Shi-Jiang Zhang

Adiponectin protects rat myocardium against chronic intermittent hypoxia-induced injury via inhibition of endoplasmic reticulum stress.

Obstructive sleep apnea syndrome (OSAS) is associated with many cardiovascular disorders such as heart failure, hypertension, atherosclerosis, and arrhythmia and so on. Of the many associated factors, chronic intermittent hypoxia (CIH) in particular is the primary player in OSAS. To assess the effects of CIH on cardiac function secondary to OSAS, we established a model to study the effects of CIH on Wistar rats. Specifically, we examined the possible underlying cellular mechanisms of hypoxic tissue damage and the possible protective role of adiponectin against hypoxic insults. In the first treatment group, rats were exposed to CIH conditions (nadir O2, 5–6%) for 8 hours/day, for 5 weeks. Subsequent CIH-induced cardiac dysfunction was measured by echocardiograph. Compared with the normal control (NC) group, rats in the CIH-exposed group experienced elevated levels of left ventricular end-systolic dimension and left ventricular end-systolic volume and depressed levels of left ventricular ejection fraction and left ventricular fractional shortening (p<0.05). However, when adiponectin (Ad) was added in CIH + Ad group, we saw a rescue in the elevations of the aforementioned left ventricular function (p<0.05). To assess critical cardiac injury, we detected myocardial apoptosis by Terminal deoxynucleotidyl transfer-mediated dUTP nick end-labeling (TUNEL) analysis. It was showed that the apoptosis percentage in CIH group (2.948%) was significantly higher than that in NC group (0.4167%) and CIH + Ad group (1.219%) (p<0.05). Protein expressions of cleaved caspase-3, cleaved caspase-9, and cleaved-caspase-12 validated our TUNEL results (p<0.05). Mechanistically, our results demonstrated that the proteins expressed with endoplasmic reticulum stress and the expression of reactive oxygen species (ROS) were significantly elevated under CIH conditions, whereas Ad supplementation partially decreased them. Overall, our results suggested that Ad augmentation could improve CIH-induced left ventricular dysfunction and associated myocardial apoptosis by inhibition of ROS-dependent ER stress.

Iptakalim inhibited endothelin-1-induced proliferation of human pulmonary arterial smooth muscle cells through the activation of KATP channel

To determine whether iptakalim inhibited endothelin-1(ET-1)-induced proliferation of human pulmonary arterial smooth muscle cells (PASMCs) through the activation of ATP-sensitive potassium (K(ATP)) channel, the effect of iptakalim on the ET-1-induced proliferation of human PASMCs was examined by [3H]thymidine incorporation, staining with propidium iodide and flow cytometry analyses, measurement of cytosolic free Ca2+ concentration ([Ca2+]cyt) and Western blot for the phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in vitro. The results showed that iptakalim inhibited the ET-1-induced proliferation of human PASMCs, including [3H]thymidine incorporation and the transition of cell cycle phase, and blocked the ET-1-induced transient raise of [Ca2+]cyt, and the ET-1-induced phosphorylation of ERK1/2 in the human PASMCs. Iptakalim exerted a similar role as pinacidil did in human PASMCs and both inhibited the [3H] thymidine incorporation and the transition of cell cycle phase induced by ET-1 in the human PASMCs. Furthermore, we found that the inhibition of iptakalim and pinacidil on the ET-1-induced proliferation of human PASMCs was blocked by glyburide, a selective K(ATP) channel antagonist. These findings provide a strong evidence to support that iptakalim acts as a specific K(ATP) channel opener to antagonize the proliferating effect of ET-1 in the human PASMCs. This study provides further evidence that iptakalim may serve as another candidate drug to treat pulmonary hypertension.

Prevalence and risk factors of sleep disordered breathing in patients with rheumatic valvular heart disease.

STUDY OBJECTIVES Sleep disordered breathing (SDB) is common in patients with chronic heart failure secondary to non-valvular heart disease; however, the prevalence and characteristics of SDB in patients with rheumatic valvular heart disease (RVHD) are unclear. This study was designed to determine the prevalence, characteristics, and risk factors for SDB in RVHD patients. METHODS A cross-sectional study was conducted in 260 RVHD patients. The following data were recorded: types of heart valve lesions, electrocardiographic, echocardiographic, arterial blood gas analysis findings, baseline medication, 6-minute walk test (6MWT) distance, and sleep parameters. RESULTS Compared to patients with single leftsided valve lesions, patients with left- and rightsided valve lesions had a higher prevalence of SDB (46.2% vs. 31.2%, p = 0.013); the increased prevalence of SDB only involved central sleep apnea (CSA) (31.1% vs. 14.1%, p = 0.001). Patients with obstructive sleep apnea (OSA) or CSA were older and had a shorter 6MWT distance, lower left ventricle ejection fraction and PaO₂, a longer lung-to-finger circulation time, and a higher prevalence of atrial fibrillation (AF) and hypertension (all p < 0.05) as compared with patients without SDB. Multinomial logistic regression analysis showed that PaO2 ≤ 85 mm Hg was the only risk factor for OSA. Male gender, AF, 6MWT distance ≤ 300 m, PaO₂ ≤ 85 mmHg, and PaCO₂ ≤ 40 mm Hg were risk factors for CSA. CONCLUSIONS Patients with RVHD had a high prevalence of SDB (predominantly CSA). RVHD patients with SDB, particularly those who had CSA, manifested more severe symptoms and greater impairment of cardiac function. Assessments of clinical manifestations of cardiac dysfunction may be important for predicting the risk factors for SDB.

Safety and feasibility of chronic transvenous phrenic nerve stimulation for treatment of central sleep apnea in heart failure patients.

Central sleep apnea (CSA) is common in patients with heart failure (HF) and is associated with poor quality of life and prognosis. Early acute studies using transvenous phrenic nerve stimulation (PNS) to treat CSA in HF have shown a significantly reduction of CSA and improvement of key polysomnographic parameters. In this study, we evaluated the safety of and efficiency chronic transvenous PNS with an implanted neurostimulator in HF patients with CSA.

Idiopathic isolated fibrotic atrial cardiomyopathy underlies unexplained scar-related atrial tachycardia in younger patients

Aims Unexplained scar-related atrial tachycardia (AT) has been frequently encountered in clinical practice. We hypothesized that idiopathic, isolated fibrotic atrial cardiomyopathy (ACM) underlies this rhythm disorder. This study was aimed to characterize the underlying substrate and to explore the aetiology of this unexplained scar-related AT. Methods and results Twenty-six (11 men, aged 46 ± 13 years) of 52 non-surgical scar-related AT patients identified by three-dimensional voltage mapping were enrolled in this prospective observational study. Multimodality image examinations (echocardiography, cardiac magnetic resonance, 99Tc single-photon emission computed tomography), ventricular voltage mapping, and intracardiac pressure curve recording ruled out ventricular involvement. Catheter ablation was acutely successful for all the patients, and pacemaker implantation was performed in seven patients who presented sinus node dysfunction or atrial standstill after termination of the AT. In three patients with multiple AT recurrences, the diseased areas of the right atrium were resected and dechannelled via mini-invasive surgical interventions. Histological examinations revealed profound fibrosis without amyloidosis or adipose deposition. Viral and familial investigations yielded negative results. Fibrosis progression over a median of 45 (5-109) months of follow-up manifested as atrial arrhythmia recurrence in seven patients and atrial lead non-capture due to newly developed atrial standstill in two patients. Two patients suffered four ischaemic stroke events before receiving anticoagulation treatment. Conclusion Isolated, fibrotic ACM may underlie the idiopathic scar-related ATs. This novel cardiomyopathy has unique clinical characteristics with high morbidity including stroke and warrants specific therapeutic strategies. Further investigations are required to determine the aetiology and mechanism.

Overnight fluid shifts in subjects with and without obstructive sleep apnea

OBJECTIVE To investigate the characteristics of baseline body fluid content and overnight fluid shifts between non-obstructive sleep apnea (non-OSA) and obstructive sleep apnea (OSA) subjects. METHODS A case-controlled study was performed between February 2013 and January 2014, with 36 (18 OSA and 18 non-OSA) outpatients enrolled in this study. Polysomnographic parameters and results of body fluid were compared between the two groups. RESULTS There were no differences in age, weight, and body mass index (BMI) between groups. Compared with the non-OSA group, OSA group had significantly higher neck circumference (NC) and fluid volume shift in the legs. OSA patients had higher left and right leg fluid indices than non-OSA subjects. There were significant correlations between apnoea-hypopnoea index and baseline fluid indices in both legs as well as the reduction in overnight change in both legs fluid volume. The increase in NC was also significantly correlated with the reduction in overnight change in both legs fluid volume, but not with the change in head and neck fluid volume. There were significant correlations between change in NC and increased fluid shifts in head and neck volume. CONCLUSIONS OSA patients had a higher baseline fluid content in both legs as compared with non-OSA subjects, which may be the basic factor with regards to fluid shifts in OSA patients. The increase in head and neck fluid shift volume did not directly correlate with the severity of OSA.

A Rare Life-threatening Kodamaea ohmeri Endocarditis Associated With Hemophagocytic Lymphohistiocytosis

We report the case of a 57-year-old man with a 3-month history of intermittent pyrexia. He received irregular antibacterial therapy and thrombolysis in a local hospital due to occlusion of the right distal popliteal artery. His medical history included multiple fractures, allergic purpura, and hypertension. His medications included prednisone (30 mg orally per day), metoprolol, and amlodipine. On physical examination, breath sounds were clear and a 3/6 pansystolic murmur was auscultated at the right sternal border. Swelling of the right leg and gangrene at the fifth toe were found. Abdominal palpation revealed mild splenomegaly. The following abnormal laboratory results were identified: white cell count, 3.20 10/L; platelet count, 30 10/L; hemoglobin, 8.80 g/dL; albumin, 2.99 g/dL; erythrocyte sedimentation rate, 42 mm/h; C-reactive protein, 13.30 mg/L; and ferritin, 674 mg/L. Three blood cultures were positive and a gram stain showed budding yeast cells. The isolate, after being subcultured on CHROMagar (Becton Dickinson, Paris, France), showed membranous colonies that changed color from pink to blue within 48 hours (Figure A). On corn meal agar (Becton Dickinson), pseudohyphae and blastoconidia were seen 24 hours later (Figure B). The yeasts were identified as Kodamaea ohmeri (K. ohmeri). Drug sensitivity testing showed that this strain was susceptible to voriconazole, fluconazole, itraconazole, and amphotericin B. Bone marrow aspiration, performed due to the cytopenia, showed phagocytosis of hematopoietic cells by activated macrophages (Figure C). Thoracoabdominal computed tomography revealed splenomegaly and mild bilateral pleural effusion. Transthoracic echocardiography showed a large vegetation (30 mm 12 mm) on the aortic valve with mild regurgitation and stenosis. On hospital day 5, the patient developed persistent pyrexia with a temperature of 39 8C despite antifungal therapy with intravenous voriconazole. Urgent surgery was performed and a large fragile and loose vegetation was found on the aortic valve that almost

Sex-dependent aortic valve pathology in patients with rheumatic heart disease

Background Rheumatic heart disease is an autoimmune disease caused by group A streptococci infection and frequently affects the aortic valve. Sex differences are common in the disease progression, treatment, and outcome. However, little is known about the sex differences in the pathology of aortic valves in rheumatic heart disease. Design We studied the end-stage calcific aortic valves from male versus female patients to reveal the sex-dependent pathology differences and molecular changes associated with requiring valve replacement. Methods Aortic valves from 39 patients with rheumatic heart disease (19 males and 20 females) were collected at the time of aortic valve replacement for comparative pathology, immunohistochemistry, and gene expression analyses. Clinical characteristics were also analyzed and compared between the two groups. Results Aortic valves from female patients exhibited increased expression of collagens, infiltration of monocytes/macrophages and neovascularization. Aortic valves from female patients also had increased expression of inflammatory genes involved in the NFKB pathway (phosphorylated NFKB p65 subunit, IL8, and NOS3) and Th1 cytokine genes (IFNA and IL12B). The severe valve pathology in female patients was correlated with a higher serum level of anti-streptolysin O antibodies. Conclusion Inflammation is more prominent in aortic valves of female patients with rheumatic heart disease. This sex difference may contribute to the severe valve pathology and worse outcome of female patients.

Elimination of central sleep apnea by cardiac valve replacement: a continuous follow-up study in patients with rheumatic valvular heart disease

BACKGROUND Recent studies have suggested that cardiac surgery may affect sleep-disordered breathing (SDB) in chronic heart failure patients. However, the dynamic changes in sleep apnea and heart function after cardiac surgery and the mechanisms responsible for these changes remain unknown. METHODS Patients with rheumatic valvular heart disease (RVHD) and SDB were enrolled and followed up at three, six and 12 months after cardiac valve replacement (CVR). Baseline and follow-up clinical data consisting of NYHA classification, 6min walk distance (6-MWD), medications, echocardiography, electrocardiography, chest X-ray, arterial blood gas, lung-to-finger circulation time (LFCT), and sleep data were collected and evaluated. RESULTS Twenty-four central sleep apnea (CSA) patients and 15 obstructive sleep apnea (OSA) patients completed three follow-up assessments. Comparison of the baseline parameters between OSA patients and CSA patients showed that CSA patients had a worse baseline cardiac function assessed by higher NYHA class, shorter 6-MWD, larger left atrial diameter, longer LFCT, and enhanced chemosensitivity (higher pH and lower arterial carbon dioxide tension (PaCO2)). A continuous significant elevation in 6-MWD and left ventricular ejection fraction and decrease in NYHA class, plasma BNP, and left atrial diameter were found in both CSA and OSA patients. When comparing CSA and OSA patients, the CSA indices were remarkably reduced at month 3 post CVR and sustained throughout the trial, whereas there were no significant decreases in OSA index and hypopnea index. pH values and LFCT were markedly decreased and PaCO2 markedly increased in patients with CSA at the end of the third months following CVR. These changes were sustained until the end of the trial. CONCLUSIONS CSA patients with RVHD had a worse baseline cardiac function, enhanced chemosensitivity and disordered hemodynamic as compared with OSA patients with RVHD. CSA were eliminated after CVR; however, there were no changes in OSA. The elimination of CSA, post CVR, is associated with the combined efficacies of improvement of cardiac function, normalized chemosensitivity, and stabilized hemodynamic.

A Unique Life-Threatening Mediastinal Liposarcoma Mimicking Pleural Effusion

A 38-year-old woman with schizophrenia reported progressive dyspnea. Arterial blood gases showed type 2 respiratory failure. Her chest X-ray suggested a complete right pleural effusion (Figure 1A). Enhanced chest computed tomography revealed a unique giant encapsulated mass with adipose tissue (Figure 1B, arch arrow) and atelectasis (asterisk), indicative of liposarcoma or teratoma. A diagnosis of well-differentiated and myxoid mediastinal liposarcoma was confirmed following thoracotomy (Figures E1 and E2 in the online supplement). The presence of a mutation within PIK3CA is associated with a shortened survival (1). Strikingly, sequencing of PIK3CA identified three novel point mutations (Figure 2, upper panel ) and a frameshift mutation (lower panel) at exon 10. Kinome profiling of myxoid liposarcoma demonstrates nuclear factor-kB and Src to be the two most active pathways (2, 3). Combining technologies will allow for efficient clinical translation (4). Intrathoracic liposarcoma, although extremely rare, should be included in the differential diagnosis of pleural effusion.