GeneSTAR Research Program - Study of Atherosclerosis Risk in Families
Small Vessel Cerebrovascular Disease and Occult Coronary Disease in High Risk Families
This is a series of studies in GeneSTAR participants using brain magnetic resonance imaging (3 Tesla) to examine pre-clinical small vessel cerebrovascular disease in high risk European and American families. Done in concert with the Departments of Neurology and Neuroradiology, the studies are ongoing.
Small vessel cerebrovascular disease (SVCD) is generally silent and is identified by white matter hyperintensities and small focal brain infarcts on magnetic resonance imaging (MRI). These lesions double the risk of subsequent stroke. We found a markedly increased prevalence of silent SVCD (73%) on MRI in a pilot study of apparently healthy middle-aged siblings of probands with known premature coronary artery disease (CAD). Siblings also underwent exercise perfusion tomography to detect occult CAD. Of subjects with occult CAD, 88% had any SVCD, and 62% had significant SVCD on MRI, while only 5.5% without occult CAD had these findings.
Our discovery that occult CAD and SVCD appear to co-occur in premature CAD families provided an opportunity to study models for pre-clinical small vessel disease in the brain and heart. In both clinically manifest strokes and CAD, classical risk factor models markedly underestimate incident events, suggesting that other factors, including genetic susceptibility, may be contributory. In addition, there is strong clustering of both cerebrovascular disease and CAD in families, consistent with a genetic contribution to the disease process.
To determine potential shared and unique mechanism-derived biomarkers and known risk factors related to pre-clinical vascular disease in the brain and the heart, and the contribution of attendant mechanism-specific genes, we are conducting an epidemiologic study of the of  SVCD using MRI determination of white matter hyperintensity volumes and ratios, lacunar infarcts, and occult CAD using stress sestamibi tomography of the heart.
We have used a biological model of vascular disease to select measurements of mechanism-derived inflammatory (IL-6, TNF-α, hs-CRP, sVCAM-1, sICAM1, and MCP-1) and prothrombotic factors (PAI-1, Lp(a) and fibrinogen), endothelium dependent vascular reactivity (flow mediated dilatation [FMD] ) of the brachial artery, and traditional vascular disease risk factors.
We are examining examine these markers in 800-1000 apparently healthy 35-75 year old siblings and adult offspring from families with documented premature CAD. We will also examine associations between genetic variants and SVCD using a panel of 213 biologically-derived candidate genes previously genotyped for over 3000 single nucleotide polymorphisms. More genetic variants are available through our 1M genome wide scan.
Genetic analyses will be performed separately in whites and African Americans using mixed model analysis to leverage family structures. Such models accommodate individual polymorphism effects or haplotypes.
This study is the first to examine small vessel disease in the brain and the heart in high risk family members who are notably susceptible to coronary heart disease and cerebrovascular disease. The study also includes extensive characterization of cognitive function and measures of mental well being, as well as comorbid events that may predispose to the neurocognitive decline associated with aging.  The study is spearheaded by Dr. Paul A. Nyquist, Neurology, Dr. Diane M. Becker, and Dr. Brian Kral. MRI support is provided by Dr. David Yousem, Director of Neuroimaging.
Paul A. Nyquist, MD