5-Aminosalicylic Acid Attenuates Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats by Increasing the Expression of Nur77.

The aim of this study is to investigate the effect of 5-aminosalicylic acid (5-ASA) on monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) in rats and its molecular mechanism. Sixty male Sprague-Dawley rats (250-300 g) were evenly randomized into six groups: control group; PAH group induced by MCT intraperitoneal injection (50 mg/kg) on day 1; and four PAH groups treated for 30 days from day 2 with 5-ASA at 50 (5-ASA-50 group), 100 (5-ASA-100 group), 150 (5-ASA-150 group), and 200 mg/kg/day (5-ASA-200 group), respectively. Body mass, weight increment, survival rates, pulmonary artery pressure (PAP), right ventricular hypertrophy index (RVHI), and the signal pathway regulated by 5-ASA were assessed. (1) Compared with the control group, the PAH group had lower body mass and weight increment, and relative to the latter, 5-ASA-treated groups had larger body mass and weight increment except for groups 5-ASA-150 and 5-ASA-200 and greater overall survival rates; (2) SPAP, DPAP, MPAP, and RVHI in 5-ASA-treated groups, except for MPAP and RVHI in 5-ASA-200 group, were lower than those in the PAH group; (3) compared with the PAH group, Nur77 expression in the pulmonary arteries of 5-ASA-treated groups was increased; and (4) expression of inflammatory mediators (NF-κB p65) was lower, while that of IκBα was higher in the pulmonary arteries of 5-ASA-treated groups and control group than that in the PAH group (all P < 0.05). 5-ASA attenuates PAH in MCT-injected rats, reducing pulmonary arterial pressures and right ventricular hypertrophy and improving survival rates, via the Nur77-NF-κB/IκBα pathway involved in modulating the pulmonary vascular remodeling.

The Application of Intravascular Ultrasound to Evaluate Pulmonary Vascular Properties and Mortality in Patients with Pulmonary Arterial Hypertension.

BACKGROUND: The aim of this study was to explore the application of intravascular ultrasound (IVUS) to evaluate pulmonary vascular properties and mortality in patients with pulmonary arterial hypertension (PAH). METHODS: Patients (n = 51) with systolic pulmonary artery pressures ≥ 40 mm Hg on echocardiography were prospectively enrolled. All patients underwent right-heart catheterization and IVUS and were divided into three groups: PAH associated with connective tissue diseases (group 1, n = 25), PAH due to other causes (group 2, n = 15), and patients with connective tissue diseases without pulmonary hypertension (group 3, n = 11). PAH groups (groups 1 and 2) were divided into distal (n = 22) and proximal (n = 18) remodeling subtypes on the basis of IVUS results. All patients were followed (19 ± 10 months) to compare the differences among clinical variables, pulmonary vascular properties, and survival rates. RESULTS: A total of 408 segments of pulmonary arteries were studied. The PAH groups demonstrated a greater mean wall thickness than group 3 (P < .01 for all). Pulmonary vascular mechanical properties, including compliance, distensibility, elastic modulus, and stiffness index ß, were found to be worse in the PAH groups than in group 3 (P < .01 for all), but they tended to be better in group 1 than in group 2. An inverse exponential association was found between pulmonary vascular mechanical properties and hemodynamics, with R(2) values ranging from 0.54 to 0.78 (P < .001). In the PAH groups, the mortality in group 1 was similar to that in group 2 (12% vs 13%, P > .05), while the distal remodeling subtype had higher mortality than the proximal remodeling subtype (23% vs 0%, P < .05). CONCLUSIONS: IVUS is useful in PAH assessment by evaluating pulmonary vascular properties and predicting mortality. The classification of the proximal and distal remodeling type of PAH may be proposed to predict mortality and evaluate the prognosis of patients with PAH in clinical practice.

Two-dimensional echocardiography in the assessment of long-term prognosis in patients with pulmonary arterial hypertension.

OBJECTIVE: To investigate the relationship between cardiac diastolic dysfunction and outcomes in patients with pulmonary arterial hypertension (PAH) and to clarify the potential effect of two-dimensional echocardiography (2D-echo) on prognostic value in patients with PAH. METHODS: Patients diagnosed with PAH (as WSPH (World Symposia on Pulmonary Hypertension) classification I) confirmed by right heart catheterization (RHC), received targeted monotherapy or combination therapy. 2D-echo parameters, World Health Organization (WHO) functional classification and 6-minute walking distance (6MWD) were recorded. The clinical prognosis of patients was assessed by the correlation between echo parameters and clinical 6MWD using receiver operating characteristic (ROC) curve analysis. RESULTS: Fifty-eight patients were included. Left and right ventricular diastolic dysfunction (LVDD and RVDD) scores measured by 2D-echo had good correlation with 6MWD at baseline (rLVDD  = -0.699; rRVDD  = -0.818, both P < 0.001) and at last follow-up (rLVDD  = -0.701; rRVDD  = -0.666, both P<0.001). Furthermore, bi-ventricular (LVDD + RVDD) scores measured by 2D-echo had a better correlation with 6MWD at baseline and last follow-up (r =  0.831; r = -0.771, both P < 0.001). ROC curve analysis showed that the area under curves (AUCs) for LVDD score, RVDD score and (LVDD + RVDD) scores were 0.823 (P < 0.0001), 0.737 (P = 0.0002), and 0.825 (P < 0.0001), respectively. Compared with ROC analysis of other single parameters, cardiac diastolic function score was more accurate in predicting survival in patients with PAH. CONCLUSION: LVDD score, RVDD score and (LVDD + RVDD) scores yielded a comprehensive quantitative assessment of LV and RV diastolic function that correlated moderately with clinical functional parameters and might be useful in the assessment of PAH.

[Clinical analysis of 150 patients with idiopathic pulmonary arterial hypertension].

OBJECTIVE: To explore the demographic characteristics and clinical features of patients with idiopathic pulmonary arterial hypertension (IPAH) in China. METHODS: Between March 2007 and September 2010, IPAH diagnosis was confirmed by right heart catheterization in 150 adult patients from 31 clinical centers in China. Clinical and hemodynamic data were analyzed and patients were divided into WHO functional class I/II and WHO functional class III/IV group. RESULTS: The mean age of 150 patients were 36 ± 13 years with female patient/male patient ratio of 2:1, and mean BMI was (21.3 ± 3.5) kg/m(2). Fatigue (n = 123, 82.0%) and dyspnea (n = 112, 74.7%) are the most common symptoms. Accentuated pulmonic second sound (P(2)) was detected in 92.0% (n = 138) of patients during physical examination, which was also the most common sign. About 49.0% (n = 73) patients were WHO functional class I/II patients and 46.0% (n = 68) patients were WHO functional class III/IV patients. Six minutes walking distance (6MWD) and Borg dyspnea score was (337 ± 101) m and 2.0 (2.0, 4.0), respectively. Right ventricular hypertrophy was suggested by ECG in 93.1% (n = 140) patients. Right atrial pressure was (10 ± 6) mm Hg, mean pulmonary artery pressure was (61 ± 16) mm Hg, cardiac index was (2.3 ± 0.8) L×min(-1)×m(-2) and pulmonary vascular resistance (1484 ± 699) dyn×s(-1)×cm(-5) in this cohort. 6 MWD (305 m ± 89 m vs. 377 m ± 88 m) was significantly shorter while Borg dyspnea score [3.0 (3.0, 5.0) vs. 2.0 (2.0, 3.0)] was significantly higher in WHO functional class III/IV patients than in WHO functional class I/II patients. Similarly hemodynamic parameters were also worse in WHO functional class III/IV patients than in WHO functional class I/II patients (all P < 0.05). CONCLUSION: Idiopathic pulmonary arterial hypertension patients in this cohort affect mostly young adults, dominated by female gender and lower body mass index. Fatigue and dyspnea are the most common symptoms and accentuated pulmonic second sound (P(2)) is the most common sign. IPAH patients are often displaying severe functional and hemodynamic disturbance at first visit to hospitals. Dyspnea and hemodynamic impairment are related to 6MWD and WHO functional class.

Oral sildenafil therapy for Chinese patients with pulmonary arterial hypertension: a multicenter study.

The impact of sildenafil on pulmonary arterial hypertension (PAH) in Chinese patients has been less investigated. A prospective, open-label, uncontrolled and multicenter study, therefore, was carried out to address this issue. Ninety patients with multicause-induced PAH received oral sildenafil (75 mg/day) for 12 weeks. The 6-minute walk test (SMWT) and cardiac catheterization were performed at the beginning and the end of the 12 weeks. The primary endpoint was the changes in exercise capacity assessed by the SMWT; the secondary endpoint included assessment of functional class, evaluation of cardiopulmonary hemodynamics, and clinical worsening. Drug safety and tolerability were also examined. The results showed that there was a significant improvement in SMWT distances (342 ± 93 m vs 403 ± 88 m, P < .0001), Borg dyspnea score (2.9 ± 2.6 vs 2.4 ± 2.0, P = .0046), World Health Organization functional class, and cardiopulmonary hemodynamics (mean pulmonary artery pressure, P < .0001; cardiac index, P < .0001; pulmonary vascular resistance, P < .0001) after 12 weeks of oral sidenafil therapy. Almost all enrolled patients did not experience significant clinical worsening. This study confirms and extends the findings of previous studies relating to effects of sildenafil on PAH, suggesting that oral sildenafil is safe and effective for the treatment of adult patients with PAH in the Chinese population.

Pharmacoinvasive therapy for ST elevation myocardial infarction in China: a pilot study.

Most patients with acute ST-elevation myocardial infarction (STEMI) cannot receive timely primary percutaneous coronary intervention (PCI) because of lack of facilities or delays in patient transfer or catheterization team mobilization. In these patients, early routine post-thrombolysis PCI might be a reasonable, useful strategy. This study investigated feasibility and safety of early PCI after successful half-dose alteplase reperfusion in a Chinese population. Patients with STEMI received half-dose alteplase if expected time delay to PCI was ≥90 min. Patients who reached clinical criteria of successful thrombolysis reperfusion were recommended to undergo diagnostic angiography within 3-24 h after thrombolysis. Patients with residual stenosis ≥70% in the infarct-related artery underwent PCI, regardless of flow or patency status. Epicardial arterial flow was assessed using thrombolysis in myocardial infarction (TIMI) flow grade and TIMI frame count (CTFC). Myocardial perfusion was assessed using myocardial blush grade (MBG) and TIMI myocardial perfusion frame count (TMPFC). Forty-nine patients were enrolled and underwent diagnostic angiography 3-11.3 h (median 6.5 h) after thrombolysis. Forty-six patients underwent PCI. No procedure-related complications occurred, except two patients who had no reflow after PCI. Twenty-two (47.8%) patients had TIMI grade 3 flow before PCI and 33 (71.7%) after PCI. CTFC was significantly improved after PCI (48.5 ± 32.1 vs. 37.9 ± 25.6, P = 0.01). MBG and TMPFC exhibited a similar improving trend after PCI, and the best myocardial perfusion tended to be achieved 3-12 h after lysis. During the 30-day follow-up, there were two deaths. The composite end point of death, cardiogenic shock, heart failure, reinfarction, and recurrent ischemia occurred in four patients. TIMI minor bleeding occurred in four patients. No TIMI major bleeding and stroke occurred. Early routine PCI after half-dose alteplase thrombolysis in Chinese population appears feasible. A larger clinical trial should be designed to further elucidate its efficacy and safety. Early PCI after thrombolysis in STEMI: The EARLY-PCI pilot feasibility study, ChiCTR-TNC-11001363.

Factors affecting thrombolysis in myocardial infarction myocardial perfusion frame count: insights of myocardial tissue-level reperfusion from a novel index for assessing myocardial perfusion.

BACKGROUND: Myocardial tissue-level perfusion failure is associated with adverse outcomes following ST-elevation myocardial infarction (STEMI) despite successful epicardial recanalization. We have developed a new quantitative index-thrombolysis in myocardial infarction (TIMI) myocardial perfusion frame count (TMPFC)--for assessing myocardial tissue level perfusion. However, factors affecting this novel index of myocardial perfusion are currently unknown. METHODS: A total of 255 consecutive STEMI patients undergoing primary angioplasty were enrolled. Myocardial tissue level perfusion was assessed by TMPFC, which measures the filling and clearance of contrast in the myocardium using cine-angiographic frame counting. We differentiate three groups with two cut off values for TMPFC: a TMPFC of 90 frames was the upper boundary of the 95% confidence interval (CI) for the TMPFC observed in normal arteries, and a TMPFC of 130 was the 75th percentile of TMPFC. RESULTS: STEMI patients with TMPFC > 130 frames (68 patients, 26.7%) had higher clinical and angiographic risk factor profiles as well as a higher 30-day MACE rate compared with those with TMPFC ≤ 90 frames and those with TMPFC > 90 and ≤ 130 frames. Multivariable analysis identified that the independent predictors of TMPFC > 130 frames were age ≥ 75 years (OR 2.08, 95%CI 1.21 to 3.58, P = 0.007), diabetes (OR 1.37, 95%CI 1.01 to 1.86, P = 0.042), Killip class ≥ 2 (OR 1.52, 95%CI 1.05 to 2.21, P = 0.027), and prolonged pain-to-balloon time (OR 1.73, 95%CI 1.07 to 2.79, P = 0.013). TMPFC > 130 frames was identified as the strongest independent predictor of 30-day major adverse cardiac event (MACE) (OR 2.77, 95%CI 1.21 to 6.31, P = 0.008), along with age ≥ 75 years (OR 2.19, 95%CI 1.11 to 4.33, P = 0.016), female gender (OR 1.67, 95%CI 1.03 to 2.70, P = 0.038), and Killip class ≥ 2 (OR 1.83, 95%CI 1.07 to 3.14, P = 0.021). CONCLUSIONS: STEMI patients with poor myocardial perfusion assessed by TMPFC had higher risk factor profiles. Advanced age, diabetes, higher Killip class, and longer ischemia time were independent predictors of impaired TMPFC after primary percutaneous coronary intervention. These results emphasize that particular attention should be paid on myocardial microvascular reperfusion in STEMI patients with these risk factors.

Vardenafil in pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled study.

RATIONALE: Although the phosphodiesterase type 5 inhibitors sildenafil and tadalafil have demonstrated efficacy in patients with pulmonary arterial hypertension (PAH), monotherapy with these agents has not been conclusively shown to reduce clinical worsening events. OBJECTIVES: To evaluate the safety and efficacy of the phosphodiesterase type 5 inhibitor vardenafil in Chinese patients with PAH. METHODS: In a randomized, double-blind, placebo-controlled study, 66 patients with PAH were randomized 2:1 to vardenafil (5 mg once daily for 4 wk then 5 mg twice daily; n = 44) or placebo (n = 22) for 12 weeks. Patients completing this phase were then treated with open-label vardenafil (5 mg twice daily) for a further 12 weeks. MEASUREMENTS AND MAIN RESULTS: At Week 12, the mean placebo-corrected 6-minute walking distance was increased with vardenafil (69 m; P < 0.001), and this improvement was maintained for at least 24 weeks. Vardenafil also increased the mean placebo-corrected cardiac index (0.39 L·min(-1)·m(-2); P = 0.005) and decreased mean pulmonary arterial pressure and pulmonary vascular resistance (-5.3 mm Hg, P = 0.047; -4.7 Wood U, P = 0.003; respectively) at Week 12. Four patients in the placebo group (20%) and one in the vardenafil group (2.3%) had clinical worsening events (hazard ratio 0.105; 95% confidence interval, 0.012-0.938; P = 0.044). Vardenafil was associated with only mild and transient adverse events. CONCLUSIONS: Vardenafil is effective and well tolerated in patients with PAH at a dose of 5 mg twice daily.

[Preliminary study on the efficacy and safety of oral sildenafil in pulmonary arterial hypertension in China].

OBJECTIVE: Sildenafil has been shown to be effective in pulmonary arterial hypertension (PAH). However, the impact of sildenafil on PAH has been under-investigated in China. The aim of the present study was to evaluate the efficacy and safety of oral sildenafil in PAH patients in China. METHODS: In this prospective, open-label and multi-center study, 90 patients were recruited from 14 centers to receive oral sildenafil (75 mg/d) for 12 weeks. They underwent a six-minute walk test (SMWT) and cardiac catheterization at the beginning and the end of 12 weeks. The primary endpoint was the changes in exercise capacity as assessed by SMWT. And the secondary endpoints included assessment of functional class, evaluation of cardiopulmonary hemodynamics and clinical deterioration (defined as death, transplantation and re-hospitalization for PAH). Drug safety and tolerability were also examined. RESULTS: There were 19 males and 71 females with an average age of 32.5 ± 12.1 years old (range: 18 - 61). Their etiologies were idiopathic (n = 15), related with congenital heart disease (n = 60), or related with connective tissue disease (n = 9) and chronic thromboembolic pulmonary hypertension (n = 6). Oral sildenafil significantly increased the SMWT distances [(342 ± 93) m vs. (403 ± 88) m, P < 0.001]. There was also remarkable improvement in Borg dyspnea score (2.9 ± 2.6 vs. 2.4 ± 2.0, P = 0.005). Furthermore, significant improvements in World Healthy Organization (WHO) functional class and cardiopulmonary hemodynamics were also found (mean pulmonary artery pressure, P < 0.001; cardiac index, P < 0.001; pulmonary vascular resistance, P < 0.001). Side effects were mild and consistent with other reports. CONCLUSION: This study confirms and extends previous studies. Oral sildenafil is both safe and effective for the treatment of adult PAH patients in China.

Efficacy, safety and tolerability of bosentan in Chinese patients with pulmonary arterial hypertension.

BACKGROUND: Bosentan has an established role in the management of pulmonary arterial hypertension (PAH). This clinical trial assessed the benefits of bosentan in the Chinese population. METHODS: We investigated the efficacy and safety of bosentan in 92 Chinese citizens (mean +/- standard deviation age, 29.0 +/- 3.8 years) with PAH for a minimum of 12 weeks. All received bosentan (62.5 mg twice daily) for 4 weeks; then, patients who weighed <40 kg received 62.5 mg bosentan twice daily and patients who weighed >40 kg received 125 mg twice daily. All patients were eligible to continue bosentan beyond 12 weeks. The primary end point was a change in exercise capacity from baseline to 12 and 24 weeks. Secondary end points included a change in World Health Organization (WHO) functional class and changes in cardiopulmonary hemodynamics. RESULTS: At baseline, 66 patients (72%) were in WHO functional class III; presentation was 37 (40%) with idiopathic PAH (iPAH), 34 (37%) with PAH related to congenital heart disease (CHD), and 21 (23%) with PAH related to connective tissue disease (CTD). Exercise capacity increased to 67.8 m after 12 weeks and 92.6 m after 24 weeks (p < 0.001). After 24 weeks, WHO functional class decreased (-0.8 +/- 0.6; p < 0.001), mean pulmonary artery pressure and pulmonary vascular resistance decreased (p < 0.01), and cardiac output increased (p < 0.001). Twelve patients (13%) experienced at least 1 adverse event. CONCLUSIONS: Bosentan improved exercise capacity, functional class, and cardiopulmonary hemodynamics in this patient cohort and was well tolerated.

TIMI myocardial perfusion frame count: a new method to assess myocardial perfusion and its predictive value for short-term prognosis.

OBJECTIVES: We sought to develop a new quantitative method to evaluate the degree of myocardial perfusion. BACKGROUND: Currently available methods for assessing myocardial perfusion, both TIMI myocardial perfusion grading (TMPG) and myocardial blush grading (MBG), are subjective. METHODS: TIMI Myocardial Perfusion Frame Count (TMPFC), an objective method that measures the filling and clearance of contrast in the myocardium using cine-angiographic frame-counting, was developed to quantify myocardial perfusion. Myocardial perfusion of 45 normal coronary arteries in 15 patients, and 137 culprit arteries in 137 patients immediately after primary angioplasty, was successfully assessed with TMPFC. RESULTS: The mean TMPFC in the normal arteries was 83.47 +/- 17.96 frames (95% CI: 78.07 frames

[Prognostic value of plasma brain natriuretic peptide and C-reactive protein in patients with acute coronary syndromes underwent percutaneous coronary intervention].

OBJECTIVE: To evaluate the prognostic value of plasma brain natriuretic peptide (BNP) and C-reactive protein (CRP) in patients with acute coronary syndromes (ACS) underwent percutaneous coronary intervention (PCI). METHODS: Patients with ACS underwent PCI in our hospital from December 2004 to September 2005 were included in this study. Plasma BNP (n = 189) and CRP (n = 141) were measured at a median of (34.2 +/- 16.3) hours from symptom onset, total mortality and the risk for major adverse cardiac events (MACE, including death, recurrent MI, recurrent angina, heart failure, readmission for any reason) at 30 days and at 3 months was analyzed. RESULTS: Patients were divided into 4 groups according to their BNP levels (BNP 100 ng/L to 300 ng/L to 600 ng/L) and the 3-month mortality was 0%, 1.4%, 7.7%, 48.3% and 3-month incidence of MACE was 7.9%, 17.1%, 57.7%, 79.3% respectively. Multivariate logistic regression analyses showed that the plasma BNP level predicted 30-day (r = 0.8515, P < 0.01) and 3-month (r = 0.9201, P < 0.01) mortality and 30-day (r = 0.7066, P < 0.01) and 3-month (r = 0.7090, P < 0.01) incidence of MACE independent of other known prognostic factors such as age, gender, family heredity, hypercholesterolemia diabetes, hypertension, smoking and LVEF. Patients were divided into 3 groups according to their CRP levels (CRP 8.0 mg/L to 32.0 mg/L) and 3-month mortality was 2.7%, 7.7% and 28.6% and 3-month incidence of MACE was 28.4%, 41.0% and 60.7% respectively. CRP predicted 30-day (r = 0.5882, P = 0.0044) and 3-month (r = 0.5235, P = 0.0038) mortality independent of traditional risk factors, and predicted 30-day (r = 0.2705, P = 0.0380) and 3-month (r = 0.2290, P = 0.0429) incidence of MACE after adjustment for patient age. CRP lost its predictive value after BNP was introduced into the model, while BNP was still an independent predictor for mortality and incidence of MACE at 30 days and 3 months in ACS patients underwent PCI. CONCLUSION: Both plasma BNP and CRP are good predictors for early mortality and MACE incidence in ACS patients underwent PCI.