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European Heart Journal Advance Access originally published online on May 5, 2007
European Heart Journal 2007 28(12):1440-1447; doi:10.1093/eurheartj/ehm101
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© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Additive beneficial cardiovascular and metabolic effects of combination therapy with ramipril and candesartan in hypertensive patients{dagger}

Kwang Kon Koh1,*, Michael J. Quon2, Yonghee Lee3, Seung Hwan Han1, Jeong Yeal Ahn4, Wook-Jin Chung1, Jeong-a Kim2 and Eak Kyun Shin1

1 Cardiology, Gachon Medical School, Incheon, Korea
2 Diabetes Unit, NCCAM +, NIH, Bethesda, Maryland, USA
3 Department of Statistics, Ewha Womans University, Seoul, Korea
4 Laboratory Medicine, Gachon Medical School, Incheon, Korea

Received 31 October 2006; revised 13 March 2007; accepted 15 March 2007; online publish-ahead-of-print 5 May 2007.

* Corresponding author: Professor of Medicine Director, Vascular Medicine and Atherosclerosis Unit Cardiology, Gil Heart Center, Gachon Medical School 1198 Kuwol-dong, Namdong-gu, Incheon 405-760, Korea. Tel: +82 32 460 3683; fax: +82 32 460 3117/467 9302. E-mail address: kwangk{at}gilhospital.com


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Acknowledgement
 References
 
Aims: Ramipril and candesartan have distinct mechanisms of action to improve endothelial function. Therefore, we hypothesized that combination therapy has additive beneficial effects to simultaneously improve endothelial dysfunction and adipocytokine profiles in patients with hypertension.

Methods and results: Thirty-four patients were given ramipril 10 mg and placebo, ramipril 10 mg and candesartan 16 mg, or candesartan 16 mg and placebo daily in a randomized, double-blind, placebo-controlled cross-over trial with three treatment arms and two washout periods (each 2 months). Ramipril, candesartan, or combination therapy reduced blood pressure, improved flow-mediated dilation, and increased plasma adiponectin levels when compared with baseline values. However, combination therapy improved these outcome measures to a greater extent than either ramipril or candesartan alone (P < 0.001 and P = 0.016 for systolic and diastolic blood pressure, P < 0.001 and P = 0.048 for flow-mediated dilation and adiponectin levels by ANOVA). In addition, combination therapy reduced plasma leptin levels to a greater extent than either ramipril or candesartan alone (P = 0.042 by ANOVA). There were correlations between percent changes in adiponectin levels and percent changes in insulin sensitivity (determined by QUICKI) (r = 0.319, P = 0.066) following ramipril therapy, percent changes in QUICKI (r = 0.374, P = 0.029) following combination therapy, and percent changes in QUICKI (r = 0.607, P < 0.001) following candesartan therapy.

Conclusion: Ramipril in combination with candesartan improves blood pressure, endothelial function, and adipocytokine profiles to a greater extent than monotherapy with either drug in hypertensive patients.

Key Words: ACE-inhibitor • Angiotensin II receptor blocker • Endothelial function • Insulin resistance • Adipocytokines

{dagger} We presented in part at the American College of Cardiology 55th Annual Scientific Session in Atlanta, GA, 7–10 March 2006, and published in abstracts form (J Am Coll Cardiol. 2006;110:Supplement III-811) and in the World Congress (European Society) of Cardiology 2006, Barcelona, Spain, September 2–6, 2006 and in the American Heart Association 2006, Chicago, IL, November 12–15, 2006. Back


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Acknowledgement
 References
 
Hypertension and coronary heart disease are cardiovascular diseases characterized by endothelial dysfunction that frequently cluster with disorders of metabolic homeostasis including obesity and type-2 diabetes that are characterized by insulin resistance.1,2 These co-morbidities may be explained, at least in part, by reciprocal relationships between endothelial dysfunction and insulin resistance.1,2 Monotherapy with either ramipril or candesartan improves endothelial dysfunction leading to retardation or prevention of progression of coronary heart disease.3,4 Moreover, ramipril or candesartan therapy for cardiovascular diseases reduces the incidence of type-2 diabetes5,6 while therapy with insulin sensitizers has beneficial effects on hypertension.7 The mechanisms underlying these simultaneous cardiovascular and metabolic benefits may relate to the common ability of disparate therapies to target the vicious synergy between endothelial dysfunction and insulin resistance.8–10

Endothelial dysfunction associated with diabetes, obesity, metabolic syndrome, and other insulin resistant states is characterized by impaired insulin-stimulated nitric oxide (NO) release from endothelium with decreased blood flow and reduced delivery of substrates.11 Thus, improvement in endothelial function is predicted to improve insulin sensitivity and this may be one mechanism by which ramipril and candesartan decrease the incidence of new onset diabetes.1,2 Adiponectin and leptin are adipocytokines secreted specifically by adipose cells.12,13 In humans, plasma levels of adiponectin are negatively correlated with adiposity and insulin resistance. Indeed, decreased plasma adiponectin levels are observed in patients with diabetes.14 We have recently reported that either ramipril or candesartan increases adiponectin levels and insulin sensitivity in patients without changing body mass index.8–10 Thus, decreased levels of adiponectin may play a key role in the development of insulin resistance. Angiotensin II increases leptin secretion in cell culture studies.15 Therefore, in addition to its important role in regulation of energy homeostasis and bone metabolism,16 leptin may also play an important role in atherosclerotic lesion formation and progression.17

Angiotensin-converting enzyme (ACE) inhibitors reduce angiotensin II production and also prevent bradykinin breakdown. However, continued production of angiotensin II by non-ACE-dependent pathways may occur. Angiotensin II type 1 (AT1) receptor blockers (ARBs) inhibit the actions of AT1 receptors resulting in compensatory increases in angiotensin II that may have biological consequences mediated by other receptors that are distinct from AT1 receptors.18 Since ramipril (ACE-inhibitor) and candesartan (ARB) target the renin-angiotensin system by distinct mechanisms, we hypothesized that combination therapy may have additive beneficial effects to improve endothelial dysfunction and adipocytokine profiles in patients with hypertension.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Acknowledgement
 References
 
Study population and design
Thirty-eight hypertensive patients participated in this study. We defined hypertension as systolic and diastolic blood pressure ≥ 140 or ≥ 90 mmHg, respectively according to the ESH–ESC guidelines.19 We excluded patients with severe hypertension, unstable angina, acute myocardial infarction, renal insufficiency (serum creatinine level ≥ 1.3 mg/dL), diabetes, or a history of vascular cerebral disease. No patient had taken any lipid-lowering agent, ACE-inhibitors, ARBs, other anti-hypertensive drugs including aldosterone antagonists during the preceding 2 months. Blood pressure measured in the right arm in the sitting position using a standard sphygmomanometer with appropriate sized cuff was recorded as the mean of two successive readings (subjects were seated for at least 10 min prior to measurements).8,20 To minimize acute side effects, study medication was titrated from 5 to 10 mg of ramipril and from 8 to 16 mg of candesartan upwards over a 2-week period if no hypotension (systolic blood pressure < 100 mmHg) was noted. At the end of this time, participants were receiving either ramipril 10 mg or candesartan 16 mg per day. Thirty-four among 38 patients tolerated ramipril 10 mg or candesartan 16 mg with regard to maintaining systolic blood pressure >100 mmHg for 3 h after drug administration, and experienced no adverse effects from therapy. Two patients who were hypotensive and the others who suffered from a dry cough were withdrawn from the study. Thus, data from a total of 34 patients were analysed. The mean age of our subjects was 46 ± 2 (range 32–62) years and the male:female proportion was 23:11. The mean body mass index was 25.2 ± 0.4 kg/m2. The number of current smokers was 11 (32%). Five (15%) patients took beta-adrenergic blockers and three (9%) took calcium channel blockers to control blood pressure only during washout periods because they complained of high blood-pressure-related symptoms. Patients were randomly assigned to one of the three initial treatments—ramipril 10 mg and placebo, ramipril 10 mg and candesartan 16 mg, or candesartan 16 mg and placebo daily during 2 months. This study design was randomized, double blind, placebo controlled, with three treatment arms (each 2 months), and crossover with two washout periods (each 2 months). Patients were seen at 14-day intervals (or more frequently) during the study. Calcium channel or beta-adrenergic blockers were withheld for ≥ 48 h before the study to avoid the effects of these drugs. The study was approved by the Gil Hospital Institute Review Board and all participants gave written, informed consent.

Laboratory assays and vascular studies
Blood samples for laboratory assays were obtained at approximately 8:00 a.m. following overnight fasting before and at the end of each 2-month treatment period. These samples were immediately coded so that investigators performing laboratory assays were blinded to subject identity or study sequence. Assays for plasma insulin, malondialdehyde (MDA), adiponectin, leptin, and resistin were performed in duplicate by immunoradiometric assay (INSULIN-RIABEAD® II, SRL, Inc., Tokyo, Japan) and by ELISA (BIOXYTECH® LPO-586, OxisResearch, Portland, Oregon; R & D Systems, Inc., Minneapolis, Minnesota) as previously described.8–10,20 The inter-assay and intra-assay coefficients of variation were < 6%. Quantitative Insulin-Sensitivity Check Index (QUICKI), a surrogate index of insulin sensitivity, was calculated as follows (insulin is expressed in microU/mL and glucose in mg/dL): QUICKI = 1/[log(insulin)+ log(glucose)].21 Imaging studies of the right brachial artery were performed using an ATL HDI 3000 ultrasound machine (Bothell, WA, USA) equipped with a 10 MHz linear-array transducer, based on a previously published technique.8–10,20

Statistical analysis
Data are expressed as mean ± SEM or median (range: 25–75%). After testing data for normality, we used Student’s paired t-test or Wilcoxon Signed Rank test to compare values before and after each treatment and the relative changes in values in response to treatment, as reported in Table 1. The effects of the three therapies on blood pressure, lipids, vascular function, adipocytokines, and insulin sensitivity relative to baseline values were analysed by Friedman’s repeated ANOVA on ranks. After demonstration of significant differences among therapies by ANOVA, post hoc comparisons between treatment pairs were made with the Student-Newman–Keuls procedure for multiple comparisons. Spearman correlation coefficient analysis was used to assess associations between measured parameters. We calculated that 30 subjects would provide 80% power for detecting an absolute increase of 2.1% or greater in flow-mediated dilation of the brachial artery between baseline and candesartan, with {alpha} = 0.05 based on our previous studies.22 The comparison of endothelium-dependent dilation among the three treatment schemes was prospectively designated as the primary endpoint of the study. All other comparisons were considered secondary and exploratory. Therefore, P-values less than the Bonferroni-adjusted {alpha} of 0.05/3 = 0.017 are deemed as statistically significant for the primary hypothesis. No adjustments were made for the number of secondary hypotheses.


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  		Table 1 Effects of ramipril, combined therapy, and candesartan in 34 hypertensive patients

 

   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Acknowledgement
 References
 
When baseline values before each treatment period were compared among the three treatment arms, no significant differences were noted in any of the parameters measured (Table 1). To rule out the possibility of a carryover effect from one treatment period to the other, we compared baseline values before the first treatment period to those before the second and third treatment periods. There were no significant differences in any of the measured parameters in this analysis.

Blood pressure and lipids
Ramipril, candesartan, or combination therapy significantly reduced systolic and diastolic blood pressure after 2 months administration when compared with respective baseline values. However, combination therapy significantly reduced systolic and diastolic blood pressure to a greater extent than ramipril or candesartan monotherapy (P < 0.001 and P = 0.016 by ANOVA, respectively; Table 1). Lipoprotein profiles were not significantly altered by any of the three therapeutic regimens.

Vasomotor function and malondialdehyde
Ramipril, candesartan, or combination therapy significantly improved the percent flow-mediated dilator response to hyperaemia relative to respective baseline measurements by 56 ± 8%, 55 ± 8%, and 104 ± 14%, respectively. Importantly, combination therapy improved this response to a greater extent than therapy with either ramipril or candesartan alone (P < 0.001 by ANOVA; Figure 1; Table 1). The brachial artery dilator response to nitroglycerine was similar for all three therapies and not significantly different from respective baseline values. In addition, combination therapy significantly decreased plasma MDA levels relative to baseline measurements (Table 1).


Figure 1
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  		Figure 1 Percent change in flow-mediated dilation from respective pre-treatment values after treatment with ramipril alone, combined therapy, and candesartan alone (P < 0.001 by ANOVA). SEM is identified by bars.

 
Adipocytokines and insulin resistance
We observed positive correlations between baseline adiponectin levels and baseline HDL-cholesterol levels (r = 0.449, P = 0.008 before combination therapy; r = 0.327, P = 0.059 before candesartan). Ramipril, combination therapy, or candesartan significantly increased plasma adiponectin levels relative to baseline measurements by 17 ± 6%, 25 ± 5%, and 14 ± 6%, respectively. Combination therapy significantly increased plasma adiponectin levels more than either ramipril or candesartan alone (P = 0.048 by ANOVA; Figure 2A; Table 1). Baseline insulin and glucose levels were similar among all three treatment arms. Only combination therapy significantly reduced plasma insulin levels and increased QUICKI relative to baseline measurements (Table 1).


Figure 2
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  		Figure 2 (A) Percent change in adiponectin levels from respective pre-treatment values after treatment with ramipril alone, combined therapy, and candesartan alone (P = 0.048 by ANOVA). (B) Percent change in leptin levels from respective pre-treatment values after treatment with ramipril alone, combined therapy, and candesartan alone (P = 0.042 by ANOVA). SEM is identified by bars.

 
We observed significant correlations between baseline leptin levels and baseline body mass index (r = 0.411, P = 0.016 before ramipril; r = 0.409, P = 0.017 before combination therapy; r = 0.374, P = 0.030 before candesartan). In addition, there were correlations between baseline leptin levels and baseline adiponectin levels (r = 0.392, P = 0.022 before ramipril; r = 0.351, P = 0.042 before combination therapy; r = 0.330, P = 0.056 before candesartan). Combination therapy decreased plasma leptin levels relative to respective baseline measurements by 21 ± 4% to a greater extent than either ramipril or candesartan monotherapy (P = 0.042 by ANOVA; Figure 2B; Table 1). Ramipril, combination therapy, or candesartan increased plasma resistin levels relative to respective baseline measurements by 8 ± 4%, 8 ± 4%, and 12 ± 4%, respectively. The magnitude of increase observed in response to the three therapies was similar (P = 0.625 by ANOVA; Table 1). Plasma resistin levels were not correlated with either insulin sensitivity or body mass index. There were no significant correlations between percent changes in adiponectin levels and percent changes in leptin or resistin levels following each therapy (–0.034 ≤ r ≤ 0.287).

The reduction of blood pressure by each therapy may result in improvement of endothelial dysfunction and adipocytokine profiles. Therefore, we investigated whether changes in the percent flow-mediated dilator response to hyperaemia, plasma levels of adiponectin, leptin, and resistin, and insulin resistance were related to reduction of systolic or diastolic blood pressure. There were no significant correlations between these changes and reduction of systolic blood pressure (–0.332 ≤ r ≤ 0.247) or between these changes and reduction of diastolic blood pressure (–0.252 ≤ r ≤ 0.190). However, there were significant correlations between percent changes in adiponectin levels and percent changes in insulin (r = – 0.407, P = 0.017) and QUICKI (r = 0.319, P = 0.066) following ramipril therapy, percent changes in insulin (r = – 0.352, P = 0.042) and QUICKI (r = 0.374, P = 0.029) following combination therapy, and percent changes in insulin (r= – 0.673, P < 0.001) and QUICKI (r = 0.607, P < 0.001) following candesartan therapy (Figure 3).


Figure 3
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  		Figure 3 Scatter plots showing the correlation between percent changes in adiponectin levels and percent changes in QUICKI (r = 0.319, P = 0.066) following ramipril therapy (A), percent changes in QUICKI (r = 0.374, P = 0.029) following combined therapy (B), and percent changes in QUICKI (r = 0.607, P < 0.001) following candesartan therapy (C). The line shows the predicted regression line.

 
Potassium, renin, and aldosterone
Ramipril, combination therapy, or candesartan increased plasma potassium levels. However, we did not observe any effects related to hyperkalaemia. Ramipril, combination therapy, or candesartan increased plasma renin activity levels and decreased plasma aldosterone levels relative to baseline measurements. However, the magnitude of these changes was not significantly different among the three treatment arms.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Acknowledgement
 References
 
Dysregulation of the renin-angiotensin system plays a major role in essential hypertension.23 We reasoned that distinct biological mechanisms of action for ramipril and candesartan to target the renin-angiotensin system may result in beneficial additive effects of combination therapy. Ramipril inhibits ACE and enhances the effects of local bradykinin by decreasing its degradation and by increasing B2 receptor sensitivity. Clinical and laboratory studies demonstrate that blockade of the B2 receptor attenuates the antihypertensive, antihypertrophic, and antiatherosclerotic effects of ACE-inhibitors.24 Candesartan blocks the binding of angiotensin II to the AT1 receptor. Therefore, combination therapy may increase NO bioavailability to a greater extent than monotherapy with either drug. Our current study demonstrated beneficial effects of combination therapy to improve blood pressure, endothelial dysfunction, insulin resistance, and adipocytokine profiles that went beyond the effects of monotherapy with either ramipril or candesartan. The number of patients in the current study was 34. However, given the SD of 2.0% of the differences in flow-mediated dilation between combination therapy and candesartan or ramipril, the statistical power to accept our observation was at least 90%. Since there are multiple aetiologies for atherosclerosis and cardiovascular diseases, combination therapy with drugs that have distinct and separate mechanisms of action may confer more benefit in the treatment of cardiovascular diseases than individual monotherapies. Indeed, we have demonstrated that combination therapy with simvastatin/losartan or ramipril has beneficial additive effects on endothelial function in hypercholesterolemic, hypertensive patients8,20 and combination therapy with candesartan or atorvastatin/fenofibrate has beneficial additive effects on endothelial function in combined hyperlipidaemia.10,25 This may be due to combined effects of the respective monotherapies to further improve endothelial function.

Adiponectin is an adipose-derived factor that augments and mimics metabolic and vascular actions of insulin.13 In our study, each 2-month treatment arm increased adiponectin levels without a change in body weight or body mass index. This raises the possibility that drug therapy is directly altering adiponectin levels independent of adiposity. Thus, it is possible that increased adiponectin levels are contributing to improvement in insulin sensitivity rather than simply reflecting a change in adiposity. It is important to note that in our Korean cohort, a BMI of 25 is considered overweight. The proportion and the distribution of body fat in Asians differs from that of Caucasians. A BMI of 25 among Asians corresponds to a higher percentage of body fat and visceral fat in particular than observed in Caucasians. It follows that even at BMI level of 25, Asians may have increased risk for type-2 diabetes and cardiovascular disease.26,27 Increasing adiponectin levels would be predicted to improve both insulin sensitivity and endothelial function by multiple mechanisms.13 Regulation of metabolic homeostasis and haemodynamic homeostasis may be coupled by vascular actions of insulin to stimulate production of NO.28 In the current study, there were significant correlations between percent changes in adiponectin levels and percent changes in insulin and QUICKI following combined therapy. In cell culture studies, angiotensin II does not inhibit expression of adiponectin. However, in our current study, ramipril and candesartan significantly increased plasma levels of adiponectin. Thus, there may be additional mechanisms to improve insulin sensitivity and adiponectin levels in addition to improving endothelial function by blockade of the renin angiotensin system. For example, cross talk between angiotensin II receptor signalling and insulin signalling pathways may contribute to insulin resistance.29 In addition, ramipril and candesartan may have direct effects to augment insulin-stimulated glucose uptake, promote adipogenesis,30 and induce peroxisome proliferator-activated receptor-{gamma} activity that promotes differentiation of adipocytes.31 Recently, it was reported that quinapril increases insulin-stimulated endothelial function and vascular expression of adiponecin in patients with type-2 diabetes.32 Moreover, combination therapy may reduce insulin resistance by additional mechanisms including reduced oxidant stress that enhance NO bioavailability.

Angiotensin II increases leptin secretion from cultured human fat cells. Candesartan abolishes the effect of angiotensin II to promote leptin production.15 Leptin may potentiate pressor effects of hyperinsulinaemia in insulin resistant states. Therefore, interactions between angiotensin II and insulin with leptin may have deleterious cardiovascular effects in obesity. Additionally, leptin appears to stimulate vascular inflammation, oxidative stress, and vascular smooth muscle hypertophy. These actions may contribute to the pathogenesis of hypertension, atherosclerosis, and left ventricular hypertrophy.17,33 In the current study, the effects of combination therapy to reduce plasma leptin levels to a greater extent than monotherapy with either candesartan or ramipril may be relevant to the additive beneficial effects of combination therapy to simultaneously improve cardiovascular and metabolic phenotypes in hypertensive patients.

Serum resistin is increased in type-2 diabetic or obese subjects.34,35 Resistin reduces glucose uptake in differentiated preadipocytes34 and promotes endothelial cell activation and upregulates adhesion molecules and chemokines.36 In this fashion, resistin may be mechanistically linked to cardiovascular disease in the metabolic syndrome. Serum resistin levels are associated with the presence and severity of coronary artery disease and significant correlations between resistin levels and both fasting insulin levels and insulin resistance.37 However, in the current study, ramipril and candesartan significantly increased plasma resistin levels relative to baseline measurements; however, combination therapy did not. We also observed that resistin levels were not correlated with insulin sensitivity or body mass index. This is consistent with other reports that circulating resistin levels are not correlated with the insulin sensitivity, body mass index, or blood pressure.34,35,38,39

It is controversial whether combination therapy with ACE-inhibitors and ARBs has beneficial effects greater than ACE-inhibitor therapy alone. The Valsartan in Acute Myocardial Infarction (VALIANT) trial shows no additive effects with combined therapy with respect to the primary endpoint of all cause mortality.40 However, the authors also compared the effects of captopril, valsartan, and their combination on atherosclerotic events.41 In that analysis, the number of individuals adjudicated as having a fatal or non-fatal myocardial infarction in the captopril group was 559 (total investigator reported events 798), 587 (796) in the valsartan group, and 554 (756) in the combination group; valsartan vs. captopril, P = 0.651; combination vs. captopril, P = 0.187. These data, although not conclusive, support the hypothesis that combination therapy may have a small additional anti-infarction effect, a possibility that needs to be prospectively tested. The results of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Added trial demonstrates additional benefits when candesartan is combined with ACE-inhibitors.4 The benefit of adding candesartan to the therapeutic regimen is preserved in patients taking a higher dose of ACE-inhibitor and in patients maintaining a high dose of ACE-inhibitor throughout follow-up.42 These clinical findings support the pharmacologic evidence that ACE-inhibitors and ARBs have distinct mechanisms of action and show that their combined use improves outcomes in patients with heart failure more than ACE-inhibitor therapy alone (although these studies were not performed in patients with hypertension). Importantly, losartan combined with trandolapril safely retards progression of non-diabetic renal disease to a greater extent than monotherapy.43 Large prospective trials are under way to more definitively evaluate these issues.44

Most studies evaluating effects of combination therapy with ACE-inhibitors and ARBs have focused on cardiovascular phenotypes. An important finding of our current study is that combination therapy with ACE-inhibitors and ARBs has beneficial effects on metabolic parameters including adipocytokine profiles that may regulate metabolism, energy homeostasis, and insulin sensitivity. This suggests that therapeutic interventions aimed at improving haemodynamic regulation have important consequences to improve metabolic function as well. These effects were observed in a young population in the current study. With increasing age, prevalence of metabolic syndrome increases. Thus, similar or greater effects are likely to be observed in older people than in young people. Using multiple drugs to target different points in the vicious cycle between endothelial dysfunction and insulin resistance may be an effective therapeutic strategy for simultaneously improving cardiovascular and metabolic health.

In summary, our study demonstrates that combination therapy with ramipril and candesartan improves blood pressure, endothelial dysfunction, insulin resistance, and plasma adipocytokine profiles to a greater extent than monotherapy with either drug in hypertensive patients. Thus, combining drugs that target different aspects of the renin angiotensin system may have merit in the treatment of both cardiovascular and metabolic diseases, which are characterized by reciprocal relationships between endothelial dysfunction and insulin resistance.


   Acknowledgement
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgement
References
 
We are very greatly in debt regarding his critical and devoted review to Myron A. Waclawiw, PhD, (Office of Biostatistics Research, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA). This study was partly supported by grants from established investigator award (2005-1), Gil Medical Center, Gachon Medical School and Korea Society of Hypertension (KSH-2005).

Conflict of interest: none declared.


   Footnotes
 
{dagger} We presented in part at the American College of Cardiology 55th Annual Scientific Session in Atlanta, GA, 7–10 March 2006, and published in abstracts form (J Am Coll Cardiol. 2006;110:Supplement III-811) and in the World Congress (European Society) of Cardiology 2006, Barcelona, Spain, September 2–6, 2006 and in the American Heart Association 2006, Chicago, IL, November 12–15, 2006. Back


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgement
 References
 

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