Physiological Study of Human Cholesterol Metabolism and Excretion
Condition: Coronary Heart Disease; Cardiovascular Disease; Dyslipidemia; Disorder of Cholesterol Metabolism
MeSH terms: Cardiovascular Diseases; Heart Diseases; Coronary Disease; Coronary Artery Disease; Myocardial Ischemia; Dyslipidemias
Study type: Interventional
Phase: Phase 1

Summary: 
      The underlying hypothesis is that whole body cholesterol - including cholesterol present in
      tissues that cannot be measured by standard blood tests - is related to heart disease risk.
      Endogenous cholesterol will be labeled with an intravenous infusion of one type of
      cholesterol tracer and dietary cholesterol will be labeled with another. These tracers will
      be used to measure how fast cholesterol is synthesized and excreted using mass spectrometry
      to distinguish the tracers. Data will be related to circulating biomarkers (blood tests) and
      to the thickness of the lining of the carotid artery. The effect of the drug ezetimibe on
      these processes will also be determined. Successful completion of this study will give us
      more knowledge about cholesterol metabolism that may be useful in designing new drugs and
      treatments for patients with heart disease, especially those that are already receiving
      maximum amounts of current medications.
    

Detailed description: 
      The central hypothesis of this proposal is that reverse cholesterol transport is related to
      coronary heart disease (CHD) risk. It is complementary to the concept that reduction of
      cholesterol biosynthesis with statin drugs prevents CHD, but it focuses on whole body
      cholesterol metabolism and kinetic cholesterol transport rather than on static levels of
      circulating lipoproteins. Although this is an old idea, it has not been adequately tested in
      humans because of lack of suitable methods. In this proposal we will apply innovative stable
      isotope and mass spectroscopic technology to study reverse cholesterol transport in human
      subjects. The first specific aim is to improve the preparation of intravenous deuterated
      cholesterol tracer, a critical limiting element in the study of whole body cholesterol
      metabolism. The second aim is to use that intravenous tracer, along with a different oral
      tracer, to partition fecal cholesterol into excreted endogenous cholesterol, unabsorbed
      dietary cholesterol and newly-synthesized cholesterol derived from the liver and intestine.
      Measurements will be made during consumption of a controlled diet provided by the metabolic
      kitchen. The pool size of the rapidly-mixing body cholesterol pool will be measured along
      with the fractional rate of cholesterol catabolism. These direct measures of reverse
      cholesterol transport will be correlated with plasma biomarkers and with metabolic
      covariates. The relation of reverse cholesterol transport to carotid intima-media thickness
      will be determined. The third specific aim will use similar methods to study the mechanism of
      action for the widely-used drug ezetimibe. The fractional rate of endogenous cholesterol
      excretion and the rate of plasma cholesterol turnover will be determined in two periods, one
      with drug and one with placebo treatment. This work represents a new direction for
      cholesterol research with the potential to develop new and complementary methods of reducing
      CHD risk that can be added to diet and statin drug treatment.
    

Intervention name(s): Ezetimibe
Intervention type(s): Drug
Intervention description(s): Ezetimibe 10 mg/day or placebo will be given for 6 weeks
Other intervention name(s): Zetia
Intervention MeSH terms: Ezetimibe
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: Cholesterol; Spectrometry, mass; Deuterium; Kinetics; Cholesterol absorption; Coronary Heart Disease