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Elevated blood cholesterol and triglyceride levels induced by secondary causes are frequently observed. The identification and appropriate handling of these causes are essential for secondary dyslipidemia treatment. Major secondary causes of hypercholesterolemia and hypertriglyceridemia include an unhealthy diet, diseases and metabolic conditions affecting lipid levels, and therapeutic side effects. It is imperative to correct secondary causes prior to initiating conventional lipid-lowering therapy. Guideline-based lipid therapy can then be administered based on the subsequent lipid levels.

While light-driven water splitting offers a means to produce renewable H2 fuel, water oxidation limits performances and yields low-value products. Here, authors demonstrate a photoelectrochemical cell that converts lignocellulosic biomass into valuable products alongside H2.

Identifying the mechanisms underlying the early inflammatory phase of aortic valve disease is crucial for disease prevention. Here the authors perform single-cell RNA sequencing to show the immunomodulatory role of PPARγ in valvular endothelial cells during hyperlipidemia.

Familial hypercholesterolemia (FH) is the most common monogenic disorder. Due to the marked elevation of cardiovascular risk, the early detection, diagnosis, and proper management of this disorder are critical. Herein, the 2022 Korean guidance on this disease is presented. Clinical features include severely elevated low-density lipoprotein cholesterol (LDL-C) levels, tendon xanthomas, and premature coronary artery disease. Clinical diagnostic criteria include clinical findings, family history, or pathogenic mutations in the LDLR, APOB, or PCSK9. Proper suspicion of individuals with typical characteristics is essential for screening. Cascade screening is known to be the most efficient diagnostic approach. Early initiation of lipid-lowering therapy and the control of other risk factors are important. The first-line pharmacological treatment is statins, followed by ezetimibe, and PCSK9 inhibitors as required. The ideal treatment targets are 50% reduction and < 70 or < 55 mg/dL (in the presence of vascular disease) of LDL-C, although less strict targets are frequently used. Homozygous FH is characterized by untreated LDL-C > 500 mg/dL, xanthoma since childhood, and family history. In children, the diagnosis is made with criteria, including items largely similar to those of adults. In women, lipid-lowering agents need to be discontinued before conception.

Abstract Background Chronic diseases like hypertension need comprehensive lifetime management. This study assessed clinical and patient-reported outcomes and compared them by treatment patterns and adherence at 6 months among uncontrolled hypertensive patients in Korea. Methods This prospective, observational study was conducted at 16 major hospitals where uncontrolled hypertensive patients receiving anti-hypertension medications (systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg) were enrolled during 2015 to 2016 and studied for the following 6 months. A review of medical records was performed to collect data on treatment patterns to determine the presence of guideline-based practice (GBP). GBP was defined as: (1) maximize first medication before adding second or (2) add second medication before reaching maximum dose of first medication. Patient self-administered questionnaires were utilized to examine medication adherence, treatment satisfaction and quality of life (QoL). Results A total of 600 patients were included in the study. Overall, 23% of patients were treated based on GBP at 3 months, and the GBP rate increased to 61.4% at 6 months. At baseline and 6 months, 36.7 and 49.2% of patients, respectively, were medication adherent. The proportion of blood pressure-controlled patients reached 65.5% at 6 months. A higher blood pressure control rate was present in patients who were on GBP and also showed adherence than those on GBP, but not adherent, or non-GBP patients (76.8% vs. 70.9% vs. 54.2%, P

Abstract Sacubitril/valsartan is superior to enalapril in reducing the risks of cardiovascular death and preventing hospitalization in patients with heart failure and reduced ejection fraction (HFrEF). However, patients often do not receive sacubitril/valsartan because of concerns about hypotension. We examined the feasibility of initiating sacubitril/valsartan at a very low dose (VLD) in potentially intolerant patients with HFrEF and subsequent dose up-titration, treatment persistence and outcomes. We analyzed 206 patients with HFrEF grouped according to starting sacubitril/valsartan dose. The VLD group (n = 106) commenced 25 mg twice daily, and the standard-dose (SD) group (n = 100) started on ≥ 50 mg twice daily. Baseline systolic blood pressure was 103 ± 12 mmHg vs. 119 ± 14 mmHg in the SD group (P

Background This study aimed to evaluate the cardiovascular risk and outcomes after lipid reduction in patients with severe hypercholesterolemia using a nationwide cohort. Methods and Results This study used the database from the National Health Insurance Service of Korea. Among individuals who underwent regular health examination and follow‐up, 2 377 918 were enrolled and categorized into 3 groups with severe hypercholesterolemia according to low‐density lipoprotein cholesterol (LDL‐C) levels, namely, ≥260, 225 to 259, and 190 to 224 mg/dL groups, and a control group (

Abstract In this retrospective study, we investigated whether lipid-lowering therapy (LLT) escalation has clinical benefits in patients with atherosclerotic cardiovascular disease (ASCVD) and low-density lipoprotein cholesterol (LDL-C) levels of 55–99 mg/dL (1.4–2.6 mmol/L), post high-intensity. Out of 6317 Korean patients screened in 2005–2018, 1159 individuals with ASCVD and LDL-C levels of 55–99 mg/dL after statin use equivalent to 40 mg atorvastatin were included. After 1:2 propensity score matching, 492 patients (164 with LLT escalation, 328 controls without LLT escalation) were finally analysed. Primary outcome variables were major adverse cardiovascular and cerebrovascular events (MACCE) and all-cause death. At median follow-up (1.93 years), the escalation group had a lower MACCE rate (1.72 vs. 3.38 events/100 person-years; hazard ratio [HR] 0.34, 95% confidence interval [CI] 0.14–0.83; p = 0.018) than the control group. The incidence of all-cause death (0.86 vs. 1.02 events/100 person-years; HR 0.58, 95% CI 0.15–2.19; p = 0.42) and each MACCE component did not differ between groups. Kaplan–Meier curves exhibited lower risk of MACCE in the escalation group (HR 0.36, 95% CI 0.12–0.97; p = 0.040) but a difference not statistically significant in all-cause death (HR 0.30, 95% CI 0.04–2.48; p = 0.26). LLT escalation was associated with reduced cardiovascular risk, supporting more aggressive LLT in this population.

Abstract Aims Sacubitril/valsartan (SV) reduced heart failure hospitalization and cardiovascular mortality compared with enalapril in the Prospective Comparison of ARNI with ACE‐I to Determine Impact on Global Mortality and Morbidity in Heart Failure trial. However, this trial excluded patients with end stage of renal disease (ESRD); thus, the efficacy and safety of SV in heart failure with reduced ejection fraction (HFrEF) with ESRD remains uncertain. Methods and results We retrospectively analysed the clinical and laboratory data of 501 HFrEF patients who administered with SV from March 2017 to April 2019 in a single tertiary university hospital. A total of 23 HFrEF patients with ESRD on dialysis [58.3% non‐ischaemic heart failure; left ventricular ejection fraction (LVEF): 29.7 ± 4.4%] were included in this study. At baseline and follow‐up visit, we evaluated cardiovascular biomarkers such as high‐sensitive troponin T (hsTnT), soluble ST2 (sST2), echocardiographic parameters, and clinical and adverse events. The mean dose of SV was 90 ± 43 mg/day at baseline and 123 ± 62 mg/day at last follow‐up (follow‐up duration: median 132 days). The level of hsTnT was significantly reduced from 236.2 ± 355.3 to 97.0 ± 14.0 pg/mL (P = 0.002), and the sST2 level was significantly reduced from 40.4 ± 44.0 to 19.6 ± 14.1 ng/mL (P = 0.005). LVEF was significantly improved from 29.7 ± 4.4% to 40.8 ± 10.4% (P = 0.002). During the follow‐up, up‐titration, down‐titration, and maintenance of SV dosing were observed in 7 (30%), 5 (21.7%), and 11 patients (47.8%), respectively. SV down‐titration group had adverse events including symptomatic hypotension (systolic blood pressure

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.

BackgroundAlthough the strong association between low-density lipoprotein cholesterol (LDL-C) and cardiovascular disease (CVD) is well-known, the threshold LDL-C level at which the risk of CVD begins to increase in individuals without diabetes mellitus (DM) remains unknown. We aimed to evaluate the association between incident CVD and serum LDL-C levels with or without statin use in individuals without DM.MethodsWe identified 4,182,117 individuals without previous CVD who underwent a health screening examination in 2009 and 2011 from the Korean National Health Insurance Cohort database. The primary endpoint was a composite of cardiovascular deaths, myocardial infarction (MI) cases, and ischemic stroke cases.ResultsDuring the median follow-up of 6 years, there were 51,961 CVD events that included 17,392 MI cases, 33,779 ischemic stroke cases, and 2,039 cardiovascular deaths. The LDL-C levels that were associated with an increased risk of CVD were ≥100 mg/dL in non-statin users and ≥130 mg/dL in statin users. However, even in individuals with lower LDL-C levels, all those with fasting plasma glucose (FPG) levels ≥110 mg/dL had a significantly higher risk of CVD.ConclusionsWe demonstrated that LDL-C levels ≥100 mg/dL were correlated with an increased risk of CVD in individuals without DM and a history of CVD. We found that a glucose, cholesterol interaction increased CVD risk, and modestly elevated FPG levels (110–125 mg/dL) were associated with a higher CVD risk even in individuals with well-controlled LDL-C levels.

Objective: Study findings of the relationship of each arterial stiffness index with incident heart failure (HF) are conflicting. We aimed to compare the association between the indices of arterial stiffness and the risk of HF.Methods: We analysed 3,034 patients from a prospective cohort that enrolled patients with high cardiovascular risk. They underwent brachial-ankle pulse wave velocity (baPWV), brachial pulse pressure (PP), carotid-femoral pulse wave velocity (cfPWV), and central PP measurements.Results: Over a median follow-up of 4.7 years (interquartile range, 3.4–5.8 years), 65 HF events occurred. The incidence rate of HF was 4.7 per 1,000 person-years [95% confidence interval (CI), 3.7–6.0]. There was no difference in baPWV in those with and without HF events (1,561 ± 401 and 1,520 ± 321 cm/s, respectively, P = 0.415); however, there was a significant difference in brachial PP (63.2 ± 16.9 vs. 52.3 ± 11.5 mmHg, P < 0.001), cfPWV (11.0 ± 3.1 vs. 9.4 ± 2.4 m/s, P < 0.001) and central PP (56.6 ± 19.9 vs. 42.9 ± 13.8 mmHg, P < 0.001). In the multivariable-adjusted model, brachial PP [hazards ratio (HR) per standard deviation unit (SDU), 1.48; 95% CI, 1.19–1.84, P < 0.001], cfPWV (HR per SDU, 1.29; 95% CI, 1.02–1.63, P = 0.032) and central PP (HR per SDU, 1.44; 95% CI, 1.17–1.78; P < 0.001) were associated with incident HF, but baPWV was not (HR per SDU, 0.83; 95% CI, 0.63–1.10; P = 0.198). In the receiver operating characteristic analysis, the area under the curve (AUC) of brachial PP (P < 0.001), cfPWV (P = 0.003) or central PP (P = 0.001) was larger than that of baPWV, and there was no difference in the AUCs of brachial PP, cfPWV and central PP.Conclusion: Among arterial stiffness indices, brachial PWV was less associated with the risk of heart failure, and brachial PP and measures representing central hemodynamics were highly associated with incident HF.

Alterations in xanthine oxidase activity are known to be pathologically influential on coronary artery disease (CAD), but the association between purine-related blood metabolites and CAD has only been partially elucidated. We performed global metabolomics profiling and network analysis on blood samples from the Wonju and Pyeongchang (WP) cohort study (n = 2055) to elucidate the importance of purine related metabolites associated with potential CAD risk. Then, 5 selected serum metabolites were quantified from the WP cohort, Shinchon cohort (n = 259), and Shinchon case control (n = 424) groups to develop machine learning models for 10-year risk prediction, relapse within 10 years and diagnosis of the disease via 100 repeated 5-fold cross-validations of logistic models. The combination of purine metabolite levels or only xanthine levels in blood could be applied for machine learning model development for major adverse cardiac and cerebrovascular event (MACCE, cerebrovascular death, nonfatal myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass graft, and stroke) risk prediction, relapse of MACCEs among patients with myocardial infarction history and diagnosis of stable CAD. In particular, our research provided initial evidence that blood xanthine and uric acid levels play different roles in the development of machine learning models for primary/secondary prevention or diagnosis of CAD. In this research, we determined that purine-related metabolites in blood are applicable to machine learning model development for CAD risk prediction and diagnosis. Also, our work advances current CAD biomarker discovery strategies mainly relying on clinical features; emphasizes the differential biomarkers in first/secondary prevention or diagnosis studies.

Summary: Background: Coronary artery calcium (CAC) score is a clinically validated marker of cardiovascular disease risk. We developed and validated a novel cardiovascular risk stratification system based on deep-learning-predicted CAC from retinal photographs. Methods: We used 216 152 retinal photographs from five datasets from South Korea, Singapore, and the UK to train and validate the algorithms. First, using one dataset from a South Korean health-screening centre, we trained a deep-learning algorithm to predict the probability of the presence of CAC (ie, deep-learning retinal CAC score, RetiCAC). We stratified RetiCAC scores into tertiles and used Cox proportional hazards models to evaluate the ability of RetiCAC to predict cardiovascular events based on external test sets from South Korea, Singapore, and the UK Biobank. We evaluated the incremental values of RetiCAC when added to the Pooled Cohort Equation (PCE) for participants in the UK Biobank. Findings: RetiCAC outperformed all single clinical parameter models in predicting the presence of CAC (area under the receiver operating characteristic curve of 0·742, 95% CI 0·732–0·753). Among the 527 participants in the South Korean clinical cohort, 33 (6·3%) had cardiovascular events during the 5-year follow-up. When compared with the current CAC risk stratification (0, >0–100, and >100), the three-strata RetiCAC showed comparable prognostic performance with a concordance index of 0·71. In the Singapore population-based cohort (n=8551), 310 (3·6%) participants had fatal cardiovascular events over 10 years, and the three-strata RetiCAC was significantly associated with increased risk of fatal cardiovascular events (hazard ratio [HR] trend 1·33, 95% CI 1·04–1·71). In the UK Biobank (n=47 679), 337 (0·7%) participants had fatal cardiovascular events over 10 years. When added to the PCE, the three-strata RetiCAC improved cardiovascular risk stratification in the intermediate-risk group (HR trend 1·28, 95% CI 1·07–1·54) and borderline-risk group (1·62, 1·04–2·54), and the continuous net reclassification index was 0·261 (95% CI 0·124–0·364). Interpretation: A deep learning and retinal photograph-derived CAC score is comparable to CT scan-measured CAC in predicting cardiovascular events, and improves on current risk stratification approaches for cardiovascular disease events. These data suggest retinal photograph-based deep learning has the potential to be used as an alternative measure of CAC, especially in low-resource settings. Funding: Yonsei University College of Medicine; Ministry of Health and Welfare, Korea Institute for Advancement of Technology, South Korea; Agency for Science, Technology, and Research; and National Medical Research Council, Singapore.

Background The mechanism through which high‐density lipoprotein (HDL) induces cardioprotection is not completely understood. We evaluated the correlation between cholesterol efflux capacity (CEC), a functional parameter of HDL, and coronary collateral circulation (CCC). We additionally investigated whether A1BP (apoA1‐binding protein) concentration correlates with CEC and CCC. Methods and Results In this case‐control study, clinical and angiographic data were collected from 226 patients (mean age, 58 years; male, 72%) with chronic total coronary occlusion. CEC was assessed using a radioisotope and J774 cells, and human A1BP concentration was measured using enzyme‐linked immunosorbent assay. Differences between the good and poor CCC groups were compared, and associations between CEC, A1BP, and other variables were evaluated. Predictors of CCC were identified by multivariable logistic regression analysis. The CEC was higher in the good than in the poor CCC group (22.0±4.6% versus 20.2±4.7%; P=0.009). In multivariable analyses including age, sex, HDL‐cholesterol levels, age (odds ratio [OR], 0.96; P=0.003), and CEC (OR, 1.10; P=0.004) were identified as the independent predictors of good CCC. These relationships remained significant after additional adjustment for diabetes mellitus, acute coronary syndrome, and Gensini score. The A1BP levels were not significantly correlated with CCC (300 pg/mL and 283 pg/mL in the good CCC and poor CCC groups, respectively, P=0.25) or CEC. Conclusions The relationship between higher CEC and good CCC indicates that well‐functioning HDL may contribute to CCC and may be cardioprotective; this suggests that a specific function of HDL can have biological and clinical consequences.

In recent studies, the reported prevalence of heterozygous familial hypercholesterolemia (FH) has been higher than in previous reports. Although cascade genetic screening is a good option for efficient identification of affected patients, diagnosis using only clinical criteria is more common in real clinical practice. Cardiovascular risk is much higher in FH patients due to longstanding low density lipoprotein cholesterol (LDL-C) burden and is also influenced by other risk factors. Although guidelines emphasize aggressive LDL-C reduction, the majority of patients cannot reach the LDL-C goal by conventional pharmacotherapy. Novel therapeutics such as proprotein convertase subtilisin/kexin type 9 inhibitors have shown strong lipid lowering efficacy and are expected to improve treatment results in FH patients.

AimAlthough the atheroprotective effects of statins and angiotensin II receptor blockers (ARBs) are well-established, little is known about their additive effects, especially during the early period of atherosclerosis. The aim of this study was to investigate whether combination of a statin and an ARB exerts synergistic anti-atherosclerotic effects, and to elucidate the mechanisms of combined effects.MethodsAtherosclerotic plaques were developed in arteries of 23 rabbits using a high-cholesterol diet (HCD) and intra-arterial balloon inflation. Rabbits received one of five different treatment strategies for 4 weeks: positive control [n = 5, HCD]; negative control [n = 3, regular chow diet]; statin [n = 5, HCD and rosuvastatin 10 mg]; ARB [n = 5, HCD and olmesartan 20 mg]; and combination [n = 5, HCD and statin+ARB].ResultsHistological analysis demonstrated that development of atherosclerotic plaques was inhibited more in combination group than in statin group (P = 0.001). Although macrophage infiltration identified by RAM11 staining was not significantly different between combination and individual treatment groups (31.76±4.84% [combination] vs. 38.11±6.53% [statin; P = 0.35] or 35.14±2.87% [ARB; P = 0.62]), the relative proportion of pro-inflammatory M1-macrophages was significantly lower in combination group than in ARB group (3.20±0.47% vs. 5.20±0.78%, P = 0.02). Furthermore, M2-macrophage polarization was higher in combination group than in statin group (17.70±3.04% vs. 7.86±0.68%, P = 0.001).ConclusionCombination treatment with a statin and an ARB produced synergistic protective effects for atherosclerosis initiation and progression, which may be attributed to modulation of macrophage characteristics in the early period of atherosclerosis.

Atherosclerosis is a well-known cause of cardiovascular disease and is associated with a variety of inflammatory reactions. However, an adequate large-animal model of advanced plaques to investigate the pathophysiology of atherosclerosis is lacking. Therefore, we developed and assessed a swine model of advanced atherosclerotic plaques with macrophage polarization.Mini-pigs were fed a 2% high-cholesterol diet for 7 weeks followed by withdrawal periods of 4 weeks. Endothelial denudation was performed using a balloon catheter on 32 coronary and femoral arteries of 8 mini-pigs. Inflammatory proteins (high-mobility group box 1 [HMGB1] or tumor necrosis factor alpha (TNF-α) were injected via a micro-infusion catheter into the vessel wall. All lesions were assessed with angiography and optical coherence tomography and all tissues were harvested for histological evaluation.Intima/plaque area was significantly higher in the HMGB1- and TNF-α-injected groups compared to the saline-injected group (p = 0.002). CD68 antibody detection and polarization of M1 macrophages significantly increased in the inflammatory protein-injected groups (p

Fibrates are used in patients with dyslipidemia and high cardiovascular risk. However, information regarding drug response to fibrate has been highly limited. We investigated treatment results and factors associated with triglyceride reduction after fenofibrate therapy using large-scale real-world data. Patients with one or more cardiovascular risk factors, at low-density lipoprotein-cholesterol goal but with triglyceride level ≥150 mg/dL, and undergoing treatment with fenofibrate 135-160 mg for the first time were included in this retrospective observational study. The outcome variable was the percentage changes of TG levels. The achievement rate of triglyceride

Increased consumption of Western-type diets and environmental insults lead to wide-spread increases in the plasma levels of saturated fatty acids and lipoprotein oxidation. The aim of this study is to examine whether palmitate and minimally modified low-density lipoprotein (mmLDL) exert an additive effect on macrophage activation. We found that CXCL2 and TNF-α secretion as well as ERK and p38 phosphorylation were additively increased by co-treatment of J774 macrophages with palmitate and mmLDL in the presence of lipopolysaccharide (LPS). Furthermore, the analysis of differentially expressed genes using the KEGG database revealed that several pathways, including cytokine-cytokine receptor interaction, and genes were significantly altered. These results were validated with real-time PCR, showing upregulation of Il-6, Csf3, Il-1β, and Clec4d. The present study demonstrated that palmitate and mmLDL additively potentiate the LPS-induced activation of macrophages. These results suggest the existence of synergistic mechanisms by which saturated fatty acids and oxidized lipoproteins activate immune cells.

BackgroundThis study investigated whether a mean blood pressure (BP) of

BackgroundA recent study reported that morning hypertension is associated with poor cardiovascular outcomes in hypertensive patients. However, it is unclear whether morning hypertension associated with sustained nocturnal hypertension and that associated with morning blood pressure (BP) surge differ in terms of their effects on cardiovascular target organ damage and clinical outcomes. The present study aimed to determine the association of morning hypertension with/without nocturnal hypertension with vascular target organ damage and central hemodynamics in patients at high risk for cardiovascular disease. Methods and ResultsAmbulatory BP monitoring was performed and central BP was measured in 1070 consecutive patients with high cardiovascular risk. We grouped morning hypertension into the following 3 subtypes: (I) morning normotension; (II) morning hypertension without nocturnal hypertension; and (III) morning hypertension with nocturnal hypertension. Morning hypertension was noted in 469 (43.8%) patients and morning hypertension with nocturnal hypertension was noted in 374 (34.9%) patients. The central systolic/diastolic BP and carotid to femoral pulse wave velocity were significantly higher in the subtype III group than in the subtype I and II groups (all P

Screening of variants, related to lipid metabolism in patients with extreme cholesterol levels, is a tool used to identify targets affecting cardiovascular outcomes. The aim of this study was to examine the prevalence and characteristics of rare and common variants of APOB and PCSK9 in Korean patients with extremely low low-density lipoprotein-cholesterol (LDL-C) levels.Among 13,545 participants enrolled in a cardiovascular genome cohort, 22 subjects, whose LDL-C levels without lipid-lowering agents were ≤1 percentile (48 mg/dL) of Korean population, were analyzed. Two target genes, APOB and PCSK9, were sequenced by targeted next-generation sequencing. Prediction of functional effects was conducted using SIFT, PolyPhen-2, and Mutation Taster, and matched against a public database of variants.Eight rare variants of the two candidate genes (five in APOB and three in PCSK9) were found in nine subjects. Two subjects had more than two different rare variants of either gene (one subject in APOB and another subject in APOB/PCSK9). Conversely, 12 common variants (nine in APOB and three in PCSK9) were discovered in 21 subjects. Among all variants, six in APOB and three in PCSK9 were novel. Several variants previously reported functional, including c.C277T (p.R93C) and c.G2009A (p.G670E) of PCSK9, were found in our population.Rare variants of APOB or PCSK9 were identified in nine of the 22 study patients with extremely low LDL-C levels, whereas most of them had common variants of the two genes. The common novelty of variants suggested polymorphism of the two genes among them. Our results provide rare genetic information associated with this lipid phenotype in East Asian people.

BackgroundStudies on factors which may predict the risk of diabetes are scarce. This prospective cohort study was conducted to determine the association between adiponectin and type 2 diabetes among Korean men and women.MethodsA total of 42,845 participants who visited one of seven health examination centers located in Seoul and Gyeonggi province, Republic of Korea between 2004 and 2008 were included in this study. The incidence rates of diabetes were determined through December 2011. To evaluate the effects of adiponectin on type 2 diabetes, the Cox proportional hazard model was used.ResultsOf the 40,005 participants, 959 developed type 2 diabetes during a 6-year follow-up. After the adjustment for age, body mass index (BMI), and waist circumference, the risks for type 2 diabetes in participants with normoglycemia had a 1.70-fold (95% confidence interval [CI], 1.21 to 2.38) increase in men and a 1.83-fold (95% CI, 1.17 to 2.86) increase in women with the lowest tertile of adiponectin when compared to the highest tertile of adiponectin. For participants with impaired fasting glucose (IFG), the risk for type 2 diabetes had a 1.46-fold (95% CI, 1.17 to 1.83) increase in men and a 2.52-fold (95% CI, 1.57 to 4.06) increase in women with the lowest tertile of adiponectin. Except for female participants with normoglycemia, all the risks remained significant after the adjustment for fasting glucose and other confounding variables. Surprisingly, BMI and waist circumference were not predictors of type 2 diabetes in men or women with IFG after adjustment for fasting glucose and other confounders.ConclusionA strong association between adiponectin and diabetes was observed. The use of adiponectin as a predictor of type 2 diabetes is considered to be useful.

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.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).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.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.

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.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

BackgroundSpinal cord ischemia with resulting paraplegia remains one of the most common complications after repair of thoracoabdominal aortic aneurysms or dissection. Inducible nitric oxide synthase (iNOS) is known to have both neuroprotective and neurotoxic effects in the central nervous system. We investigated the possible relationship between the effect of pre-ischemic isoflurane exposure on mild spinal cord ischemia and the inducible nitric oxide synthase (iNOS) expression by using iNOS-specific antibody and pyrrolidinedithio carbamate (PDTC), NF-κB inhibitor, in the ventral horn of spinal cord in rats.MethodsThe animals were divided into five groups (n = 6 in each group): sham group, control group, PDTC-treated group, isoflurane-treated group, and PDTC/ isoflurane-treated group. In the PDTC-treated groups, 2% 100 mg/kg PDTC was administered intraperitoneally at 1 h before operation and at 24 h and 48 h after reperfusion. The rats in the isoflurane-treated groups received 30 min inhalation of 2.8% isoflurane at 24 h before spinal cord ischemia. Immunohistochemistry was performed to detect iNOS expression in the motor neuron of the ventral horn in spinal cord.ResultsPreconditioning with isoflurane increased the iNOS expression when compared to the control group (P < 0.05), whereas pre-treatment with both PDTC and isoflurane significantly decreased the iNOS expression compared to isoflurane-treated group (P < 0.05).ConclusionsPre-ischemic isoflurane exposure was related with increase of the iNOS expression via a pathway modulated by NF-κB. iNOS may act as an important mediator of delayed preconditioning with isoflurane for the protective effect against spinal cord ischemia.

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.

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.

Lipid metabolites are indispensable regulators of physiological and pathological processes, including atherosclerosis and coronary artery disease (CAD). However, the complex changes in lipid metabolites and metabolism that occur in patients with these conditions are incompletely understood. We performed lipid profiling to identify alterations in lipid metabolism in patients with angina and myocardial infarction (MI). Global lipid profiling was applied to serum samples from patients with CAD (angina and MI) and age-, sex-, and body mass index-matched healthy subjects using ultra-performance liquid chromatography/quadruple time-of-flight mass spectrometry and multivariate statistical analysis. A multivariate analysis showed a clear separation between the patients with CAD and normal controls. Lysophosphatidylcholine (lysoPC) and lysophosphatidylethanolamine (lysoPE) species containing unsaturated fatty acids and free fatty acids were associated with an increased risk of CAD, whereas species of lysoPC and lyso-alkyl PC containing saturated fatty acids were associated with a decreased risk. Additionally, PC species containing palmitic acid, diacylglycerol, sphingomyelin, and ceramide were associated with an increased risk of MI, whereas PE-plasmalogen and phosphatidylinositol species were associated with a decreased risk. In MI patients, we found strong positive correlation between lipid metabolites related to the sphingolipid pathway, sphingomyelin, and ceramide and acute inflammatory markers (high-sensitivity C-reactive protein). The results of this study demonstrate altered signatures in lipid metabolism in patients with angina or MI. Lipidomic profiling could provide the information to identity the specific lipid metabolites under the presence of disturbed metabolic pathways in patients with CAD.

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.

Saturated fatty acids are known to activate macrophages and induce vascular inflammation. Although cytokines from activated macrophage influence other vascular cells, the influence of saturated fatty acids on the paracrine effect of macrophages is not fully understood yet. Here we examined the impact of palmitate on the effect of macrophages on vascular smooth muscle cells (SMCs) and their mediators. SMCs proliferation increased significantly after treatment with conditioned media from palmitate-stimulated RAW264.7 cells. SMC migration was found to be greater after treatment with palmitate-conditioned media. SM α-actin and SM22α were decreased in SMCs treated with palmitate-conditioned media. When stimulated with palmitate, RAW264.7 cells secreted more bone morphogenetic protein (BMP)2 and BMP4 into the cell culture media. SMC proliferation, migration, and phenotypic changes were attenuated after treatment of neutralizing antibodies against BMPs or knockdown of BMPs with siRNA. The influences of these proteins were further confirmed by direct treatment of recombinant BMP2 and BMP4 on SMCs. Particularly, the effects of BMPs on SMC migration on phenotypic change were obvious, whereas their effect on SMC proliferation seemed not significant or modest. In conclusion, palmitate promoted macrophages' paracrine effects on SMC proliferation, migration, and phenotypic change. The effect of stimulated macrophages was mediated, at least in part, by BMP2 and BMP4. These results suggest a novel mechanism linking saturated fatty acids and the progression of vascular diseases that is possibly mediated by BMPs from macrophages.

Purpose: There are few studies in the literature on the dosage of statin that equivalently reduces low-density lipoprotein cholesterol (LDL-C) compared to an ezetimibe combination and whether such regimens have differences in safety. We compared the lipidmodifying efficacy and safety of 5 mg rosuvastatin/10 mg ezetimibe to those of 20 mg rosuvastatin. Materials and Methods: A literature search was conducted using the PubMed, EMBASE, Cochrane, Web of Sciences, and SCOPUS databases up to December 2021. Human studies investigating the two aforementioned regimens with a randomized controlled design were selected. Outcome variables included the percentage reduction in LDL-C and other lipid parameters and rates of composite adverse events (AEs), including muscle-related symptoms. A random-effects meta-analysis was performed after heterogeneity testing between studies. Results: Seven studies were included in this meta-analysis. The percentage LDL-C reduction did not differ between the combination and monotherapy groups [standardized mean difference (SMD) 0.08; 95% confidence interval (CI) -0.09 to 0.26; p=0.35]. The risk of composite AEs (odds ratio 0.50; 95% CI 0.15 to 1.72; p=0.27) of the combination was not different compared to the monotherapy group. The percentage of total cholesterol reduction was greater in the combination group (SMD 0.22; p=0.02), whereas that of triglyceride reduction and high-density lipoprotein cholesterol elevation did not differ between the two groups. Conclusion: This meta-analysis showed that 5 mg rosuvastatin/10 mg ezetimibe had largely comparable lipid-modifying efficacy and tolerability as 20 mg rosuvastatin. [ABSTRACT FROM AUTHOR]