FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2906403444> ?p ?o ?g. }

• W2906403444 abstract "HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 39, No. 1Highlighting Residual Atherosclerotic Cardiovascular Disease Risk Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBHighlighting Residual Atherosclerotic Cardiovascular Disease Risk Yunosuke Matsuura, Jenny E. Kanter and Karin E. Bornfeldt Yunosuke MatsuuraYunosuke Matsuura From the Department of Medicine, University of Washington Medicine Diabetes Institute, University of Washington School of Medicine, Seattle (Y.M., J.E.K., K.E.B.) Search for more papers by this author , Jenny E. KanterJenny E. Kanter From the Department of Medicine, University of Washington Medicine Diabetes Institute, University of Washington School of Medicine, Seattle (Y.M., J.E.K., K.E.B.) Search for more papers by this author and Karin E. BornfeldtKarin E. Bornfeldt Correspondence to Karin Bornfeldt, PhD, University of Washington Medicine Diabetes Institute, University of Washington School of Medicine, 750 Republican St, Seattle, WA 98109. Email E-mail Address: [email protected] From the Department of Medicine, University of Washington Medicine Diabetes Institute, University of Washington School of Medicine, Seattle (Y.M., J.E.K., K.E.B.) Department of Pathology, University of Washington Medicine Diabetes Institute, University of Washington School of Medicine, Seattle (K.E.B.) Search for more papers by this author Originally published26 Dec 2018https://doi.org/10.1161/ATVBAHA.118.311999Arteriosclerosis, Thrombosis, and Vascular Biology. 2019;39:e1–e9Precision medicine is increasingly moving health care from a conventional one-size-fits-all approach toward a personalized medicine strategy. For example, patients with certain types of cancer can now make treatment choices based not only on the tumor’s histological type but also on tissue expression of targeted proteins and specific gene mutations. Precision medicine has made less progress in atherosclerotic cardiovascular disease (ASCVD). What will be necessary for us to achieve effective precision medicine in patients with ASCVD? Since the landmark Scandinavian Simvastatin Survival Study demonstrated a beneficial effect of statin treatment on recurrent cardiovascular events in patients with overt hyperlipidemia,1 many subsequent studies on primary and secondary prevention have demonstrated favorable effects of LDL (low-density lipoprotein) cholesterol (LDL-C)–lowering therapies on ASCVD outcomes.2–5 These beneficial effects of statins are now known to extend to patients without clear dyslipidemia or preexisting cardiovascular disease. However, many statin-treated patients remain at a significantly elevated risk of having a major cardiovascular event that is unresolved, despite statin treatment. This is commonly referred to as residual risk.The American College of Cardiology and American Heart Association recently published the 2018 clinical practice guidelines for management of blood cholesterol.6 The guidelines suggest that the more LDL-C is reduced, the greater will be the ASCVD risk reduction. The guidelines stratify patients based on LDL-C levels, history of ASCVD events, conventional risk factors (such as diabetes mellitus) and risk-enhancing factors (such as metabolic syndrome or chronic inflammatory conditions) and recommend treatment options/intensity of treatment based on each stratum for primary and secondary ASCVD prevention. Even with more stringent treatment strategies going forward, there are several important questions to be addressed, including (1) whether optimal LDL-C control varies from person to person rather than according to overall clinical subgroup; (2) whether residual ASCVD risk could be prevented by even more aggressive LDL-C lowering using more stringent statin regimens or additional LDL-C–lowering strategies, such as inhibitors of PCSK9 (proprotein convertase subtilisin/kexin type 9),7 which has some effects distinct from those of statins on non–LDL-C risk factors8,9; and (3) to what extent non–LDL-C risk factors explain the residual risk.Type 2 diabetes mellitus is associated with dyslipidemia characterized by a number of abnormalities that have collectively been referred to as the atherogenic dyslipidemia complex10 and are believed to contribute to residual risk in these patients. Thus, high prevalence of ASCVD can be observed in type 2 diabetic patients with elevated levels of plasma triglycerides and low levels of HDL (high-density lipoprotein) cholesterol (HDL-C) and levels of glycated hemoglobin outside the target range of 7%.11,12 A large study on >270 000 patients with type 2 diabetes mellitus included in the Swedish National Diabetes Register indicated that when glycated hemoglobin, LDL-C, albuminuria, blood pressure, and smoking are all within the target range, these patients have no residual risk of myocardial infarction (MI), as compared with the general population.12 This suggests that well-controlled diabetes mellitus per se does not increase residual risk as long as LDL-C and the other assessed risk factors are well controlled.Conversely, genome-wide association studies, Mendelian randomization studies, and studies on humans with loss-of-function mutations in identified genes have made it abundantly clear that variations in genes not only related to LDL-C (eg, PCSK9, SORT1, and APOB) but also related to triglycerides (eg, APOC3, LPL, and ANGPTL3) and inflammation (eg, CXCL12 and IL6R) associate with ASCVD risk.13,14 Residual risk is, therefore, likely to be higher in certain populations of patients with genetic risk and patients who for other reasons have elevated triglycerides, low HDL-C, or increased inflammation.In this ATVB highlights article, we will review recent articles published in ATVB related to residual risk in cardiovascular disease and put this research into a wider context. We will focus primarily on TRLs (triglyceride-rich lipoproteins) and their remnants, HDL, Lp(a) (lipoprotein[a]), and inflammation as residual risk factors. Increased understanding of the contributions of those residual risk factors in different patient populations will move the field closer toward more effective precision medicine approaches to prevent ASCVD events.TRLs and Their RemnantsTreatment strategies to improve triglyceride clearance or reduce triglyceride production, especially in patients with type 2 diabetes mellitus, have become a central topic in the debate over residual risk of ASCVD. Blood concentrations of triglycerides are generally considered to reflect atherogenic lipoproteins, such as TRLs and their remnants. TRLs are converted into their remnants primarily by LPL, and subsequently, these smaller apoB (apolipoprotein B)-containing lipoprotein remnant particles can penetrate and accumulate in the subendothelial arterial space and induce local and systemic atherogenic responses. Thus, patients with familial dysbetalipoproteinemia (also known as type III hyperlipoproteinemia or remnant removal disease) exhibit markedly accelerated atherosclerosis, despite LDL-C levels being in the normal range.15 These patients exhibit elevated remnants primarily because of mutations in the APOE(apolipoprotein E) gene, which prevent effective hepatic clearance of the apoE-containing TRLs. Furthermore, increased arterial inflammation, measured as increased arterial 18F-fluorodeoxyglucose uptake, can be seen in patients with familial dysbetalipoproteinemia.16 Increased 18F-fluorodeoxyglucose uptake is closely associated with inflammatory activation of macrophages,17 suggesting that remnants cause increased activation of lesional macrophages. The elevated remnant levels result in increased lipid accumulation in circulating monocytes and increased expression of adhesion molecules in these cells, as well as monocytosis,15 which would all be predicted to increase macrophage accumulation in lesions of atherosclerosis. Thus, a marked increase in remnants results in atherogenic effects both systemically and locally.In patients without known genetic conditions affecting TRL remnant clearance, the role of remnants in ASCVD is more difficult to assess, in part, because remnants are poorly defined and are difficult to measure. One common method of assessing remnant levels is to subtract LDL-C and HDL-C from total cholesterol levels. This method is inexact, especially at high triglyceride levels. Measurements of plasma triglyceride levels, often used as a surrogate of TRLs and remnants, are also an approximation because fasting concentrations of plasma triglycerides correspond to the sum of triglyceride content in nascent VLDL (very low-density lipoprotein) and remnants. Nevertheless, fasting triglyceride levels can predict long-term and short-term cardiovascular risk in patients with acute coronary syndrome who are treated effectively with statins,18 suggesting that elevated fasting triglycerides, directly or indirectly, contribute to residual risk. Triglyceride content in plasma increases in the postprandial state because of the presence of triglyceride-rich chylomicrons and their remnants.19 Nonfasting triglycerides are also associated with increased risk of ischemic heart disease and MI20 and with a stepwise higher risk of heart failure.21 Therefore, in some patients, it is recommended to assess both nonfasting and fasting lipid profiles.22A recent article in ATVB highlights the importance of postprandial triglyceride clearance in atherosclerosis in humans. Kurihara et al23 used optical coherence tomography to visualize high-risk atherosclerotic lesions, defined as thin-cap fibroatheroma, and the association with postprandial dyslipidemia after a meal tolerance test in 30 patients with stable coronary artery disease. They demonstrated that thin-cap fibroatheromas are associated with increased levels of remnants after the meal tolerance test, and with elevated baseline apoC-III (apolipoprotein C-III) levels, suggesting baseline abnormalities in TRL clearance in patients with high-risk lesions. In another ATVB article, insulin treatment of diabetic mice was shown to reduce plasma triglycerides and cholesterol and to increase LPL (lipoprotein lipase) activity concomitant with a reduction in atherosclerosis.24 LPL hydrolyzes triglycerides and promotes uptake of fatty acids into tissues, thereby lowering plasma triglyceride levels. Interestingly, blood glucose lowering by an SGLT2 (sodium-glucose cotransporter-2) inhibitor had no such effects, suggesting that in diabetes mellitus, lipids are more important than glucose in promoting atherosclerosis,25 at least in this mouse model.Do abnormalities in triglyceride metabolism causally associate with ASCVD? A number of clinical trials evaluating the effect of triglyceride-lowering therapies on ASCVD have yielded variable results.26–28 The conflicting results between trials can be interpreted in several ways: (1) niacin, fish oils, and fibrates tested have multiple effects, including effects unrelated to triglyceride-lowering; (2) the dose setting or formulations of triglyceride-lowering drugs might have been insufficient to show a beneficial effect on ASCVD; (3) the most relevant patient populations might not have been targeted by these clinical trials; and (4) plasma triglycerides are regulated by a number of different genes and mechanisms. The recently published REDUCE-IT trial (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) tested the effect of icosapent ethyl (a pure and stable eicosapentaenoic acid ethyl ester; 4 g daily dose) in statin-treated high-risk ASCVD patients with baseline fasting plasma triglyceride levels ranging from 135 to 499 mg/dL. After a median study period of 5 years, the results showed a 25% reduction in the primary composite end points, including coronary revascularization or unstable angina, and a 26% reduction in the secondary end points composed of cardiovascular death, MI, and stroke.29 The icosapent ethyl treatment resulted in an 18% reduction in plasma triglycerides during the first year of the study. These results are similar to those of JELIS (Japan Eicosapentaenoic Acid Lipid Intervention Study), which also demonstrated a beneficial effect of eicosapentaenoic acid on ASCVD events in statin-treated subjects.30 To what extent the beneficial effects of eicosapentaenoic acid ethyl ester on ASCVD are because of triglyceride lowering needs further study. Thus, it remains unclear whether triglyceride lowering is effective in preventing ASCVD in patients with residual risk. Several additional trials are under way that will aid our understanding of the roles of TRLs in ASCVD risk.28On the contrary, recent Mendelian randomization studies strongly support the causal relationship between genes involved in triglyceride metabolism and coronary heart disease.31 Genetic and genomic studies have revealed that genes involved in triglyceride clearance, including APOC3,32–34APOA5,35ANGPTL3,36 and LPL,37 strongly associate with cardiovascular disease risk. Indeed, plasma apoC-III levels associate with high-risk coronary plaques23 and the risk of ASCVD.38 Consistently, the low risk of cardiovascular disease in patients with APOC3 loss-of-function mutations is considered to be mainly mediated by the associated low remnant cholesterol and not by the low level of LDL-C.34 Also, apoC-III is involved in the formation of small dense LDL39,40—another cardiovascular risk factor; therefore, its inhibition can potentially modify the proatherogenic properties of LDL in addition to increasing triglyceride clearance. New strategies, such as inhibition of APOC3 or ANGPTL3 (angiopoietin-like 3; which inhibits LPL), might prove to be effective therapeutic options to increase triglyceride clearance and reduce residual risk of ASCVD.28Mechanisms whereby TRL remnants or genes that impair remnant removal promote major ASCVD events are still poorly understood but are believed to include increased trapping of remnants in the artery wall, increased remnant uptake by lesional macrophages, inflammatory and proapoptotic effects on lesional cells, and procoagulant effects.41HDLLow levels of HDL-C are often associated with elevated triglycerides and are a clinical hallmark in patients with metabolic syndrome or type 2 diabetes mellitus. Reduced levels of HDL-C can also be observed in other populations. For example, a recent publication in ATVB demonstrated that HDL-C levels are reduced by environmental factors, such as traffic-related pollution.42 A large number of epidemiological studies have consistently shown a strong inverse correlation between HDL-C and the incidence of cardiovascular events; therefore, therapies to increase the level of HDL-C have been extensively tested as a strategy to reduce cardiovascular events, particularly in patients with type 2 diabetes mellitus.43HDL is a heterogeneous population of particles with sizes ranging from 7 to 14 nm that collectively contain >80 different proteins and can be divided into partly distinct subpopulations characterized by different protein composition, which may have different functions.44 We know now that small HDL particles are the most effective in removing cholesterol from cells through the cholesterol transport protein ABCA1 (ATP-binding cassette transporter A1),45 whereas large HDL contains the most cholesterol.43 A recent article published in ATVB demonstrated that the function of both small HDL (preβ-1 HDL) and large HDL (α-1+α-2 HDL) is altered in patients with coronary artery disease.46 Therefore, treatment strategies that increase levels of HDL-C would not necessarily be predicted to increase the atheroprotective cholesterol efflux capacity of HDL. Strategies to boost the atheroprotective function of HDL particles might prove to be more effective.To date, the main strategy for increasing HDL has focused on increasing HDL-C levels by inhibition of CETP (cholesteryl ester transfer protein). Because CETP transfers triglycerides from VLDL and other lipoproteins to HDL in exchange for cholesteryl esters, its inhibition results in increased levels of cholesteryl esters in HDL in humans.47 Consistently, a recent study published in ATVB used a new rabbit CETP knockout model to demonstrate that CETP deficiency results in elevated HDL-C levels, increased cholesterol efflux capacity of apoB-depleted plasma, markedly reduced levels of VLDL, and protection against cholesterol diet-induced atherosclerosis.48 Another study found that pharmacological inhibition of CETP activity reduces in-stent restenosis via inhibition of vascular smooth muscle cell proliferation,49 suggesting that CETP inhibition may be a potential strategy to protect against ASCVD and related vascular damage. Whereas these animal models show beneficial effects of loss of CETP, human studies are less conclusive. Three clinical trials using different types of CETP inhibitors failed to demonstrate a beneficial effect on cardiovascular outcomes, despite showing increased HDL-C levels.50 A recent Mendelian randomization study51 found that a common variation in the CETP gene reduced the risk of MI; however, this gene variant was also associated with a decreased level of LDL-C coupled with the increased level of HDL-C. Recently, the REVEAL trial (Randomized Evaluation of the Effects of Anacetrapib Through Lipid Modification) demonstrated that CETP inhibition by anacetrapib reduced coronary artery disease events; however, this agent not only increased the HDL-C level but also reduced the LDL-C level,52 similar to the findings observed in the above Mendelian randomization study. Taking these results together, we still cannot conclude that a low level of HDL-C is a causal risk factor of ASCVD because we are unable to exclude the effect of LDL-C lowering by CETP inhibition on the positive results.Another approach to raise HDL-C is to increase levels of apoA-I (apolipoprotein A-I)—the main structural protein of HDL.53 To date, several interventional approaches targeting apoA-I have been developed,54,55 and a few of them revealed beneficial effects against atherosclerosis in humans,56 but none of these strategies have resulted in clinical use. A recent article published in ATVB demonstrated that apoA-I vascular gene therapy targeting endothelial cells shows a protective effect against atherosclerosis in hyperlipidemic rabbits,57 suggesting that increased apoA-I expression in the endothelium is atheroprotective. In addition, apoA-I mimetic peptides have been continuously developed in parallel with the investigation of its functionality in vivo.58EL (endothelial lipase; gene name, LIPG) determines HDL-C levels by hydrolyzing HDL phospholipids, and mice deficient in EL exhibit a marked increase in fasting HDL-C and increased numbers of HDL particles.59 Consistently, LIPG gene variants have been shown to be associated with increased plasma HDL-C in humans.60,61 However, the effect of EL on atherogenesis is controversial.62,63 Recent studies published in ATVB examined rabbit and mice overexpressing human EL in the liver. In the rabbit model, HDL-C levels and atherosclerotic lesions were reduced by EL overexpression.64 In the mouse model, HDL levels were similarly reduced, but reverse cholesterol transport was not dampened unless hepatic scavenger receptor class B type I was inhibited.65 Furthermore, a Mendelian randomization study found that carriers of the LIPG 396Ser allele had higher HDL-C but similar levels of other lipid and nonlipid risk factors for MI compared with noncarriers; yet this allele was not associated with reduced risk of MI.51Moreover, a recent ATVB article on the relationship between HDL-C and mortality has shown a U-shaped curve, suggesting that an extremely high level of HDL-C is not related to a favorable outcome, in contrast, showing increased mortality.66 These results suggest that a strategy simply aimed at quantitatively increasing HDL-C levels does not improve cardiovascular outcomes. Taken together, the dogma that HDL-C is atheroprotective is not uniformly supported by human data.In this context, there is a growing debate on HDL’s functionality, rather than cholesterol content, in mediating HDL’s atheroprotective effect.43 Higher cholesterol efflux capacity of plasma HDL, measured as cholesterol mass efflux, was recently shown to be associated with lower risk of incident coronary heart disease events.67 The correlation between plasma HDL cholesterol mass efflux capacity and HDL-C in this study was modest. Furthermore, studies on the effect of exercise and weight loss have demonstrated that some measures of HDL function can be improved at least partly independently of HDL-C levels.68,69 The search for mechanisms that improve HDL function is, therefore, an intense topic of study. One such mechanism is related to sphingosine-1-phosphate (S1P), which seems to mediate some of the atheroprotective functions of HDL. Thus, Denimal et al70 demonstrated that blunted activation of eNOS (endothelial NO synthase) by HDL in patients with metabolic syndrome was mainly because of reduced levels of S1P in HDL. Apolipoprotein M is the main carrier of S1P in plasma, and a subpopulation of HDL carries apoM and binds S1P. The relative level of S1P in HDL versus apoB-containing lipoproteins is modulated by CETP.71 It has been shown that apoM-bound S1P is responsible for HDL’s ability to suppress adhesion molecule expression in the endothelium.72 These findings suggest that S1P is a mediator of at least some of the atheroprotective effects of HDL. Further studies on the functionality of HDL and regulators of its functionality will be needed.Furthermore, a series of studies have supported the idea that the concentration of HDL particles is a superior marker of ASCVD risk over HDL-C and of residual risk after statin treatment.73,74 Consistently, niacin and CETP inhibitors that raised HDL-C but did not show a beneficial effect on cardiovascular disease50,75 had only weak effects on increasing the number of HDL particles.76 Therapeutic strategies to increase HDL particle concentrations might be able to reduce the residual risk. Further investigation of the clinical significance of various HDL metrics and their effectiveness in preventing ASCVD risk is needed.Lp(a)Lp(a) (gene name, LPA) is an apo-B100–containing LDL particle covalently attached to the protein apo(a) (apolipoprotein[a]). Lp(a) levels are not generally lowered by statins, which makes Lp(a) a strong residual risk factor candidate. However, increased Lp(a) does not seem to explain the residual risk associated with diabetes mellitus.10 Instead, a series of genetic studies, including meta-analysis and Mendelian randomization studies, have suggested that genetically elevated levels of Lp(a) causally associate with cardiovascular disease risk.77 Plasma levels of Lp(a) vary >1000-fold between individuals and partly reflect acute or chronic inflammation; however, they are primarily determined by polymorphisms in the LPA gene. LPA variants associate with cardiovascular events in patients receiving statin therapy.78 Moreover, progression of carotid atherosclerosis positively associates with the level of Lp(a) in patients treated with intensive lipid-lowering medication with the goal of LDL-C <70 mg/dL.79 These findings support the notion that Lp(a) is a candidate component of residual ASCVD risk in some patients. In addition to apo(a) synthesis in hepatocytes, catabolic pathways impact plasma levels of Lp(a). A large-scale genetic study in humans found that differences in plasma Lp(a) levels are associated with APOE genotypes, suggesting that apoE can affect the catabolism of Lp(a), perhaps through competition for the hepatic clearance receptors LDLR (LDL receptor) and LRP1 (LDL receptor–related protein 1).80Given that Lp(a) might be a promising therapeutic target in some patients with increased residual risk, we need to define its therapeutic threshold value. There have been continuous efforts to determine the therapeutic cutoff value for Lp(a).81 A recent analysis estimating population impact of lowering the plasma Lp(a) level to <50 mg/dL, based on data from a large prospective cohort study, suggested that reducing Lp(a) is expected to have a significant beneficial impact on cardiovascular disease.82 Niacin,83–85 PCSK9 inhibition,9,86 apo(a) antisense oligonucleotides,87 CETP inhibition by anacetrapib,88 and the removal of Lp(a) by lipoprotein apheresis89 might be candidates for therapeutic strategies to reduce Lp(a) levels. A recent chronic renal insufficiency cohort study showed that elevated Lp(a) is independently associated with MI and death among patients with chronic kidney disease90; therefore, therapeutic intervention to lower Lp(a) might provide benefits especially in high-risk populations with prevalent chronic kidney disease.The mechanisms whereby Lp(a) promotes atherothrombotic disease are not well understood, in part, because rodents and rabbits, which are commonly used for mechanistic studies on atherogenesis, do not normally express Lp(a). Animals transgenic for Lp(a) suggest that Lp(a) promotes fatty streak formation and atherosclerotic lesion calcification, but better models are needed to understand the mechanisms.91InflammationIt is now well recognized that inflammation, orchestrated by various types of immune cells,92 their subpopulations,93 and cytokines94,95 in circulation or in the local milieu, associates with and participates in the development and progression of atherosclerosis. Moreover, interest in the relationships among inflammatory processes and ASCVD extends to the involvement of humoral immunity,96 such as the classic pathway of complement activation,97 IgM,98 and IgE.99 Conditions associated with an increased ASCVD risk, such as diabetes mellitus, are characterized by increased low-grade inflammation. In addition, it is interesting to note that ambient air pollution is associated with systemic inflammation,100 which in turn might contribute to incident cardiovascular events.101Although we have known for decades from mechanistic animal models that inflammatory processes are critically involved in atherosclerosis, whether inflammation itself can be a therapeutic target in prevention of ASCVD in humans has been a longstanding clinical question. The CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcome Study) recently offered an answer to this question by demonstrating that inhibition of the cytokine IL (interleukin)-1β can prevent ASCVD events in subjects with a prior MI and elevated hs-CRP (high-sensitivity C-reactive protein) highlighting inflammation as a nonlipid residual risk factor in these patients.102 The results of this trial showed that targeting the IL-1β innate immunity pathway with canakinumab (a human IL-1β neutralizing monoclonal antibody) at a dose of 150 mg every 3 months led to a lower rate of recurrent cardiovascular events than did placebo treatment, independent of lipid lowering.102 It is noteworthy that a majority of subjects included in the CANTOS trial were on statin therapy. Also, it is worth mentioning that this study proposed the concept of residual inflammatory risk103,104 and suggested that inflammation is a major residual risk factor of ASCVD. The CANTOS trial concurrently demonstrated that IL-1β can contribute to cardiovascular events in humans. However, it is unknown whether blocking IL-1β would be effective in the general population of patients with elevated ASCVD risk, including those who do not have increased CRP (C-reactive protein). The recent CIRT (Cardiovascular Inflammation Reduction Trial) failed to demonstrate a beneficial effect of low-dose methotrexate as an anti-inflammatory agent in ASCVD patients with a median level of hs-CRP at randomization at 1.5 mg/L (compared with >4 mg/L in CANTOS).102,105 However, methotrexate did not reduce circulating levels of IL-1β, IL-6, or hs-CRP, suggesting that the treatment did not alter the key inflammatory pathway(s).Many lines of evidence evoke IL-1β as especially important in ASCVD. Chai et al106 identified Il1b as one of the upstream regulators of enriched gene sets when comparing the transcriptome of macrophages from symptomatic atherosclerotic lesions with that of macrophages from asymptomatic lesions. Inflammasomes are essential for IL-1β secretion via activation of caspase-1.107 Thus, the inactivation of inflammasomes might be a therapeutic option to prevent cardiovascular event.108 Indeed, a recent study using apoE-deficient mice treated with a specific inhibitor of the most studied inflammasome component, NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3), showed attenuation of atherosclerosis development.109 Conversely, physiological activators of inflammasomes include saturated fatty acids,110 ceramide,111 oxidized LDL,112 and cholesterol crystals,113,114 which are present in atherosclerotic lesions. These lipids or other inflammasome activators are, therefore, likely to accelerate inflammation and lesion progression.Recently, clonal hematopoiesis of indeterminate potential has emerged as another nonlipid residual risk factor related to inflammation in older patients.115 Deficiency of one of the most common genes responsible for clonal hematopoiesis of indeterminate potential in humans, TET2 (tet methylcytosine dioxygenase 2), was shown to promote atherogenesis in mouse models through an IL-1β–dependent and NLRP3 inflammasome- dependent mechanism.115 Taken together, activation of the NLRP3 inflammasome—a mediator associated with both cell death and inflammation—can be a potential mechanism underlying the formation of the large necrotic cores and accumulation of inflammatory cells, which characterize the high-risk plaque.Defective" @default.
• W2906403444 created "2019-01-01" @default.
• W2906403444 creator A5002224107 @default.
• W2906403444 creator A5011658040 @default.
• W2906403444 creator A5022889313 @default.
• W2906403444 date "2019-01-01" @default.
• W2906403444 modified "2023-10-11" @default.
• W2906403444 title "Highlighting Residual Atherosclerotic Cardiovascular Disease Risk" @default.
• W2906403444 cites W120848922 @default.
• W2906403444 cites W1561041814 @default.
• W2906403444 cites W1708837772 @default.
• W2906403444 cites W1805934449 @default.
• W2906403444 cites W1927101378 @default.
• W2906403444 cites W1972483153 @default.
• W2906403444 cites W1974185581 @default.
• W2906403444 cites W1975371452 @default.
• W2906403444 cites W1976894444 @default.
• W2906403444 cites W1990324513 @default.
• W2906403444 cites W2020915011 @default.
• W2906403444 cites W2028545985 @default.
• W2906403444 cites W2036035171 @default.
• W2906403444 cites W2050838276 @default.
• W2906403444 cites W2050997693 @default.
• W2906403444 cites W2061100095 @default.
• W2906403444 cites W2094742960 @default.
• W2906403444 cites W2095507444 @default.
• W2906403444 cites W2098518124 @default.
• W2906403444 cites W2116775019 @default.
• W2906403444 cites W2120640025 @default.
• W2906403444 cites W2124481954 @default.
• W2906403444 cites W2128361838 @default.
• W2906403444 cites W2131881234 @default.
• W2906403444 cites W2133450634 @default.
• W2906403444 cites W2142347023 @default.
• W2906403444 cites W2145813488 @default.
• W2906403444 cites W2150538035 @default.
• W2906403444 cites W2150702412 @default.
• W2906403444 cites W2152789823 @default.
• W2906403444 cites W2159449551 @default.
• W2906403444 cites W2159738130 @default.
• W2906403444 cites W2164324917 @default.
• W2906403444 cites W2164750952 @default.
• W2906403444 cites W2165605025 @default.
• W2906403444 cites W2165628592 @default.
• W2906403444 cites W2165961239 @default.
• W2906403444 cites W2166423227 @default.
• W2906403444 cites W2169582126 @default.
• W2906403444 cites W2169918634 @default.
• W2906403444 cites W2170009139 @default.
• W2906403444 cites W2253359374 @default.
• W2906403444 cites W2280502801 @default.
• W2906403444 cites W2285780972 @default.
• W2906403444 cites W2294885876 @default.
• W2906403444 cites W2322095705 @default.
• W2906403444 cites W2342969428 @default.
• W2906403444 cites W2345841042 @default.
• W2906403444 cites W2463902228 @default.
• W2906403444 cites W2521514852 @default.
• W2906403444 cites W2541850373 @default.
• W2906403444 cites W2549729760 @default.
• W2906403444 cites W2554189810 @default.
• W2906403444 cites W2556080334 @default.
• W2906403444 cites W2561460915 @default.
• W2906403444 cites W2566626230 @default.
• W2906403444 cites W2570683458 @default.
• W2906403444 cites W2580782968 @default.
• W2906403444 cites W2586892149 @default.
• W2906403444 cites W2588744787 @default.
• W2906403444 cites W2597657713 @default.
• W2906403444 cites W2598425213 @default.
• W2906403444 cites W2604768034 @default.
• W2906403444 cites W2605682675 @default.
• W2906403444 cites W2606698948 @default.
• W2906403444 cites W2616060150 @default.
• W2906403444 cites W2617110182 @default.
• W2906403444 cites W2618037890 @default.
• W2906403444 cites W2623772047 @default.
• W2906403444 cites W2623847043 @default.
• W2906403444 cites W2624767141 @default.
• W2906403444 cites W2735307121 @default.
• W2906403444 cites W2736338239 @default.
• W2906403444 cites W2741800441 @default.
• W2906403444 cites W2743654611 @default.
• W2906403444 cites W2748400555 @default.
• W2906403444 cites W2748800769 @default.
• W2906403444 cites W2749554026 @default.
• W2906403444 cites W2758507511 @default.
• W2906403444 cites W2759443181 @default.
• W2906403444 cites W2762777606 @default.
• W2906403444 cites W2763338206 @default.
• W2906403444 cites W2764023940 @default.
• W2906403444 cites W2765937888 @default.
• W2906403444 cites W2767490708 @default.
• W2906403444 cites W2769675829 @default.
• W2906403444 cites W2774613779 @default.
• W2906403444 cites W2781143840 @default.
• W2906403444 cites W2782406355 @default.
• W2906403444 cites W2782482496 @default.
• W2906403444 cites W2783047364 @default.
• W2906403444 cites W2785228758 @default.

• next