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.
The authors declare no conflict of interest in this article.
Versión en PDF - Versión para imprimir
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 . 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 . 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.
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) . 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 . 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) . It has a particular affinity for small, dense LDL fragments that are believed to be more highly pathogenic .
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 . 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 . 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) .
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 .
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 . 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 . 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 . 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 . Lp-PLA2 expression above median in carotid plaques was linked to a three-fold increase in risk for cardiovascular events (Figure 2) .
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 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 . 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) .
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 . 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) .
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 .
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 .
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 . 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.
- Loyd-Jones D, Adams RJ, Brown TM, et al: Executive summary. Heart disease and stroke statistics-2010 update: a report from The American Heart Association. Circulation 2010; 121: 948-954.
- Murphy SA, Cannon CP, Wiviott SD, McCabe CH, Braunwald E: Reduction in recurrent cardiovascular events with intensive lipid-lowering statin therapy compared with moderate lipid-lowering statin therapy after acute coronary syndromes from the PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22) trial. JACC 2009; 54: 2358-2362.
- Waters DD: Clinical insights from the Treating to New Targets trial. Prog Cardiovasc Dis 2009; 51: 487-502.
- La Rosa JC, Deedwania PC, Shepherd J, et al: Comparison of 80 versus 10 mg of atorvastatin on occurrence of cardiovascular events after the first event (from the Treating to New Targets [TNT] trial). Am J Cardiol 2010; 105: 283-287.
- Macphee CH, Nelson J, Zalewski A: Role of lipoprotein-associated phospholipase A2 in atherosclerosis and its potential as a therapeutic target. Curr Opin Pharmacol 2006; 6: 154-161.
- Madjid M, Ali M, Willerson JO: Lipoprotein-associated phospholipase A2 as a novel risk marker for cardiovascular disease: a systematic review of the literature: Tex Heart Inst J 2010; 37: 25-39.
- Lonn E: Lipoprotein.associated phospholipase A2: a new therapeutic target. Can J Cardiol 2010 (Suppl A): 27A-31A.
- Mannheim D, Herrmann J, Versari D, et al: Enhanced expression of Lp-PLA2 and lysophosphatidylcholine in symptomatic carotid atherosclerotic plaques. Stroke 2008; 39: 1448-1455.
- Kolodgie FD, Burke AP, Skorija KS, et al: Lipoprotein-associated phospholipase A2 protein expression in the natural progression of human coronary atherosclerosis. Arterioscler Thromb Vasc Biol 2006; 26: 2523-2529.
- Wilensky RL, Shi Y, Mohler ER 3rd, et al: Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development. Nat Med 2008; 14: 1059-1066.
- White H: Why inhibition of lipoprotein-associated phospholipase A2 has the potential to improve patient outcomes (Editorial). Curr Opin Cardiol 2010; 25: 299-301.
- Levi S, McConnell JP, Rihal CS, et al: Local production of lipoprotein-associated phospholipase A2 and lysophosphatidylcholine in the coronary circulation: association with early coronary atherosclerosis and endothelial dysfunction in humans. Circulation 2007; 115: 2715-2721.
- Thompson A, Gao P, Orfei L, et al: Lipoprotein-associated phospholipase A(2) and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies. Lancet 2010; 375: 1536-1544.
- Packard CJ, O’Reilly DS, Caslake MJ, et al: Lipoprotein-associates phospholipase A2 as an independent predictor of coronary heart disease. West of Scotland Coronary Prevention Study Group. NEJM 2000; 343: 1148-1155.
- Ballantyne CM, Hoogeveen RC, Bang H, et al: Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) Study. Circulation 2004; 109: 837-842.
- O’Donoghue M, Morrow DA, Sabatine MS, et al: Lipoprotein-associated phospholipase A2 and its association with cardiovascular outcomes in patients with acute coronary syndromes in the PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction) trial. Circulation 2006; 113: 1745-1752.
- Herrmann J, Mannheim D, Wohlert C, et al: Expression of lipoprotein-associated phospholipase A(2) in carotid artery plaques predicts long-term cardiac outcome. Eur Heart J 2009; 30: 2930-2938.
- Bui QT, Wilensky RL: Darapladib. Expert Opin Investig Drugs 2010; 19:161-168.
- Mohler ER 3rd, Ballantyne CM, Davidson MH, et al: The effect of darapladib on plasma lipoprotein-associated phospholipase A2 activity and cardiovascular biomarkers in patients with stable coronary heart disease or coronary heart disease risk equivalent: the results of a multicenter, randomized, double-blind, placebo-controlled study. JACC 2008; 51: 1632-1641.
- Serruys PW, Garcia-Garcia HM, Buszman P, et al: Effects of the direct lipoprotein associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque. Circulation 2008; 118: 1172-1182.
- The stabilization of atherosclerotic plaque by initiation of darapladib therapy trial (STABILITY). ClinicalTrials.gov 2009. In.
- The Stabilization of Plaques Using Darapladib-Thrombolysis in Myocardial Infarction (SOLID-TIMI): ClinicalTrials.gov 2009. In.
- Yamada Y, Izawa H, Ichihara S, et al: Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. NEJM 2002; 347: 1916-1923.
He swallowed a lot of wisdom, but it seemed as if all of it had gone down
the wrong way.
Publicación: Diciembre 2010