Jeong Bae Park

Ferritin Is Independently Associated With the Presence of Coronary Artery Calcium in 12 033 Men

Objective—Ferritin concentrations are often increased in patients with metabolic syndrome and type 2 diabetes mellitus, but few reports have examined the associations between ferritin and atherosclerosis. We investigated whether any relationship between ferritin and coronary artery calcium score (CACS) >0 (as a marker of atherosclerosis) was independent of potential confounders, such as iron-binding capacity (transferrin), low-grade inflammation, and cardiovascular risk factors. Methods and Results—Data were analyzed from a South Korean occupational cohort of 12 033 men who underwent a cardiac computed tomography estimation of CACS and measurements of multiple cardiovascular risk factors. One-thousand three- hundred-fifteen of 12 033 (11.2%) subjects had a CACS >0. For people with a CACS >0, median (interquartile range) ferritin concentration was 196.8 (136.3–291.9) compared with 182.2 (128.1–253.6) in people with a CACS=0; P<0.001. In the highest ferritin quartile, 14.7% (442/3008) of subjects had a CACS >0 compared with 9.7% (292/3010) in the lowest quartile (P<0.0001). With increasing ferritin quartiles, there were also higher proportions of people with diabetes mellitus (P<0.0001), hypertension (P<0.0001), coronary heart disease (P=0.003), and a Framingham Risk Score >10% (P<0.0001). In logistic regression modeling with CACS >0 as the outcome, ferritin but not transferrin was independently associated with CACS >0 (odds ratio for highest quartile versus lowest quartile, 1.66 [95% CI, 1.3–1.98]; P=0.0001). Conclusion—Increased ferritin concentrations are associated with the presence of a marker of early coronary artery atherosclerosis, independently of traditional cardiovascular risk factors including Framingham risk score, transferrin, preexisting vascular disease, diabetes mellitus, metabolic syndrome factors, and low-grade inflammation.

Efficacy and Tolerability of Once-Daily Oral Fimasartan 20 to 240 mg/d in Korean Patients with Hypertension: Findings from Two Phase II, Randomized, Double-Blind, Placebo-Controlled Studies

BACKGROUND Fimasartan is a selective angiotensin II receptor blocker developed for once-daily dosing. OBJECTIVES To meet the regulatory requirements for approval of an antihypertensive treatment in Korea, this pair of studies was conducted to evaluate the efficacy and tolerability of fimasartan, to determine its dose-response relationship and minimum effective dose, and to characterize its blood pressure (BP)-reduction profile over the dosing interval. METHODS These 2 Phase II, randomized, double-blind, placebo-controlled, parallel-group, and dose-response studies enrolled male or nonchildbearing female Korean patients aged 18 to 65 years (study 1) or 18 to 70 years (study 2) with essential hypertension (sitting diastolic BP [DBP] 95-<115 mm Hg [study 1] or 90-<110 mm Hg [study 2]). Patients were randomly assigned to receive fimasartan 20, 60, 120, or 180 mg (study 1) or 20, 60, 120, or 240 mg (study 2) or placebo in the same ratio, once daily for 4 weeks (study 1) or 8 weeks (study 2). Clinic BP was measured at trough, and change from baseline in DBP at week 4 (study 1) or 8 (study 2) was the primary efficacy end point. In study 1, 24-hour ambulatory BP monitoring (ABPM) was conducted. Treatment-emergent adverse events (TEAEs) were assessed using a structured questionnaire, laboratory testing, physical examination, and ECG readings. RESULTS Totals of 61 and 195 patients participated in studies 1 and 2, respectively (68% male; mean age, 50.1 and 55.1 years; DBP, 98.7 and 103.6 mm Hg; systolic BP, 147.0 and 158.1 mm Hg), of whom 52 (85.2%) and 169 (86.7%) completed each study. Data from ABPM were obtained from 45 patients (73.8%), and safety profile was evaluated in 225 participants. Four-week treatment with fimasartan 180 mg once daily was associated with a significantly greater mean reduction in DBP compared with placebo in study 1 (-16.4 vs -5.5 mm Hg; P = 0.022). In study 2, fimasartan 60, 120, and 240 mg once daily were associated with significantly greater reductions in DBP after 8 weeks of treatment compared with placebo (-14.4, -14.1, and -12.7 vs -5.8 mm Hg, respectively; P < 0.0001-< 0.005). Fimasartan 60 mg once daily was the minimum effective dose, and the dose-response relationship was flat at doses >60 mg once daily. BP reduction was maintained over the full 24-hour dosing interval (trough-to-peak ratios: 0.41-0.98). The proportions of patients who experienced TEAEs were comparable among the treatment groups in both studies, with headache (9.8%) and dizziness (4.4%) being most commonly reported. No serious AEs were reported. CONCLUSIONS Once-daily oral administration of fimasartan was well tolerated and efficacious in reducing BP in these hypertensive Korean patient populations. ClinicalTrials.gov identifiers: NCT00937651 and NCT00923611.

Arterial stiffness, fatty liver and the presence of coronary artery calcium in a large population cohort

BackgroundWe tested whether fatty liver, brachial-ankle pulse wave velocity (baPWV) and conventional cardiovascular risk factors were associated with a coronary artery calcium (CAC) score > 0 (as a marker of the presence of early atherosclerosis) in a cohort of healthy Korean adults.MethodThe study population consisted of individuals who underwent a comprehensive health examination in 2010 at Kangbuk Samsung Hospital, College of Medicine, Sungkyunkwan University in South Korea. The 6009 subjects of total 7371 participants who had an assigned CAC score following coronary computed tomography (CT) scanning and baPWV were analyzed.ResultsAmong the study subjects, 39.2% of the population had evidence of fatty liver by ultrasound and 4.6% of the population had evidence of CAC score > 0. Among individuals with a CAC score = 0, 38% of the individuals had fatty liver compared with 58% of the individuals with a CAC score > 0. The individuals with a CAC score > 0 also had higher blood pressure and had more metabolic abnormalities. The prevalence of CAC score > 0 was increased according to baPWV quartiles and was higher in the fatty liver group in comparison with those without fatty liver. The odds ratio for CAC score > 0, after adjusting for clinical risk factors, showed a significant elevation with increasing quartiles of baPWV and the presence of fatty liver.ConclusionWe showed that both fatty liver and baPWV are independently associated with the presence of CAC, a marker of preclinical atherosclerosis. These associations are independent of conventional risk factors and medical history.

Pregnancy-Induced Hypertension, But Not Gestational Diabetes Mellitus, Is a Risk Factor for Venous Thromboembolism in Pregnancy

Background and Objectives The aim of this study was to identify the association of pregnancy-induced hypertension (PIH) or gestational diabetes mellitus (GDM) with the development of venous thromboembolism (VTE). Subjects and Methods This was a retrospective study of 57,009 pregnancies during 2002-2008 at Cheil General Hospital, Kwandong University. The diagnosis of VTE {deep vein thrombosis or pulmonary embolism (PE)} was based on clot visualization via ultrasound or computed tomography. Results In total, 27 cases (PE, 20 cases) were detected. The incidence of VTE was 0.47 per 1,000 pregnancies. To determine risk factors associated with pregnancy-induced VTE, univariate analysis using a chi-square test was performed. Cesarean (C)-section, multiple pregnancy, PIH, placenta previa, and assisted reproduction technique (ART) were statistically significant compared to the controls (all, p=0.000). However, age, premature rupture of membrane, and GDM were not statistically related to VTE. Logistic regression analysis was used to calculate the odds ratios for the risk factors. Placenta previa showed a 12.6-fold higher risk, while PIH had a 9.8-fold higher risk for the occurrence of VTE. C-section and ART procedures increased the risk of VTE by 4.2 times compared to that of the controls. Conclusion Placenta previa and PIH were significant risk factors for VTE, whereas the known traditional risk factors of increased age and GDM were not found to be associated with VTE.

A Comparison of the Prevalence of the MS and Its Complications Using Three Proposed Definitions in Korean Subjects

To compare the prevalence of the metabolic syndrome (MS) using 3 definitions (World Health Organization [WHO], Adult Treatment Panel [ATP III], and International Diabetes Foundation [IDF]) in Korean subjects, we reviewed 6,196 participants (3,436 men and 2,760 women; mean age 51 +/- 11 and 49 +/- 12 years) who underwent a general health status evaluation and had findings of MS components, including serum insulin and microalbuminuria. The prevalence of the MS according to the WHO, ATP III, and IDF definitions (male and female) was 17.1% and 10.3%, 26% and 19.3%, and 22% and 25.4%, respectively. The degrees of agreement according to the k statistics (WHO and IDF, WHO and ATP III, and IDF and ATP III) were modest in both genders. The diagnosis of the MS was associated with a high odds ratio for nonalcoholic fatty liver disease but with a significantly varying prevalence of a Framingham risk score of >10%. The MS was seen in 10% to 30% of otherwise healthy middle-age Korean subjects presenting for health screening and the prevalence varied widely according to the criteria of its definition. The effect of the diagnosis of the MS in terms of cardiovascular risk varies significantly according to the criteria used. In conclusion, a universally accepted definition of the MS is needed for clinical and population-based studies.

A Prospective Study of Fatty Liver Index and Incident Hypertension: The KoGES-ARIRANG Study

Background Although non-alcoholic fatty liver disease is the hepatic manifestation of metabolic syndrome, its influence on hypertension development is poorly understood. We investigated whether fatty liver disease, as assessed by the fatty liver index, could predict the development of hypertension independently of systemic insulin resistance, inflammatory status and adipokine levels. Methods Prospective cohort study of 1,521 adults (484 men and 1037 women) aged 40 to 70 years without baseline hypertension examined. An equation was used to calculate fatty liver index and classify patients as follows: fatty liver index <30, no non-alcoholic fatty liver disease; fatty liver index ≥60, non-alcoholic fatty liver disease; and 30≤ fatty liver index <60, intermediate fatty liver index. Results During an average of 2.6 years of follow-up, 153 subjects (10.06%) developed hypertension. Fatty liver index was positively associated with baseline blood pressure, homeostasis model assessment of insulin resistance, urinary albumin/creatinine excretion, and high sensitivity C-reactive protein. After adjustment for confounding factors, including markers of insulin resistance, systemic inflammation and adiponectin levels, the odds ratio [95% confidence interval] for the incident hypertension increased in a graded manner with fatty liver index (<30 vs. 30–59 vs. ≥60 = 1 vs. 1.83 [1.16~2.88] vs. 2.09 [1.08~4.055], respectively). Conclusions Non-alcoholic fatty liver disease assessed by fatty liver index was an independent risk factor for hypertension. Our findings suggest that fatty liver index, a simple surrogate indicator of fatty liver disease, might be useful for identifying subjects at high risk for incident hypertension in clinical practice.

2013 Korean Society of Hypertension guidelines for the management of hypertension. Part II—treatments of hypertension

Treatment strategies are provided in accordance with the level of global cardiovascular risk, from lifestyle modification in the lower risk group to more comprehensive treatment in the higher risk group. Considering the common trend of combination drug regimen, the choice of the first drug is suggested more liberally according to the physician’s discretion.

Are metabolic risk factors and target organ damage more frequent in masked hypertension than in white coat hypertension

Patients with masked hypertension (MH) tend to have a higher risk than those with white-coat hypertension (WCH). Therefore, we evaluated the characteristics of MH and WCH in Korean patients receiving medical treatment for hypertension. We enrolled 1019 outpatients (56 ± 10 y, 488 males) with diagnosed hypertension who had not changed oral anti-hypertensive medication for 6 months. Clinic blood pressure (CBP) was checked by a nurse and doctor twice per visit. Home BP (HBP) was checked every morning and evening for 1 week. In the MH patients, mean CBP was 130/80 mmHg, whereas HBP was 137/86 mmHg. In the WCH patients, mean CBP was 149/86 mmHg by physician and 143/85 mmHg by nurse and mean HBP was 124/75 mmHg. Age and gender did not differ between the groups. Waist and hip circumferences and the level of fasting glucose were higher in patients with MH than in patients with WCH (p = 0.008, 0.016, 0.009, respectively). Metabolic risk factors were more frequent in patients with WCH, MH, and uncontrolled hypertension than in patients with controlled hypertension. The incidence of metabolic risk factors, however, did not differ between patients with WCH and MH. Heart damage was more frequent in MH than in WCH (p = 0.03). The incidence of metabolic risk factors did not differ between patients with WCH and those with MH. Target organ damage was more closely related to MH than to WCH. Home BP measurement was a useful tool for discriminating WCH and MH in patients with hypertension.

A Randomized, Multicenter, Double-blind, Placebo-controlled, 3 × 3 Factorial Design, Phase II Study to Evaluate the Efficacy and Safety of the Combination of Fimasartan/Amlodipine in Patients With Essential Hypertension

PURPOSE The objective of this study was to evaluate the efficacy and safety of a fimasartan/amlodipine combination in patients with hypertension and to determine the optimal composition for a future single-pill combination formulation. METHODS This Phase II study was conducted by using a randomized, multicenter, double-blind, placebo-controlled, 3 × 3 factorial design. After a 2-week placebo run-in period, eligible hypertensive patients (with a sitting diastolic blood pressure [SiDBP] between 90 and 114 mm Hg) were randomized to treatment. They received single or combined administration of fimasartan at 3 doses (0, 30, and 60 mg) and amlodipine at 3 doses (0, 5, and 10 mg) for 8 weeks. The primary efficacy end point was the change in SiDBP from baseline and at week 8; secondary end points included the change in SiDBP from baseline and at week 4 and the changes in sitting systolic blood pressure from baseline and at weeks 4 and 8. Treatment-emergent adverse events (AEs) were also assessed. FINDINGS 420 Korean patients with mild to moderate hypertension were randomly allocated to the 9 groups. Mean (SD) SiDBP changes in each group after 8 weeks were as follows: placebo, -6.0 (8.5) mm Hg; amlodipine 5 mg, -10.6 (9.2) mm Hg; amlodipine 10 mg, -15.9 (7.2) mm Hg; fimasartan 30 mg, -10.1 (9.1) mm Hg; fimasartan 60 mg, -13.0 (10.0) mm Hg; fimasartan 30 mg/amlodipine 5 mg, -16.2 (8.5) mm Hg; fimasartan 30 mg/amlodipine 10 mg, -19.5 (7.5) mm Hg; fimasartan 60 mg/amlodipine 5 mg, -16.6 (6.9) mm Hg; and fimasartan 60 mg/amlodipine 10 mg, -21.5 (8.3) mm Hg. All treatment groups produced significantly greater reductions in blood pressure compared with the placebo group. In addition, all combination treatment groups had superior reductions in blood pressure compared with the monotherapy groups. In the combination treatment groups, doubling fimasartan dose in the given dose of amlodipine did not show further BP reduction, whereas doubling amlodipine dose showed significantly further BP reduction in the given dose of fimasartan. During the study period, 75 (17.9%) of 419 patients experienced 110 AEs. Ninety-five AEs were mild, 9 were moderate, and 6 were severe in intensity. Eight patients discontinued the study due to AEs. There was no significant difference in incidence of AEs among groups (P = 0.0884). The most common AE was headache (12 patients [2.9%]), followed by dizziness (11 patients [2.6%]) and elevated blood creatine phosphokinase levels (6 patients [1.4%]). IMPLICATIONS Fimasartan combined with amlodipine produced superior blood pressure reductions and low levels of AEs compared with either monotherapy. Therefore, a single-pill combination with fimasartan 60 mg/amlodipine 10 mg will be developed. ClinicalTrials.gov: NCT01518998.

The effect of body mass index and fasting glucose on the relationship between blood pressure and incident diabetes mellitus: a 5-year follow-up study

There is no consensus on the relationship between high blood pressure (BP) and incident diabetes mellitus (DM). Therefore, the aim of the current study was to investigate the independent association between BP and incident DM and identify the metabolic components that influence incident DM in Korean subjects. The current study included 14 054 non-diabetic subjects (mean age of 41 years) at the start of the study who were followed for an average of 5 years. We measured the risk for incident DM according to the subjects’ baseline BP. Subjects were separated into three groups as follows: normotensive (<120/80 mm Hg), pre-hypertensive (120/80 mm Hg ⩽BP <140/90 mm Hg) and hypertensive (⩾140/90 mm Hg). The overall incidence of DM was 1.8% (246 subjects), comprising 0.9% of the normotensive group, 1.9% of the pre-hypertensive group and 4.0% of the hypertensive group (P<0.01). Within the hypertensive group, subjects with high body mass index (BMI) and high fasting-glucose levels were 40 times more likely to develop DM compared with those with low BMI and low glucose levels (0.3 vs. 13.2%, P=0.001). The risk for incident DM was significantly higher in the hypertensive group compared with that in the normotensive group (OR 3.41 vs. 1.00, P<0.0001). However, the significance disappeared after making adjustments for the baseline BMI and fasting glucose levels (OR 1.18 vs. 1.00, P=0.83). We found that the significance of high BP in predicting incident DM was influenced by the baseline BMI and fasting glucose levels of the subjects.