Recent Developments with Lipoprotein-Associated Phospholipase A2 Inhibitors

Ross R: Atherosclerosis—an inflammatory disease. N Engl J Med 1999, 340:115–126. Hansson GK, Libby P: The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol 2006, 6:508–519. Wilensky RL: Vulnerable plaque: scope of the problem. J Interv Cardiol 2008, 21:443–451. Cannon CP, Braunwald E, McCabe CH, et al.: Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004, 350:1495–1504. Yusuf S, Sleight P, Pogue J, et al.: Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000, 342:145–153. Steg PG, Bhatt DL, Wilson PW, et al.: One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA 2007, 297:1197–1206. Zalewski A, Macphee C: Role of lipoprotein-associated phospholipase A2 in atherosclerosis: biology, epidemiology, and possible therapeutic target. Arterioscler Thromb Vasc Biol 2005, 25:923–931. Nambi V, Ballantyne CM: Lipoprotein-associated phospholipase A2: pathogenic mechanisms and clinical utility for predicting cardiovascular events. Curr Atheroscler Rep 2006, 8:374–381. MacPhee CH, Moores KE, Boyd HF, et al.: Lipoprotein-associated phospholipase A2, platelet-activating factor acetylhydrolase, generates two bioactive products during the oxidation of low-density lipoprotein: use of a novel inhibitor. Biochem J 1999, 338(Pt 2):479–487. Davis B, Koster G, Douet LJ, et al.: Electrospray ionization mass spectrometry identifies substrates and products of lipoprotein-associated phospholipase A2 in oxidized human low density lipoprotein. J Biol Chem 2008, 283:6428–6437. • Tsimikas S, Tsironis LD, Tselepis AD: New insights into the role of lipoprotein(a)-associated lipoprotein-associated phospholipase A2 in atherosclerosis and cardiovascular disease. Arterioscler Thromb Vasc Biol 2007, 27:2094–2099. This review focuses on the characteristics of Lp-PLA 2 ’s association with Lp(a) and its role in atherosclerosis development. Kougias P, Chai H, Lin PH, et al.: Lysophosphatidylcholine and secretory phospholipase A2 in vascular disease: mediators of endothelial dysfunction and atherosclerosis. Med Sci Monit 2006, 12:RA5–RA16. Stafforini DM, McIntyre TM, Zimmerman GA, et al.: Platelet-activating factor acetylhydrolases. J Biol Chem 1997, 272:17895–17898. Henig NR, Aitken ML, Liu MC, et al.: Effect of recombinant human platelet-activating factor-acetylhydrolase on allergen-induced asthmatic responses. Am J Respir Crit Care Med 2000, 162(2 Pt 1):523–527. Opal S, Laterre PF, Abraham E, et al.: Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial. Crit Care Med 2004, 32:332–341. Macphee CH, Nelson JJ, Zalewski A: Lipoprotein-associated phospholipase A2 as a target of therapy. Curr Opin Lipidol 2005, 16:442–446. Garza CA, Montori VM, McConnell JP, et al.: Association between lipoprotein-associated phospholipase A2 and cardiovascular disease: a systematic review. Mayo Clin Proc 2007, 82:159–165. Shi Y, Zhang P, Zhang L, et al.: Role of lipoprotein-associated phospholipase A2 in leukocyte activation and inflammatory responses. Atherosclerosis 2007, 191:54–62. Carpenter KL, Challis IR, Arends MJ: Mildly oxidised LDL induces more macrophage death than moderately oxidised LDL: roles of peroxidation, lipoprotein-associated phospholipase A2 and PPARgamma. FEBS Lett 2003, 553:145–150. Gautier EL, Huby T, Witztum JL, et al.: Macrophage apoptosis exerts divergent effects on atherogenesis as a function of lesion stage. Circulation 2009, 119:1795–1804. Perez R, Balboa MA, Balsinde J: Involvement of group VIA calcium-independent phospholipase A2 in macrophage engulfment of hydrogen peroxide-treated U937 cells. J Immunol 2006, 176:2555–2561. Aprahamian T, Rifkin I, Bonegio R, et al.: Impaired clearance of apoptotic cells promotes synergy between atherogenesis and autoimmune disease. J Exp Med 2004, 199:1121–1131. 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. • Anderson JL: Lipoprotein-associated phospholipase A2: an independent predictor of coronary artery disease events in primary and secondary prevention. Am J Cardiol 2008, 101:23F–33F. This is an informative summary of studies evaluating the role of Lp-PLA2 as a biomarker of increased cardiovascular risk. •• 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. This article demonstrates that selective inhibition of Lp-PLA 2 inhibited progression to advanced coronary atheroscelerostic lesions in a large animal model of complex coronary artery disease, confirming the important independent role of vascular inflammation in the development of high-risk coronary lesions. •• 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. J Am Coll Cardiol 2008, 51:1632–1641. This is a large-scale evaluation of darapladib’s effects on lipid levels, inflammation, and biomarkers of platelet activation. Key results include a reduction of interleukin-6 on treatment and no adverse effects on platelet function. •• 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. This is the initial study evaluating potential antiatherogenic effects of darapladib in humans. The primary end point of plaque deformability determined via IVUS was not significant, although a reduction in necrotic core size was observed in darapladib-treated participants. Virmani R, Burke AP, Farb A, et al.: Pathology of the vulnerable plaque. J Am Coll Cardiol 2006, 47(8 Suppl):C13–C18. Filippatos TD, Gazi IF, Liberopoulos EN, et al.: The effect of orlistat and fenofibrate, alone or in combination, on small dense LDL and lipoprotein-associated phospholipase A2 in obese patients with metabolic syndrome. Atherosclerosis 2007, 193:428–437. Robins SJ, Collins D, Nelson JJ, et al.: Cardiovascular events with increased lipoprotein-associated phospholipase A(2) and low high-density lipoprotein-cholesterol: the Veterans Affairs HDL Intervention Trial. Arterioscler Thromb Vasc Biol 2008, 28:1172–1178. Kuvin JT, Dave DM, Sliney KA, et al.: Effects of extended-release niacin on lipoprotein particle size, distribution, and inflammatory markers in patients with coronary artery disease. Am J Cardiol 2006, 98:743–745. Muhlestein JB, May HT, Jensen JR, et al.: The reduction of inflammatory biomarkers by statin, fibrate, and combination therapy among diabetic patients with mixed dyslipidemia: the DIACOR (Diabetes and Combined Lipid Therapy Regimen) study. J Am Coll Cardiol 2006, 48:396–401.