Clinical features and survival in Takayasu's arteritis-associated pulmonary hypertension: a nationwide study.

AIMS: This study aimed to assess the clinical characteristics and long-term survival outcome in patients with Takayasu's arteritis-associated pulmonary hypertension (TA-PH). METHODS AND RESULTS: We conducted a nationally representative cohort study of TA-PH using data from the National Rare Diseases Registry System of China. Patients with pulmonary artery involvement who fulfilled the diagnostic criteria of Takayasu's arteritis and pulmonary hypertension were included. The primary outcome was the time from diagnosis of TA-PH to the occurrence of all-cause death. Between January 2007 and January 2019, a total of 140 patients were included, with a mean age of 41.4 years at diagnosis, and a female predominance (81%). Patients with TA-PH had severely haemodynamic and functional impairments at diagnosis. Significant improvements have been found in N-terminal pro-B-type natriuretic peptide (NT-proBNP) and haemodynamic profiles in patients with TA-PH receiving drugs approved for pulmonary arterial hypertension. The overall 1-, 3-, and 5-year survival rates in TA-PH were 94.0%, 83.2%, and 77.2%, respectively. Predictors associated with an increased risk of all-cause death were syncope [adjusted hazard ratio (HR) 5.38 (95% confidence interval 1.77-16.34), P = 0.003], NT-proBNP level [adjusted HR 1.04 (1.03-1.06), P < 0.001], and mean right atrial pressure [adjusted HR 1.07 (1.01-1.13), P = 0.015]. CONCLUSION: Patients with TA-PH were predominantly female and had severely compromised haemodynamics. More than 80% of patients in our cohort survived for at least 3 years. Medical treatment was based on investigators' personal opinions, and no clear risk-to-benefit ratio can be derived from the presented data.

[Effect of microRNA-133b on Myocardial Fibrosis].

Objective To investigate the effect of microRNA-133b(miR-133b)on cardiac fibrosis and its mechanism.Methods Human cardiac fibroblasts(CFs)were harvested.The proliferation of CFs was detected by CCK8 during the overexpression and knock-down of miR-133b.The expressions of connective tissue growth factor(CTGF),α-smooth muscle actin(α-SMA),collagen Ⅰ,and collagen Ⅲ were detected with qRT-PCR and Western blot analysis after miR-133b overexpression or downexpression.Target genes of miR-133b were predicted by bioinformatics software.Dual-luciferase activity assay were used to verify a target gene of miR-133b.Results qRT-PCR showed that the expression level of miR-133b in the miR-133b mimic group was significantly higher than that in the negative control group(t=26.219,P=0.000).The expression level of miR-133b in the miR-133b inhibitor group was significantly lower than that in the negative control group(t=6.738,P=0.003).After 21,45,69,93,and 117 hours of transfection,the proliferation ability of CFs significantly decreased in the miR-133b mimic group but significantly increased in the miR-133b group(all P<0.05,compared with the negative control group).After overexpression of miR-133b,the mRNA and protein levels of CTGF(t=9.213,P=0.001;t=8.195,P=0.001),α-SMA(t=6.511,P =0.003;t=4.434,P=0.011),collagenⅠ(t=3.172,P=0.034;t=4.053,P=0.015)and collagen Ⅲ(t=6.404,P=0.003;t=5.319,P=0.006)were significantly down-regulated.After the expression of miR-133b was knocked down,the mRNA and protein levels of CTGF(t=9.439,P=0.001;t=14.100,P=0.000),α-SMA(t=4.519,P=0.011;t=4.377,P=0.012),collagen Ⅰ(t=5.966,P=0.004;t=5.514,P=0.005)and collagen Ⅲ(t=4.622,P=0.010;t=4.996,P=0.008)were significantly increased.The relative luciferase activity of the cells co-transfected with miR-133b mimic and WT 3'UTR expression vector was significantly lower than that of the cells co-transfected with mimic control and WT 3'UTR expression vectors(t=5.654,P=0.005);however,there was no significant difference in relative luciferase activity between cells co-transfected with miR-133b mimic and MUT 3'UTR expression vectors and cells co-transfected with mimic control and MUT 3'UTR expression vectors(t=0.380,P=0.724).Conclusion miR-133b may affect the activation and proliferation of CFs by targeting CTGF and thus improve cardiac fibrosis.

Resistin may be an independent predictor of subclinical atherosclerosis formale smokers.

To investigate whether resistin is associated with early atherosclerosis in male smokers. The present study consecutively enrolled 50 male smokers. Their serum resistin contents were detected with enzyme linked immunosorbent assay (ELISA), and subclinical atherosclerosis indices, including carotid inner middle thickness (IMT) and arterial elasticity indices (C1 and C2), were measured. The association between serum resistin levels and IMT, C1 and C2 were respectively evaluated with the Pearson's correlation coefficient method. The results showed that the serum resistin level had a positive association with IMT (r = 0.307, p = .030), but were both inversely associated with C1 (r = -0.440, p = .001) and C2 (r = -0.381, p = .006). These associations remained significant even after adjustment for cardiovascular confounders. In conclusion, serum resistin concentration was independently associated with early atherosclerosis in male smokers.

The effects of the 5-HT2A receptor antagonist sarpogrelate hydrochloride on chronic hypoxic pulmonary hypertension in rats.

PURPOSE OF THE STUDY: This study investigated whether sarpogrelate hydrochloride (SPG), a 5-HT2A receptor antagonist, alleviates chronic hypoxic pulmonary hypertension (CH-PH) in rats by stimulating apoptosis and inhibiting proliferation in pulmonary artery smooth muscle cells (PASMCs). MATERIALS AND METHODS: Forty male Sprague-Dawley rats were pretreated with SPG (50 mg/kg/day by oral gavage) or saline vehicle and then subjected to chronic hypoxia (CH) (hypobaric chamber set to 380 mmHg, 10% oxygen) or normoxia for 14 days. Mean pulmonary artery pressure (PAP) and right ventricular hypertrophy (RVH) were measured. Hypertensive pulmonary vascular remodeling was assayed by light microscopy. Terminal deoxynucletidyl transferase dUTP nick end ligase (TUNEL) assays, western blotting, and real-time polymerase chain reaction were used to assess apoptosis, proliferation and underlying signaling pathways in PASMCs from lung tissue and isolated pulmonary artery rings. RESULTS: CH increased mean PAP and RVH. CH increased the percentage of muscularized arteries in the peripheral pulmonary vasculature and medial wall thickness in small muscular arteries. CH increased pulmonary protein and mRNA levels of the B-cell lymphoma protein 2 (Bcl-2), pyruvate dehydrogenase kinase (PDK), phosphorylation of extracellular signal-regulated kinases 1 and 2 (pERK1/2), cyclin D1, proliferating cell nuclear antigen (PCNA) and decreased protein and mRNA levels of Bcl-2-associated X protein (BAX), cleaved caspase-3. Pretreatment with SPG, which has been shown previously to inhibit ERK1/2 phosphorylation and PDK, countered all of these effects. Isolated pulmonary artery rings incubated with 5-HT increased pERK1/2, PDK, and Bcl-2 expression, and decreased Bax expression. CONCLUSION: Administration of SPG ameliorated the development of CH-PH by stimulating apoptosis in and inhibiting proliferation of PASMCs.

Targeted disruption of the prostaglandin E2 E-prostanoid 2 receptor exacerbates vascular neointimal formation in mice.

OBJECTIVE: Restenosis after angioplasty remains a major clinical problem. Prostaglandin E(2) (PGE(2)) plays an important role in vascular homeostasis. The PGE(2) receptor E-prostanoid 2 (EP2) is involved in the proliferation and migration of various cell types. We aimed to determine the role of EP2 in the pathogenesis of neointimal formation after vascular injury. METHODS AND RESULTS: Wire-mediated vascular injury was induced in the femoral arteries of male wild-type (EP2+/+) and EP2 gene-deficient (EP2-/-) mice. In EP2+/+ mice, EP2 mRNA expression was increased in injured vessels for at least 4 weeks after vascular injury. Neointimal hyperplasia was markedly accelerated in EP2-/- mice, which was associated with increased proliferation and migration of vascular smooth muscle cells (VSMCs) and increased cyclin D1 expression in the neointima layer. Platelet-derived growth factor-BB (PDGF-BB) treatment resulted in more significant cell proliferation and migration in VSMCs of EP2-/- mice than in those of EP2+/+ mice. Activation and overexpression of EP2 attenuated PDGF-BB-elicited cell proliferation and migration, induced G(1)→S-phase arrest and reduced PDGF-BB-stimulated extracellular signal-regulated kinase phosphorylation in EP2+/+ VSMCs. CONCLUSIONS: These findings reveal a novel role of the EP2 receptor in neointimal hyperplasia after arterial injury. The EP2 receptor may represent a potential therapeutic target for restenosis after angioplasty.

Role of prostaglandin E and its receptors in the process of ductus arteriosus maturation and functional closure in the rabbit.

1. Patent ductus arteriosus (PDA) is a common congenital heart defect in premature infants. The present study was designed to determine the role of the prostaglandin (PG) E(2) pathway in the process of ductus arteriosus (DA) maturation and functional closure. 2. Changes in PGE(2) pathway-related enzymes and receptors in DA in preterm and term rabbits were examined at both the mRNA and protein levels. In addition, responses of DA rings to Po(2) and PGE(2) were determined. 3. Circulating PGE(2) levels remained high until 2 h after birth. High levels of the EP(4) receptor were found in preterm DA. These tissues were sensitive to PGE(2), which caused vessel dilation, but were insensitive to increased Po(2). In contrast, DA tissues from term rabbits exhibited an immediate contractile response to increased Po(2) and PGE(2) treatment resulted in vasoconstriction, which was associated with increased EP(3) and decreased EP(4) receptor expression in term DA. 4. In conclusion, the preterm PDA is maintained by high levels of PGE(2), which mainly binds to the EP(4) receptor under conditions of hypoxia. In contrast, in the term DA, in which levels of the EP(3) receptor are higher than in preterm DA, exposure to PGE(2) resulted in vasoconstriction under normoxic conditions. These findings suggest that blocking the EP(4) receptor may represent a more selective treatment for the preterm PDA, whereas activating the EP(3) receptor may be more suitable for the treatment of the term PDA.

[Clinical observation of heparin-induced thrombocytopenia].

OBJECTIVE: To explore the treatment of heparin-induced thrombocytopenia (HIT) in venous thromboembolism. METHODS: A total of 202 patients with venous thromboembolism without anticoagulation contraindications were enrolled. All of them were treated with low molecular weight heparin (LMWH) and/or unfractionated heparin (UFH). The peripheral blood cells were examined regularly. RESULTS: HIT occurred in 6 patients. And argatroban was used to treat HIT. The overall incidence rate of HIT in this study was 2.97%. The time of occurrence of HIT was about Days 3 - 9 after using heparin. The platelet recovered to the basic level at Days 3 - 7 after withdrawing heparin and initiating argatroban. CONCLUSION: The count of platelet should be measured in the patients receiving regular LMWH and/or UFH therapy. And the above regimen should be discontinued timely when the platelet count declined progressively by over 50%. Argatroban was effective.

Nicotine may affect the secretion of adipokines leptin, resistin, and visfatin through activation of KATP channel.

OBJECTIVE: It has been confirmed that adipokines are associated with atherosclerosis. Cigarette smoking was found to possibly influence adipokine secretion. However, the precise role of smoking in adipokine secretion and the underlying mechanisms are largely unknown. The aim of this study was to determine whether nicotine, the principal active ingredient of cigarettes, can influence adipokine secretion and its potential mechanism. METHODS: The present study consecutively enrolled 96 men, including 50 smokers with early atherosclerosis and 46 nonsmokers. Serum adipokines, including leptin, resistin, and visfatin, were determined with enzyme-linked immunosorbent assay in all participants. Furthermore, the effect of nicotine on secretion of these adipokines was examined in differentiated 3T3-L1 preadipocytes under the conditions of ATP-dependent potassium (KATP) channel blocked or unblocked. RESULTS: Compared with the control group, serum levels of leptin, resistin, and visfatin in smokers were significantly higher. In 3T3-L1 adipocytes, nicotine treatment significantly increased the levels of these adipokines (P = 0.014, 0.001, and 0.029, respectively). When the KATP channel was blocked, secretion of resistin and visfatin was reduced (P < 0.001), but no change was found in the leptin secretion (P = 0.522). CONCLUSIONS: Nicotine may affect the secretion of adipokines leptin, resistin, and visfatin through activation of KATP channel.

Serotonin inhibits apoptosis of pulmonary artery smooth muscle cell by pERK1/2 and PDK through 5-HT1B receptors and 5-HT transporters.

BACKGROUND: Decreased apoptosis of pulmonary artery smooth muscle cells (PASMCs) plays a key role in pulmonary vascular remodeling in pulmonary hypertension (PH). However, the cause and mechanism of this decrease in apoptosis are still unclear. Serotonin (5-HT) has been shown to be involved in PH by inducing PASMC proliferation through the activation of 5-HT1B receptors (5-HT1BR) and 5-HT transporter (5-HTT). 5-HT1BR and 5-HTT are also involved in abnormal apoptosis in many other pathological processes. Therefore, we hypothesized that 5-HT induces decreases in PASMC apoptosis through 5-HT1BR and 5-HTT. METHODS: PASMCs were treated with 5-HT, and their proliferation and apoptosis were assayed. 5-HT1BR agonists, 5-HT1BR antagonist, 5-HTT antagonist, combined 5-HT1BR/5-HTT antagonists, extracellular signal-regulated kinase (ERK1/2) activation inhibitor peptide I (EPI) and pyruvate dehydrogenase kinase (PDK) inhibitor sodium dichloroacetate (DCA) were used to explore the mechanism by which 5-HT induce decrease in PASMC apoptosis. RESULTS: PASMCs stimulated by 5-HT showed an increase in proliferation and a decrease in apoptosis, accompanied by increase in pERK1/2, PDK, and mitochondrial transmembrane potential. The effects of 5-HT on the proliferation and apoptosis of PASMCs were similar to those of 5-HT1BR agonists and were markedly prevented by 5-HT1BR antagonist, 5-HTT antagonist, combined 5-HT1BR/5-HTT antagonists, EPI, or DCA. CONCLUSIONS: 5-HT inhibits PASMC apoptosis through 5-HT1BR or 5-HTT. pERK1/2 and PDK are involved in the process of 5-HT inhibition PASMC apoptosis through 5-HT1BR or 5-HTT.

Oestradiol supplement minimises coronary occlusion-induced myocardial infarction and ventricular dysfunction in oophorectomised female rats.

BACKGROUND: Endogenous oestrogen deficiency after menopause is associated with high risk of acute cardiac events and the protection of exogenous oestrogen supplements remains uncertain. This study investigates whether oestrogen therapy protects the heart from ischemic injury in oophorectomised rats. METHODS: Sexually mature female Sprague-Dawley rats (6 for each group) with bilateral oophorectomy underwent selective ligation (occlusion) of left coronary artery for 4 weeks. 17ß-oestradiol (E2) supplements (10 µg, i.m., every other day) were started before (preventive-therapeutic supplement) or after coronary occlusion (therapeutic supplement). RESULTS: In oophorectomised rats plasma levels of E2 declined from 1301 ± 80 to 196 ± 48 pmol/L (p<0.01) and cardiac expression of oestrogen receptors (ER) decreased by ∼60%. E2 supplements recovered the ER expression. Selective ligation of left coronary led myocardial infarction in the left ventricle, with an increase in plasma cardiac troponin I (cTn-I), decrease in systolic blood pressure (SBP), and reduction of left ventricular pressures. Preventive-therapeutic but not therapeutic E2 supplement reduced cTn-I levels (from 21.9 ± 2.0 to 6.0 ± 0.3 ng/mL, p<0.01), minimised infarction (from 37.0 ± 1.2% to 18.1 ± 2.3%, p<0.05), increased SBP (from 82 ± 4.2 to 97 ± 4.4mm Hg, p<0.05), and improved left ventricular end pressures in the oophorectomised rats following coronary occlusion. CONCLUSION: Postmenopausal (ooporectomised) oestrogen supplement commenced before establishment of myocardial ischemia minimises myocardial infarction and ventricular dysfunction following the coronary artery occlusion. Cellular and molecular mechanisms underlying the cardiac protection of oestrogen therapy remain unclear, in which activation of cardiac ER expression and increasing in circulating CD90(+) stem cells may be involved.