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STABILITY and SOLID-TIMI 52: Lipoprotein associated phospholipase A2 (Lp-PLA2) as a biomarker or risk factor for cardiovascular diseases.

Hassan M - Glob Cardiol Sci Pract (2015)

Bottom Line: In addition, darapladib was associated with significantly higher rates of drug discontinuation, and adverse side effects such as diahrrea and malodorous feces, urine, and skin, as compared to placebo.It also challenges the notion that inhibition of Lp-PLA2 is a worthwhile approach in patients with CHD.Alternate therapies that target inflammation are awaited to reduce residual risk in patients with CV diseases.

View Article: PubMed Central - PubMed

ABSTRACT
Lipoprotein associated phospholipase A2 (Lp-PLA2) - an enzyme with several pro-inflammatory properties - has been hypothesized to be involved in the pathogenesis of atherosclerosis and plaque vulnerability. Lp-PLA2 activity has been demonstrated to be an independent predictor of coronary heart disease (CHD) and ischemic stroke. However, it has been recently reported that carriers of loss of function variants in PLA2G7 gene (encoding Lp-PLA2) had no lower CHD risk than non-carriers. The Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY), and the Stabilization of Plaque Using Darapladib - Thrombolysis in Myocardial Infarction 52 (SOLID-TIMI 52) studies are two phase III, randomized, placebo-controlled, clinical trials that were conducted to evaluate the clinical efficacy and safety of the Lp-PLA2 inhibitor (darapladib), against a background of optimal medical therapy, in patients with stable CHD and acute coronary syndrome, respectively. In both studies, darapladib failed to reduce the risk of major coronary events as compared to placebo. In addition, darapladib was associated with significantly higher rates of drug discontinuation, and adverse side effects such as diahrrea and malodorous feces, urine, and skin, as compared to placebo. These data suggest that Lp-PLA2 may be a biomarker of vascular inflammation rather than a causal pathway of cardiovascular (CV) diseases. It also challenges the notion that inhibition of Lp-PLA2 is a worthwhile approach in patients with CHD. Alternate therapies that target inflammation are awaited to reduce residual risk in patients with CV diseases.

No MeSH data available.


Related in: MedlinePlus

The controversial role of Lp-PLA2 (From Munzel et al. European Heart Journal 2009; 30: 2829–2831).4
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fig1: The controversial role of Lp-PLA2 (From Munzel et al. European Heart Journal 2009; 30: 2829–2831).4

Mentions: The biological role of Lp-PLA2 has been controversial (Figure 1) with initial reports demonstrating atheroprotective effects thought to be a consequence of the enzymatic catabolism of the pro-inflammatory mediator PAF and its analogues formed upon oxidation of LDL.1,2 However, recent findings have ascribed several pro-inflammatory properties for this enzyme that could be pro-atherogenic; Lp-PLA2 hydrolyzes oxidized phospholipids generated during LDL oxidation and leads to the formation of lysophosphatidyl-choline and oxidized non-esterified fatty acids, which up-regulate monocyte adhesion molecules and monocyte chemotactic protein-1 that elicit several inflammatory responses.2,3 Lp-PLA2 acts preferentially on oxidized phospholipids with no effect on naturally occurring phospholipids in cellular membranes.


STABILITY and SOLID-TIMI 52: Lipoprotein associated phospholipase A2 (Lp-PLA2) as a biomarker or risk factor for cardiovascular diseases.

Hassan M - Glob Cardiol Sci Pract (2015)

The controversial role of Lp-PLA2 (From Munzel et al. European Heart Journal 2009; 30: 2829–2831).4
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4374099&req=5

fig1: The controversial role of Lp-PLA2 (From Munzel et al. European Heart Journal 2009; 30: 2829–2831).4
Mentions: The biological role of Lp-PLA2 has been controversial (Figure 1) with initial reports demonstrating atheroprotective effects thought to be a consequence of the enzymatic catabolism of the pro-inflammatory mediator PAF and its analogues formed upon oxidation of LDL.1,2 However, recent findings have ascribed several pro-inflammatory properties for this enzyme that could be pro-atherogenic; Lp-PLA2 hydrolyzes oxidized phospholipids generated during LDL oxidation and leads to the formation of lysophosphatidyl-choline and oxidized non-esterified fatty acids, which up-regulate monocyte adhesion molecules and monocyte chemotactic protein-1 that elicit several inflammatory responses.2,3 Lp-PLA2 acts preferentially on oxidized phospholipids with no effect on naturally occurring phospholipids in cellular membranes.

Bottom Line: In addition, darapladib was associated with significantly higher rates of drug discontinuation, and adverse side effects such as diahrrea and malodorous feces, urine, and skin, as compared to placebo.It also challenges the notion that inhibition of Lp-PLA2 is a worthwhile approach in patients with CHD.Alternate therapies that target inflammation are awaited to reduce residual risk in patients with CV diseases.

View Article: PubMed Central - PubMed

ABSTRACT
Lipoprotein associated phospholipase A2 (Lp-PLA2) - an enzyme with several pro-inflammatory properties - has been hypothesized to be involved in the pathogenesis of atherosclerosis and plaque vulnerability. Lp-PLA2 activity has been demonstrated to be an independent predictor of coronary heart disease (CHD) and ischemic stroke. However, it has been recently reported that carriers of loss of function variants in PLA2G7 gene (encoding Lp-PLA2) had no lower CHD risk than non-carriers. The Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY), and the Stabilization of Plaque Using Darapladib - Thrombolysis in Myocardial Infarction 52 (SOLID-TIMI 52) studies are two phase III, randomized, placebo-controlled, clinical trials that were conducted to evaluate the clinical efficacy and safety of the Lp-PLA2 inhibitor (darapladib), against a background of optimal medical therapy, in patients with stable CHD and acute coronary syndrome, respectively. In both studies, darapladib failed to reduce the risk of major coronary events as compared to placebo. In addition, darapladib was associated with significantly higher rates of drug discontinuation, and adverse side effects such as diahrrea and malodorous feces, urine, and skin, as compared to placebo. These data suggest that Lp-PLA2 may be a biomarker of vascular inflammation rather than a causal pathway of cardiovascular (CV) diseases. It also challenges the notion that inhibition of Lp-PLA2 is a worthwhile approach in patients with CHD. Alternate therapies that target inflammation are awaited to reduce residual risk in patients with CV diseases.

No MeSH data available.


Related in: MedlinePlus