Our findings provide new insights into LDL biology and show that targeting PCSK9 using heparan sulfate mimetics is a potential therapeutic strategy in coronary artery disease.PCSK9 interacts with LDL receptor, causing its degradation, and consequently reduces the clearance of LDL.Here, Gustafsen et al. show that PCSK9 interacts with heparan sulfate proteoglycans and this binding favors LDLR degradation.
The secondary end points are (1) MACE developed from visit 1 to visit 2 (day 30); (2) MACE developed from visit 2 (day 30) to visit 5 (day 730); (3) treatment rate by lipid-lowering therapies (any statin or intensive, PCSK9 inhibitor, fibrates and ezetimibe); (4) incidence of events by the addition of the following outcomes to the primary end point: coronary revascularisation due to myocardial ischaemia, revascularisation other than coronary artery, inpatient treatment for occurrence or exacerbation of heart failure, transient ischaemic attack, acute arterial occlusion, central retinal artery occlusion and other adverse events prolonging or requiring hospitalisation and (5) proportion of subjects achieving target lipid levels.
The GLAGOV trial compared the effect of the PCSK9 inhibitor, evolocumab, and placebo on progression of coronary atherosclerosis in patients treated with at least moderate intensity statin therapy.
In a randomized, double-blind, placebo-controlled study, 968 patients with symptomatic coronary artery disease were treated with statins alone or combined with the PCSK9 inhibitor, evolocumab, and assessed for change in percent, total volume, and regression of coronary atheroma.
Increased sortilin and its independent effect on circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) in statin-naive patients with coronary artery disease.
Those with variants leading to reduced PCSK9 have lower LDL-cholesterol levels and a reduced risk of coronary heart disease, and this has led to the development of various strategies aimed at reducing circulating PCSK9.
We confirmed previously observed significant associations between coronary artery disease and low-frequency missense variants in the genes LPA and PCSK9.
In statin treated asymptomatic FH patients, elevated PCSK9 and Lp(a) levels are independently associated with the presence and severity of CAC, a good predictor of coronary artery disease.
In contrast, the regulatory effects of other GWAS risk SNPs were tissue-specific; abdominal fat emerged as an important gene-regulatory site for blood lipids, such as for the low-density lipoprotein cholesterol and coronary artery disease risk gene PCSK9 STARNET provides insights into gene-regulatory mechanisms for CMD risk loci, facilitating their translation into opportunities for diagnosis, therapy, and prevention.
It is an autosomal dominant disease, caused by variants in Ldlr, ApoB or Pcsk9, which results in high levels of LDL-cholesterol (LDL-C) leading to early coronary heart disease.
Gain-of-function PCSK9 mutations are associated with high low-density lipoprotein cholesterol (LDL-C) levels and increased risk of coronary artery disease, while loss-of-function variants result in low LDL-C and decreased risk of cardiovascular events.
The associations between proprotein convertase subtilisin/kexin type 9E670G polymorphism and the risk of coronary artery disease and serum lipid levels: a meta-analysis.
Recent evidence indicates that PCSK9 also modulates the metabolism of triglyceride-rich apolipoprotein B (apoB) lipoproteins, another important coronary heart disease risk factor.
Loss-of-function mutations in PCSK9 cause familial hypobetalipoproteinemia, which appears to lower risk for coronary artery disease and has no adverse sequelae.
This review aims to discuss the impact of natural mutations in the PCSK9 gene on cholesterol metabolism and thus coronary artery disease, as well as molecular mechanisms and therapeutic strategies for PCSK9 inhibition.
Loss-of-function mutations in PCSK9 result in significantly decreased LDL-cholesterol levels and a disproportionately large reduction in coronary heart disease risk by reducing the exposure to LDL-cholesterol throughout life.
Accordingly, PCSK9 could represent a safe and effective pharmacological target to increase clearance of LDL-C and to reduce the risk of coronary heart disease.
Familial Hypercholesterolaemia (FH) is an autosomal dominant disease, caused by mutations in LDLR, APOB or PCSK9, which results in high levels of LDL-cholesterol (LDL-C) leading to early coronary heart disease.
Since the loss-of-function mutations in humans are associated with protection against coronary heart disease, and with no apparent deleterious effects, PCSK9 inhibition is becoming attractive as a new strategy for lowering LDL cholesterol (LDL-C) levels, particularly in combination with statins.