Key result
Higher regular-to-larger LDL-C ratio tracks with ~2-fold greater atherosclerotic severity in familial hypercholesterolemia.
Why the study?
To characterize coronary plaque development and elucidate underlying mechanisms of inter-individual variation in disease severity in an adult porcine model of familial hypercholesterolemia.
Does a distinct LDL profile correlate with inter-individual variation in coronary atherosclerosis severity in a familial hypercholesterolemia pig model?
Does a distinct LDL profile correlate with inter-individual variation in coronary atherosclerosis severity in a familial hypercholesterolemia pig model?
Answers are grounded in this paper and cite their sources.
A distinct profile of regular and larger LDL particles is associated with the severity of coronary atherosclerosis in a familial hypercholesterolemia pig model, offering a potential early biomarker.
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.
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Hoogendoorn et al. (2019) studied Familial hypercholesterolemia and coronary atherosclerosis (n=13). Atherogenic diet was evaluated on Regular to larger LDL-C ratio at 3 months (p=0.008). In an adult pig model of familial hypercholesterolemia, inter-individual differences in atherosclerotic disease severity were directly related to a distinct LDL profile with a higher regular to larger LDL-C ratio (1.7 vs 0.8, P=0.008).
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