Coronary Artery Disease

HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 40, No. 7Coronary Artery Disease Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBCoronary Artery Disease Harsh Agrawal, Ho-hin K Choy, Jason Liu, Matthew Auyoung and Michelle A. Albert Harsh AgrawalHarsh Agrawal Correspondence to: Harsh Agrawal, MD, Division of Cardiology, Department of Medicine, University of California San Francisco, 505 Parnassus Ave, San Francisco, CA 94143. Email E-mail Address: [email protected] From the Center for the Study of Adversity and Cardiovascular Disease (NURTURE Center), Division of Cardiology, Department of Medicine, University of California San Francisco (H.A., M.A.A.) , Ho-hin K ChoyHo-hin K Choy Division of Cardiology, Department of Medicine, California Pacific Medical Center, San Francisco (H.-h.K.C., J.L., M.A.). , Jason LiuJason Liu Division of Cardiology, Department of Medicine, California Pacific Medical Center, San Francisco (H.-h.K.C., J.L., M.A.). , Matthew AuyoungMatthew Auyoung Division of Cardiology, Department of Medicine, California Pacific Medical Center, San Francisco (H.-h.K.C., J.L., M.A.). and Michelle A. AlbertMichelle A. Albert From the Center for the Study of Adversity and Cardiovascular Disease (NURTURE Center), Division of Cardiology, Department of Medicine, University of California San Francisco (H.A., M.A.A.) Originally published24 Jun 2020https://doi.org/10.1161/ATVBAHA.120.313608Arteriosclerosis, Thrombosis, and Vascular Biology. 2020;40:e185–e192Since its inception, articles published in Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB) have contributed to our understanding of coronary artery disease (CAD) and its different complex pathophysiological processes. Here, we review articles related to CAD published in ATVB in the past 2 years from 2018 to 2019.Genetics: Coronary Artery DiseaseIn the past decade, remarkable strides have been made in understanding the genetics of cardiovascular disease (CVD). McPherson1 demonstrated that the genetic architecture of CAD is largely determined by the combined effects of multiple common genetic variants of which, individually, contribute little to disease risk. This is opposed to rare genetic variants that have large effects on coronary disease risk. Discovery of these common variants comes at the heel of large genome-wide association studies now being conducted on an increasingly larger scale.2,3 As the name of these studies would suggest, these findings only associate genetic variants, such as single nucleotide polymorphisms, with likelihood of disease, while subsequent studies serve to clarify a causative mechanism.Veluchamy et al4 showed that among 2 novel genome-wide significant loci corresponding to the gene for retinal venular tortuosity, and COL4A2 for retinal arteriolar tortuosity. ACTN4/CAPN12 demonstrates additional association with CAD and atrial fibrillation, suggesting the possibility of using retinal vascular traits as predictors of CVD, albeit further studies are needed to elicit a causative mechanism.Zhao et al5 showed a strong association between genetic variation on chromosome 15q26.1 and susceptibility to CAD. At this locus, the likely CAD-associated single nucleotide polymorphism is located in the noncoding region of the FURIN gene. Indeed, prior studies indicate that FURIN is produced predominantly by macrophages and expressed in atherosclerotic plaques.6 Using a reporter gene assay and isogenic monocyte cell lines created by clustered regularly interspaced short palindromic repeats, the risk allele had higher transcriptional activity and resulted in greater FURIN expression. Using lentivirus-mediated FURIN overexpression or small hairpin RNA-induced FURIN knockdown in monocyte/macrophage cell lines, they further demonstrated that FURIN overexpression promoted migration, increased proliferation, and reduced apoptosis.In other work by Li et al,7 3 novel intragenic single nucleotide polymorphisms demonstrated association with CAD, of these only 2 had transcriptional effects and were associated with decreased expression of the genes SCML4 and THSD7A, a risk allele and protective allele, respectively. Using small interfering RNA to inhibit translation, they demonstrated that knockdown of SCML4 resulted in upregulation of IL-6, E-selectin, and ICAM resulting in increased endothelial cell susceptibility to apoptosis. Furthermore, in a rat model with partial carotid ligation, adenovirus-mediated small hairpin RNA knockdown of SCML4 resulted in significantly lower luminal section area compared with controls. Separately, in a monocyte/macrophage line, they demonstrated that small interfering RNA knockdown of THSD7A attenuated monocyte adhesion by decreasing expression of ICAM, L-selectin, and ITGB2.Further elucidating the role of endothelial dysfunction in CAD, Jones et al8 explored the role of a CAD-associated variant at 10p11.23 within the JCAD gene, which encodes an endothelial junction protein. This study demonstrated that JCAD interacts with LATS1/2 and negatively regulates Hippo signaling pathways in endothelial cells. Emerging studies indicate that YAP/TAZ, the transcriptional effectors downstream of the Hippo pathway are key mediators of atherosclerosis at sites of perturbed blood flow and in response to proinflammatory cytokines.9 Taken together, this work suggests that in persons with the high-risk genotype, increased JCAD expression is associated with lower LATS1/2 activity and decreased YAP/TAZ phosphorylation. Subsequently, more active YAP with resultant leading to proproliferative, antiapoptotic, and proinflammatory genes endothelial dysfunction and CAD.Gromovsky et al10 demonstrated that Fads1-driven polyunsaturated fatty acid (PUFA) biosynthesis and enrichment of membrane phospholipids likely influence chronic unresolved inflammation in cardio-metabolic disease. Although underappreciated, it is thought that PUFA-derived lipid mediators play a role in the initiation and resolution of inflammation which potentially explains the observed benefit of PUFA supplementation in cardio-metabolic disease. Additionally, they demonstrated that Fads1 loss-of-function results in diminished levels of arachidonic acid-, eicosapentaenoic acid- (EPA-), and docosahexaenoic-derived proresolving lipid mediators. Moreover, although Fads1 knockdown suppressed hepatic lipogenesis, atherosclerosis and hepatic inflammation were promoted in a diet-specific manner. To better understand the role of Fads1 in mediating inflammation, using in vitro and in vivo studies, the authors showed that ASO-knockdown of Fads1 resulted in skewing towards classic activation of M1 macrophages which are generally proinflammatory in nature, as opposed to M2 macrophages which are believed to resolve inflammation. These findings potentially suggest a mechanism whereby altered expression of Fads1 in several human genetic studies may explain propensity towards dyslipidemia and CAD.Genetics: Familial HypercholesterolemiaWith the advent of PCSK (proprotein convertase subtilisin/kexin type)-9 inhibitors, significant progress has ensued regarding the management of familial hypercholesterolemia (FH). Thedrez et al11 showed that residual LDL-R (low-density lipoprotein receptor) expression in homozygous FH is a major determinant of the LDL lowering effect of Evolocumab. For example, they showed that the LDL-R expression on peripheral lymphocytes varied by the patient with those derived from FH-1/FH-2 (LDL-R defective/negative) patients displaying the lowest LDL-R expression followed by those derived from FH-1/FH-1 (LDL-R defective/defective) patients. Lymphocytes displaying higher LDL-R expression were isolated from patients presenting with the lowest levels of LDL and apolipoprotein B before and after 24 weeks of treatment with Evolocumab.Dyslipidemia: ProteinsAssociations between proteins and lipids have helped us improve our biological understanding of CVD. In abnormal concentrations, TG (triglycerides), total cholesterol, LDL, and HDL (high-density lipoprotein) all have strong associations with CAD. In addition, high TG and low HDL are key abnormalities in patients with metabolic syndrome (MetS) which comprise of obesity, insulin resistance, and type II diabetes mellitus. The central role of lipids in the pathophysiology of CAD arises from their interaction with circulating proteins. Figarska et al12 investigated this association and studied the casual effect of protein levels on lipid levels using Mendelian randomization methods. Mendelian randomization is a method which uses genetic variation to examine casual relationships from observational data. Analyzing 57 proteins from 3 population-based cohorts (Epi-Health, Prospective Study of the Vasculature in Uppsala Seniors, and Uppsala Longitudinal Study of Adult Men), they found that 42 proteins demonstrated association with different lipid fractions—35 proteins were associated with TG, 15 with total cholesterol, 9 with LDL cholesterol, and 24 with HDL cholesterol. Some of these proteins including KIM-1 (kidney injury molecule 1), TNFR (TNF [tumor necrosis factor] receptor) 1 and 2, TRAIL-R2 (TRAIL [TNF-related apoptosis-inducing ligand] receptor 2), and RETN (resistin) were associated with all 4 lipid fractions. These proteins should be studied further to identify their potential effects on lipid metabolism.Substantial risk for CVD persists even in patients treated with cholesterol-lowering medications such as statins or PCSK-9 inhibitors. Experimental models and genetic studies have shown that TRLs (triglyceride-rich lipoproteins) play a role in CAD pathogenesis. ANGPTL-3 (angiopoietin-like protein 3) is a protein secreted by the liver and is as a potent inhibitor of lipoprotein lipase which clears TRL from the circulation. Loss-of-function variants in the ANGPTL-3 have been associated with reduced cholesterol proportion within TRLs. Tikkanen et al13 showed that ANGPTL-3 deficiency is characterized by substantial reductions in VLDL particles and their remnants and lower cholesterol content. Furthermore, complete ANGPTL-3 deficiency leads to virtual absence of postprandial increase in TRL. These findings support the increasing body of evidence indicating that genetic inhibition of ANGPTL-3 causes a broad range of beneficial lipid changes without adverse compensatory metabolic effects. Additional studies are needed in this area to explore potential pharmacological interventions capitalizing on the ANGPTL-3 pathway.Dyslipidemia: Lipoprotein ACurrent European Society of Cardiology14 and American Heart Association/American College of Cardiology guidelines15 recommend screening high-risk individuals for Lp(a) (lipoprotein A) levels. High Lp(a) levels are considered a risk enhancing factor for the development of CVD. But in terms of secondary prevention, it is unclear whether high Lp(a) levels lead to recurrent CVD events. While post hoc analysis of the FOURIER trial16 showed an increased risk of CVD with increasing concentrations of Lp(a), real-world data on the risk of recurrent CVD events in patients based on Lp(a) concentration is less clear.17 Madsen et al18 studied a prospective cohort of 2527 from the Copenhagen General Population Study and showed that high concentrations of Lp(a) were associated with higher risk of recurrent CVD events in individuals from the general population with preexisting CVD. They estimated that lowering Lp(a) by 50 mg/dL in the short-term (ie, 5 years) achieved a 20% major adverse cardiovascular event risk reduction in a secondary prevention setting. Lp(a) may represent and unmet need in the secondary prevention setting.Dyslipidemia: HDLEmerging work leans towards shifting the approach from using HDL concentration alone as a predictive biomarker for CVD towards capturing both HDL composition and function to reflect CVD risk.19,20 Among a range of atheroprotective functions of HDL, one important function is the promotion of cholesterol efflux from macrophage foam cells, the first step in the reverse cholesterol transport pathway. In a prospective cohort 8267 patients, Ebtehaj et al21 showed that baseline cholesterol efflux capacity (CEC) was associated with the development of future CVD events. CEC was inversely associated with incident CVD events (odds ratio, 0.73 [95% CI, 0.62–0.86; P<0.001), and this association remained significant after adjustments for clinical covariates such as HDL-C, hsCRP, and kidney. Thus, this independent relationship of impaired CEC with incident CVD events in the general population is intriguing and requires further elucidation.Building upon the research of Ebtehaj et al, Sarzynski et al22 studied the effect of regular exercise on HDL function by examining effect of different doses of exercise on CEC and its indirect measure (HDL apolipoprotein A-I exchange). They examined the effect of 6 months of exercise training in 2 clinical trial cohorts (Studies of Targeted Risk Reduction Interventions through Defined Exercise, in individuals with Pre-Diabetes and Examination of Mechanisms of exercise-induced weight compensation, but overall found little effect of exercise training on CEC and HDL apolipoprotein A-I exchange. Only the highest doses of exercise were associated with improved radiolabeled efflux capacity. More studies are needed to determine the effects of exercise on the atheroprotective properties of HDL and associated mediating mechanisms.The MetS and CVD are clinically related. As a result, it is not surprising that HDL particle composition and function are also relevant within the former context.23 Khan et al24 characterized the relationship between HDL composition, metabolism, and function in patients with MetS examining how the HDL lipidome changed after weight loss and exercise. They studied plasma samples from patients with MetS and healthy individuals with subsets of the MetS group undergoing weight loss and weight loss plus exercise interventions. HDL lipidome composition normalized toward healthy levels in the weight loss and weight loss plus exercise groups after 12 weeks. In addition, there was a trend toward greater effect specifically in the weight loss plus exercise group. The relationship between HDL structure and function may identify novel targets for further therapies.Dyslipidemia: TGsWhile elevated serum TG levels are a risk factor for CAD, the significance of TG reduction on clinical outcomes and the pathophysiological aspects of atherosclerosis remains uncertain. ApoB-48 (Apolipoprotein B-48) is a TGRL (triglyceride-rich lipoprotein) that acts as the primary structural component of chylomicrons.25 Prior studies show that an elevated fasting serum ApoB-48 level is independently correlated with CAD.26 Currently, research about ApoB-48 levels and unstable plaque in CAD during acute coronary syndrome remains lacking. Kurihara et al27 examined the correlation between postprandial TG levels and the presence of thin-cap fibroatheromas in nonculprit CAD lesions. Among 30 patients with stable CAD, they showed that a larger increase in ApoB-48 levels from baseline correlated with the presence of thin-cap fibroatheromas in nonculprit lesions as evaluated by optical computed tomography. Their results suggest that postprandial hyperchylomicronemia may be a residual risk factor for acute coronary syndrome and thus further investigations of larger sample size and comparative groups are needed.Dyslipidemia: N-3 PUFAsEpidemiological studies from several countries suggest that increased intake of dietary long-chain polyunsaturated n-3 fatty acids, such as EPA and docosahexaenoic acid, is inversely related to the CAD risk. Indeed, emerging randomized controlled trials show that consumption of N-3 PUFAs have beneficial effects on atherosclerosis and prevent myocardial infarction (MI). The REDUCE-IT trial (Cardiovascular Risk Reduction With Icosapent Ethyl for Hypertriglyceridemia)28 revealed that 2 g of icosapent ethyl (a purified EPA ethyl ester) twice daily reduced the risk of ischemic events, including CVD death. However, detailed distribution of n-3 PUFAs in coronary plaque and their relevance in disease progression is uncertain. In an animal model, Sato et al29 showed that EPA was preferentially accumulated into thin-cap plaque in a mouse model of atherosclerosis 3 weeks after administration. Administered EPA was incorporated from the vascular lumen and existed in plaque as cholesteryl esters. The amount of EPA in atherosclerotic plaque inversely correlated with intima-media thickness of the plaque and with the presence of anti-inflammatory mediators. Administration of EPA resulted in the preferential localization of free EPA at thin-cap plaque and increased the levels of anti-inflammatory mediators associated with regression of atherosclerosis. Further research is needed to fully understand the dose and protective effect of N-3 PUFAs in atherosclerosis.Atherosclerosis: Autoimmunity and InflammationData suggest that the body's immune response to different antigens contributes to atherosclerosis. Accumulation of LDL particles in the arterial intima elicits an immune response, which causes chronic inflammation with resultant propagation of atherosclerotic plaques. LDL particles themselves are a major antigenic factor that drives an adaptive immune response.30,31 In addition, components of LDL elicit a B-cell response leading to the production of autoantibodies.32 Genetic mouse models provide important insight into the pathogenesis of atherosclerosis. One of the most widely used mouse models is the apoE (apolipoprotein E) deficient mouse which has a targeted deletion of the ApoE gene.33,34 The ApoE-deficient mouse model shows several similarities to MetS in humans, including chronic inflammation and insulin resistance. Centa et al35 designed a mouse model system that allowed for acute conversion to hyperlipidemia in adult mice. This acute transition to hyperlipidemia was accompanied by adaptive immune responses such as expansion of T lymphocyte helper cells, T follicular helper cells, and the formation of germinal centers. This immune response, in turn, led to atherosclerotic plaque development.Evidence supporting a link between CAD and type 2 immunity is emerging. It is thought that specific IgE on mast cells, including those in coronary arteries, could increase the inflammatory response to dietary glycolipids. Galactose-α-1,3-galactose (α-Gal) is a regularly consumed glycolipid found in red meat that in humans is a target of natural IgM, IgA, and IgG antibodies. The IgE antibody to α-Gal is the primary cause of α-Gal syndrome or delayed anaphylaxis to red meat.36 Wilson et al37 showed that an allergic reaction to α-Gal in mammalian meat is associated with increased atherosclerotic plaque burden as demonstrated on intravascular ultrasound imaging in patients undergoing cardiac catheterization. Increased atheroma burden and plaques with more unstable features were associated with IgE to α-Gal especially in persons <65 years old. More research is needed in this area, but IgE sensitization to α-Gal may represent a potentially modifiable risk vector for atherosclerosis.Atherosclerosis: Proteins and ReceptorsMMP (Matrix metalloprotease)-1 protease are recognized as regulators of plaque stability. The contribution of MMPs as direct signaling molecules that perpetuate the chronic proinflammatory events in atherosclerosis is understudied. PAR-1 (Protease-activated receptor 1) is a high infinity thrombin receptor in platelets and is enriched in endothelium overlying atherosclerotic plaques.38 Rana et al39 found that plasma MMP-1 correlated with coronary atherosclerotic burden as determined by angiography in patients with CAD and acute coronary syndrome undergoing cardiac catheterization (R=0.33; P=0.0015). Additionally, they showed that targeting the MMP-1-PAR-1 system with inhibitors of PAR-1 significantly decreased total atherosclerotic burden, macrophage infiltration, and plaque neo-angiogenesis in mouse models of atherosclerosis. They found that a PAR-1 inhibitor (PZ-128), currently under testing as an antithrombotic agent in the acute setting in the TRIP-PCI trial (Thrombin Receptor Inhibitory Pepducin-Percutaneous Coronary Intervention) caused a significant decrease in total atherosclerotic burden by 58% to 70% (P<0.05) and resulted in a decrease in plaque macrophage content by 54% (P<0.05) in apoE-deficient mice. This study supports further research on the effects of chronic treatment of CAD with inhibitors of the MMP-PAR-1 axis.Increased activation of the aldosterone-binding MR (mineralocorticoid receptor) is associated with increased risk of CVD events. Animal models reveal that MR activation promotes atherosclerosis and conversely pharmacological MR inhibition attenuates atherosclerosis.40 Indeed, Moss et al41 showed that endothelial MRs contribute to vascular inflammation in a sex-specific manner in a mouse model. For example, in male mice, MR regulates the expression of endothelial adhesion molecules leading to enhanced leukocyte recruitment to the vasculature and accumulation of inflammatory cells in atherosclerotic plaques, an effect not demonstrated in female mice. Compared with male mice, female mice were noted to have less plaque inflammation despite larger plaque size and similar molecular biomarker levels. This finding is intriguing and perhaps in a sex-specific manner suggests that MR inhibitor therapy might be a useful tool for attenuation of vascular inflammation in male patients with atherosclerosis.Atherosclerosis: Cardiac BiomarkersAutoantibodies targeting ApoA-I are proposed as novel cardiac biomarkers as they have been identified as a component of the inflammatory milieu associated with CVD progression. In a cohort of 5000 patients, 20% of patients tested positive for ApoA-I antibodies and their presence correlated with the development of incident CAD.42 Henson et al43 showed that lower levels of ApoA-I/IgG immune complexes are related to adverse CVD outcomes in patients with CAD independent of traditional cardiovascular risk factors. Decreased levels of ApoA-I/IgG immune complexes were associated with an increased risk of death, MI, and stroke in patients with CAD. This data highlights the importance of further analysis of the complete anti-ApoA-I antibody profile and promotes continued efforts to research the ApoA-I/IgG immune complexes in relation to atherosclerosis.Accumulating evidence suggests that leukocyte recruitment and adhesion to vascular tissue are involved in the inflammatory response in atherosclerosis. TNFSF-14 (Tumor necrosis factor superfamily 14) is a transmembrane protein found on T cells, dendritic cells, monocytes, and granulocytes which is involved in innate and adaptive immune responses.44 Hsu et al45 examined the relationship between circulating TNFSF-14 levels and cardiovascular events among stable patients with CAD with a history of percutaneous coronary intervention. They demonstrated that baseline circulating TNFSF-14 levels predicted clinical outcomes independent of age, sex, and established CVD. Higher levels of circulating TNFSF-14 were associated with a 14% increased risk of subsequent cardiovascular events during a 2-year mean follow-up period. This is the first study to demonstrate that increased TNFSF-14 levels were associated with the occurrence of CVD events in patients with stable CAD. The level of circulating TNFSF-14 could be an independent predictor of future CVD events in patients with stable CAD and warrants further research in this area.Therapies: StatinsStatin medications have long been widely used in the primary and secondary prevention of CAD due to their cholesterol-lowering effects. Recent research suggests that the beneficial effects of statins extend beyond their lipid-lowering effects and likely also protects against atherosclerosis via lipid-lowering independent mechanisms.46,47 Yu et al48 tested a mouse model of spontaneous coronary artery atherosclerosis and showed that rosuvastatin treatment protected against coronary artery atherosclerosis, platelet accumulation in atherosclerotic coronary arteries, cardiac fibrosis, and cardiomegaly. These beneficial effects occurred despite increased plasma cholesterol levels and involved the reduction of accumulated oxidized phospholipids in the walls of affected arteries as well reducing macrophage foam cell formation.The endothelium serves a crucial role in wound healing and acts as a barrier to control transit of leukocytes.49,50 An important function of statin medications is the modulation of endothelial function which is crucial to wound healing and as a barrier in the atherosclerotic process. Endothelial barrier function is impaired in atherosclerosis preceding MI. Leenders et al51 studied the effect of statins on endothelial barrier function in atherosclerotic ApoE-deficient mice after MI. Treatment with statins lowered permeability and reduced the transit of unfavorable inflammatory leukocytes into the infarcted tissue. This led to improved function of statin-treated hearts at day 21 after MI. Statin treatment improved endothelial barrier function of the infarct and blocked progressive scar formation after MI. This research shows that statin treatment after MI is pivotal for infarct healing.Therapies: EzetimibeCurrent research shows that residual risk of CVD events remains even after treatment with statins.52 LDL lowering by statins is counteracted by enhanced absorption of atherogenic lipids such as oxysterols from the small intestine.53 Ezetimibe lowers serum cholesterol, including oxysterols, by blocking cholesterol transporters in the small intestine. In a rabbit model that mimics the pathology of spontaneous atherothrombosis in patients with coronary plaque erosion, Honda et al54 showed that ezetimibe decreases thrombotic occlusion after endothelial injury and reduces circulating oxysterols. These study results support the administration of ezetimibe in addition to statin treatment as an adjunctive therapy to treat residual CVD risks in patients with CAD.Therapies: Bempedoic AcidBempedoic acid (BemA) is a novel drug that targets hepatic ATP-citrate lyase to reduce cholesterol biosynthesis. In phase II studies, BemA lowered elevated LDL cholesterol in hypercholesterolemic patients. Burke et al55 examined the ability of BemA to decrease plasma cholesterol and LDL levels in a large animal model (ie, Yucatan Miniature Pigs). Yucatan miniature pigs heterozygous or homozygous for LDL-R) deficiency generated by gene targeting were fed a high-fat, cholesterol-containing diet and orally administered placebo or BemA. They showed that in a large animal model of LDL-R deficiency and atherosclerosis, long-term treatment with BemA reduced LDL levels and attenuated the development of aortic/coronary atherosclerosis. These LDL lowering results were further demonstrated in humans in the recent large-scale CLEAR harmony trial (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen).56 Over a 52-week trial period, BemA added to maximally tolerated statin therapy led to significantly lower LDL cholesterol levels with no significant adverse effects.56 Further studies are being conducted to assess safety and outcome data during long-term exposure.Conclusions: Coronary Artery DiseaseArticles on CAD and its relevant pathophysiology remain a cornerstone of content published in Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB). Highlighting the importance of genetics in CAD, research has shown that the genetic architecture of CAD is largely determined by the combined effects of multiple common genetic variants of which, individually, contribute little to disease risk. A number of prior large, genome-wide association studies have demonstrated association between common genetic variants and CAD. With regards to lipoprotein biology, ATVB continues to explore the numerous associations between lipoproteins and CVD, such as the role of TG-rich lipoproteins in the persistence of CVD risk despite treatment with cholesterol-lowering medications such as statins or PCSK-9. HDL also remains a popular topic and in particular the measurement of CEC as a more predictive measure of CVD risk and how exercise impacts CEC. The role of the autoimmune response and effects of genetic variants in promoting inflammation and ongoing atherosclerotic processes are also explored. Also, the role of matrix metalloproteinases in promoting chronic proinflammatory signals raises the possibility of exploiting this mechanism for therapeutics. Finally, ATVB continues to push the boundaries of our understanding of current lipid-lowering therapies, demonstrating that we have yet to fully understand the numerous mechanisms through which current treatments protect against CVD.Nonstandard Abbreviations and Acronymsα-Galgalactose-α-1,3-galactoseANGPTL-3angiopoietin-like protein 3apoB-48apolipoprotein B-48ATVBArteriosclerosis, Thrombosis, and Vascular BiologyBemAbempedoic acidCADcoronary artery diseaseCECcholesterol efflux capacityCLEARCholesterol Lowering via BempedoicharmonyAcid, an ACL-Inhibiting RegimenCVDcardiovascular diseaseEPAeicosapentaenoic acidFHfamilial hypercholesterolemiaHDLhigh-density lipoproteinKIM-1kidney injury molecule 1LDLlow-density lipoproteinLp (a)lipoprotein AMetSmetabolic syndromeMImyocardial infarctionMMPsmatrix metalloprotease-1MRmineralocorticoid receptorPAR-1protease-activated receptor 1PCSK-9proprotein convertase subtilisin/kexin type 9PUFApolyunsaturated fatty acidREDUCE-ITCardiovascular Risk Reduction With Icosapent Ethyl for HypertriglyceridemiaRETNresistinTGtriglyceridesTGRLtriglyceride-rich lipoproteinTNFRTNF (tumor necrosis factor) receptorTNFSF-14tu