Atherosclerosis is initiated by functional changes in the endothelium accompanied by accumulation, oxidation, and glycation of LDL-cholesterol in the inner layer of the arterial wall and continues ...with the expression of adhesion molecules and release of chemoattractants. PCSK9 is a proprotein convertase that increases circulating LDL levels by directing hepatic LDL receptors into lysosomes for degradation. The effects of PCSK9 on hepatic LDL receptors and contribution to atherosclerosis via the induction of hyperlipidemia are well defined. Monoclonal PCSK9 antibodies that block the effects of PCSK9 on LDL receptors demonstrated beneficial results in cardiovascular outcome trials. In recent years, extrahepatic functions of PCSK9, particularly its direct effects on atherosclerotic plaques have received increasing attention. Experimental trials have revealed that PCSK9 plays a significant role in every step of atherosclerotic plaque formation. It contributes to foam cell formation by increasing the uptake of LDL by macrophages via scavenger receptors and inhibiting cholesterol efflux from macrophages. It induces the expression of inflammatory cytokines, adhesion molecules, and chemoattractants, thereby increasing monocyte recruitment, inflammatory cell adhesion, and inflammation at the atherosclerotic vascular wall. Moreover, low shear stress is associated with increased PCSK9 expression. PCSK9 may induce endothelial cell apoptosis and autophagy and stimulate the differentiation of smooth muscle cells from the contractile phenotype to synthetic phenotype. Increasing evidence indicates that PCSK9 is a molecular target in the development of novel approaches toward the prevention and treatment of atherosclerosis. This review focuses on the molecular roles of PCSK9 in atherosclerotic plaque formation.
Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of morbidity and mortality despite excellent pharmacological and revascularization approaches. Low-density lipoproteins (LDL) ...are undoubtedly the most significant biochemical variables associated with atheroma, however, compelling data identify inflammation as critical for the maintenance of the atherosclerotic process, underlying some of the most feared vascular complications. Although its causal role is questionable, high-sensitivity C-reactive protein (hs-CRP) represents a major biomarker of inflammation and associated risk in CVD. While statin-associated reduced risk may be related to the lowering of both LDL-C and hs-CRP, PCSK9 inhibitors leading to dramatic LDL-C reductions do no alter hs-CRP levels. On the other hand, hs-CRP levels identify groups of patients with a high risk of CV disease achieving better ASCVD prevention in response to PCSK9 inhibition. In the FOURIER study, even in patients with extremely low levels of LDL-C, there was a stepwise risk increment according to the values of hs-CRP: +9% (<1 mg/L), +10.8% (1–3 mg/L) and +13.1% (>3 mg/L). Likewise, in the SPIRE-1 and -2 studies, bococizumab patients with hs-CRP> 3 mg/L had a 60% greater risk of future CV events. Most of the patients enrolled in the PCSK9 trials were on maximally tolerated statin therapy at baseline, and an elevated hs-CRP may reflect residual inflammatory risk after standard LDL-C lowering therapy. Moreover, data on changes in inflammation markers in carriers of PCSK9 loss-of-function mutations are scanty and not conclusive, thus, evidence from the effects of anti-inflammatory molecules on PCSK9 levels might help unravel this hitherto complex tangle.
•PCSK9 monoclonal antibodies dramatically reduce LDL-C, but not hs-CRP.•The two-dose regimen of inclisiran (300 mg), a siRNA direct against PCSK9, reduced hs-CRP by 16.7%.•hs-CRP levels identify ASCVD patients who better respond to PCSK9 monoclonal antibodies.•In the Anitschkow study, evolocumab modestly reduced Lp(a) with no changes of hs-CRP or arterial inflammation.
Abstract
Recent advances in human genetics, together with a large body of epidemiologic, preclinical, and clinical trial results, provide strong support for a causal association between triglycerides ...(TG), TG-rich lipoproteins (TRL), and TRL remnants, and increased risk of myocardial infarction, ischaemic stroke, and aortic valve stenosis. These data also indicate that TRL and their remnants may contribute significantly to residual cardiovascular risk in patients on optimized low-density lipoprotein (LDL)-lowering therapy. This statement critically appraises current understanding of the structure, function, and metabolism of TRL, and their pathophysiological role in atherosclerotic cardiovascular disease (ASCVD). Key points are (i) a working definition of normo- and hypertriglyceridaemic states and their relation to risk of ASCVD, (ii) a conceptual framework for the generation of remnants due to dysregulation of TRL production, lipolysis, and remodelling, as well as clearance of remnant lipoproteins from the circulation, (iii) the pleiotropic proatherogenic actions of TRL and remnants at the arterial wall, (iv) challenges in defining, quantitating, and assessing the atherogenic properties of remnant particles, and (v) exploration of the relative atherogenicity of TRL and remnants compared to LDL. Assessment of these issues provides a foundation for evaluating approaches to effectively reduce levels of TRL and remnants by targeting either production, lipolysis, or hepatic clearance, or a combination of these mechanisms. This consensus statement updates current understanding in an integrated manner, thereby providing a platform for new therapeutic paradigms targeting TRL and their remnants, with the aim of reducing the risk of ASCVD.
Graphical Abstract
Formation of triglyceride-rich lipoprotein remnants and their role in atherogenesis. Metabolic scheme for the generation and clearance of triglyceride-rich lipoprotein remnant particles (A). In hypertriglyceridaemia, overproduction and inefficient lipolysis of both very low-density lipoprotein and chylomicrons lead to increased remnant formation. Triglyceride-rich lipoprotein remnants contribute to the initiation and progression of atherosclerotic lesions (B). Particle retention in the subendothelial space is followed by inflammation, cholesterol deposition, and macrophage foam cell formation.
Abstract
This 2022 European Atherosclerosis Society lipoprotein(a) Lp(a) consensus statement updates evidence for the role of Lp(a) in atherosclerotic cardiovascular disease (ASCVD) and aortic valve ...stenosis, provides clinical guidance for testing and treating elevated Lp(a) levels, and considers its inclusion in global risk estimation. Epidemiologic and genetic studies involving hundreds of thousands of individuals strongly support a causal and continuous association between Lp(a) concentration and cardiovascular outcomes in different ethnicities; elevated Lp(a) is a risk factor even at very low levels of low-density lipoprotein cholesterol. High Lp(a) is associated with both microcalcification and macrocalcification of the aortic valve. Current findings do not support Lp(a) as a risk factor for venous thrombotic events and impaired fibrinolysis. Very low Lp(a) levels may associate with increased risk of diabetes mellitus meriting further study. Lp(a) has pro-inflammatory and pro-atherosclerotic properties, which may partly relate to the oxidized phospholipids carried by Lp(a). This panel recommends testing Lp(a) concentration at least once in adults; cascade testing has potential value in familial hypercholesterolaemia, or with family or personal history of (very) high Lp(a) or premature ASCVD. Without specific Lp(a)-lowering therapies, early intensive risk factor management is recommended, targeted according to global cardiovascular risk and Lp(a) level. Lipoprotein apheresis is an option for very high Lp(a) with progressive cardiovascular disease despite optimal management of risk factors. In conclusion, this statement reinforces evidence for Lp(a) as a causal risk factor for cardiovascular outcomes. Trials of specific Lp(a)-lowering treatments are critical to confirm clinical benefit for cardiovascular disease and aortic valve stenosis.
Abstract
Cardiovascular disease is the leading cause of death in women and men globally, with most due to atherosclerotic cardiovascular disease (ASCVD). Despite progress during the last 30 years, ...ASCVD mortality is now increasing, with the fastest relative increase in middle-aged women. Missed or delayed diagnosis and undertreatment do not fully explain this burden of disease. Sex-specific factors, such as hypertensive disorders of pregnancy, premature menopause (especially primary ovarian insufficiency), and polycystic ovary syndrome are also relevant, with good evidence that these are associated with greater cardiovascular risk. This position statement from the European Atherosclerosis Society focuses on these factors, as well as sex-specific effects on lipids, including lipoprotein(a), over the life course in women which impact ASCVD risk. Women are also disproportionately impacted (in relative terms) by diabetes, chronic kidney disease, and auto-immune inflammatory disease. All these effects are compounded by sociocultural components related to gender. This panel stresses the need to identify and treat modifiable cardiovascular risk factors earlier in women, especially for those at risk due to sex-specific conditions, to reduce the unacceptably high burden of ASCVD in women.
Graphical Abstract
Graphical Abstract
Key messages from this EAS position statement. In addition to sex-specific risk factors, women are disproportionately impacted by some lifestyle factors which increase cardiometabolic risk, and atherosclerotic cardiovascular disease presentation differs from that in men. Action is needed to change the perception of risk, assess and treat elevated risk factors early, and address gaps in the management and understanding of cardiovascular risk in women. CAD, coronary artery disease; CV, cardiovascular; FH, familial hypercholesterolaemia; Lp(a), lipoprotein(a).
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