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1.  The Impact of Diabetes Mellitus on Vascular Biomarkers in Patients with End-Stage Renal Disease 
Yonsei Medical Journal  2016;58(1):75-81.
Purpose
Diabetes mellitus (DM) is the most common cause of end-stage renal disease (ESRD) and an important risk factor for cardiovascular (CV) disease. We investigated the impact of DM on subclinical CV damage by comprehensive screening protocol in ESRD patients.
Materials and Methods
Echocardiography, coronary computed tomography angiogram, 24-h ambulatory blood pressure monitoring, and central blood pressure with pulse wave velocity (PWV) were performed in 91 ESRD patients from the Cardiovascular and Metabolic disease Etiology Research Center-HIgh risk cohort.
Results
The DM group (n=38) had higher systolic blood pressure than the non-DM group (n=53), however, other clinical CV risk factors were not different between two groups. Central aortic systolic pressure (148.7±29.8 mm Hg vs. 133.7±27.0 mm Hg, p= 0.014), PWV (12.1±2.7 m/s vs. 9.4±2.1 m/s, p<0.001), and early mitral inflow to early mitral annulus velocity (16.7±6.4 vs. 13.7±5.9, p=0.026) were higher in the DM group. Although the prevalence of coronary artery disease (CAD) was not different between the DM and the non-DM group (95% vs. 84.4%, p=0.471), the severity of CAD was higher in the DM group (p=0.01). In multivariate regression analysis, DM was an independent determinant for central systolic pressure (p=0.011), PWV (p<0.001) and the prevalence of CAD (p=0.046).
Conclusion
Diabetic ESRD patients have higher central systolic pressure and more advanced arteriosclerosis than the non-DM control group. These findings suggest that screening for subclinical CV damage may be helpful for diabetic ESRD patients.
doi:10.3349/ymj.2017.58.1.75
PMCID: PMC5122655  PMID: 27873498
End-stage renal disease; diabetes mellitus; target organ damage; coronary artery disease; hypertension
2.  The Association between Parameters of Socioeconomic Status and Hypertension in Korea: the Korean Genome and Epidemiology Study 
Journal of Korean Medical Science  2016;31(12):1922-1928.
We investigated the association between socioeconomic status and hypertension in Korea, a country that has experienced a dynamic socioeconomic transition. We analyzed participants of a prospective cohort study—the Korean Genome and Epidemiology Study—enrolled between 2001 and 2003. We recruited 7,089 subjects who underwent a 4-year follow up till 2007. Education and income levels, which are important parameters for socioeconomic status, were stratified into 4 groups. Education level was defined as short (≤ 6 years), mid-short (7–9 years), mid-long (10–12 years), and long (≥ 12 years). Monthly income level was stratified as low (< 500,000 KRW), mid-low (500,000–1,499,999 KRW), mid-high (1,500,000–2,999,999 KRW) or high (≥ 3,000,000 KRW). At baseline, 2,805 subjects (39.5%) were diagnosed with hypertension. Education and income levels were inversely associated with the prevalence and incidence of hypertension (P < 0.001). In multivariate analysis, a shorter duration of education was significantly associated with a higher prevalence of hypertension (P < 0.001), but income level was not (P = 0.305). During the follow-up, 605 subjects (14.2%) were newly diagnosed with hypertension. In multivariate adjusted analysis, the hazard ratios (95% confidence interval) for incident hypertension across the longer education groups were 0.749 (0.544–1.032), 0.639 (0.462–0.884), and 0.583 (0.387–0.879), compared with the shortest education group. There was no significant association between incident hypertension and income across higher income groups: 0.988 (0.714–1.366), 0.780 (0.542–1.121), and 0.693 (0.454–1.056), compared with the lowest income group. In conclusion, education and income levels are associated with the prevalence and incidence of hypertension, but only education is an independent prognostic factor in Korea.
Graphical Abstract
doi:10.3346/jkms.2016.31.12.1922
PMCID: PMC5102855  PMID: 27822930
Social Class; Education; Income; Hypertension; Incidence; Prevalence
3.  Cardiac Dysfunction in Association with Increased Inflammatory Markers in Primary Aldosteronism 
Endocrinology and Metabolism  2016;31(4):567-576.
Background
Oxidative stress in primary aldosteronism (PA) is thought to worsen aldosterone-induced damage by activating proinflammatory processes. Therefore, we investigated whether inflammatory markers associated with oxidative stress is increased with negative impacts on heart function as evaluated by echocardiography in patients with PA.
Methods
Thirty-two subjects (mean age, 50.3±11.0 years; 14 males, 18 females) whose aldosterone-renin ratio was more than 30 among patients who visited Severance Hospital since 2010 were enrolled. Interleukin-1β (IL-1β), IL-6, IL-8, monocyte chemoattractant protein 1, tumor necrosis factor α (TNF-α), and matrix metalloproteinase 2 (MMP-2), and MMP-9 were measured. All patients underwent adrenal venous sampling with complete access to both adrenal veins.
Results
Only MMP-2 level was significantly higher in the aldosterone-producing adenoma (APA) group than in the bilateral adrenal hyperplasia (BAH). Patients with APA had significantly higher left ventricular (LV) mass and A velocity, compared to those with BAH. IL-1β was positively correlated with left atrial volume index. Both TNF-α and MMP-2 also had positive linear correlation with A velocity. Furthermore, MMP-9 showed a positive correlation with LV mass, whereas it was negatively correlated with LV end-systolic diameter.
Conclusion
These results suggest the possibility that some of inflammatory markers related to oxidative stress may be involved in developing diastolic dysfunction accompanied by LV hypertrophy in PA. Further investigations are needed to clarify the role of oxidative stress in the course of cardiac remodeling.
doi:10.3803/EnM.2016.31.4.567
PMCID: PMC5195834  PMID: 27834080
Cytokines; Hyperaldosteronism; Heart diseases
4.  Effect of fixed‐dose combinations of ezetimibe plus rosuvastatin in patients with primary hypercholesterolemia: MRS‐ROZE (Multicenter Randomized Study of ROsuvastatin and eZEtimibe) 
Cardiovascular Therapeutics  2016;34(5):371-382.
Summary
Aim
We aimed to compare the effects of fixed‐dose combinations of ezetimibe plus rosuvastatin to rosuvastatin alone in patients with primary hypercholesterolemia, including a subgroup analysis of patients with diabetes mellitus (DM) or metabolic syndrome (MetS).
Method
This multicenter eight‐week randomized double‐blind phase III study evaluated the safety and efficacy of fixed‐dose combinations of ezetimibe 10 mg plus rosuvastatin, compared with rosuvastatin alone in patients with primary hypercholesterolemia. Four hundred and seven patients with primary hypercholesterolemia who required lipid‐lowering treatment according to the ATP III guideline were randomized to one of the following six treatments for 8 weeks: fixed‐dose combinations with ezetimibe 10 mg daily plus rosuvastatin (5, 10, or 20 mg daily) or rosuvastatin alone (5, 10, or 20 mg daily).
Results
Fixed‐dose combination of ezetimibe plus rosuvastatin significantly reduced LDL cholesterol, total cholesterol, and triglyceride levels compared with rosuvastatin alone. Depending on the rosuvastatin dose, these fixed‐dose combinations of ezetimibe plus rosuvastatin provided LDL cholesterol, total cholesterol, and triglyceride reductions of 56%–63%, 37%–43%, and 19%–24%, respectively. Moreover, the effect of combination treatment on cholesterol levels was more pronounced in patients with DM or MetS than in non‐DM or non‐MetS patients, respectively, whereas the effect of rosuvastatin alone did not differ between DM vs non‐DM or MetS vs non‐MetS patients.
Conclusion
Fixed‐dose combinations of ezetimibe and rosuvastatin provided significantly superior efficacy to rosuvastatin alone in lowering LDL cholesterol, total cholesterol, and triglyceride levels. Moreover, the reduction rate was greater in patients with DM or MetS.
doi:10.1111/1755-5922.12213
PMCID: PMC5108468  PMID: 27506635
Cholesterol; Diabetes mellitus; Ezetimibe; Hypercholesterolemia; Metabolic syndrome; Rosuvastatin
5.  Statin Intensity and Clinical Outcome in Patients with Stable Coronary Artery Disease and Very Low LDL-Cholesterol 
PLoS ONE  2016;11(11):e0166246.
Background
Although intensive statin therapy is recommended for high risk patients, evidence of its benefit in patients with stable coronary artery disease (CAD) and very low low-density lipoprotein-cholesterol (LDL-C) has been very rare. In this study, we investigated whether higher statin intensity reduces cardiovascular risks in this population.
Methods
In this retrospective study, a total of 5234 patients with stable CAD were screened at three tertiary hospitals in Korea; 449 patients (mean age: 65 years, male: 69%) with LDL-C <80 mg/dL were finally analyzed. The statin intensities were classified according to the 2013 American College of Cardiology/American Heart Association guidelines. Patients who received statins equivalent to or weaker than atorvastatin 10 mg (group 1) were compared with those who took statins equivalent to or stronger than atorvastatin 20 mg (group 2). The impact of statin intensity on major adverse cardiac events (MACE) was evaluated during follow-up.
Results
Group 1 and group 2 consisted of 181 patients (40.3%) and 268 patients (59.7%), respectively. The mean LDL-C level decreased to 52 and 57 mg/dL in group 1 and group 2, respectively, during follow-up. In a median follow-up of 4.5 years, patients of group 2 had a lower incidence of MACE (30 [16.6%] vs. 12 [4.5%], p <0.001), which were mostly related to a lower incidence of coronary revascularization. Cox proportional hazard analyses identified the statin intensity of group 2 (adjusted hazard ratio: 0.25, confidence interval: 0.11–0.55, p <0.001) and the baseline high-density lipoprotein-cholesterol level as independent determinants of MACE.
Conclusion
This study provides evidence that higher intensity statins are beneficial for cardiovascular outcomes in patients with stable CAD and very low LDL-C. Statins equivalent to or stronger than atorvastatin 20 mg are more effective than lower intensity statins.
doi:10.1371/journal.pone.0166246
PMCID: PMC5100958  PMID: 27824924
6.  Target Blood Pressure in Patients with Diabetes: Asian Perspective 
Yonsei Medical Journal  2016;57(6):1307-1311.
Recently, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) blood pressure (BP) trial enrolled 4733 participants with type 2 diabetes and randomized them to a target systolic blood pressure (SBP) of less than 120 mm Hg or 140 mm Hg. Despite the significant difference in the achieved SBP, there was no significant difference in the incidence of primary outcomes. Based on this evidence, the target SBP for diabetics has been revised in the majority of major guidelines. However, there is a steeper association between SBP and stroke in Asians than other ethnicities, with stroke being the leading cause of cardiovascular mortality. This suggests that target BP in the Asian region should be tailored towards prevention of stroke. In the ACCORD study, the intensive BP treatment was associated with significant reductions in both total stroke and non-fatal stroke. The results from the ACCORD study are supported by a subgroup analysis from the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) study, which showed that, in diabetic patients, the risk of stroke continues to decrease to a SBP value of 115 mm Hg with no evidence of J curve. As diabetes is highly associated with underlying coronary artery disease, there is a justified concern for adverse effects resulting from too much lowering of BP. In a post hoc analysis of 6400 diabetic subjects enrolled in the International Verapamil SR-Trandolapril (INVEST) study, subjects with SBP of less than 110 mm Hg were associated with a significant increase in all-cause mortality. In the ONTARGET study, at any levels of achieved SBP, diastolic blood pressure (DBP) below 67 mm Hg was associated with increased risk for cardiovascular outcomes. As such, a prudent approach would be to target a SBP of 130–140 mm Hg and DBP of above 60 mm Hg in diabetics with coronary artery disease. In conclusion, hypertension, in association with diabetes, has been found to be significantly correlated with an elevated risk for cardiovascular events. As the association between stroke and BP is stronger in Asians, compared to other ethnicities, consideration should be given for a target BP of 130/80 mm Hg in Asians.
doi:10.3349/ymj.2016.57.6.1307
PMCID: PMC5011260  PMID: 27593856
Diabetes; hypertension; blood pressure; stroke J-curve; coronary artery disease
7.  Lack of Superiority for Soluble ST2 over High Sensitive C-Reactive Protein in Predicting High Risk Coronary Artery Calcium Score in a Community Cohort 
Yonsei Medical Journal  2016;57(6):1347-1353.
Purpose
Soluble ST2 (sST2) is an emerging prognostic biomarker in patients with cardiovascular disease (CVD). A recent study showed that sST2 predicted incident hypertension. High sensitive C-reactive protein (hsCRP) has been a widely-used biomarker for risk-stratifying in CVD. We compared the abilities of sST2 and hsCRP to predict high risk coronary artery calcium score (CACS).
Materials and Methods
The CACS was assessed by cardiac computed tomography, and sST2 was measured in 456 subjects enrolled in the Mapo-gu community cohort. In accordance with the 2013 ACC/AHA guidelines, we defined the high risk CACS group as individuals with a CACS ≥300 Agatston units (AU).
Results
There were 99 (21.7%) subjects with a CACS ≥300 AU. There was a strong correlation between log sST2 and log hsCRP (r=0.128, p=0.006), and both log sST2 and log hsCRP showed significant associations with CACS (r=0.101, p=0.031 for sST2, r=0.101, p=0.032 for hsCRP). In net reclassification improvement (NRI) analysis, the NRI for hsCRP over sST2 was significant [continuous NRI 0.238, 95% confidence interval (CI) 0.001–0.474, integrated discrimination index (IDI) 0.022, p=0.035], while the NRI for sST2 over hsCRP was not significant (continuous NRI 0.212, 95% CI -0.255–0.453, IDI 0.002, p=0.269).
Conclusion
sST2 does not improve net reclassification for predicting a high risk CACS. Using hsCRP provides superior discrimination and risk reclassification for coronary atherosclerosis, compared with sST2.
doi:10.3349/ymj.2016.57.6.1347
PMCID: PMC5011265  PMID: 27593861
Soluble ST2; high sensitive C-reactive protein; coronary artery calcium score; atherosclerosis
8.  The Effect of FLT1 Variant on Long-Term Cardiovascular Outcomes: Validation of a Locus Identified in a Previous Genome-Wide Association Study 
PLoS ONE  2016;11(10):e0164705.
Background
Data on genetic variants that can predict follow-up cardiovascular events are highly limited, particularly for Asians. The aim of this study was to validate the effects of two variants in FLT1 and 9p21 on long-term cardiovascular outcomes in high-risk Korean patients.
Methods
We examined the prognostic values of the rs9508025 and rs1333049 variants that were found to be associated with coronary artery disease (CAD) risk in a previous Korean genome-wide association study. A total of 2693 patients (mean age: 55.2 years; male: 55.2%) with CAD or its risk factors at baseline were enrolled and followed for major adverse cardiac events (MACE).
Results
During the mean follow-up of 8.8 years, 15.4% of the patients experienced MACE. Kaplan-Meier curves showed that MACE-free survival was different according to the genotype of rs9508025 (log rank p = 0.02), whereas rs1333049 genotype did not correlate with the prognosis. Multivariate Cox proportional hazard analysis showed that C-allele of rs9508025 was significantly associated with a high rate of MACE, while rs1333049 was not. Further analyses demonstrated that the association of the rs9508025 variant with MACE was mainly due to its relation to coronary revascularization, which was also associated with the rs1333049 variant. In an additional analysis, rs9508025 was found to be an independent determinant of the outcome only in the subgroup with history of CAD.
Conclusions
rs9508025 in FLT1 was significantly associated with long-term cardiovascular events, particularly in patients with prior CAD. The association of rs1333049 in 9p21 was not significant.
doi:10.1371/journal.pone.0164705
PMCID: PMC5063388  PMID: 27736948
9.  Development of Advanced Atherosclerotic Plaque by Injection of Inflammatory Proteins in a Rabbit Iliac Artery Model 
Yonsei Medical Journal  2016;57(5):1095-1105.
Purpose
Appropriate animal models of atherosclerotic plaque are crucial to investigating the pathophysiology of atherosclerosis, as well as for the evaluation of the efficacy and safety of vascular devices. We aimed to develop a novel animal model that would be suitable for the study of advanced atherosclerotic lesions in vivo.
Materials and Methods
Atherosclerotic plaque was induced in 24 iliac arteries from 12 rabbits by combining a high cholesterol diet, endothelial denudation, and injection into the vessel wall with either saline (n=5), olive oil (n=6), or inflammatory proteins [n=13, high-mobility group protein B1 (HMGB1) n=8 and tumor necrosis factor (TNF)-α n=5] using a Cricket™ Micro-infusion catheter. Optical coherence tomography (OCT) was performed to detect plaque characteristics after 4 weeks, and all tissues were harvested for histological evaluation.
Results
Advanced plaque was more frequently observed in the group injected with inflammatory proteins. Macrophage infiltration was present to a higher degree in the HMGB1 and TNF-α groups, compared to the oil or saline group (82.1±5.1% and 94.6±2.2% compared to 49.6±14.0% and 46.5±9.6%, p-value<0.001), using RAM11 antibody staining. On OCT, lipid rich plaques were more frequently detected in the inflammatory protein group [saline group: 2/5 (40%), oil group: 3/5 (50%), HMGB1 group: 6/8 (75%), and TNF-α group: 5/5 (100%)].
Conclusion
These data indicate that this rabbit model of atherosclerotic lesion formation via direct injection of pro-inflammatory proteins into the vessel wall is useful for in vivo studies investigating atherosclerosis.
doi:10.3349/ymj.2016.57.5.1095
PMCID: PMC4960374  PMID: 27401639
Rabbit model; atherosclerosis; balloon injury; inflammatory protein
10.  The Role of Home Blood Pressure Telemonitoring for Blood Pressure Control 
Pulse  2016;4(2-3):78-84.
Despite improvements in hypertension awareness and treatment, the blood pressure (BP) control rate still remains at around 50%. One of the major determinants of low BP control results from therapeutic inertia of the physician and suboptimal compliance of the patients. Home BP self-measurement and monitoring improves patients' awareness and helps the management of hypertension. Recent technological advances are allowing for accurate measurement and telemonitoring of home BP, with a number of randomized clinical trials demonstrating the efficacy of telemonitoring for BP control. Home BP telemonitoring combined with self-adjustment based on prespecified treatment algorithms has been shown to improve BP control. Additionally, telemonitoring with active intervention by medical professionals has been shown to improve drug compliance and increase the target BP achievement rate. Although nothing can replace the tried and tested doctor-patient relationship in the office, telemonitoring of home BP will be an important tool for treating hypertension in the future.
doi:10.1159/000448375
PMCID: PMC5052691  PMID: 27752479
Hypertension; Blood pressure control; Home blood pressure telemonitoring; Self-measurement of blood pressure; Remote physician care
11.  Higher Blood Pressure Variability in White Coat Hypertension; from the Korean Ambulatory Blood Pressure Monitoring Registry 
Korean Circulation Journal  2016;46(3):365-373.
Background and Objectives
Blood pressure variability (BPV) was recently shown to be a risk factor of stroke. White coat hypertension (WCH) used to be regarded as innocuous, but one long-term follow-up study reported that WCH increased stroke rate compared to normotension (NT). In this study, we aimed to evaluate the relationship between WCH and BPV.
Subjects and Methods
We analyzed 1398 subjects from the Korean Ambulatory Blood Pressure Registry, who were divided into NT (n=364), masked hypertension (n=122), white coat hypertension (n=254), and sustained hypertension (n=658) groups.
Results
Baseline characteristics were similar among groups. The average real variability (ARV), a highly sensitive BPV parameter, was highest in the WCH group, followed by the sustained hypertension, masked hypertension, and NT groups. The results persisted after being adjusted for covariates. The WCH vs. sustained hypertension results (adjusted mean±standard error) were as follows: 24-h systolic ARV, 22.9±0.8 vs. 19.4±0.6; 24-h diastolic ARV, 16.8±0.6 vs. 14.3±0.5; daytime systolic ARV, 21.8±0.8 vs. 16.8±0.6; and daytime diastolic ARV, 16.2±0.6 vs. 13.4±0.5 (p<0.001 for all comparisons).
Conclusion
From the registry data, we found that subjects with WCH or masked hypertension had higher BPV than NT. However, long-term follow-up data assessing the clinical influences of WCH on stroke are needed.
doi:10.4070/kcj.2016.46.3.365
PMCID: PMC4891601  PMID: 27275173
Blood pressure monitoring; Ambulatory; Blood pressure variability; White coat hypertension
13.  Prevalence of resistant hypertension and associated factors for blood pressure control status with optimal medical therapy using Korean ambulatory blood pressure monitoring registry data 
Background
Resistant hypertension (RH) may be one of the cause of the plateau in improving the control rate in hypertension (HT) management. The misdiagnosis of RH by clinic blood pressure (BP) is important clinical problem. Aim of the study were to investigate the prevalence of RH by ambulatory blood pressure monitoring (ABPM) and the factor associated with control status of ambulatory BPs.
Methods
For 1230 subjects taking one or more antihypertensive medication (AHM) enrolled in the Korean Ambulatory Blood Pressure Monitoring (Kor-ABP) registry, the prevalence of RH was calculated which was defined as uncontrolled BP by three AHM classes including diuretic or BP in need of four or more AHM classes. The prevalence determined by clinic versus ambulatory BP was compared.
Results
The age was 59.3 ± 12.5 years, and 44.3 % were female (n = 1230). Among them 72 subjects were taking three AHM drugs including diuretics and 105 subjects were taking four or more AHM classes. With uncontrolled daytime ambulatory BP in 41 among 72 subjects, prevalence of RH was 11.9 % (146/1230). By using nighttime BP criteria, there was significant difference in the prevalence of RH for clinic versus nighttime BP (146/177 vs. 159/177, p = 0.0124). For control status of daytime BP, masked uncontrolled BP was 16.9 % and controlled BP with white-coat effect was 14.1 %. For nighttime BP control status, odd ratios for smoking (0.624), drinking (1.512), coronary artery disease (0.604), calcium antagonist (1.705), and loop diuretics (0.454) were all significant.
Conclusion
The prevalence itself was 11.9 % by daytime BP and it was significantly higher when using nighttime BP criteria. Control status of daytime BP was misclassified in 31.0 %. Smoking, drinking, coronary artery disease, calcium antagonist, and loop diuretics were associated with nighttime BP control status.
doi:10.1186/s40885-016-0045-x
PMCID: PMC4750808  PMID: 26893941
Hypertension Resistant to Conventional Therapy; Ambulatory blood pressure monitoring; Masked hypertension; White-coat hypertension; Hypertension
14.  Circulating Anti-Elastin Antibody Levels and Arterial Disease Characteristics: Associations with Arterial Stiffness and Atherosclerosis 
Yonsei Medical Journal  2015;56(6):1545-1551.
Purpose
Elastin is a major arterial structural protein, and elastin-derived peptides are related to arterial change. We previously reported on a novel assay developed using aortic elastin peptides; however, its clinical implications remain unclear. In this study, we assessed whether anti-elastin antibody titers reflect the risk of coronary artery disease (CAD) or its characteristics.
Materials and Methods
We included 174 CAD patients and 171 age- and sex-matched controls. Anti-elastin antibody titers were quantified by enzyme-linked immunosorbent assay. Parameters of arterial stiffness, including the augmentation index (AI) and heart-to-femoral pulse wave velocity (hfPWV), were measured non-invasively. The clinical and angiographic characteristics of CAD patients were also evaluated. Associations between anti-elastin levels and vascular characteristics were examined by linear regression analysis.
Results
The median blood level of anti-elastin was significantly lower in the CAD group than in the controls [197 arbitrary unit (a.u.) vs. 63 a.u., p<0.001]. Levels of anti-elastin were significantly lower in men and in subjects with hypertension, diabetes mellitus, hyperlipidemia, or high hfPWV. Nevertheless, anti-elastin levels were not dependent on atherothrombotic events or the angiographic severity of CAD. In a multivariate analysis, male sex (β=-0.38, p<0.001), diabetes mellitus (β=-0.62, p<0.001), hyperlipidemia (β=-0.29, p<0.001), and AI (β=-0.006, p=0.02) were ultimately identified as determinants of anti-elastin levels.
Conclusion
Lower levels of anti-elastin are related to CAD. The association between antibody titers and CAD is linked to arterial stiffness rather than the advancement of atherosclerosis.
doi:10.3349/ymj.2015.56.6.1545
PMCID: PMC4630041  PMID: 26446635
Elastin; antibody formation; vascular stiffness; coronary artery disease; atherosclerosis
15.  Clinical Features of Obstructive Sleep Apnea That Determine Its High Prevalence in Resistant Hypertension 
Yonsei Medical Journal  2015;56(5):1258-1265.
Purpose
Resistant hypertension (HTN) occurs in 15-20% of treated hypertensive patients, and 70-80% of resistant hypertensive patients have obstructive sleep apnea (OSA). The characteristics of resistant HTN that predispose patients to OSA have not been reported. Therefore, we aimed to determine the clinical, laboratory, and polysomnographic features of resistant HTN that are significantly associated with OSA.
Materials and Methods
Hypertensive patients (n=475) who underwent portable polysomnography were enrolled. The patients were categorized into controlled (n=410) and resistant HTN (n=65) groups. The risk factors for the occurrence of OSA in controlled and resistant hypertensive patients were compared, and independent risk factors that are associated with OSA were analyzed.
Results
Out of 475 patients, 359 (75.6%) were diagnosed with OSA. The prevalence of OSA in resistant HTN was 87.7%, which was significantly higher than that in controlled HTN (73.7%). Age, body mass index, neck circumference, waist circumference, and hip circumference were significantly higher in OSA. However, stepwise multivariate analyses revealed that resistant HTN was not an independent risk factor of OSA.
Conclusion
The higher prevalence and severity of OSA in resistant HTN may be due to the association of risk factors that are common to both conditions.
doi:10.3349/ymj.2015.56.5.1258
PMCID: PMC4541655  PMID: 26256968
Resistant hypertension; sleep apnea; polysomnography; obesity; body mass index
16.  Insulin Protects Cardiac Myocytes from Doxorubicin Toxicity by Sp1-Mediated Transactivation of Survivin 
PLoS ONE  2015;10(8):e0135438.
Insulin inhibits ischemia/reperfusion-induced myocardial apoptosis through the PI3K/Akt/mTOR pathway. Survivin is a key regulator of anti-apoptosis against doxorubicin-induced cardiotoxicity. Insulin increases survivin expression in cardiac myocytes to mediate cytoprotection. However, the mechanism by which survivin mediates the protective effect of insulin against doxorubicin-associated injury remains to be determined. In this study, we demonstrated that pretreatment of H9c2 cardiac myocytes with insulin resulted in a significant decrease in doxorubicin-induced apoptotic cell death by reducing cytochrome c release and caspase-3 activation. Doxorubicin-induced reduction of survivin mRNA and protein levels was also significantly perturbed by insulin pretreatment. Reducing survivin expression with survivin siRNA abrogated insulin-mediated inhibition of caspase-3 activation, suggesting that insulin signals to survivin inhibited caspase-3 activation. Interestingly, pretreatment of H9c2 cells with insulin or MG132, a proteasome inhibitor, inhibited doxorubicin-induced degradation of the transcription factor Sp1. ChIP assay showed that pretreatment with insulin inhibited doxorubicin-stimulated Sp1 dissociation from the survivin promoter. Finally using pharmacological inhibitors of the PI3K pathway, we showed that insulin-mediated activation of the PI3K/Akt/mTORC1 pathway prevented doxorubicin-induced proteasome-mediated degradation of Sp1. Taken together, insulin pretreatment confers a protective effect against doxorubicin-induced cardiotoxicity by promoting Sp1-mediated transactivation of survivin to inhibit apoptosis. Our study is the first to define a role for survivin in cellular protection by insulin against doxorubicin-associated injury and show that Sp1 is a critical factor in the transcriptional regulation of survivin.
doi:10.1371/journal.pone.0135438
PMCID: PMC4535909  PMID: 26271039
17.  ASSOCIATION OF CENTRAL HEMODYNAMICS WITH ESTIMATED 24-HOUR URINARY SODIUM IN PATIENTS WITH HYPERTENSION 
Journal of hypertension  2011;29(8):1502-1507.
Objective
High salt intake is known to be the most pivotal environmental factor in the pathogenesis of hypertension. However, the association of high sodium intake with central hemodynamics in hypertensive subjects has not been well defined. Here, we determined the association of estimated 24-hour urine sodium and potassium excretion estimated from a spot urine analysis with parameters of central pulse wave analysis in 515 hypertensive subjects.
Methods
Fasting spot urine samples were obtained in the early morning after the first void, and estimated 24-hour urine sodium and potassium excretion were estimated from measurement of urine sodium, potassium, and creatinine. Central hemodynamics and arterial stiffness parameters were assessed via pulse wave analysis of the radial artery.
Results
The estimated 24-hour sodium and potassium excretion values were 150 ± 40 and 49 ± 10 mEq, respectively. There was a step-wise decrease in pulse pressure amplification with increasing estimated 24-hour urine sodium excretion. Multiple linear regression analyses revealed that both estimated 24-hour urine sodium excretion and sodium/potassium ratio were independently associated with increases in central pulse pressure, augmented aortic pressure, augmentation index and were inversely associated with pulse pressure amplification.
Conclusion
The estimated 24-hour urinary sodium excretion is independently associated with central hemodynamics. This may provide the basis for prospective interventional studies of epidemiologic scale to determine the potential beneficial effects of reduced salt consumption on central hemodynamics.
doi:10.1097/HJH.0b013e3283486311
PMCID: PMC4535170  PMID: 21666493
Hypertension; sodium; pulse pressure amplification; central pulse pressure
18.  Characterization of CD8+CD57+ T cells in patients with acute myocardial infarction 
Cellular and Molecular Immunology  2014;12(4):466-473.
Although T cells are known to be involved in the pathogenesis of coronary artery disease, it is unclear which subpopulation of T cells contributes to pathogenesis in acute myocardial infarction (MI). We studied the immunological characteristics and clinical impact of CD8+CD57+ T cells in acute MI patients. The frequency of CD57+ cells among CD8+ T cells was examined in peripheral blood sampled the morning after acute MI events. Interestingly, the frequency of CD57+ cells in the CD8+ T-cell population correlated with cardiovascular mortality 6 months after acute MI. The immunological characteristics of CD8+CD57+ T cells were elucidated by surface immunophenotyping, intracellular cytokine staining and flow cytometry. Immunophenotyping revealed that the CD8+CD57+ T cells were activated, senescent T cells with pro-inflammatory and tissue homing properties. Because a high frequency of CD8+CD57+ T cells is associated with short-term cardiovascular mortality in acute MI patients, this specific subset of CD8+ T cells might contribute to acute coronary events via their pro-inflammatory and high cytotoxic capacities. Identification of a pathogenic CD8+ T-cell subset expressing CD57 may offer opportunities for the evaluation and management of acute MI.
doi:10.1038/cmi.2014.74
PMCID: PMC4496543  PMID: 25152079
acute myocardial infarction; CD8+CD57+ T cells; immunosenescence
19.  Genetic Testing of Korean Familial Hypercholesterolemia Using Whole-Exome Sequencing 
PLoS ONE  2015;10(5):e0126706.
Familial hypercholesterolemia (FH) is a genetic disorder with an increased risk of early-onset coronary artery disease. Although some clinically diagnosed FH cases are caused by mutations in LDLR, APOB, or PCSK9, mutation detection rates and profiles can vary across ethnic groups. In this study, we aimed to provide insight into the spectrum of FH-causing mutations in Koreans. Among 136 patients referred for FH, 69 who met Simon Broome criteria with definite family history were enrolled. By whole-exome sequencing (WES) analysis, we confirmed that the 3 known FH-related genes accounted for genetic causes in 23 patients (33.3%). A substantial portion of the mutations (19 of 23 patients, 82.6%) resulted from 17 mutations and 2 copy number deletions in LDLR gene. Two mutations each in the APOB and PCSK9 genes were verified. Of these anomalies, two frameshift deletions in LDLR and one mutation in PCSK9 were identified as novel causative mutations. In particular, one novel mutation and copy number deletion were validated by co-segregation in their relatives. This study confirmed the utility of genetic diagnosis of FH through WES.
doi:10.1371/journal.pone.0126706
PMCID: PMC4427254  PMID: 25962062
20.  The N-Glycoform of sRAGE is the Key Determinant for Its Therapeutic Efficacy to Attenuate Injury-elicited Arterial Inflammation and Neointimal Growth 
Journal of molecular medicine (Berlin, Germany)  2013;91(12):10.1007/s00109-013-1091-4.
Signaling of the receptor for advanced glycation end products (RAGE) has been implicated in the development of injury-elicited vascular complications. Soluble RAGE (sRAGE) acts as a decoy of RAGE, and has been used to treat pathological vascular conditions in animal models. However, previous studies using sRAGE produced in insect Sf9 cells (sRAGESf9) used a high dose and multiple injections to achieve the therapeutic outcome. Here, we explore whether modulation of sRAGE N-glycoform impacts its bioactivity and augments its therapeutic efficacy. We first profiled carbohydrate components of sRAGECHO to show that a majority of its N-glycans belong to sialylated complex-types that are not shared by sRAGESf9. In cell-based NF-κB activation and vascular smooth muscle cell (VSMC) migration assays, sRAGECHO exhibited a significantly higher bioactivity relative to sRAGESf9 to inhibit RAGE alarmin ligand-induced NF-κB activation and VSMC migration. We next studied whether this N-glycoform-associated bioactivity of sRAGECHO is translated to higher in vivo therapeutic efficacy in a rat carotid artery balloon injury model. Consistent with the observed higher bioactivity in cell assays, sRAGECHO significantly reduced injury-induced neointimal growth and the expression of inflammatory markers in injured vasculature. Specifically, a single dose of 3 ng/g of sRAGECHO reduced neointimal hyperplasia by over 70%, whereas the same dose of sRAGESf9 showed no effect. The administered sRAGECHO is rapidly and specifically recruited to the injured arterial locus, suggesting that early intervention of arterial injury with sRAGECHO may offset an inflammatory circuit and reduce the ensuing tissue remodeling. Our findings showed that the N-glycoform of sRAGE is the key determinant underlying its bioactivity, and thus is an important glycobioengineering target to develop a highly potent therapeutic sRAGE for future clinical applications.
doi:10.1007/s00109-013-1091-4
PMCID: PMC3846495  PMID: 24132651
sRAGE; N-glycoform; arterial injury; arterial inflammation; neointimal hyperplasia; therapeutic window
21.  Vessel Ultrasound Sonographic Assessment of Soluble Receptor for Advanced Glycation End Products Efficacy in a Rat Balloon Injury Model 
Objective
We aimed to assess the therapeutic efficacy of differentially modified soluble receptor for advanced glycation end products (sRAGE) in vivo using vessel ultrasound sonography and to compare the sonography data with those from postmortem histomorphologic analyses to have a practical reference for future clinical applications.
Methods
Vessel ultrasound sonography was performed in a sRAGE-treated rat carotid artery balloon injury model at different time points after the surgery, and therapeutic efficacy of different doses of sRAGE produced in Chinese hamster ovary cells and with different N-glycoform modifications were assessed.
Results
Vessel ultrasound sonography found that sRAGE produced in Chinese hamster ovary cells with complex N-glycoform modifications is highly effective, and is consistent with our recent findings in the same model assessed with histology. We also found that sonography is less sensitive than histology when a higher dose of sRAGE is administered.
Conclusions
Sonograph results are consistent with those obtained from histology; that is, sRAGE produced in Chinese hamster ovary cells has significantly higher efficacy than insect cell-originated sRAGE cells.
doi:10.1016/j.curtheres.2014.08.001
PMCID: PMC4229510  PMID: 25408789
neointima; N-glycosylationl; soluble receptor for advanced glycation end products; vascular injury; vessel sonography
22.  Gender Differences in the Association between Serum γ-Glutamyltransferase and Blood Pressure Change: A Prospective Community-Based Cohort Study 
Journal of Korean Medical Science  2014;29(10):1379-1384.
We evaluated the gender differences in the relation of baseline serum γ-glutamyltransferase (GGT) levels to blood pressure (BP) change during 4 yr. 4,025 normotensive subjects (1,945 men and 2,080 women) who aged 40-69 yr at baseline participated in the Ansung-Ansan cohort of the Korean Genome Epidemiology Study were included. The associations of GGT with baseline BP or 4-yr change of BP were evaluated. GGT levels were associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) at baseline after adjusting for age, body mass index (BMI), HDL-cholesterol, triglyceride, C-reactive protein (CRP), current smoking status and alcohol intake (SBP, β=1.28, P<0.001; DBP, β=1.41, P<0.001). GGT levels were also associated with 4-yr change in BP after adjusting for age, BMI, HDL-cholesterol, triglyceride, CRP, current smoking status, alcohol intake and SBP (SBP, β=1.08, P=0.001; DBP, β=0.64, P=0.003). This association was statistically significant in men (SBP, β=1.82, P<0.001; DBP, β=1.05, P=0.001), but not in women (SBP, β=0.38, P=0.466; DBP, β=-0.37, P=0.304). Remarkably, this association between GGT and BP was significant in men at 40-49 yr of age. In summary, we found positive associations between GGT levels at baseline and the change of BP. The relation of GGT level and the change of BP was only significant in men, not in women, which warrants further studies to elucidate the biologic mechanisms.
Graphical Abstract
doi:10.3346/jkms.2014.29.10.1379
PMCID: PMC4214938  PMID: 25368491
Blood Pressure; γ-Glutamyltransferase; Gender
24.  Neck Circumference and Lowest Oxygen Saturation Are Independently Associated with High Coexistence of Hypertension in Obstructive Sleep Apnea 
Yonsei Medical Journal  2014;55(5):1310-1317.
Purpose
Obstructive sleep apnea (OSA) is considered an independent risk factor for hypertension. However, it is still not clear which clinical factors are related with the presence of hypertension in OSA patients. We aimed to find different physical features and compare the sleep study results which are associated with the occurrence of hypertension in OSA patients.
Materials and Methods
Medical records were retrospectively reviewed for patients diagnosed with OSA at Severance Cardiovascular Hospital between 2010 and 2013. Males with moderate to severe OSA patients were enrolled in this study. Clinical and polysomnographic features were evaluated to assess clinical variables that are significantly associated with hypertension by statistical analysis.
Results
Among men with moderate to severe OSA, age was negatively correlated with hypertension (odds ratio=0.956), while neck circumference was positively correlated with the presence of hypertension (odds ratio=1.363). Among the polysomnographic results, the lowest O2 saturation during sleep was significantly associated with the presence of hypertension (odds ratio=0.900).
Conclusion
Age and neck circumference should be considered as clinically significant features, and the lowest blood O2 saturation during sleep should be emphasized in predicting the coexistence or development of hypertension in OSA patients.
doi:10.3349/ymj.2014.55.5.1310
PMCID: PMC4108817  PMID: 25048490
Sleep apnea; hypertension; polysomnography; neck circumference; lowest oxygen saturation level
25.  Combination of a peroxisome proliferator‐activated receptor‐gamma agonist and an angiotensin II receptor blocker attenuates myocardial fibrosis and dysfunction in type 2 diabetic rats 
Abstract
Aims/Introduction
We aimed to examine the effect of an angiotensin II receptor blocker (ARB), a peroxisome proliferator‐activated receptor (PPAR)‐gamma agonist, and their combination on myocardial fibrosis and function in type 2 diabetic rats.
Materials and Methods
Five male Long‐Evans Tokushima Otsuka (LETO) rats and 20 male Otsuka Long‐Evans Tokushima Fatty (OLETF) rats were used. OLETF rats were assigned to four groups (n = 5 per group) at 28 weeks‐of‐age: untreated, losartan‐treated, rosiglitazone‐treated and combination‐treated. The ARB, losartan, was administered at a dose of 5 mg/kg/day, and the PPAR‐gamma agonist, rosiglitazone, was administered at a dose of 3 mg/kg/day by oral gavage for 12 weeks. Urine and blood samples were collected, and two‐dimensional echocardiograms and strain rate imaging were obtained at 28 and 40 weeks. Cytokines were evaluated by reverse transcriptase polymerase chain reaction, and histological analysis was carried out at 40 weeks.
Results
At 40 weeks, the global radial strains of the losartan‐treated (55.7 ± 4.5%, P = 0.021) and combination‐treated groups (59.3 ± 6.7%, P = 0.001) were significantly higher compared with the untreated OLETFs (44.3 ± 10.5%). No difference was observed when compared with LETO rats. Although the rosiglitazone‐treated group showed a better metabolic profile than the untreated OLETF group, there was no difference in the global radial strain (49.8 ± 6.0 vs 44.3 ± 10.5, P = 0.402). The expression of pro‐inflammatory cytokines, and collagen type I and III were consistently attenuated in the losartan‐treated and combination‐treated OLETF groups, but not in the rosiglitazone‐treated group.
Conclusions
A combination of rosiglitazone and losartan attenuates myocardial fibrosis and dysfunction in type 2 diabetic rats.
doi:10.1111/jdi.12153
PMCID: PMC4210065  PMID: 25411595
Angiotensin II receptor blocker; Diabetic cardiomyopathy; Peroxisome proliferator‐activated receptor‐gamma agonist

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