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1.  Red Cell Distribution Width as an Independent Predictor of Exercise Intolerance and Ventilatory Inefficiency in Patients with Chronic Heart Failure 
Yonsei Medical Journal  2014;55(3):635-643.
Peak oxygen uptake (peak VO2) and ventilatory inefficiency (VE/VCO2 slope) have proven to be strong prognostic markers in patients with chronic heart failure (CHF). Recently increased red cell distribution width (RDW) has emerged as an additional predictor of poor outcome in CHF. We sought to evaluate the relationship between RDW and cardiopulmonary exercise test (CPET) parameters in CHF patients and healthy controls.
Materials and Methods
85 ambulatory CHF patients (68 men, 54±10 years) and 107 healthy controls, who underwent a symptom-limited CPET on a treadmill according to the modified Bruce ramp protocol, were enrolled. CHF patients and healthy controls were divided into RDW tertile groups and laboratory, echocardiographic, and CPET results were analyzed.
For patients with CHF, compared with patients in the lowest RDW tertile, those in the highest tertile had lower peak VO2 (22 mL/kg/min vs. 28 mL/kg/min, p<0.001) and higher VE/VCO2 slope (31 vs. 25, p=0.004). Multivariate regression analysis revealed RDW to be an independent predictor for peak VO2 (β=-0.247, p=0.035) and VE/VCO2 slope (β=0.366, p=0.004). The optimal cutoff value of RDW for predicting peak VO2 ≤20 mL/kg/min and VE/VCO2 slope ≥34 was 13.6% (sensitivity 53%, specificity 89%) and 13.4% (sensitivity 75%, specificity 82%), respectively. In contrast, for healthy controls, RDW was not related to both peak VO2 and VE/VCO2 slope.
Higher RDW is independently related to peak VO2 and VE/VCO2 slope only in patients with CHF. RDW assessment, an inexpensive and simple method, might help predict functional capacity and ventilatory efficiency in these patients.
PMCID: PMC3990060  PMID: 24719129
Cardiopulmonary exercise test; heart failure; red cell distribution width
2.  Protective Effect of Survivin in Doxorubicin-Induced Cell Death in H9c2 Cardiac Myocytes 
Korean Circulation Journal  2013;43(6):400-407.
Background and Objectives
Apoptosis has been known to be an important mechanism of doxorubicin-induced cardiotoxicity. Survivin, which belongs to the inhibitor of apoptosis protein family, is associated with apoptosis and alteration of the cardiac myocyte molecular pathways. Therefore, we investigated the anti-apoptotic effect and cellular mechanisms of survivin using a protein delivery system in a doxorubicin-induced cardiac myocyte injury model.
Materials and Methods
We constructed a recombinant survivin which was fused to the protein transduction domain derived from HIV-TAT protein. In cultured H9c2 cardiac myocytes, TAT-survivin (1 µM) was added for 1 hour prior to doxorubicin (1 µM) treatment for 24 hours. Cell viability and apoptosis were evaluated by 2-(4,5-dimethyltriazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, caspase-3 activity, and terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling assay. We measured the expression levels of several apoptosis-related signal proteins.
The survivin level was significantly reduced in a dose dependent manner up to 1 µM of doxorubicin in concentration. Purified recombinant TAT-survivin protein was efficiently delivered to H9c2 cardiac myocytes, and its transduction showed an anti-apoptotic effect, demonstrated by reduced caspase-3 activity and the apoptotic index, concomitantly with increased cell viability against doxorubicin injury. The phosphorylation of p38 mitogen-activated protein (MAP) kinase and the release of Smac from mitochondria were suppressed and the expression levels of Bcl-2 and cAMP response element-binding protein (CREB), the transcription factor of Bcl-2, were recovered following TAT-survivin transduction, indicating that survivin had an anti-apoptotic effect against doxorubicin injury.
Our results suggest that survivin has a potentially cytoprotective effect against doxorubicin-induced cardiac myocyte apoptosis through mechanisms that involve a decrease in the phosphorylation of p38 MAP kinase, mitochondrial Smac release, and increased expression of Bcl-2 and CREB.
PMCID: PMC3717423  PMID: 23882289
Apoptosis; Doxorubicin; Myocytes, cardiac
3.  Plasma Adiponectin Concentration and Its Association with Metabolic Syndrome in Patients with Heart Failure 
Yonsei Medical Journal  2011;53(1):91-98.
Plasma adiponectin concentrations are inversely related with metabolic syndrome (MetS), and MetS is associated with increased risk for heart failure (HF). However, the relationship between adiponectin and MetS in HF remains undetermined. Therefore, we tested whether MetS was associated with the degree of plasma adiponectin concentrations in HF patients.
Materials and Methods
One hundred twenty eight ambulatory HF patients with left ventricular ejection fraction of <50% (80 males, 61.8±11.9 years old) were enrolled for this cross-sectional study. Echocardiographic measurements were performed, and plasma concentrations of adiponectin, lipoproteins, apolipoproteins (apoB, apoA1) and high sensitive C-reactive protein (hsCRP) were measured.
Adiponectin concentrations in HF patients with MetS (n=43) were significantly lower than those without MetS (n=85) (9.7±7.0 vs. 15.8±10.9 µg/mL, p=0.001). Higher concentrations of apoB (p=0.017), apoB/A1 ratio (p<0.001), blood urea nitrogen (p=0.034), creatinine (p=0.003), and fasting insulin (p=0.004) were observed in HF patients with MetS compared with those without MetS. In HF patients with MetS, adiponectin concentrations were negatively correlated with hsCRP (r=-0.388, p=0.015) and positively correlated with the ratio of early mitral inflow velocity to early diastolic mitral annular velocity, E/E' (r=0.399, p=0.015). There was a significant trend towards decreased adiponectin concentrations with an increasing number of components of MetS (p for trend=0.012).
Our study demonstrated that adiponectin concentrations decreased in HF patients with MetS, and that relationship between adiponectin, inflammation and abnormal diastolic function, possibly leading to the progression of HF.
PMCID: PMC3250329  PMID: 22187237
Adiponectin; metabolic syndrome; heart failure
4.  Clinical and Echocardiographic Findings of Newly Diagnosed Acute Decompensated Heart Failure in Elderly Patients 
Yonsei Medical Journal  2010;52(1):33-38.
Elderly patients (pts) (EPs; ≥ 65 years old) with newly diagnosed-acute decompensated heart failure (ND-ADHF) have not yet been studied. The aim of the present study was to investigate clinical characteristics, including echocardiographic findings and prognosis, for EPs with ND-ADHF and to compare those with non-elderly pts (NEPs).
Materials and Methods
We retrospectively investigated 256 pts (144 males, 63.0 ± 14.8 years old) who were admitted to our hospital between January 2005 and March 2009 with ND-ADHF. Clinical characteristics and echocardiographic parameters were analyzed in EPs (n = 135, 58 males) and NEPs (n = 121, 86 males).
In intergroup comparison, female gender, diabetes mellitus, previous stroke and hypertension were more common in EPs. Body mass index (22.3 ± 4.5 vs. 24.0 ± 4.4 kg/m2), estimated glomerular filtration rate (54.8 ± 24.3 vs. 69.2 ± 30.7 mL/min/m2), C-reactive protein (28.5 ± 46.9 vs. 7.6 ± 11.6 mg/dL), hemoglobin (12.3 ± 2.1 vs. 13.6 ± 2.3 g/dL) and N-terminal pro-brain natriuretic peptide level (10,538.2 ± 10,942.3 vs. 6,771.0 ± 8,964.7 pg/mL) were significantly different (p < 0.05 for all). Early mitral inflow velocity to early diastolic mitral annular velocity (E/E') was significantly higher in EPs than in NEPs (21.2 ± 9.4 vs. 18.0 ± 8.9, p < 0.05). During follow-up (44.7 ± 14.5 months), there were no significant differences in in-hospital mortality, re-hospitalization and cardiovascular mortality between EPs and NEPs (p = NS for all).
EPs with ND-ADHF have different clinical characteristics and higher LV filling pressure when compared with NEPs. However, the clinical outcomes for NEPs with ND-ADHF are not necessarily more favorable than those for EPs.
PMCID: PMC3017705  PMID: 21155032
Acute heart failure; elderly patients; echocardiography
5.  Permanent Pacemaker for Syncope after Heart Transplantation with Bicaval Technique 
Yonsei Medical Journal  2009;50(4):588-590.
Sinus node dysfunction occurs occasionally after heart transplantation and may be caused by surgical trauma, ischemia to the sinus node, rejection, drug therapy, and increasing donor age. However, the timing and indication of permanent pacemaker insertion due to sinus node dysfunction following heart transplantation is contentious. Here, we report a case of a permanent pacemaker insertion for syncope due to sinus arrest after heart transplantation, even with a bicaval technique, which has been known to associate with few incidences of sinus node dysfunction.
PMCID: PMC2730626  PMID: 19718412
Permanent pacemaker; sinus arrest; heart transplantation
6.  Primary Idiopathic Chylopericardium Associated with Cervicomediastinal Cystic Hygroma 
Yonsei Medical Journal  2005;46(3):439-444.
Chylopericardium is a rare clinical entity in which chylous fluid accumulates in the pericardial cavity. We report a case of primary idiopathic chylopericardium associated with multiple, small cervicomediastinal cystic hygromas occurring in an asymptomatic 43-year-old woman with no history of trauma, thoracic surgery, malignancy, infection or tuberculosis. Echocardiography showed a large amount of pericardial effusions and pericardial fluid analysis revealed inappropriately elevated triglyceride. We did not demonstrate communication between the thoracic duct and the pericardial sac by lymphangiography and chest computed tomography. She successfully responded to 30 days of continuous pericardial drainage and 15 days of a medium-chain triglyceride diet after 30 days of total parenteral nutrition. Follow-up echocardiography 6 months after treatment commencement showed a minimal reaccumulation of pericardial fluid without symptom. We conclude that if a patient is asymptomatic and can well tolerate daily life, surgery including pericardiectomy or ligation of the thoracic duct is not necessarily required.
PMCID: PMC2815824  PMID: 15988819
Chylopericardium; pericardial effusions
7.  Histological and Biochemical Comparisons between Right Atrium and Left Atrium in Patients with Mitral Valvular Atrial Fibrillation 
Korean Circulation Journal  2014;44(4):233-242.
Background and Objectives
It has been known that the dominant driver of atrial fibrillation (AF) exists in the left atrium (LA) and the incidence of systemic thromboembolism is higher than that of pulmonary thromboembolism in patients with AF. Therefore, we hypothesized that histological and biochemical characteristics of the LA and the right atrium (RA) are different in patients with mitral valvular AF.
Subjects and Methods
We analyzed the histology and messenger ribonucleic acid (mRNA) or protein expression associated with endothelial function and thrombogenesis in 33 human atrial appendage tissues (20 LA tissues, 13 RA tissues) taken from 25 patients {57.7±11.3 years old, 44% males, AF: sinus rhythm (SR)=17:8} with mitral valve disease. We also performed whole mRNA quantification in 8 tissues (both LA and RA tissues from 4 patients) by using next generation sequencing (NGS).
1) The degree of fibrosis (p=0.001) and subendocardial smooth muscle thickness (p=0.004) were significantly greater in the LA than in the RA. 2) More advanced matrix fibrosis was found in the LA of patients with AF than in the LA of patients with SR (p=0.046), but not in the RA. 3) There was no LA-RA difference in protein (Western blot) and mRNA {quantitative real-time polymerase chain reaction (qRT-PCR)} expressions of NF-κB, 3-NT, CD31, E-selectin, inducible NO synthase, stromal cell-derived factor-1α, Endothelin-1, platelet-derived growth factor, myeloperoxidase, or NCX, except for higher mRNA expression of HCN4 in the RA (qRT-PCR, p=0.026) and that of KCNN1 in the LA (NGS, p=0.016).
More advanced matrix and subendocardial remodeling were noticed in the LA than in the RA in patients with mitral valvular AF. However, the expressions of tissue factors associated with thrombogenesis were not significantly different between the RA and the LA.
PMCID: PMC4117844  PMID: 25089135
Atrial fibrillation; Mitral valve disease; Fibrosis; Subendocardium
8.  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 
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.
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.
A combination of rosiglitazone and losartan attenuates myocardial fibrosis and dysfunction in type 2 diabetic rats.
PMCID: PMC4210065  PMID: 25411595
Angiotensin II receptor blocker; Diabetic cardiomyopathy; Peroxisome proliferator‐activated receptor‐gamma agonist
10.  C-Reactive Protein Inhibits Survivin Expression via Akt/mTOR Pathway Downregulation by PTEN Expression in Cardiac Myocytes 
PLoS ONE  2014;9(5):e98113.
C-reactive protein (CRP) is one of the most important biomarkers for arteriosclerosis and cardiovascular disease. Recent studies have shown that CRP affects cell cycle and inflammatory process in cardiac myocytes. Survivin is also involved in cardiac myocytes replication and apoptosis. Reduction of survivin expression is associated with less favorable cardiac remodeling in animal models. However, the effect of CRP on survivin expression and its cellular mechanism has not yet been studied. We demonstrated that treatment of CRP resulted in a significant decrease of survivin protein expression in a concentration-dependent manner in cardiac myocytes. The upstream signaling proteins of survivin, such as Akt, mTOR and p70S6K, were also downregulated by CRP treatment. In addition, CRP increased the protein and mRNA levels of PTEN. The siRNA transfection or specific inhibitor treatment for PTEN restored the CRP-induced downregulation of Akt/mTOR/p70S6K pathway and survivin protein expression. Moreover, pretreatment with a specific p53 inhibitor decreased the CRP-induced PTEN expression. ERK-specific inhibitor also blocked the p53 phosphorylation and PTEN expression induced by CRP. Our study provides a novel insight into CRP-induced downregulation of survivin protein expression in cardiac myocytes through mechanisms that involved in downregulation of Akt/mTOR/p70S6K pathway by expression of PTEN.
PMCID: PMC4035334  PMID: 24866016
11.  Trends in Hospitalized Acute Myocardial Infarction Patients with Heart Failure in Korea at 1998 and 2008 
Journal of Korean Medical Science  2014;29(4):544-549.
Heart failure (HF) complicating acute myocardial infarction (AMI) is common and is associated with poor clinical outcome. Limited data exist regarding the incidence and in-hospital mortality of AMI with HF (AMI-HF). We retrospectively analyzed 1,427 consecutive patients with AMI in the five major university hospitals in Korea at two time points, 1998 (n = 608) and 2008 (n = 819). Two hundred twenty eight patients (37.5%) in 1998 and 324 patients (39.5%) in 2008 of AMI patients complicated with HF (P = 0.429). AMI-HF patients in 2008 were older, had more hypertension, previous AMI, and lower systolic blood pressure than those in 1998. Regarding treatments, AMI-HF patients in 2008 received more revascularization procedures, more evidence based medical treatment and adjuvant therapy, such as mechanical ventilators, intra-aortic balloon pulsation compared to those in 1998. However, overall in-hospital mortality rates (6.4% vs 11.1%, P = 0.071) of AMI-HF patients were unchanged and still high even after propensity score matching analysis, irrespective of types of AMI and revascularization methods. In conclusion, more evidence-based medical and advanced procedural managements were applied for patients with AMI-HF in 2008 than in 1998. However the incidence and in-hospital mortality of AMI-HF patients were not significantly changed between the two time points.
PMCID: PMC3991798  PMID: 24753702
Acute Myocardial Infarction; Heart Failure; Temporal Trend; Hospital Mortality
12.  SUrvey of Guideline Adherence for Treatment of Systolic Heart Failure in Real World (SUGAR): A Multi-Center, Retrospective, Observational Study 
PLoS ONE  2014;9(1):e86596.
Clinical practice guidelines have been slowly and inconsistently applied in clinical practice, and certain evidence-based, guideline-driven therapies for heart failure (HF) have been significantly underused. The purpose of this study was to survey guideline compliance and its effect on clinical outcomes in the treatment of systolic HF in Korea.
Method and Results
The SUrvey of Guideline Adherence for Treatment of Systolic Heart Failure in Real World (SUGAR) trial was a multi-center, retrospective, observational study on subjects with systolic HF (ejection fraction <45%) admitted to 23 university hospitals. The guideline adherence indicator (GAI) was defined as a performance measure on the basis of 3 pharmacological classes: angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor II blocker (ARB), beta-blocker (BB), and aldosterone antagonist (AA). Based on the overall adherence percentage, subjects were divided into 2 groups: those with good guideline adherence (GAI ≥50%) and poor guideline adherence (GAI <50%). We included 1319 regional participants as representatives of the standard population from the Korean national census in 2008. Adherence to drugs at discharge was as follows: ACEI or ARB, 89.7%; BB, 69.2%; and AA, 65.9%. Overall, 82.7% of the patients had good guideline adherence. Overall mortality and re-hospitalization rates at 1 year were 6.2% and 37.4%, respectively. Survival analysis by log-rank test showed a significant difference in event-free survival rate of mortality (94.7% vs. 89.8%, p = 0.003) and re-hospitalization (62.3% vs. 56.4%, p = 0.041) between the good and poor guideline-adherence groups.
Among patients with systolic HF in Korea, adherence to pharmacologic treatment guidelines as determined by performance measures, including prescription of ACEI/ARB and BB at discharge, was associated with improved clinical outcomes.
PMCID: PMC3903552  PMID: 24475154
13.  Arterial stiffness, fatty liver and the presence of coronary artery calcium in a large population cohort 
We 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.
The 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.
Among 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.
We 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.
PMCID: PMC3826844  PMID: 24191863
baPWV; Arterial stiffness; Coronary artery calcium (CAC) score; Atherosclerosis; Fatty liver
14.  Association between CDH13 Variants and Cardiometabolic and Vascular Phenotypes in a Korean Population 
Yonsei Medical Journal  2013;54(6):1305-1312.
Although some CDH13 single nucleotide polymorphisms (SNPs) have been shown to be determinants of blood adiponectin levels, the clinical implications of CDH13 variants are not yet completely understood. The purpose of this study was to evaluate the effects of SNPs of CDH13 on metabolic and vascular phenotypes.
Materials and Methods
We included 238 hypertensive subjects and 260 age- and sex-matched controls. Seven tagging-SNPs were identified in the CDH13 gene by whole gene sequencing. The association between these SNP variants and the risk of hypertension, metabolic traits, and carotid intima-media thickness (IMT) was examined.
Minor allele carriers of rs12444338 had a lower risk of hypertension, but the association turned out just marginal after adjusting confoudners. Blood glucose levels were higher in the minor allele carriers of c.1407C>T (p=0.01), whereas low-density lipoprotein-cholesterol levels were greater in those of rs6565105 (p=0.02). The minor allele of rs1048612 was associated with a higher body mass index (p=0.01). In addition, the mean carotid IMT was significantly associated with rs12444338 (p=0.02) and rs1048612 (p=0.02).
These results provide evidence that CDH13 variants are associated with metabolic traits and carotid atherosclerosis in Koreans. This study shows the multifaceted effects of CDH13 variants on cardiometabolic risk.
PMCID: PMC3809859  PMID: 24142632
CDH13 protein; human; hypertension; atherosclerosis; glucose; cholesterol
15.  Integrins protect cardiomyocytes from ischemia/reperfusion injury 
The Journal of Clinical Investigation  2013;123(10):4294-4308.
Ischemic damage is recognized to cause cardiomyocyte (CM) death and myocardial dysfunction, but the role of cell-matrix interactions and integrins in this process has not been extensively studied. Expression of α7β1D integrin, the dominant integrin in normal adult CMs, increases during ischemia/reperfusion (I/R), while deficiency of β1 integrins increases ischemic damage. We hypothesized that the forced overexpression of integrins on the CM would offer protection from I/R injury. Tg mice with CM-specific overexpression of integrin α7β1D exposed to I/R had a substantial reduction in infarct size compared with that of α5β1D-overexpressing mice and WT littermate controls. Using isolated CMs, we found that α7β1D preserved mitochondrial membrane potential during hypoxia/reoxygenation (H/R) injury via inhibition of mitochondrial Ca2+ overload but did not alter H/R effects on oxidative stress. Therefore, we assessed Ca2+ handling proteins in the CM and found that β1D integrin colocalized with ryanodine receptor 2 (RyR2) in CM T-tubules, complexed with RyR2 in human and rat heart, and specifically bound to RyR2 amino acids 165–175. Integrins stabilized the RyR2 interdomain interaction, and this stabilization required integrin receptor binding to its ECM ligand. These data suggest that α7β1D integrin modifies Ca2+ regulatory pathways and offers a means to protect the myocardium from ischemic injury.
PMCID: PMC3784521  PMID: 24091324
16.  The Prognostic Implication of Metabolic Syndrome in Patients with Heart Failure 
Korean Circulation Journal  2013;43(2):87-92.
Background and Objectives
Metabolic syndrome (MetS) increases the risk of heart failure (HF). The purpose of this study was to identify the prevalence of MetS in patients with HF and determine the syndrome's association with HF in clinical and laboratory parameters.
Subjects and Methods
A total of 3200 HF patients (67.6±14.5 years) enrolled in a nationwide prospective Korea HF Registry between Jan. 2005 and Oct. 2009. Patients were divided into two groups according to the presence or absence of MetS at admission: group I (presence, n=1141) and group II (absence, n=2059).
The prevalence of MetS was 35.7% across all subjects and was higher in females (56.0%). The levels of white blood cells, platelets, creatinine, glucose, and cholesterol were significantly higher in group I than in group II. Left ventricular dimension and volume was smaller and ejection fraction was higher in group I than in group II. An ischemic cause of HF was more frequent in group I. The rates of valvular and idiopathic cause were lower in group I than in group II. The rate of mortality was lower in group I than in group II (4.9% vs. 8.3%, p<0.001).
Despite the increased cardiovascular risks in MetS, MetS was found to be associated with decreased mortality in HF.
PMCID: PMC3596669  PMID: 23508725
Metabolic syndrome; Heart failure
17.  Safety and Efficacy of Fimasartan in Patients with Arterial Hypertension (Safe-KanArb Study) 
Angiotensin II receptor blockers (ARBs) play a key role in hypertension therapy. Recently, fimasartan, the ninth ARB, was developed, but its safety and efficacy have not been well established.
The objective of this study was to determine whether age, sex, concomitant disease, and current antihypertensive medications affect the safety and efficacy of fimasartan in patients with arterial hypertension.
This was a large-scale, open-label observational study to determine the safety and efficacy of fimasartan in patients with hypertension. Patients who were treated for more than 2 months with fimasartan (60 or 120 mg, once daily) were recruited, and the data were systematically collected using electronic case report forms. Written informed consent forms were obtained from all patients.
A total of 14,151 patients (50.7 % males; mean age 59 ± 12 years) were evaluated, of whom 37.9 % were never treated with fimasartan, 53.5 % were switched to fimasartan, and 8.5 % had fimasartan added to their treatment. Overall, fimasartan reduced systolic blood pressure (SBP) from 145.4 ± 18.1 to 126.8 ± 12.6 mmHg and diastolic blood pressure (DBP) from 88.7 ± 11.8 to 79.0 ± 8.7 mmHg (all p < 0.001). The pulse rate decreased from 74.4 ± 10.3 to 71.9 ± 9.2 beats/min in comparison with before treatment (p < 0.001). The reductions were similar between sexes, age groups, and patients with and without co-morbidities, and were not dependent on prior or concomitant treatment with other antihypertensive drugs. Adverse events were reported in 3.31 % (treatment-emergent) and 2.35 % (drug-related) of patients; there were no dose differences for adverse events. The most frequent adverse events were dizziness (1.55 %) and headache (0.52 %); other adverse events were rare. The responder rate (DBP to <90 mmHg or a reduction of ≥10 mmHg) and the goal rate (combined SBP/DBP <140/90 mmHg) were 85.0 and 75.6 %, respectively. Global drug compliance was rated as excellent, very good, good, and poor in 68.1, 26.9, 3.4, and 1.7 % of patients, respectively.
The safety, efficacy, and compliance of fimasartan were found to be excellent in a large patient population that included patients potentially at higher risk for adverse events.
Electronic supplementary material
The online version of this article (doi:10.1007/s40256-013-0004-9) contains supplementary material, which is available to authorized users.
PMCID: PMC3572372  PMID: 23344912
18.  Prognostic Estimation of Advanced Heart Failure With Low Left Ventricular Ejection Fraction and Wide QRS Interval 
Korean Circulation Journal  2012;42(10):659-667.
Background and Objectives
Cardiac resynchronization therapy (CRT) has been known to improve the outcome of advanced heart failure (HF) but is still underutilized in clinical practice. We investigated the prognosis of patients with advanced HF who were suitable for CRT but were treated with conventional strategies. We also developed a risk model to predict mortality to improve the facilitation of CRT.
Subjects and Methods
Patients with symptomatic HF with left ventricular ejection fraction ≤35% and QRS interval >120 ms were consecutively enrolled at cardiovascular hospital. After excluding those patients who had received device therapy, 239 patients (160 males, mean 67±11 years) were eventually recruited.
During a follow-up of 308±236 days, 56 (23%) patients died. Prior stroke, heart rate >90 bpm, serum Na ≤135 mEq/L, and serum creatinine ≥1.5 mg/dL were identified as independent factors using Cox proportional hazards regression. Based on the risk model, points were assigned to each of the risk factors proportional to the regression coefficient, and patients were stratified into three risk groups: low- (0), intermediate-(1-5), and high-risk (>5 points). The 2-year mortality rates of each risk group were 5, 31, and 64 percent, respectively. The C statistic of the risk model was 0.78, and the model was validated in a cohort from a different institution where the C statistic was 0.80.
The mortality of patients with advanced HF who were managed conventionally was effectively stratified using a risk model. It may be useful for clinicians to be more proactive about adopting CRT to improve patient prognosis.
PMCID: PMC3493802  PMID: 23170093
Heart failure; Prognosis; Cardiac resynchronization therapy
19.  Plasma phospholipid fatty acid composition and estimated desaturase activity in heart failure patients with metabolic syndrome 
Metabolic syndrome is one of the major factors to increase the incidence of heart failure. In our study, we compared plasma fatty acid compositions among heart failure patients with and without Metabolic syndrome. Fatty acid (FA) composition of plasma phospholipids was analyzed and the activities of desaturase were estimated as the ratio of substrate and product fatty acids in 85 stable heart failure patients. Fatty acid and estimated desaturase activities were further examined for their associations with Metabolic syndrome components. Heart failure patients with Metabolic syndrome showed significant changes in fatty acid composition in comparison to those without Metabolic syndrome, which had a decreased proportion of lauric acid (C12:0) and an increased proportion of dihomo-γ-linolenic acid (C20:3n-6). Also, estimated desaturase activities (D5D and D6D) were closely related to Metabolic syndrome condition among heart failure patients. The content of dihomo-γ-linolenic acid showed positive correlations with BMI, waist circumference, and plasma triglyceride levels. D6D were positively associated with plasma triglyceride levels, whereas D5D showed a negative correlation with plasma triglyceride levels and waist circumferences. The content of dihomo-γ-linolenic acid as well as estimated D6D and D5D were altered in heart failure patients with Metabolic syndrome.
PMCID: PMC3432827  PMID: 22962535
heart failure; fatty acid; metabolic syndrome; dihomo-γ-linolenic acid; desaturase
20.  Relationship between dietary folate intake and plasma monocyte chemoattractant protein-1 and interleukin-8 in heart failure patients 
This study aimed to examine the association of dietary vitamin intakes with plasma pro-inflammatory cytokine levels in Korean heart failure patients. Stable outpatients with heart failure were recruited and finally 91 patients were included. Dietary intakes were estimated by a developed semi-quantitative food frequency questionnaire. The simultaneous measurement of 17 cytokines was performed along with analysis of plasma C-reactive protein. Plasma C-reactive protein levels significantly correlated with dietary intakes of vitamin C (r = −0.30, p<0.005), β-carotene (r = −0.23, p<0.05), and folate (r = −0.31, p<0.005). However, these associations were no longer significant after adjusting for traditional risk factors for heart failure. On the other hand, plasma levels of monocyte chemoattractant protein-1 significantly correlated with dietary folate intake (r = −0.31, p<0.001), and plasma interleukin-8 levels significantly correlated with dietary intakes of vitamin C (r = −0.38, p<0.001), β-carotene (r = –0.42, p<0.001), and folate (r = −0.38, p<0.001) after the adjustment. Dietary folate intake was found as a primary influencing factor on plasma levels of monocyte chemoattractant protein-1 (p<0.005, R2 = 0.20) and interleukin-8 (p<0.001, R2 = 0.32) through a stepwise multiple linear regression analysis. Dietary folate intake was significantly associated with plasma levels of monocyte chemoattractant protein-1 and interleukin-8 which indicates dietary folate may have a potentially beneficial role in the prevention and treatment of heart failure.
PMCID: PMC3128299  PMID: 21765609
dietary folate; inflammation; heart failure; interleukin-8; MCP-1
21.  Characteristics, Outcomes and Predictors of Long-Term Mortality for Patients Hospitalized for Acute Heart Failure: A Report From the Korean Heart Failure Registry 
Korean Circulation Journal  2011;41(7):363-371.
Background and Objectives
Acute heart failure (AHF) is associated with a poor prognosis and it requires repeated hospitalizations. However, there are few studies on the characteristics, treatment and prognostic factors of AHF. The aims of this study were to describe the clinical characteristics, management and outcomes of the patients hospitalized for AHF in Korea.
Subjects and Methods
We analyzed the clinical data of 3,200 hospitalization episodes that were recorded between June 2004 and April 2009 from the Korean Heart Failure (KorHF) Registry database. The mean age was 67.6±14.3 years and 50% of the patients were female.
Twenty-nine point six percent (29.6%) of the patients had a history of previous HF and 52.3% of the patients had ischemic heart disease. Left ventricular ejection fraction (LVEF) was reported for 89% of the patients. The mean LVEF was 38.5±15.7% and 26.1% of the patients had preserved systolic function (LVEF ≥50%), which was more prevalent in the females (34.0% vs. 18.4%, respectively, p<0.001). At discharge, 58.6% of the patients received beta-blockers (BB), 53.7% received either angiotensin converting enzyme-inhibitors or angiotensin receptor blockers (ACEi/ARB), and 58.4% received both BB and ACEi/ARB. The 1-, 2-, 3- and 4-year mortality rates were 15%, 21%, 26% and 30%, respectively. Multivariate analysis revealed that advanced age {hazard ratio: 1.023 (95% confidence interval: 1.004-1.042); p=0.020}, a previous history of heart failure {1.735 (1.150-2.618); p=0.009}, anemia {1.973 (1.271-3.063); p=0.002}, hyponatremia {1.861 (1.184-2.926); p=0.007}, a high level of serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) {3.152 (1.450-6.849); p=0.004} and the use of BB at discharge {0.599 (0.360-0.997); p=0.490} were significantly associated with total death.
We present here the characteristics and prognosis of an unselected population of AHF patients in Korea. The long-term mortality rate was comparable to that reported in other countries. The independent clinical risk factors included age, a previous history of heart failure, anemia, hyponatremia, a high NT-proBNP level and taking BB at discharge.
PMCID: PMC3152730  PMID: 21860637
Heart failure; Registries; Outcome
22.  Integrins, Focal Adhesions and Cardiac Fibroblasts 
How the myocardium undergoes geometric, structural and molecular alterations that results in an end phenotype as might be seen in patients with dilated cardiomyopathy or following myocardial infarction (MI), is still poorly understood. Structural modification of the left ventricle which occurs during these pathological states results from chronic changes in loading conditions and is commonly referred to as “remodeling.” Remodeling may occur from increased wall stress in the face of hypertensive heart disease, valvular disease or perhaps most dramatically, following permanent coronary occlusion(Opie et al., 2006). A fundamental derangement of myocyte function is the most common perception for the basis of “remodeling” but the role of cells in the heart other than the muscle cell must of course be considered. While studies of the myocyte have been extensive, cardiac fibroblasts (CFs) have been studied less than myocytes. The fibroblast has a broad range of functions in the myocardium ranging from elaboration and remodeling of the extracellular matrix (ECM), to communication of a range of signals within the heart, including electrical, chemical and mechanical ones(Baudino et al., 2006). Integrins are cell surface receptors that are instrumental in mediating cell-matrix interactions in all cells of the organism, including all types within the myocardium. This review will focus on the role of integrins and related proteins in the remodeling process, with a particular emphasis on the cardiac fibroblast. We will illustrate this function by drawing upon two unique mouse models with perturbation of proteins linked to integrin function.
PMCID: PMC2810503  PMID: 19952893
23.  Association of Plasma Retinol-Binding Protein 4, Adiponectin, and High Molecular Weight Adiponectin with Insulin Resistance in Non-Diabetic Hypertensive Patients 
Yonsei Medical Journal  2010;51(3):375-384.
The aim of this study was to determine whether retinol-binding protein 4 (RBP4), adiponectin and high molecular weight (HMW) adiponectin are associated with insulin resistance (IR) and metabolic parameters in non-diabetic hypertensive patients. Also, we sought to compare the predictive values of these adipocytokines for IR in non-diabetic hypertensive patients.
Materials and Methods
Analyses of RBP4, adiponectin, and HMW adiponectin were performed on 308 non-diabetic hypertensives (148 males, age 58 ± 10 years, 189 non-metabolic syndrome and 119 metabolic syndrome). The homeostasis model assessment (HOMA) index for IR, lipid profiles, and anthropometric measure-ments were assessed.
There was no significant difference in RBP4 levels according to the presence of metabolic syndrome, although adiponectin and HMW adiponectin were significantly lower in metabolic syndrome. Correlation analysis of log RBP4 with IR and metabolic indices revealed that there was no significant correlation of RBP4 with waist circumference (r = 0.056, p = 0.324), HDL cholesterol (r = 0.005, p = 0.934), ApoB/ApoAI ratio (r = 0.066, p = 0.270), and the HOMA index (r = 0.017, p = 0.756). However, adiponectin and HMW adiponectin showed significant correlations with the HOMA index (r = - 0.247, p < 0.001; r = - 0.296, p < 0.001) and metabolic parameters. With IR defined as HOMA index ≥ 2.5, HMW adiponectin did not demonstrate a superior predictive value for IR compared to adiponectin (AUC = 0.680 vs. 0.648, p = 0.083). The predictive value of RBP4 for IR was minimal (AUC = 0.534).
RBP4 was not associated with IR or metabolic indices and the predictive value for IR was minimal in hypertensives. HMW adiponectin didn't have a superior predictive value for IR compared to adiponectin. Therefore, we can suggest that RBP4 and HMW adiponectin don't have more additive information than adiponectin in non-diabetic hypertensives.
PMCID: PMC2852793  PMID: 20376890
Retinol-binding proteins; adiponectin; hypertension; insulin resistance
24.  Recovery and recurrence of left ventricular systolic dysfunction in patients with idiopathic dilated cardiomyopathy 
The Canadian Journal of Cardiology  2009;25(5):e147-e150.
Some patients with nonischemic left ventricular (LV) systolic failure recover to have normal LV systolic function. However, few studies on the rates of recovery and recurrence have been reported, and no definitive indicators that can predict the recurrence of LV dysfunction in recovered idiopathic dilated cardiomyopathy (IDCMP) patients have been determined. It was hypothesized that patients who recovered from nonischemic LV dysfunction have a substantial risk for recurrent heart failure.
Forty-two patients (32 men) with IDCMP (mean [± SD] age 56.9±8.7 years) who recovered from systolic heart failure (LV ejection fraction [LVEF] of 26.5±6.9% at initial presentation) to a near-normal state (LVEF of 40% or greater, and a 10% increase or greater in absolute value) were monitored for recurrence of LV systolic dysfunction. Patients with significant coronary artery disease were excluded. Patients were monitored for 41.0±26.3 months after recovery (LVEF 53.4±7.6%) from LV dysfunction.
LV systolic dysfunction reappeared (LVEF 27.5±8.1%) during the follow-up period in eight of 42 patients (19.0%). No significant difference between the groups with or without recurrent heart failure was observed in the baseline clinical and echocardiographic characteristics. However, more patients in the recurred IDCMP group than those in the group that maintained the recovery state had discontinued antiheart failure medication (62.5% versus 5.9%, P<0.05).
LV dysfunction recurs in some patients with reversible IDCMP. The recurrence was significantly correlated with the discontinuation of antiheart failure drugs. The results suggest that continuous medical therapy may be mandatory in patients who recover from LV systolic dysfunction.
PMCID: PMC2707172  PMID: 19417864
Congestive heart failure; DCMP; Prognosis
25.  The Utility of Multi-detector Row Spiral CT for Detection of Coronary Artery Stenoses 
Yonsei Medical Journal  2005;46(1):86-94.
Contrast-enhanced multi-detector row spiral computed tomography (MDCT) was introduced as a promising noninvasive method for vascular imaging. This study examined the accuracy of this technique for detecting significant coronary artery stenoses. Both MDCT(Sensation 16, Siemens, Germany, 12 × 0.75 mm collimation and 0.42 sec rotation speed, 120 kV, 500 effective mA, and 2.7 mm/rotation table-feed) and invasive coronary angiography (CAG) were performed on 61 patients (mean age 59.2 ± 10, 44 men) who were suspected of having coronary artery disease. All patients were treated with atenolol (25 - 50 mg) prior to imaging and the heart rate was maintained below 65 beats per minutes during image acquisition. The images were reconstructed in the diastole around TI - 400 ms with a 0.5 mm increment and a 1.0 mm thickness. All coronary arteries with a diameter of 2.0 mm or more were assessed for the presence of a stenosis (> 50% luminal narrowing). Two independent radiologists who were unaware of the results of the invasive CAG evaluated the MDCT data, and the results were compared with those from the invasive CAG (interval 1- 27, mean 11 days). An evaluation of the CT coronary angiogram (CTCA) was possible in 58 of the 61 patients (95%). Image acquisition of the major coronary arteries including the left main trunk was available in 229 out of 244 arteries. Invasive CAG showed that 35 out of 58 patients had significant coronary artery stenoses by. patient analysis of those who could be evaluated showed that CT coronary angiography correctly classified 30 out of 35 patients as having at least 1 coronary stenosis (sensitivity 85.7%, specificity 91.3%, positive predictive value 93.8%, negative predictive value 80.8%). By analyzing each coronary artery, CAG found 62 stenotic coronary arteries in the 229 coronary arteries that could be evaluated. MDCT correctly detected 50 out of 62 stenotic coronary arteries and an absence of stenosis was correctly identified in 156 out of 167 normal coronary arteries (sensitivity 80.6%, specificity 93.4%, positive predictive value 81.9%, negative predictive value 92.8%). The non-invasive technique of MDCT for examining the coronary artery appears to be a useful method for detecting coronary artery stenoses with a high accuracy particularly with the proximal portion and large arteries.
PMCID: PMC2823063  PMID: 15744810
Coronary artery stenoses; computed tomography; imaging; stent; MDCT

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