刘伟华
中国医学科学院阜外医院 19病区
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.
Clinical and experimental hypertension (New York, N.Y. : 1993) 2018
BACKGROUND:Obstructive sleep apnea (OSA) can result in hypertension and significantly increase cardiovascular morbidity and mortality. There are few reports on the long-term effects of continuous positive airway pressure (CPAP) on blood pressure in patients with uncontrolled hypertension with coronary heart disease (CHD) and OSA.METHODS:We conducted a prospective, long-term follow-up study in 83 patients with uncontrolled hypertension, CHD, and OSA randomized to control or CPAP groups. Daytime systolic blood pressure (SBP), diastolic blood pressure (DBP), and severe cardiovascular and cerebrovascular events (SCCEs) were recorded at baseline and follow-up.RESULTS:Seventy-three patients completed the study with a median follow-up of 36 (interquartile range = 24-54) months. The 2 groups had similar characteristics at baseline. CPAP was used for 4.5±1.1 hour/night. SBP in the CPAP group was significantly reduced at follow-up (143±7 mm Hg vs. 139±7 mm Hg, P = 0.04), and SBP decreased by 8mm Hg (95% confidence interval = 1.4-9.9; P = 0.01). Hypertension control was improved (CPAP, 69.4% for CPAP users vs. 43.2% for control subjects; P = 0.02); however, DBP did not reach statistical difference between the groups (81±10 mm Hg vs. 79±8 mm Hg; P = 0.49). In the CPAP group, the Epworth Sleepiness Scale was markedly reduced (7.0±3.4 vs. 3.7±2.3; P < 0.001). There was 1 SCCE in the CPAP group (heart failure), and 5 SCCEs in the control group (acute myocardial infarction: 2 (with 1 death); stroke: 3), but there was no significant difference identified.CONCLUSIONS:Long-term CPAP application in uncontrolled hypertension with CHD and OSA significantly reduced daytime SBP, improved hypertension control and daytime sleepiness, and decreased the trend in SCCEs compared with control subjects.CLINICAL TRIAL REGISTRATION NUMBER:ClinicalTrials.gov NCT02059993.
American journal of hypertension 2015
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 (Spearman's r=-0.438, P<.001), and a positive correlation was observed between hepcidin-25 and ferritin (Spearman's 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.
Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology 2015
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.
Heart, lung & circulation 2014
OBJECTIVES:We observed the pulmonary function and exercise capacity of idiopathic dilated cardiomyopathy (IDCM) and idiopathic pulmonary arterial hypertension (IPAH) patients using cardiopulmonary exercise testing (CPX). We evaluated and compared the two groups.BACKGROUND:Pulmonary abnormalities and decreased exercise capacity are common in IDCM and IPAH. Little is known about the differences in these two syndromes.METHODS:Sixty-three patients were involved the study, 23 with IDCM and 40 with IPAH. All patients underwent pulmonary function testing at rest and CPX.RESULTS:Patients with IPAH had a higher peak respiratory frequency (32.40 ± 7.88 vs 29.60 ± 6.50 b/min), peak dead space volume/tidal volume (29.33 ± 4.55 vs 26.30 ± 3.31%), peak end-tidal partial pressure of O2 (125.18 ± 5.88 vs 115.17 ± 6.06 mm Hg), peak minute ventilation/CO2 production (50.14 ± 13.26 vs 33.50 ± 6.80 L/min/L/min), and a lower peak oxygen uptake (1262.70 ± 333.34 vs 742.76 ± 194.72 ml/min), peak minute ventilation (38.20 ± 13.07 vs 45.33 ± 12.31 L), peak oxygen uptake/heart rate (5.11 ± 1.47 vs 9.43 ± 2.79 ml/b) and peak end-tidal partial pressure of CO2 (23.73 ± 5.39 vs 35.30 ± 5.45 mm Hg) during exercise.CONCLUSIONS:Compared to IDCM, patients with IPAH had worse pulmonary function and exercise capacity resulting from severe ventilation/perfusion mismatching and gas exchange abnormalities.
Heart & lung : the journal of critical care 2014
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.
Thrombosis research 2014
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 AND 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 ∆PetCO2 and ∆VE/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.
Medical science monitor : international medical journal of experimental and clinical research 2014
