Efficacy and Safety of Policosanol Plus Fenofibrate Combination Therapy in Elderly Patients with Mixed Dyslipidemia: A Randomized, Controlled Clinical Study.

BACKGROUND: Policosanol is a mixture of long-chain alcohols isolated from sugar cane. This controlled, randomized clinical trial was designed to compare the efficacy and safety of fenofibrate, policosanol and a combination of these 2 in lowering low-density-lipoprotein cholesterol (LDL-C) in elderly patients with mixed dyslipidemia. METHODS: A total of 102 patients aged ≥60years were randomly assigned into 3 groups: patients receiving a 24-week therapy of fenofibrate (200 mg/day), policosanol (20 mg/day) or fenofibrate + policosanol combination. Lipids were evaluated at baseline, after 16 and after 24 weeks of therapy. Brachial-ankle pulse wave velocity (ba-PWV) was performed, and SF-36 questionnaires were used to evaluate the patients' quality of life. The primary endpoint was the percentage reduction in LDL-C. The secondary end points included percentage change in nonhigh density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), triglyceride, high-density-lipoprotein cholesterol (HDL-C), ba-PWV and SF-36 scores. Safety was assessed by adverse events and laboratory parameters. RESULTS: LDL-C, non-HDL-C and TC were decreased, respectively after treatment with policosanol for 24 weeks (P < 0.01). Treatment with policosanol + fenofibrate resulted in significantly greater reductions in TC, non-HDL-C and LDL-C compared to fenofibrate alone (P < 0.01, respectively). There were significant increases in SF-36 scores in the policosanol and policosanol + fenofibrate groups (P < 0.05), and significant improvements of ba-PWV in the 2 groups (P < 0.01). There were no serious adverse events or significant changes in laboratory variables after any of the treatment regimens. CONCLUSIONS: Policosanol + fenofibrate combination therapy significantly improved lipid parameters, arterial stiffness, and quality of life, with good tolerability.

Differential ERK1/2 Signaling and Hypertrophic Response to Endothelin-1 in Cardiomyocytes from SHR and Wistar-Kyoto Rats: A Potential Target for Combination Therapy of Hypertension.

Extracellular signal regulated kinase½ (ERK1/2) signaling is critical to endothelin-1 (ET-1)-induced cardiomyocyte hypertrophy. This study was to investigate ERK1/2 signaling and hypertrophic response to ET-1 stimulation in cardiomyocytes (CMs) from spontaneous hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Primary neonatal SHR and WKY CMs were exposed to ET-1 for up to 24 hrs. Minimal basal ERK1/2 phosphorylation was present in WKY CMs, while a significant baseline ERK1/2 phosphorylation was observed in SHR CMs. ET-1 induced a time- and dose-dependent increase in ERK1/2 phosphorylation in both SHR and WKY CMs. However, ET-1-induced ERK1/2 activation occurred much earlier with significantly higher peak phosphorylation level, and stayed elevated for longer duration in SHR CMs than that in WKY CMs. ET-1-induced hypertrophic response was more prominent in SHR CMs than that in WKY CMs as reflected by increased cell surface area, intracellular actin density, and protein synthesis. Pre-treatment with ERK1/2 phosphorylation inhibitor PD98059 completely prevented ET-1-induced ERK1/2 phosphorylation and increases in cell surface area and protein synthesis in SHR and WKY CMs. The specific PI3 kinase inhibitor LY294002 blocked ET-1-induced Akt and ERK1/2 phosphorylation, and protein synthesis in CMs. These data indicated that ERK1/2 signaling was differentially enhanced in CMs, and was associated with increased cardiac hypertrophic response to ET-1 in SHR. ET-1-induced ERK1/2 activation and cardiac hypertrophy appeared to be mediated via PI3 kinase/Akt signaling in SHR and WKY. The differential ERK1/2 activation in SHR CMs by ET-1 might represent a potential target for combination therapy of hypertension.

Adventitial gene transfer of catalase attenuates angiotensin II-induced vascular remodeling.

Vascular adventitia and adventitia­derived reactive oxygen species (ROS) contribute to vascular remodeling following vascular injury. A previous ex vivo study in adventitial fibroblasts showed that catalase, one of most important anti­oxide enzymes, was downregulated by angiotensin II (AngII). The aim of the present study was to investigate whether adventitial gene transfer of catalase affects AngII­induced vascular remodeling in vivo. Adenoviruses co­expressing catalase and enhanced green fluorescent protein (eGFP) or expressing eGFP only were applied to the adventitial surface of common carotid arteries of Sprague­Dawley rats. Alzet minipumps administering AngII (0.75 mg/kg/day) were then implanted subcutaneously for 14 days. Systolic blood pressure and biological parameters of vascular remodeling were measured in each group. Adventitial fibroblasts were cultured and p38 mitogen­activated protein kinase (MAPK) phosphorylation was measured using western blot analysis. The results showed that adventitial gene transfer of catalase had no effect on AngII­induced systolic blood pressure elevation. However, catalase adenovirus transfection significantly inhibited AngII­induced media hypertrophy compared with that of the control virus (P<0.05). In addition, catalase transfection significantly attenuated AngII­induced ROS generation, macrophage infiltration, collagen deposition and adventitial α­smooth muscle actin expression. Furthermore, catalase transfection significantly inhibited the AngII­induced increase in p38MAPK phosphorylation. In conclusion, the results of the present study demonstrated that adventitial gene transfer of catalase significantly attenuated AngII­induced vascular remodeling in rats via inhibition of adventitial p38MAPK phosphorylation.

[Association between total antioxidant status and atherosclerosis in elderly patients with essential hypertension].

OBJECTIVE: To investigate the association between plasma total antioxidant status (TAS) and association with brachial-ankle pulsewave velocity (baPWV) in the elderly patients with essential hypertension(EH). METHODS: A total of 133 consecutive EH patients older than 60 years were enrolled and another 92 elderly non-EH healthy subjects served as control. According to blood pressure level, EH patients were further classified into three subgroups. The concentration of plasma total antioxidant status was measured by using chemical luminescence method. High-sensitive CRP, urine microalbumin, uric acid, blood lipids and blood glucose levels were also measured. Carotid intima-media thickness was determined by color Doppler ultrasonography and the degree of arteriosclerosis was investigated with baPWV and ankle-brachial index (ABI). RESULTS: (1) Plasma levels of TAS in EH patients were significant lower than in control group [(1.123 ± 0.126)mmol/L vs. (1.258 ± 0.125) mmol/L, P < 0.05], and were similar among hypertension subgroups (P > 0.05).(2) Stepwise multiple regression analysis showed that age, gender, body mass index, systolic blood pressure, diastolic blood pressure, high-sensitive CRP, UA were dependent variables of TAS. Multivariate regression analysis showed that high-sensitivity CRP, UA were independent factors affecting TAS (ß = -0.03, standardized ß = -0.01, P < 0.05). (3) Compared with the control group, baPWV was significantly higher in elderly EH patients left baPWV (1914 ± 341) cm/s vs. (1817 ± 322) cm/s, right baPWV (1899 ± 330) cm/s vs. (1772 ± 345) cm/s(P < 0.05)and baPWV tended to increase with the level of blood pressure of EH group (P < 0.05) . (4) After adjusting for age, CRP, UA, partial correlation analysis showed that plasma TAS was negatively correlated with baPWV (r = -0.459, P < 0.05). CONCLUSIONS: Our results indicate that TAS and arterial elasticity are decreased while arterial stiffness is increased in elderly hypertensive patients. The decline in antioxidant capacity may be responsible for vascular damage and arterial elasticity decrease in elderly EH patients.

Gamma-glutamyltransferase level and risk of hypertension: a systematic review and meta-analysis.

BACKGROUND: Several prospective observational studies suggest that gamma-glutamyltransferase(GGT) level is positively associated with risk of hypertension. However, these studies draw inconsistent conclusions. Therefore, we conducted a systematic review and meta-analysis to evaluate the exact association between GGT level and subsequent development of hypertension. METHODS: We searched Pubmed, Embase, and Science Citation Index (ISI Web of Science) for prospective cohort studies examining the association between GGT level and hypertension. Then, pooled effect estimates (RRs) for the association between GGT level and hypertension were calculated. RESULTS: A total of 13 prospective cohort studies including 43314 participants and 5280 cases of hypertension were included. The pooled RR of hypertension was 1.94(95%CI: 1.55-2.43; P<0.001) when comparing the risk of hypertension between the highest versus lowest category of GGT levels. Moreover, the risk of hypertension increased by 23% (summary RR: 1.23; 95%CI: 1.13-1.32; P<0.001) per 1 SD logGGT increment. Subgroup analyses showed significant positive associations in each subgroup except in ≧160/95 subgroup (RR: 2.56, 95%CI: 0.87-7.54; P = 0.088) and nondrinkers subgroup (RR: 1.76, 95%CI: 0.88-3.53; P = 0.113). Sensitivity analyses showed no single study significantly affects the pooled RRs. No publication bias was found in our meta-analysis. CONCLUSIONS: GGT level is positively associated with the development of hypertension. Further studies are needed to confirm our findings and elucidate the exact mechanisms between GGT level and the incidence of hypertension.

Differential expression of alpha-enolase in the normal and pathological cardiac growth.

OBJECTIVES: It was found that alpha-enolase was dramatically up-regulated in the hypertrophic hearts of SHR in our previous study. The purposes of this study were to examine the expression pattern of alpha-enolase in pre- and postnatal myocardium of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats, and to explore the relationship between the overexpression of alpha-enolase and left ventricular hypertrophy. METHODS: HE staining was used for the measurement of cardiac hypertrophy. Immunohistochemical technique was used to evaluate the location of alpha-enolase. The expressions of alpha-enolase in the left cardiac ventricles at different development times were examined by Real-time RT-PCR and Western blot. RESULTS: Cardiac hypertrophy was found in SHR rats at 4 weeks of age and remained up to 24 weeks of age. The signals of alpha-enolase protein were strong and existed extensively in hypertrophic myocardium in SHR, while in the normal myocardium of WKY, the signals were scarcely found and weak. The levels of alpha-enolase mRNA and protein in SHR and WKY hearts during fetal stage and newborn stage were similar, while from 4 weeks of age to 24 weeks of age, accompanied by the cardiac hypertrophy, the levels of alpha-enolase mRNA and protein in left ventricle of SHR were significantly higher than that in WKY. CONCLUSIONS: The expressions of alpha-enolase in the left ventricle of the rats during normal and pathological cardiac development were different. This phenomenon provides the potential clues to understanding pathophysiological mechanisms in cardiac hypertrophy of SHR.

Circulating endothelial progenitor cells in Chinese patients with acute stroke.

To test the hypothesis that a mobilization of endothelial progenitor cells (EPCs) occurs after acute cerebrovascular diseases, we evaluated the number of EPCs in the process of acute stroke. A total of 203 individuals were examined, including 100 patients with ischemic strokes, 36 patients with hemorrhagic strokes and 67 healthy controls. Ninety-eight patients were observed at days 1, 7, 14 and 28 after acute stroke. Circulating EPCs were defined by the surface markers CD133/KDR and analyzed by flow cytometry. Serum high sensitivity C-reactive protein (hs-CRP) concentrations were determined by particle-enhanced immunonephelometry using the N high sensitivity CRP Reagent. Patients with acute stroke had lower numbers of EPCs (0.037+/-0.001/100 peripheral blood mononuclear cells (PMNCs) vs. 0.06+/-0.002/100 PMNCs, P<0.05) and higher levels of serum hs-CRP (1.99 vs. 0.03 mg per 100 ml, P<0.05) than control subjects after adjusting for age, sex, body mass index (BMI) and blood pressure. There were no differences in EPCs counts or serum hs-CRP levels between patients with ischemic and hemorrhagic stroke. In univariate analyses, BMI, age, systolic blood pressure (SBP), diastolic blood pressure, low-density lipoprotein (LDL), total cholesterol (T-cho), blood glucose and hs-CRP (P<0.001) were inversely correlated with EPCs counts. Multivariate analyses showed SBP and total cholesterol as independent predictors of EPCs levels. The number of EPCs gradually increased at day 7 after acute onset, remained elevated at day 14; and returned to baseline by day 28. Our results suggest a possible contribution of circulating EPCs in acute stroke. SBP and total cholesterol are independent factors of reduced EPCs numbers. A transient early increment of EPCs may result from the mobilization of EPCs in response to stroke stress.

Efficacy and safety of benidipine therapy of essential hypertension in elderly Chinese patients.

BACKGROUND: Benidipine (CAS 105979-17-7) is a dihydropyridine calcium channel blocker used in the treatment of hypertension and angina pectoris. OBJECTIVE: To examine the efficacy and safety of therapy with benidipine in elderly hypertensive patients. METHODS: Chinese patients >60 years of age with mild to moderate essential hypertension were enrolled. The patients were prescribed benidipine at the dose of 8 mg once daily for 12 weeks. Detailed laboratory examinations and 24-h ambulatory blood pressure monitoring were performed before and after the treatment. RESULTS: One hundred and sixty-four of the 180 patients enrolled completed the 12-week active treatment phase. Sitting systolic blood pressure (SBP) and diastolic blood pressure (DBP) reductions at the end of treatment were 21.50 +/- 12.83 and 10.60 +/- 8.04 mmHg, respectively; the proportion of patients showing a good treatment response was 95.1% for SBP and 96.9% for DBP. Benidipine significantly reduced the mean 24-h ambulatory blood pressure (p < 0.001 vs. baseline) exhibiting smooth, sustained effects and high trough-to-peak ratios (T/P ratio) (0.87 for SBP and 0.72 for DBP). Moreover, benidIpine significantly reduced the systolic morning blood pressure surge and urinary albumin, and it was well tolerated. No serious adverse events were noted. CONCLUSION: Benidipine was welltolerated and effective in elderly Chinese patients with essential hypertension.

Circulating endothelial progenitor cells, C-reactive protein and severity of coronary stenosis in Chinese patients with coronary artery disease.

We sought to investigate whether numbers and activity of circulating endothelial progenitor cells (EPCs) correlate with severity of coronary stenosis as well as cardiovascular risk factors in patients with stable coronary artery disease (CAD). Number of circulating EPCs was analyzed in 104 consecutive patients with proven or clinically suspected CAD. Adhesive and migratory activity was also determined. The number of EPCs was lower in patients with a single diseased coronary artery (Group II, n=35, p<0.05 vs. Group I) or multiple diseased arteries (Group III, n=25, p<0.01 vs. Group I, p<0.05 vs. Group II) compared to those with normal coronary arteries (Group I, n=44). The number of EPCs was also related with angiographic Gensini score (r=-0.355, p=0.006). In addition, concentrations of C-reactive protein (CRP) were elevated in patients with CAD, and positively correlated with Gensini score (r=0.476, p=0.001). As for the risk factors, the number of EPCs was also inversely correlated with age (p=0.001), high sensitivity-CRP (p=0.012), hypertension (p=0.042) and family history of CAD (p=0.043). Most importantly, the migratory capacity of EPCs was compromised in patients with CAD, and inversely correlated with the angiographic Gensini score (r=-0.315, p=0.021). EPCs isolated from patients with CAD also showed an impaired adhesive activity (p<0.05). In conclusion, in patients with stable CAD, reduction in the number and impairment in the function of circulating EPCs were correlated with the severity of coronary stenosis. CRP may play an important role in reducing the number of EPCs and accelerating atherosclerosis. Given the important role of EPCs in neovascularization of ischemic tissue, a decrease in the number and activity of EPCs may contribute to the impaired vascularization in patients with CAD.

[Number of circulating endothelial progenitor cells inversely correlate with the severity of coronary artery disease in patients with stable coronary artery disease].

OBJECTIVE: To investigate whether the number of circulating endothelial progenitor cells (EPCs) correlate with the severity of coronary stenosis in patients with stable coronary artery disease (CAD). METHODS: 80 consecutive patients who underwent coronary angiography (exclusion of acute coronary syndrome and myocardial infarction) were enrolled. Physical examination and blood tests were performed to assess the disease severity and cardiovascular risk factors. Circulating EPCs as measured by the number of CD133/KDR double positive cells were detected by FACS. RESULTS: The number of EPCs inversely correlated with age, creatinine clearance (Ccr) and left ventricular mass index (LVMI) (P = 0.004, 0.015, 0.014 respectively). Patients with hypertension showed significant reduction in number of EPCs compared to those without hypertension (P = 0.004). Moreover, the number of EPCs in patients with coronary artery disease was significantly lower than that of those with normal coronary artery (P < 0.01). EPCs also inversely correlated with angiographic Gensini score (n = 49, r = -0.305, P = 0.039). CONCLUSIONS: In patients with stable CAD, the numbers of circulating EPCs correlate with the severity of CAD as well as cardiovascular risk factors.