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 45 apparently healthy middle-aged siblings of probands with known premature coronary artery disease (CAD). Siblings also underwent exercise thallium 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 co-occur in premature CAD families provides 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 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 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 will conduct an epidemiologic study of the of SVCD using MRI determination of white matter hyperintensity volumes and ratios, and lacunar infarcts, and occult CAD using stress thallium tomography of the heart. We have used a biological model of vascular disease to select measurements of mechanism-derived inflammatory (IL-6, TNF-?, 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 will examine these markers in 1000 apparently healthy 35-75 year old siblings 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. 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 will be 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.

Public Health Relevance

This study will focus on the occurrence of vascular disease in the heart and brain and is designed to examine new epidemiologic models of atherosclerosis that include mechanisms such as inflammation, thrombosis and vascular function. It is also focused on the genes that may increase the susceptibility to small vessel disease in high risk families with a history of disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS062059-04
Application #
8209067
Study Section
Neurological, Aging and Musculoskeletal Epidemiology (NAME)
Program Officer
Gwinn, Katrina
Project Start
2009-01-15
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
4
Fiscal Year
2012
Total Cost
$601,029
Indirect Cost
$188,003
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Nyquist, Paul A; Bilgel, Murat S; Gottesman, Rebecca et al. (2014) Extreme deep white matter hyperintensity volumes are associated with African American race. Cerebrovasc Dis 37:244-50
Kral, Brian G; Nyquist, Paul; Vaidya, Dhananjay et al. (2013) Relation of subclinical coronary artery atherosclerosis to cerebral white matter disease in healthy subjects from families with early-onset coronary artery disease. Am J Cardiol 112:747-52
Bilgel, Murat; Roy, Snehashis; Carass, Aaron et al. (2013) AUTOMATED ANATOMICAL LABELING OF THE CEREBRAL ARTERIES USING BELIEF PROPAGATION. Proc SPIE Int Soc Opt Eng 866918:
Brown, Rochelle V; Kral, Brian G; Yanek, Lisa R et al. (2012) Ethnic-specific determinants of exercise capacity in a healthy high-risk population. Med Sci Sports Exerc 44:1150-6
Nyquist, Paul (2010) Management of acute intracranial and intraventricular hemorrhage. Crit Care Med 38:946-53