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Lipoprotein(a) (Lp[a]) is a low-density lipoprotein (LDL) cholesterol-like particle, the concentration of which is mainly determined by genetics, in different populations Significant differences.
Epidemiological and observational studies have shown that elevated lipoprotein(a) is associated with atherosclerotic cardiovascular disease (ASCVD) and calcified aortic stenosis (AS). ), there is a potential causal relationship. Although there is no universally accepted absolute risk threshold, approximately 20%-25% of the global population has lipoprotein(a) levels of 50 mg/dL or higher. According to the European Arteriosclerosis Society (EAS), cardiovascular risk increases despite optimization of traditional risk factors.
JAMA Cardiology recently published a review reviewing the biology and pathophysiology of lipoprotein(a), data on existing therapies, and new therapies under development. Let’s take a look together!
Structure and pathogenicity of Lp(a)
Lp(a) The core component is similar to LDL, consisting of triglycerides and cholesteryl esters, and the protein structure includes a single copy of apolipoprotein B-100 (apoB), which is covalently and non-covalently linked to an apolipoprotein (a) (apo [a]) Particle binding.
Lp(a)structure
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Lp(a) promotes ASCVD and calcific aortic stenosis (AS) through 4 mechanisms: vascular inflammation, atherosclerosis, calcification, and thrombosis.
LDL(a) can promote the formation of atherosclerotic plaques. Lp(a), the only apoB-containing lipoprotein, carries oxidized phospholipids, and when Lp(a) concentrations are high, these phospholipids are delivered to injured blood vessels and aortic valve leaflets, leading to endothelial dysfunction, lipid accumulation, calcification and inflammation. The Lp(a) loop is thought to attach to fibrin and promote thrombus formation.
Therefore, Lp(a) may represent the missing link between atherosclerosis, AS and thrombosis.
Evidence that Lp(a) is associated with cardiovascular disease
from pathophysiological, Strong evidence from observational and genetic studies suggests a possible causal relationship between high Lp(a) levels, atherosclerotic cardiovascular disease, and calcified aortic stenosis. More evidence suggests that elevated lipoprotein(a) levels are associated with residual cardiovascular risk despite traditional risk factor optimization, including lowering LDL cholesterol.
These findings led to the lipoprotein(a) hypothesis that lowering Lp(a) leads to cardiac Reduced vascular risk reinforces the search for lipoprotein(a)-lowering therapies. Lifestyle changes, statins, and ezetimibe have no effect on lowering Lp(a); proprotein convertase subtilase type 9 inhibitors (PCSK9 inhibitors) have little effect on lowering lipoprotein(a); niacin Adverse effects and cardiovascular benefits of drug therapy such as mipomersen and mipomersen are unclear; regular lipoprotein dialysis is not realistic. These are major challenges to currently available therapies.
However, emerging nucleic acid-based therapies such as antisense oligonucleotide pelacarsen and small interfering RNA olpasiran , has attracted much attention due to its powerful Lp(a)-lowering effect. In future trials, it will be important to assess new-onset diabetes in patients who achieve very low lipoprotein(a) levels.
Lp(a) associated with cardiovascular disease p>
Laboratory detection of Lp(a)
Each Lp(a) particle consists of 1 mole of apo(a) ) and 1 molar apoB composition, regardless of the size of apo(a), measuring molarity can circumvent the heterogeneity of mass measurements.
Lp(a) plasma levels are 90% genetically determined, inversely proportional to the KIV2 repeat number, and remain stable throughout an individual’s lifetime.
Lp(a) levels had a direct linear relationship with ASCVD risk, rather than a threshold effect that caused a sharp rise in risk at the highest concentrations.
Establish a general risk profileChallenges for entry points include:
Differences in measurement units and techniques; p>
Heterogeneity of values reported in different studies;
Different ethnic groups Significant differences in Lp(a) concentrations in patients with comorbidities (eg, chronic kidney disease, liver disease, and hypothyroidism).
Timing to measure Lp(a) concentrations
The panel disagrees on the indication for measuring Lp(a) concentrations. Currently, the European Society of Cardiology/European Society of Atherosclerosis Guidelines, the Canadian Society of Cardiovascular Guidelines, and the Indian Expert Consensus Guidelines all support universal routine measurement to improve cardiovascular risk classification.
The 2021 European Guidelines for the Prevention of Cardiovascular Diseases acknowledge that the reclassification potential of Lp(a) remains limited and further research is needed. Both guidelines and expert statements encourage Lp(a) measurements in individuals with a family history of premature ASCVD. Although cascade screening of persons with elevated Lp(a) is not widely supported, systematic screening from patients with a history of high Lp(a) and familial hypercholesterolemia may be useful in identifying Lp(a) ) raised relatives are valid.
Effective treatments for elevated Lp(a)
FOURIER trial and ODYSSEY OUTCOMES The two studies of the trial showed that lowering Lp(a) was an independent factor in reducing MACE, mainly benefiting patients with higher baseline levels and/or significantly lower Lp(a). Although PCSK9i reduced Lp(a) by approximately 15% to 25% from baseline, it is difficult to quantify the reduction in cardiovascular events attributable to Lp(a) reduction, as these drugs also reduced LDL-C by 50% to 25% 60%.
A post hoc analysis of the ODYSSEY OUTCOMES trial showed that LDL-C was below 70 mg/dL only when Lp(a) levels were above the median (13.7 mg/dL). Only patients with dL had a 30% reduction in the risk of MACE associated with alirocumab.
These results suggest that decreased Lp(a) may contribute to increased cardiovascular benefit, or that high Lp(a) identifies plaques more susceptible to PCSK9i-stabilizing properties of patients. Overall, these drugs are well tolerated and may rarely cause mild local injection site reactions without prompting excessive drug discontinuation.
Ongoing clinical study of Lp(a)
Elevated Lp(a)New treatments and future prospects
< Novel therapeutic approaches for elevated span>Lp(a) target the messenger RNA (mRNA) product of the LPA gene, including antisense oligonucleotides (ASOs) and small interfering RNA (siRNA) drugs. ASOs are single-stranded nucleic acid sequences that promote RNase H-mediated mRNA destruction. siRNAs are double-stranded molecules that lead to the destruction of target mRNAs through RNA-induced silencing complexes.
A more comprehensive understanding of the physiology, metabolism and pathogenicity of Lp(a) is desirable, Because Lp(a)-lowering therapies are being developed and may be clinically available in the near future. Extensive standardization of commercial Lp(a) immunoassays will help to interpret the results of future studies and establish therapeutic thresholds.
Clinical trials evaluating the clinical benefit of Lp(a) reduction in ASCVD and AS are ongoing, with siRNA and ASO therapy is leading the way.
Conclusion
Epidemiological and Genetic Studies suggested a potential causal relationship between elevated lipoprotein(a) levels, atherosclerotic cardiovascular disease, and aortic valve stenosis.
Emerging nucleic acid-based therapeutics have strong lipoprotein(a)-lowering effects and are relatively safe. Phase 3 trials will determine whether they improve cardiovascular disease outcomes.
Source:
Lipoprotein(a) and its Significance in Cardiovascular Disease: A Review. JAMA Cardiol.2022 May 18. doi: 10.1001/jamacardio.2022.0987.
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