Tae Hoon 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.

Trial of Everolimus-Eluting Stents or Bypass Surgery for Coronary Disease

BACKGROUND Most trials comparing percutaneous coronary intervention (PCI) with coronary-artery bypass grafting (CABG) have not made use of second-generation drug-eluting stents. METHODS We conducted a randomized noninferiority trial at 27 centers in East Asia. We planned to randomly assign 1776 patients with multivessel coronary artery disease to PCI with everolimus-eluting stents or to CABG. The primary end point was a composite of death, myocardial infarction, or target-vessel revascularization at 2 years after randomization. Event rates during longer-term follow-up were also compared between groups. RESULTS After the enrollment of 880 patients (438 patients randomly assigned to the PCI group and 442 randomly assigned to the CABG group), the study was terminated early owing to slow enrollment. At 2 years, the primary end point had occurred in 11.0% of the patients in the PCI group and in 7.9% of those in the CABG group (absolute risk difference, 3.1 percentage points; 95% confidence interval [CI], -0.8 to 6.9; P=0.32 for noninferiority). At longer-term follow-up (median, 4.6 years), the primary end point had occurred in 15.3% of the patients in the PCI group and in 10.6% of those in the CABG group (hazard ratio, 1.47; 95% CI, 1.01 to 2.13; P=0.04). No significant differences were seen between the two groups in the occurrence of a composite safety end point of death, myocardial infarction, or stroke. However, the rates of any repeat revascularization and spontaneous myocardial infarction were significantly higher after PCI than after CABG. CONCLUSIONS Among patients with multivessel coronary artery disease, the rate of major adverse cardiovascular events was higher among those who had undergone PCI with the use of everolimus-eluting stents than among those who had undergone CABG. (Funded by CardioVascular Research Foundation and others; BEST ClinicalTrials.gov number, NCT00997828.).

Multiple predictors of coronary restenosis after drug-eluting stent implantation in patients with diabetes

Objectives: To identify parameters influencing the likelihood of restenosis after implantation of drug-eluting stents (DES) in patients with diabetes. Methods: Stented patients (n  =  840) with DES were retrospectively reviewed for inclusion in the study from the Multicenter PCI Database Registry. From this database, 211 (25.1%) of 840 patients with six-month angiographic follow up had diabetes. Predictors of coronary restenosis were identified with univariate and multivariate logistic regression analyses. Results: Restenosis occurred in 92 of 629 (14.6%) patients without diabetes and in 44 (20.9%) of 211 patients with diabetes (p < 0.001). Multivariate parameters for predicting restenosis in the diabetic group were current smoking (odds ratio (OR) 1.923, 95% confidence interval (CI) 1.055 to 4.725, p  =  0.036), higher C reactive protein concentration (OR 1.031, 95% CI 1.011 to 1.075, p  =  0.043), use of the paclitaxel-eluting stent (OR 2.638, 95% CI 1.338 to 5.200, p  =  0.005), longer stent length (OR 1.065, 95% CI 1.021 to 1.119, p  =  0.033), smaller reference diameter before DES implantation (OR 0.501, 95% CI 0.110 to 0.965, p  =  0.040), smaller reference diameter (OR 0.455, 95% CI 0.120 to 0.814, p  =  0.026) and minimum lumen diameter (OR 0.447, 95% CI 0.068 to 0.876, p  =  0.039) after DES implantation. Conclusion: Even with the introduction of DES, diabetes remains a significant predictor of coronary restenosis, especially in cases of a small baseline vessel size, small vessel size after percutaneous coronary intervention, longer stent length, use of the paclitaxel-eluting stent, current smoking and high C reactive protein concentration.

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.

Low-molecular-weight heparin versus unfractionated heparin in acute ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention with drug-eluting stents

BACKGROUND Whether low-molecular-weight heparin (LMWH) is superior to unfractionated heparin (UFH) in acute ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI) with drug-eluting stents (DESs) remains unclear. METHODS A total of 3,372 STEMI patients who underwent primary PCI with DESs received either LMWH (n = 1,531 patients, subcutaneous enoxaparin 1 mg/kg, bid for 3-5 days plus reduced dose of UFH [50 U/kg] during PCI) or UFH alone (n = 1,841 patients, intravenous bolus injection of 5,000 U, followed by 24,000 U/d infusion for at least 48 hours). The bleeding events and clinical outcomes during in-hospital and at 8 months were compared. RESULTS The incidences of major and minor bleeding events were similar between the 2 groups. Multivariable Cox regression analysis showed that LMWH group had lower incidences of cardiac death (adjusted odds ratio [OR] 0.55, 95% CI 0.39-0.77, P < .001), total death (adjusted OR 0.50, 95% CI 0.37-0.68, P < .001), and total major adverse cardiac events (adjusted OR 0.77, 95% CI 0.62-0.95, P = .017) at 8 months as compared with UFH group. Similar results were obtained across different subgroups including different DESs, age, and sex. CONCLUSIONS The LMWH enoxaparin combined with reduced dose of UFH (50 U/kg) administration as an adjunctive antithrombotic therapy in STEMI patients undergoing primary PCI with DESs seems to be safe and efficacious. However, randomized clinical trials are needed to confirm this conclusion.

Comparison of inflammatory markers and angiographic outcomes after implantation of sirolimus and paclitaxel-eluting stents

Objective: We compared the degree of systemic inflammation and its relation to the angiographic outcomes after drug-eluting stent (DES) implantations. Methods: We implanted a single DES in 79 stable angina patients (50 men; 60.4 (9.5) years of age; sirolimus-eluting stent (SES), n = 38; paclitaxel-eluting stent (PES), n = 41). The high-sensitivity C-reactive protein (hs-CRP) and interleukin 6 (IL-6) levels were determined before and at 24 hours, 72 hours, and 4 weeks after the percutaneous coronary intervention (PCI). An angiography and intravascular ultrasound (IVUS) were performed. Results: The hs-CRP and IL-6 levels at baseline did not differ between the two groups. The hs-CRP increased significantly from baseline at 24 hours and 72 hours after the PCI in both groups and there was a significant increase in the IL-6 level at 24 hours after the PCI in both groups. However, there was no significant difference between the two groups in any of the hs-CRP or IL-6 measurements. At follow-up, the late lumen loss was significantly higher in the PES group than in the SES group (0.57 (0.56) mm vs 0.28 (0.58) mm, respectively, p = 0.020). The neointimal hyperplasia (NIH) volume in the PES group was significantly higher than that in the SES group (23.1 (22.7) vs 3.8 (7.1) mm3, respectively, p = 0.000). The percentage luminal volume reduction was higher in the PES group than in the SES group (18.9 vs 3.9%, p = 0.002). The absolute values or change in the inflammatory markers did not correlate with the NIH or stent volume reduction. Conclusions: Our study showed that the benefits obtained from the SES, which reduce neointimal proliferation, are not probably mediated by the attenuation of the systemic inflammatory markers hs-CRP or IL-6.

Effect of hormone replacement therapy on tissue factor activity, C-reactive protein, and the tissue factor pathway inhibitor

W have previously observed that hormone replacement therapy (HRT) significantly increased tissue factor (TF) activity in healthy women1 and tended to increase prothrombin fragment 1 2 levels in 20 hypertensive and/or overweight postmenopausal women.2 However, we did not measure other indexes of coagulation activation or inhibition, nor did we measure C-reactive protein (CRP), which in experimental preparations stimulates the synthesis and release of the coagulation activator TF.3 TF pathway inhibitor (TFPI) may interact with TF to maintain homeostasis.4,5 Thus, this study examines (1) whether HRT increases TF activity, which may facilitate thrombin formation in hypertensive and/or overweight postmenopausal women, and (2) whether HRT-induced TF activity is associated with changes in CRP or TFPI that might provide mechanistic insight. • • • Thirty postmenopausal women (mean SD 59 6 years) participated in this study. Inclusion criteria have been previously reported.2 Eight, 8, and 14 women were overweight, hypertensive, and both, respectively. Seven of 22 were obese. Mean body mass index was 28.7 3.4. We treated hypertensive women with a low salt diet and/or diuretics (hydrochlorothiazide or furosemide) alone to avoid drug effects on hemostasis. This study was randomized, double-blind, and crossover in design. Study participants received micronized progesterone (MP) 100 mg or medroxyprogesterone acetate (MPA) 2.5 mg with conjugated equine estrogen (CEE) 0.625 mg daily for 2 months with the second treatment period initiated upon completion of the first treatment period. The study was approved by the Gil Hospital institute review board and all participants gave written, informed consent. Assays for hemostasis were performed as previously described.6,7Blood samples for laboratory assays were obtained from an antecubital vein after an overnight fast, before and at the end of treatment. Because of the circadian variation of fibrinolytic activity, blood collection was restricted to the hours of 8 to 9 A.M. We measured parameters of coagulation system activation. Prothrombin fragment 1 2 and thrombin-antithrombin complexes were measured by enzyme-linked immunosorbent assays (ELISA) (Behring Diagnostics Inc., San Jose, California). TF and TFPI antigen and activity were measured in duplicate by ELISA and actichrome assays (American Diagnostica, Greenwich, Connecticut). In all patients, serum was collected for the measurement of CRP levels. CRP levels were determined with an immunonephelometry system according to methods described by the manufacturer (Rate nephelometry; IMMAGE, Beckman Coulter, Brea, California). The measurement range was 0.1 to 98 mg/dl. All samples from the same patient (batch samples) were measured in blinded pairs with the same ELISA kit to minimize run-to-run variability. The interand intraassay coefficients of variation were 8%. Data are expressed as mean SEM or median (range 25% to 75%). After testing data for normality, we used Student’s paired t test or the Wilcoxon signed-rank test to compare values at baseline and after each therapy, as reported in Table 1. We assumed that the second baseline after the washout would not be different from the first baseline, because we saw no carryover effect of CEE and progestagen after 6 weeks in our previous studies.6,8 Thus, we decided on a treatment period of 2 months without washout. The effects of the 2 therapies on markers of hemostasis relative to baseline values were analyzed by 1-way repeated measures analysis of variance or Friedman’s repeated analysis of variance on ranks. After demonstration of significant differences among therapies by analysis of variance, post hoc comparisons between treatment pairs were made using the Student-Newman-Keuls multiple comparison procedures. Pearson’s correlation coefficient analysis was used to assess associations between measured parameters. In light of the multiple comparisons generated by the exploratory nature of this study, a p value 0.001 (rather than 0.05) was used to indicate statistical significance. There were no carryover effects from the initial treatment periods to the next treatment period. The effects of therapies on hemostasis are shown in Table 1. CEE MP and CEE MPA therapies tended to increase CRP levels from baseline values (p 0.107 by analysis of variance). Both therapies significantly decreased TF antigen but increased TF activity from From the Departments of Cardiology, Clinical Pathology, and Preventive Medicine (Biostatistics), Gachon Medical School, Incheon, Korea. This study was supported by grants (2000-1-20500-1) from the Basic Research Program, Korea Science and Engineering Foundation, Taejeon, Korea. Dr. Koh’s address: Vascular Medicine and Atherosclerosis Unit, Cardiology, Gil Heart Center, Gachon Medical School, 1198 Kuwol-dong, Namdong-gu, Incheon, Korea 405-760. E-mail: kwangk@ghil.com. Manuscript received July 15, 2002; revised manuscript received and accepted September 19, 2002.

Echocardiographic Assessments of Left Atrial Strain and Volume in Healthy Patients and Patients With Mitral Valvular Heart Disease by Tissue Doppler Imaging and 3-Dimensional Echocardiography

Background and Objectives The purpose of the current study was to assess left atrial (LA) physiology in relation to associations between LA volume change and regional tissue velocities and strains, and to extend this information to patients with mitral stenosis (MS) or mitral regurgitation (MR). Subjects and Methods Twenty-two healthy persons, 22 patients with moderate-to-severe MS, and 22 patients with moderate-to-severe MR were studied. Tissue velocities, strains, and time-volume curves of the LA were acquired using tissue Doppler imaging and 3-dimensional echocardiography. Results In healthy controls, the maximal LA volume was negatively correlated with the posterior wall longitudinal systolic strain (r=-0.45, p=0.03). The time-to-maximal LA volume was positively correlated with the time-to-posterior wall longitudinal peak strain (r=0.46, p=0.03) and the time-to-circumferential peak strain (r=0.59, p=0.004). The LA active emptying fraction (LAactEF) was positively correlated with the posterior wall longitudinal peak systolic and late diastolic tissue velocities. In patients with MS, the maximal LA volume was negatively correlated with the posterior wall radial peak systolic velocity and the longitudinal late diastolic velocity. In patients with MS, the LAactEF had an additional positive correlation with the anterior wall longitudinal and circumferential systolic velocities, whereas the patients with MR had an additional positive correlation between the LAactEF and the lateral wall longitudinal peak strain as compared with the healthy cantrols. Conclusion LA longitudinal and circumferential deformations are more related than radial deformation to determining LA volume and function. The LA of patients with MS revealed a greater pathologic physiology than those of patients with MR.