From the Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine (X.L., S.B.R., L.M., R.E.O.), Program in Physical Therapy (S.B.R.), Division of Biostatistics (M.W.), and Cardiovascular Imaging and Clinical Research Core Laboratory, Cardiovascular Division, Department of Medicine (V.G.D.-R.), Washington University School of Medicine, St. Louis, MO.
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Objective—Epidemiological studies strongly suggest that lipid factors independent of low-density lipoprotein cholesterol contribute significantly to cardiovascular disease risk. Because circulating lipoproteins comprise only a small fraction of total body cholesterol, the mobilization and excretion of cholesterol from plasma and tissue pools may be an important determinant of cardiovascular disease risk. Our hypothesis is that fecal excretion of endogenous cholesterol is protective against atherosclerosis.Approach and Results—Cholesterol metabolism and carotid intima–media thickness were quantitated in 86 nondiabetic adults. Plasma cholesterol was labeled by intravenous infusion of cholesterol-d7 solubilized in a lipid emulsion and dietary cholesterol by cholesterol-d5 and the nonabsorbable stool marker sitostanol-d4. Plasma and stool samples were collected while subjects consumed a cholesterol- and phytosterol-controlled metabolic kitchen diet and were analyzed by mass spectrometry. Carotid intima–media thickness was negatively correlated with fecal excretion of endogenous cholesterol (r=−0.426; P<0.0001), total cholesterol (r=−0.472; P≤0.0001), and daily percent excretion of cholesterol from the rapidly mixing cholesterol pool (r=−0.343; P=0.0012) and was positively correlated with percent cholesterol absorption (r=+0.279; P=0.0092). In a linear regression model controlling for age, sex, systolic blood pressure, hemoglobin A1c, low-density lipoprotein, high-density lipoprotein cholesterol, and statin drug use, fecal excretion of endogenous cholesterol remained significant (P=0.0008).Conclusions—Excretion of endogenous cholesterol is strongly, independently, and negatively associated with carotid intima–media thickness. The reverse cholesterol transport pathway comprising the intestine and the rapidly mixing plasma, and tissue cholesterol pool could be an unrecognized determinant of cardiovascular disease risk not reflected in circulating lipoproteins. Further work is needed to relate measures of reverse cholesterol transport to atherosclerotic disease.Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01603758.