Jielin Pu

Iloprost for pulmonary vasodilator testing in idiopathic pulmonary arterial hypertension

The aim of this study was to confirm the utility of aerosolised iloprost for identifying long-term responders to calcium channel blockers (CCBs) in patients with idiopathic pulmonary arterial hypertension (IPAH). While undergoing right heart catheterisation, 74 patients with IPAH sequentially received incremental infusions of adenosine and aerosolised iloprost. The effects of the two vasodilators on haemodynamic parameters were recorded. All acute responders identified by aerosolised iloprost were subsequently treated with high doses of a CCB and were re-evaluated after 12 months. Both adenosine and iloprost produced significant decreases in mean pulmonary arterial pressure and pulmonary vascular resistance, and significant increases in cardiac index. Adverse effects were experienced by 35 out of the 74 patients with adenosine, but by only two with iloprost. Aerosolised iloprost identified more acute responders than infused adenosine (10 versus eight, respectively) according to the criteria recommended in recent consensus guidelines. Nine responders identified by iloprost were followed-up after 12 months of high-dose CCB therapy. Five had normal or near-normal haemodynamics and a World Health Organization functional classification of I or II after 12 months. Aerosolised iloprost is an appropriate new agent to identify long-term responders to CCBs in patients with IPAH. It is as effective in this regard as infused adenosine but is better tolerated.

Vardenafil treatment for patients with pulmonary arterial hypertension: a multicentre, open-label study

Background: Vardenafil is a new phosphodiesterase-5 inhibitor that has shown some efficacy in the treatment of pulmonary arterial hypertension (PAH). Objective: To examine the long-term effects of vardenafil in patients with PAH. Methods: A multicentre, open-label study of 1-year’s duration was undertaken in 45 patients with PAH to determine the long-term safety and efficacy of vardenafil (5 mg once daily for the first 4 weeks, then 5 mg twice daily) and make a preliminary assessment of its monthly acquisition cost compared with other PAH-active treatments. The patients’ clinical features, exercise capacity, WHO functional class and haemodynamic variables were measured at baseline and at 3 and at least 9 months after initiating vardenafil treatment. Results: At the 3 months and a mean (SD) of 14 (3) months (range 9–18) follow-up assessments, the 6 min walking distance was significantly increased from baseline by 70.7 (78.4) m (p<0.001) and 83.4 (91.8) m (p<0.001), respectively. Furthermore, long-term treatment with vardenafil for a mean duration of >1 year was also associated with improvements in haemodynamic parameters, WHO functional class and serum uric acid concentrations. Overall, vardenafil treatment was well tolerated. No patients were withdrawn owing to adverse events and none died during the course of the study. Conclusion: Long-term treatment with vardenafil is well tolerated and has sustained beneficial effects on PAH, as measured by patients’ exercise capacity, WHO functional class and haemodynamic parameters.

The J wave and fragmented QRS complexes in inferior leads associated with sudden cardiac death in patients with chronic heart failure

AIMS To investigate the relationship between electrocardiogram (ECG) parameters [J wave, fragmented QRS (fQRS), QTc, the peak-to-end interval of T wave (Tp-Te)], and sudden cardiac death (SCD) in chronic heart failure (CHF). METHODS AND RESULTS The ECGs of 1570 CHF patients, 572 cases with dilated cardiomyopathy (DCM) and 998 cases with ischaemic cardiomyopathy (ICM) were analysed with the endpoint being an SCD or non-SCD (NSCD). During a median follow-up period of 36 months (0.40-65 months), 438 (27.89%) patients died, of which 158 (35.84%) were SCD. Overall, the occurrence of J wave, fQRS, and long Tp-Te were greater in SCD patients than that of NSCD patients (all P< 0.01). For DCM cases, more SCD patients had J waves observed in the inferior leads than that in the NSCD group (26.78 vs. 13.07%, P<0.001). However, ICM cases with SCD did have more fQRS in the inferior leads than that with NSCD (42.16 vs. 26.67%, P= 0.01). After adjusting for other risk factors, Cox regression analysis revealed that presence of J wave or fQRS in the inferior leads predicted a higher risk for SCD in DCM [hazard ratio (HR), 4.095; 95% confidence interval (CI), 2.132-7.863] and ICM (HR, 2.714; 95% CI, 1.809-4.072) patients. A left ventricular ejection fraction ≤ 30% also predicted SCD and NSCD in DCM and ICM patients. In contrast, the predictive value of QTc and Tp-Te for SCD was not significant. CONCLUSIONS Presence of J wave or fQRS in the inferior leads predicted higher risk of SCD in DCM and ICM patients and might serve as independent predictors for SCD in patients with CHF.

Pulmonary function testing in patients with pulmonary arterial hypertension

BACKGROUND Although previous studies have shown that peripheral airway obstruction can occur in idiopathic PAH (IPAH), pulmonary function tests have not been well-studied in patients with PAH associated with congenital heart disease (CHD-PAH) and connective tissue disease (CTD-PAH). METHODS A multicenter prospective study was performed in PAH patients in China. Pulmonary function tests were evaluated in 190 PAH patients. RESULTS Total lung capacity (TLC), residual volume (RV) and total airway resistance (Rtot) were similar in PAH patients and controls. However, measures of airflow, including vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in 1s (FEV(1)), FEV(1)/FVC and MEF(50) were decreased in PAH group. Single-breath diffusion capacity for carbon monoxide (DL(CO)) was also decreased in PAH patients. Expiratory flow-volume curves showed reduction and a curvilinear appearance in patients with PAH. Similar changes were observed among the various subgroups of IPAH, CHD-PAH, and CTD-PAH patients. More CTD-PAH patients had abnormal DL(CO). CONCLUSIONS Airway obstruction is common in IPAH, CHD-PAH and CTD-PAH patients. CTD-PAH patients have lower DL(CO). Hemodynamics, serum markers and exercise capacity parameters did not correlate well with pulmonary function indices.

The predictive values of beta1-adrenergic and M2 muscarinic receptor autoantibodies for sudden cardiac death in patients with chronic heart failure

Clinical and animal studies suggest that beta1‐adrenergic and M2 muscarinic receptor autoantibodies (beta1‐AAbs and M2‐AAbs) play important roles in the pathophysiological process of chronic heart failure (CHF). Removal of these autoantibodies improved haemodynamic parameters and left ventricular ejection fraction patients with CHF. The goal of this project is to evaluate whether beta1‐AAbs and M2‐AAbs predict prognosis and sudden cardiac death (SCD) in CHF.

Potential diagnostic biomarkers in serum of idiopathic pulmonary arterial hypertension

BACKGROUND The pathogenesis of idiopathic pulmonary arterial hypertension (IPAH) is unknown, and the syndrome of IPAH remains a diagnostic and therapeutic challenge. The present study investigated the disease-specific proteins that aid in the diagnosis of IPAH and thus to study their role in the disease process. METHODS A comparative proteomic analysis was used for clinical screening of serum proteins in 10 patients with IPAH and compared with 10 normal subjects. Furthermore, enzyme linked immunosorbent assay (ELISA) was performed for comparison with serum proteins between individual IPAH patients and controls. RESULTS Nine proteins and their isoforms, including leucine-rich alpha-2-glycoprotein (LRG), haptoglobin precursor, albumin isoform 2, transferrin variant, C3 complement, hydroxypyruvate reductase isoform 1, RAF1, fibrinogen isoformgamma-A and fibrinogen isoformgamma-B showed significant changes in serum of IPAH patients compared with controls by proteomic analysis. And significant higher serum levels of LRG in IPAH patients compared with controls were found by ELISA. Correlation analysis disclosed a significant association between serum LRG concentrations and New York Heart Association (NYHA) functional class (r=0.71, P<0.01) and cardiac output (CO) (r=-0.65, P<0.01). CONCLUSIONS These results indicate that there are significant differences in the expression of proteins in the serum of patients with IPAH and normal subjects. And the measurement of LRG, RAF1 and C3 complement levels in the serum may be helpful for the diagnosis of IPAH. In particular, LRG may be a specific prognostical biomarker of IPAH.

Common RyR2 variants associate with ventricular arrhythmias and sudden cardiac death in chronic heart failure

Ca2+ cycling plays a critical role in heart failure and lethal arrhythmias. As susceptibility to sudden cardiac death is considered to be a heritable trait in general population, we have therefore investigated whether potentially functional variants of genes encoding RyR2 (ryanodine receptor 2) and the L-type Ca2+ channel are related to the risk of ventricular arrhythmias and sudden cardiac death in CHF (chronic heart failure) in a case-control study. We found that the A allele of rs3766871 in RYR2 was associated with an increased risk of ventricular arrhythmias in patients with CHF {odds ratio, 1.66 [95% CI (confidence interval), 1.21-2.26]; P=0.002}. During a median follow-up period of 32 months in 1058 (85.0%) patients, 296 (28.0%) patients died from heart failure, of whom 141 (47.6%) had sudden cardiac death. After adjustment for age, gender and suspected risk factors, patients carrying the A allele of rs3766871 had an increased risk of cardiac death {HR (hazard ratio), 1.53 [95% CI, 1.11-2.12]; P=0.010} and sudden cardiac death [HR, 1.92 (95% CI, 1.25-2.94); P=0.003]. Patients carrying the A allele of rs790896 in RYR2 had a reduced risk of sudden cardiac death [HR, 0.65 (95% CI, 0.45-0.92); P=0.015]. In conclusion, the A allele of rs3766871 in RYR2 not only associates with ventricular arrhythmias, but also serves as an independent predictor of sudden cardiac death, and the A allele of rs790896 in RYR2 is a protective factor against sudden cardiac death in patients with CHF.

Comparison of read-through effects of aminoglycosides and PTC124 on rescuing nonsense mutations of HERG gene associated with long QT syndrome.

Aminoglycosides promote the readthrough of premature stop codons introduced by nonsense mutations to produce full-length proteins in genetic disease models. The read-through effects of different aminoglycosides and PTC124 on HERG gene have yet to be adequately elucidated. The wild-type (WT) or mutant genes were transiently transfected in HEK293 cells. The read-through effect was examined by adding drugs into culture medium for 24 h. Western blot analysis and patch clamping were performed to evaluate the expression and function of the genes. The mRNA levels were determined using qPCR. The results showed that G418 and PTC124 significantly increased the protein expression of R1014X mutant in a dose-dependent manner and produced a full-length protein. The maximal protein levels after G418, gentamicin or PTC124 treatment were 39.1±2.4, 18.6±0.3 or 10.3±1.0%, respectively, of the WT level. Tobramycin did not exhibit a read-through effect. The mRNA levels, however, did not differ between WT and mutant gene. The tail current densities of R1014X channels at 40 mV were 22.57±2.26 pA/pF for G418, 16.21±1.49 pA/pF for gentamicin and 9.62±0.73 pA/pF for PTC124. The leftward shift of the activation curve was corrected only by G418 and gentamicin. The read-through effects of W927X, R863X and E698X revealed that as the mutation site approached the N-terminal, the rescue efficiency was decreased. The above results suggest that aminoglycosides and PTC124 induced different effects on rescue nonsense mutations of the HERG gene. The mutation site was a significant factor in determining the pharmacological rescue efficiency.

The efficacy and safety of sildenafil in Chinese patients with pulmonary arterial hypertension.

Sildenafil has been suggested to be a cost-effective treatment for pulmonary arterial hypertension (PAH). On account of the lack of data confirming its benefit in PAH patients, sildenafil has not been adopted in China for the treatment of PAH. The purpose of this study was to evaluate the efficacy, safety and 1-year survival of Chinese patients with PAH treated with sildenafil. Sixty Chinese patients with PAH were enrolled in this preliminary study. Their 6-min walk distance, WHO functional class and hemodynamic parameters (such as right atrial pressure, pulmonary arterial pressure, cardiac index and pulmonary vascular resistance) at both baseline and 16 weeks after initiation of sildenafil treatment were recorded. In addition, 1-year overall survival was assessed in this cohort. The 6-min walk distance improved from 392.13±91.35 to 467.22±80.38 m during the course of treatment (P<0.001). There was a significant decrease in the mean pulmonary vascular resistance (15.28±8.12–14.99±7.88 Woods units; P=0.02) and a significant increase in the mean cardiac index (2.39±0.90–2.75±0.92 l/min/m2, P=0.006) of the included patients at 16 weeks. The mean systemic oxygen saturation improved significantly at 16 weeks (91.44±7.54%–94.11±4.28%; P=0.002). No serious adverse reactions were reported. The Kaplan–Meier analysis showed that the 1-year survival rate improved significantly in the sildenafil-treated cohort compared with predicted survival (94.7% compared with 63.3%, P=0.03). In conclusion, sildenafil may be a safe and effective treatment for Chinese PAH patients. Sildenafil, when added to conventional therapy, was associated with improvements in exercise capacity, hemodynamic parameters and overall survival in a cohort of Chinese patients with PAH.

Changing Profile of Infective Endocarditis: A Clinicopathologic Study of 220 Patients in a Single Medical Center from 1998 through 2009

The epidemiologic profile of infective endocarditis has changed substantially over the past few years, especially in industrialized countries. Our study evaluates the clinical and pathologic characteristics of infective endocarditis patients treated by cardiac surgery in China during a 12-year period. We retrospectively evaluated 220 surgically treated infective endocarditis patients and analyzed their changes from the beginning of 1998 through 2009. The mean age of the patients increased from 36.9 to 42.7 years during those 12 years (P=0.036). The chief predisposing disease was congenital heart disease (32.8%), rather than rheumatic heart disease (13.2%); this rate did not change significantly during the 12 years. The prevalent congenital lesion was bicuspid aortic valve, the rate of which (55.6%) increased significantly over the 3 time intervals studied (P=0.016). The frequency of infective endocarditis after non-dental surgical and nonsurgical intervention was significantly greater (23.3%) during 1998 through 2001, compared with the 2 intervals that followed (9%; P=0.019). Streptococcus viridans was the most frequent causative agent overall (25.6%). Forty-seven of the 220 patients (21.4%) carried the clinical diagnosis of some other form of heart disease before surgery, but at surgery they were found to have infective endocarditis as the fundamental disease process. Of 47 patients, 33 (70.2%) had either very small or no vegetations but had focal necrosis and inflammation of valve tissue that supported the diagnosis of infective endocarditis.