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

Arterioscler Thromb Vasc Biol. 2019 Nov;39(11):2338-2352. doi: 10.1161/ATVBAHA.119.313246. Epub 2019 Sep 26.

Abstract

Objective: In an adult porcine model of familial hypercholesterolemia (FH), coronary plaque development was characterized. To elucidate the underlying mechanisms of the observed inter-individual variation in disease severity, detailed lipoprotein profiles were determined. Approach and Results: FH pigs (3 years old, homozygous LDLR R84C mutation) received an atherogenic diet for 12 months. Coronary atherosclerosis development was monitored using serial invasive imaging and histology. A pronounced difference was observed between mildly diseased pigs which exclusively developed early lesions (maximal plaque burden, 25% [23%-34%]; n=5) and advanced-diseased pigs (n=5) which developed human-like, lumen intruding plaques (maximal plaque burden, 69% [57%-77%]) with large necrotic cores, intraplaque hemorrhage, and calcifications. Advanced-diseased pigs and mildly diseased pigs displayed no differences in conventional risk factors. Additional plasma lipoprotein profiling by size-exclusion chromatography revealed 2 different LDL (low-density lipoprotein) subtypes: regular and larger LDL. Cholesterol, sphingosine-1-phosphate, ceramide, and sphingomyelin levels were determined in these LDL-subfractions using standard laboratory techniques and high-pressure liquid chromatography mass-spectrometry analyses, respectively. At 3 months of diet, regular LDL of advanced-diseased pigs contained relatively more cholesterol (LDL-C; regular/larger LDL-C ratio 1.7 [1.3-1.9] versus 0.8 [0.6-0.9]; P=0.008) than mildly diseased pigs, while larger LDL contained more sphingosine-1-phosphate, ceramides, and sphingomyelins. Larger and regular LDL was also found in plasma of 3 patients with homozygous FH with varying LDL-C ratios.

Conclusions: In our adult FH pig model, inter-individual differences in atherosclerotic disease severity were directly related to the distribution of cholesterol and sphingolipids over a distinct LDL profile with regular and larger LDL shortly after the diet start. A similar LDL profile was detected in patients with homozygous FH.

Keywords: animal model; atherosclerosis; biomarker; coronary artery disease; familial hypercholesterolemia; hypercholesterolemia; sphingolipids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cholesterol, LDL / blood*
  • Cholesterol, LDL / classification
  • Coronary Artery Disease / blood*
  • Coronary Artery Disease / pathology*
  • Diet, Atherogenic
  • Disease Models, Animal
  • Female
  • Humans
  • Hyperlipoproteinemia Type II / blood*
  • Hyperlipoproteinemia Type II / diagnostic imaging
  • Hyperlipoproteinemia Type II / pathology*
  • Male
  • Plaque, Atherosclerotic / blood*
  • Plaque, Atherosclerotic / diagnostic imaging
  • Plaque, Atherosclerotic / pathology*
  • Severity of Illness Index
  • Sphingolipids / blood
  • Swine

Substances

  • Cholesterol, LDL
  • Sphingolipids