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Publicaciones > Revista > 10V39N4

Lp-PLA2, Why does it matter?

CHRISTOPHER P. CANNON, THOMAS F. O’DONNEL

Harvard Medical School.
Postal Adress: Christopher P. Cannon. Harvard Medical School.
Brigham and Women’s Hospital. 75 Francis Street. Boston. MA 02115. USA.
E-mail
The authors declare no conflict of interest in this article.

 


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Despite continued progress in the field of coronary artery disease (CAD), cardiovascular events remain high, and heart disease is still the leading cause of death among Americans [1]. The PROVE IT-TIMI 22 trial found that despite high dose statin therapy, patients had a 22.4% residual risk for death or major adverse cardiovascular events in the two years after an acute coronary syndrome [2]. In the Treating to New Targets trial, patients with stable coronary artery disease treated with intense statin therapy still had an 8.7% residual risk of a major adverse cardiovascular event within 4 years [3,4]. Consequently, new therapies are needed to augment the current standard of care if progress is to be made.

 

Lp-PLA2
Lipoprotein-associated Phospholipase A2 (Lp-PLA2) is an enzyme produced and secreted by many cells of the immune system (monocytes, macrophages, T-lymphocytes and mast cells) [5]. In humans, 80% of Lp-PLA2 in plasma circulates bound to the c-terminus of ApoB in low density lipoprotein (LDL) fragments. The remaining fraction circulates bound to high density lipoprotein (HDL) or is produced locally at the site of inflammation [6]. After LDL is oxidized at a site of inflammation such as a neointimal plaque, Lp-PLA2 cleaves it into two inflammatory mediators, lysophos­phati­dylcholine (Lyso-PC) and oxidized nonesterified fatty acids (oxNEFAs) [5]. It has a particular affinity for small, dense LDL fragments that are believed to be more highly pathogenic [7].

 

Lp-PLA2 AND VULNERABLE PLAQUES
Lp-PLA2 has been shown to be highly upregulated in vulnerable and ruptured plaques, with significantly lower levels of expression in stable plaques [8,9]. Lp-PLA2 may contribute to as well as be a marker for plaque instability [10]. Both of its products, Lyso-PC and oxNEFAs, are chemoattractants for macrophages, and Lyso-PC has been shown to induce the apoptosis of macrophages in a plaque [9]. The Lp-PLA2 on LDL particles that enter a developing plaque produce Lyso-PC, which recruits macrophages to the site. These migrating macrophages then produce and secrete additional Lp-PLA2 before being induced to apoptose by Lyso-PC. The resultant positive feedback loop may drive the progression and expansion of the necrotic core and thinning of the fibrous cap (Figure 1) [11].

Figure 1. Targeting Lp-PLA2, a hey player in atherosclerosis. Progression and expansion of the necrotic core. Lp-PLA2 is carried into plaques by LDL particles, where it breaks down LDL into Lyso-PC and oxNEFAs, which promote inflammation and apoptosis and contribute to the formation of the necrotic core and thinning of the fibrous cap. (Adapted from Zalewski and Macphee. ATVB.2005)

 

Lp-PLA2 and Lyso-PC also contribute to atherosclerosis through the induction of endothelial dysfunction. Lyso-PC causes an increase in oxidative stress, downregulation of endothelial nitric oxide synthase, and decreased endothelial cell migration to sites of damage [12].

 

Lp-PLA2 AND CARDIOVASCULAR DISEASE
Lp-PLA2 has been shown to be a reliable marker of increased risk for cardiovascular events. A meta-analysis of 32 studies showed that Lp-PLA2 mass and activity were associated with increased risk of coronary heart disease, ischemic stroke, and vascular mortality independent of conventional risk factors and hs-CRP [13]. The West of Scotland Coronary Prevention Study (WOSCOPS) found plasma Lp-PLA2 mass to be independently associated with a doubling of risk of nonfatal MI, death from coronary heart disease, or need for revascularization in patients with established coronary heart disease [14]. In patients with LDL levels <130 mg/dL in the Atherosclerosis Risk in Communities (ARIC) study, elevated plasma Lp-PLA2 mass was associated with a higher incidence of cardiovascular events [14]. The PROVE-IT study showed that Lp-PLA2 activity at 30 days after ACS is associated with an increased risk of cardiovascular events independent of hs-CRP and LDL [16]. Lp-PLA2 expression above median in carotid plaques was linked to a three-fold increase in risk for cardiovascular events (Figure 2) [17].

Figure 2. Carotid Lp-PLA2 expression and CV Outcomes. Carotid plaque expression of  Lp-PLA2, above the median linked to 3-fold increase in cardiac event rate (A), and increased rate of revscularization (B). (Herrmann, J. et al. Eur Heart J 2009;30:2930)

 

DARAPLADIB
Darapladib is a selective, reversible, potent, competitive inhibitor of Lp-PLA2 that has been shown to reduce Lp-PLA2 activity up to 95% in a dose-dependent manner [18]. Darapladib also remains effective as an adjunct to current lipid lowering therapies.  Even in the presence of intensive statin therapy, darapladib reduced Lp-PLA2 activity by 66% at the 160 mg/day dose (Figure 3) [19].

Figura 3. Effect of Darapladib on Lp-PLA2 activity in patients with stable coronary heart disease. Darapladib significantly reduces Lp-PLA2 activity as an adjunct to current intensive statin therapies. Darapladib 160 mg dose reduced Lp-PLA2 activity by 66% when used in conjunction with statin therapy. (Mohler ER, et al. JACC 2008; 51: 1632-1641)

 

Inhibition of Lp-PLA2 has been shown to limit plaque development and improve patient outcomes. In diabetic, high cholesterol swine, darapladib reduced the progress of atherosclerosis [10]. The Integrated Biomarkers and Imaging Study (IBIS-2) showed that darapladib use resulted in a 50% reduction in Lp-PLA2 activity and halted the expansion of the necrotic core.  In the placebo group, the necrotic core continued to expand despite adherence to standard of care (Figure 4) [20].

 

Figura 4. IBIS-2 Results. Change in necrotic core volume at follow-up. Results from the Integrated Biomarkers and Imaging Study (IBIS-2). IBIS-2 showed that darapladib halted the expansion of the necrotic core. In the lacebo group, necrotic core continued to expand. (Serruys PW, et al. Circulation 2008)

 

Two ongoing trials have been designed to further investigate darapladib and its therapeutic potential. The Stabilization of Atherosclerotic Plaque by Inhibition of Darapladib Therapy Trial (STABILITY) is a phase III, multicenter, randomized, double-blind, placebo controlled study of darapladib vs. placebo in patients with chronic CAD. It is intended to test whether darapladib reduces the risk of death by cardiovascular event, nonfatal MI, or nonfatal stroke. STABILITY has a target enrollment of 15,500 patients and an expected follow-up of 3 years [21].

The Stabilization of Plaques Using Darapladib Trial (SOLID-TIMI 52) is designed to investigate a higher risk group that STABILITY. Instead of patients with stable CAD, it is studying the therapeutic utility of darapladib when started within 30 days of an ACS. It is also a Phase III, multicenter, randomized, double-blind, placebo controlled study of darapladib vs placebo. SOLID has a target enrollment of 11,500 patients and a median follow-up of 3 years [22].

 

POSSIBLE ATHEROPROTECTIVE EFFECTS OF Lp-PLA2
When first discovered, Lp-PLA2 was described as an atheroprotective factor. Subsequent studies suggest that the pro-atherothrombotic effects outweigh any possibly atheroprotective abilities, but some contro­versy remains. Lp-PLA2 was initially discovered and described as Platelet Activating Factor Acetyl­hydrolase (PAF-AH) because of its ability to degrade PAF in vitro. This effect, however, has not been shown to persist in vivo [20]. Initial studies of groups with missense mutations in the Lp-PLA2 gene that result in reduced expression have yielded mixed results. The first two studies found a higher prevalence of cardiovascular disease in carriers of the mutation, but a larger, more recent study with greater power found no evidence of increased risk [18,23]. STABILITY and SOLID should provide more insight into the role of Lp-PLA2 and the potential therapeutic benefit of its inhibition by darapladib.

 

BIBLIOGRAPHY

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He swallowed a lot of wisdom, but it seemed as if all of it had gone down the wrong way.

LICHTENBERG

 

Publicación: Diciembre 2010

 


 

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