Variation in Coronary Atherosclerosis Severity Related to a Distinct LDL (Low-Density Lipoprotein) Profile: Findings From a Familial Hypercholesterolemia Pig Model
| Autor: | Ludovic Drouet, Jurgen Ligthart, Ayla Hoogendoorn, Monique T. Mulder, Maaike te Lintel Hekkert, Jolanda J. Wentzel, Kristien Dorst, Kim Van der Heiden, Eline M J Hartman, Dirk J. Duncker, Kim van Gaalen, Jeanine E. Roeters van Lennep, Sandra den Hoedt, Leonie C. van Vark-van der Zee, Ilona Krabbendam-Peters, Antonius F.W. van der Steen, Karen Witberg |
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| Přispěvatelé: | Cardiology, Internal Medicine |
| Rok vydání: | 2019 |
| Předmět: |
Male
medicine.medical_specialty Swine Familial hypercholesterolemia Coronary Artery Disease 030204 cardiovascular system & hematology Severity of Illness Index Coronary artery disease Hyperlipoproteinemia Type II 03 medical and health sciences 0302 clinical medicine Animal model Translational Sciences Coronary plaque Internal medicine Medicine Animals Humans Coronary atherosclerosis 030304 developmental biology 2. Zero hunger 0303 health sciences Sphingolipids familial hypercholesterolemia hypercholesterolemia business.industry animal model Pig model LDL - Low density lipoprotein Cholesterol LDL medicine.disease Atherosclerosis Plaque Atherosclerotic Lipoproteins LDL Disease Models Animal Endocrinology ComputingMethodologies_DOCUMENTANDTEXTPROCESSING Biomarker (medicine) biomarker Diet Atherogenic lipids (amino acids peptides and proteins) Female Cardiology and Cardiovascular Medicine business |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology Arteriosclerosis Thrombosis & Vascular Biology, 39(11), 2338-2352. Lippincott Williams & Wilkins |
| ISSN: | 1524-4636 1079-5642 |
| Popis: | Supplemental Digital Content is available in the text. 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. |
| Databáze: | OpenAIRE |
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