Retrospective on global pulmonary hypertension clinical trials: 1999-2021.

Background: Data are quite sparse on the comprehensive analyses of pulmonary hypertension (PH) clinical trials worldwide. Methods: Information including participating countries (developed or developing), intervention type, trial size, PH categories, sponsorship, study phase, design strategies, and participants' demographic characteristics was extracted from PH trials registered on ClinicalTrials.gov from 1999 to 2021. Results: A total of 203 eligible clinical PH trials were screened, involving 23,402 participants, 67.8% of whom were females. Major clinical trials were designed to test drug interventions (95.6%), sponsored solely by industries in 59.5%, and targeting Group 1 PH patients in 76.3%. A large number of countries participated in PH clinical trials; however, most clinical trials were conducted in developed countries (84.2%). Developing countries were involved in clinical trials with larger sample sizes (P<0.01). Additionally, the differences between developed and developing countries centered on interventions, sponsors, PH groups, and design strategies. Furthermore, developing countries participated in multinational clinical trials with good quality, homogeneity, reliability, and data authenticity. All pediatric participants were diagnosed with Group 1 PH and were only involved in drug intervention trials. Children participated in far fewer clinical trials than adults (P<0.01), and most were enrolled in PH clinical trials in developed countries. Among the entire clinical trial population, younger patients with Group 1 PH had a much higher participation to prevalence ratio (PPR). There was no difference in women's PPRs between developed and developing countries. However, developing countries had higher PPRs for PH Groups I and IV (1.28 vs. 1.22, P<0.01), while developed countries had a lower PPR for Group III (P=0.02). Conclusions: PH is attracting increasing global attention, which is not at the same level of progress in developed and developing countries. Women and children with this disease have unique characteristics and require more attention.

CTRP5-Overexpression Attenuated Ischemia-Reperfusion Associated Heart Injuries and Improved Infarction Induced Heart Failure.

Aims: C1q/tumor necrosis factor (TNF)-related protein 5 (CTRP5) belongs to the C1q/TNF-α related protein family and regulates glucose, lipid metabolism, and inflammation production. However, the roles of CTRP5 in ischemia/reperfusion (I/R) associated with cardiac injuries and heart failure (HF) needs to be elaborated. This study aimed to investigate the roles of CTRP5 in I/R associated cardiac injuries and heart failure. Materials and Methods: Adeno-associated virus serum type 9 （AAV9）vectors were established for CTRP5 overexpression in a mouse heart (AAV9-CTRP5 mouse). AAV9-CTRP5, AMPKα2 global knock out （AMPKα2-/-）and AAV9-CTRP5+ AMPKα2-/- mice were used to establish cardiac I/R or infarction associated HF models to investigate the roles and mechanisms of CTRP5 in vivo. Isolated neonatal rat cardiomyocytes (NRCMS) transfected with or without CTRP5 adenovirus were used to establish a hypoxia/reoxygenation (H/O) model to study the roles and mechanisms of CTRP5 in vitro. Key Findings: CTRP5 was up-regulated after MI but was quickly down-regulated. CTRP5 overexpression significantly decreased I/R induced IA/AAR and cardiomyocyte apoptosis, and attenuated infarction area, and improved cardiac functions. Mechanistically, CTRP5 overexpression markedly increased AMPKα2 and ACC phosphorylation and PGC1-α expression but inhibited mTORC1 phosphorylation. In in vitro experiments, CTRP5 overexpression could also enhance AMPKα2 and ACC phosphorylation and protect against H/O induced cardiomyocytes apoptosis. Finally, we showed that CTPR5 overexpression could not protect against I/R associated cardiac injuries and HF in AMPKα2-/- mice. Significance: CTRP5 overexpression protected against I/R induced mouse cardiac injuries and attenuated myocardial infarction induced cardiac dysfunction by activating the AMPKαsignaling pathway.

Hyperoside Suppresses Lipopolysaccharide-induced Inflammation and Apoptosis in Human Umbilical Vein Endothelial Cells.

Finding the novel drug from the effective components of traditional Chinese herbal medicine is a hotspot of the modern pharmacological research. Hyperoside (HYP) belongs to flavonoid glycosides, and it has various properties, such as anti-inflammation, anti-spasm, anti-diuretic, antitussive, lowering blood pressure, and lowering cholesterol effects as well as protective effects for the cardiac and cerebral blood vessels. The purpose of this study was to investigate the effects of HYP on inflammatory and apoptotic responses in vascular endothelial cells stimulated by lipopolysaccharide (LPS) and further to identify the possible mechanisms underlying these effects. In our study, human umbilical vein endothelial cells (HUVECs) were stimulated with 1 µg/mL LPS in the presence or absence of HYP (10, 20 and 50 µmol/L). Our results indicated that HYP alone exerted no cytotoxicity on HUVECs, while it had an up-regulatory effect on the viability of HUVECs induced by LPS in a dose-dependent manner; increased mRNA expression of IL-1ß, IL-6, TNFα and iNOS induced by LPS was attenuated after treatment with HYP both in a dose-and time-dependent manner; LPS-induced HUVECs apoptosis and cleaved-caspase 8, 9, 3 were all significantly reduced by HYP. Furthermore, the possible pathway involved in apoptosis and inflammation by HYP was detected, and the results showed that when treated with HYP, LPS-induced mitochondrial membrane instability was significantly inhibited through up-regulation of Bcl-2 and down-regulation of Bax. Furthermore, the expression of TLR4 and the phosphorylation of IκBα and p65 in LPS-treated cells were blocked by HYP. Our results suggested that HYP treatment prevented HUVECs from LPSinduced inflammation and apoptosis responses, which might be mediated by inhibiting TLR4/NFκB pathway.

Circulating obestatin levels correlate with fasting insulin and HOMA-IR but not with hypertension in elderly men.

Obestatin, encoded by the same gene as ghrelin, was first described as a physiological opponent of ghrelin. The association between circulating obestatin levels and blood pressure remains unclear. Furthermore, adequate information is non-existent regarding the older male population with hypertension. For this purpose, we enrolled 185 unrelated hypertensive male patients aged ≥ 80 years (range 80-102 years). One hundred seventy nine age-matched healthy subjects served as controls. Plasma levels of obestatin and insulin were measured using commercial ELISA and RIA. HOMA-IR was calculated using standard method. We found that plasma obestatin levels correlated significantly with insulin levels (P = 0.034) and homeostasis model assessment index for insulin resistance (HOMA-IR: P = 0.028). However, plasma obestatin differed non-significantly between hypertensive (5.06 ± 0.68 ng/mL) and non-hypertensive (4.72 ± 0.82 ng/mL) individuals. Plasma obestatin levels were not associated with systolic (P = 0.818) or diastolic (P = 0.564) blood pressure, waist-to-hip ratio (WHR: P = 0.725), uric acid (P = 0.603), total cholesterol (TC: P = 0.589), low-density lipoprotein cholesterol (LDL-C: P = 0.057); high-density lipoprotein cholesterol (HDL-C: P = 0.432), triglyceride (TG: P = 0.418), and fasting blood glucose (FBG: P = 0.101). We, therefore, concluded that fasting circulating obestatin levels did not directly correlate with blood pressure in men aged ≥ 80 years.

Reciprocal relationship between plasma ghrelin level and arterial stiffness in hypertensive subjects.

Arterial stiffness, considered an independent predictor of cardiovascular morbidity and mortality, is closely associated with hypertension. Futhermore, the role of ghrelin in the development of hypertension has been widely recognized. The purpose of the present study was to explore the potential relationship between circulating ghrelin and arterial stiffness in hypertensive subjects. A total of 192 patients with primary hypertension and 107 normotensive (NT) control subjects were enrolled in the present cross-sectional study. Plasma ghrelin was determined by ELISA. Arterial stiffness was assessed by brachial-ankle pulse wave velocity (baPWV) and the augmentation index (AIx). Both baPWV and AIx values were markedly higher in the hypertensive compared with NT group (P < 0.01). In contrast, plasma ghrelin concentrations were significantly lower in hypertensive patients compared with NT subjects (P < 0.01). Plasma ghrelin concentrations were negatively correlated with age (odds ratio (OR) -1.836; P < 0.001), smoking (OR -1.347; P = 0.042), baPWV (OR -1.762; P < 0.001) and AIx (OR -1.516; P = 0.005), but positively associated with fasting plasma glucose (OR 1.293; P = 0.047) and HbA1c (OR 1.413; P = 0.025). The inverse correlation between circulating ghrelin and the extent of arterial stiffness suggests that ghrelin is an independent determinant of arterial stiffness, even after adjustment for confounding cardiovascular risk factors, and it actively participates in the pathophysiology of arterial stiffness in hypertensive subjects.

Clostridium difficile infection associated with antituberculous agents in a patient with tuberculous pericarditis.

Clostridium difficile can cause pseudomembranous colitis (PMC). Antimicrobial agent exposure is a risk factor for Clostridium difficile-associated disease, whereas the use of antituberculous (anti-TB) agents is not. We herein report a case of PMC-associated with antituberculous therapy. A 63-year-old woman with tuberculous pericarditis treated with anti-TB agents was admitted for abdominal pain and diarrhea. On colonoscopy, mucoid exudate and yellowish plaque lesions were observed. The anti-TB agents were discontinued, and the patient was treated with metronidazole and clostridium butyricum. Her symptoms were relieved and did not recur when the anti-TB agents were restarted. In this report, we review the literature and discuss the pathogenesis, clinical manifestations, diagnosis and treatment of this case.

[Effects of Ghrelin on hypertension and insulin resistance in fructose-fed rats].

OBJECTIVE: To explore the effects and mechanisms of Ghrelin on hypertension and insulin resistance in fructose-fed rats. METHODS: A total of 32 male Sprague-Dawley (SD) rats were randomized into control (A) and fructose-fed groups (B). Rats in group B were fed with 10% fructose solution for 4 weeks. Then the rats in group A were randomized into intraperitoneal saline (group GA1) or intraperitoneal 50 nmol/kg Ghrelin (group GA2) and those in group B into intraperitoneal saline (group GB1) or intraperitoneal 50 nmol/kg Ghrelin (group GB2) twice daily for 6 weeks. Caudal arterial pressure was measured weekly. Plasma blood glucose, insulin concentration and lipid profile were measured. And insulin resistance (IR) was calculated by the method of homeostasis model assessment (HOMA). Plasma level of 15-F2t-isoprostane was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Ghrelin caused a significant reduction of systolic pressure at Week 3 in group GB2 versus group GB1 (P < 0.05). Maximal effect appeared at Week 5 ((127 ± 5) vs (120 ± 6) mm Hg, P < 0.05, 1 mm Hg = 0.133 kPa), but blood pressure failed to reach normal value. Ghrelin also decreased plasma insulin concentration and HOMA-IR ((9.6 ± 2.6) vs (13.1 ± 3.6) µU/ml, P < 0.05;1.92 ± 0.12 vs 2.78 ± 0.14, P < 0.01). Plasma level of 15-F2t-isoprostane was lower in group GB2 than that in group GB1 ((75 ± 11) vs (102 ± 14) pg/ml, P < 0.01). CONCLUSION: Ghrelin may lower blood pressure, ameliorate insulin resistance and improve insulin sensitivity through inhibiting oxidative stress in fructose-induced rats.

[Effects of domestic rosuvastatin on coronary plaque in patients with mild-to-moderate coronary artery stenosis as evaluated by virtual histology-intravascular ultrasound].

OBJECTIVE: To evaluate the effects of domestic rosuvastatin tablets on coronary plaque in the patients with mild-to-moderate coronary artery stenosis through virtual histology-intravascular ultrasound (VH-IVUS). METHODS: Eighty-three patients with mild-to-moderate coronary artery stenosis of acute coronary syndrome (ACS) were enrolled and randomized into test group (domestic rosuvastatin, 10 mg/day, n = 42) or control group (CRESTOR, 10 mg/day, n = 41). The serum lipid levels, diameter stenosis (DS) on quantitative coronary angiography (QCA), MLA (minimal lumen area), plaque burden and component of target lesion on VH-IVUS were evaluated at baseline and at 6-month follow-up. RESULTS: After 6 months, the levels of total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and triglyceride (TG) significantly decreased while the high density lipoprotein cholesterol (HDL-C) level significantly increased in two groups(P < 0.05). VH-IVUS analysis showed that the proportion of necrotic core significantly decreased (domestic rosuvastatin: 14.8% ± 7.0% vs 22.6% ± 7.5%, P < 0.05, crestor: 14.9% ± 7.1% vs 23.1% ± 7.7%, P < 0.05) and the proportion of fibrous tissue significantly increased (domestic rosuvastatin: 51.5% ± 9.9% vs 44.5% ± 9.7%, P < 0.05, crestor: 51.4% ± 10.1% vs 44.3% ± 9.8%, P < 0.05) in two groups. There were no significant changes in DS, plaque burden, MLA or the proportion of dense calcium and fibro-fatty tissue of target lesion in two groups (P > 0.05). And no significant differences existed in serum lipid levels, DS, MLA, plaque burden and component between two group(P > 0.05). CONCLUSION: The 6-month treatment of rosuvastatin may stabilize the atherosclerosis plaque and prevent its progression in patients with mild-to-moderate coronary artery stenosis.

[Influences of recombinant adeno-associated virus-mediated Decorin gene transfection on cell cycle and apoptosis of SiHa cells].

BACKGROUND & OBJECTIVE: Decorin (DCN), a multi-efficiency factor, has many important functions, such as influencing fibril stability, and interacting with extracellular matrix molecules to influence cell adhesion. This study was to investigate influences of DCN on cell cycle and apoptosis of SiHa cells via recombinant adeno-associated virus-mediated DCN gene (rAAV.DCN) transfection. METHODS: Based on the cDNA sequence of DCN reported by GenBank, DCN segment with open reading frame was cloned into plasmid UF(1) (UF(1)-DCN) after DNA sequencing. rAAV.DCN, containing high titer of DCN, was produced by transfecting into 293 cells with calcium phosphate-DNA sedimentation method, and transfected into SiHa cells, rAAV.LacZ-infected cells and non-infected cells were used as controls. Expression of DCN was determined by Western blot. Cell cycle and apoptosis were analyzed by flow cytometry (FCM). RESULTS: High titer of rAAV .DCN was produced successfully. After transfected with rAAV.DCN, SiHa cells effectively expressed DCN. The percentage of G(1) phase in rAAV.DCN-transfected cells was significantly higher than that in control cells [(72.3+/-2.3)% vs. (59.5+/-2.5)%, P<0.05], while the percentages of S phase, and G(2) phase in rAAV.DCN-transfected cells were significantly lower than those in control cells [(11.9+/-1.9)% vs. (17.8+/-0.8)%, and (13.4+/-1.1)% vs. (21.5+/-0.9)%, P<0.05]. No change of apoptosis was detected in rAAV.DCN-transfected cells. CONCLUSION: Cell cycle of SiHa cells may be arrested by high expression of DCN.