Qiongying Wang

Tetrahydrobiopterin improves endothelial function in cardiovascular disease: a systematic review.

Background. Tetrahydrobiopterin (BH4) is a cofactor of nitric oxide synthase (NOS). Nitric oxide (NO) bioavailability is reduced during the early stage of vascular diseases, such as coronary artery disease, hypercholesterolemia, hypertension, and diabetic vasculopathy, and even throughout the entire progression of atherosclerosis. Methods. A literature search was performed using electronic databases (up to January 31, 2014), including MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL), using an established strategy. Results. Fourteen articles were selected with a total of 370 patients. Ten of the fourteen studies showed a significant improvement in the endothelial dysfunction of various cardiovascular disease groups with BH4 supplementation compared with the control groups or placebos. Three studies showed no positive outcome, and one study showed that low-dose BH4 had no effect but that high-dose BH4 did have a significantly different result. Conclusions. This review concludes that supplementation with BH4 and/or augmentation of the endogenous levels of BH4 will be a novel approach to improve the endothelial dysfunction observed in various cardiovascular diseases. BH4 might be considered to be a new therapeutic agent to prevent the initiation and progression of cardiovascular disease.

Argonaute proteins in cardiac tissue contribute to the heart injury during viral myocarditis

MicroRNAs (miRNAs) are a group of short, noncoding, regulatory RNA molecules the dysregulation of which contributes to the pathogenesis of myocarditis. Argonaute proteins are essential components of miRNA-induced silencing complex and play important roles during miRNA biogenesis and function. However, the expression pattern of four AGO family members has not yet been detected in the coxsackievirus B3 (CVB3)-induced myocarditis tissue samples. In this study, we detected the expression of four AGOs in the CVB3-infected mouse heart tissues and found that AGO1 and AGO3 up-regulated significantly at 4 and 8h after CVB3 infection. Further in vitro research indicated that up-regulated AGO1 and AGO3 are related to the down-regulated TNFAIP3, which is a negative regulator of NF-κB pathway. Subsequently, we confirmed that TNFAIP3 is a direct target of miR-19a/b, and during CVB3 infection, the expression of miR-19a/b and miR-125a/b is not significantly changed. TNFAIP3 level is mainly reduced by up-regulated AGO1 and AGO3. This research sheds light on the relationship between overexpressed AGO proteins and CVB3-induced myocarditis, and this provides potential therapeutic target for viral myocarditis.

Association between Antihypertensive Drug Use and the Incidence of Cognitive Decline and Dementia: A Meta-Analysis of Prospective Cohort Studies

Background Antihypertensive drug use is inconsistently associated with the risk of dementia, Alzheimers disease, cognitive impairment, and cognitive decline. Therefore, we conducted a meta-analysis of available prospective cohort studies to summarize the evidence on the strength of these relationships. Methods Three electronic databases including MedLine, Embase, and the Cochrane Library were searched to identify studies from inception to April 2017. Only prospective cohort studies that reported effect estimates with corresponding 95% confidence intervals (CIs) of dementia, Alzheimers disease, cognitive impairment, and cognitive decline for antihypertensive drug use versus not using antihypertensive drugs were included. Results We included 10 prospective cohort studies reporting data on 30,895 individuals. Overall, participants who received antihypertensive drugs had lower incidence of dementia (relative risk [RR]: 0.86; 95% CI: 0.75–0.99; p = 0.033), while there was no significant effect on the incidence of Alzheimers disease (RR: 0.83; 95% CI: 0.64–1.09; p = 0.154), cognitive impairment (RR: 0.89; 95% CI: 0.57–1.38; p = 0.596), and cognitive decline (RR: 1.11; 95% CI: 0.86–1.43; p = 0.415). Further, the incidence of Alzheimers disease might be affected by antihypertensive drug use in participants with specific characteristics. Conclusions Antihypertensive drug use was associated with a significantly reduced risk of dementia, but not with the risk of Alzheimers disease, cognitive impairment, and cognitive decline.

OS 36-05 TETRAHYDROBIOPTERIN REVERSE LEFT VENTRICULAR HYPERTROPHY AND DIASTOLIC DYSFUNCTION THROUGH THE PI3K/p-Akt PATHWAY IN SPONTANEOUSLY HYPERTENSIVE RATS.

Objective: Hypertension induced hypertrophy and diastolic dysfunction and is associated with cardiac oxidation and reduced NO production. We hypothesized that tetrahydrobiopterin (BH4) can regulate the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway and reverse cardiac hypertrophy and diastolic dysfunction in spontaneously hypertensive rats. Design and Method: Ten-week-old male spontaneously hypertensive rats (SHR) and age-matched normotensive control Wistar-Kyoto (WKY) rats were divided into five groups, WKY,WKY + BH4, SHR, SHR + BH4 and SHR + VAL. Diastolic function were assessed by echocardiography and hemodynamics. The expression and phosphorylation level of PI3Kand Akt were assayed with western blot analysis. High performance liquid chromatography (HPLC) analysis was used to measure BH4 and biopterins. Quantitative real-time- Polymerase Chain Reaction (PCR) and immunohistochemistry were used to test cardiac hypertrophic genes and expression of Bax and Bcl-2 in the myocardium. Results: In SHR diastolic dysfunction was accompanied by concentric hypertrophy,cardiac oxidation, a reduction in cardiac BH4 and NO production. Administered with BH4 and Valsartan for four weeks, the data showed that both can reverse hypertrophy and improve diastolic function.BH4 and Valsartan blunted the expression of hypertrophy markers &agr;-skeletal actin (&agr;-SA) and &bgr;-myosin heavy chain (&bgr;-MHC), only BH4 reduced hypertension induced myocardial fibrosis and expression of transforming growth factor-&bgr;1(TGF-&bgr;1). BH4 reduced cardiac oxidant stress and increased NO production. Exogenous BH4 increased the phosphorylated Akt level and enhanced expression of Bcl-2. Conclusions: Less BH4 and reduced NO increases myocardial hypertrophy and cardiac oxidative stress, which exacerbates diastolic dysfunction. Exogenous BH4 ameliorates cardiac hypertrophy and diastolic dysfunction through the PI3K/p-Akt pathway. BH4 may be a potent therapy for hypertension with diastolic dysfunction.

Local delievery of thalidomide to inhibit neointima formation in rat model with artery injury

OBJECTIVE To observe the effect of local administration of thalidomide on neointimal formation after balloon-induced carotid artery injury in rats. METHODS Forty-eight male Sprague-Dawley rats were randomly divided into 3 groups (n = 16): Sham operation group (group A), alone operation group (group B) and Thalidomide group (group C). The carotid arteries of group B and group C were injured by a conventional percutaneous transluminal coronary angioplasty (PTCA) balloon catheter. Group C was treated by local delivery of thalidomide, and group B did not receive thalidomide. The arteries of group A were not injured. Seven and 14 days after balloon injury, rats were sacrificed. Serum concentrations of vascular endothelial growth factor (VEGF) and tumor necrosis factor-α (TNF-α) were measured using enzyme-linked immunosorbent assay (ELISA). Neointima area, lumen area, macrophage infiltration and local expression of VEGF were measured using morphometric and immunohistochemical analyses. Real-time reverse transcriptase polymerase chain reaction (RT-PCR) was used to examine VEGF mRNA expression. RESULTS The VEGF levels were significantly increased in group B than in group C at 7 days (4.82 ± 0.17 pg/mL vs 0.98 ± 0.1 pg/mL, P < 0.01) and 14 days (6.3 ± 0.16 pg/mL vs 1.03 ± 0.09 pg/mL, P < 0.01). The TNF-α levels were also significantly increased in group B than in group C at 7 days (83 ± 1.01 pg/mL vs 76.37 ± 0.75 pg/mL, P < 0.01) and 14 days (84.06 ± 1.11 pg/mL vs 78.46 ± 0.94 pg/mL, P < 0.01). However, the area of neointimal formation was significantly reduced in group C than in group B at 14 days (0.07± 0.01 mm2 vs 0.12± 0.04 mm2, P < 0.01). Macrophage infiltration and local expression of VEGF in the injured arteries were significantly reduced in group C than in group B at 14 days. VEGF mRNA expression was significantly reduced in Group C than in group B at 14 days (6.3 ± 0.16 vs 1.02 ± 0.1, P < 0.01). CONCLUSIONS Thalidomide, which is a specific VEGF inhibitor, significantly inhibited neointimal hyperplasia and vascular restenosis after balloon injury to the carotid artery in rats, thus potentially providing a novel method for the prevention and treatment of restenosis, especially in-stent restenosis.

Effect of antihypertensive drugs on breast cancer risk in female hypertensive patients: Evidence from observational studies

ABSTRACT This systematic review aimed to evaluate the association between antihypertensive drugs and risk of breast cancer, and provide therapeutic implications for female hypertensive patients with different physical appearance. The prevalence of hypertension and female breast cancer is on the rise with age. It has been suggested that ARBs (angiotensin receptor blockers), ACEi (angiotensin-converting enzyme inhibitor), CCBs (calcium channel blockers), and BBs (beta-blockers) were widely used in hypertensive patients. Some researches have shown ARBs, ACEis, and beta-blockers to be effective drugs for blood pressure lowering as well as for reducing the risk of breast cancer in women. However, the research conclusions were inconsistent. To address the conflicting evidence from previous study, the study evaluates the risk of breast cancer in hypertensive women. In conclusion, we report the evidence that beta-blockers can reduce the risk of breast cancer recurrence, while ACEi and CCBs were not associated with an increased risk of breast cancer.

Astragalus Membranaceus Improving Asymptomatic Left Ventricular Diastolic Dysfunction in Postmenopausal Hypertensive Women with Metabolic Syndrome: A Prospective, Open-Labeled, Randomized Controlled Trial

Background: Postmenopausal women with metabolic syndrome (MetS) have increased cardiovascular morbidity and left ventricular diastolic dysfunction (LVDD). The various protective effects of astragalus membranaceus (AM) have been described in previous studies. Therefore, this study aimed to evaluate the effects of different doses of AM on diastolic function in postmenopausal hypertensive women with MetS. Methods: This was a prospective, randomized controlled study. The postmenopausal hypertensive patients with MetS were enrolled from Lanzhou University Second Hospital from March 2014 to April 2015. Patients were divided into three groups: control group (received conventional medical treatment), AM Group 1 (received AM capsules at 5 g/d additionally), and AM Group 2 (received AM capsules at 10 g/d additionally). Echocardiographic and clinical characteristics were evaluated before and 12 months after treatment. Quantitative data were analyzed using unpaired t-test, analysis of variance, and multiple linear regression analysis. Results: A total of 154 patients were subjected to final analysis. In the AM Group 2, significant improvements were noted in diastolic function 12 months after treatment than those of the control group, including the early diastolic mitral annular velocity (E’; 0.065 ± 0.007 m/s vs. 0.061 ± 0.008 m/s, P = 0.014), the ratio of the early diastolic mitral peak flow velocity to the late diastolic mitral peak flow velocity (E/A; 0.81 ± 0.05 vs. 0.80 ± 0.06, P = 0.012), the ratio of E’ to the late diastolic mitral annular velocity (E’/A’; 0.56 ± 0.12 vs. 0.51 ± 0.13, P = 0.048), and the ratio of the early diastolic mitral peak flow velocity (E) to E’ (E/E’; 10.70 ± 1.30 vs. 11.37 ± 1.73, P = 0.031). After treatment, E/E’ (10.70 ± 1.30 vs. 11.24 ± 1.56, P = 0.021), deceleration time (DT; 261.49 ± 44.41 ms vs. 268.74 ± 53.87 ms, P = 0.046), and E’/A’ (0.56 ± 0.12 vs. 0.52 ± 0.13, P = 0.019) values improved more significantly than those of AM Group 2 before treatment. Besides, waist circumference was positively correlated with E’ (r = 0.472; P = 0.003) and E’/A’ (r = 0.321; P = 0.047). In addition, the waist-to-hip ratio was a significant predictor of DT (r = 0.276; P = 0.041), E’ (r = −0.590; P < 0.001), E/E’ (r = 0.454; P = 0.004), and E’/A’ (r = −0.377; P = 0.018). Conclusions: Conventional medical plus AM therapy improved diastolic function. Moreover, WC and WHR might be risk factors for LVDD. Chinese Clinical Trial Register: ChiCTR-TRC-11001747. http://www.chictr.org.cn/showprojen.aspx?proj=7798.

PS 08-03 STUDY ON THE RELATIONSHIP BETWEEN RED CELL DISTRIBUTION WIDTH AND THE INCREASE OF URIC ACID IN CHINESE HYPERTENSIVE PATIENTS

Objective: We hypothesized that red cell distribution width (RDW) would be associated with increases in serum uric acid (UA) in hypertension patients. Design and method: All subjects were participants of the China Stroke Primary Prevention Trial (CSPPT, clinicaltrials.gov identifier: NCT00794885). This study was a randomized, doubleblind clinical trial conducted from May 19, 2008, to August 24, 2013. 15486 participants provided written informed consent. Eligible participants were men and women aged 45 to 75 years old who had hypertension, defined as seated resting systolic blood pressure of 140 mmHg or higher or diastolic blood pressure of 90 mmHg or higher at both the screening and recruitment visits or were taking an antihypertensive medication. Participants were scheduled for follow-up every 3 months. At each follow-up visit, vital signs, study drug adherence, concomitant medication use, adverse events, and possible endpoint events were documented by trained research staff and physicians. For testing the primary hypothesis, the efficacy analyses for the primary outcome were conducted according to the ITT principle. All analyses were performed using EmpowerStats (http://www.empowerstats.com) and the statistical package R. Data are presented as mean ± standard deviation (SD) or proportions. Results: There was a strong relationship between RDW level and UA increase. In the following cases, we can see the same relationship: UA increase value and the increase rate rised with RDW increasing in patients less than and greater than 60 years old (P < 0.05). Whether hypertensive patients taking enalapril or enalapril-folic acid tablets, the level of UA and RDW were into a significant positive correlation (P < 0.05). In patients with normal or elevated mean-SBP, UA also rised with the rising of RDW (P < 0.05). Conclusions: In hypertension patients, the UA increase with the rising of RDW. We also evaluated the relationship could not be affected by other variables including gender, age, anti-hypertensive drugs mean-SBP and mean-DBP.

MPS 15-02 GENDER BASED COMPARISON OF THE PROTECTIVE EFFECTS OF ASTRAGALUS ON CARDIOVASCULAR SYSTEM IN HYPERTENSIVE PATIENTS WITH METABOLIC SYNDROME

Objective: To investigate the influence of Astragalus in the protection of cardiovascular structure and function in essential hypertensive patients with metabolic syndrome (MetS) depending on gender. Design and Method: This is a prospective, open labeled, parallel randomized controlled trial. 206 hypertensive patients with MetS between 18 and 60 years were randomly assigned to control group, Astragalus group 1 (Astragalus 10 g/d) and Astragalus group 2 (Astragalus 5 g/d). Metabolic related indexes were measured by laboratory blood tests. Left ventricular end diastolic dimension (LVEDd), interventricular septal thickness (IVST), left ventricular diastolic posterior wall thickness (LVPWT), deceleration time (DT), early diastolic mitral annular velocity/late diastolic velocity of tricuspid annulus (E’/A’), pulmonary venous arterial reversal velocity (Ar) and mitral flow velocity (Vp) were measured by ultrasound echocardiogram. Cardio-ankle vascular index (CAVI) and ankle brachial index (ABI) were obtained by arteriosclerotic instrument. Aortic pulse wave analyzer was used to measure the carotid and femoral artery pulse wave velocity (cf-PWV) and augmentation index (AIx). All of the indicators were compared between pre-treatment and post-treatment after a 12 months follow-up. This research program is registered under the Chinese Clinical Trial Register Website (ChiCTR-TRC-11001747). Results: Triglyceride (TG), E’/A’ and Vp were significantly improved after treatment with Astragalus in females as compared to males (P = 0.026, P = 0.031, P = 0.042 respectively). CAVI and AIx were also reduced significantly in females (P = 0.036, P = 0.017 respectively). However, other indicators showed no difference after treatment (P > 0.05). In males, most indicators had no significant difference except total cholesterol (TC) and ABI which were reduced significantly after treatment (P = 0.033, P = 0.029 respectively). Conclusions: The protective effect of Astragalus on cardiovascular structure and function is better in female patients than male. The sex hormones might have a role in it. A further long term study would be helpful in confirming the efficacy of Astragalus extract.

PS 10-07 TETRAHYDROBIOPTERIN EFFECTS LEFT VENTRICULAR DIASTOLIC FUNCTION BY UPREGULATING PROTEIN KINASE Cε SIGNALING PATHWAY IN DESOXYCORTICOSTERONE ACETATE-SALT HYPERTENSIVE MICE:

Objective: To identify the influence of tetrahydrobiopterin (BH4) on left ventricular diastolic function and the expression of protein kinase C &egr;(PKC&egr;) in desoxycorticosterone acetate (DOCA)-salt hypertensive mice. Design and method: We used the DOCA-salt mouse model, which demonstrates mild hypertension, myocardial oxidative stress, and diastolic dysfunction. Mice were divided into DOCA group(n = 22), DOCA + BH4 group(n = 22), SHAM group(n = 20) and SHAM + BH4 group(n = 20). Arterial pressure, echocardigraphy and hemodynamic method were used to investigate the DOCA model establishment, cardiac structure and function. Cyclic guanosine monophosphate(cGMP), malonaldehydeby, BH4 and PKC &egr; were detected by enzyme linked immunosorbent assay(ELASA), western-blot or high-performance liquid chromatography(HPLC) in cardiac tissues of all groups. Results: Compared to Sham group, systolic blood pressure (SBP) and diastolic blood pressure (DBP) in DOCA group were increased (P < 0.05), but between DOCA + BH4 group and DOCA group, there was no significant statistical differences in blood pressure (P > 0.05). The ratio of left-ventricular early diastolic filling velocity to early diastolic mitral annular velocity (E/E’), end-diastolic pressure-volume relation (EDPVR) and Tau index were increased in DOCA group when compared with Sham group [(14.27 ± 0.79) vs (10.6 ± 0.52) ms, (38.49 ± 3.91) vs (25.77 ± 5.21), (0.22 ± 0.05) vs (0.15 ± 0.02) mm, all P < 0.05]. After BH4 treatment in DOCA mice, EDPVR and Tau index were reduced [(0.17 ± 0.04) vs (0.22 ± 0.05), (12.05 ± 1.35) vs (14.27 ± 0.79), P < 0.05]. Superoxide dismutase (SOD) and nitric oxide (NO) in DOCA group were reduced when compared with Sham group. After BH4 treatment in DOCA mice, SOD and NO were increased. Compared to Sham group, the protein level of PKC &egr; in DOCA group was decreased (P < 0.05), while it was increased in DOCA + BH4 group as compared with DOCA group (P < 0.05). Conclusions: BH4 had little effect on BP, but it could improve left ventricular diastolic dysfunction in hypertensive mice, which was related to lowering the levels of oxidative stress, increasing amounts of NO by upregulating PKC &egr; signaling pathway.