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Abstract
Loss-of-function variants in PCSK9 (proprotein convertase subtilisin-kexin type 9) are associated with lower lifetime risk of atherosclerotic cardiovascular disease) events. Confirmation of these genetic observations in large, prospective clinical trials in participants with atherosclerotic cardiovascular disease has provided guidance on risk stratification and enhanced our knowledge on hitherto unresolved and contentious issues concerning the efficacy and safety of markedly lowering LDL-C (low-density lipoprotein cholesterol). PCSK9 has a broad repertoire of molecular effects. Furthermore, clinical trials with PCSK9 inhibitors demonstrate that reductions in atherosclerotic cardiovascular disease events are more effective in patients with recent myocardial infarction, multiple myocardial infarctions, multivessel coronary artery disease, and lower extremity arterial disease. The potent LDL-C lowering efficacy of PCSK9 inhibitors provides the opportunity for more aggressive LDL-lowering strategies in high-risk patients with atherosclerotic cardiovascular disease and supports the notion that there is no lower limit for LDL-C. Aggressive LDL-C lowering with fully human PCSK9 monoclonal antibodies has been associated by a safety profile superior to that of other classes of LDL-lowering agents. These clinical trials provide evidence that LDL lowering with PCSK9 inhibitors is an effective therapy for lowering cardiovascular events in high-risk patients with LDL-C levels ≥70 mg/dL on maximally tolerated oral therapies, including statins and ezetimibe.
Numerous prospective cohort studies, natural randomization (also called Mendelian randomization) studies, and randomized clinical trials (RCTs) confirm a causal relationship between absolute exposure of vessels to LDL-C (low-density lipoprotein cholesterol) and the risk of atherosclerotic cardiovascular disease (ASCVD) events.1 LDL-C is lowered by reduced intake of total calories in obese individuals, by reduced intake of saturated fat, and by several classes of cholesterol-lowering therapies.2,3 Of the multiple cholesterol-lowering therapies, statins (HMG-CoA [3-hydroxy 3-methyl glutaryl coenzyme A] reductase inhibitors) constitute the most extensively studied therapeutic class for lowering LDL-C and ASCVD events.4 However, maximally tolerated statin therapy may be inadequate to achieve the LDL-C lowering needed to reduce ASCVD risk in certain patients.5 Furthermore, incremental lowering of LDL-C by 24% with ezetimibe in statin-treated patients after an acute coronary syndrome (ACS) reduced the risk of recurrent cardiovascular events to 32.7% in the simvastatin-ezetimibe group as compared to 34.7% in the simvastatin-monotherapy group, corresponding to an absolute risk reduction (ARR) of 2% (hazard ratio [HR], 0.936) after 7 years of treatment.6 The introduction of PCSK9 (proprotein convertase subtilisin kexin type 9) inhibitors has opened new options for patients at high risk to achieve unprecedented low LDL-C levels for further residual risk reduction.7 These data have emerged from large-scale clinical outcome trials with monoclonal antibodies directed against PCSK9.8–13
In this state-of-the-art review, we review (1) the proatherogenic mechanisms of PCSK9 in experimental models and human studies; (2) the importance of human genetics in linking PCSK9 mutations to altered ASCVD risk; and (3) clinical trial data with PCSK9 inhibitors in patients with cardiovascular disease and other high-risk individuals.
PCSK9 and Lipoprotein Metabolism
PCSK9 is a zymogen that after autocatalysis acts both intracellularly and extracellularly to ultimately inhibit the recycling of the LDLR (LDL receptor), primarily in the liver.14–18 The LDLR normally clusters within clathrin-coated pits at the hepatocyte surface and binds LDL particles via the receptor-binding region of circulating apoB, initiating receptor-mediated endocytosis, which also engages LDLAP1 (LDLR adaptor protein 1 or ARH) as a chaperone.15 Within late endosomes and lysosomes, as the pH increases, the LDL particle is degraded, whereas the receptor separates and recycles back to the cell surface, where receptor-mediated endocytosis begins anew and is repeated hundreds of times over the receptor’s lifetime.15 When low intracellular levels of cholesterol are sensed, SREBP-2 (sterol regulatory element-binding protein-2) is upregulated, initiating transcription of both the receptor and the precursor Pro-PCSK9.16,17 After autocatalytic cleavage within the endoplasmic reticulum, the prodomain is released but then reamalgamates with PCSK9 and in so doing activates it.17 An additional check at the Golgi stage is provided by furin, which to a variable degree cleaves and inactivates PCSK9 before it reaches the cell surface.17 Intracellular PCSK9 can interact with some LDLRs before they are even secreted, directing them towards an abbreviated route towards lysosomal degradation.17 Once it is secreted into plasma, PCSK9 serves as one of many potential ligands for the LDLR.7 Furthermore, about half of circulating PCSK9 is bound to either LDL or the related Lp(a) (lipoprotein [a]) particle. After endocytosis, if PCSK9 is entwined with the LDL-LDLR complex, the receptor fails to exit the lysosome, becomes degraded with its other contents, and fails to recycle.16 The huge molar excess of receptors to PCSK9 means that only rarely can an individual PSCK9 molecule insinuate itself into the LDLR-LDL complex; most often PCSK9 is absent, allowing unimpeded repeated recycling of the receptor.7 There is also a suggestion that intracellular PCSK9 may itself sometimes be recycled so that a single PCSK9 molecule might contribute multiple times to receptor degradation.7
PCSK9 and Atherosclerosis
The effects of PCSK9 on atherosclerosis include global effects on LDL metabolism, local effects on LDL metabolism within an atherosclerotic lesion, and effects on other atherogenic mechanisms such as inflammation (Figure 1). Atherosclerosis is a chronic inflammatory disease of the arterial wall that is characterized by endothelial cell activation, accumulation of mononuclear cells, and vascular smooth muscle cells (VSMCs). Atherosclerotic lesions are site-specific and develop preferentially in regions of low wall shear stress.19 Low wall shear stress augments human and mouse endothelial cell and smooth muscle cell PCSK9 expression, which is mediated by NADPH oxidase–induced reactive oxygen species production.20 The associations between PCSK9 expression and mononuclear cell chemotaxis and adhesion in low wall shear stress regions suggest an association between PCSK9 and inflammation.
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