Genetic Variants Associated with Adverse Events after Angiotensin-Converting Enzyme Inhibitor Use: Replication after GWAS-Based Discovery

Purpose@#Angiotensin-converting enzyme inhibitors (ACEIs) are medications generally prescribed for patients with high cardiovascular risk; however, they are suboptimally used due to frequent adverse events (AEs). The present study aimed to identify and replicate the genetic variants associated with ACEI-related AEs in the Korean population. @*Materials and Methods@#A two-stage approach employing genome-wide association study (GWAS)-based discovery and replication through target sequencing was used. In total, 1300 individuals received ACEIs from 2001 to 2007; among these, 228 were selected for GWAS. An additional 336 patients were selected for replication after screening 1186 subjects treated from 2008 to 2018.Candidate genes for target sequencing were selected based on the present GWAS, previous GWASs, and data from the PharmGKB database. Furthermore, association analyses were performed between no AE and AE or cough groups after target sequencing. @*Results@#Five genes, namely CRIM1, NELL1, CACNA1D, VOPP1, and MYBPC1, were identified near variants associated with ACEIrelated AEs. During target sequencing of 34 candidate genes, six single-nucleotide polymorphisms (SNPs; rs5224, rs8176786, rs10766756, rs561868018, rs4974539, and rs10946364) were replicated for association with all ACEI-related AEs. Four of these SNPs and rs147912715 exhibited associations with ACEI-related cough, whereas four SNPs (rs5224, rs81767786, rs10766756, and rs4974539 near BDKRB2, NELL1, NELL1 intron, and CPN2, respectively) were significantly associated with both categories of AEs. @*Conclusion@#Several variants, including novel and known variants, were successfully replicated and found to have associations with ACEI-related AEs. These results provide rare and clinically relevant information for safer use of ACEIs.

Role of Genetics in Preventive Cardiology: Focused on Dyslipidemia

Dyslipidemia is a strong risk factor for cardiovascular disease as well as a major target for its prevention. Along with the progress in genetic research techniques and bioinformatics analysis, genetic knowledge helps manage individuals with dyslipidemia. Familial hypercholesterolemia, the most common monogenic lipid disorder, can be diagnosed clinically without confirming pathogenic mutations. However, it can be difficult to do so due to uncertain family history, and genetic testing is of vital importance in such cases.Conversely, recent studies have revealed that combination effect of rare and common variants is frequent in people with other extreme lipid phenotypes. Genetic characteristics are helpful for prediction and selection of patients with high risk for cardiovascular disease or poor response to lipid-lowering therapy. In the past decade, studies using new genetic techniques have identified novel associations among lipid metabolism-associated genes, intermediate lipid phenotypes, and cardiovascular health. Such findings shed light on new drug targets.With improvements in the platforms and processes for drug development, several recent clinical trials showed promising results regarding lipid control and potential cardiovascular disease prevention.

Nlrp3, Csf3, and Edn1 in Macrophage Response to Saturated Fatty Acids and Modified Low-Density Lipoprotein

Background and Objectives@#The relationship between metabolic stress, inflammation, and cardiovascular disease is being studied steadily. The aim of this study was to evaluate the effect of palmitate (PA) and minimally modified low-density lipoprotein (mmLDL) on macrophages and to identify the associated pathways. @*Methods@#J774 macrophages were incubated with PA or mmLDL and lipopolysaccharide (LPS). Secretion of inflammatory chemokines and the expression of corresponding genes were determined. The phosphorylation of extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase was also assessed. RNA sequencing of macrophages was performed to identify the genes regulated by PA or mmLDL. Some of the genes regulated by the 2 agents were validated by knocking down the cells using small interfering RNA. @*Results@#PA or mmLDL promoted the secretion of interleukin (IL)-6 and IL-1β in LPSstimulated macrophages, and this was accompanied by higher phosphorylation of ERK. RNA sequencing revealed dozens of genes that were regulated in this process, such as Csf3 and Edn1, which were affected by PA and mmLDL, respectively. These agents also increased Nlrp3 expression. The effect of Csf3 or Edn1 silencing on inflammation was modest, whereas toll-like receptor (TLR) 4 inhibition reduced a large proportion of macrophage activation. @*Conclusions@#We demonstrated that the proinflammatory milieu with high levels of PA or mmLDL promoted macrophage activation and the expression of associated genes such as Nlrp3, Csf3, and Edn1. Although the TLR4 pathway appeared to be most relevant, additional role of other genes in this process provided insights regarding the potential targets for intervention.

Nlrp3, Csf3, and Edn1 in Macrophage Response to Saturated Fatty Acids and Modified Low-Density Lipoprotein

Background and Objectives@#The relationship between metabolic stress, inflammation, and cardiovascular disease is being studied steadily. The aim of this study was to evaluate the effect of palmitate (PA) and minimally modified low-density lipoprotein (mmLDL) on macrophages and to identify the associated pathways. @*Methods@#J774 macrophages were incubated with PA or mmLDL and lipopolysaccharide (LPS). Secretion of inflammatory chemokines and the expression of corresponding genes were determined. The phosphorylation of extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase was also assessed. RNA sequencing of macrophages was performed to identify the genes regulated by PA or mmLDL. Some of the genes regulated by the 2 agents were validated by knocking down the cells using small interfering RNA. @*Results@#PA or mmLDL promoted the secretion of interleukin (IL)-6 and IL-1β in LPSstimulated macrophages, and this was accompanied by higher phosphorylation of ERK. RNA sequencing revealed dozens of genes that were regulated in this process, such as Csf3 and Edn1, which were affected by PA and mmLDL, respectively. These agents also increased Nlrp3 expression. The effect of Csf3 or Edn1 silencing on inflammation was modest, whereas toll-like receptor (TLR) 4 inhibition reduced a large proportion of macrophage activation. @*Conclusions@#We demonstrated that the proinflammatory milieu with high levels of PA or mmLDL promoted macrophage activation and the expression of associated genes such as Nlrp3, Csf3, and Edn1. Although the TLR4 pathway appeared to be most relevant, additional role of other genes in this process provided insights regarding the potential targets for intervention.

Lipid-Lowering Efficacy and Safety of a New Generic Rosuvastatin in Koreans: an 8-Week Randomized Comparative Study with a Proprietary Rosuvastatin

Objective@#The aim of this study was to investigate whether a new generic rosuvastatin is non-inferior to a proprietary one in terms of lipid-lowering efficacy. We also evaluated its non-lipid effects including adverse events. @*Methods@#One-hundred and fifty-eight patients with cardiovascular risks requiring pharmacological lipid-lowering therapy were screened. After a 4-week run-in period, 126 individuals who met the lipid criteria for drug therapy were randomly assigned to receive the new generic or proprietary rosuvastatin 10 mg daily for 8 weeks. The primary outcome variables were low-density lipoprotein-cholesterol (LDL-C) reduction and LDL-C target achievement. Hematological and biochemical parameters and adverse events were assessed. @*Results@#After 8 weeks of drug treatment, the mean percentage change in LDL-C was not different between the groups (−45.5%±19.9% and −45.1%±19.0% for generic and proprietary rosuvastatin, respectively; p=0.38). The LDL-C target achievement rate was similar between the groups (75.0% and 77.1% for generic and proprietary rosuvastatin, respectively; p=0.79). The percentage change in the other lipid profiles was not significantly different. Although generic- and proprietary rosuvastatins modestly affected creatine kinase and blood pressure, respectively, the changes were all within normal ranges. Incidence of adverse events did not differ between the receivers of the 2 formulations. @*Conclusion@#The new generic rosuvastatin was non-inferior to the proprietary rosuvastatin in terms of lipid-lowering efficacy. The rosuvastatin formulations did not exhibit clinically significant non-lipid effects with good safety profiles. Our study provides comprehensive data regarding 2 rosuvastatin formulations in East Asian subjects.

Current state of total knee arthroplasty

Total knee arthroplasty (TKA) is a successful and cost-effective treatment for end-stage degenerative arthritis. The aging of society and an increase in the prevalence of obesity has led to increases in the prevalence of arthritis and the incidence of TKA. Currently, the total number of procedures in Korea per year has reached 90,000. With the rapid growth, we need to know about the current state of TKA. The purpose of this review is to summarize the recent literature regarding TKA. The main indication for TKA is end-stage arthritis with severe pain, reduced function, and no response to conservative management. Metal on the polyethylene-bearing surface and cobalt alloy are used in most TKAs. Despite good clinical outcomes and long-term survival rates after TKA in many papers, 20% of patients are dissatisfied with the outcome of surgery. To improve the patient’s satisfaction, surgeons should understand factors affecting patient’s satisfaction, including patient’s expectations, age, and preoperative mental state. Navigationassisted surgery and robotic surgery have been introduced in knee arthroplasty to achieve more precise and accurate alignment. There is some evidence to suggest that computer-assisted surgery reduces revision rates. However, clinical efficacy is also controversial, and a long-term follow-up study is required. The common complications of TKA include infection, polyethylene wear, loosening, stiffness, periprosthetic fracture, and thromboembolism. An understanding of the potential complications and pitfalls of TKA is essential for prevention.

Novel Associations between Related Proteins and Cellular Effects of High-Density Lipoprotein

BACKGROUND AND OBJECTIVES@#Recent studies have examined the structure-function relationship of high-density lipoprotein (HDL). This study aimed to identify and rank HDL-associated proteins involved in several biological function of HDL.@*METHODS@#HDLs isolated from 48 participants were analyzed. Cholesterol efflux capacity, effect of HDL on nitric oxide production, and vascular cell adhesion molecule-1 expression were assessed. The relative abundance of identified proteins in the highest vs. lowest quartile was expressed using the normalized spectral abundance factor ratio.@*RESULTS@#After adjustment by multiple testing, six proteins, thyroxine-binding globulin, alpha-1B-glycoprotein, plasma serine protease inhibitor, vitronectin, angiotensinogen, and serum amyloid A-4, were more abundant (relative abundance ratio ≥2) in HDLs with the highest cholesterol efflux capacity. In contrast, three proteins, complement C4-A, alpha-2-macroglobulin, and immunoglobulin mu chain C region, were less abundant (relative abundance ratio <0.5). In terms of nitric oxide production and vascular cell adhesion molecule-1 expression, no proteins showed abundance ratios ≥2 or <0.5 after adjustment. Proteins correlated with the functional parameters of HDL belonged to diverse biological categories.@*CONCLUSIONS@#In summary, this study ranked proteins showing higher or lower abundance in HDLs with high functional capacities and newly identified multiple proteins linked to cholesterol efflux capacity.

Femoral Tunnel Drilling Techniques in Anterior Cruciate Ligament Reconstruction / 대한정형외과학회잡지

The most recent concept in anterior cruciate ligament reconstruction is an anatomical single bundle anterior cruciate ligamentreconstruction. For an anatomical anterior cruciate ligament reconstruction, the tibial tunnel is made anterior than before, and the femoraltunnel is made in a lower and oblique direction compared to the classical method using the transtibial technique. The anteromedial portaltechnique, outside-in technique, and modified transtibial technique have been performed to produce femoral tunnels with anatomicalpositions. Each method has different advantages and disadvantages and is chosen based on the operator’s preferences, experience,instruments, and implants.

Novel Associations between Related Proteins and Cellular Effects of High-Density Lipoprotein

BACKGROUND AND OBJECTIVES: Recent studies have examined the structure-function relationship of high-density lipoprotein (HDL). This study aimed to identify and rank HDL-associated proteins involved in several biological function of HDL.METHODS: HDLs isolated from 48 participants were analyzed. Cholesterol efflux capacity, effect of HDL on nitric oxide production, and vascular cell adhesion molecule-1 expression were assessed. The relative abundance of identified proteins in the highest vs. lowest quartile was expressed using the normalized spectral abundance factor ratio.RESULTS: After adjustment by multiple testing, six proteins, thyroxine-binding globulin, alpha-1B-glycoprotein, plasma serine protease inhibitor, vitronectin, angiotensinogen, and serum amyloid A-4, were more abundant (relative abundance ratio ≥2) in HDLs with the highest cholesterol efflux capacity. In contrast, three proteins, complement C4-A, alpha-2-macroglobulin, and immunoglobulin mu chain C region, were less abundant (relative abundance ratio <0.5). In terms of nitric oxide production and vascular cell adhesion molecule-1 expression, no proteins showed abundance ratios ≥2 or <0.5 after adjustment. Proteins correlated with the functional parameters of HDL belonged to diverse biological categories.CONCLUSIONS: In summary, this study ranked proteins showing higher or lower abundance in HDLs with high functional capacities and newly identified multiple proteins linked to cholesterol efflux capacity.

Effects of Statins for Primary Prevention in the Elderly: Recent Evidence

The number of the elderly individuals is steeply increasing, and their absolute cardiovascular risk is higher than that of younger age groups. However, very few statin trials have included elderly patients alone. Recently, we published the SCOPE-75 study, which analyzed the effect of statins for primary prevention in elderly Koreans (>75 years). In this study, statin users showed significantly fewer cardiovascular events and a lower all-cause mortality rate, supporting more active use of statins in this population. In the current review, we further compare and discuss similar studies reported in the past decades and in recent years.

Characteristics of Acute Cerebral Infarction in Patients with Familial Hypercholesterolemia

BACKGROUND: The patients with familial hypercholesterolemia (FH) suffer from early onset atherosclerotic vascular disease due to high level of cholesterol and subsequent vascular inflammation, especially in the form of coronary artery disease. We investigated the clinical characteristics of FH associated cerebral infarction and its possible mechanism. METHODS: Between January 2014 and May 2017, acute cerebral infarction patients who admitted to Chung-Ang University Hospital were reviewed from stroke registry and the diagnosis of FH was made based on the Dutch Lipid Clinic Network Diagnostic Criteria for FH. We reviewed their initial laboratory and brain imaging information, prescribed medication and followed lipid profile after discharge. Stroke mechanism was determined based on Trial of ORG 10172 in Acute Stroke Treatment classification. RESULTS: Among 1,401 acute cerebral infarction or transient ischemic attack patients, one probable and three possible FH stroke patients were detected. All the patients denied of previous coronary artery disease history and initial lipid panel revealed high levels of total cholesterol (378±75 mg/dL) and low-density lipoprotein-cholesterol (238±56 mg/dL). Stroke mechanisms were heterogeneous, including one atherosclerotic, two vertebral artery dissection cases and one coagulation disorder. All the patients were combined with noticeable degree of intracranial atherosclerosis and were maintained with statin treatment. CONCLUSIONS: This study illustrates diverse stroke mechanism among stroke patients with FH. Further research is required to disclose exact incidence of FH among stroke population and effective treatment strategy.

2018 Guidelines for the Management of Dyslipidemia in Korea

No abstract available.

Dyslipidemia and Rate of Under-Target Low-Density Lipoprotein-Cholesterol in Patients with Coronary Artery Disease in Korea

OBJECTIVE: The aim of this study was to evaluate under target rates of low-density lipoprotein-cholesterol (LDL-C) in Korean patients with stable coronary artery disease (CAD) or an acute coronary syndrome (ACS) in real world practice. METHODS: Dyslipidemia International Study II was an international observational study of patients with stable CAD or an ACS. Lipid profiles and use of lipid-lowering therapy (LLT) were documented at enrollment, and for the ACS cohort, 4 months follow-up was recommended. Rates of under target LDL-C as per European guidelines, were evaluated, and multivariate regression was performed to identify predictive factors of patients presenting under the target. RESULTS: A total of 808 patients were enrolled in Korea, 500 with stable CAD and 308 with ACS. Of these, 90.6% and 52.6% were being treated with LLT, respectively. In the stable CAD group, 40.0% were under target LDL-C, while in ACS group, the rate was 23.7%. A higher statin dose was independently associated with under target LDL-C in both groups (OR, 1.03; p=0.046 [stable CAD] and OR, 1.05; p=0.01 [ACS]). The mean statin dosage (atorvastatin equivalent) was 17 mg/day. In the 79 ACS patients who underwent the follow-up examination, the LDL-C under target rate rose to 59.5%. CONCLUSION: Only a minority of patients with stable CAD or ACS were under their target LDL-C level at enrollment. The statin dose was not sufficient in the majority of patients. These results indicate a considerable LLT gap in Korean patients with established CAD.

Effect of Niacin on Carotid Atherosclerosis in Patients at Low-Density Lipoprotein-Cholesterol Goal but High Lipoprotein (a) Level: a 2-Year Follow-Up Study

OBJECTIVE: To examine the effect of niacin on the progression of carotid intima-media thickness (IMT) in patients with high level of lipoprotein (Lp) (a). METHODS: Patients at low-density lipoprotein-cholesterol goal but with Lp (a) >25 mg/dL and mean carotid IMT >0.75 mm were included. Eligible patients were randomized at a 1:2 ratio into one of two groups for 24 months: control or 1,500 mg extended release niacin. The primary study outcomes were the percentage changes in mean and maximal carotid IMT. The percentage change in lipid profiles including Lp (a) was analyzed as a secondary study outcome. RESULTS: Among 96 randomized patients, 31 completed the study (mean age: 65 years; male: 44%). At follow-up, the percentage change in mean carotid IMT was not significantly different between the two groups (−1.4%±15.5% and −1.1%±7.3% in the control and niacin groups, respectively, p=0.95). The percentage change in maximal carotid IMT was also similar in the two groups (0.7%±16.5% and −4.4%±11.6%, respectively, p=0.35). Elevation of high-density lipoprotein-cholesterol tended to be higher in the niacin group (p=0.07), and there was a significant difference in the percentage change in hemoglobin A1c between the two groups (−1.9%±2.2% and 3.3%±6.7%, respectively, p=0.02). Reduction of Lp (a) was greater in the niacin-treated group compared to placebo, but the difference was not statistically significant. CONCLUSION: Treatment with niacin for two years did not inhibit the progression of carotid intima-media thickening in patients with high Lp (a) level. However, this study may have been underpowered to evaluate the primary study outcome.

Lipid-Lowering Therapy Guidelines / 대한내과학회지

The major guidelines for lipid-lowering therapy (LLT) have been revised recently. Although “higher cardiovascular risk-aggressive LLT with greater absolute clinical benefit” is the main idea underlying all guidelines, there are some differences in the details among them. The US guidelines recommend pharmacological LLT based on a patient's risk category, independently of their low-density lipoprotein-cholesterol (LDL-C) level. However, the European and Korean guidelines consider the patient's risk category and LDL-C at the same time. Lifestyle modifications are suggested in parallel in all guidelines. The newest US guidelines have characteristically revived target LDL-C values in some patient groups and indications for non-statin drugs (ezetimibe and PCSK9 inhibitors), whereas the European and Korean guidelines have maintained target LDL-C values as usual. It is universally accepted that statins are the first-line agent. Adding ezetimibe, bile acid sequestrants, or PCSK9 inhibitors is recommended as a second line treatment. Appreciating the trend and background of the newest LLT guidelines will be essential to maximize cardiovascular prevention in patients.

Erratum: 2018 Guidelines for the management of dyslipidemia in Korea

The title and author names are incorrect.

Lipid-Lowering Therapy Guidelines / 대한내과학회지

The major guidelines for lipid-lowering therapy (LLT) have been revised recently. Although “higher cardiovascular risk-aggressive LLT with greater absolute clinical benefit” is the main idea underlying all guidelines, there are some differences in the details among them. The US guidelines recommend pharmacological LLT based on a patient's risk category, independently of their low-density lipoprotein-cholesterol (LDL-C) level. However, the European and Korean guidelines consider the patient's risk category and LDL-C at the same time. Lifestyle modifications are suggested in parallel in all guidelines. The newest US guidelines have characteristically revived target LDL-C values in some patient groups and indications for non-statin drugs (ezetimibe and PCSK9 inhibitors), whereas the European and Korean guidelines have maintained target LDL-C values as usual. It is universally accepted that statins are the first-line agent. Adding ezetimibe, bile acid sequestrants, or PCSK9 inhibitors is recommended as a second line treatment. Appreciating the trend and background of the newest LLT guidelines will be essential to maximize cardiovascular prevention in patients.

Variants of Lipolysis-Related Genes in Korean Patients with Very High Triglycerides

We investigated the prevalence and characteristics of variants of five lipolysis-related genes in Korean patients with very high triglycerides (TGs). Twenty-six patients with TG levels >885 mg/dL were selected from 13545 Korean subjects. Five candidate genes, LPL, APOC2, GPIHBP1, APOA5, and LMF1, were sequenced by targeted next-generation sequencing. Predictions of functional effects were performed and matched against public databases of variants. Ten rare variants of three genes were found in nine (34.6%) patients (three in LPL, four in APOA5, and three in LMF1). Five were novel and all variants were suspected of being disease-causing. Nine were heterozygous, and one (3.8%) had a homozygous rare variant of LPL. Six common variants of four genes were observed in 25 (96.2%) patients (one in LPL, one in GPIHBP1, two in APOA5, and two in LMF1). The c.G41T variant of GPIHBP1 and c.G533T variant of APOA5 were most frequent and found in 15 (57.7%) and 14 (53.8%) patients, respectively. Rare homozygous variants of the genes were very uncommon, while diverse rare heterozygous variants were commonly identified. Taken together, most study subjects may be manifesting the combined effects of rare heterozygous variants and common variants.

Screening, Diagnosis, and Treatment of Familial Hypercholesterolemia: Symposium of the Education Committee, Korean Society of Lipid and Atherosclerosis

Familial hypercholesterolemia (FH) is typically associated with single gene mutation that is inherited by autosomal dominant manner. Due to high cardiovascular risk, aggressive discovery, diagnosis, and treatment of FH are critical. Although FH is being increasingly spotlighted, we do not have sufficient data on Korean patients with FH. Here, we present the content of symposium of the Education Committee, Korean Society of Lipid and Atherosclerosis held in May 2018: 1) epidemiology, clinical diagnosis, Korean FH data, and regulation in Korea; 2) genes associated with FH, sequencing process in suspicious proband, cascade screening, and difficulty in genetic diagnosis in FH; 3) the importance of lipid-lowering therapy in FH, conventional and novel therapeutics for FH; 4) diagnosis of FH in children and adolescence, screening, and treatment of FH in children and adolescence; 5) history of FH studies in Korea, the structure and current status of FH registry of Korean Society of Lipid and Atherosclerosis; and 6) difficulty in diagnosis of heterozygous and homozygous FH, drug intolerance and achievement of treatment target. Discussion between speakers and panels were also added. We hope that this article is helpful for understanding FH and future studies performed in Korea.

Three-Dimensional Reconstruction Computed Tomography Evaluation of the Tunnel Location and Angle in Anatomic Single-Bundle Anterior Cruciate Ligament Reconstruction: A Comparison of the Anteromedial Portal and Outside-in Techniques

PURPOSE: The purpose of this study was to compare the geometry and position of the femoral tunnel between the anteromedial portal (AMP) and outside-in (OI) techniques after anatomic single-bundle anterior cruciate ligament (ACL) reconstruction. MATERIALS AND METHODS: We evaluated 82 patients undergoing single-bundle ACL reconstruction with hamstring autografts using either the AMP (n=40) or OI (n=42) technique. The locations of the tunnel apertures were assessed by postoperative 3-dimensional computed tomography imaging. The femoral graft bending angle, femoral tunnel aperture shape, femoral tunnel length, and posterior wall breakage were also measured. RESULTS: The mean femoral tunnel position parallel to the Blumensaat line was more caudally positioned in the AMP group than in the OI group (p=0.025) The mean femoral graft angle in the OI group (99.6°±7.1°) was significantly more acute than that of the AMP group (108.9°±10.2°, p<0.001). The mean height/width ratio of the AMP group (1.21±0.20) was significantly more ellipsoidal than that of the OI group (1.07±0.09, p<0.001). CONCLUSIONS: The mean femoral tunnel position was significantly shallower in the AMP technique than in the OI technique. The OI technique might be more disadvantageous than the AMP technique in terms of the more acute bending angle.