Myocardial ischemia and lipoprotein lipase activity.

Lipoprotein lipase is a key enzyme in the regulation of lipid fuel disposal,3 and it provides fatty acids for tissue utilization by catalyzing the hydrolysis of triacylglycerol circulating in triglyceride-rich lipoproteins. Anchored to the surface of the capillary endothelium by glycosaminoglycans, lipoprotein lipase hydrolyzes plasma chylomicrons and VLDL to remnant particles. As such, lipoprotein lipase is the rate-limiting enzyme responsible for the removal of plasma triglyceride-rich lipoproteins from the circulation. Although expressed in most tissues of the body, in particular, skeletal and heart muscle and adipose tissue, lipoprotein lipase is also expressed and secreted by macrophages. Lipoprotein lipase is important for the transfer of phospholipids and apolipoproteins to HDL and, thus, is critical for the formation of this particle.4 Apolipoprotein C-II is an essential cofactor for the activation of lipoprotein lipase activity, whereas apolipoprotein C-III inhibits activity.5 A number of polymorphisms in the lipoprotein lipase gene have been associated with varying degrees of plasma lipoprotein levels and the severity of coronary artery disease.6 Low levels of lipoprotein lipase activity, as seen with a partial deficiency of lipoprotein lipase, have been associated with the progression of coronary atherosclerosis.7 Decreased lipoprotein lipase activity and the resultant elevated triglyceride levels and reduced HDL cholesterol levels increase the risk of ischemic heart disease.6 Low HDL cholesterol levels reduce reverse cholesterol transport. Elevated triglyceride levels indicate that lipoprotein remnants and partially delipidized lipoproteins of differing size and composition, such as VLDL, IDL, chylomicron remnants, and lipoprotein B-containing particles (LP-B:C, LP-B:C:E, and LP-AII:B:C:D:E), are present in the plasma.8 Consistent with these findings are data from 2 large serial coronary angiographic clinical trials indicating that apolipoprotein C-III, a marker of triglyceride-rich lipoprotein metabolism and the clearance of chylomicron and VLDL particles,5 is an independently significant predictor of the progression of coronary atherosclerosis.9,10 These data implicate the inefficient removal of triglyceride-rich lipoproteins by lipoprotein lipase in the progression of atherosclerosis. Decreased removal of chylomicrons and VLDL particles prolongs circulatory residence time and, therefore, increases the exposure of the arterial wall to these atherogenic particles.8 Low lipoprotein lipase activity may also contribute to atherosclerosis by promoting postprandial lipemia. In this issue of Circulation, Kastelein et al11 present further evidence for the relationship between coronary heart disease and lipoprotein lipase activity. The authors demonstrate, in a subgroup of men from the Regression Growth Evaluation Statin Study (REGRESS), a significant relationship between lipoprotein lipase activity and mass and ischemic heart disease, as determined by the severity of angina pectoris according to the New York Heart Association classification for angina pectoris and silent myocardial ischemia on 24-hour ambulatory ECG monitoring. Lipoprotein lipase activity is important in determining both fasting and postprandial triglyceride-rich lipoprotein levels. With a reduced capacity to catabolize triglyceride-rich lipoproteins, there is an increased exposure of the arterial wall to postprandial lipoproteins, which are particularly atherogenic.12 Because transient elevations in triglyceride-rich lipoproteins and postprandial lipemia can impair endotheliumdependent vascular function,13 a possible mechanism for the association of reduced levels of lipoprotein lipase activity and myocardial ischemia involves a reduction in endotheliumdependent vascular reactivity. The symptoms of postprandial ischemia seen in clinical practice are consistent with these findings, but whether endothelial dysfunction causes myocardial ischemia remains to be definitively determined.14 It would be remiss not to point out, however, that not all studies consistently demonstrate impaired endothelium-dependent vascular function with elevations of triglyceride-rich lipoproteins or low levels of lipoprotein lipase activity.15,16 Nevertheless, the report by Kastelein et al11 is important, because we spend most of our lives in the postprandial state. Triglyceride-rich lipoproteins clearly play an important role in the progression of atherosclerosis.8 In fact, both lipoprotein lipase activity7 and apolipoprotein C-III10 are independently associated with the progression of mild to moderate lesions (,50% diameter stenosis), the very lesions that predict clinical coronary events.17 Although lipoprotein lipase may play an important role in atherosclerosis, this role is not straightforward. On the one hand, because efficient lipolysis of triglyceride-rich lipoproteins results in a nonThe opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Atherosclerosis Research Unit, Division of Cardiology, University of Southern California School of Medicine, Los Angeles. Correspondence to Howard N. Hodis, MD, Atherosclerosis Research Unit, Division of Cardiology, University of Southern California School of Medicine, 2250 Alcazar Street, CSC 132, Los Angeles, CA 90033. (Circulation. 2000;102:1600-1601.) © 2000 American Heart Association, Inc.