The union of vascular and metabolic actions of insulin in sickness and in health.
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Blood Vessels↗
Biomedical subjects
Kwang Kon Koh
Publications and source records attributed to Kwang Kon Koh.
Beneficial effects of fenofibrate to improve endothelial dysfunction and raise adiponectin levels in patients with primary hypertriglyceridemia.
OBJECTIVE: Improvement in endothelial function is predicted to improve insulin sensitivity, and this may be one mechanism by which fenofibrate decreases the incidence of coronary heart disease. We hypothesize fenofibrate improves endothelial function by enhancing insulin sensitivity. RESEARCH DESIGN AND METHODS: We administered placebo or fenofibrate 200 mg daily for 8 weeks to 46 patients with primary hypertriglyceridemia (24 had metabolic syndrome). This study was randomized, double blind, placebo controlled, and crossover in design. RESULTS: Compared with placebo, fenofibrate decreased total cholesterol, non-HDL cholesterol, apolipoprotein B, and triglycerides and increased HDL cholesterol and apolipoprotein A-I (all P < 0.001) while tending to decrease LDL cholesterol (P = 0.069). Fenofibrate significantly improved percent flow-mediated dilator response to hyperemia by 48 +/- 5% (P < 0.001) and lowered plasma levels of high-sensitivity C-reactive protein (hsCRP) relative to baseline measurements from 0.80 to 0.70 mg/l (P = 0.001) and fibrinogen levels by 16 +/- 3% (P < 0.001). Compared with placebo, fenofibrate therapy significantly increased plasma levels of adiponectin by 14 +/- 5% (P = 0.008) and increased insulin sensitivity (assessed by quantitative insulin sensitivity check index [QUICKI]) by 6 +/- 2% (P = 0.048). There were significant correlations between percent changes in adiponectin levels and percent changes in flow-mediated dilation (r = 0.401, P = 0.006), hsCRP (r = -0.443, P = 0.002), or QUICKI (r = 0.292, P = 0.049). Multivariate regression analysis showed that only changes in adiponectin levels persisted as an independent predictor of changes in flow-mediated dilation (r = 0.504, P = 0.013). Overall, we observed similar results in 24 patients with metabolic syndrome. CONCLUSIONS: Fenofibrate therapy significantly improved percent flow-mediated dilator response to hyperemia, reduced inflammation marker levels, increased adiponectin levels, and improved insulin sensitivity in hypertriglyceridemic or metabolic syndrome patients.
Adiponectin↗
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.
Adiponectin↗
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.
Angina Pectoris↗
Comparison of effects of losartan, irbesartan, and candesartan on flow-mediated brachial artery dilation and on inflammatory and thrombolytic markers in patients with systemic hypertension.
We administered placebo, losartan 100 mg/day, irbesartan 300 mg/day, and candesartan 16 mg/day during 2 months to 122 patients with mild to moderate hypertension. Compared with placebo, angiotensin II type-1 receptor blockers significantly improved the percent flow-mediated dilator response to hyperemia (p = 0.019 by analysis of variance [ANOVA]) and reduced plasma levels of malondialdehyde (p = 0.005 by ANOVA). However, only irbesartan and candesartan therapies significantly lowered plasma levels of plasminogen activator inhibitor type-1 antigen (p <0.001 by ANOVA) with no differences between the 2, and only candesartan therapy significantly lowered plasma levels of monocyte chemoattractant protein-1 (p = 0.004 by ANOVA).
Angiotensin II↗
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.
Antithrombin III↗
Should progestins be blamed for the failure of hormone replacement therapy to reduce cardiovascular events in randomized controlled trials?
Many observational studies and experimental and animal studies have demonstrated that estrogen replacement therapy (ERT) or hormone replacement therapy (HRT) (estrogen plus progestin) significantly reduces the risk of coronary heart disease. Nonetheless, recent randomized controlled trials demonstrated some trends toward an increased risk of cardiovascular events rather than a reduction of risk. Recently, both the HRT and ERT arms of the Women's Health Initiative (WHI) study were terminated early because of an increased/no incidence of invasive breast cancer, increased incidence of stroke, and increased trend/no protective effects of cardiovascular disease. We discuss the controversial effects of HRT and ERT on cardiovascular system and provide a hypothesis that the failure of HRT and ERT in reducing the risk of cardiovascular events in postmenopausal women might be because of the stage of their atherosclerosis at the time of initiation of HRT or ERT.
Aged↗
Protruding left atrial myxoma presented with congestive heart failure and transient ischemic attack.
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Echocardiography, Doppler↗
Effects of fenofibrate on lipoproteins, vasomotor function, and serological markers of inflammation, plaque stabilization, and hemostasis.
We investigated the effects of fenofibrate, peroxisome proliferator-activated receptors (PPARs) agonist, on endothelial function in patients with hypertriglyceridemia. We administered placebo or fenofibrate 200 mg daily to 25 patients with hypertriglyceridemia for 8 weeks. This study was randomized, double-blind, placebo-controlled, crossover in design. Compared with placebo, fenofibrate significantly changed lipoprotein levels including non-HDL cholesterol and significantly improved the percent flow-mediated dilator response to hyperemia by 13 +/- 6% (P < 0.001) and lowered plasma levels of tumor necrosis factor-alpha by 13 +/- 3% (P < 0.001). Fenofibrate reduced fibrinogen and plasminogen activator inhibitor type 1 antigen levels by 17 +/- 3 and 10 +/- 3%, respectively (P < 0.001 and P = 0.014, respectively). However, fenofibrate did not significantly change plasma levels of nitrate, malondialdehyde, tissue factor activity, and serological markers of plaque stabilization. Fenofibrate significantly changed lipoprotein levels and improved the percent flow-mediated dilator response to hyperemia as well as lowered levels of tumor necrosis factor-alpha (TNF-alpha), fibrinogen, and plasminogen activator inhibitor type 1 antigen.
Adult↗
Vascular effects of simvastatin combined with ramipril in hypercholesterolemic patients with coronary artery disease, compared with simvastatin alone: a randomized, double-blind, placebo-controlled, crossover study.
Because the mechanisms of the biological effects of statin and angiotensin converting enzyme inhibitor therapies differ, we studied the vascular responses to these therapies in hypercholesterolemic patients with coronary artery disease. We administered simvastatin 20 mg and placebo or ramipril 10 mg daily during 2 months with washout 2 months to 32 hypercholesterolemic patients with coronary artery disease. This study was randomized, double-blind, placebo-controlled, crossover in design. Simvastatin alone or combined with ramipril significantly changed lipoproteins, and improved the percent flow-mediated dilator response to hyperemia relative to baseline measurements by 33 +/- 6% and by 50 +/- 14%, respectively (both P <0.001) and reduced plasma levels of nitrate relative to baseline measurements (P=0.413 and 0.037, respectively), the plasma MDA levels relative to baseline measurements by 8 +/- 8% and by 18 +/- 9% (P=0.039 and P <0.001, respectively) and MCP-1 relative to baseline measurements by 7 +/- 4% and by 13 +/- 3%, respectively (P=0.019 and P <0.001, respectively), and CRP from 0.22 to 0.14 mg/dl and from 0.22 to 0.15 mg/dl, respectively (P=0.124 and 0.002, respectively), and PAI-1 antigen relative to baseline measurements (P=0.690 and 0.018, respectively). However, simvastatin combined with ramipril changed to greater but statistically insignificant extent the percent flow-mediated dilator response to hyperemia and plasma levels of nitrate, MDA, MCP-1, and PAI-1 antigen than simvastatin alone. Simvastatin alone or combined with ramipril showed significant beneficial effects on endothelial function in hypercholesterolemic patients with coronary artery disease. However, simvastatin combined with ramipril did not significantly change, compared with simvastatin alone.
Anticholesteremic Agents↗
Angiotensin II type 1 receptor blockers reduce tissue factor activity and plasminogen activator inhibitor type-1 antigen in hypertensive patients: a randomized, double-blind, placebo-controlled study.
Angiotensin II stimulates the expression of tissue factor (TF) and plasminogen activator inhibitor type-1 (PAI-1), and AT1 receptor blockade (ARB) reduces PAI-1 and TF activities in experimental studies. We investigated the effects of ARBs on TF activity, tissue plasminogen activator (tPA), PAI-1 antigen levels, plasma renin activity (PRA) and aldosterone levels in hypertensive patients. Placebo, losartan 100mg, irbesartan 300 mg, and candesartan 16 mg daily were administered to 122 patients for 2 months. Compared with placebo, ARBs significantly reduced TF activity (P <0.001 by ANOVA), and candesartan was the most potent. Compared with placebo or losartan, irbesartan and candesartan significantly lowered plasma levels of PAI-1 antigen (P <0.001 by ANOVA) with no differences between the two. Compared with placebo, all ARBs lowered plasma levels of aldosterone (P=0.012 by ANOVA) and increased PRA (P=0.005 by ANOVA). There were significant correlations between the degree of change in TF activity and PAI-1 antigen levels (r=0.458, P <0.0001) and between the change in TF activity and PRA (r=-0.296, P=0.006), but not with the magnitude of reduction in blood pressure following ARB therapy. ARBs significantly reduced TF activity, PAI-1 antigen levels, and aldosterone levels in hypertensive patients. The clinical significance of the varying potency of some ARBs needs to be further investigated.
Angiotensin II Type 1 Receptor Blockers↗
Vascular effects of diet and statin in hypercholesterolemic patients.
OBJECTIVE: We investigated whether statin improves nitric oxide (NO) bioactivity and reduces serological markers of oxidant stress and inflammation and whether statin-induced reduction in markers of oxidant stress and inflammation is mediated by improvement in NO bioactivity or lipoprotein changes, compared with American Heart Association Step I Diet (Diet). METHODS: We administered diet+placebo and diet+simvastatin 20 mg daily during 14 weeks with randomized order to 31 and 32 patients with coronary artery disease, respectively, with a randomized design. RESULTS: Compared with diet alone, simvastatin significantly improved the percent flow-mediated dilator response to hyperemia and lowered plasma levels of tumor necrosis factor (TNF)-alpha, intercellular adhesion molecule type-1 (ICAM-1), serum levels of CRP, and fibrinogen (P<0.001, P<0.001, P=0.035, P<0.001 and P=0.014, respectively). Compared with diet alone, simvastatin lowered but statistically insignificant plasma levels of nitrate and malondialdehyde (MDA) (P=0.164 and P=0.150, respectively). Further, we observed that patients with the highest pretreatment TNF-alpha, ICAM-1, and CRP levels showed the greatest extent of reductions on simvastatin. There were significant inverse correlation between low-density lipoprotein (LDL) cholesterol or the ratio of LDL to HDL cholesterol levels and flow-mediated dilation percent (r=-0.342, P=0.009 and r=-0.356, P=0.006, respectively). Of interest, there were significant inverse correlations between flow-mediated dilation percent and TNF-alpha levels (r=-0.329, P=0.010). However, no significant correlations between lipoprotein levels and levels of inflammation markers were determined. Despite the significant changes of lipoproteins, diet alone did not decrease the markers of inflammation. CONCLUSIONS: Compared with diet alone, simvastatin significantly reduced markers of inflammation more. These effects were independent of lipoprotein changes.
Biomarkers↗
Comparative effects of statin and fibrate on nitric oxide bioactivity and matrix metalloproteinase in hyperlipidemia.
OBJECTIVE: Because the lipoprotein effects of statin and fibric acid derivatives therapies differ, we studied the effects of these therapies in patients with hyperlipidemia on lipoproteins, vasomotor function, and plaque stability. METHODS: We administered simvastatin, 20 mg daily, to 27 patients with hypercholesterolemia and coronary artery disease, or fenofibrate, 200 mg daily, to 27 patients with pure hypertriglyceridemia during 8 weeks. RESULTS: As expected, simvastatin significantly lowered total cholesterol and low-density lipoprotein cholesterol (LDL-C) more, and fenofibrate decreased triglyceride and increased high-density lipoprotein cholesterol (HDL-C) more than either therapy. Simvastatin and fenofibrate significantly improved the percent flow-mediated dilator response to hyperemia by 183+/-41% and by 30+/-7%, respectively (each P<0.001); however, simvastatin significantly improved more (P<0.001). Simvastatin and fenofibrate significantly lowered plasma levels of tumor necrosis factor alpha (TNF-alpha) by 13+/-4% and by 10+/-4%, respectively (P=0.009 and P=0.006, respectively) with a similar degree (P=0.614). Simvastatin significantly reduced plasma levels of total MMP-9 and TIMP-1 more (P=0.005 and P=0.036, respectively), compared with fenofibrate showing no reduction. There were significant correlations between the degree of changes in TNF-alpha and the degree of changes in MMP-9 activity (r=0.376, P=0.053). CONCLUSIONS: Simvastatin and fenofibrate demonstrated antiatherosclerotic effects via different mechanisms.
Brachial Artery↗
Vascular effects of step I diet in hypercholesterolemic patients with coronary artery disease.
We administered a step I diet to 50 hypercholesterolemic patients with coronary artery disease during 12 weeks. Compared with baseline, the step I diet significantly changed lipoprotein levels, significantly improved the percent flow-mediated dilation response to hyperemia by 32 +/- 7% (p <0.001), increased plasma levels of nitrate by 45 +/- 12% (p = 0.013), and lowered plasma levels of malondialdehyde by 7 +/- 4% (p = 0.011). However, the step I diet did not significantly change serologic markers of inflammation, plaque stability, and thrombosis. Step I diet therapy improved endothelium-dependent vasodilation with an increase in plasma nitrogen oxide and a decrease in oxidant stress in hypercholesterolemic patients with coronary artery disease.
Aged↗
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.
Angiotensin Receptor Antagonists↗
Significant differential effects of hormone therapy or tibolone on markers of cardiovascular disease in postmenopausal women: a randomized, double-blind, placebo-controlled, crossover study.
OBJECTIVE: The objective was to compare the effects of tibolone and hormone therapy (HT) on lipid profile, vasodilation, and factors associated with inflammation and hemostasis. METHODS AND RESULTS: Fifty-three women received micronized progesterone (MP, 100 mg) with conjugated equine estrogen (CEE, 0.625 mg) or tibolone (2.5 mg) daily for 2 months, with a 2-month washout period. Compared with HT, tibolone significantly reduced total cholesterol (P<0.001), triglyceride (P<0.001), and HDL cholesterol (P<0.001) levels as well as triglyceride/HDL cholesterol ratios (P<0.001) but not LDL cholesterol levels. Tibolone significantly improved flow-mediated brachial artery dilator response to hyperemia from baseline values (P<0.001) by a magnitude similar to that found with HT (P=0.628). Compared with tibolone, which showed no changes, HT significantly increased high-sensitivity C-reactive protein (hsCRP, P=0.030) and reduced antithrombin III (P<0.001). HT and tibolone significantly increased prothrombin fragment 1+2 (F1+2) from baseline values (P<0.001 and P=0.004, respectively). The effects of HT and tibolone on hsCRP, antithrombin III, and F1+2 were significantly different. HT and tibolone significantly reduced plasma levels of plasminogen activator inhibitor type 1 antigen from baseline levels (P=0.006 and P=0.005, respectively) to a similar degree (P=0.988). CONCLUSIONS: Tibolone significantly improved flow-mediated brachial artery dilator response by a magnitude similar to that found with CEE+MP; however, tibolone did not significantly change hsCRP and antithrombin III, and tibolone increased F1+2 less than did CEE+MP.
Antithrombin III↗
Comparative effects of diet and simvastatin on markers of thrombogenicity in patients with coronary artery disease.
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Anticholesteremic Agents↗
Effect of hormone replacement therapy on tissue factor activity, C-reactive protein, and the tissue factor pathway inhibitor.
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Analysis of Variance↗