Lipoprotein-associated atherosclerosis is the leading cause of death and disability in cardiovascular and cerebrovascular diseases. In addition to dyslipidemia, inflammation and oxidative stress are also important mechanisms for the pathophysiology and development of atherosclerosis.
However, many patients without traditional risk factors still have cardiovascular and cerebrovascular disease events [1], and the incidence of cardiovascular and cerebrovascular diseases is getting younger and younger, and the traditional testing program has limited risk assessment capabilities for cardiovascular and cerebrovascular adverse events, so there is an urgent need for better indicators to predict and monitor cardiovascular and cerebrovascular diseases in the clinic and laboratory. A large number of studies have confirmed that lipoprotein-associated phospholipase A2 (Lp-PLA2) is a specific marker of vascular endothelial inflammation, an independent risk assessment index for cardiovascular and cerebrovascular diseases, and can make up for the shortcomings of traditional testing projects.
I. Overview of lipoprotein-related phospholipase A2
Atherosclerosis (AS) is the main cause and pathological basis of cardiovascular and cerebrovascular diseases, 1976 R · Ross proposed the theory of injury response, arguing that atherosclerosis is an inflammatory disease, and that inflammatory cells and the products they release are the most important factors in pro-atherosclerosis. Inflammatory mediators are involved in atherosclerotic plaque formation, progression, and eventual rupture [2].
The "Chinese Expert Consensus on Primary Prevention of Atherosclerotic Diseases" proposes the concept of primary prevention of cardiovascular and cerebrovascular diseases, that is, effectively controlling the causative factors in the early pathological stage before the appearance of symptoms will delay or prevent the development of asymptomatic atherosclerosis into clinical cardiovascular diseases. Traditional risk factors are deficient, and new biomarkers in the clinic and laboratory are urgently needed to predict and monitor cardiovascular disease.
Lp-PLA2 is a recently discovered biological marker with a strong pro-inflammatory effect, also known as platelet activating factor acetyl hydrolase, secreted by macrophages, T cells, and mast cells in the lining of blood vessels. Its main role is to hydrolyze the oxidized lecithin on LDL, generate pro-inflammatory substances hemolytic lecithin and oxidize free fatty acids, and promote the formation of atherosclerosis.
1. Lp-PLA2 is involved in the formation of atherosclerotic plaques
Lp-PLA2 is a marker of vascular-specific inflammation that expresses significant upregulation in atherosclerotic plaques. Lp-PLA2 hydrolyzed and oxidized phospholipids in low-density lipoproteins (OX-LDL) to generate lipid pro-inflammatory substances such as hemolytic lecithin and oxidized free fatty acids, resulting in a variety of atherosclerotic effects, including endothelial cell apoptosis and abnormal endothelial function, stimulating the production of adhesion factors and cytokines. These substances can further produce self-reinforcing cycles by chemotaxis inflammatory cells, producing more pro-inflammatory substances[1].
Figure 1. Lp-PLA2 is involved in the process of plaque formation
2. Lp-PLA2 induces an increase in the instability of atherosclerotic plaques
Lp-PLA2 can induce an increase in plaque instability, making the plaque fragile and ruptured, leading to thrombosis and ischemic stroke.
In addition, high levels of Lp-PLA2 indicate increased instability of atherosclerotic plaques, more prone to rupture, and an increased risk of cardiovascular and cerebrovascular malignant events.
Figure 2. Schematic diagram of Lp-PLA2 and plaque stability
3. Lp-PLA2 opens up a new way for atherosclerosis treatment
The preliminary study in Advances in the Study of Atherosclerotic Unstable Plaques found that by inhibiting phospholipase A2, the deposition of lipids in the vascular wall and the infiltration of macrophages could be reduced. It is of great significance for the prediction, treatment and prognosis of cardiovascular and cerebrovascular embolism diseases.
Second, the clinical application of lipoprotein-related phospholipase A2
(1) Recommendations for international and Chinese guidelines
The international recognition and attention to Lp-PLA2 is gradually increasing, and it is recommended that Lp-PLA2 be used for screening, differential diagnosis, risk assessment, treatment and prognosis and other aspects of cardiovascular and cerebrovascular diseases.
Table 2: Recommendations for international Lp-PLA2 guidelines
Based on the above research evidence and the recommendations of international guidelines, China launched the "Chinese Expert Recommendations for the Clinical Application of Lipoprotein-associated Phospholipase A2" in 2015, which pointed out that Lp-PLA2 is an independent risk factor for vascular endothelial inflammation and is also a new indicator for the detection of vascular endothelial inflammation.
(2) The application value of Lp-PLA2 in risk prediction
The American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) 2010 Cardiovascular Risk Assessment Guidelines for Asymptomatic Adults recommend that Lp-PLA2 testing in moderate-risk asymptomatic adults may be considered to further assess the risk of cardiovascular events (Recommended Level II.b) [3].
The 2011 AHA/AFC Stroke Primary Prevention Guidelines recommend that testing for inflammatory markers such as hs-CRP or Lp-PLA2 identify patients at high risk of stroke (recommended level II.b, evidence level B) [4].
The U.S. AACE clearly states Lp-PLA2 levels:
< 200 ng/mL for normal or low-risk populations;
≥ 200 ng/mL and < 223 ng/mL is a moderate risk group;
≥ 223ng/mL is a high-risk group
More than 25 prospective epidemiological studies have investigated the association between Lp-PLA2 and long-term cardiovascular events: high levels of Lp-PLA2 in asymptomatic high-risk populations have twice the risk of cardiovascular and cerebrovascular disease as low-level populations, and can be used as a risk predictor of cardiovascular events [5].
Figure 3. Risk prediction of Lp-PLA2 and end-event cardiovascular disease
Lp-PLA2 has been significantly associated with the risk of cardiovascular death, myocardial infarction, coronary reconstruction, UA hospitalization, or stroke complex end-time events, and elevated Lp-PLA2 levels in stable cardiovascular and cerebrovascular diseases are significant predictors of nonfatal adverse cardiovascular disease independent of traditional clinical risk factors and hs-CRP [6].
(3) The application value of Lp-PLA2 in prognosis assessment
The European Society of Cardiology's 2012 Clinical Practice Guidelines for the Prevention of Cardiovascular Disease recommend that Lp-PLA2 be detected in patients at high risk of recurrence of acute atherosclerotic thrombotic events to further assess the risk of recurrence (Recommendation Ii.b, Evidence Level B).
Figure 4. The Lancet magazine published a meta-analysis of 32 prospective Lp-PLA2 and coronary heart disease studies
In 2010, The Lancet published the results of a meta-analysis of 32 prospective studies of Lp-PLA2 and coronary heart disease, showing that Lp-PLA2 levels were linearly logarithmically correlated with coronary heart disease and vascular death. After adjusting for routine risk factors, the risk ratios of Lp-PLA2 to coronary heart disease, ischemic stroke, vascular death, and nonvascular death were 1.11, 1.14, 1.13, and 1.10, respectively[7].
(4) The application value of Lp-PLA2 in guiding treatment
Statins have a good lipid-lowering effect and are commonly used drugs for cardiovascular and cerebrovascular diseases. Studies have shown that after 12 weeks of treatment, the Lp-PLA2 content decreased by 22.1% and 7.8% in the statin treatment group and the placebo group, respectively, with a significant difference (P<0.001). Dynamic monitoring of Lp-PLA2 levels facilitates the evaluation of the effectiveness of statins in lipid-lowering therapy [8].
Third, Lp-PLA2 is recommended to test the population
The Chinese Expert Recommendation on the Clinical Application of Lipoprotein-Associated Phospholipase A2 recommends that Lp-PLA2 levels be detected in the following populations to predict the risk of cardiovascular events [9]:
(1) Screening of asymptomatic high-risk groups: especially in people at medium risk of atherosclerotic cardiovascular disease, Lp-PLA2 can be detected on the basis of traditional risk factor assessment to further assess the risk of future cardiovascular disease.
(2) In patients who have received statin therapy and have good cholesterol levels, Lp-PLA2 levels can improve the predictive value of cardiovascular disease event risk.
(3) In patients with acute thrombotic events, including ACS and atherosclerotic ischemic stroke, Lp-PLA2 contributes to long-term risk assessment, such as combined testing with hs-CRP to improve predictive value [10].
Figure 5. Lp-PLA2 is recommended to examine the population
IV. Influencing Factors of Lp-PLA2[1,11]
(1) Because Lp-PLA2 is subject to very small physiological variations and is basically not affected by receptor position changes and daily activities, there is no need to fix the position and time when collecting specimens, but strenuous exercise should be avoided 2 h before measurement.
(2) The serum Lp-PLA2 level of women is lower than that of men, which may be related to estrogen, and women who are receiving estrogen therapy have a serum Lp-PLA2 quality and activity level that is about 10% lower than that of men, but is still in the normal range.
(3) Lp-PLA2 levels will be affected during treatment with related drugs (such as statins).
Advantages of Lp-PLA2 in predicting cardiovascular disease
Lp-PLA2 has an irreplaceable advantage in cardiovascular disease prediction and plays an important role in predicting the occurrence and development of cardiovascular disease at an early stage.
Table 3. Advantages of Lp-PLA2 in predicting cardiovascular disease
Sixth, chemiluminescence detection advantages
New Industry Biology is currently the manufacturer with the most detectable items among chemiluminescent manufacturers. Shenzhen Nanshan Hospital compared the performance indicators of Shenzhen New Industry Biological Lp-PLA2 Detection Reagent (Luminescence Method) with the PLAC ELISA method of DiaDexus, the most commonly used in clinical practice, and published the comparison results in the authoritative journal CCA. For the detection of 122 clinical samples, the new industrial chemiluminescence method had a significant correlation with the DiaDexus test results (R2=0.979)[12]; compared with the PLAC ELISA method, the new industrial chemiluminescence method detected faster and the first result could be produced in 17 minutes; the detection range was wider, the detection sensitivity was higher, and it was better than other methods such as enzyme immunity, which fully met the clinical needs.
Figure 6.Correlation analysis between new industry biology and DiaDexus ELISA[12]
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The emergency department program was born
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Small footprint: MAGLUMI® X3 occupies a small footprint of less than 0.68m2, solving the problem of limited space in the outpatient/emergency room and emergency room;
Fast detection speed: MAGLUMI® X3 detection speed of 200T/H, the leading detection speed in desktop;
Supports multiple specimen types: serum, plasma;
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New Industry Bio provides the perfect solution for cardiovascular and myocardial marker detection
Suitable for the emergency department fully automated chemiluminescence analysis system, after the patient specimen has been centrifuged in the blood routine, it can accurately, quantitatively and rapidly detect cardiovascular and myocardial markers at the same time.
【Reference】
[1] Cardiovascular and Cerebrovascular Disease Professional Committee of Chinese Gerontology Society, Cardiovascular and Cerebrovascular Disease Professional Committee of Laboratory Physician Branch of Chinese Laboratory Society. Chinese expert recommendations for the clinical application of lipoprotein-associated phospholipase A2[J].Chinese Journal of Cardiovascular Diseases.2015,10.43(10): 843-847.
[2] Ross R, John A, et al. The Pathogenesis of Atherosclerosis-(First of Two Parts)[J]. N Engl J Med, 1976, 295(7): 369-77.
[3] GreenlandP, AlpertJS,BellerGA, et al. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults:a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines[J]. J Am Coll Cardiol, 2010, 56(25): e50–e103.
[4] GoldsteinLB, BushnellCD, AdamsRJ, et al. Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association[J]. Stroke, 2011, 42(2): 517–584.
[5] Marshall A, Corson, MD,et al. Review of the Evidence for the Clinical Utility of LipoproteinAssociated Phospholipase A2 as a Cardiovascular Risk Marker[J]. Am J Card Suppl 2008:101 (41F-50F)
[6] Marc S, David A, et al. Prognostic Utility of Lipoprotein-Associated Phospholipase A2 for Cardiovascular Outcomes in Patients With Stable Coronary Artery Disease[J]. Journal of The American Heart Association, 2007, 27:2463-2469.
[7] Lipoprotein-associated phospholipase A2 and risk of coronary disease,stroke,and mortality: collaborative analysis of 32 prospective studies[J]. Lancet,2010, 375(9725):1536-1544.
[8] Michelle A, Robert J, et al. The effect of statin therapy on lipoprotein associated phospholipase A2 levels[J]. Atherosclerosis, 2005, 182(1): 193-198.
[9] Sullivan L M, Massaro J M, D'Agostino R B. Presentation of multivariate data for clinical use: The Framingham Study risk score functions[J]. 2004.
[10] Muriel, J, Caslake, et al. Lipoprotein-associated phospholipase A2, inflammatory biomarkers, and risk of cardiovascular disease in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER)[J]. Atherosclerosis, 2010, 210(1):28-34.
[11] Gregson J, Stirnadel-Farrant H A, Doobaree I U, et al. Variation of lipoprotein associated phospholipase A2 across demographic characteristics and cardiovascular risk factors:A systematic review of the literature[J]. Atherosclerosis, 2012, 225(1).
[12] Chen J, Zhang H, Chen W. Chemiluminescence immunoassay for sensing lipoprotein-associated phospholipase A2 in cardiovascular risk evaluation[J]. Clin Chim Acta, 2019,488:143-149.