism disorder. These differences in the PASMCs in endarterectomized tissue of CTEPH patients may prove useful in understanding the pathobiology of CTEPH.

Fibrinogen Aα Thr312Ala polymorphism specifically contributes to chronic thromboembolic pulmonary hypertension by increasing fibrin resistance.

BACKGROUND: Polymorphisms are associated with chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary thromboembolism (PTE), but no polymorphism specific to CTEPH but not PTE has yet been reported. Fibrin resistance is associated with CTEPH, but the mechanism has not been elucidated. METHODS: Polymorphisms were analyzed in 101 CTEPH subjects, 102 PTE subjects and 108 healthy controls by Massarray or restriction fragment length polymorphism (RFLP). Plasmin-mediated cleavage of fibrin was characterized in 69 subjects (29 with CTEPH, 21 with PTE and 19 controls). RESULTS: Genotype frequencies and allele frequencies of fibrinogen Aα Thr312Ala were significantly higher in CTEPH subjects than in controls and PTE subjects, while there was no difference between PTE subjects and controls. The odd ratio (OR 2.037) and 95% confidence interval (95% CI, 1.262-3.289) showed that Thr312Ala polymorphism was a risk factor for CTEPH but not PTE. Fibrin from CTEPH subjects was more resistant to lysis than that from PTE subjects and controls. Fibrin resistance was significantly different between Aα Thr312Ala (A/G) genotypes within CTEPH subjects, and the fibrin with GG genotype was more resistant than that with AA and AG genotype. CONCLUSIONS: Fibrinogen Aα Thr312Ala (A/G) polymorphism was associated with CTEPH, but not PTE, suggesting that the fibrinogen Aα Thr312Ala polymorphism may act as a potential biomarker in identifying CTEPH from PTE. GG genotype polymorphism contributes to CTEPH through increasing fibrin resistance, implying that PTE subjects with fibrinogen Aα GG genotype may need long-term anticoagulation therapy.

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.

The wall eclipsing sign on pulmonary artery computed tomography angiography is pathognomonic for pulmonary artery sarcoma.

BACKGROUND: The objective of this study was to evaluate the imaging characteristics of pulmonary artery sarcoma (PAS) on pulmonary artery computed tomography angiography (PACTA) that can be used to differentiate between PAS and pulmonary thromboembolic diseases, including chronic thromboembolic pulmonary hypertension (CTEPH) and acute pulmonary embolism (APE). METHODS: The clinical data and imaging characteristics of 12 patients with PAS, 156 patients with CTEPH, and 426 patients with APE who were treated at Beijing Anzhen Hospital from January 2007 to August 2013 were retrospectively analyzed. All patients underwent PACTA before treatment, and the diagnoses of PAS and CTEPH were all confirmed by surgical biopsy. RESULTS: All 12 PAS patients were initially misdiagnosed and received inappropriate thrombolytic and/or anticoagulant therapy before they were referred for surgical intervention. The mean time from PACTA to surgical intervention was 5.5±3.7 months (range 2-11 months). On PACTA, the PAS lesion always eclipsed the wall of the pulmonary artery before infiltrating outside the pulmonary artery, which was termed the wall eclipsing sign. This sign was observed in all PAS patients but was not observed in any CTEPH or APE patients. CONCLUSIONS: PAS is a rare neoplasm with a poor prognosis, and is easily misdiagnosed as thromboembolic disease. The wall eclipsing sign on PACTA is pathognomonic for PAS, and patients with this sign should be investigated to confirm the diagnosis and should undergo surgical intervention as soon as possible, rather than receiving thrombolytic or anticoagulant therapy.

High volume practice proved the safety of off-pump coronary artery bypass surgery in left main coronary artery lesions: a two-year single center experience.

BACKGROUND: Left main coronary artery (LMCA) stenosis has been recognized as a risk factor for early death among patients undergoing coronary artery bypass grafting (CABG). This study aimed to assess if LMCA lesions pose an additional risk of early or mid-term mortality and/or a major adverse cardiac and cerebrovascular event (MACCE) after off-pump coronary artery bypass grafting (OPCABG), compared with non-left main coronary artery stenosis (non-mainstem disease). METHODS: From January 1, 2009 to December 31, 2010, 4869 patients had a primary isolated OPCABG procedure at Beijing Anzhen Hospital. According to the pathology of LMCA lesions, they were retrospectively classified as a non-mainstem disease group (n = 3933) or a LMCA group (n = 936). Propensity scores were used to match the two groups, patients from the non-mainstem disease group (n = 831) were also randomly selected to match patients from the LMCA group (n = 831). Freedom from MACCE in the two groups was calculated using the Kaplan-Meier method. RESULTS: The difference in the mortality and the rate of MACCE during the first 30 days between the non-mainstem disease group and the LMCA group did not reach statistical significance (P = 0.429, P = 0.127 respectively). With a mean follow-up of (12.8 ± 7.5) months and a cumulative follow-up of 1769.6 patient-years, the difference in the freedom from MACCEs between the two groups, calculated through Kaplan-Meier method, did not reach statistical significance (P = 0.831). CONCLUSION: Analysis of a high volume of OPCABG procedures proved that LMCA lesions do not pose additional early and mid-term risk to OPCABG. Therefore, a LMCA lesion is as safe as non-mainstem disease lesion during the OPCABG procedure.

Ostial left main coronary artery stenosis as an additional risk factor in off-pump coronary artery bypass grafting.

BACKGROUND: Our aim was to determine whether general left main coronary artery stenosis (LMS) and ostial LMS pose additional risks after off-pump coronary artery bypass grafting (CABG) relative to non-left main coronary artery stenosis. METHODS: From January 1, 2008, to December 31, 2009, 4366 patients underwent primary isolated off-pump CABG at Beijing Anzhen Hospital. Disease was retrospectively classified as non-left main disease (n = 3523), nonostial LMS (n = 765), and ostial LMS (n = 78). Groups were propensity score matched. Kaplan-Meier freedoms from major adverse cardiac and cerebrovascular events (MACCEs) were calculated. RESULTS: During the first 30 postoperative days, mortality was significantly higher in the ostial LMS group (6.41%) than in non-left main disease (0.855%, χ(2) = 7.78, P = .005) and nonostial LMS (1.28%, χ(2) = 4.71, P = .03) groups. Incidence of MACCEs was significantly higher in the ostial LMS group (20.5%) than in non-left main disease (5.98%, P = .000) and nonostial LMS (9.62%, P = .002) groups. Odds ratio for early MACCEs of ostial LMS versus non-left main disease was 3.74 (95% confidence interval, 1.72-8.17). At mean follow-up 12.8 ± 7.5 months and cumulative follow-up 498.5 patient-years, difference among groups in freedom from MACCEs did not reach statistical significance (χ(2) = 2.39, P = .303). CONCLUSIONS: Ostial LMS poses additional early risks of mortality and MACCEs in off-pump CABG. Off-pump CABG for ostial LMS should proceed with greater of intraoperative surveillance and lower threshold for converting to on-pump CABG.