Variation in Coronary Atherosclerosis Severity Related to a Distinct LDL (Low-Density Lipoprotein) Profile Findings From a Familial Hypercholesterolemia Pig Model

OBJECTIVE: In an adult porcine model of familial hypercholesterolemia (FH), coronary plaque development was characterized. \nTo elucidate the underlying mechanisms of the observed inter-individual variation in disease severity, detailed lipoprotein \nprofiles were determined. \nAPPROACH AND RESULTS: FH pigs (3 years old, homozygous LDLR R84C mutation) received an atherogenic diet for 12 months. \nCoronary atherosclerosis development was monitored using serial invasive imaging and histology. A pronounced difference \nwas observed between mildly diseased pigs which exclusively developed early lesions (maximal plaque burden, 25% [23%\xe2\x80\x93 \n34%]; n=5) and advanced-diseased pigs (n=5) which developed human-like, lumen intruding plaques (maximal plaque burden, \n69% [57%\xe2\x80\x9377%]) with large necrotic cores, intraplaque hemorrhage, and calcifications. Advanced-diseased pigs and mildly \ndiseased pigs displayed no differences in conventional risk factors. Additional plasma lipoprotein profiling by size-exclusion \nchromatography revealed 2 different LDL (low-density lipoprotein) subtypes: regular and larger LDL. Cholesterol, sphingosine1-phosphate, ceramide, and sphingomyelin levels were determined in these LDL-subfractions using standard laboratory \ntechniques and high-pressure liquid chromatography mass-spectrometry analyses, respectively. At 3 months of diet, regular \nLDL of advanced-diseased pigs contained relatively more cholesterol (LDL-C; regular/larger LDL-C ratio 1.7 [1.3\xe2\x80\x931.9] versus \n0.8 [0.6\xe2\x80\x930.9]; P=0.008) than mildly diseased pigs, while larger LDL contained more sphingosine-1-phosphate, ceramides, and \nsphingomyelins. Larger and regular LDL was also found in plasma of 3 patients with homozygous FH with varying LDL-C ratios. \nCONCLUSIONS: In our adult FH pig model, inter-individual differences in atherosclerotic disease severity were directly related to \nthe distribution of cholesterol and sphingolipids over a distinct LDL profile with regular and larger LDL shortly after the diet \nstart. A similar LDL profile was detected in patients with homozygous FH