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- Human ALDH1B1 Polymorphisms may Affect the Metabolism of Acetaldehyde and All-trans retinaldehyde-In Vitro Studies and Computational Modeling. [JOURNAL ARTICLE]
- Pharm Res 2014 Nov 21.
To elucidate additional substrate specificities of ALDH1B1 and determine the effect that human ALDH1B1 polymorphisms will have on substrate specificity.Computational-based molecular modeling was used to predict the binding of the substrates propionaldehyde, 4-hydroxynonenal, nitroglycerin, and all-trans retinaldehyde to ALDH1B1. Based on positive in silico results, the capacity of purified human recombinant ALDH1B1 to metabolize nitroglycerin and all-trans retinaldehyde was explored. Additionally, metabolism of 4-HNE by ALDH1B1 was revisited. Databases queried to find human polymorphisms of ALDH1B1 identified three major variants: ALDH1B1*2 (A86V), ALDH1B1*3 (L107R), and ALDH1B1*5 (M253V). Computational modeling was used to predict the binding of substrates and of cofactor (NAD(+)) to the variants. These human polymorphisms were created and expressed in a bacterial system and specific activity was determined.ALDH1B1 metabolizes (and appears to be inhibited by) nitroglycerin and has favorable kinetics for the metabolism of all-trans retinaldehyde. ALDH1B1 metabolizes 4-HNE with higher apparent affinity than previously described, but with low throughput. Recombinant ALDH1B1*2 is catalytically inactive, whereas both ALDH1B1*3 and ALDH1B1*5 are catalytically active. Modeling indicated that the lack of activity in ALDH1B1*2 is likely due to poor NAD(+) binding. Modeling also suggests that ALDH1B1*3 may be less able to metabolize all-trans retinaldehyde and that ALDH1B1*5 may bind NAD(+) poorly.ALDH1B1 metabolizes nitroglycerin and all-trans-retinaldehyde. One of the three human polymorphisms, ALDH1B1*2, is catalytically inactive, likely due to poor NAD(+) binding. Expression of this variant may affect ALDH1B1-dependent metabolic functions in stem cells and ethanol metabolism.
- Three-Dimensional Echocardiographic Evaluation of Mitral Apparatus during Preload Manipulation in Patients with Hypertrophic Cardiomyopathy. [JOURNAL ARTICLE]
- Echocardiography 2014 Nov 20.
The three-dimensional (3D) dynamic change of mitral geometry during preload manipulation has not been fully investigated. We investigated how preload manipulation affected the mitral apparatus geometry in hypertrophic cardiomyopathy (HCM) patients using 3D echocardiography.Twenty five HCM patients, thirteen with obstructive HCM (HOCM) and twelve with nonobstructive HCM (HNCM), and six healthy controls were studied. Subjects underwent 3D echocardiography during rest, leg raising, the Valsalva maneuver, and the Valsalva maneuver after nitroglycerin intake (NTG-Valsalva). Left ventricular outflow tract (LVOT) pressure gradients, mitral annular area, annular circumference, and the tenting volume of the mitral leaflets were measured. Standardized annular area significantly decreased during the NTG-Valsalva maneuver in all 3 groups (▵2.23 mm(2) /m(2) in control, P = 0.031; ▵0.46 mm(2) /m(2) in HNCM, P = 0.012; ▵1.3 mm(2) /m(2) in HOCM, P = 0.013). Standardized annular area decrease during the Valsalva maneuver alone was more prominent in HNCM patients (▵0.57 mm(2) /m(2) , P = 0.009) than HOCM patients (▵0.3 mm(2) /m(2) , P = 0.094). Standardized mitral tenting volume during the NTG-Valsalva maneuver significantly decreased only in HOCM patients (▵1.18 mm(3) /m(2) , P = 0.046).Decreased mitral annular area and changes in leaflets tenting volume during preload reduction might affect the development of LVOT obstruction. Our data suggest the importance of preserving the saddle-shaped of the mitral annulus in management of HCM with LVOT obstruction.
- Comparative Effectiveness of Di'ao Xin Xue Kang Capsule and Compound Danshen Tablet in Patients With Symptomatic Chronic Stable Angina. [Journal Article]
- Sci Rep 2014.:7058.
A high proportion of patients with stable angina remains symptomatic despite multiple treatment options. Di'ao Xinxuekang (XXK) capsule and Compound Danshen (CDS) tablet have been approved for treating angina pectoris for more than 20 years in China. We compare the anti-anginal effectiveness of XXK capsule and CDS tablet in patients with symptomatic chronic stable angina. A randomized, multicenter, double-blind, parallel-group, superiority trial was conducted in 4 study sites. 733 patients with symptomatic chronic stable angina were included in the full analysis set. The primary outcomes were the proportion of patients who were angina-free and the proportion of patients with normal electrocardiogram (ECG) recordings during 20 weeks treatment. Compared with CDS, XXK significantly increased the proportion of angina-free patients, but no significant difference was noted in the proportion of patients with normal ECG recordings. Weekly angina frequency and nitroglycerin use were significantly reduced with XXK versus CDS at week 20. Moreover, XXK also improved the quality of life of angina patients as measured by the SAQ score and Xueyu Zheng (a type of TCM syndrome) score. We demonstrate that XXK capsule is more effective for attenuating anginal symptoms and improving quality of life in patients with symptomatic chronic stable angina, compared with CDS tablet.
- Clonidine versus nitroglycerin infusion in laparoscopic cholecystectomy. [Journal Article]
- JSLS 2014 Jul; 18(3)
Laparoscopic surgery offers the advantages of minimally invasive surgery; however, pneumoperitoneum and the patient's position induce pathophysiological changes that may complicate anesthetic management. We studied the effect of clonidine and nitroglycerin on heart rate and blood pressure, if any, in association with these drugs or the procedure, as well as the effect of these drugs, if any, on end-tidal carbon dioxide pressure and intraocular pressure.Sixty patients (minimum age of 20 years and maximum age of 65 years, American Society of Anesthesiologists class I or II) undergoing laparoscopic cholecystectomy were randomized into 3 groups and given an infusion of clonidine (group I), nitroglycerin (group II), or normal saline solution (group III) after induction and before creation of pneumoperitoneum. We observed and recorded the following parameters: heart rate, mean arterial blood pressure, end-tidal carbon dioxide pressure, and intraocular pressure. The mean and standard deviation of the parameters studied during the observation period were calculated for the 3 treatment groups and compared by use of analysis of variance tests. Intragroup comparison was performed with the paired t test. The critical value of P, indicating the probability of a significant difference, was taken as < .05 for comparisons.Statistically significant differences in heart rate were observed among the various groups, whereas comparisons of mean arterial pressure, intraocular pressure, and end-tidal carbon dioxide pressure showed statistically significant differences only between groups I and III and between groups II and III.We found clonidine to be more effective than nitroglycerin at preventing changes in hemodynamic parameters and intraocular pressure induced by carbon dioxide insufflation during laparoscopic cholecystectomy. It was also found not to cause hypotension severe enough to stop the infusion and warrant treatment.
- Venepuncture during head-up tilt testing in patients with suspected vasovagal syncope - implications for the test protocol. [JOURNAL ARTICLE]
- Eur J Neurol 2014 Nov 10.
Head-up tilt (HUT) testing is a widely used diagnostic tool in patients with suspected vasovagal syncope (VVS). However, no gold standard exists for this examination and the various protocols used have a limited sensitivity and specificity. Our aim was to determine the sensitivity of a sequential HUT testing protocol including venepuncture (VP) and sublingual nitroglycerin application.This was a retrospective analysis of the diagnostic gain of a sequential HUT testing protocol including VP applied 10 min after the start of HUT testing and sublingual application of nitroglycerin 20 min after the start of the test protocol in 106 patients with a final diagnosis of VVS. The sensitivity of the test protocol was compared between patients with positive and negative history for VP induced VVS.Overall, pre-syncope or syncope occurred in 68 patients (64.2%). Only 17% of all patients fainted spontaneously within 10 min of passive HUT. Another 39.6% fainted within 20 min. Application of nitroglycerin after 20 min of HUT evoked syncope in another 7.5% until the end of 45 min of HUT. The sensitivity of the test protocol for evoking (pre-)syncope was 94.4% in patients with a positive history for VP associated VVS and 58% in patients with a negative history (P < 0.01**); 85.7% of patients with a positive history and 42.9% of patients with a negative history fainted within 20 min of HUT testing (P < 0.01**).Implementation of VP in sequential HUT testing protocols allows the sensitivity of HUT testing to be increased, especially in patients with a positive history for VP associated VVS.
- Endothelial dysfunction is present only in the microvasculature and microcirculation of early diffuse systemic sclerosis patients. [Journal Article]
- Clin Exp Rheumatol 2014 Nov-Dec; 32 Suppl 86(6):154-60.
To evaluate endothelial function and vascular stiffness in large, medium, small and microcirculatory blood vessels in very early diffuse systemic sclerosis (SSc).We studied consecutive early diffuse SSc patients, defined as <2 years from first SSc symptom who did not have a prior cardiovascular event. Age, gender and race-matched controls were recruited. All underwent assessment of aortic pulse wave velocity (PWV), carotid intima-media thickness (IMT) brachial flow-mediated dilation (FMD), digital peripheral artery tonometer (EndoPAT) assessment and laser speckle contrast imaging (LSCI).Fifteen early diffuse SSc and controls were evaluated. The average age was 49 years, 63% were female and 93% were Caucasian. There were no differences in body mass index, hypertension, diabetes or hyperlipidaemia between controls and SSc patients. Mean SSc disease duration was 1.3 years. In the large central vessels, there was no difference in aortic PWV (p=0.71) or carotid IMT (p=0.92) between SSc patients and controls. Similarly, there was no difference in endothelial dysfunction with brachial artery FMD after ischaemia (p=0.55) and nitroglycerin administration (p=0.74). There were significantly lower values for digital EndoPAT measures (p=0.0001) in SSc patients. LSCI revealed a distinct pattern of microcirculatory abnormalities in response to ischaemia in SSc patients compared to controls. Imaging demonstrated a blunted microcirculatory hyperaemia of the hand with greater subsequent response to nitroglycerin.These findings suggest that the earliest endothelial changes occur in smaller arterioles and microvascular beds, but not in medium or macrovascular beds, in early diffuse SSc.
- GTP cyclohydrolase I gene polymorphisms are associated with endothelial dysfunction and oxidative stress in patients with type 2 diabetes mellitus. [Journal Article]
- PLoS One 2014; 9(11):e108587.
The genetic background of atherosclerosis in type 2 diabetes mellitus (T2DM) is complex and poorly understood. Studying genetic components of intermediate phenotypes, such as endothelial dysfunction and oxidative stress, may aid in identifying novel genetic components for atherosclerosis in diabetic patients.Five polymorphisms forming two haplotype blocks within the GTP cyclohydrolase 1 gene, encoding a rate limiting enzyme in tetrahydrobiopterin synthesis, were studied in the context of flow and nitroglycerin mediated dilation (FMD and NMD), intima-media thickness (IMT), and plasma concentrations of von Willebrand factor (vWF) and malondialdehyde (MDA).Rs841 was associated with FMD (p = 0.01), while polymorphisms Rs10483639, Rs841, Rs3783641 (which form a single haplotype) were associated with both MDA (p = 0.012, p = 0.0015 and p = 0.003, respectively) and vWF concentrations (p = 0.016, p = 0.03 and p = 0.045, respectively). In addition, polymorphism Rs8007267 was also associated with MDA (p = 0.006). Haplotype analysis confirmed the association of both haplotypes with studied variables.Genetic variation of the GCH1 gene is associated with endothelial dysfunction and oxidative stress in T2DM patients.
- Traditional Chinese medicine for stable angina pectoris via TCM pattern differentiation and TCM mechanism: study protocol of a randomized controlled trial. [Journal Article]
- Trials 2014; 15(1):422.
Stable angina pectoris is experienced as trans-sternal or retro-sternal pressure or pain that may radiate to the left arm, neck or back. Although available evidence relating to its effectiveness and mechanism are weak, traditional Chinese medicine is used as an alternative therapy for stable angina pectoris. We report a protocol of a randomized controlled trial using traditional Chinese medicine to investigate the effectiveness, mechanism and safety for patients with stable angina pectoris.This is a north-east Chinese, multi-center, multi-blinded, placebo-controlled and superiority randomized trail. A total of 240 patients with stable angina pectoris will be randomly assigned to three groups: two treatment groups and a control group. The treatment groups will receive Chinese herbal medicine consisting of Yi-Qi-Jian-Pi and Qu-Tan-Hua-Zhuo granule and Yi-Qi-Jian-Pi and Qu-Tan-Hua-Yu granule, respectively, and conventional medicine. The control group will receive placebo medicine in addition to conventional medicine. All 3 groups will undergo a 12-week treatment and 2-week follow-up. Four visits in sum will be scheduled for each subject: 1 visit each in week 0, week 4, week 12 and week 14. The primary outcomes include: the frequency of angina pectoris attack; the dosage of nitroglycerin; body limited dimension of Seattle Angina Questionnaire. The secondary outcomes include: except for the body limited dimension of SAQ, traditional Chinese medicine pattern questionnaire and so on. Therapeutic mechanism outcomes, safety outcomes and endpoint outcomes will be also assessed.The primary aim of this trial is to develop a standard protocol to utilize high-quality EBM evidence for assessing the effectiveness and safety of SAP via TCM pattern differentiation as well as exploring the efficacy mechanism and regulation with the molecular biology and systems biology.ChiCTR-TRC-13003608, registered 18 June 2013.
- Fixed-dose combination of losartan and hydrochlorothiazide significantly improves endothelial function in uncontrolled hypertension by low-dose amlodipine: A randomized study. [JOURNAL ARTICLE]
- Anadolu Kardiyol Derg 2014 Oct 23.
Flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD) in the brachial artery are well-known indices for evaluating endothelial function (ECF). The blood pressure-lowering effects of the combination of losartan (ARB) and low-dose hydrochlorothiazide (H: ARB-H; ARB, 50 mg and H, 12.5 mg) are useful. The aim of the present study was to examine whether the combination of losartan and low-dose hydrochlorothiazide could improve ECF.To investigate the effect of ARB-H on ECF in patients with uncontrolled hypertension despite the use of amlodipine (2.5 mg daily), we performed a randomized controlled open-labeled study by using the envelope method and assigned 42 patients to either a control (CTRL) group or an ARB-H combination group, both of which received amlodipine 2.5 mg daily during the treatment period. In addition, both the CTRL (n=21, 69±7 years old) and ARB-H groups (n=21, 69±7 years old) received additional behavioral modification. Before and after 8 weeks of therapy, FMD and NMD were measured in both groups using novel FMD equipment (UNEXEF18G).Although baseline FMD was not different between the two groups, post-therapy FMD increased in the ARB-H group (2.97±1.56 to 3.95±1.86%, p<0.05) but did not change significantly in the CTRL group (2.95±1.43 to 3.11±1.27%, NS). No significant change was seen in NMD when comparing baseline and post-therapy values in either group. No treatment complications were observed.A fixed-dose combination of losartan and hydrochlorothiazide enhances ECF, suggesting that this combination might have both anti-hypertensive and anti-atherosclerotic effects in patients with hypertension.
- [Multiple effect of simvastatin on vascular endothelium of hypercholesterolemia patients]. [English Abstract, Journal Article]
- Beijing Da Xue Xue Bao 2014 Oct 18; 46(5):703-6.
To observe the multiple influence of cholesterol-lowering drug (simvastatin) on ankle brachial index (ABI), flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD) of brachial artery blood vessel endothelium, and plasma level of monocyte chemotactic protein 1 (MCP-1) of hypercholesterolemia patients without coronary heart disease (CHD).In the study, 51 patients with hypercholesterolemia application were treated with simvastatin (20 mg/d) therapy for 12 weeks. The metabolic index, ankle brachial index (ABI), FMD of brachial artery blood vessel endothelium detected by color doppler ultrasound instrument, the NMD of artery endothelial and the level of MCP 1 were measured before and after therapy respectively. All the results were analyzed and compared with another 30 cases of hypercholesterolemia patients selected without simvastatin treatment.After simvastatin therapy, the TC (total cholesterol) and LDL-C (low density lipoprotein cholesterin) levels were reduced apparently,the values decreased from the original (6.06 ± 1.03) mmol/L and (3.60 ± 0.82) mmol/L to (4.98 ± 1.34) mmol/L and (3.41 ± 0.10) mmol/L respectively (P<0.01, P< 0.05). Compared with no simvastatin treatment, the bilateral ABI levels were significantly elevated. The right side of ABI (ABIR) elevated from 1.11 ± 0.06 to 1.19 ± 0.07, and the left side of ABI (ABIL) also elevated from 1.12 ± 0.06 to 1.19 ± 0.10 (both sides were P<0.01). The FMD significantly increased from 7.75% ± 11.30% to 14.20% ± 15.39% (P < 0.05). The plasma levels of MCP-1 were apparently reduced from (112.0 ± 7.8) ng/L to (108.9 ± 6.2) ng/L (P < 0.05). All these items showed no obvious change within the control group.The API, FMD and plasma levels of MCP-1 of hypercholesterolemia patients without clear coronary heart disease can be improved by simvastatin treatment.