Lipoprotein Lipase Correlates Positively and Hepatic Lipase Inversely With Calcific Atherosclerosis in Homozygous Familial Hypercholesterolemia

Abstract

Homozygous familial hypercholesterolemia (FH) is a rare genetic disorder that leads to premature atherosclerosis due to a defective LDL receptor. There is, however, a large degree of phenotypic heterogeneity at the level of atherosclerosis even in patients with identical mutations of the LDL receptor protein. Lipoprotein lipase (LPL) and hepatic lipase (HL) are crucial enzymes in lipoprotein metabolism, and both have been proposed as having proatherogenic as well as antiatherogenic effects. To evaluate a potential role for these enzymes in the severity of atherosclerosis, we correlated postheparin LPL mass and activity as well as HL activity with the volume of total calcific atherosclerosis (heart and thoracic aorta), coronary artery calcific atherosclerosis, and Achilles tendon width as measured by computed tomography in 15 FH homozygotes. LPL dimer and total mass were positively correlated with all three parameters ( r =.65 to .87, P <.01) as was LPL activity ( r =.52 to .63, P <.05). HL activity was negatively correlated with total and coronary artery calcified lesion volume ( r =−.55 to .57, P <.05). In a multiple regression model of the coronary artery lesion volume, LPL dimer mass and HL activity together accounted for 84% of the variability ( r =.92, P< .0001). In a multiple regression model of the total calcified lesion volume, HL activity, total cholesterol, age, and LPL dimer mass together accounted for 85% of the variability ( r =.92, P =.0005). These data demonstrate a significant correlation of LPL mass and activity with the extent of calcific atherosclerosis in homozygous FH. It is not clear whether LPL is the cause or consequence of the observed correlation, but if the association between LPL and coronary artery lesions is also present in patients with other genetic dyslipoproteinemias, LPL could constitute a new risk factor for cardiovascular disease.