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.
Abstract
Aims
Proprotein convertase subtilisin/kexin type-9 (PCSK9), a molecular determinant of low-density lipoprotein (LDL) receptor (LDLR) fate, has emerged as a promising therapeutic target for ...atherosclerotic cardiovascular diseases. However, the precise mechanism by which PCSK9 regulates the internalization and lysosomal degradation of LDLR is unknown. Recently, we identified adenylyl cyclase-associated protein 1 (CAP1) as a receptor for human resistin whose globular C-terminus is structurally similar to the C-terminal cysteine-rich domain (CRD) of PCSK9. Herein, we investigated the role of CAP1 in PCSK9-mediated lysosomal degradation of LDLR and plasma LDL cholesterol (LDL-C) levels.
Methods and results
The direct binding between PCSK9 and CAP1 was confirmed by immunoprecipitation assay, far-western blot, biomolecular fluorescence complementation, and surface plasmon resonance assay. Fine mapping revealed that the CRD of PCSK9 binds with the Src homology 3 binding domain (SH3BD) of CAP1. Two loss-of-function polymorphisms found in human PCSK9 (S668R and G670E in CRD) were attributed to a defective interaction with CAP1. siRNA against CAP1 reduced the PCSK9-mediated degradation of LDLR in vitro. We generated CAP1 knock-out mice and found that the viable heterozygous CAP1 knock-out mice had higher protein levels of LDLR and lower LDL-C levels in the liver and plasma, respectively, than the control mice. Mechanistic analysis revealed that PCSK9-induced endocytosis and lysosomal degradation of LDLR were mediated by caveolin but not by clathrin, and they were dependent on binding between CAP1 and caveolin-1.
Conclusion
We identified CAP1 as a new binding partner of PCSK9 and a key mediator of caveolae-dependent endocytosis and lysosomal degradation of LDLR.
Purpose To evaluate 2-stage arthroscopic findings of the patellofemoral joint before and after medial open-wedge high tibial osteotomy (HTO) and verify whether the patellofemoral joint would be ...influenced by medial open-wedge HTO. Methods We prospectively reviewed 114 cases of medial open-wedge HTO for the treatment of osteoarthritis with a varus knee. First-look arthroscopy was performed during HTO. The mean age at the time of HTO was 56.34 ± 5.4 years (range, 40-69 years). Second-look arthroscopy was performed concomitantly with plate removal at an average of 26.1 ± 6.0 months (range, 21.6-32.0 months) after HTO. We assessed the patellofemoral joint using the International Cartilage Repair Society (ICRS) grading system by first- and second-look arthroscopy and compared it before and after HTO. Postoperative anterior knee pain was also evaluated. Results Compared with first-look findings, second-look arthroscopic ICRS grading was changed as follows: In terms of the patella, 89 cases (78.1%) were not progressed whereas 25 cases (21.9%) were progressed. In terms of the femoral trochlea, 67 cases (58.8%) were not progressed whereas 47 cases (41.2%) were progressed. There was significant progression of the ICRS grade of the patella ( P = .001) and femoral trochlea ( P < .001) compared with first-look arthroscopic findings. The incidence of postoperative anterior knee pain was 11.4% (13 cases), and it was related to the ICRS grade of the patellofemoral joint at the time of second-look arthroscopy ( P < .001 for patella and P < .001 for trochlea). Conclusions This study showed that the patellofemoral joint might be adversely affected by medial open-wedge HTO. Although the incidence of postoperative anterior knee pain was low, it was clinically correlated with patellofemoral arthritis. Level of Evidence Level IV, therapeutic case series.
Although lipid-lowering therapy has become a mainstay in preventive cardiology, many people do not realize how individual's genetic information and current genetic knowledge can be used in clinical ...practice. Genetic testing is one of the methods to find etiology in monogenic or polygenic dyslipidemia. Pharmacogenetic data may provide guidance for selection of treatment-eligible patients and lipid-lowering therapeutics. In addition, recent progress in research regarding genetics, bioinformatics, and pharmacological platforms accelerated drug target discovery and drug development in the field of dyslipidemia and cardiovascular disease prevention.
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.
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 (<160 mg/dL). Risks of composite cardiovascular events (myocardial infarction, coronary revascularization, and ischemic stroke) and total mortality were compared. In statin new users, the outcomes after statin use were further analyzed according to posttreatment LDL-C levels. The prevalence of individuals with LDL-C≥190 mg/dL was 1 of 106. Adjusted hazard ratios of composite events and total mortality (median follow-up, 6.1 years) in the groups ranged up to 2.4 (log-rank
<0.0001) and 2.3 (log-rank
=0.0002), respectively, and were dependent on LDL-C levels. The risks of each event were up to 4.1-, 3.8-, and 1.9-fold higher, respectively, in these groups. The risk of composite events (median follow-up, 6.2 years) was lower after lipid lowering; particularly, the risk was lowest in the group showing LDL-C<100 mg/dL after treatment (hazard ratio, 0.56, log-rank
=0.043). Conclusions Using large Korean cohort data, our study proved incrementally elevated cardiovascular risk and clinical benefit associated with LDL-C<100 mg/dL in individuals with severe hypercholesterolemia. These results support aggressive lipid lowering and provide evidence for the LDL-C target in this population.
The fabrication of carbon fibre-reinforced polymer (CFRP)-based shape memory alloy hybrid composite (SMAHC) beams is highly challenging because conductive carbon fibres alter the electrical ...characteristics of the beams when driven by an electrical current. Here, we propose and fabricate a CFRP-based SMAHC beam with embedded SMA actuators using the electrical insulation methods. We firstly implemented a self-sensing-based deflection control of the CFRP-based SMAHC beam for unit-step and sinusoidal wave targets using its resistance as a feedback signal for estimating self-sensed deflection. The results reveal that the deflection was well controlled; however, the responses were slightly delayed. Therefore, in our future studies, we will concentrate on overcoming this response delay. Nevertheless, we found that the proposed SMAHC beam is highly feasible and can form the basis for future self-sensing-based controllable CFRP composite morphing structures.
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 < 0.001). The maximal target dose achievement rate was higher in the SD group (27.0% vs 9.4%, p = 0.001) and the VLD group experienced more dose up-titrations and fewer down-titrations than the SD group. The VLD group had a decrease in N-terminal prohormone of brain natriuretic peptide (NT-proBNP) similar to the SD group and a similar increase in left ventricular ejection fraction. There were no significant differences in symptomatic hypotension, worsening renal function, hyperkalemia, cardiovascular mortality, and rehospitalization due to HF between the two groups during follow-up period. In patients considered by the treating physician likely to be intolerant of sacubitril/valsartan, initiation with 25 mg twice daily was generally possible and patients remained in therapy, with similar decreases in NT-proBNP and increases in left ventricular ejection fraction to those observed in patients receiving SD sacubitril/valsartan.
Activated macrophages show increased expression of vimentin, an intermediate filament protein. Macrophages secrete vimentin into extracellular space; however, the functions of extracellular vimentin ...and the process of vimentin secretion are not clearly defined. We found that oxidized low-density lipoproteins (oxLDL) via CD36 induced vimentin secretion in macrophages. We also revealed that extracellular vimentin induced macrophages to release inflammatory cytokines and augmented oxLDL-induced release of TNF-α and IL-6. Extracellular vimentin activated NF-κB signaling via phosphorylation of focal adhesion kinase (p-FAK) and IκB kinase (p-IκK). Extracellular vimentin also amplified the oxLDL-induced p-IκK increase and IκB decrease. Vimentin-induced TNF-α release was not dependent on Dectin-1, which is known to bind vimentin. We measured serum vimentin concentrations and found that patients with atherosclerotic coronary artery disease had higher levels of serum vimentin than normal subjects. Circulating oxLDL and vimentin concentrations showed a high degree of correlation. In mouse experiments, vimentin concentration was higher in the sera of apoE null mice with western diet–induced atherosclerosis than in the sera of chow diet–fed apoE null mice without atherosclerosis. We concluded that vimentin is secreted by oxLDL/CD36 interaction in macrophages and extracellular vimentin promotes macrophage release of pro-inflammatory cytokines. This may contribute to atherosclerotic inflammation and based on our analysis of serum vimentin, we suggest serum vimentin as a predictive marker for atherosclerosis.
Key messages
OxLDL via CD36 induces secretion of vimentin, a cytoskeletal protein in macrophages.
Extracellular vimentin induces macrophages to release proinflammatory cytokines such as tumor necrotizing factor-alpha (TNF-α) and this process is mediated by activation of focal adhesion kinase (FAK) and NF-ƙB signaling.
Serum concentrations of vimentin in coronary artery disease patients are higher than that in control group.
Vimentin concentration is strongly correlated with oxLDL concentration in serum.
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<0.001). In addition, advanced atherosclerotic plaques were observed more in the inflammatory protein-injected groups compared with the control upon histologic evaluation.
Direct injection of inflammatory proteins was associated with acceleration of atherosclerotic plaque formation with M1 macrophage polarization. Therefore, direct delivery of inflammatory proteins may induce a pro-inflammatory response, providing a possible strategy for development of an advanced atherosclerotic large-animal model in a relatively short time period.
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