Clinical Trial: The Association of SAA With Apolipoprotein B Affects Cardiovascular Risk

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Observational

Official Title: The Association of SAA With Apolipoprotein B Affects Cardiovascular Risk

Brief Summary: Cardiovascular disease (CVD) is the leading cause of death in developed nations and a major health issue in Veterans. Despite a number of different treatments, cardiovascular disease remains a major health burden, thus further treatments are needed. Individuals with obesity and/or diabetes are at particularly high risk for cardiovascular disease, and research suggests that elevated levels of serum amyloid A (SAA) may contribute to cardiovascular disease, particularly atherosclerosis. In preliminary studies in both mouse and human the investigators have identified that SAA appears to shift between lipid particles. SAA is mainly found on high density lipoprotein (HDL) particles; however, the investigators have found that in both mice and humans with obesity and/or diabetes SAA is found on low density lipoprotein (LDL) and very low density lipoprotein (VLDL) particles, and the investigators hypothesize that the presence of SAA on LDL or VLDL makes these particles more likely to cause cardiovascular disease. To determine what leads SAA to shift between lipid particles, SAA knockout mice will be injected with HDL containing SAA then blood collected at several time points over 24 hours, and the lipid particles will be isolated to measure SAA. In some experiments the investigators will compare different isoforms of SAA, different types of HDL particles, or induce expression of enzymes likely involved in shifting SAA between particles. To determine if the presence of SAA makes lipid particles bind vascular matrix more strongly, the investigators will collect carotid arteries and compare the extent of lipid particles bound to the vascular matrix in the vessel wall when the particles have or do not have SAA present. If this research confirms this hypothesis then the presence of SAA on LDL or VLDL may 1) be a new marker indicating humans at highest risk for cardiovascular disease and 2) be a new target of therapy to prevent cardiovascular disease.

Detailed Summary:

Clinical burden of CVD: CVD is the leading cause of death in developed nations and the VA population is no exception. Despite decades of research, technical, and pharmacological advances, CVD remains a major public health problem. This is partly due to our impaired ability to identify subjects at greatest risk for CVD events and thus the best candidates for pharmacological risk reducing therapies, and partly due to incomplete use or efficacy of currently available therapies. Epidemiological studies have identified major risk factors for CVD including elevated LDL cholesterol, low HDL cholesterol, hypertension, smoking and diabetes. However, despite targeting individuals with these risk factors with aggressive pharmacological interventions, CVD remains a major public health problem. Furthermore, even in individuals with risk factors who are treated with pharmacological or lifestyle interventions the CVD event rates are higher than in those who never had the risk factors. Recent epidemiologic data evaluating the American Heart Association-identified cardiovascular health metrics reported that the prevalence of having CVD risk factors at ideal levels is < 2%10; implying that >98% of the population are candidates for risk reduction. Clearly, health systems cannot cope with pharmacological interventions for such enormous target populations. Thus, additional risk stratifying markers are needed to identify those at highest risk for events and thus at greatest likelihood of benefit. Several biomarkers, including the acute phase reactants C reactive protein (CRP) and serum amyloid A (SAA) have been studied for their role in predicting CVD events. Both CRP and SAA are chronically elevated in individuals with obesity, metabolic syndrome (MetS), diabetes, rheumatoid arthritis, lupus and other chronic inflammatory conditions associated with increased CVD rates, raising the question of whether these biomarkers merely reflect und
Sponsor: Lisa Tannock

Current Primary Outcome:

• Post-prandial SAA content on apoB containing lipoproteins after consumption of a high fat shake [ Time Frame: Baseline and once every hour for 8 hours. Study completed in a single day ]
  Subjects will arrive at the clinic fasted and have an IV line established. A baseline blood sample will be drawn at hour zero. The subject will then consume a high fat shake within a 15 minute window. Blood samples will then be drawn every hour for eight hours to determine the time course of SAA shifting from HDL to apoB containing lipoproteins.
• Degree of insulin resistance [ Time Frame: 4.5 hour study completed in a single day ]
  Subjects will arrive at the clinic fasted. The subject will have IV sites established in both arms and two baseline blood samples will be drawn (-30 and -10 minute). At time zero, a bolus of glucose will be injected followed by blood sample collection. Blood will be collected at the following time points in minutes; 0, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 19. At time 20 minutes, the subject will receive an IV bolus of insulin and frequent blood sampling will continue at the following time points in minutes; 20, 22, 23, 24, 25, 27, 30, 40, 50, 70, 90, 100, 120, 140 ,160, 180, 210, 240. A total of 32 blood samples will be collected over the course of 4.5 hours.

Original Primary Outcome: Post-prandial SAA content on apoB containing lipoproteins after consumption of a high fat shake [ Time Frame: Baseline and once every hour for 8 hours. ]

Current Secondary Outcome:

Original Secondary Outcome: Degree of insulin resistance [ Time Frame: 4 hour study completed in a single office visit ]

Dates:
Date Received: May 11, 2015
Date Started: February 2014
Date Completion: February 2018
Last Updated: April 10, 2017
Last Verified: April 2017