Qunying Xi

Red cell distribution width predicts chronic thromboembolic pulmonary hypertension in patients with acute pulmonary embolism in a long-term follow-up.

Chronic thromboembolic pulmonary hypertension (CTEPH) is defined as mean pulmonary arterial pressure > 25 mm Hg that persists 6 months after pulmonary embolism (PE) is diagnosed [1]. It occurs in 1%–4% of patients after acute PE [2, 3] and in up to 10% of those with a history of recurrent PE [4]. CTEPH represents a serious predicament that leads to progressive right ventricular dysfunction and death. However, previous studies have demonstrated that the likelihood of developing CTEPH diminishes with more intense treatment of acute PE [5]. Hence, a rapid and reliable predictor of CTEPH might help physicians in the early detection of patients requiring closer monitoring and possibly benefiting from more effective treatment. Red blood cell distribution width (RDW), an index of heterogeneity of erythrocytes, is routinely reported as part of the complete blood count. It has been reported in studies that elevated RDW on admission is an independent predictor of short-term mortality in acute PE [6]. However, the prognostic role of RDW for long-term outcomes in patients with acute PE has not been investigated. We, therefore, explored in this study whether RDW is useful to predict CTEPH in a Chinese cohort with acute PE. A total of 214 consecutive adult patients with symptomatic acute PE that were admitted to the Center for Pulmonary Vascular Disease of Fuwai Hospital, a tertiary teaching hospital in Beijing, China from January 2009 through December 2012 were analyzed in this study. The symptomatic acute PE confirmed by objective examination was included, and the exclusion criteria were any of the following: 1) a prior documented episode of PE or deep venous thrombosis (DVT); 2) a life expectancy of < 6 months; 3) recent blood transfusion history (within 3 months before admission); 4) patients receiving hemodialysis. Data collection included demographic information, medical history, baseline clinical characteristics, laboratory data, treatment received, and clinical outcomes. The study was approved by the Institutional Review Board of Fuwai Hospital and written informed consent was obtained from all patients. The diagnosis was made using a standard protocol as we reported previously [7]. The provoked PE patients were defined as those with trigger factors including active cancer, prolonged immobilization, chronic heart or respiratory failure, recent trauma, surgical intervention, pregnancy, and the use of oral contraceptives or hormone replacement therapy. All other patients were classified as unprovoked PE. Anticoagulation with unfractioned heparin or low molecular weight heparin was initiated without delay aQunying Xi and Yong Wang contributed equally to this work. *Corresponding author: Prof. Zhihong Liu, Center for Pulmonary Vascular Diseases, Fuwai Hospital and Cardiovascular Institute, 167 Beilishi Road, Beijing 100037, P.R. China, Phone: +86 010 88396589, Fax: +86 010 88396589, E-mail: fuwaipumc@163.com Qunying Xi: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China; and Center for Pulmonary Vascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China Yong Wang, Zhihui Zhao and Qin Luo: Center for Pulmonary Vascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China

High Frequency of Pulmonary Hypertension-Causing Gene Mutation in Chinese Patients with Chronic Thromboembolic Pulmonary Hypertension

The pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH) is unknown. Histopathologic studies revealed that pulmonary vasculature lesions similar to idiopathic pulmonary arterial hypertension (PAH) existed in CTEPH patients as well. It’s well-known that genetic predisposition plays an important role in the mechanism of PAH. So we hypothesized that PAH-causing gene mutation might exist in some CTEPH patients and act as a background to facilitate the development of CTEPH. In this study, we analyzed 7 PAH-causing genes including BMPR2, ACVRL1, ENG, SMAD9, CAV1, KCNK3, and CBLN2 in 49 CTEPH patients and 17 patients recovered from pulmonary embolism (PE) but without pulmonary hypertension(PH). The results showed that the nonsynonymous mutation rate in CTEPH patients is significantly higher than that in PE without PH patients (25 out of 49 (51%) CTEPH patients vs. 3 out of 17 PE without PH patients (18%); p = 0.022). Four CTEPH patients had the same point mutation in ACVRL1 exon 10 (c.1450C>G), a mutation approved to be associated with PH in a previous study. In addition, we identified two CTEPH associated SNPs (rs3739817 and rs55805125). Our results suggest that PAH-causing gene mutation might play an important role in the development of CTEPH.

Differences in Exercise Capacity in Patients with Chronic Left Heart Failure and Chronic Right Heart Failure

BACKGROUND Exercise impairment is common in chronic left heart failure and pulmonary arterial hypertension (PAH). Exercise impairment degree is a strong predictor of clinical outcome. Our purpose was to evaluate differences in exercise capacity using cardiopulmonary exercise testing (CPX) in patients with chronic left and right heart failure, and determine which factors were related to exercise impairment. METHODS 102 patients with class II/III New York Heart Association were involved in the study (41 with chronic left heart failure, 61 with chronic right heart failure secondary to PAH). All patients underwent CPX to evaluate exercise capacity. RESULTS Patients with right heart failure had significantly lower peak oxygen uptake (VO2), peak VO2/kg ratio, peak oxygen uptake/heart rate (VO2/HR) ratio and increases in oxygen uptake/increase in work rate (ΔVO2/ΔWR) slope, and had higher minute ventilation/CO2 production ratio and peak dead space volume/tidal volume during exercise. In patients with left heart failure, peak VO2/HR ratio was positively correlated with ΔVO2/ΔWR slope. However, VO2 and VO2/HR ratio were positively correlated with ΔVO2/ΔWR slope in patients with right heart failure. CONCLUSIONS Compared with left heart failure, patients with right heart failure showed worse exercise capacity resulting from worse pulmonary and cardiovascular adaptation to exercise.

The lowest VE/VCO2 ratio best identifies chronic thromboembolic pulmonary hypertension

INTRODUCTION The natural history of acute pulmonary embolism (PE) under treatment is about a gradual resolution of the thrombi, and uncommonly, the development of chronic thromboembolic pulmonary hypertension (CTEPH). We hypothesized that ventilatory efficiency parameters during cardiopulmonary exercise testing (CPET) may be able to monitor the process and predict CTEPH. METHODS 15 patients rehabilitated from acute PE (total resolution of thrombi), 44 patients with chronic PE (with residual thrombi), 66 patients with CTEPH, and 36 sedentary healthy controls performed incremental CPET. RESULTS The lowest VE/VCO₂ was higher in CTEPH patients than that in chronic PE and rehabilitated patients (43.4 L/min vs 29.9 L/min vs 27.1 L/min, p<0.005). The VE/VCO₂ slope (48.4 L/min/L/min vs 29.9 L/min/L/min vs 28.0 L/min/L/min, p<0.005) and oxygen uptake efficiency plateau (OUEP) (37.1 L/min vs 27.0 L/min vs 25.2L/min, p<0.005) had the similar changes. In logistic regression analysis, the lowest VE/VCO₂ ≥ 34.35 L/min was the best predictor of CTEPH (OR 159.0, 95% CI 36.0-702.3, p<0.001). The lowest VE/VCO₂ was higher in chronic PE patients compared with the controls (29.9 L/min vs 26.5 L/min, p<0.05), but there was no difference between the rehabilitated patients and the controls. In multiple linear regression analysis, the percentage of vascular obstruction by ventilation-perfusion lung scanning (PVO) was the most significant independent predictor for indices of ventilatory efficiency in chronic PE and rehabilitated patients. CONCLUSIONS CTEPH is associated with weakened ventilatory efficiency. The lowest VE/VCO₂ ratio has the best capability to predict CTEPH. Ventilatory inefficiency improves along with recovery of acute PE.

Red blood cell distribution width predicts responsiveness of acute pulmonary vasodilator testing in patients with idiopathic pulmonary arterial hypertension.

BACKGROUND Red blood cell distribution width (RDW) has been shown to predict clinical outcomes in cardiopulmonary vascular diseases. We investigated whether RDW is useful to predict responsiveness of acute pulmonary vasodilator testing in patients with idiopathic pulmonary arterial hypertension (IPAH). METHODS RDW was determined in 167 IPAH patients who underwent acute pulmonary vasodilator testing. All subjects were followed up for 20 ± 10 months. RESULTS Nineteen out of 167 patients (11.4%) were acute pulmonary vasodilator testing responders. Patients with lower RDW levels ≤ 13.65% (sensitivity 89.5%, specificity 52.7%; AUC: 0.747, 95% CI: 0.632 to 0.861) were more likely to have a positive response. Multivariate logistic regression analysis showed that RDW ≤ 13.65% independently predicted responsiveness of vasodilator testing in patients with IPAH (OR 18.453, 95% CI 2.279-149.391, p = 0.006). RDW correlated with disease severity evaluated by clinical parameters. Patients with increased RDW (> 13.65%) had significantly increased risk of all-cause death (Log-rank p = 0.007). CONCLUSIONS RDW independently predicts responsiveness of acute pulmonary vasodilator testing in patients with IPAH. RDW is associated with disease severity and all-cause death.

Chronic thromboembolic pulmonary hypertension is not associated with iron overload.

BACKGROUND Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized as the incomplete resolution of emboli after pulmonary embolism (PE) and the subsequent fibrotic organization and remodeling of pulmonary vascular bed. It has been reported that abnormal fibrin probably contributes to the incomplete resolution of emboli. And there is evidence that free iron could convert fibrinogen into fibrin which is remarkably resistant to lysis. Thus, we hypothesized that persistent iron overload might participate in the development of CTEPH. MATERIALS AND METHODS A case-control study was conducted. Forty-five CTEPH patients were enrolled as cases, and 36 age and sex frequency-matched chronic PE patients without pulmonary hypertension were selected as controls. Levels of free iron, soluble transferrin receptor (sTfR), ferritin, sTfR/ferritin ratio, hepcidin-25, tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and malondialdehyde (MDA) were compared between the two groups. Logistic regression analysis was carried out to estimate odds ratios. RESULTS There was no difference of the levels of free iron, hepcidin-25, sTfR, ferritin, sTfR/ferritin ratio, TNF-α, and MDA between CTEPH patients and the controls. Levels of sTfR and ferritin in both groups were within the normal limits. Levels of IL-6 in CTEPH patients were significantly higher than that in the controls. A negative correlation was observed between hepcidin-25 and sTfR (Spearmans r=-0.438, P<.001), and a positive correlation was observed between hepcidin-25 and ferritin (Spearmans r=0.503, P<.001). In the univariate logistic regression model, there was no association observed between CTEPH and free iron, hepcidin-25, sTfR, ferritin, sTfR/ferritin ratio, TNF-α, IL-6, and MDA. CONCLUSIONS CTEPH has no association with iron overload. The iron status evaluated by sTfR and ferritin is within the normal limits in this CTEPH population.

Predictors of Blood Pressure Fall With Continuous Positive Airway Pressure Treatment in Hypertension With Coronary Artery Disease and Obstructive Sleep Apnea

BACKGROUND The present study aimed to investigate the predictors of changes in blood pressure (BP) with continuous positive airway pressure (CPAP) treatment in hypertensive patients with coronary heart disease (CHD) and obstructive sleep apnea (OSA). METHODS Seventy-one hypertensive patients with CHD and OSA were enrolled in this study. Daytime systolic BP (SBP), diastolic BP (DBP), Epworth Sleepiness Scale (ESS), and anthropometric characteristics were assessed at baseline and follow-up. RESULTS Sixty-six patients completed the study. The median follow-up period was 36 months (interquartile range, 24-60 months). The mean duration of CPAP application was 4.3 ± 1.2 hours per night. From baseline to follow-up, SBP and DBP were reduced by 5.6 mm Hg (95% confidence interval [CI], 3.0-8.1) and 3.0 mm Hg (95% CI, 0.8-5.3), respectively. Daytime somnolence was significantly improved (ESS, from 9.5 ± 3.4 at baseline to 3.6 ± 2.0 at follow-up; P < 0.001); the mean improvement in ESS was 6.0 (95% CI, 5.1-6.9). Correlation analysis of the fall in mean BP (MBP) showed that baseline MBP, change in ESS, heart rate, and CPAP compliance showed a positive correlation, whereas the baseline body mass index (BMI) and ESS had an inverse relationship. Stepwise multiple linear regression analysis, however, indicated that only baseline BMI, baseline MBP, and CPAP compliance were independently correlated with the fall in MBP. CONCLUSIONS Long-term CPAP treatment reduces BP in hypertensive patients with CHD and moderate/severe OSA; baseline BMI, baseline MBP, and CPAP compliance are independent predictors of the decrease in BP with CPAP treatment in these patients.

Inhibition of the RhoA/Rho-associated, coiled-coil-containing protein kinase-1 pathway is involved in the therapeutic effects of simvastatin on pulmonary arterial hypertension

ABSTRACT Background: Recent research has shown that statins improve pulmonary arterial hypertension (PAH), but their mechanisms of action are not fully understood. This study aimed to investigate the role of RhoA/ROCK1 regulation in the therapeutic effects of simvastatin on PAH. Methods: For in vivo experiments, rats (N = 40) were randomly assigned to four groups: control, simvastatin, monocrotaline (MCT), and MCT + simvastatin. The MCT group and MCT + simvastatin groups received proline dithiocarbamate (50 mg/kg, i.p.) on the first day of the study. The MCT + simvastatin group received simvastatin (2 mg/kg) daily for 4 weeks, after which pulmonary arterial pressure was measured by right heart catheterization. The protein and mRNA levels of Rho and ROCK1 were measured by immunohistochemistry, Western blot, and PCR. For in vitro experiments, human pulmonary endothelial cells were divided into seven groups: control, simvastatin, monocrotaline pyrrole (MCTP), MCTP + simvastatin, MCTP + simvastatin + mevalonate, MCTP + simvastatin + farnesyl pyrophosphate (FPP), and MCTP + simvastatin + FPP + geranylgeranyl pyrophosphate (GGPP). After 72 h exposed to the drugs, the protein and mRNA levels of RhoA and ROCK1 were measured by Western blot and PCR. Results: The MCT group showed increased mean pulmonary arterial pressure, marked vascular remodeling, and increased protein and mRNA levels of RhoA and ROCK1 compared to the other groups (P < 0.05). In vitro, the MCTP group showed a marked proliferation of vascular endothelial cells, as well as increased protein and mRNA levels of RhoA and ROCK1 compared to the MCTP + simvastatin group. The MCTP + simvastatin + mevalonate group, MCTP + simvastatin+ FPP group, and MCTP + simvastatin + FPP + GGPP group showed increased mRNA levels of RhoA and ROCK1, as well as increased protein levels of RhoA, compared to the MCTP + simvastatin group. Conclusions: Simvastatin improved vascular remodeling and inhibited the development of PAH. The effects of simvastatin were mediated by inhibition of RhoA/ROCK1. Simvastatin decreased RhoA/ROCK1 overexpression by inhibition of mevalonate, FPP, and GGPP synthesis.

Pulmonary function differences in patients with chronic right heart failure secondary to pulmonary arterial hypertension and chronic left heart failure.

Background Pulmonary abnormalities are found in both chronic heart failure (CHF) and pulmonary arterial hypertension (PAH). The differences of pulmonary function in chronic left heart failure and chronic right heart failure are not fully understood. Material/Methods We evaluated 120 patients with stable CHF (60 with chronic left heart failure and 60 with chronic right heart failure). All patients had pulmonary function testing, including pulmonary function testing at rest and incremental cardiopulmonary exercise testing (CPX). Results Patients with right heart failure had a significantly lower end-tidal partial pressure of CO2 (PetCO2), higher end-tidal partial pressure of O2 (PetO2) and minute ventilation/CO2 production (VE/VCO2) at rest. Patients with right heart failure had a lower peak PetCO2, and a higher peak dead space volume/tidal volume (VD/VT) ratio, peak PetO2, peak VE/VCO2, and VE/VCO2 slope during exercise. Patients with right heart failure had more changes in ΔPetCO2 and ΔVE/VCO2, from rest to exercise. Conclusions Patients with right heart failure had worse pulmonary function at rest and exercise, which was due to severe ventilation/perfusion (V/Q) mismatching, severe ventilation inefficiency, and gas exchange abnormality.