Byung Ryul Cho

Vitamin D signaling pathway plays an important role in the development of heart failure after myocardial infarction

Accumulating evidence suggests that vitamin D deficiency plays a crucial role in heart failure. However, whether vitamin D signaling itself plays an important role in cardioprotection is poorly understood. In this study, we examined the mechanism of modulating vitamin D signaling on progression to heart failure after myocardial infarction (MI) in mice. Vitamin D signaling was activated by administration of paricalcitol (PC), an activated vitamin D analog. Wild-type (WT) mice underwent sham or MI surgery and then were treated with either vehicle or PC. Compared with vehicle group, PC attenuated development of heart failure after MI associated with decreases in biomarkers, apoptosis, inflammation, and fibrosis. There was also improvement of cardiac function with PC treatment after MI. Furthermore, vitamin D receptor (VDR) mRNA and protein levels were restored by PC treatment. Next, to explore whether defective vitamin D signaling exhibited deleterious responses after MI, WT and VDR knockout (KO) mice underwent sham or MI surgery and were analyzed 4 wk after MI. VDR KO mice displayed a significant decline in survival rate and cardiac function compared with WT mice after MI. VDR KO mice also demonstrated a significant increase in heart failure biomarkers, apoptosis, inflammation, and fibrosis. Vitamin D signaling promotes cardioprotection after MI through anti-inflammatory, antifibrotic and antiapoptotic mechanisms.

Ischemia-related changes in naive and mutant forms of ubiquitin and neuroprotective effects of ubiquitin in the hippocampus following experimental transient ischemic damage.

Ubiquitin binds to short-lived proteins and denatured proteins produced by various forms of injury. The loss of ubiquitin leads to an accumulation of abnormal proteins and may affect cellular structure and function. The aim of the present study is to observe the chronological changes in ubiquitin naive form and its mutant form (ubiquitin(+1)) in the hippocampal CA1 region (CA1) after transient cerebral ischemia in gerbils. Delayed neuronal death in the CA1 was confirmed 4 days after ischemic insult with NeuN immunohistochemistry. Ubiquitin immunoreactivity and protein level in the CA1 were lowest at 12 h after ischemia/reperfusion; thereafter, they were increased with time. Ubiquitin(+1) immunoreactivity and protein levels in the CA1 were slightly decreased at 3 h after ischemia/reperfusion, and they were significantly increased 1 day after ischemia/reperfusion. In addition, ubiquitin and ubiquitin(+1) immunoreaction was expressed in astrocytes after delayed neuronal death in the ischemic CA1. To elucidate the protective effect of ubiquitin on ischemic damage, the animals were treated with ubiquitin (1.5 mg/kg body weight) intravenously via the femoral vein. Ubiquitin treatment significantly reduced ischemia-induced locomotor hyperactivity, neuronal death and reactive gliosis such as astrocytes and microglia. In addition, 5 days after ubiquitin treatment in the ischemic group, ubiquitin immunoreactivity was similar to that in the ubiquitin-treated sham group, however, ubiquitin(+1) immunoreactivity was higher than that in the ubiquitin-treated sham group. These findings indicate that the depletion of ubiquitin and the accumulation of ubiquitin(+1) in CA1 pyramidal neurons after transient cerebral ischemia may inhibit ubiquitin proteolytic pathway and this leads to delayed neuronal death of CA1 pyramidal neurons directly or indirectly after transient cerebral ischemia.

Clinical features of familial hypercholesterolemia in Korea: Predictors of pathogenic mutations and coronary artery disease – A study supported by the Korean Society of Lipidology and Atherosclerosis

BACKGROUND Proper screening and diagnosis of familial hypercholesterolemia (FH) is of critical importance for cardiovascular prevention. However, the clinical diagnosis of FH remains difficult partly because its phenotype can vary between different ethnicities. The aim of this study was to determine the clinical features and the best diagnostic approach in Korean FH patients. The predictors of putative pathogenic mutations and coronary artery disease (CAD) were also identified. METHODS AND RESULTS Ninety-seven patients with low-density lipoprotein-cholesterol >190 mg/dL and xanthoma or FH-compatible family history were included. Putative pathogenic mutations in LDLR, APOB, or PCSK9 genes were identified in 32% of the enrolled patients. The subjects were classified according to four sets of clinical criteria (Simon Broome, Dutch, MEDPED, Japanese). The mutation rates in definite type FH of Simon Broome or Dutch criteria were 35%-37% and lower in our patients than in those of other countries. The mutation detection rate by MEDPED criteria was 67%-75% and higher than those based on other criteria. The best low-density lipoprotein-cholesterol (LDL-C) threshold for predicting mutations was 225 mg/dL. LDL-C was found to be the only independent predictor of mutation carriers, while hypertension and low high-density lipoprotein-cholesterol were predictive of CAD. CONCLUSIONS The conventional clinical criteria showed limited mutation detection power and low specificities in Korean FH patients, in whom the best LDL-C threshold for putative mutation was 225 mg/dL. Traditional cardiovascular risk factors were also significantly associated with CAD risk in this population.

Nonalcoholic fatty liver disease is associated with coronary artery disease in Koreans

AIM To investigate whether nonalcoholic fatty liver disease (NAFLD) affects coronary artery disease (CAD) and identify candidate mediators. METHODS Patients who underwent coronary angiography were consecutively recruited. The patients were classified into four groups by coronary artery stenosis: A, insignificant; B, one-vessel disease; C, two-vessel disease; and D, three-vessel disease. Abdominal ultrasonography was performed to determine the presence of a fatty liver and categorize by grade: 0, no evidence; 1, mild; 2, moderate; and 3, severe. We measured not only known CAD risk factors, but also serum insulin, HOMA-index, adiponectin, interleukin-6, tumor necrosis factor-α and high-sensitivity C-reactive protein levels. RESULTS Of the 134 patients who met the inclusion criteria, 82 (61.2%) had ultrasonographically diagnosed NAFLD. Among the 46 patients with CAD, 37 (80.4%) had evidence of a fatty liver. The two groups (A vs B-D) were significantly different in terms of age, total cholesterol, triglycerides, low-density lipoprotein levels and fatty liver. Coronary artery stenosis was strongly associated with fatty liver in a grade-dependent manner (P = 0.025). In binary logistic regression, NAFLD was a significant independent predictor of CAD (P = 0.03, OR = 1.685; 95%CI: 1.051-2.702). Among the candidate mediators, the serum adiponectin level showed a trend toward lowering based on CAD progression (P = 0.071). CONCLUSION NAFLD is an independent risk factor for CAD in a grade-dependent manner. Moreover, adiponectin might be related to the pathogenesis of NAFLD.

P-Hydroxybenzyl alcohol-containing biodegradable nanoparticle improves functional blood flow through angiogenesis in a mouse model of hindlimb ischemia

Therapeutic angiogenesis has achieved promising results for ischemic diseases or peripheral artery disease in preclinical and early-phase clinical studies. We examined the therapeutic angiogenic effects of HPOX, which is biodegradable polymer composing the antioxidant p-hydroxybenzyl alcohol (HBA), in a mouse model of hindlimb ischemia. HPOX effectively stimulated blood flow recovery, compared with its degraded compounds HBA and 1,4-cyclohexendimethanol, via promotion of capillary vessel density in the ischemic hindlimb. These effects were highly correlated with levels of angiogenic inducers, vascular endothelial cell growth factor (VEGF), heme oxygenase-1 (HO-1), and Akt/AMPK/endothelial nitric oxide synthase (eNOS) in ischemic mouse hindlimb muscle. Blood perfusion and neovascularization induced by HPOX were reduced in eNOS(-/-) and HO-1(+/-) mice. HPOX also elevated the endothelial cell markers VEGF receptor-2, CD31, and eNOS mRNAs in the ischemic hindlimb, indicating that HPOX increases endothelial cell population and angiogenesis in the ischemic muscle. However, this nanoparticle suppressed expression levels of several inflammatory genes in ischemic tissues. These results suggest that HPOX significantly promotes angiogenesis and blood flow perfusion in the ischemic mouse hindlimb via increased angiogenic inducers, along with suppression of inflammatory gene expression. Thus, HPOX can be used potentially as a noninvasive drug intervention to facilitate therapeutic angiogenesis.

Long‐Term Outcome of 4 Korean Families With Hypertrophic Cardiomyopathy Caused by 4 Different Mutations

We sought to describe the long‐term outcome of individuals in 4 Korean families with hypertrophic cardiomyopathy (HCM) with known mutations.

Genetic Testing of Korean Familial Hypercholesterolemia Using Whole-Exome Sequencing

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.

Current Practice of Transradial Coronary Angiography and Intervention: Results from the Korean Transradial Intervention Prospective Registry

Background and Objectives Although increasing evidence has indicated that radial access is a beneficial technique, few studies have focused on Korean subjects. The aim of this study was to evaluate current practice of coronary angiography (CAG) and percutaneous coronary intervention (PCI) using radial access in South Korea. Subjects and Methods A total of 6338 subjects were analyzed from Korean Transradial Intervention prospective registry that was conducted at 20 centers in Korea. After evaluating the initial access, subjects intended for radial access were assessed for their baseline, procedure-related, and complication data. Subjects were categorized into three groups: group of overall subjects (n=5554); group of subjects who underwent PCI (n=1780); and group of subjects who underwent primary percutaneous coronary intervention (PPCI) (n=167). Results The rate of radial artery as an initial access and the rate of access site crossover was 87.6% and 4.4%, respectively, in overall subjects. Those rates were 82.4% and 8.1%, respectively, in subjects who underwent PCI, and 60.1% and 4.8%, respectively, in subjects who underwent PPCI. For subjects who underwent CAG, a 6-F introducer sheath and a 5-F angiographic catheter was the most commonly used. During PCI, a 6-F introducer sheath (90.6%) and a 6-F guiding catheter were standardly used. Conclusion The large prospective registry allowed us to present the current practice of CAG and PCI using radial access. These data provides evidence to achieve consensus on radial access in CAG and PCI in the Korean population.

Very Early Onset of Amiodarone-Induced Pulmonary Toxicity

Amiodarone is a widely used antiarrhythmic agent. Among its various adverse effects, amiodarone-induced pulmonary toxicity (APT) is the most life threatening complication, which has been described mostly in patients who have been in treatment with high accumulative doses for a long duration of time. However, amiodarone therapy in short-term duration induced APT was rarely reported. We describe a case of a 54-year-old man who is presented with symptoms of APT after a few days of therapy for post-myocardial infarction ventricular tachycardia. For early diagnosis and successful treatment, awareness and high suspicion of this rare type of early onset APT is crucial in patients with amiodarone therapy.

Effects of critical pathway on the management of patients with ST-elevation acute myocardial infarction in an emergency department.

BACKGROUND AIMS Critical pathways (CP) are clinical management plans that provide the sequence and timing of actions of medical staff. The main goal of a CP is to provide optimal patient care and to improve time-effectiveness. Current guidelines for the treatment of ST-segment elevation myocardial infarction (STEMI) recommend a door-to-balloon time of <90 minutes for patients undergoing primary percutaneous coronary intervention (PCI). The aim of this study was to identify the effects of CP on the management of patients with STEMI in an emergency department. METHODS The study population consisted of 175 patients undergoing primary PCI for STEMI who presented to the emergency department of Kangwon National University Hospital (Chuncheon, South Korea) with chest pain from July 1, 2005 to November 30, 2010. We retrospectively analyzed medication use, symptom onset-to-door times, door-to-balloon times, total ischemic times, and the reperfusion rate within 90 minutes. We also measured the 30-day and 1-year total mortality rates pre- and post-CP implementation. RESULTS The effects of CP implementation on the medication use outcomes in patients with acute myocardial infarction were increased between the pre- and post-CP patients groups. The median door-to-balloon time declined significantly from 85 to 64 minutes after CP implementation (P = 0.001), and the primary PCI rate within 90 minutes was significantly increased (57% vs. 79%, P = 0.01). However, the symptom to door time was not changed between the pre- and post-CP groups (150 minutes vs. 149 minutes; P = 0.841). Although the total ischemic time was decreased after CP implementation, it was not statistically insignificant (352.5 minutes vs. 281 minutes; P = 0.397). Moreover, the 30-day and 1-year total mortality rates of the 2 groups did not change (12.0% vs. 12.0%, P > 0.999; 13.0% vs. 17.3%, P = 0.425, respectively). However, the 1-year mortality rates of 2 groups based on a total ischemic time of 240 minutes, which was median value, decreased significantly from 19.0% to 9.0%. (P = 0. 018) CONCLUSION:: Implementation of a CP resulted in greater use of recommended medications and reductions in the median door-to-balloon time. However, it did not reduce the symptom onset-to-door time, total ischemic time, or the 30-day and 1-year mortality rates. Therefore, additional strategies are needed to reduce mortality in patients with acute myocardial infarction undergoing primary PCI.