Jeong Yeal Ahn

Additive Beneficial Effects of Losartan Combined With Simvastatin in the Treatment of Hypercholesterolemic, Hypertensive Patients

Background—Biological mechanisms underlying statin and angiotensin II type 1 receptor blocker therapies differ. Therefore, we compared vascular and metabolic responses to these therapies either alone or in combination in hypercholesterolemic, hypertensive patients. Methods and Results—This was a randomized, double-blind, placebo-controlled crossover trial with 3 treatment arms (each 2 months) and 2 washout periods (each 2 months). Forty-seven hypertensive, hypercholesterolemic patients were given simvastatin 20 mg and placebo, simvastatin 20 mg and losartan 100 mg, or losartan 100 mg and placebo daily during each 2-month treatment period. Losartan alone or combined therapy significantly reduced blood pressure compared with simvastatin alone. Compared with losartan alone, simvastatin alone or combined therapy significantly changed lipoproteins. All 3 treatment arms significantly improved flow-mediated dilator response to hyperemia and decreased plasma malondialdehyde and monocyte chemoattractant protein-1 levels relative to baseline measurements. However, these parameters were changed to a greater extent with combined therapy compared with simvastatin or losartan alone (both P<0.001 and P=0.030 for monocyte chemoattractant protein-1 by ANOVA). Combined therapy or losartan alone significantly increased plasma adiponectin levels and insulin sensitivity (determined by QUICKI) relative to baseline measurements. These changes were significantly greater than in the group treated with simvastatin alone (P<0.001 for adiponectin, P=0.029 for QUICKI by ANOVA). Conclusions—Simvastatin combined with losartan improves endothelial function and reduces inflammatory markers to a greater extent than monotherapy with either drug in hypercholesterolemic, hypertensive patients.

Pleiotropic effects of angiotensin II receptor blocker in hypertensive patients.

OBJECTIVES We investigated the vascular effects of candesartan in hypertensive patients. BACKGROUND The renin-angiotensin system may contribute to atherogenesis through the promotion of endothelial dysfunction. The plausible mechanisms are that angiotensin II promotes superoxide anion generation, endothelial dysfunction, inflammation, and impaired fibrinolysis. The effects of candesartan on these conditions have not been clearly observed. METHODS We administered placebo or candesartan 16 mg daily during two months to 45 patients with mild-to-moderate hypertension. This was a randomized, double-blind, placebo-controlled, crossover study in design. RESULTS Candesartan did not significantly change lipoprotein levels. However, compared with placebo, candesartan significantly reduced plasma levels of malondialdehyde from 1.50 +/- 0.07 to 1.29 +/- 0.09 microM (p = 0.009); improved the percent flow-mediated dilator response to hyperemia from 5.17 +/- 0.24 to 6.22 +/- 0.26% (p < 0.001); and, furthermore, reduced plasma levels of monocyte chemoattractant protein (MCP-1) from 213 +/- 8 to 190 +/- 7 pg/ml (p = 0.003), tumor necrosis factor-alpha from 2.93 to 2.22 pg/ml (p = 0.026), and plasminogen activator inhibitor type 1 from 74 +/- 4 to 53 +/- 4 ng/ml (p < 0.001) but not C-reactive protein (CRP), matrix metalloproteinase protein, and fibrinogen. There were no significant correlations between these changes and reduction of systolic blood pressure (BP) (-0.247 < or = r < or = 0.195) and between these changes and reduction of diastolic BP (-0.262 < or = r < or = 0.197). There were no significant correlations between markers of inflammation and flow-mediated dilation percent or reduction of oxidant stress (-0.119 < or = r < or = 0.127). Furthermore, we observed no significant correlations between CRP and MCP-1 levels (r = -0.162). CONCLUSIONS Inhibition of the angiotensin II type 1 (AT1) receptor in hypertensive patients reverses endothelial dysfunction, measured as an improvement in flow-mediated dilation and fibrinolysis and reduction of oxidant stress and inflammatory cytokines, suggesting that AT1 receptor blocker therapy has antiatherogenic effects.

Vascular and Metabolic Effects of Combined Therapy With Ramipril and Simvastatin in Patients With Type 2 Diabetes

Mechanisms underlying biological effects of statin and angiotensin-converting enzyme inhibitor therapies differ. Therefore, we compared vascular and metabolic responses to these therapies either alone or in combination in patients with type 2 diabetes. This was a randomized, double-blind, placebo-controlled crossover trial with 3 treatment arms (each 2 months) and 2 washout periods (each 2 months). Fifty patients with type 2 diabetes were given simvastatin 20 mg and placebo, simvastatin 20 mg and ramipril 10 mg, or ramipril 10 mg and placebo daily during each 2-month treatment period. Ramipril alone or combined therapy significantly reduced blood pressure when compared with simvastatin alone. When compared with ramipril alone, simvastatin alone or combined therapy significantly improved the lipoprotein profile. All 3 treatment arms significantly improved flow-mediated dilator response to hyperemia and reduced plasma levels of malondialdehyde relative to baseline measurements. However, these parameters were changed to a greater extent with combined therapy when compared with simvastatin or ramipril alone (P<0.001 by ANOVA). When compared with simvastatin or ramipril alone, combined therapy significantly reduced high-sensitivity C-reactive protein levels (P=0.004 by ANOVA). Interestingly, combined therapy or ramipril alone significantly increased plasma adiponectin levels and insulin sensitivity relative to baseline measurements. These changes were significantly greater than in the group treated with simvastatin alone (P<0.015 by ANOVA). Ramipril combined with simvastatin had beneficial vascular and metabolic effects when compared with monotherapy in patients with type 2 diabetes.

Effects of Conventional or Lower Doses of Hormone Replacement Therapy in Postmenopausal Women

Objective—The effects of hormone replacement therapy (HRT) can affect many aspects relevant to cardiovascular disease, including vasomotor function, inflammation, and hemostasis. Recent studies have demonstrated that current doses of HRT exert a mixture of both protective and adverse effects. In the current study, we compared the effects of lower doses of HRT (L-HRT) and conventional doses of HRT (C-HRT) on a variety of relevant cardiovascular parameters. Methods and Results—This randomized, double-blind, crossover study included 57 women who received micronized progesterone 100 mg with either conjugated equine estrogen 0.625 mg (C-HRT) or 0.3 mg (L-HRT) daily for 2 months. L-HRT showed comparable effects to C-HRT on high-density lipoprotein cholesterol and triglyceride levels, but not on low-density lipoprotein cholesterol levels. C-HRT and L-HRT significantly improved the percent flow-mediated dilator response to hyperemia from baseline values (both P <0.001) by a similar degree (P =0.719). C-HRT significantly increased high-sensitivity C-reactive protein (hsCRP) levels from baseline values (P <0.001); however, L-HRT did not significantly change hsCRP (P =0.874). C-HRT and L-HRT significantly decreased antithrombin III from baseline values (P <0.001 and P =0.042, respectively). C-HRT significantly increased prothrombin fragment 1+2 (F1+2) from baseline values (P <0.001); however, L-HRT did not significantly change F1+2 (P =0.558). Of interest, the effects of C-HRT and L-HRT on hsCRP, antithrombin III, and F1+2 were significantly different (all P <0.001). C-HRT and L-HRT significantly reduced plasma PAI-1 antigen levels from baseline values (P =0.002 and P =0.038, respectively) to a similar degree (P =0.184). Conclusions—Compared with C-HRT, L-HRT has comparable effects on lipoproteins, flow-mediated dilation, and PAI-1 antigen levels. However, L-HRT did not increase hsCRP or F1+2 levels, and it decreased antithrombin III less than C-HRT.

Effects of statin on plaque stability and thrombogenicity in hypercholesterolemic patients with coronary artery disease

OBJECTIVE Plaque stability and thrombogenicity contribute to development and clinical expression of atherosclerosis. Experimental studies have shown that lipoproteins or mevalonate regulate matrix metalloproteinase (MMP)-9, tissue factor (TF), plasminogen activator inhibitor-1 (PAI-1) expression, providing nonlipid mechanism. METHODS We administered simvastatin 20 mg daily during 14 weeks to 32 hypercholesterolemic patients with coronary artery disease. RESULTS Compared with pretreatment values, simvastatin significantly lowered lipoprotein levels (all P<0.01). Compared with pretreatment values, simvastatin significantly lowered plasma levels of MMP-9, TF, and PAI-1 (P=0.009, P=0.032, and P=0.007, respectively). There were significant inverse correlations between pretreatment MMP-9, TF activity or PAI-1 antigen and the degree of change in those levels after simvastatin (r=-0.793, P<0.001; r=-0.482, P=0.005 and r=-0.590, P<0.001, respectively). Of interest, there were significant correlation between pretreatment or percent changes in MMP-9 levels and pretreatment or percent changes in PAI-1 antigen (r=0.293, P=0.019 and r=0.375, P=0.034, respectively). However, no significant correlations between lipoprotein levels and levels of plaque stability or thrombogenicity markers were determined. CONCLUSIONS Reduction of plaque stability and thrombogenicity markers with statin may contribute to the cardiovascular event reduction and explain the early clinical benefit in clinical trials, independent of lipoprotein changes.

Vascular effects of estrogen in type II diabetic postmenopausal women

OBJECTIVES We assessed the effects of estrogen on vascular dilatory and other homeostatic functions potentially affected by nitric oxide (NO)-potentiating properties in type II diabetic postmenopausal women. BACKGROUND There is a higher cardiovascular risk in diabetic women than in nondiabetic women. This would suggest that women with diabetes do not have the cardioprotection associated with estrogen. METHODS We administered placebo or conjugated equine estrogen, 0.625 mg/day for 8 weeks, to 20 type II diabetic postmenopausal women in a randomized, double-blinded, placebo-controlled, cross-over design. RESULTS Compared with placebo, estrogen tended to lower low-density lipoprotein (LDL) cholesterol levels by 15 +/- 23% (p = 0.007) and increase high-density lipoprotein (HDL) cholesterol levels by 8 +/- 16% (p = 0.034). Thus, the ratio of LDL to HDL cholesterol levels significantly decreased with estrogen, by 20 +/- 24%, as compared with placebo (p = 0.001). Compared with placebo, estrogen tended to increase triglyceride levels by 16 +/- 48% and lower glycosylated hemoglobin levels by 3 +/- 13% (p = 0.295 and p = 0.199, respectively). However, estrogen did not significantly improve the percent flow-mediated dilatory response to hyperemia (17 +/- 75% vs. placebo; p = 0.501). The statistical power to accept our observation was 81.5%. Compared with placebo, estrogen did not significantly change E-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, monocyte chemoattractant protein-1 or matrix metalloproteinase-9 levels. Compared with placebo, estrogen tended to decrease tissue factor antigen and increase tissue factor activity levels by 7 +/- 46% and 5 +/- 34%, respectively (p = 0.321 and p = 0.117, respectively) and lower plasminogen activator inhibitor-1 levels by 16 +/- 31% (p = 0.043). CONCLUSIONS The effects of estrogen on endothelial, vascular dilatory and other homeostatic functions were less apparent in type II diabetic postmenopausal women, despite the beneficial effects of estrogen on lipoprotein levels.

Effect of hormone replacement therapy on nitric oxide bioactivity and monocyte chemoattractant protein-1 levels

BACKGROUND Vascular inflammation plays an important role in the pathogenesis of atherosclerosis. We investigated the effect of hormone replacement therapy (HRT) on vasomotor function and monocyte chemoattractant protein (MCP)-1 levels, an important serological marker of inflammation. METHODS We administered micronized progesterone (MP) 200 mg for 10 days with conjugated equine estrogen (CEE) 0.625 mg for 25 days and remaining 5 days off cyclically during 2 months to 20 healthy postmenopausal women (PMW). We measured NO bioactivity and plasma levels of MCP-1 before and after HRT in 20 PMW. And we measured plasma levels of MCP-1 in each 20 subjects of premenopausal women, men <50, and men >50 years, respectively. RESULTS MP combined with CEE significantly improved the percent flow-mediated dilator response to hyperemia relative to baseline measurements (P<0.001). PMW receiving HRT had lower levels of MCP-1 than those not receiving HRT (121+/-38 versus 146+/-44 pg/ml, P<0.001). In all comparisons, subjects with high estrogen status had significantly lower MCP-1 levels than subjects with low estrogen status (P<0.001 by ANOVA). Premenopausal women had lower levels of MCP-1 than men of a similar age (106+/-14 versus 164+/-40 pg/ml, P<0.001). PMW not receiving HRT had similar levels of MCP-1 compared with men of a similar age (146+/-44 versus 143+/-29 pg/ml, P=0.816). Premenopausal women had markedly lower levels of MCP-1 than PMW not receiving HRT (106+/-14 versus 146+/-44 pg/ml, P=0.001). PMW receiving HRT had similar levels of MCP-1 compared with premenopausal women (121+/-38 versus 106+/-14 pg/ml, P=0.323). CONCLUSION These findings might provide at least a partial explanation for the protection against cardiovascular disease experienced by premenopausal women, and the loss of that protection following menopause.

Simvastatin combined with ramipril treatment in hypercholesterolemic patients

Mechanisms underlying biological effects of statin and angiotensin-converting enzyme inhibitor therapies differ. Thus, we studied vascular responses to combination therapy in hypercholesterolemic patients. A randomized, double-blind, placebo-controlled, crossover trial was conducted with 50 hypercholesterolemic patients with simvastatin and either placebo or ramipril (study I) and in 45 hypercholesterolemic diabetic patients with simvastatin or ramipril with placebo or simvastatin combined with ramipril (study II) for 2 months with 2 months washout. In study I simvastatin combined with ramipril significantly reduced blood pressure after 2 months. Simvastatin alone or combined with ramipril significantly changed lipoproteins, improved percent flow-mediated dilator response to hyperemia by 30±5% and 53±6%, respectively (P <0.001), and reduced plasma levels of malondialdehyde by 4±7% (P =0.026) and 25±4% (P <0.001), respectively. Monocyte chemoattractant protein-1 levels decreased by 3±3% and 12±2%, respectively (P =0.049 and P <0.001, respectively), C-reactive protein levels changed by 0% and 18%, respectively (P =0.036 and P <0.001, respectively), and plasminogen activator inhibitor-1 antigen levels changed by −7±7% and 17±5%, respectively (P =0.828 and P <0.001, respectively). In study II ramipril alone did not significantly change lipoproteins and C-reactive protein levels, however, simvastatin combined with ramipril significantly changed lipoproteins and C-reactive protein levels more than ramipril alone (P <0.001 and P =0.048 by ANOVA, respectively). Ramipril alone or simvastatin combined with ramipril significantly improved the percent flow-mediated dilator response to hyperemia (both P <0.001), however, simvastatin combined with ramipril showed significantly more improvement than ramipril alone (P <0.001 by ANOVA). Simvastatin combined with ramipril significantly improved endothelium-dependent vasodilation and fibrinolysis potential and reduced plasma levels of oxidant stress and inflammation markers in hypercholesterolemic patients.

Effects of hormone replacement therapy on plaque stability, inflammation, and fibrinolysis in hypertensive or overweight postmenopausal women ☆

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Amlodipine improves endothelial function and metabolic parameters in patients with hypertension

BACKGROUND Reciprocal relationships between endothelial dysfunction and insulin resistance imply that improvement in endothelial dysfunction will have beneficial metabolic consequences. We hypothesized that amlodipine therapy in hypertensive subjects will improve endothelial dysfunction and metabolic parameters. METHODS Amlodipine (10 mg daily for 8 weeks) or placebo was given to each 45 patients with mild to moderate hypertension in a randomized, double-blind, placebo-controlled, and parallel study. Age, sex, and body mass index were matched. RESULTS Amlodipine therapy significantly reduced systolic and diastolic blood pressure and increased HDL-cholesterol to greater extent than placebo therapy (all P<0.001). Amlodipine therapy significantly improved flow-mediated dilator response to hyperemia and reduced plasma malondialdehyde levels to a greater extent than placebo (P<0.001 and P=0.035). Amlodipine therapy significantly increased plasma adiponectin levels (P=0.009) and decreased plasma leptin and resistin levels (P<0.001 and P=0.025, respectively) to a greater extent than placebo. Correlations were noted between percent changes in adiponectin levels and percent changes in HDL-cholesterol (r=0.348, P=0.019) and QUICKI (r=0.326, P=0.029) following amlodipine therapy. Only changes in HDL-cholesterol (beta=0.469, P=0.019) and QUICKI (beta=1.786, P=0.069) were independent predictors of changes in adiponectin levels (multivariate regression analysis). We also observed inverse correlations between percent changes in leptin levels and percent changes in QUICKI (r=-0.569, P<0.001) following amlodipine therapy with changes in QUICKI (beta=1.810, P<0.001) as an independent predictor of changes in leptin levels. CONCLUSIONS Amlodipine therapy improves blood pressure, endothelial function, and metabolic parameters in patients with hypertension.