Determinants of coronary artery calcification development and progression.

Coronary artery disease (CAD) is a major cause of morbidity and mortality in the U.S. Atherosclerosis is the major cause of CAD. Since half of those who suffer CAD events such as myocardial infarction and sudden death were previously asymptomatic, studies of individuals with atherosclerosis, but without symptoms, contribute to understanding predictors of subclinical disease. Coronary artery calcification (CAC) is part of the atherosclerosis process. CAC, quantified accurately and non-invasively by electron beam computed tomography, correlates with plaque area and predicts coronary artery stenosis better than established CAD risk factors. Serial measurements of CAC can be used to detect change in coronary atherosclerotic burden over time. Little is known about determinants of the development and progression of subclinical CAC. CAC progression is predictive of CAD events. One major risk factor for CAC progression is the previous magnitude of CAC burden. The aims of this dissertation are to identify risk factors for CAC development and progression and to examine the genetic contribution to variation in CAC progression. First I identify traditional CAD risk factors associated with development of CAC. These risk factors aid in determining the probability of developing detectable CAC, even beyond information based on gender and age. Next, I examine the relationship between obesity measures and CAC progression. Obesity measures are significantly associated with CAC progression, among individuals considered to be at lower risk of a CAD event based on traditional CAD risk factors including age, gender, measures of lipids, blood pressure and current smoking. Then, I establish that CAC progression is heritable, even after accounting for baseline quantity of CAC, which is also heritable. Finally, I investigate associations between candidate genes and CAC progression. In summary, modifiable risk factors are associated with CAC incidence and progression. There is evidence for a role of genes in CAC progression. This work represents a first step to identifying people who may benefit from specific interventions that may reduce the atherosclerotic burden and ultimately CAD events.PhDEpidemiologyHealth and Environmental SciencesPublic healthUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/125977/2/3224834.pd